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Sample records for falciparum malaria vaccine

  1. A multilateral effort to develop DNA vaccines against falciparum malaria.

    Science.gov (United States)

    Kumar, Sanjai; Epstein, Judith E; Richie, Thomas L; Nkrumah, Francis K; Soisson, Lorraine; Carucci, Daniel J; Hoffman, Stephen L

    2002-03-01

    Scientists from several organizations worldwide are working together to develop a multistage, multigene DNA-based vaccine against Plasmodium falciparum malaria. This collaborative vaccine development effort is named Multi-Stage DNA-based Malaria Vaccine Operation. An advisory board of international experts in vaccinology, malariology and field trials provides the scientific oversight to support the operation. This article discusses the rationale for the approach, underlying concepts and the pre-clinical development process, and provides a brief outline of the plans for the clinical testing of a multistage, multiantigen malaria vaccine based on DNA plasmid immunization technology.

  2. Development of vaccines against Plasmodium falciparum malaria: taking lessons from naturally acquired protective immunity

    DEFF Research Database (Denmark)

    Hviid, Lars

    2007-01-01

    The acquisition of substantial anti-malarial protection in people naturally exposed to P. falciparum is often cited as evidence that malaria vaccines can be developed, but is rarely used to guide the development. We are pursuing the development of vaccines based on antigens and immune responses...

  3. Novel Plasmodium falciparum malaria vaccines: evidence-based searching for variant surface antigens as candidates for vaccination against pregnancy-associated malaria

    DEFF Research Database (Denmark)

    Staalsoe, Trine; Jensen, Anja T R; Theander, Thor G

    2002-01-01

    Malaria vaccine development has traditionally concentrated on careful molecular, biochemical, and immunological characterisation of candidate antigens. In contrast, evidence of the importance of identified antigens in immunity to human infection and disease has generally been limited......) in particular, to provide robust evidence of a causal link between the two in order to allow efficient and evidence-based identification of candidate antigens for malaria vaccine development....... to statistically significant co-variation with protection rather than on demonstration of causal relationships. We have studied the relationship between variant surface antigen-specific antibodies and clinical protection from Plasmodium falciparum malaria in general, and from pregnancy-associated malaria (PAM...

  4. A malaria vaccine that elicits in humans antibodies able to kill Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    2005-11-01

    Full Text Available BACKGROUND: Plasmodium falciparum merozoite surface protein 3 is a malaria vaccine candidate that was identified, characterised, and developed based on a unique immuno-clinical approach. The vaccine construct was derived from regions fully conserved among various strains and containing B cell epitopes targeted by human antibodies (from malaria-immune adults that are able to mediate a monocyte-dependent parasite killing effect. The corresponding long synthetic peptide was administered to 36 volunteers, with either alum or Montanide ISA720 as adjuvant. METHODS AND FINDINGS: Both formulations induced cellular and humoral immune responses. With alum, the responses lasted up to 12 mo. The vaccine-induced antibodies were predominantly of cytophilic classes, i.e., able to cooperate with effector cells. In vitro, the antibodies induced an inhibition of the P. falciparum erythrocytic growth in a monocyte-dependent manner, which was in most instances as high as or greater than that induced by natural antibodies from immune African adults. In vivo transfer of the volunteers' sera into P. falciparum-infected humanized SCID mice profoundly reduced or abrogated parasitaemia. These inhibitory effects were related to the antibody reactivity with the parasite native protein, which was seen in 60% of the volunteers, and remained in samples taken 12 mo postimmunisation. CONCLUSION: This is the first malaria vaccine clinical trial to clearly demonstrate antiparasitic activity by vaccine-induced antibodies by both in vitro and in vivo methods. The results, showing the induction of long-lasting antibodies directed to a fully conserved polypeptide, also challenge current concepts about malaria vaccines, such as unavoidable polymorphism, low antigenicity, and poor induction of immune memory.

  5. A malaria vaccine that elicits in humans antibodies able to kill Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Pierre Druilhe

    2005-11-01

    Full Text Available Plasmodium falciparum merozoite surface protein 3 is a malaria vaccine candidate that was identified, characterised, and developed based on a unique immuno-clinical approach. The vaccine construct was derived from regions fully conserved among various strains and containing B cell epitopes targeted by human antibodies (from malaria-immune adults that are able to mediate a monocyte-dependent parasite killing effect. The corresponding long synthetic peptide was administered to 36 volunteers, with either alum or Montanide ISA720 as adjuvant.Both formulations induced cellular and humoral immune responses. With alum, the responses lasted up to 12 mo. The vaccine-induced antibodies were predominantly of cytophilic classes, i.e., able to cooperate with effector cells. In vitro, the antibodies induced an inhibition of the P. falciparum erythrocytic growth in a monocyte-dependent manner, which was in most instances as high as or greater than that induced by natural antibodies from immune African adults. In vivo transfer of the volunteers' sera into P. falciparum-infected humanized SCID mice profoundly reduced or abrogated parasitaemia. These inhibitory effects were related to the antibody reactivity with the parasite native protein, which was seen in 60% of the volunteers, and remained in samples taken 12 mo postimmunisation.This is the first malaria vaccine clinical trial to clearly demonstrate antiparasitic activity by vaccine-induced antibodies by both in vitro and in vivo methods. The results, showing the induction of long-lasting antibodies directed to a fully conserved polypeptide, also challenge current concepts about malaria vaccines, such as unavoidable polymorphism, low antigenicity, and poor induction of immune memory.

  6. Strain-specific Plasmodium falciparum growth inhibition among Malian children immunized with a blood-stage malaria vaccine.

    Science.gov (United States)

    Laurens, Matthew B; Kouriba, Bourema; Bergmann-Leitner, Elke; Angov, Evelina; Coulibaly, Drissa; Diarra, Issa; Daou, Modibo; Niangaly, Amadou; Blackwelder, William C; Wu, Yukun; Cohen, Joe; Ballou, W Ripley; Vekemans, Johan; Lanar, David E; Dutta, Sheetij; Diggs, Carter; Soisson, Lorraine; Heppner, D Gray; Doumbo, Ogobara K; Plowe, Christopher V; Thera, Mahamadou A

    2017-01-01

    The blood-stage malaria vaccine FMP2.1/AS02A, comprised of recombinant Plasmodium falciparum apical membrane antigen 1 (AMA1) and the adjuvant system AS02A, had strain-specific efficacy against clinical malaria caused by P. falciparum with the vaccine strain 3D7 AMA1 sequence. To evaluate a potential correlate of protection, we measured the ability of participant sera to inhibit growth of 3D7 and FVO strains in vitro using high-throughput growth inhibition assay (GIA) testing. Sera from 400 children randomized to receive either malaria vaccine or a control rabies vaccine were assessed at baseline and over two annual malaria transmission seasons after immunization. Baseline GIA against vaccine strain 3D7 and FVO strain was similar in both groups, but more children in the malaria vaccine group than in the control group had 3D7 and FVO GIA activity ≥15% 30 days after the last vaccination (day 90) (49% vs. 16%, pvaccine group was 7.4 times the mean increase in the control group (pvaccination (day 364) and did not correlate with efficacy in the extended efficacy time period to day 730. In Cox proportional hazards regression models with time-varying covariates, there was a slight suggestion of an association between 3D7 GIA activity and increased risk of clinical malaria between day 90 and day 240. We conclude that vaccination with this AMA1-based malaria vaccine increased inhibition of parasite growth, but this increase was not associated with allele-specific efficacy in the first malaria season. These results provide a framework for testing functional immune correlates of protection against clinical malaria in field trials, and will help to guide similar analyses for next-generation malaria vaccines. Clinical trials registry: This clinical trial was registered on clinicaltrials.gov, registry number NCT00460525.

  7. Towards an RTS,S-based, multi-stage, multi-antigen vaccine against falciparum malaria: progress at the Walter Reed Army Institute of Research

    NARCIS (Netherlands)

    Heppner, D. Gray; Kester, Kent E.; Ockenhouse, Christian F.; Tornieporth, Nadia; Ofori, Opokua; Lyon, Jeffrey A.; Stewart, V. Ann; Dubois, Patrice; Lanar, David E.; Krzych, Urszula; Moris, Philippe; Angov, Evelina; Cummings, James F.; Leach, Amanda; Hall, B. Ted; Dutta, Sheetij; Schwenk, Robert; Hillier, Collette; Barbosa, Arnoldo; Ware, Lisa A.; Nair, Lalitha; Darko, Christian A.; Withers, Mark R.; Ogutu, Bernhards; Polhemus, Mark E.; Fukuda, Mark; Pichyangkul, Sathit; Gettyacamin, Montip; Diggs, Carter; Soisson, Lorraine; Milman, Jessica; Dubois, Marie-Claude; Garçon, Nathalie; Tucker, Kathryn; Wittes, Janet; Plowe, Christopher V.; Thera, Mahamadou A.; Duombo, Ogobara K.; Pau, Maria G.; Goudsmit, Jaap; Ballou, W. Ripley; Cohen, Joe

    2005-01-01

    The goal of the Malaria Vaccine Program at the Walter Reed Army Institute of Research (WRAIR) is to develop a licensed multi-antigen, multi-stage vaccine against Plasmodium falciparum able to prevent all symptomatic manifestations of malaria by preventing parasitemia. A secondary goal is to limit

  8. Progress with Plasmodium falciparum sporozoite (PfSPZ)-based malaria vaccines.

    Science.gov (United States)

    Richie, Thomas L; Billingsley, Peter F; Sim, B Kim Lee; James, Eric R; Chakravarty, Sumana; Epstein, Judith E; Lyke, Kirsten E; Mordmüller, Benjamin; Alonso, Pedro; Duffy, Patrick E; Doumbo, Ogobara K; Sauerwein, Robert W; Tanner, Marcel; Abdulla, Salim; Kremsner, Peter G; Seder, Robert A; Hoffman, Stephen L

    2015-12-22

    Sanaria Inc. has developed methods to manufacture, purify and cryopreserve aseptic Plasmodium falciparum (Pf) sporozoites (SPZ), and is using this platform technology to develop an injectable PfSPZ-based vaccine that provides high-grade, durable protection against infection with Pf malaria. Several candidate vaccines are being developed and tested, including PfSPZ Vaccine, in which the PfSPZ are attenuated by irradiation, PfSPZ-CVac, in which fully infectious PfSPZ are attenuated in vivo by concomitant administration of an anti-malarial drug, and PfSPZ-GA1, in which the PfSPZ are attenuated by gene knockout. Forty-three research groups in 15 countries, organized as the International PfSPZ Consortium (I-PfSPZ-C), are collaborating to advance this program by providing intellectual, clinical, and financial support. Fourteen clinical trials of these products have been completed in the USA, Europe and Africa, two are underway and at least 12 more are planned for 2015-2016 in the US (four trials), Germany (2 trials), Tanzania, Kenya, Mali, Burkina Faso, Ghana and Equatorial Guinea. Sanaria anticipates application to license a first generation product as early as late 2017, initially to protect adults, and a year later to protect all persons >6 months of age for at least six months. Improved vaccine candidates will be advanced as needed until the following requirements have been met: long-term protection against natural transmission, excellent safety and tolerability, and operational feasibility for population-wide administration. Here we describe the three most developed whole PfSPZ vaccine candidates, associated clinical trials, initial plans for licensure and deployment, and long-term objectives for a final product suitable for mass administration to achieve regional malaria elimination and eventual global eradication. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  9. Strain-specific Plasmodium falciparum growth inhibition among Malian children immunized with a blood-stage malaria vaccine.

    Directory of Open Access Journals (Sweden)

    Matthew B Laurens

    Full Text Available The blood-stage malaria vaccine FMP2.1/AS02A, comprised of recombinant Plasmodium falciparum apical membrane antigen 1 (AMA1 and the adjuvant system AS02A, had strain-specific efficacy against clinical malaria caused by P. falciparum with the vaccine strain 3D7 AMA1 sequence. To evaluate a potential correlate of protection, we measured the ability of participant sera to inhibit growth of 3D7 and FVO strains in vitro using high-throughput growth inhibition assay (GIA testing. Sera from 400 children randomized to receive either malaria vaccine or a control rabies vaccine were assessed at baseline and over two annual malaria transmission seasons after immunization. Baseline GIA against vaccine strain 3D7 and FVO strain was similar in both groups, but more children in the malaria vaccine group than in the control group had 3D7 and FVO GIA activity ≥15% 30 days after the last vaccination (day 90 (49% vs. 16%, p<0.0001; and 71.8% vs. 60.4%, p = 0.02. From baseline to day 90, 3D7 GIA in the vaccine group was 7.4 times the mean increase in the control group (p<0.0001. In AMA1 vaccinees, 3D7 GIA activity subsequently returned to baseline one year after vaccination (day 364 and did not correlate with efficacy in the extended efficacy time period to day 730. In Cox proportional hazards regression models with time-varying covariates, there was a slight suggestion of an association between 3D7 GIA activity and increased risk of clinical malaria between day 90 and day 240. We conclude that vaccination with this AMA1-based malaria vaccine increased inhibition of parasite growth, but this increase was not associated with allele-specific efficacy in the first malaria season. These results provide a framework for testing functional immune correlates of protection against clinical malaria in field trials, and will help to guide similar analyses for next-generation malaria vaccines. Clinical trials registry: This clinical trial was registered on clinicaltrials

  10. The case for PfEMP1-based vaccines to protect pregnant women against Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Hviid, Lars

    2011-01-01

    Vaccines are very cost-effective tools in combating infectious disease mortality and morbidity. Unfortunately, vaccines efficiently protecting against infection with malaria parasites are not available and are not likely to appear in the near future. An alternative strategy would be vaccines...... to develop a vaccine protecting pregnant women and their offspring against mortality and morbidity caused by the accumulation of Plasmodium falciparum-infected erythrocytes in the placenta. It is based on a detailed understanding of the parasite antigen and the host receptor involved in this accumulation......, as well as knowledge regarding the protective immune response that is acquired in response to placental P. falciparum infection. Nevertheless, it remains controversial in some quarters whether such a vaccine would have the desired impact, or indeed whether the strategy is meaningful. This article...

  11. Assessment of the Plasmodium falciparum Preerythrocytic Antigen UIS3 as a Potential Candidate for a Malaria Vaccine.

    Science.gov (United States)

    Longley, Rhea J; Halbroth, Benedict R; Salman, Ahmed M; Ewer, Katie J; Hodgson, Susanne H; Janse, Chris J; Khan, Shahid M; Hill, Adrian V S; Spencer, Alexandra J

    2017-03-01

    Efforts are under way to improve the efficacy of subunit malaria vaccines through assessments of new adjuvants, vaccination platforms, and antigens. In this study, we further assessed the Plasmodium falciparum antigen upregulated in infective sporozoites 3 (PfUIS3) as a vaccine candidate. PfUIS3 was expressed in the viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) and used to immunize mice in a prime-boost regimen. We previously demonstrated that this regimen could provide partial protection against challenge with chimeric P. berghei parasites expressing PfUIS3. We now show that ChAd63-MVA PfUIS3 can also provide partial cross-species protection against challenge with wild-type P. berghei parasites. We also show that PfUIS3-specific cellular memory responses could be recalled in human volunteers exposed to P. falciparum parasites in a controlled human malaria infection study. When ChAd63-MVA PfUIS3 was coadministered with the vaccine candidate P. falciparum thrombospondin-related adhesion protein (PfTRAP) expressed in the ChAd63-MVA system, there was no significant change in immunogenicity to either vaccine. However, when mice were challenged with double chimeric P. berghei - P. falciparum parasites expressing both PfUIS3 and PfTRAP, vaccine efficacy was improved to 100% sterile protection. This synergistic effect was evident only when the two vaccines were mixed and administered at the same site. We have therefore demonstrated that vaccination with PfUIS3 can induce a consistent delay in patent parasitemia across mouse strains and against chimeric parasites expressing PfUIS3 as well as wild-type P. berghei ; when this vaccine is combined with another partially protective regimen (ChAd63-MVA PfTRAP), complete protection is induced. Copyright © 2017 Longley et al.

  12. Comparative testing of six antigen-based malaria vaccine candidates directed toward merozoite-stage Plasmodium falciparum

    DEFF Research Database (Denmark)

    Arnot, David E; Cavanagh, David R; Remarque, Edmond J

    2008-01-01

    Immunogenicity testing of Plasmodium falciparum antigens being considered as malaria vaccine candidates was undertaken in rabbits. The antigens compared were recombinant baculovirus MSP-1(19) and five Pichia pastoris candidates, including two versions of MSP-1(19), AMA-1 (domains I and II), AMA-1......G concentrations. The two P. pastoris-produced MSP-1(19)-induced IgGs conferred the lowest growth inhibition. Comparative analysis of immunogenicity of vaccine antigens can be used to prioritize candidates before moving to expensive GMP production and clinical testing. The assays used have given discriminating...

  13. Plasmodium falciparum CS protein - prime malaria vaccine candidate: definition of the human CTL domain and analysis of its variation

    Directory of Open Access Journals (Sweden)

    Denise L. Doolan

    1992-01-01

    Full Text Available Studies in mice have shown that immunity to malaria sporozoites is mediated primarily by citotoxic T lymphocytes (CTL specific for epitopes within the circumsporozoite (CS protein. Humans, had never been shown to generate CTL against any malaria or other parasite protein. The design of a sub-unit vaccine for humans ralies on the epitopes recognized by CTL being identified and polymorphisms therein being defined. We have developed a novel technique using an entire series of overlapping synthetic peptides to define the epitopes of the Plasmodium falciparum CS protein recognized by human CTL and have analyzed the sequence variation of the protein with respect to the identified CTL epitopic domain. We have demonstrated that some humans can indeed generate CTL. against the P. falciparum CS protein. Furthermore, the extent of variation observed for the CTL recognition domain is finite and the combination of peptides necessary for inclusion in a polyvalent vaccine may be small. If ways can be found to increase immune responsiveness, then a vaccine designed to stimulate CS protein-specific CTL activity may prevent malaria.

  14. Vaccines against malaria.

    Science.gov (United States)

    Ouattara, Amed; Laurens, Matthew B

    2015-03-15

    Despite global efforts to control malaria, the illness remains a significant public health threat. Currently, there is no licensed vaccine against malaria, but an efficacious vaccine would represent an important public health tool for successful malaria elimination. Malaria vaccine development continues to be hindered by a poor understanding of antimalarial immunity, a lack of an immune correlate of protection, and the genetic diversity of malaria parasites. Current vaccine development efforts largely target Plasmodium falciparum parasites in the pre-erythrocytic and erythrocytic stages, with some research on transmission-blocking vaccines against asexual stages and vaccines against pregnancy-associated malaria. The leading pre-erythrocytic vaccine candidate is RTS,S, and early results of ongoing Phase 3 testing show overall efficacy of 46% against clinical malaria. The next steps for malaria vaccine development will focus on the design of a product that is efficacious against the highly diverse strains of malaria and the identification of a correlate of protection against disease. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  15. Vaccines against malaria.

    Science.gov (United States)

    Hill, Adrian V S

    2011-10-12

    There is no licenced vaccine against any human parasitic disease and Plasmodium falciparum malaria, a major cause of infectious mortality, presents a great challenge to vaccine developers. This has led to the assessment of a wide variety of approaches to malaria vaccine design and development, assisted by the availability of a safe challenge model for small-scale efficacy testing of vaccine candidates. Malaria vaccine development has been at the forefront of assessing many new vaccine technologies including novel adjuvants, vectored prime-boost regimes and the concept of community vaccination to block malaria transmission. Most current vaccine candidates target a single stage of the parasite's life cycle and vaccines against the early pre-erythrocytic stages have shown most success. A protein in adjuvant vaccine, working through antibodies against sporozoites, and viral vector vaccines targeting the intracellular liver-stage parasite with cellular immunity show partial efficacy in humans, and the anti-sporozoite vaccine is currently in phase III trials. However, a more effective malaria vaccine suitable for widespread cost-effective deployment is likely to require a multi-component vaccine targeting more than one life cycle stage. The most attractive near-term approach to develop such a product is to combine existing partially effective pre-erythrocytic vaccine candidates.

  16. Humoral immune response to Plasmodium falciparum vaccine candidate GMZ2 and its components in populations naturally exposed to seasonal malaria in Ethiopia

    DEFF Research Database (Denmark)

    Mamo, Hassen; Esen, Meral; Ajua, Anthony

    2013-01-01

    . The significantly higher antibody prevalence and level detected against GMZ2 compared to either of its subunits separately, in naturally exposed populations, suggests the synergistic effect of GLURP-R0 and MSP3 and that GMZ2 could be a more relevant blood-stage malaria vaccine candidate than the individual......ABSTRACT: BACKGROUND: In Ethiopia, the general population is vulnerable to unpredictable epidemics of Plasmodium falciparum malaria. However, there is little information on the anti-malaria immune profile of the population in the endemic regions of the country. METHODS: The study was designed...... for malaria infection microscopically and by the rapid diagnostic test (RDT). Sera were tested by using enzyme-linked immunosorbent assay (ELISA) for total immunoglobulin (Ig) G against P. falciparum blood-stage vaccine candidate GMZ2 and its subunits (Glutamate-rich protein (GLURP-R0), merozoite surface...

  17. Immunogenicity of a virosomally-formulated Plasmodium falciparum GLURP-MSP3 chimeric protein-based malaria vaccine candidate in comparison to adjuvanted formulations

    DEFF Research Database (Denmark)

    Tamborrini, Marco; Stoffel, Sabine A; Westerfeld, Nicole

    2011-01-01

    In clinical trials, immunopotentiating reconstituted influenza virosomes (IRIVs) have shown great potential as a versatile antigen delivery platform for synthetic peptides derived from Plasmodium falciparum antigens. This study describes the immunogenicity of a virosomally-formulated recombinant...... fusion protein comprising domains of the two malaria vaccine candidate antigens MSP3 and GLURP....

  18. Improving the malaria transmission-blocking activity of a Plasmodium falciparum 48/45 based vaccine antigen by SpyTag/SpyCatcher mediated virus-like display

    DEFF Research Database (Denmark)

    Singh, Susheel K; Thrane, Susan; Janitzek, Christoph M

    2017-01-01

    Malaria is a devastating disease caused by Plasmodium parasites, resulting in almost 0.5 million deaths per year. The Pfs48/45 protein exposed on the P. falciparum sexual stages is one of the most advanced antigen candidates for a transmission-blocking (TB) vaccine in the clinical pipeline. However...

  19. Identification of Protective B-Cell Epitopes within the Novel Malaria Vaccine Candidate Plasmodium falciparum Schizont Egress Antigen 1.

    Science.gov (United States)

    Nixon, Christina E; Park, Sangshin; Pond-Tor, Sunthorn; Raj, Dipak; Lambert, Lynn E; Orr-Gonzalez, Sachy; Barnafo, Emma K; Rausch, Kelly M; Friedman, Jennifer F; Fried, Michal; Duffy, Patrick E; Kurtis, Jonathan D

    2017-07-01

    Naturally acquired antibodies to Plasmodium falciparum schizont egress antigen 1 (PfSEA-1A) are associated with protection against severe malaria in children. Vaccination of mice with SEA-1A from Plasmodium berghei (PbSEA-1A) decreases parasitemia and prolongs survival following P. berghei ANKA challenge. To enhance the immunogenicity of PfSEA-1A, we identified five linear B-cell epitopes using peptide microarrays probed with antisera from nonhuman primates vaccinated with recombinant PfSEA-1A (rPfSEA-1A). We evaluated the relationship between epitope-specific antibody levels and protection from parasitemia in a longitudinal treatment-reinfection cohort in western Kenya. Antibodies to three epitopes were associated with 16 to 17% decreased parasitemia over an 18-week high transmission season. We are currently designing immunogens to enhance antibody responses to these three epitopes. Copyright © 2017 American Society for Microbiology.

  20. Priming with an adenovirus 35-circumsporozoite protein (CS) vaccine followed by RTS,S/AS01B boosting significantly improves immunogenicity to Plasmodium falciparum CS compared to that with either malaria vaccine alone

    NARCIS (Netherlands)

    Stewart, V. Ann; McGrath, Shannon M.; Dubois, Patrice M.; Pau, Maria G.; Mettens, Pascal; Shott, Joseph; Cobb, Michelle; Burge, J. Robert; Larson, David; Ware, Lisa A.; Demoitie, Marie-Ange; Weverling, Gerrit Jan; Bayat, Babak; Custers, Jerome H. H. V.; Dubois, Marie-Claude; Cohen, Joe; Goudsmit, Jaap; Heppner, D. Gray

    2007-01-01

    The RTS,S/AS02A protein-based vaccine consistently demonstrates significant protection against infection with Plasmodium falciparum malaria and also against clinical malaria and severe disease in children in areas of endemicity. Here we demonstrate with rhesus macaques that priming with a

  1. Anaemia in a phase 2 study of a blood stage falciparum malaria vaccine

    Directory of Open Access Journals (Sweden)

    Guindo Aldiouma

    2011-01-01

    Full Text Available Abstract Background A Phase 1-2b study of the blood stage malaria vaccine AMA1-C1/Alhydrogel was conducted in 336 children in Donéguébougou and Bancoumana, Mali. In the Phase 2 portion of the study (n = 300, no impact on parasite density or clinical malaria was seen; however, children who received the study vaccine had a higher frequency of anaemia (defined as haemoglobin Methods To further investigate the possible impact of vaccination on anaemia, additional analyses were conducted including patients from the Phase 1 portion of the study and controlling for baseline haemoglobin, haemoglobin types S or C, alpha-thalassaemia, G6PD deficiency, and age. A multiplicative intensity model was used, which generalizes Cox regression to allow for multiple events. Frailty effects for each subject were used to account for correlation of multiple anaemia events within the same subject. Intensity rates were calculated with reference to calendar time instead of time after randomization in order to account for staggered enrollment and seasonal effects of malaria incidence. Associations of anaemia with anti-AMA1 antibody were further explored using a similar analysis. Results A strong effect of vaccine on the incidence of anaemia (risk ratio [AMA1-C1 to comparator (Hiberix]= 2.01, 95% confidence interval [1.26,3.20] was demonstrated even after adjusting for baseline haemoglobin, haemoglobinopathies, and age, and using more sophisticated statistical models. Anti-AMA1 antibody levels were not associated with this effect. Conclusions While these additional analyses show a robust effect of vaccination on anaemia, this is an intensive exploration of secondary results and should, therefore, be interpreted with caution. Possible mechanisms of the apparent adverse effect on haemoglobin of vaccination with AMA1-C1/Alhydrogel and implications for blood stage vaccine development are discussed. The potential impact on malaria-associated anaemia should be closely

  2. A Peptide-Based Plasmodium falciparum Circumsporozoite Assay To Test for Serum Antibody Responses to Pre-Erythrocyte Malaria Vaccines

    NARCIS (Netherlands)

    Kostense, Stefan; Mommaas, Bregje; Hendriks, Jenny; Verhoeven, Mariëlle; ter Haak, Mariska; Tirion, Felicia; Wiesken, Edison; Pau, Maria Grazia; Radosevic, Katarina; Goudsmit, Jaap

    2011-01-01

    Various pre-erythrocyte malaria vaccines are currently in clinical development, and among these is the adenovirus serotype 35-based circumsporozoite (CS) vaccine produced on PER.C6 cells. Although the immunological correlate of protection against malaria remains to be established, the CS antibody

  3. Identification of Plasmodium falciparum reticulocyte binding protein homologue 5-interacting protein, PfRipr, as a highly conserved blood-stage malaria vaccine candidate.

    Science.gov (United States)

    Ntege, Edward H; Arisue, Nobuko; Ito, Daisuke; Hasegawa, Tomoyuki; Palacpac, Nirianne M Q; Egwang, Thomas G; Horii, Toshihiro; Takashima, Eizo; Tsuboi, Takafumi

    2016-11-04

    Genetic variability in Plasmodium falciparum malaria parasites hampers current malaria vaccine development efforts. Here, we hypothesize that to address the impact of genetic variability on vaccine efficacy in clinical trials, conserved antigen targets should be selected to achieve robust host immunity across multiple falciparum strains. Therefore, suitable vaccine antigens should be assessed for levels of polymorphism and genetic diversity. Using a total of one hundred and two clinical isolates from a region of high malaria transmission in Uganda, we analyzed extent of polymorphism and genetic diversity in four recently reported novel blood-stage malaria vaccine candidate proteins: Rh5 interacting protein (PfRipr), GPI anchored micronemal antigen (PfGAMA), rhoptry-associated leucine zipper-like protein 1 (PfRALP1) and Duffy binding-like merozoite surface protein 1 (PfMSPDBL1). In addition, utilizing the wheat germ cell-free system, we expressed recombinant proteins for the four candidates based on P. falciparum laboratory strain 3D7 sequences, immunized rabbits to obtain specific antibodies (Abs) and performed functional growth inhibition assay (GIA). The GIA activity of the raised Abs was demonstrated using both homologous 3D7 and heterologous FVO strains in vitro. Both pfripr and pfralp1 are less polymorphic but the latter is comparatively more diverse, with varied number of regions having insertions and deletions, asparagine and 6-mer repeats in the coding sequences. Pfgama and pfmspdbl1 are polymorphic and genetically diverse among the isolates with antibodies against the 3D7-based recombinant PfGAMA and PfMSPDBL1 inhibiting merozoite invasion only in the 3D7 but not FVO strain. Moreover, although Abs against the 3D7-based recombinant PfRipr and PfRALP1 proteins potently inhibited merozoite invasion of both 3D7 and FVO, the GIA activity of anti-PfRipr was much higher than that of anti-PfRALP1. Thus, PfRipr is regarded as a promising blood-stage vaccine

  4. A brief review on features of falciparum malaria during pregnancy

    Directory of Open Access Journals (Sweden)

    Alexandre Manirakiza

    2017-12-01

    Full Text Available Malaria in pregnancy is a serious public health problem in tropical areas. Frequently, the placenta is infected by accumulation of Plasmodium falciparum-infected erythrocytes in the intervillous space. Falciparum malaria acts during pregnancy by a range of mechanisms, and chronic or repeated infection and co-infections have insidious effects. The susceptibility of pregnant women to malaria is due to both immunological and humoral changes. Until a malaria vaccine becomes available, the deleterious effects of malaria in pregnancy can be avoided by protection against infection and prompt treatment with safe, effective antimalarial agents; however, concurrent infections such as with HIV and helminths during pregnancy are jeopardizing malaria control in sub-Saharan Africa.

  5. Plasmodium falciparum malaria

    African Journals Online (AJOL)

    resistance has developed.' Extensive research now supports the implementation of artemisinin-based combination therapies to improve cure rates, decrease malaria transmission and delay resistance.8'9 To determine whether current levels of SP resistance remain adequate to support its use in combination.

  6. The use of a P. falciparum specific coiled-coil domain to construct a self-assembling protein nanoparticle vaccine to prevent malaria.

    Science.gov (United States)

    Karch, Christopher P; Doll, Tais A P F; Paulillo, Sara M; Nebie, Issa; Lanar, David E; Corradin, Giampietro; Burkhard, Peter

    2017-09-06

    The parasitic disease malaria remains a major global public health concern and no truly effective vaccine exists. One approach to the development of a malaria vaccine is to target the asexual blood stage that results in clinical symptoms. Most attempts have failed. New antigens such as P27A and P27 have emerged as potential new vaccine candidates. Multiple studies have demonstrated that antigens are more immunogenic and are better correlated with protection when presented on particulate delivery systems. One such particulate delivery system is the self-assembling protein nanoparticle (SAPN) that relies on coiled-coil domains of proteins to form stable nanoparticles. In the past we have used de novo designed amino acid domains to drive the formation of the coiled-coil scaffolds which present the antigenic epitopes on the particle surface. Here we use naturally occurring domains found in the tex1 protein to form the coiled-coil scaffolding of the nanoparticle. Thus, by engineering P27A and a new extended form of the coiled-coil domain P27 onto the N and C terminus of the SAPN protein monomer we have developed a particulate delivery system that effectively displays both antigens on a single particle that uses malaria tex1 sequences to form the nanoparticle scaffold. These particles are immunogenic in a murine model and induce immune responses similar to the ones observed in seropositive individuals in malaria endemic regions. We demonstrate that our P27/P27A-SAPNs induce an immune response akin to the one in seropositive individuals in Burkina Faso. Since P27 is highly conserved among different Plasmodium species, these novel SAPNs may even provide cross-protection between Plasmodium falciparum and Plasmodium vivax the two major human malaria pathogens. As the SAPNs are also easy to manufacture and store they can be delivered to the population in need without complication thus providing a low cost malaria vaccine.

  7. Plasmodium falciparum malaria in children aged 0-2 years: the role of foetal haemoglobin and maternal antibodies to two asexual malaria vaccine candidates (MSP3 and GLURP.

    Directory of Open Access Journals (Sweden)

    David Tiga Kangoye

    Full Text Available Children below six months are reported to be less susceptible to clinical malaria. Maternally derived antibodies and foetal haemoglobin are important putative protective factors. We examined antibodies to Plasmodium falciparum merozoite surface protein 3 (MSP3 and glutamate-rich protein (GLURP, in children in their first two years of life in Burkina Faso and their risk of malaria.A cohort of 140 infants aged between four and six weeks was recruited in a stable transmission area of south-western Burkina Faso and monitored for 24 months by active and passive surveillance. Malaria infections were detected by examining blood smears using light microscopy. Enzyme-linked immunosorbent assay was used to quantify total Immunoglobulin G to Plasmodium falciparum antigens MSP3 and two regions of GLURP (R0 and R2 on blood samples collected at baseline, three, six, nine, 12, 18 and 24 months. Foetal haemoglobin and variant haemoglobin fractions were measured at the baseline visit using high pressure liquid chromatography.A total of 79.6% of children experienced one or more episodes of febrile malaria during monitoring. Antibody titres to MSP3 were prospectively associated with an increased risk of malaria while antibody responses to GLURP (R0 and R2 did not alter the risk. Antibody titres to MSP3 were higher among children in areas of high malaria risk. Foetal haemoglobin was associated with delayed first episode of febrile malaria and haemoglobin CC type was associated with reduced incidence of febrile malaria.We did not find any evidence of association between titres of antibodies to MSP3, GLURP-R0 or GLURP-R2 as measured by enzyme-linked immunosorbent assay and early protection against malaria, although anti-MSP3 antibody titres may reflect increased exposure to malaria and therefore greater risk. Foetal haemoglobin was associated with protection against febrile malaria despite the study limitations and its role is therefore worthy further investigation.

  8. Antibody responses to a novel Plasmodium falciparum merozoite surface protein vaccine correlate with protection against experimental malaria infection in Aotus monkeys.

    Science.gov (United States)

    Cavanagh, David R; Kocken, Clemens H M; White, John H; Cowan, Graeme J M; Samuel, Kay; Dubbeld, Martin A; Voorberg-van der Wel, Annemarie; Thomas, Alan W; McBride, Jana S; Arnot, David E

    2014-01-01

    The Block 2 region of the merozoite surface protein-1 (MSP-1) of Plasmodium falciparum has been identified as a target of protective immunity by a combination of seroepidemiology and parasite population genetics. Immunogenicity studies in small animals and Aotus monkeys were used to determine the efficacy of recombinant antigens derived from this region of MSP-1 as a potential vaccine antigen. Aotus lemurinus griseimembra monkeys were immunized three times with a recombinant antigen derived from the Block 2 region of MSP-1 of the monkey-adapted challenge strain, FVO of Plasmodium falciparum, using an adjuvant suitable for use in humans. Immunofluorescent antibody assays (IFA) against erythrocytes infected with P. falciparum using sera from the immunized monkeys showed that the MSP-1 Block 2 antigen induced significant antibody responses to whole malaria parasites. MSP-1 Block 2 antigen-specific enzyme-linked immunosorbent assays (ELISA) showed no significant differences in antibody titers between immunized animals. Immunized animals were challenged with the virulent P. falciparum FVO isolate and monitored for 21 days. Two out of four immunized animals were able to control their parasitaemia during the follow-up period, whereas two out of two controls developed fulminating parasitemia. Parasite-specific serum antibody titers measured by IFA were four-fold higher in protected animals than in unprotected animals. In addition, peptide-based epitope mapping of serum antibodies from immunized Aotus showed distinct differences in epitope specificities between protected and unprotected animals.

  9. Development of a Metabolically Active, Non-Replicating Sporozoite Vaccine to Prevent Plasmodium falciparum Malaria

    Science.gov (United States)

    2009-10-01

    the live attenuated sporozoite vaccine approach, sera and and intramuscular (IM) routes. In addition, Sanaria scientists . T cells from volunteers...infectious agent vaccines. This is in part because adjuvants like transportation is used routinely for biological sample collec- aluminum hydroxide

  10. Premunition in Plasmodium falciparum malaria

    African Journals Online (AJOL)

    STORAGESEVER

    2010-03-08

    Mar 8, 2010 ... immune responses to malaria are partly due to immune evasion strategies of the parasite caused by antigenic polymorphism ... use of antimalaria drugs and its possible strategic role in vaccine development against the .... the parasite's ability to divert the immune system (Moelans et al., 1992). Very often ...

  11. Safety and immunogenicity of a malaria vaccine, Plasmodium falciparum AMA-1/MSP-1 chimeric protein formulated in montanide ISA 720 in healthy adults.

    Directory of Open Access Journals (Sweden)

    Jinhong Hu

    Full Text Available BACKGROUND: The P. falciparum chimeric protein 2.9 (PfCP-2.9 consisting of the sequences of MSP1-19 and AMA-1 (III is a malaria vaccine candidate that was found to induce inhibitory antibodies in rabbits and monkeys. This was a phase I randomized, single-blind, placebo-controlled, dose-escalation study to evaluate the safety and immunogenicity of the PfCP-2.9 formulated with a novel adjuvant Montanide ISA720. Fifty-two subjects were randomly assigned to 4 dose groups of 10 participants, each receiving the test vaccine of 20, 50, 100, or 200 microg respectively, and 1 placebo group of 12 participants receiving the adjuvant only. METHODS AND FINDINGS: The vaccine formulation was shown to be safe and well-tolerated, and none of the participants withdrew. The total incidence of local adverse events (AEs was 75%, distributed among 58% of the placebo group and 80% of those vaccinated. Among the vaccinated, 65% had events that were mild and 15% experienced moderate AEs. Almost all systemic adverse reactions observed in this study were graded as mild and required no therapy. The participants receiving the test vaccine developed detectable antibody responses which were boosted by the repeated vaccinations. Sixty percent of the vaccinated participants had high ELISA titers (>1:10,000 of antigen-specific antibodies which could also recognize native parasite proteins in an immunofluorescence assay (IFA. CONCLUSION: This study is the first clinical trial for this candidate and builds on previous investigations supporting PfCP-2.9/ISA720 as a promising blood-stage malaria vaccine. Results demonstrate safety, tolerability (particularly at the lower doses tested and immunogenicity of the formulation. Further clinical development is ongoing to explore optimizing the dose and schedule of the formulation to decrease reactogenicity without compromising immunogenicity. TRIAL REGISTRATION: Chinese State Food and Drug Administration (SFDA 2002SL0046; Controlled

  12. Humoral immune response to Plasmodium falciparum vaccine candidate GMZ2 and its components in populations naturally exposed to seasonal malaria in Ethiopia.

    Science.gov (United States)

    Mamo, Hassen; Esen, Meral; Ajua, Anthony; Theisen, Michael; Mordmüller, Benjamin; Petros, Beyene

    2013-02-05

    In Ethiopia, the general population is vulnerable to unpredictable epidemics of Plasmodium falciparum malaria. However, there is little information on the anti-malaria immune profile of the population in the endemic regions of the country. The study was designed to investigate the nature of humoral immune response to malaria in two ethnic groups in two endemic localities: Shewa Robit in north, and Boditi in south Ethiopia which are characterized by varying levels of malaria transmission and altitude. In a cross-sectional study, the study participants were diagnosed for malaria infection microscopically and by the rapid diagnostic test (RDT). Sera were tested by using enzyme-linked immunosorbent assay (ELISA) for total immunoglobulin (Ig) G against P. falciparum blood-stage vaccine candidate GMZ2 and its subunits (Glutamate-rich protein (GLURP-R0), merozoite surface protein 3 (MSP3); as well as IgG subclasses against GLURP-R0 and MSP3. Whereas 23(8.6%) blood smear-positive cases for P. falciparum were detected in Boditi, all Shewa Robit study participants had no detectable P. falciparum infection. In both localities, total IgG prevalence and levels to GMZ2 were significantly higher than the response to the component domains indicating the strong recognition of GMZ2 by antibodies acquired through natural exposure. Total IgG and subclass prevalence and levels were higher in Shewa Robit than Boditi, suggesting difference in the intensity of malaria transmission in the two localities and/or genetic differences between the two populations in their response to the antigens. In both study sites, IgG subclass levels to GLURP-R0 were significantly higher than that to MSP3 for all corresponding subclasses in most individuals, indicating the higher relative antigenicity and probably protective potential of GLURP-R0 compared to MSP3. Against both GLURP-R0 and MSP3, the ratio of cytophilic to noncytophilic antibodies was >1 in the majority of the study participants, in both

  13. The march toward malaria vaccines.

    Science.gov (United States)

    Hoffman, Stephen L; Vekemans, Johan; Richie, Thomas L; Duffy, Patrick E

    2015-11-27

    In 2013 there were an estimated 584,000 deaths and 198 million clinical illnesses due to malaria, the majority in sub-Saharan Africa. Vaccines would be the ideal addition to the existing armamentarium of anti-malaria tools. However, malaria is caused by parasites, and parasites are much more complex in terms of their biology than the viruses and bacteria for which we have vaccines, passing through multiple stages of development in the human host, each stage expressing hundreds of unique antigens. This complexity makes it more difficult to develop a vaccine for parasites than for viruses and bacteria, since an immune response targeting one stage may not offer protection against a later stage, because different antigens are the targets of protective immunity at different stages. Furthermore, depending on the life cycle stage and whether the parasite is extra- or intra-cellular, antibody and/or cellular immune responses provide protection. It is thus not surprising that there is no vaccine on the market for prevention of malaria, or any human parasitic infection. In fact, no vaccine for any disease with this breadth of targets and immune responses exists. In this limited review, we focus on four approaches to malaria vaccines, (1) a recombinant protein with adjuvant vaccine aimed at Plasmodium falciparum (Pf) pre-erythrocytic stages of the parasite cycle (RTS,S/AS01), (2) whole sporozoite vaccines aimed at Pf pre-erythrocytic stages (PfSPZ Vaccine and PfSPZ-CVac), (3) prime boost vaccines that include recombinant DNA, viruses and bacteria, and protein with adjuvant aimed primarily at Pf pre-erythrocytic, but also asexual erythrocytic stages, and (4) recombinant protein with adjuvant vaccines aimed at Pf and Plasmodium vivax sexual erythrocytic and mosquito stages. We recognize that we are not covering all approaches to malaria vaccine development, or most of the critically important work on development of vaccines against P. vivax, the second most important cause of

  14. Virosome-formulated Plasmodium falciparum AMA-1 & CSP derived peptides as malaria vaccine: randomized phase 1b trial in semi-immune adults & children.

    Directory of Open Access Journals (Sweden)

    Patrick Georges Cech

    Full Text Available This trial was conducted to evaluate the safety and immunogenicity of two virosome formulated malaria peptidomimetics derived from Plasmodium falciparum AMA-1 and CSP in malaria semi-immune adults and children.The design was a prospective randomized, double-blind, controlled, age-deescalating study with two immunizations. 10 adults and 40 children (aged 5-9 years living in a malaria endemic area were immunized with PEV3B or virosomal influenza vaccine Inflexal®V on day 0 and 90.No serious or severe adverse events (AEs related to the vaccines were observed. The only local solicited AE reported was pain at injection site, which affected more children in the Inflexal®V group compared to the PEV3B group (p = 0.014. In the PEV3B group, IgG ELISA endpoint titers specific for the AMA-1 and CSP peptide antigens were significantly higher for most time points compared to the Inflexal®V control group. Across all time points after first immunization the average ratio of endpoint titers to baseline values in PEV3B subjects ranged from 4 to 15 in adults and from 4 to 66 in children. As an exploratory outcome, we found that the incidence rate of clinical malaria episodes in children vaccinees was half the rate of the control children between study days 30 and 365 (0.0035 episodes per day at risk for PEV3B vs. 0.0069 for Inflexal®V; RR  = 0.50 [95%-CI: 0.29-0.88], p = 0.02.These findings provide a strong basis for the further development of multivalent virosomal malaria peptide vaccines.ClinicalTrials.gov NCT00513669.

  15. DNA prime/Adenovirus boost malaria vaccine encoding P. falciparum CSP and AMA1 induces sterile protection associated with cell-mediated immunity.

    Directory of Open Access Journals (Sweden)

    Ilin Chuang

    Full Text Available BACKGROUND: Gene-based vaccination using prime/boost regimens protects animals and humans against malaria, inducing cell-mediated responses that in animal models target liver stage malaria parasites. We tested a DNA prime/adenovirus boost malaria vaccine in a Phase 1 clinical trial with controlled human malaria infection. METHODOLOGY/PRINCIPAL FINDINGS: The vaccine regimen was three monthly doses of two DNA plasmids (DNA followed four months later by a single boost with two non-replicating human serotype 5 adenovirus vectors (Ad. The constructs encoded genes expressing P. falciparum circumsporozoite protein (CSP and apical membrane antigen-1 (AMA1. The regimen was safe and well-tolerated, with mostly mild adverse events that occurred at the site of injection. Only one AE (diarrhea, possibly related to immunization, was severe (Grade 3, preventing daily activities. Four weeks after the Ad boost, 15 study subjects were challenged with P. falciparum sporozoites by mosquito bite, and four (27% were sterilely protected. Antibody responses by ELISA rose after Ad boost but were low (CSP geometric mean titer 210, range 44-817; AMA1 geometric mean micrograms/milliliter 11.9, range 1.5-102 and were not associated with protection. Ex vivo IFN-γ ELISpot responses after Ad boost were modest (CSP geometric mean spot forming cells/million peripheral blood mononuclear cells 86, range 13-408; AMA1 348, range 88-1270 and were highest in three protected subjects. ELISpot responses to AMA1 were significantly associated with protection (p = 0.019. Flow cytometry identified predominant IFN-γ mono-secreting CD8+ T cell responses in three protected subjects. No subjects with high pre-existing anti-Ad5 neutralizing antibodies were protected but the association was not statistically significant. SIGNIFICANCE: The DNA/Ad regimen provided the highest sterile immunity achieved against malaria following immunization with a gene-based subunit vaccine (27%. Protection

  16. Priming with an Adenovirus 35-Circumsporozoite Protein (CS) Vaccine followed by RTS,S/AS01B Boosting Significantly Improves Immunogenicity to Plasmodium falciparum CS Compared to That with Either Malaria Vaccine Alone▿

    Science.gov (United States)

    Stewart, V. Ann; McGrath, Shannon M.; Dubois, Patrice M.; Pau, Maria G.; Mettens, Pascal; Shott, Joseph; Cobb, Michelle; Burge, J. Robert; Larson, David; Ware, Lisa A.; Demoitie, Marie-Ange; Weverling, Gerrit Jan; Bayat, Babak; Custers, Jerome H. H. V.; Dubois, Marie-Claude; Cohen, Joe; Goudsmit, Jaap; Heppner, D. Gray

    2007-01-01

    The RTS,S/AS02A protein-based vaccine consistently demonstrates significant protection against infection with Plasmodium falciparum malaria and also against clinical malaria and severe disease in children in areas of endemicity. Here we demonstrate with rhesus macaques that priming with a replication-defective human adenovirus serotype 35 (Ad35) vector encoding circumsporozoite protein (CS) (Ad35.CS), followed by boosting with RTS,S in an improved MPL- and QS21-based adjuvant formulation, AS01B, maintains antibody responses and dramatically increases levels of T cells producing gamma interferon and other Th1 cytokines in response to CS peptides. The increased T-cell responses induced by the combination of Ad35.CS and RTS,S/AS01B are sustained for at least 6 months postvaccination and may translate to improved and more durable protection against P. falciparum infection in humans. PMID:17307942

  17. Immunogenicity of a virosomally-formulated Plasmodium falciparum GLURP-MSP3 chimeric protein-based malaria vaccine candidate in comparison to adjuvanted formulations

    Directory of Open Access Journals (Sweden)

    Tamborrini Marco

    2011-12-01

    Full Text Available Abstract Background In clinical trials, immunopotentiating reconstituted influenza virosomes (IRIVs have shown great potential as a versatile antigen delivery platform for synthetic peptides derived from Plasmodium falciparum antigens. This study describes the immunogenicity of a virosomally-formulated recombinant fusion protein comprising domains of the two malaria vaccine candidate antigens MSP3 and GLURP. Methods The highly purified recombinant protein GMZ2 was coupled to phosphatidylethanolamine and the conjugates incorporated into the membrane of IRIVs. The immunogenicity of this adjuvant-free virosomal formulation was compared to GMZ2 formulated with the adjuvants Montanide ISA 720 and Alum in three mouse strains with different genetic backgrounds. Results Intramuscular injections of all three candidate vaccine formulations induced GMZ2-specific antibody responses in all mice tested. In general, the humoral immune response in outbred NMRI mice was stronger than that in inbred BALB/c and C57BL/6 mice. ELISA with the recombinant antigens demonstrated immunodominance of the GLURP component over the MSP3 component. However, compared to the Al(OH3-adjuvanted formulation the two other formulations elicited in NMRI mice a larger proportion of anti-MSP3 antibodies. Analyses of the induced GMZ2-specific IgG subclass profiles showed for all three formulations a predominance of the IgG1 isotype. Immune sera against all three formulations exhibited cross-reactivity with in vitro cultivated blood-stage parasites. Immunofluorescence and immunoblot competition experiments showed that both components of the hybrid protein induced IgG cross-reactive with the corresponding native proteins. Conclusion A virosomal formulation of the chimeric protein GMZ2 induced P. falciparum blood stage parasite cross-reactive IgG responses specific for both MSP3 and GLURP. GMZ2 thus represents a candidate component suitable for inclusion into a multi-valent virosomal

  18. Humoral immune response to Plasmodium falciparum vaccine candidate GMZ2 and its components in populations naturally exposed to seasonal malaria in Ethiopia

    OpenAIRE

    Mamo, Hassen; Esen, Meral; Ajua, Anthony; Theisen, Michael; Mordm?ller, Benjamin; Petros, Beyene

    2013-01-01

    Background In Ethiopia, the general population is vulnerable to unpredictable epidemics of Plasmodium falciparum malaria. However, there is little information on the anti-malaria immune profile of the population in the endemic regions of the country. Methods The study was designed to investigate the nature of humoral immune response to malaria in two ethnic groups in two endemic localities: Shewa Robit in north, and Boditi in south Ethiopia which are characterized by varying levels of malaria...

  19. Preparing for future efficacy trials of severe malaria vaccines.

    Science.gov (United States)

    Gonçalves, Bronner P; Prevots, D Rebecca; Kabyemela, Edward; Fried, Michal; Duffy, Patrick E

    2016-04-07

    Severe malaria is a major cause of mortality in children, but comprises only a small proportion of Plasmodium falciparum infections in naturally exposed populations. The evaluation of vaccines that prevent severe falciparum disease will require clinical trials whose primary efficacy endpoint will be severe malaria risk during follow-up. Here, we show that such trials are feasible with fewer than 1000 participants in areas with intense malaria transmission during the age interval when severe malaria incidence peaks. Published by Elsevier Ltd.

  20. Plasmodium falciparum malaria associated with ABO blood ...

    African Journals Online (AJOL)

    The present study was carried out to investigate the relationship between blood group types and P. falciparum malaria, as well as malaria preventive measures. The venous blood specimens were collected, processed, Giemsa-stained and examined microscopically. ABO groups were determined by agglutination test using ...

  1. Alanine metabolism in acute falciparum malaria

    NARCIS (Netherlands)

    Pukrittayakamee, S.; Krishna, S.; ter Kuile, F.; Wilaiwan, O.; Williamson, D. H.; White, N. J.

    2002-01-01

    We investigated the integrity of the gluconeogenic pathway in severe malaria using alanine metabolism as a measure. Alanine disposition and liver blood flow, assessed by indocyanine green (ICG) clearance, were measured simultaneously in 10 patients with falciparum malaria (six severe and four

  2. Severe falciparum malaria associated with massive pulmonary ...

    African Journals Online (AJOL)

    Microthrombotic complications are the best described; however, a number of cases of thrombosis involving larger vessels have been published in the literature. Herein, we describe the case of a woman with malaria associated with massive pulmonary embolism. Keywords: Falciparum, malaria, pulmonary embolism ...

  3. Malaria vaccine: a step toward elimination.

    Science.gov (United States)

    Jindal, Harashish; Bhatt, Bhumika; Malik, Jagbir S; Sk, Shashikantha; Mehta, Bharti

    2014-01-01

    Malaria has long been recognized as a public health problem. At the community level, vector control, and antimalarial medicines are the main means for reducing incidence, morbidity, and mortality of malaria. A vaccine not only would bring streamlining in the prevention of morbidity and mortality from malaria but also would be more accessible if integrated with Expanded Programme of Immunization (EPI). Globally, an estimated 3.4 billion people are at risk of malaria. Most cases (80%) and deaths (90%) occurred in Africa, and most deaths (77%) are in children under 5 years of age. An effective vaccine has long been envisaged as a valuable addition to the available tools for malaria control. Although research toward the development of malaria vaccines has been pursued since the 1960s, there are no licensed malaria vaccines. The RTS,S/AS01 vaccine, which targets P. falciparum, has reached phase 3 clinical trials and results are promising. Malaria Vaccine Technology Road Map 2013 has envisaged the world aiming for a licensed vaccine by 2030 that would reduce malaria cases by 75% and be capable of eliminating malaria. It will not only fill the gaps of today's interventions but also be a cost-effective method of decreasing morbidity and mortality from malaria.

  4. RTS,S malaria vaccine efficacy and immunogenicity during Plasmodium falciparum challenge is associated with HLA genotype.

    Science.gov (United States)

    Nielsen, C M; Vekemans, J; Lievens, M; Kester, K E; Regules, J A; Ockenhouse, C F

    2018-03-14

    Although RTS,S remains the most advanced malaria vaccine, the factors influencing differences in vaccine immunogenicity or efficacy between individuals or populations are still poorly characterised. The analyses of genetic determinants of immunogenicity have previously been restricted by relatively small sample sizes from individual trials. Here we combine data from six Phase II RTS,S trials and evaluate the relationship between HLA allele groups and RTS,S-mediated protection in controlled human malaria infections (CHMI), using multivariate logistic or linear regression. We observed significant associations between three allele groups (HLA-A ∗ 01, HLA-B ∗ 08, and HLA-DRB1 ∗ 15/ ∗ 16) and protection, while another three allele groups (HLA-A ∗ 03, HLA-B ∗ 53, and HLA-DRB1 ∗ 07) were significantly associated with lack of protection. It is noteworthy that these 'protective' allele groups are thought to be at a lower prevalence in sub-Saharan African populations than in the UK or USA where these Phase II trials occurred. Taken together, the analyses presented here give an indication that HLA genotype may influence RTS,S-mediated protective efficacy against malaria infection. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

  5. Immunoinformatics of Placental Malaria Vaccine Development

    DEFF Research Database (Denmark)

    Jessen, Leon Eyrich

    Malaria is an infectious disease caused by a protozoan parasite of the genus Plasmodium, which is transferred by female Anopheles mosquitos. WHO estimates that in 2012 there were 207 million cases of malaria, of which 627,000 were fatal. People living in malaria-endemic areas, gradually acquire...... immunity with multiple infections. Placental malaria (PM) is caused by P. falciparum sequestering in the placenta of pregnant women due to the presence of novel receptors in the placenta. An estimated 200,000 infants die a year as a result of PM. In 2004 the specific protein responsible...... and development in the field of placental malaria vaccine development....

  6. A Research Agenda for Malaria Eradication: Vaccines

    Science.gov (United States)

    2011-01-01

    Vaccines could be a crucial component of efforts to eradicate malaria. Current attempts to develop malaria vaccines are primarily focused on Plasmodium falciparum and are directed towards reducing morbidity and mortality. Continued support for these efforts is essential, but if malaria vaccines are to be used as part of a repertoire of tools for elimination or eradication of malaria, they will need to have an impact on malaria transmission. We introduce the concept of “vaccines that interrupt malaria transmission” (VIMT), which includes not only “classical” transmission-blocking vaccines that target the sexual and mosquito stages but also pre-erythrocytic and asexual stage vaccines that have an effect on transmission. VIMT may also include vaccines that target the vector to disrupt parasite development in the mosquito. Importantly, if eradication is to be achieved, malaria vaccine development efforts will need to target other malaria parasite species, especially Plasmodium vivax, where novel therapeutic vaccines against hypnozoites or preventive vaccines with effect against multiple stages could have enormous impact. A target product profile (TPP) for VIMT is proposed and a research agenda to address current knowledge gaps and develop tools necessary for design and development of VIMT is presented. PMID:21311586

  7. Phase 1 study in malaria naïve adults of BSAM2/Alhydrogel®+CPG 7909, a blood stage vaccine against P. falciparum malaria.

    Directory of Open Access Journals (Sweden)

    Ruth D Ellis

    Full Text Available A Phase 1 dose escalating study was conducted in malaria naïve adults to assess the safety, reactogenicity, and immunogenicity of the blood stage malaria vaccine BSAM2/Alhydrogel®+ CPG 7909. BSAM2 is a combination of the FVO and 3D7 alleles of recombinant AMA1 and MSP1(42, with equal amounts by weight of each of the four proteins mixed, bound to Alhydrogel®, and administered with the adjuvant CPG 7909. Thirty (30 volunteers were enrolled in two dose groups, with 15 volunteers receiving up to three doses of 40 µg total protein at Days 0, 56, and 180, and 15 volunteers receiving up to three doses of 160 µg protein on the same schedule. Most related adverse events were mild or moderate, but 4 volunteers experienced severe systemic reactions and two were withdrawn from vaccinations due to adverse events. Geometric mean antibody levels after two vaccinations with the high dose formulation were 136 µg/ml for AMA1 and 78 µg/ml for MSP1(42. Antibody responses were not significantly different in the high dose versus low dose groups and did not further increase after third vaccination. In vitro growth inhibition was demonstrated and was closely correlated with anti-AMA1 antibody responses. A Phase 1b trial in malaria-exposed adults is being conducted.Clinicaltrials.gov NCT00889616.

  8. Design and pre-clinical profiling of a Plasmodium falciparum MSP-3 derived component for a multi-valent virosomal malaria vaccine

    Directory of Open Access Journals (Sweden)

    Boato Francesca

    2009-12-01

    Full Text Available Abstract Background Clinical profiling of two components for a synthetic peptide-based virosomal malaria vaccine has yielded promising results, encouraging the search for additional components for inclusion in a final multi-valent vaccine formulation. This report describes the immunological characterization of linear and cyclized synthetic peptides comprising amino acids 211-237 of Plasmodium falciparum merozoite surface protein (MSP-3. Methods These peptides were coupled to phosphatidylethanolamine (PE; the conjugates were intercalated into immunopotentiating reconstituted influenza virosomes (IRIVs and then used for immunizations in mice to evaluate their capacity to elicit P. falciparum cross-reactive antibodies. Results While all MSP-3-derived peptides were able to elicit parasite-binding antibodies, stabilization of turn structures by cyclization had no immune-enhancing effect. Therefore, further pre-clinical profiling was focused on FB-12, a PE conjugate of the linear peptide. Consistent with the immunological results obtained in mice, all FB-12 immunized rabbits tested seroconverted and consistently elicited antibodies that interacted with blood stage parasites. It was observed that a dose of 50 μg was superior to a dose of 10 μg and that influenza pre-existing immunity improved the immunogenicity of FB-12 in rabbits. FB-12 production was successfully up-scaled and the immunogenicity of a vaccine formulation, produced according to the rules of Good Manufacturing Practice (GMP, was tested in mice and rabbits. All animals tested developed parasite-binding antibodies. Comparison of ELISA and IFA titers as well as the characterization of a panel of anti-FB-12 monoclonal antibodies indicated that at least the majority of antibodies specific for the virosomally formulated synthetic peptide were parasite cross-reactive. Conclusion These results reconfirm the suitability of IRIVs as a carrier/adjuvant system for the induction of strong humoral

  9. Designing malaria vaccines to circumvent antigen variability✩

    Science.gov (United States)

    Ouattara, Amed; Barry, Alyssa E.; Dutta, Sheetij; Remarque, Edmond J.; Beeson, James G.; Plowe, Christopher V.

    2016-01-01

    Prospects for malaria eradication will be greatly enhanced by an effective vaccine, but parasite genetic diversity poses a major impediment to malaria vaccine efficacy. In recent pre-clinical and field trials, vaccines based on polymorphic Plasmodium falciparum antigens have shown efficacy only against homologous strains, raising the specter of allele-specific immunity such as that which plagues vaccines against influenza and HIV. The most advanced malaria vaccine, RTS,S, targets relatively conserved epitopes on the P. falciparum circumsporozoite protein. After more than 40 years of development and testing, RTS,S, has shown significant but modest efficacy against clinical malaria in phase 2 and 3 trials. Ongoing phase 2 studies of an irradiated sporozoite vaccine will ascertain whether the full protection against homologous experimental malaria challenge conferred by high doses of a whole organism vaccine can provide protection against diverse strains in the field. Here we review and evaluate approaches being taken to design broadly cross-protective malaria vaccines. PMID:26475447

  10. Designing malaria vaccines to circumvent antigen variability.

    Science.gov (United States)

    Ouattara, Amed; Barry, Alyssa E; Dutta, Sheetij; Remarque, Edmond J; Beeson, James G; Plowe, Christopher V

    2015-12-22

    Prospects for malaria eradication will be greatly enhanced by an effective vaccine, but parasite genetic diversity poses a major impediment to malaria vaccine efficacy. In recent pre-clinical and field trials, vaccines based on polymorphic Plasmodium falciparum antigens have shown efficacy only against homologous strains, raising the specter of allele-specific immunity such as that which plagues vaccines against influenza and HIV. The most advanced malaria vaccine, RTS,S, targets relatively conserved epitopes on the P. falciparum circumsporozoite protein. After more than 40 years of development and testing, RTS,S, has shown significant but modest efficacy against clinical malaria in phase 2 and 3 trials. Ongoing phase 2 studies of an irradiated sporozoite vaccine will ascertain whether the full protection against homologous experimental malaria challenge conferred by high doses of a whole organism vaccine can provide protection against diverse strains in the field. Here we review and evaluate approaches being taken to design broadly cross-protective malaria vaccines. Copyright © 2015. Published by Elsevier Ltd.

  11. Glucose production and gluconeogenesis in adults with uncomplicated falciparum malaria

    NARCIS (Netherlands)

    Dekker, E.; Romijn, J. A.; Ekberg, K.; Wahren, J.; van Thien, H.; Ackermans, M. T.; Thuy, L. T.; Chandramouli, V.; Kager, P. A.; Landau, B. R.; Sauerwein, H. P.

    1997-01-01

    Although glucose production is increased in severe malaria, the influence of uncomplicated malaria on glucose production is unknown. Therefore, we measured in eight adult Vietnamese patients with uncomplicated falciparum malaria and eight healthy Vietnamese controls glucose production (by infusion

  12. Naturally acquired immunity to Plasmodium falciparum malaria in Africa

    DEFF Research Database (Denmark)

    Hviid, Lars

    2005-01-01

    Infection by Plasmodium falciparum parasites can lead to substantial protective immunity to malaria, and available evidence suggest that acquisition of protection against some severe malaria syndromes can be fairly rapid. Although these facts have raised hopes that the development of effective...... antigens on the surface of the infected erythrocytes, can explain some of the difficulties in relating particular immune responses with specificity for well-defined antigenic targets to clinical protection, and suggests a radically new approach to controlling malaria-related morbidity and mortality...... vaccines against this major cause of human misery is a realistic goal, the uncertainty regarding the antigenic targets of naturally acquired protective immunity and the immunological mechanisms involved remain major vaccine development obstacles. Nevertheless, a coherent theoretical framework of how...

  13. Solution structure of a Plasmodium falciparum AMA-1/MSP 1 chimeric protein vaccine candidate (PfCP-2.9 for malaria

    Directory of Open Access Journals (Sweden)

    Jin Changwen

    2010-03-01

    Full Text Available Abstract Background The Plasmodium falciparum chimeric protein PfCP-2.9 is a promising asexual-stage malaria vaccine evaluated in clinical trials. This chimeric protein consists of two cysteine-rich domains: domain III of the apical membrane antigen 1 (AMA-1 [III] and the C-terminal region of the merozoite surface protein 1 (MSP1-19. It has been reported that the fusion of these two antigens enhanced their immunogenicity and antibody-mediated inhibition of parasite growth in vitro. Methods The 15N-labeled and 13C/15N-labeled PfCP-2.9 was produced in Pichia pastoris for nuclear magnetic resonance (NMR structure analysis. The chemical shift assignments of PfCP-2.9 were compared with those previously reported for the individual domains (i.e., PfAMA-1(III or PfMSP 1-19. The two-dimensional spectra and transverse relaxation rates (R2 of the PfMSP1-19 alone were compared with that of the PfCP-2.9. Results Confident backbone assignments were obtained for 122 out of 241 residues of PfCP-2.9. The assigned residues in PfCP-2.9 were very similar to those previously reported for the individual domains. The conformation of the PfMSP1-19 in different constructs is essentially the same. Comparison of transverse relaxation rates (R2 strongly suggests no weak interaction between the domains. Conclusions These data indicate that the fusion of AMA-1(III and MSP1-19 as chimeric protein did not change their structures, supporting the use of the chimeric protein as a potential malaria vaccine.

  14. Plasmodium falciparum malaria and antimalarial interventions in ...

    African Journals Online (AJOL)

    Plasmodium falciparum malaria is one of the most important parasitic diseases affecting sub-Saharan Africa, despite the availability of interventions. It exerts tremendous socio-economic and medical burden on the continent, particularly in under five children and pregnant women. In this review, we have attempted to ...

  15. Resistance patterns of plasmodium falciparum malaria to ...

    African Journals Online (AJOL)

    Resistance patterns of plasmodium falciparum malaria to chloroquine in Kampala, Uganda. ... Sixty three (65.6%) patients showed clinical improvement, 29 (30.2%) deteriorated and four (4.2%) had no change. Adequate parasitogical response was seen in 71 (74 %), moderate in four (4.2%) and poor in 21 (21.8%) patients.

  16. Acute Pancreatitis in a Patient with Complicated Falciparum Malaria.

    Science.gov (United States)

    Barman, Bhupen; Bhattacharya, Prasanta Kumar; Lynrah, Kryshan G; Ete, Tony; Issar, Neel Kanth

    2016-01-01

    Malaria is one of the most common protozoan diseases, especially in tropical countries. The clinical manifestation of malaria, especially falciparum malaria varies from mild acute febrile illness to life threatening severe systemic complications involving one or more organ systems. We would like to report a case of complicated falciparum malaria involving cerebral, renal, hepatic system along with acute pancreatitis. The patient was successfully treated with anti malarial and other supportive treatment. To the best of our knowledge there are very few reports of acute pancreatitis due to malaria. Falciparum malaria therefore should be added to the list of infectious agents causing acute pancreatitis especially in areas where malaria is endemic.

  17. Effect of ingested human antibodies induced by RTS, S/AS01 malaria vaccination in children on Plasmodium falciparum oocyst formation and sporogony in mosquitoes

    DEFF Research Database (Denmark)

    Miura, Kazutoyo; Jongert, Erik; Deng, Bingbing

    2014-01-01

    falciparum CS protein, but the ability of serum from vaccinated individuals to inhibit sporogony in mosquitoes has not been evaluated. METHODS: Previously a double-blind, randomized trial of RTS,S/AS01 vaccine, as compared with rabies vaccine, in five- to 17-month old children in Tanzania was conducted....... In this study, polyclonal human antibodies were purified from the pools of sera taken one month after the third vaccination. IgGs were purified from four pools of sera from 25 RTS,S/AS01 vaccinated children each, and two pools of sera from 25 children vaccinated with rabies vaccine each. The ability...

  18. Drug and Vaccine Evaluation in the Human Aotus Plasmodium Falciparum Model

    National Research Council Canada - National Science Library

    Obaldia

    2002-01-01

    The purpose of this report is to present data on the evaluation of drugs and vaccines in the human malaria/Aotus lemurinus lemurinus monkey model experimentally infected with Plasmodium falciparum or vivax...

  19. Important advances in malaria vaccine research

    Directory of Open Access Journals (Sweden)

    Priyanka Jadhav

    2012-01-01

    Full Text Available Malaria is one of the most widespread parasitic infection in Asian countries affecting the poor of the poor. In an effort to develop an effective vaccine for the treatment of malaria, various attempts are being made worldwide. If successful, such a vaccine can be effective for treatment of both Plasmodium vivax and Plasmodium falciparum. This would also be able to avoid complications such as drug resistance, resistance to insecticides, nonadherence to the treatment schedule, and eventually high cost of treatment in the resource-limited settings. In the current compilation, the details from the literature were collected by using PubMed and Medline as search engines and searched for terms such as malaria, vaccine, and malaria treatment. This review collates and provides glimpses of the information on the recent malaria vaccine development. The reader will be taken through the historical perspective followed by the approaches to the malaria vaccine development from pre-erythrocytic stage vaccines, asexual stage vaccines, transmission blocking vaccines, etc. Looking at the current scenario of the malaria and treatment strategies, it is an absolute need of an hour that an effective malaria vaccine should be developed. This would bring a revolutionary breakthrough in the treatment modalities especially when there is increasing emergence of resistance to existing drug therapy. It would be of great purpose to serve those living in malaria endemic region and also for travelers which are nonimmune and coming to malaria endemic region. As infection by P. vivax is more prevalent in India and other Asian subcontinent and is often prominent in areas where elimination is being attempted, special consideration is required of the role of vaccines in blocking transmission, regardless of the stages being targeted. Development of vaccines is feasible but with the support of private sector and government organization in terms of regulatory and most importantly

  20. Steady progress toward a malaria vaccine.

    Science.gov (United States)

    Lyke, Kirsten E

    2017-10-01

    Great progress has been made in reducing malaria morbidity and mortality, yet the parasite continues to cause a startling 200 million infections and 500 000 deaths annually. Malaria vaccine development is pushing new boundaries by steady advancement toward a licensed product. Despite 50 years of research, the complexity of Plasmoidum falciparum confounds all attempts to eradicate the organism. This very complexity has pushed the boundaries of vaccine development to new heights, yet it remains to be seen if an affordable vaccine can provide durable and high-level protection. Novel vaccines such as RTS,S/AS01E are on the edge of licensure, but old techniques have resurged with the ability to deliver vialed, whole organism vaccines. Novel adjuvants, multistage/multiantigen approaches and transmission blocking vaccines all contribute to a multipronged battle plan to conquer malaria. Vaccines are the most cost-effective tools to control infectious diseases, yet the complexity of malaria has frustrated all attempts to develop an effective product. This review concentrates on recent advances in malaria vaccine development that lend hope that a vaccine can be produced and malaria eradicated.

  1. Acute Pancreatitis in a Patient with Complicated Falciparum Malaria

    OpenAIRE

    Barman, Bhupen; Bhattacharya, Prasanta Kumar; Lynrah, Kryshan G; Ete, Tony; Issar, Neel Kanth

    2016-01-01

    Malaria is one of the most common protozoan diseases, especially in tropical countries. The clinical manifestation of malaria, especially falciparum malaria varies from mild acute febrile illness to life threatening severe systemic complications involving one or more organ systems. We would like to report a case of complicated falciparum malaria involving cerebral, renal, hepatic system along with acute pancreatitis. The patient was successfully treated with anti malarial and other supportive...

  2. Adjunctive therapy for cerebral malaria and other severe forms of Plasmodium falciparum malaria

    OpenAIRE

    John, Chandy C; Kutamba, Elizabeth; Mugarura, Keith; Opoka, Robert O

    2010-01-01

    Severe malaria due to Plasmodium falciparum causes more than 800,000 deaths every year. Primary therapy with quinine or artesunate is generally effective in controlling P. falciparum parasitemia, but mortality from cerebral malaria and other forms of severe malaria remains unacceptably high. Long-term cognitive impairment is also common in children with cerebral malaria. Of the numerous adjunctive therapies for cerebral malaria and severe malaria studied over the past five decades, only one (...

  3. Malaria vaccine clinical trials: what’s on the horizon

    Science.gov (United States)

    Moreno, Alberto; Joyner, Chester

    2015-01-01

    Significant progress towards a malaria vaccine, specifically for Plasmodium falciparum, has been made in the past few years with the completion of numerous clinical trials. Each trial has utilized a unique combination of antigens, delivery platforms, and adjuvants, and the data that has been obtained provides critical information that has poises the research community for the development of next generation malaria vaccines. Despite the progress towards a P. falciparum vaccine, P. vivax vaccine research requires more momentum and additional investigations to identify novel vaccine candidates. In this review, recently completed and ongoing malaria vaccine clinical trials as well as vaccine candidates that are in the development pipeline are reviewed. Perspectives for future research using post-genomic mining, nonhuman primate models, and systems biology are also discussed. PMID:26172291

  4. Plasmodium falciparum malaria resistance to chloroquine in five ...

    African Journals Online (AJOL)

    Chloroquine is still a first-line antimalarial drug in uncomplicated falciparum malaria. Increasing resistance to chloroquine has been reported in many parts of Nigeria. Clinical and parasitological responses and classes of resistance to chloroquine in falciparum malaria in five communities in Delta region, southern Nigeria ...

  5. Prevalence of falciparum malaria amongst pregnant women in Aba ...

    African Journals Online (AJOL)

    Malaria during pregnancy poses a substantial risk to mother and foetus especially an infection with Plasmodium falciparum. This study was undertaken to assess the prevalence of falciparum malaria among pregnant women in Aba South Local Government Area, Abia State, south-east Nigeria. Blood samples from 432 ...

  6. Mosquito Vectors and the Globalization of Plasmodium falciparum Malaria.

    Science.gov (United States)

    Molina-Cruz, Alvaro; Zilversmit, Martine M; Neafsey, Daniel E; Hartl, Daniel L; Barillas-Mury, Carolina

    2016-11-23

    Plasmodium falciparum malaria remains a devastating public health problem. Recent discoveries have shed light on the origin and evolution of Plasmodium parasites and their interactions with their vertebrate and mosquito hosts. P. falciparum malaria originated in Africa from a single horizontal transfer between an infected gorilla and a human, and became global as the result of human migration. Today, P. falciparum malaria is transmitted worldwide by more than 70 different anopheline mosquito species. Recent studies indicate that the mosquito immune system can be a barrier to malaria transmission and that the P. falciparum Pfs47 gene allows the parasite to evade mosquito immune detection. Here, we review the origin and globalization of P. falciparum and integrate this history with analysis of the biology, evolution, and dispersal of the main mosquito vectors. This new perspective broadens our understanding of P. falciparum population structure and the dispersal of important parasite genetic traits.

  7. Spatial and temporal distribution of falciparum malaria in China

    Directory of Open Access Journals (Sweden)

    Lin Hualiang

    2009-06-01

    Full Text Available Abstract Background Falciparum malaria is the most deadly among the four main types of human malaria. Although great success has been achieved since the launch of the National Malaria Control Programme in 1955, malaria remains a serious public health problem in China. This paper aimed to analyse the geographic distribution, demographic patterns and time trends of falciparum malaria in China. Methods The annual numbers of falciparum malaria cases during 1992–2003 and the individual case reports of each clinical falciparum malaria during 2004–2005 were extracted from communicable disease information systems in China Center for Diseases Control and Prevention. The annual number of cases and the annual incidence were mapped by matching them to corresponding province- and county-level administrative units in a geographic information system. The distribution of falciparum malaria by age, gender and origin of infection was analysed. Time-series analysis was conducted to investigate the relationship between the falciparum malaria in the endemic provinces and the imported falciparum malaria in non-endemic provinces. Results Falciparum malaria was endemic in two provinces of China during 2004–05. Imported malaria was reported in 26 non-endemic provinces. Annual incidence of falciparum malaria was mapped at county level in the two endemic provinces of China: Yunnan and Hainan. The sex ratio (male vs. female for the number of cases in Yunnan was 1.6 in the children of 0–15 years and it reached 5.7 in the adults over 15 years of age. The number of malaria cases in Yunnan was positively correlated with the imported malaria of concurrent months in the non-endemic provinces. Conclusion The endemic area of falciparum malaria in China has remained restricted to two provinces, Yunnan and Hainan. Stable transmission occurs in the bordering region of Yunnan and the hilly-forested south of Hainan. The age and gender distribution in the endemic area is

  8. [Congenital malaria due to Plasmodium falciparum and Plasmodium malariae].

    Science.gov (United States)

    Zenz, W; Trop, M; Kollaritsch, H; Reinthaler, F

    2000-05-19

    Increasing tourism and growing numbers of immigrants from malaria-endemic countries are leading to a higher importation rate of rare tropical disorders in European countries. We describe, to the best of our knowledge, the first case of connatal malaria in Austria. The patient is the first child of a 24 year old mother who was born in Ghana and immigrated to Austria one and a half years before delivery. She did not stay in an endemic region during this period and did not show fever or any other signs of malaria. The boy was healthy for the first six weeks of his life. In the 8th week of life he was admitted to our hospital due to persistent fever of unknown origin. On physical examination he showed only mild splenomegaly. Routine laboratory testing revealed mild hemolytic anemia with a hemoglobin value of 8.3 g/l. In the blood smear Plasmodium falciparum and Plasmodium malariae were detected. Oral therapy with quinine hydrochloride was successful and blood smears became negative for Plasmodia within 6 days. This case shows that congenital malaria can occur in children of clinically healthy women who were born in malaria-endemic areas even one and a half year after they have immigrated to non-endemic regions.

  9. The path of malaria vaccine development: challenges and perspectives.

    Science.gov (United States)

    Arama, C; Troye-Blomberg, M

    2014-05-01

    Malaria is a life-threatening disease caused by parasites of the Plasmodium genus. In many parts of the world, the parasites have developed resistance to a number of antimalarial agents. Key interventions to control malaria include prompt and effective treatment with artemisinin-based combination therapies, use of insecticidal nets by individuals at risk and active research into malaria vaccines. Protection against malaria through vaccination was demonstrated more than 30 years ago when individuals were vaccinated via repeated bites by Plasmodium falciparum-infected and irradiated but still metabolically active mosquitoes. However, vaccination with high doses of irradiated sporozoites injected into humans has long been considered impractical. Yet, following recent success using whole-organism vaccines, the approach has received renewed interest; it was recently reported that repeated injections of irradiated sporozoites increased protection in 80 vaccinated individuals. Other approaches include subunit malaria vaccines, such as the current leading candidate RTS,S (consisting of fusion between a portion of the P. falciparum-derived circumsporozoite protein and the hepatitis B surface antigen), which has been demonstrated to induce reasonably good protection. Although results have been encouraging, the level of protection is generally considered to be too low to achieve eradication of malaria. There is great interest in developing new and better formulations and stable delivery systems to improve immunogenicity. In this review, we will discuss recent strategies to develop efficient malaria vaccines. © 2014 The Association for the Publication of the Journal of Internal Medicine.

  10. Plasmodium falciparum transcriptome analysis reveals pregnancy malaria associated gene expression

    DEFF Research Database (Denmark)

    Tuikue Ndam, Nicaise; Bischoff, Emmanuel; Proux, Caroline

    2008-01-01

    BACKGROUND: Pregnancy-associated malaria (PAM) causing maternal anemia and low birth weight is among the multiple manifestations of Plasmodium falciparum malaria. Infected erythrocytes (iEs) can acquire various adhesive properties that mediate the clinical severity of malaria. Recent advances...

  11. Proteomics methods applied to malaria: Plasmodium falciparum

    International Nuclear Information System (INIS)

    Cuesta Astroz, Yesid; Segura Latorre, Cesar

    2012-01-01

    Malaria is a parasitic disease that has a high impact on public health in developing countries. The sequencing of the plasmodium falciparum genome and the development of proteomics have enabled a breakthrough in understanding the biology of the parasite. Proteomics have allowed to characterize qualitatively and quantitatively the parasite s expression of proteins and has provided information on protein expression under conditions of stress induced by antimalarial. Given the complexity of their life cycle, this takes place in the vertebrate host and mosquito vector. It has proven difficult to characterize the protein expression during each stage throughout the infection process in order to determine the proteome that mediates several metabolic, physiological and energetic processes. Two dimensional electrophoresis, liquid chromatography and mass spectrometry have been useful to assess the effects of antimalarial on parasite protein expression and to characterize the proteomic profile of different p. falciparum stages and organelles. The purpose of this review is to present state of the art tools and advances in proteomics applied to the study of malaria, and to present different experimental strategies used to study the parasite's proteome in order to show the advantages and disadvantages of each one.

  12. Differential induction of functional IgG using the Plasmodium falciparum placental malaria vaccine candidate VAR2CSA

    DEFF Research Database (Denmark)

    Pinto, Vera V; Ditlev, Sisse B; Jensen, Kamilla E

    2011-01-01

    and chondroitin sulfate A (CSA) in the placental intervillous space and lack of protective antibodies. PM impairs fetal development mainly by excessive inflammation processes. After infections during pregnancy women acquire immunity to PM conferred by antibodies against VAR2CSA. Ideally, a vaccine against PM...

  13. Clinical malaria vaccine development.

    NARCIS (Netherlands)

    Sauerwein, R.W.

    2009-01-01

    Malaria is a major economic and public health problem in mainly sub-Saharan Africa. Globally 300-500 million new infections occur each year with 1-3 million fatal cases in particular young children. The most effective way to reduce disease and death from infectious diseases is to vaccinate

  14. Phase 1 trial of AMA1-C1/Alhydrogel plus CPG 7909: an asexual blood-stage vaccine for Plasmodium falciparum malaria.

    Directory of Open Access Journals (Sweden)

    Gregory E D Mullen

    2008-08-01

    Full Text Available Apical Membrane Antigen 1 (AMA1, a polymorphic merozoite surface protein, is a leading blood-stage malaria vaccine candidate. This is the first reported use in humans of an investigational vaccine, AMA1-C1/Alhydrogel, with the novel adjuvant CPG 7909.A phase 1 trial was conducted at the University of Rochester with 75 malaria-naive volunteers to assess the safety and immunogenicity of the AMA1-C1/Alhydrogel+CPG 7909 malaria vaccine. Participants were sequentially enrolled and randomized within dose escalating cohorts to receive three vaccinations on days 0, 28 and 56 of either 20 microg of AMA1-C1/Alhydrogel+564 microg CPG 7909 (n = 15, 80 microg of AMA1-C1/Alhydrogel (n = 30, or 80 microg of AMA1-C1/Alhydrogel+564 microg CPG 7909 (n = 30.Local and systemic adverse events were significantly more likely to be of higher severity with the addition of CPG 7909. Anti-AMA1 immunoglobulin G (IgG were detected by enzyme-linked immunosorbent assay (ELISA, and the immune sera of volunteers that received 20 microg or 80 microg of AMA1-C1/Alhydrogel+CPG 7909 had up to 14 fold significant increases in anti-AMA1 antibody concentration compared to 80 microg of AMA1-C1/Alhydrogel alone. The addition of CPG 7909 to the AMA1-C1/Alhydrogel vaccine in humans also elicited AMA1 specific immune IgG that significantly and dramatically increased the in vitro growth inhibition of homologous parasites to levels as high as 96% inhibition.The safety profile of the AMA1-C1/Alhydrogel+CPG 7909 malaria vaccine is acceptable, given the significant increase in immunogenicity observed. Further clinical development is ongoing.ClinicalTrials.gov NCT00344539.

  15. Loss of cellular immune reactivity during acute Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Hviid, L; Theander, T G; Abu-Zeid, Y A

    1991-01-01

    Sixteen patients suffering from acute Plasmodium falciparum malaria were studied. All were residents of an area of unstable malaria-transmission in Eastern Sudan. Blood-samples were drawn at diagnosis, and 7 and 30 days later. Blood-samples from thirteen donors, drawn outside the malaria...... convalescence. Five donors examined by fluorescence-activated cell sorting (FACS) showed no increase in surface expression of IL-2 receptor on peripheral lymphocytes. The data indicate that acute P. falciparum malaria causes a depletion of antigen-reactive T-cells from the peripheral circulation, probably due...

  16. Population genomics diversity of Plasmodium falciparum in malaria ...

    African Journals Online (AJOL)

    Background: Plasmodium falciparum, the most dangerous malaria parasite species to humans remains an important public health concern in Okelele, a rural community in Ilorin, Kwara State, Nigeria. There is however little information about the genetic diversity of Plasmodium falciparum in Nigeria. Objective: To determine ...

  17. Clinical development of placental malaria vaccines and immunoassays harmonization

    DEFF Research Database (Denmark)

    Chêne, Arnaud; Houard, Sophie; Nielsen, Morten A

    2016-01-01

    Placental malaria caused by Plasmodium falciparum infection constitutes a major health problem manifesting as severe disease and anaemia in the mother, impaired fetal development, low birth weight or spontaneous abortion. Prevention of placental malaria currently relies on two key strategies...... that are losing efficacy due to spread of resistance: long-lasting insecticide-treated nets and intermittent preventive treatment during pregnancy. A placental malaria vaccine would be an attractive, cost-effective complement to the existing control tools. Two placental malaria vaccine candidates are currently...... in Phase Ia/b clinical trials. During two workshops hosted by the European Vaccine Initiative, one in Paris in April 2014 and the other in Brussels in November 2014, the main actors in placental malaria vaccine research discussed the harmonization of clinical development plans and of the immunoassays...

  18. Sero-epidemiological evaluation of Plasmodium falciparum malaria in Senegal.

    Science.gov (United States)

    Sylla, Khadime; Tine, Roger Clément Kouly; Ndiaye, Magatte; Sow, Doudou; Sarr, Aïssatou; Mbuyi, Marie Louise Tshibola; Diouf, Ibrahima; Lô, Amy Colé; Abiola, Annie; Seck, Mame Cheikh; Ndiaye, Mouhamadou; Badiane, Aïda Sadikh; N'Diaye, Jean Louis A; Ndiaye, Daouda; Faye, Oumar; Dieng, Thérèse; Dieng, Yémou; Ndir, Oumar; Gaye, Oumar; Faye, Babacar

    2015-07-16

    In Senegal, a significant decrease of malaria transmission intensity has been noted the last years. Parasitaemia has become lower and, therefore, more difficult to detect by microscopy. In the context of submicroscopic parasitaemia, it has become relevant to rely on relevant malaria surveillance tools to better document malaria epidemiology in such settings. Serological markers have been proposed as an essential tool for malaria surveillance. This study aimed to evaluate the sero-epidemiological situation of Plasmodium falciparum malaria in two sentinel sites in Senegal. Cross-sectional surveys were carried out in Velingara (south Senegal) and Keur Soce (central Senegal) between September and October 2010. Children under 10 years old, living in these areas, were enrolled using two-level, random sampling methods. P. falciparum infection was diagnosed using microscopy. P. falciparum antibodies against circumsporozoite protein (CSP), apical membrane protein (AMA1) and merozoite surface protein 1_42 (MSP1_42) were measured by ELISA method. A stepwise logistic regression analysis was done to assess factors associated with P. falciparum antibodies carriage. A total of 1,865 children under 10 years old were enrolled. The overall falciparum malaria prevalence was 4.99% with high prevalence in Velingara of 10.03% compared to Keur Soce of 0.3%. Symptomatic malaria cases (fever associated with parasitaemia) represented 17.37%. Seroprevalence of anti-AMA1, anti-MSP1_42 and anti-CSP antibody was 38.12, 41.55 and 40.38%, respectively. The seroprevalence was more important in Velingara and increased with age, active malaria infection and area of residence. The use of serological markers can contribute to improved malaria surveillance in areas with declining malaria transmission. This study provided useful baseline information about the sero-epidemiological situation of malaria in Senegal and can contribute to the identification of malaria hot spots in order to concentrate

  19. Safety and Immunogenicity of Pfs25-EPA/Alhydrogel®, a Transmission Blocking Vaccine against Plasmodium falciparum: An Open Label Study in Malaria Naïve Adults.

    Directory of Open Access Journals (Sweden)

    Kawsar R Talaat

    Full Text Available Transmission-blocking vaccines (TBVs that target sexual stage parasite development could be an integral part of measures for malaria elimination. Pfs25 is a leading TBV candidate, and previous studies conducted in animals demonstrated an improvement of its functional immunogenicity after conjugation to EPA, a recombinant, detoxified ExoProtein A from Pseudomonas aeruginosa. In this report, we describe results of an open-label, dose-escalating Phase 1 trial to assess the safety and immunogenicity of Pfs25-EPA conjugates formulated with Alhydrogel®. Thirty malaria-naïve healthy adults received up to four doses of the conjugate vaccine, with 8, 16, or 47 μg of conjugated Pfs25 mass, at 0, 2, 4, and 10 months. Vaccinations were generally well tolerated. The majority of solicited adverse events were mild in severity with pain at the injection site the most common complaint. Anemia was the most common laboratory abnormality, but was considered possibly related to the study in only a minority of cases. No vaccine-related serious adverse events occurred. The peak geometric mean anti-Pfs25 antibody level in the highest dose group was 88 (95% CI 53, 147 μg/mL two weeks after the 4th vaccination, and declined to near baseline one year later. Antibody avidity increased over successive vaccinations. Transmission blocking activity demonstrated in a standard membrane feeding assay (SMFA also increased from the second to the third dose, and correlated with antibody titer and, after the final dose, with antibody avidity. These results support the further evaluation of Pfs25-EPA/Alhydrogel® in a malaria-endemic population.

  20. Malaria vaccines and human immune responses.

    Science.gov (United States)

    Long, Carole A; Zavala, Fidel

    2016-08-01

    Despite reductions in malaria episodes and deaths over the past decade, there is still significant need for more effective tools to combat this serious global disease. The positive results with the Phase III trial of RTS,S directed to the circumsporozoite protein of Plasmodium falciparum have established that a vaccine against malaria can provide partial protection to children in endemic areas, but its limited efficacy and relatively short window of protection mandate that new generations of more efficacious vaccines must be sought. Evidence shows that anti-parasite immune responses can control infection against other stages as well, but translating these experimental findings into vaccines for blood stages has been disappointing and clinical efforts to test a transmission blocking vaccine are just beginning. Difficulties include the biological complexity of the organism with a large array of stage-specific genes many of which in the erythrocytic stages are antigenically diverse. In addition, it appears necessary to elicit high and long-lasting antibody titers, address the redundant pathways of merozoite invasion, and still seek surrogate markers of protective immunity. Most vaccine studies have focused on a single or a few antigens with an apparent functional role, but this is likely to be too restrictive, and broad, multi-antigen, multi-stage vaccines need further investigation. Finally, novel tools and biological insights involving parasite sexual stages and the mosquito vector will provide new avenues for reducing or blocking malaria transmission. Published by Elsevier Ltd.

  1. Defining childhood severe falciparum malaria for intervention studies.

    Directory of Open Access Journals (Sweden)

    Philip Bejon

    2007-08-01

    Full Text Available Clinical trials of interventions designed to prevent severe falciparum malaria in children require a clear endpoint. The internationally accepted definition of severe malaria is sensitive, and appropriate for clinical purposes. However, this definition includes individuals with severe nonmalarial disease and coincident parasitaemia, so may lack specificity in vaccine trials. Although there is no "gold standard" individual test for severe malaria, malaria-attributable fractions (MAFs can be estimated among groups of children using a logistic model, which we use to test the suitability of various case definitions as trial endpoints.A total of 4,583 blood samples were taken from well children in cross-sectional surveys and from 1,361 children admitted to a Kenyan District hospital with severe disease. Among children under 2 y old with severe disease and over 2,500 parasites per microliter of blood, the MAFs were above 85% in moderate- and low-transmission areas, but only 61% in a high-transmission area. HIV and malnutrition were not associated with reduced MAFs, but gastroenteritis with severe dehydration (defined by reduced skin turgor, lower respiratory tract infection (clinician's final diagnosis, meningitis (on cerebrospinal fluid [CSF] examination, and bacteraemia were associated with reduced MAFs. The overall MAF was 85% (95% confidence interval [CI] 83.8%-86.1% without excluding these conditions, 89% (95% CI 88.4%-90.2% after exclusions, and 95% (95% CI 94.0%-95.5% when a threshold of 2,500 parasites/mul was also applied. Applying a threshold and exclusion criteria reduced sensitivity to 80% (95% CI 77%-83%.The specificity of a case definition for severe malaria is improved by applying a parasite density threshold and by excluding children with meningitis, lower respiratory tract infection (clinician's diagnosis, bacteraemia, and gastroenteritis with severe dehydration, but not by excluding children with HIV or malnutrition.

  2. APPROACHING THE TARGET: THE PATH TOWARDS AN EFFECTIVE MALARIA VACCINE

    Directory of Open Access Journals (Sweden)

    Alberto L. García-Basteiro

    2012-01-01

    Full Text Available Eliciting an effective malaria vaccine has been the goal of the scientific community for many years. A malaria vaccine, added to existing tools and strategies, would further prevent and decrease the unacceptable malaria morbidity and mortality burden. Great progress has been made over the last decade, with some vaccine candidates in the clinical phases of development. The RTS,S malaria vaccine candidate, based on a recombinant P. falciparum protein, is the most advanced of such candidates, currently undergoing a large phase III trial. RTS,S has consistently shown an efficacy of around 50% against the first clinical episode of malaria, with protection in some cases extending up to 4 years of duration. Thus, it is hoped that this candidate vaccine will eventually become the first licensed malaria vaccine. This first vaccine against a human parasite is a groundbreaking achievement, but improved malaria vaccines conferring higher protection will be needed if the aspiration of malaria eradication is to be achieved

  3. Plasmodium falciparum malaria in children at a tertiary teaching ...

    African Journals Online (AJOL)

    The haemoglobin measurement was done with the haematology analyzer, Sysmex KX-21N. Malaria parasites were enumerated and the presence of malaria pigment noted. Identification of P. falciparum was done. Statistical tests used were odds ratio and chi square at a significance level of p < 0.05. Results: 24.3% of the ...

  4. High prevalence of Plasmodium falciparum malaria among Human ...

    African Journals Online (AJOL)

    Malaria and Human Immunodeficiency Virus (HIV) infections are major public health problems in Sub-Saharan Africa. Their overlapping geographical distribution and co-existence often result into high morbidity and mortality. This study was designed to establish the prevalence of Plasmodium falciparum malaria among HIV ...

  5. in vitro surveillance of drug resistant falciparum malaria in north ...

    African Journals Online (AJOL)

    Dr Oboro VO

    ABSTRACT. Background: drug resistant malaria is spreading inexorably to areas with drug sensitive malaria parasites. This study compared the in vitro sensitivities of Plasmodium falciparum fresh parasite isolates, to some standard antimalarial drugs, in Makurdi and Masaka located over 300 km apart, in north central.

  6. MALVAC 2012 scientific forum: accelerating development of second-generation malaria vaccines

    Science.gov (United States)

    2012-01-01

    The World Health Organization (WHO) convened a malaria vaccines committee (MALVAC) scientific forum from 20 to 21 February 2012 in Geneva, Switzerland, to review the global malaria vaccine portfolio, to gain consensus on approaches to accelerate second-generation malaria vaccine development, and to discuss the need to update the vision and strategic goal of the Malaria Vaccine Technology Roadmap. This article summarizes the forum, which included reviews of leading Plasmodium falciparum vaccine candidates for pre-erythrocytic vaccines, blood-stage vaccines, and transmission-blocking vaccines. Other major topics included vaccine candidates against Plasmodium vivax, clinical trial site capacity development in Africa, trial design considerations for a second-generation malaria vaccine, adjuvant selection, and regulatory oversight functions including vaccine licensure. PMID:23140365

  7. Impact of RTS,S/AS02A and RTS,S/AS01B on Genotypes of P. falciparum in Adults Participating in a Malaria Vaccine Clinical Trial

    Science.gov (United States)

    Waitumbi, John N.; Anyona, Samuel B.; Hunja, Carol W.; Kifude, Carolyne M.; Polhemus, Mark E.; Walsh, Douglas S.; Ockenhouse, Chris F.; Heppner, D. Gray; Leach, Amanda; Lievens, Marc; Ballou, W. Ripley; Cohen, Joe D.; Sutherland, Colin J.

    2009-01-01

    Objective RTS,S, a candidate vaccine for malaria, is a recombinant protein expressed in yeast containing part of the circumsporozoite protein (CSP) sequence of 3D7 strain of Plasmodium falciparum linked to the hepatitis B surface antigen in a hybrid protein. The RTS,S antigen is formulated with GSK Biologicals' proprietary Adjuvant Systems AS02A or AS01B. A recent trial of the RTS,S/AS02A and RTS,S/AS01B vaccines evaluated safety, immunogenicity and impact on the development of parasitemia of the two formulations. Parasite isolates from this study were used to determine the molecular impact of RTS,S/AS02A and RTS,S/AS01B on the multiplicity of infection (MOI) and the csp allelic characteristics of subsequent parasitemias. Design The distribution of csp sequences and the MOI of the infecting strains were examined at baseline and in break-through infections from vaccinated individuals and from those receiving a non-malarial vaccine. Setting The study was conducted in Kombewa District, western Kenya. Participants Semi-immune adults from the three study arms provided isolates at baseline and during break-through infections. Outcome Parasite isolates used for determining MOI and divergence of csp T cell–epitopes were 191 at baseline and 87 from break-through infections. Results Grouping recipients of RTS,S/AS01A and RTS,S/AS02B together, vaccine recipients identified as parasite-positive by microscopy contained significantly fewer parasite genotypes than recipients of the rabies vaccine comparator (median in pooled RTS,S groups: 3 versus 4 in controls, P = 0.0313). When analyzed separately, parasitaemic individuals in the RTS,S/AS01B group, but not the RTS,S/AS02A group, were found to have significantly fewer genotypes than the comparator group. Two individual amino acids found in the vaccine construct (Q339 in Th2R and D371 in Th3R) were observed to differ in incidence between vaccine and comparator groups but in different directions; parasites harboring Q339

  8. Malaria vaccine: the pros and cons.

    Science.gov (United States)

    Saleh, J A; Yusuph, H; Zailani, S B; Aji, B

    2010-01-01

    Malaria is an important parasitic disease of humans caused by infection with a parasite of the genus Polasmodium and transmitted by female anopheles. Infection caused by P. falciparum is the most serious of all the other species (P. ovale, P. vivax and P. malariae) especially in terms of morbidity and mortality hence the reason why most of the research has been focussed on this species. The disease affects up to about 40 per cent of the world's population with around 300-500 million people currently infected and mainly in the tropics. It has a high morbidity and mortality especially in resource-poor tropical and subtropical regions with an economic fall of about US$ 12 billion annually in Africa alone. relevant literatures were reviewed from medical journals, library search and internet source. Other relevant websites like PATH, Malaria Vaccine Initiative and Global Fund were also visited to source for information. The key words employed were: malaria, vaccine, anopheles mosquito, insecticide treated bed-nets, pyrethroids and Plasmodium. several studies have underscored the need to develop an effective human malaria vaccine for the control and possible eradication of malaria across the globe with the view to reduce the morbidity and mortality associated with the disease, improve on the social and economic losses and also protect those at risk. It is very obvious that the need for effective human malaria vaccine is not only to serve those living in malaria endemic regions but also the non-immune travellers especially those travelling to malaria endemic areas; this would offer cost effective means of preventing the disease, reducing the morbidity and mortality associated with it in addition to closing the gap left by other control measures. It is very obvious that there is no single control measure known to be effective in the control of malaria, hence the need for combination of more than one method with the aim of achieving synergy in the total control and possible

  9. Parasite Specific Antibody Increase Induced by an Episode of Acute P. falciparum Uncomplicated Malaria.

    Directory of Open Access Journals (Sweden)

    Mark Kaddumukasa

    Full Text Available There is no approved vaccine for malaria, and precisely how human antibody responses to malaria parasite components and potential vaccine molecules are developed and maintained remains poorly defined. In this study, antibody anamnestic or memory response elicited by a single episode of P. falciparum infection was investigated.This study involved 362 malaria patients aged between 6 months to 60 years, of whom 19% were early-diagnosed people living with HIV/AIDS (PLWHA. On the day malaria was diagnosed and 42 days later, blood specimens were collected. Parasite density, CD4+ cells, and antibodies specific to synthetic peptides representing antigenic regions of the P. falciparum proteins GLURP, MSP3 and HRPII were measured.On the day of malaria diagnosis, Immunoglobulin (IgG antibodies against GLURP, MSP3 and HRP II peptides were present in the blood of 75%, 41% and 60% of patients, respectively. 42 days later, the majority of patients had boosted their serum IgG antibody more than 1.2 fold. The increase in level of IgG antibody against the peptides was not affected by parasite density at diagnosis. The median CD4+ cell counts of PLWHAs and HIV negative individuals were not statistically different, and median post-infection increases in anti-peptide IgG were similar in both groups of patients.In the majority (70% of individuals, an infection of P. falciparum elicits at least 20% increase in level of anti-parasite IgG. This boost in anti-P. falciparum IgG is not affected by parasite density on the day of malaria diagnosis, or by HIV status.

  10. Genetic polymorphisms in the glutamate-rich protein of Plasmodium falciparum field isolates from a malaria-endemic area of Brazil

    DEFF Research Database (Denmark)

    Pratt-Riccio, Lilian Rose; Perce-da-Silva, Daiana de Souza; Lima-Junior, Josué da Costa

    2013-01-01

    The genetic diversity displayed by Plasmodium falciparum, the most deadly Plasmodium species, is a significant obstacle for effective malaria vaccine development. In this study, we identified genetic polymorphisms in P. falciparum glutamate-rich protein (GLURP), which is currently being tested in...

  11. Non-falciparum malaria infections in pregnant women in West Africa

    DEFF Research Database (Denmark)

    Williams, John; Njie, Fanta; Cairns, Matthew

    2016-01-01

    BACKGROUND: Non-Plasmodium falciparum malaria infections are found in many parts of sub-Saharan Africa but little is known about their importance in pregnancy. METHODS: Blood samples were collected at first antenatal clinic attendance from 2526 women enrolled in a trial of intermittent screening...... of non-falciparum malaria as well as falciparum malaria. The outcome of pregnancy did not differ between women with a non-falciparum malaria infection and those who were not infected with malaria at first ANC attendance. CONCLUSIONS: Non-falciparum infections were infrequent in the populations studied...

  12. The use of transgenic parasites in malaria vaccine research.

    Science.gov (United States)

    Othman, Ahmad Syibli; Marin-Mogollon, Catherin; Salman, Ahmed M; Franke-Fayard, Blandine M; Janse, Chris J; Khan, Shahid M

    2017-07-01

    Transgenic malaria parasites expressing foreign genes, for example fluorescent and luminescent proteins, are used extensively to interrogate parasite biology and host-parasite interactions associated with malaria pathology. Increasingly transgenic parasites are also exploited to advance malaria vaccine development. Areas covered: We review how transgenic malaria parasites are used, in vitro and in vivo, to determine protective efficacy of different antigens and vaccination strategies and to determine immunological correlates of protection. We describe how chimeric rodent parasites expressing P. falciparum or P. vivax antigens are being used to directly evaluate and rank order human malaria vaccines before their advancement to clinical testing. In addition, we describe how transgenic human and rodent parasites are used to develop and evaluate live (genetically) attenuated vaccines. Expert commentary: Transgenic rodent and human malaria parasites are being used to both identify vaccine candidate antigens and to evaluate both sub-unit and whole organism vaccines before they are advanced into clinical testing. Transgenic parasites combined with in vivo pre-clinical testing models (e.g. mice) are used to evaluate vaccine safety, potency and the durability of protection as well as to uncover critical protective immune responses and to refine vaccination strategies.

  13. Malaria Vaccine Development: The Need for Novel Approach-es: A Review Article

    Directory of Open Access Journals (Sweden)

    Shima MAHMOUDI

    2018-03-01

    Full Text Available Background: Although rigorous efforts have substantially decreased the malaria burden through decades, it still threatens the lives of millions of children. Development of an effective vaccine can provide important approach in malaria control strategies. Unfortunately, development of an effective vaccine for falciparum malaria has been hindered by the extreme complexity of malaria parasite biology, complex and diverse parasite genomes, and immune evasion by the parasites as well as the intricate nature of the parasites infection cycle. The aim of this review was to discuss the different approaches to malaria vaccine development until now.Methods: Scientific databases, including MEDLINE (via PubMed and SCOPUS were searched up to 30 Jan 2017 and the articles regarding malaria vaccine development were taken into examination.Results: Several strategies for malaria vaccine development including pre-erythrocytic vaccines, antibody-based subunit vaccines, vectored vaccines, whole sporozoite vaccines, genetically Attenuated parasites and sporozoite subunit vaccine, erythrocytic vaccines, sexual stage vaccine, transmission-blocking vaccine as well as synthetic peptides and conjugate vaccine has been introduced. However, the success has been limited thus far.Conclusion: Although development of malaria vaccine over the past 70 year has been continued, the discovery, development, and licensing of a malaria vaccine formulation, which meets safety, affordability, accessibility, applicability, and efficacy has not yet been achieved.

  14. MALARIA VACCINE: MYTH OR REALITY?

    African Journals Online (AJOL)

    Femi Olaleye

    first synthetic vaccine (Spf 66) made up in part by the CSP- 1. Human vaccine trials are also reported to have been successful. (Amador et. al., 1992). Erythrocyte Stage Antigens SPF 66. This is the first synthetically produced malaria vaccine. It is made up of a combination of three peptides (35.1, 55.1 and 83.1) whose ...

  15. A world malaria map: Plasmodium falciparum endemicity in 2007.

    Directory of Open Access Journals (Sweden)

    Simon I Hay

    2009-03-01

    Full Text Available Efficient allocation of resources to intervene against malaria requires a detailed understanding of the contemporary spatial distribution of malaria risk. It is exactly 40 y since the last global map of malaria endemicity was published. This paper describes the generation of a new world map of Plasmodium falciparum malaria endemicity for the year 2007.A total of 8,938 P. falciparum parasite rate (PfPR surveys were identified using a variety of exhaustive search strategies. Of these, 7,953 passed strict data fidelity tests for inclusion into a global database of PfPR data, age-standardized to 2-10 y for endemicity mapping. A model-based geostatistical procedure was used to create a continuous surface of malaria endemicity within previously defined stable spatial limits of P. falciparum transmission. These procedures were implemented within a Bayesian statistical framework so that the uncertainty of these predictions could be evaluated robustly. The uncertainty was expressed as the probability of predicting correctly one of three endemicity classes; previously stratified to be an informative guide for malaria control. Population at risk estimates, adjusted for the transmission modifying effects of urbanization in Africa, were then derived with reference to human population surfaces in 2007. Of the 1.38 billion people at risk of stable P. falciparum malaria, 0.69 billion were found in Central and South East Asia (CSE Asia, 0.66 billion in Africa, Yemen, and Saudi Arabia (Africa+, and 0.04 billion in the Americas. All those exposed to stable risk in the Americas were in the lowest endemicity class (PfPR2-10 5 to or = 40% areas. High endemicity was widespread in the Africa+ region, where 0.35 billion people are at this level of risk. Most of the rest live at intermediate risk (0.20 billion, with a smaller number (0.11 billion at low stable risk.High levels of P. falciparum malaria endemicity are common in Africa. Uniformly low endemic levels are

  16. A world malaria map: Plasmodium falciparum endemicity in 2007.

    Science.gov (United States)

    Hay, Simon I; Guerra, Carlos A; Gething, Peter W; Patil, Anand P; Tatem, Andrew J; Noor, Abdisalan M; Kabaria, Caroline W; Manh, Bui H; Elyazar, Iqbal R F; Brooker, Simon; Smith, David L; Moyeed, Rana A; Snow, Robert W

    2009-03-24

    Efficient allocation of resources to intervene against malaria requires a detailed understanding of the contemporary spatial distribution of malaria risk. It is exactly 40 y since the last global map of malaria endemicity was published. This paper describes the generation of a new world map of Plasmodium falciparum malaria endemicity for the year 2007. A total of 8,938 P. falciparum parasite rate (PfPR) surveys were identified using a variety of exhaustive search strategies. Of these, 7,953 passed strict data fidelity tests for inclusion into a global database of PfPR data, age-standardized to 2-10 y for endemicity mapping. A model-based geostatistical procedure was used to create a continuous surface of malaria endemicity within previously defined stable spatial limits of P. falciparum transmission. These procedures were implemented within a Bayesian statistical framework so that the uncertainty of these predictions could be evaluated robustly. The uncertainty was expressed as the probability of predicting correctly one of three endemicity classes; previously stratified to be an informative guide for malaria control. Population at risk estimates, adjusted for the transmission modifying effects of urbanization in Africa, were then derived with reference to human population surfaces in 2007. Of the 1.38 billion people at risk of stable P. falciparum malaria, 0.69 billion were found in Central and South East Asia (CSE Asia), 0.66 billion in Africa, Yemen, and Saudi Arabia (Africa+), and 0.04 billion in the Americas. All those exposed to stable risk in the Americas were in the lowest endemicity class (PfPR2-10 5 to or = 40%) areas. High endemicity was widespread in the Africa+ region, where 0.35 billion people are at this level of risk. Most of the rest live at intermediate risk (0.20 billion), with a smaller number (0.11 billion) at low stable risk. High levels of P. falciparum malaria endemicity are common in Africa. Uniformly low endemic levels are found in the

  17. Humanized HLA-DR4.RagKO.IL2RγcKO.NOD (DRAG) mice sustain the complex vertebrate life cycle of Plasmodium falciparum malaria

    OpenAIRE

    Wijayalath, Wathsala; Majji, Sai; Villasante, Eileen F; Brumeanu, Teodor D; Richie, Thomas L; Casares, Sofia

    2014-01-01

    Background Malaria is a deadly infectious disease affecting millions of people in tropical and sub-tropical countries. Among the five species of Plasmodium parasites that infect humans, Plasmodium falciparum accounts for the highest morbidity and mortality associated with malaria. Since humans are the only natural hosts for P. falciparum, the lack of convenient animal models has hindered the understanding of disease pathogenesis and prompted the need of testing anti-malarial drugs and vaccine...

  18. Levels of antibody to conserved parts of Plasmodium falciparum merozoite surface protein 1 in Ghanaian children are not associated with protection from clinical malaria

    DEFF Research Database (Denmark)

    Dodoo, D; Theander, T G; Kurtzhals, J A

    1999-01-01

    The 19-kDa conserved C-terminal part of the Plasmodium falciparum merozoite surface protein 1 (PfMSP119) is a malaria vaccine candidate antigen, and human antibody responses to PfMSP119 have been associated with protection against clinical malaria. In this longitudinal study carried out in an are...

  19. Pre-clinical and clinical development of the first placental malaria vaccine.

    Science.gov (United States)

    Pehrson, Caroline; Salanti, Ali; Theander, Thor G; Nielsen, Morten A

    2017-06-01

    Malaria during pregnancy is a massive health problem in endemic areas. Placental malaria infections caused by Plasmodium falciparum are responsible for up to one million babies being born with a low birth weight every year. Significant efforts have been invested into preventing the condition. Areas covered: Pub Med was searched using the broad terms 'malaria parasite placenta' to identify studies of interactions between parasite and host, 'prevention of placental malaria' to identify current strategies to prevent placental malaria, and 'placental malaria vaccine' to identify pre-clinical vaccine development. However, all papers from these searches were not systematically included. Expert commentary: The first phase I clinical trials of vaccines are well underway. Trials testing efficacy are more complicated to carry out as only women that are exposed to parasites during pregnancy will contribute to endpoint measurements, further it may require extensive follow-up to establish protection. Future second generation vaccines may overcome the inherent challenges in making an effective placental malaria vaccine.

  20. in Plasmodium falciparum Malaria Infected Children in Owerri ...

    African Journals Online (AJOL)

    JTEkanem

    2009-09-11

    Sep 11, 2009 ... B (1996) Plasma alpha-tocopherol retinol and carotenoids in children with falciparum malaria. Am.J.Clin.Nutr. 64: 94-100. 13. Kremsner, P. G., Greve, B., Lell, B.,. Luckner, D and Schmid, D. (2000). Malarial anaemia in African children associated with high oxygen radial production. Lancet 355: 40-41. 14.

  1. Factors contributing to anemia after uncomplicated falciparum malaria

    NARCIS (Netherlands)

    Price, R. N.; Simpson, J. A.; Nosten, F.; Luxemburger, C.; Hkirjaroen, L.; ter Kuile, F.; Chongsuphajaisiddhi, T.; White, N. J.

    2001-01-01

    The factors contributing to anemia in falciparum malaria were characterized in 4,007 prospectively studied patients on the western border of Thailand. Of these, 727 patients (18%) presented with anemia (haematocrit < 30%), and 1% (55 of 5,253) required blood transfusion. The following were found to

  2. Plasmodium falciparum multiplicity correlates with anaemia in symptomatic malaria

    NARCIS (Netherlands)

    Mockenhaupt, Frank P.; Ehrhardt, Stephan; Eggelte, Teunis A.; Markert, Miriam; Anemana, Sylvester; Otchwemah, Rowland; Bienzle, Ulrich

    2003-01-01

    In 366 Ghanaian children with symptomatic Plasmodium falciparum malaria, low haemoglobin levels and severe anaemia were associated with a high multiplicity of infection (MOI) and with distinct merozoite surface protein alleles. High MOI not only reflects premunition but may also contribute to

  3. Blood monocyte oxidative burst activity in acute P. falciparum malaria

    DEFF Research Database (Denmark)

    Nielsen, H; Theander, T G

    1989-01-01

    The release of superoxide anion from blood monocytes was studied in eight patients with acute primary attack P. falciparum malaria. Before treatment a significant enhancement of the oxidative burst prevailed, which contrasts with previous findings of a depressed monocyte chemotactic responsiveness...

  4. Strategies for Designing and Monitoring Malaria Vaccines Targeting Diverse Antigens

    Science.gov (United States)

    Barry, Alyssa E.; Arnott, Alicia

    2014-01-01

    After more than 50 years of intensive research and development, only one malaria vaccine candidate, “RTS,S,” has progressed to Phase 3 clinical trials. Despite only partial efficacy, this candidate is now forecast to become the first licensed malaria vaccine. Hence, more efficacious second-generation malaria vaccines that can significantly reduce transmission are urgently needed. This review will focus on a major obstacle hindering development of effective malaria vaccines: parasite antigenic diversity. Despite extensive genetic diversity in leading candidate antigens, vaccines have been and continue to be formulated using recombinant antigens representing only one or two strains. These vaccine strains represent only a small fraction of the diversity circulating in natural parasite populations, leading to escape of non-vaccine strains and challenging investigators’ abilities to measure strain-specific efficacy in vaccine trials. Novel strategies are needed to overcome antigenic diversity in order for vaccine development to succeed. Many studies have now cataloged the global diversity of leading Plasmodium falciparum and Plasmodium vivax vaccine antigens. In this review, we describe how population genetic approaches can be applied to this rich data source to predict the alleles that best represent antigenic diversity, polymorphisms that contribute to it, and to identify key polymorphisms associated with antigenic escape. We also suggest an approach to summarize the known global diversity of a given antigen to predict antigenic diversity, how to select variants that best represent the strains circulating in natural parasite populations and how to investigate the strain-specific efficacy of vaccine trials. Use of these strategies in the design and monitoring of vaccine trials will not only shed light on the contribution of genetic diversity to the antigenic diversity of malaria, but will also maximize the potential of future malaria vaccine candidates. PMID

  5. Strategies for designing and monitoring malaria vaccines targeting diverse antigens

    Directory of Open Access Journals (Sweden)

    Alyssa E Barry

    2014-07-01

    Full Text Available After more than 50 years of intensive research and development, only one malaria vaccine candidate, RTS,S, has progressed to Phase 3 clinical trials. Despite only partial efficacy, this candidate is now forecast to become the first licensed malaria vaccine. Hence, more efficacious second-generation malaria vaccines that can significantly reduce transmission are urgently needed. This review will focus on a major obstacle hindering development of effective malaria vaccines: parasite antigenic diversity. Despite extensive genetic diversity in leading candidate antigens, vaccines have been and continue to be formulated using recombinant antigens representing only one or two strains. These vaccine strains represent only a small fraction of the diversity circulating in natural parasite populations, leading to escape of non-vaccine strains and challenging investigators’ abilities to measure strain-specific efficacy in vaccine trials. Novel strategies are needed to overcome antigenic diversity in order for vaccine development to succeed. Many studies have now catalogued the global diversity of leading Plasmodium falciparum and Plasmodium vivax vaccine antigens. In this review, we describe how population genetic approaches can be applied to this rich data source to predict the alleles that best represent antigenic diversity, polymorphisms that contribute to it, and to identify key polymorphisms associated with antigenic escape. We also suggest an approach to summarise the known global diversity of a given antigen to predict antigenic diversity, how to select variants that best represent the strains circulating in natural parasite populations and how to investigate the strain-specific efficacy of vaccine trials. Use of these strategies in the design and monitoring of vaccine trials will not only shed light on the contribution of genetic diversity to the antigenic diversity of malaria, but will also maximise the potential of future malaria vaccine

  6. "Sexual" population structure and genetics of the malaria agent P. falciparum.

    Directory of Open Access Journals (Sweden)

    Themba Mzilahowa

    Full Text Available The population genetics and structure of P. falciparum determine the rate at which malaria evolves in response to interventions such as drugs and vaccines. This has been the source of considerable recent controversy, but here we demonstrate the organism to be essentially sexual, in an area of moderately high transmission in the Lower Shire Valley, Malawi. Seven thousand mosquitoes were collected and dissected, and genetic data were obtained on 190 oocysts from 56 infected midguts. The oocysts were genotyped at three microsatellite loci and the MSP1 locus. Selfing rate was estimated as 50% and there was significant genotypic linkage disequilibrium (LD in the pooled oocysts. A more appropriate analysis searching for genotypic LD in outcrossed oocysts and/or haplotypic LD in the selfed oocysts found no evidence for LD, indicating that the population was effectively sexual. Inbreeding estimates at MSP1 were higher than at the microsatellites, possibly indicative of immune action against MSP1, but the effect was confounded by the probable presence of null mutations. Mating appeared to occur at random in mosquitoes and evidence regarding whether malaria clones in the same host were related (presumably through simultaneous inoculation in the same mosquito bite was ambiguous. This is the most detailed genetic analysis yet of P. falciparum sexual stages, and shows P. falciparum to be a sexual organism whose genomes are in linkage equilibrium, which acts to slow the emergence of drug resistance and vaccine insensitivity, extending the likely useful therapeutic lifespan of drugs and vaccines.

  7. High levels of serum antibodies to merozoite surface protein 2 of Plasmodium falciparum are associated with reduced risk of clinical malaria in coastal Kenya.

    Science.gov (United States)

    Polley, Spencer D; Conway, David J; Cavanagh, David R; McBride, Jana S; Lowe, Brett S; Williams, Thomas N; Mwangi, Tabitha W; Marsh, Kevin

    2006-05-08

    The merozoite surface protein (MSP) 2 is a vaccine candidate antigen of Plasmodium falciparum that is polymorphic in natural populations. In a prospective cohort study in two coastal populations of Kenya using recombinant proteins derived from the two major allelic types of MSP2, high serum levels of IgG to MSP2 were associated with protection from clinical malaria. This protection was independent of that associated with antibodies to another vaccine candidate antigen (AMA1) in these populations. However, low antibody levels to MSP2 appeared to be associated with increased susceptibility to malaria within people who were parasite negative at the time of serum collection. These data suggest that an MSP2 based vaccine should be designed to induce high level antibody responses against the different MSP2 types present globally in P. falciparum populations and that MSP2 could be combined with other P. falciparum antigens to form a multi-component malaria vaccine.

  8. RIFINs are adhesins implicated in severe Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Goel, Suchi; Palmkvist, Mia; Moll, Kirsten

    2015-01-01

    Rosetting is a virulent Plasmodium falciparum phenomenon associated with severe malaria. Here we demonstrate that P. falciparum–encoded repetitive interspersed families of polypeptides (RIFINs) are expressed on the surface of infected red blood cells (iRBCs), where they bind to RBCs—preferentiall......Rosetting is a virulent Plasmodium falciparum phenomenon associated with severe malaria. Here we demonstrate that P. falciparum–encoded repetitive interspersed families of polypeptides (RIFINs) are expressed on the surface of infected red blood cells (iRBCs), where they bind to RBCs......—preferentially of blood group A—to form large rosettes and mediate microvascular binding of iRBCs. We suggest that RIFINs have a fundamental role in the development of severe malaria and thereby contribute to the varying global distribution of ABO blood groups in the human population....

  9. Complement activation in Ghanaian children with severe Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Helegbe, Gideon K; Goka, Bamenla Q; Kurtzhals, Jørgen

    2007-01-01

    BACKGROUND: Severe anaemia (SA), intravascular haemolysis (IVH) and respiratory distress (RD) are severe forms of Plasmodium falciparum malaria, with RD reported to be of prognostic importance in African children with malarial anaemia. Complement factors have been implicated in the mechanism......55)] in children with discrete clinical forms of P. falciparum malaria. The relationship between the findings and clinical parameters including coma, haemoglobin (Hb) levels and RD were investigated. RESULTS: Of the 484 samples tested, 131(27%) were positive in DCT, out of which 115/131 (87.8%) were...... malaria, possibly through induction of erythrophagocytosis and haemolysis. In contrast to other studies, this study did not find association between levels of the complement...

  10. Vaccine candidate discovery for the next generation of malaria vaccines.

    Science.gov (United States)

    Tuju, James; Kamuyu, Gathoni; Murungi, Linda M; Osier, Faith H A

    2017-10-01

    Although epidemiological observations, IgG passive transfer studies and experimental infections in humans all support the feasibility of developing highly effective malaria vaccines, the precise antigens that induce protective immunity remain uncertain. Here, we review the methodologies applied to vaccine candidate discovery for Plasmodium falciparum malaria from the pre- to post-genomic era. Probing of genomic and cDNA libraries with antibodies of defined specificities or functional activity predominated the former, whereas reverse vaccinology encompassing high throughput in silico analyses of genomic, transcriptomic or proteomic parasite data sets is the mainstay of the latter. Antibody-guided vaccine design spanned both eras but currently benefits from technological advances facilitating high-throughput screening and downstream applications. We make the case that although we have exponentially increased our ability to identify numerous potential vaccine candidates in a relatively short space of time, a significant bottleneck remains in their validation and prioritization for evaluation in clinical trials. Longitudinal cohort studies provide supportive evidence but results are often conflicting between studies. Demonstration of antigen-specific antibody function is valuable but the relative importance of one mechanism over another with regards to protection remains undetermined. Animal models offer useful insights but may not accurately reflect human disease. Challenge studies in humans are preferable but prohibitively expensive. In the absence of reliable correlates of protection, suitable animal models or a better understanding of the mechanisms underlying protective immunity in humans, vaccine candidate discovery per se may not be sufficient to provide the paradigm shift necessary to develop the next generation of highly effective subunit malaria vaccines. © 2017 The Authors. Immunology Published by John Wiley & Sons Ltd.

  11. Severe falciparum malaria: A case report

    Science.gov (United States)

    Arcelia, F.; Asymida, F.; Lubis, N. F. M.; Pasaribu, A. P.

    2018-03-01

    Plasmodium parasites caused Malaria. Indonesia is one of the countries in Southeast Asia that endemic to malaria. The burden of malaria is more in the eastern part of Indonesia than the Western part as well as the endemicity. Some cases of malaria will develop to severe form. Usually, the manifestation of children and adult are different. We reported a severe case of malaria in a 14-year-old boy who develops several manifestations such as anemia, hypoglycemia, sepsis and black water fever. We successfully treated the patient with Artesunate intravenous and continued with Dihydroartemisinin-piperaquine.

  12. Anti-phospholipid antibodies in patients with Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Jakobsen, P H; Morris-Jones, S D; Hviid, L

    1993-01-01

    Plasma levels of antibodies against phosphatidylinositol (PI), phosphatidylcholine (PC) and cardiolipin (CL) were measured by enzyme-linked immunosorbent assay (ELISA) in patients from malaria endemic area of Sudan and The Gambia. Some Sudanese adults produced IgM antibodies against all three types...... of phospholipids (PL) during an acute Plasmodium falciparum infection. The anti-PL antibody titre returned to preinfection levels in most of the donors 30 days after the disease episode. IgG titres against PI, PC and CL were low. In Gambian children with malaria, IgM antibody titres against PI and PC were...... significantly higher in those with severe malaria than in those with mild malaria. These results show that a proportion of malaria patients produce anti-PL antibodies during infection and that titres of these antibodies are associated with the severity of disease....

  13. Engineering of Genetically Arrested Parasites (GAPs) For a Precision Malaria Vaccine.

    Science.gov (United States)

    Kreutzfeld, Oriana; Müller, Katja; Matuschewski, Kai

    2017-01-01

    Continuous stage conversion and swift changes in the antigenic repertoire in response to acquired immunity are hallmarks of complex eukaryotic pathogens, including Plasmodium species, the causative agents of malaria. Efficient elimination of Plasmodium liver stages prior to blood infection is one of the most promising malaria vaccine strategies. Here, we describe different genetically arrested parasites (GAPs) that have been engineered in Plasmodium berghei, P. yoelii and P. falciparum and compare their vaccine potential. A better understanding of the immunological mechanisms of prime and boost by arrested sporozoites and experimental strategies to enhance vaccine efficacy by further engineering existing GAPs into a more immunogenic form hold promise for continuous improvements of GAP-based vaccines. A critical hurdle for vaccines that elicit long-lasting protection against malaria, such as GAPs, is safety and efficacy in vulnerable populations. Vaccine research should focus on solutions toward turning malaria into a vaccine-preventable disease, which would offer an exciting new path of malaria control.

  14. Gene disruption of Plasmodium falciparum p52 results in attenuation of malaria liver stage development in cultured primary human hepatocytes.

    Directory of Open Access Journals (Sweden)

    Ben C L van Schaijk

    Full Text Available Difficulties with inducing sterile and long lasting protective immunity against malaria with subunit vaccines has renewed interest in vaccinations with attenuated Plasmodium parasites. Immunizations with sporozoites that are attenuated by radiation (RAS can induce strong protective immunity both in humans and rodent models of malaria. Recently, in rodent parasites it has been shown that through the deletion of a single gene, sporozoites can also become attenuated in liver stage development and, importantly, immunization with these sporozoites results in immune responses identical to RAS. The promise of vaccination using these genetically attenuated sporozoites (GAS depends on translating the results in rodent malaria models to human malaria. In this study, we perform the first essential step in this transition by disrupting, p52, in P. falciparum an ortholog of the rodent parasite gene, p36p, which we had previously shown can confer long lasting protective immunity in mice. These P. falciparum P52 deficient sporozoites demonstrate gliding motility, cell traversal and an invasion rate into primary human hepatocytes in vitro that is comparable to wild type sporozoites. However, inside the host hepatocyte development is arrested very soon after invasion. This study reveals, for the first time, that disrupting the equivalent gene in both P. falciparum and rodent malaria Plasmodium species generates parasites that become similarly arrested during liver stage development and these results pave the way for further development of GAS for human use.

  15. Plasmodium falciparum var genes expressed in children with severe malaria encode CIDRα1 domains

    DEFF Research Database (Denmark)

    Jespersen, Jakob S.; Wang, Christian W.; Mkumbaye, Sixbert I.

    2016-01-01

    Most severe Plasmodium falciparum infections are experienced by young children. Severe symptoms are precipitated by vascular sequestration of parasites expressing a particular subset of the polymorphic P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion molecules. Parasites binding hum...... the hypothesis that the CIDRα1-EPCR interaction is key to the pathogenesis of severe malaria and strengthen the rationale for pursuing a vaccine or adjunctive treatment aiming at inhibiting or reducing the damaging effects of this interaction....... endothelial protein C receptor (EPCR) through the CIDRα1 domain of certain PfEMP1 were recently associated with severe malaria in children. However, it has remained unclear to which extend the EPCR-binding CIDRα1 domains epitomize PfEMP1 expressed in severe malaria. Here, we characterized the near full......-length transcripts dominating the var transcriptome in children with severe malaria and found that the only common feature of the encoded PfEMP1 was CIDRα1 domains. Such genes were highly and dominantly expressed in both children with severe malarial anaemia and cerebral malaria. These observations support...

  16. Severe falciparum malaria in young children of the Kassena-Nankana district of northern Ghana.

    Science.gov (United States)

    Oduro, Abraham R; Koram, Kwadwo A; Rogers, William; Atuguba, Frank; Ansah, Patrick; Anyorigiya, Thomas; Ansah, Akosua; Anto, Francis; Mensah, Nathan; Hodgson, Abraham; Nkrumah, Francis

    2007-07-27

    Severe falciparum malaria in children was studied as part of the characterization of the Kassena-Nankana District Ghana for future malaria vaccine trials. Children aged 6-59 months with diagnosis suggestive of acute disease were characterized using the standard WHO definition for severe malaria. Of the total children screened, 45.2% (868/1921) satisfied the criteria for severe malaria. Estimated incidence of severe malaria was 3.4% (range: 0.4-8.3%) cases per year. The disease incidence was seasonal: 560 cases per year, of which 70.4% occurred during the wet season (June-October). The main manifestations were severe anaemia (36.5%); prolonged or multiple convulsions (21.6%); respiratory distress (24.4%) and cerebral malaria (5.4%). Others were hyperpyrexia (11.1%); hyperparasitaemia (18.5%); hyperlactaemia (33.4%); and hypoglycaemia (3.2%). The frequency of severe anaemia was 39.8% in children of six to 24 months of age and 25.9% in children of 25-60 months of age. More children (8.7%) in the 25-60 months age group had cerebral malaria compared with 4.4% in the 6-24 months age group. The overall case fatality ratio was 3.5%. Cerebral malaria and hyperlactataemia were the significant risk factors associated with death. Severe anaemia, though a major presentation, was not significantly associated with risk of death. Severe malaria is a frequent and seasonal childhood disease in northern Ghana and maybe an adequate endpoint for future malaria vaccine trials.

  17. From malaria parasite point of view – Plasmodium falciparum evolution

    Directory of Open Access Journals (Sweden)

    Agata Zerka

    2015-12-01

    Full Text Available Malaria is caused by infection with protozoan parasites belonging to the genus Plasmodium, which have arguably exerted the greatest selection pressure on humans in the history of our species. Besides humans, different Plasmodium parasites infect a wide range of animal hosts, from marine invertebrates to primates. On the other hand, individual Plasmodium species show high host specificity. The extraordinary evolution of Plasmodium probably began when a free-living red algae turned parasitic, and culminated with its ability to thrive inside a human red blood cell. Studies on the African apes generated new data on the evolution of malaria parasites in general and the deadliest human-specific species, Plasmodium falciparum, in particular. Initially, it was hypothesized that P. falciparum descended from the chimpanzee malaria parasite P. reichenowi, after the human and the chimp lineage diverged about 6 million years ago. However, a recently identified new species infecting gorillas, unexpectedly showed similarity to P. falciparum and was therefore named P. praefalciparum. That finding spurred an alternative hypothesis, which proposes that P. falciparum descended from its gorilla rather than chimp counterpart. In addition, the gorilla-to-human host shift may have occurred more recently (about 10 thousand years ago than the theoretical P. falciparum-P. reichenowi split. One of the key aims of the studies on Plasmodium evolution is to elucidate the mechanisms that allow the incessant host shifting and retaining the host specificity, especially in the case of human-specific species. Thorough understanding of these phenomena will be necessary to design effective malaria treatment and prevention strategies.

  18. Acute hemorrhagic necrotizing pancreatitis in falciparum malaria

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    José Felipe Reoyo-Pascual

    Full Text Available Malaria is a pathology caused by a parasite called Plasmodium, characteristic of tropical countries. The most frequent symptomatology includes cerebral malaria, jaundice, convulsive crisis, anemia, hypoglycemia, kidney failure and metabolic acidosis, among others. We are presenting the case of a patient diagnosed with malaria who suffered from acute hemorrhagic necrotizing pancreatitis and evolved poorly, as an example of this combination of symptoms, rarely found in our country.

  19. Intrarectal quinine for treating Plasmodium falciparum malaria: a systematic review

    Science.gov (United States)

    Eisenhut, Michael; Omari, Aika; MacLehose, Harriet G

    2005-01-01

    Background In children with malaria caused by Plasmodium falciparum, quinine administered rectally may be easier to use and less painful than intramuscular or intravenous administration. The objective of this review was to compare the effectiveness of intrarectal with intravenous or intramuscular quinine for treating falciparum malaria. Methods All randomized and quasi-randomized controlled trials comparing intrarectal with intramuscular or intravenous quinine for treating people with falciparum malaria located through the following sources were included: Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS and CINAHL. Trial quality was assessed and data, including adverse event data, were extracted. Dichotomous data were analysed using odds ratios and continuous data using weighted mean difference. Results Eight randomized controlled trials (1,247 children) fulfilled the inclusion criteria. The same principal investigator led seven of the trials. Five compared intrarectal with intravenous quinine, and six compared intrarectal with intramuscular treatment. No statistically significant difference was detected for death, parasite clearance by 48 hours and seven days, parasite and fever clearance time, coma recovery time, duration of hospitalization and time before drinking began. One trial (898 children) reported that intrarectal was less painful than intramuscular administration. Conclusion No difference in the effect on parasites and clinical illness was detected for the use of intrarectal quinine compared with other routes, but most trials were small. Pain during application may be less with intrarectal quinine. Further larger trials, in patients with severe malaria and in adults, are required before the intrarectal route could be recommended. PMID:15904520

  20. Mefloquine for uncomplicated Plasmodium falciparum malaria in children.

    Science.gov (United States)

    Minodier, Philippe; Noël, Guilhem; Tall, Mamadou; Retornaz, Karine; Piarroux, Renaud; Parzy, Daniel; Ranque, Stephane

    2011-10-01

    Children with uncomplicated Plasmodium falciparum imported malaria are treated with various antimalarial regimens including mefloquine depending on national guidelines. Little is known regarding mefloquine treatment efficacy in this setting. In this prospective study, children 3 months to 16 years of age admitted in a tertiary hospital emergency ward in France with uncomplicated P. falciparum malaria were treated with oral mefloquine. Each dose was given with an antiemetic. Between 2004 and 2009, 95 children were evaluated. In all, 94% had traveled in the Indian Ocean region (Comoros and Madagascar); 79% used a malaria chemoprophylaxis, but none was fully compliant with World Health Organization recommended regimens. Main clinical features at admission were fever (91%), vomiting (44%), and headaches (44%). Hemoglobin mefloquine, and no relapse was noted within 45 days after admission. One Plasmodium vivax relapse occurred 6 months later. Vomiting within 1 hour after dosing occurred in 20% of children. Significant features associated with early vomiting by univariate analysis were a weight ≤ 15 kg, C-reactive protein ≥ 50 mg/L, and parasitemia ≥ 1%, but only low weight was significant by multivariate analysis. Mefloquine is an effective treatment for uncomplicated imported P. falciparum malaria in children returning from countries with low mefloquine resistance. Early vomiting after mefloquine dosing is frequent, especially in children < 15 kg of weight, but a second dose can be given successfully.

  1. Anti-Plasmodium falciparum invasion ligand antibodies in a low malaria transmission region, Loreto, Peru

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    Villasis Elizabeth

    2012-10-01

    Full Text Available Abstract Background Erythrocyte invasion by Plasmodium falciparum is a complex process that involves two families; Erythrocyte Binding-Like (EBL and the Reticulocyte Binding-Like (PfRh proteins. Antibodies that inhibit merozoite attachment and invasion are believed to be important in mediating naturally acquired immunity and immunity generated by parasite blood stage vaccine candidates. The hypotheses tested in this study were 1 that antibody responses against specific P. falciparum invasion ligands (EBL and PfRh differ between symptomatic and asymptomatic individuals living in the low-transmission region of the Peruvian Amazon and 2, such antibody responses might have an association, either direct or indirect, with clinical immunity observed in asymptomatically parasitaemic individuals. Methods ELISA was used to assess antibody responses (IgG, IgG1 and IgG3 against recombinant P. falciparum invasion ligands of the EBL (EBA-175, EBA-181, EBA-140 and PfRh families (PfRh1, PfRh2a, PfRh2b, PfRh4 and PfRh5 in 45 individuals infected with P. falciparum from Peruvian Amazon. Individuals were classified as having symptomatic malaria (N=37 or asymptomatic infection (N=8. Results Antibody responses against both EBL and PfRh family proteins were significantly higher in asymptomatic compared to symptomatic individuals, demonstrating an association with clinical immunity. Significant differences in the total IgG responses were observed with EBA-175, EBA-181, PfRh2b, and MSP119 (as a control. IgG1 responses against EBA-181, PfRh2a and PfRh2b were significantly higher in the asymptomatic individuals. Total IgG antibody responses against PfRh1, PfRh2a, PfRh2b, PfRh5, EBA-175, EBA-181 and MSP119 proteins were negatively correlated with level of parasitaemia. IgG1 responses against EBA-181, PfRh2a and PfRh2b and IgG3 response for PfRh2a were also negatively correlated with parasitaemia. Conclusions These data suggest that falciparum malaria patients who develop

  2. A new world malaria map: Plasmodium falciparum endemicity in 2010

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    Gething Peter W

    2011-12-01

    Full Text Available Abstract Background Transmission intensity affects almost all aspects of malaria epidemiology and the impact of malaria on human populations. Maps of transmission intensity are necessary to identify populations at different levels of risk and to evaluate objectively options for disease control. To remain relevant operationally, such maps must be updated frequently. Following the first global effort to map Plasmodium falciparum malaria endemicity in 2007, this paper describes the generation of a new world map for the year 2010. This analysis is extended to provide the first global estimates of two other metrics of transmission intensity for P. falciparum that underpin contemporary questions in malaria control: the entomological inoculation rate (PfEIR and the basic reproductive number (PfR. Methods Annual parasite incidence data for 13,449 administrative units in 43 endemic countries were sourced to define the spatial limits of P. falciparum transmission in 2010 and 22,212 P. falciparum parasite rate (PfPR surveys were used in a model-based geostatistical (MBG prediction to create a continuous contemporary surface of malaria endemicity within these limits. A suite of transmission models were developed that link PfPR to PfEIR and PfR and these were fitted to field data. These models were combined with the PfPR map to create new global predictions of PfEIR and PfR. All output maps included measured uncertainty. Results An estimated 1.13 and 1.44 billion people worldwide were at risk of unstable and stable P. falciparum malaria, respectively. The majority of the endemic world was predicted with a median PfEIR of less than one and a median PfRc of less than two. Values of either metric exceeding 10 were almost exclusive to Africa. The uncertainty described in both PfEIR and PfR was substantial in regions of intense transmission. Conclusions The year 2010 has a particular significance as an evaluation milestone for malaria global health policy. The

  3. Novel approaches to identify protective malaria vaccine candidates

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    Wan Ni eChia

    2014-11-01

    Full Text Available Efforts to develop vaccines against malaria have been the focus of substantial research activities for decades. Several categories of candidate vaccines are currently being developed for protection against malaria, based on antigens corresponding to the pre-erythrocytic, blood-stage or sexual stages of the parasite. Long lasting sterile protection from Plasmodium falciparum sporozoite challenge has been observed in human following vaccination with whole parasite formulations, clearly demonstrating that a protective immune response targeting predominantly the pre-erythrocytic stages can develop against malaria. However, most of vaccine candidates currently being investigated, which are mostly subunits vaccines, have not been able to induce substantial (>50% protection thus far. This is due to the fact that the antigens responsible for protection against the different parasite stages are still yet to be known and relevant correlates of protection have remained elusive. For a vaccine to be developed in a timely manner, novel approaches are required. In this article, we review the novel approaches that have been developed to identify the antigens for the development of an effective malaria vaccine.

  4. The establishment of a WHO Reference Reagent for anti-malaria (Plasmodium falciparum) human serum.

    Science.gov (United States)

    Bryan, Donna; Silva, Nilupa; Rigsby, Peter; Dougall, Thomas; Corran, Patrick; Bowyer, Paul W; Ho, Mei Mei

    2017-08-05

    At a World Health Organization (WHO) sponsored meeting it was concluded that there is an urgent need for a reference preparation that contains antibodies against malaria antigens in order to support serology studies and vaccine development. It was proposed that this reference would take the form of a lyophilized serum or plasma pool from a malaria-endemic area. In response, an immunoassay standard, comprising defibrinated human plasma has been prepared and evaluated in a collaborative study. A pool of human plasma from a malaria endemic region was collected from 140 single plasma donations selected for reactivity to Plasmodium falciparum apical membrane antigen-1 (AMA-1) and merozoite surface proteins (MSP-1 19 , MSP-1 42 , MSP-2 and MSP-3). This pool was defibrinated, filled and freeze dried into a single batch of ampoules to yield a stable source of naturally occurring antibodies to P. falciparum. The preparation was evaluated by an enzyme-linked immunosorbent assay (ELISA) in a collaborative study with sixteen participants from twelve different countries. This anti-malaria human serum preparation (NIBSC Code: 10/198) was adopted by the WHO Expert Committee on Biological Standardization (ECBS) in October 2014, as the first WHO reference reagent for anti-malaria (Plasmodium falciparum) human serum with an assigned arbitrary unitage of 100 units (U) per ampoule. Analysis of the reference reagent in a collaborative study has demonstrated the benefit of this preparation for the reduction in inter- and intra-laboratory variability in ELISA. Whilst locally sourced pools are regularly use for harmonization both within and between a few laboratories, the presence of a WHO-endorsed reference reagent should enable optimal harmonization of malaria serological assays either by direct use of the reference reagent or calibration of local standards against this WHO reference. The intended uses of this reference reagent, a multivalent preparation, are (1) to allow cross

  5. Interleukin-10 regulates hepcidin in Plasmodium falciparum malaria

    KAUST Repository

    Huang, Honglei

    2014-02-10

    Background: Acute malarial anemia remains a major public health problem. Hepcidin, the major hormone controlling the availability of iron, is raised during acute and asymptomatic parasitemia. Understanding the role and mechanism of raised hepcidin and so reduced iron availability during infection is critical to establish evidence-based guidelines for management of malaria anemia. Our recent clinical evidence suggests a potential role of IL-10 in the regulation of hepcidin in patients with acute P. falciparum malaria. Methods: We have measured secretion of hepcidin by primary macrophages and the hepatoma cell line HepG2 stimulated with IL-10, IL-6 and Plasmodium falciparum-infected erythrocytes. Findings: We have observed that IL-10 and IL-6 production increased in primary macrophages when these cells were co-cultured with Plasmodium falciparum-infected erythrocytes. We found that IL-10 induced hepcidin secretion in primary macrophages in a dose-dependent manner but not in HepG2 cells. These effects were mediated through signal transducer and activator of transcription (STAT) 3-phosphorylation and completely abrogated by a specific STAT3 inhibitor. Conclusion: IL-10 can directly regulate hepcidin in primary macrophages but not in HepG2 cells. This effect can be modulated by Plasmodium falciparum. The results are consistent with a role for IL-10 in modulating iron metabolism during acute phase of infection. 2014 Huang et al.

  6. Schistosomiasis coinfection in children influences acquired immune response against Plasmodium falciparum malaria antigens.

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    Tamsir O Diallo

    Full Text Available BACKGROUND: Malaria and schistosomiasis coinfection frequently occurs in tropical countries. This study evaluates the influence of Schistosoma haematobium infection on specific antibody responses and cytokine production to recombinant merozoite surface protein-1-19 (MSP1-(19 and schizont extract of Plasmodium falciparum in malaria-infected children. METHODOLOGY: Specific IgG1 to MSP1-(19, as well as IgG1 and IgG3 to schizont extract were significantly increased in coinfected children compared to P. falciparum mono-infected children. Stimulation with MSP1-(19 lead to a specific production of both interleukin-10 (IL-10 and interferon-γ (IFN-γ, whereas the stimulation with schizont extract produced an IL-10 response only in the coinfected group. CONCLUSIONS: Our study suggests that schistosomiasis coinfection favours anti-malarial protective antibody responses, which could be associated with the regulation of IL-10 and IFN-γ production and seems to be antigen-dependent. This study demonstrates the importance of infectious status of the population in the evaluation of acquired immunity against malaria and highlights the consequences of a multiple infection environment during clinical trials of anti-malaria vaccine candidates.

  7. The mechanisms of parasite clearance after antimalarial treatment of Plasmodium falciparum malaria

    NARCIS (Netherlands)

    Chotivanich, K.; Udomsangpetch, R.; Dondorp, A.; Williams, T.; Angus, B.; Simpson, J. A.; Pukrittayakamee, S.; Looareesuwan, S.; Newbold, C. I.; White, N. J.

    2000-01-01

    Studies were conducted to determine how malaria parasites are cleared from the blood after antimalarial treatment. Neither artesunate nor quinine decreased parasitized red cell deformability or increased antibody binding. In acute falciparum malaria, ring-infected erythrocyte surface antigen (RESA)

  8. The role of Plasmodium falciparum variant surface antigens in protective immunity and vaccine development

    DEFF Research Database (Denmark)

    Hviid, Lars

    2010-01-01

    that development of PfEMP1-based vaccines to protect specifically against severe malaria syndromes-in particular PAM-is feasible. This review summarizes the evidence that VSAs are important targets of NAI, discusses why VSA-based vaccines might be feasible despite the extensive intra- and interclonal variation...... of VSAs, and how vaccines based on this type of antigens fit into the current global strategy to reduce, eliminate and eventually eradicate the burden of malaria.......There is substantial immuno-epidemiological evidence that the parasite-encoded, so-called variant surface antigens (VSAs), such as PfEMP1 on the surface of infected erythrocytes (IEs) are important-in some cases probably decisive determinants of clinical outcome of P. falciparum malaria...

  9. Falciparum malaria infection with invasive pulmonary aspergillosis in immunocompetent host – case report

    Science.gov (United States)

    Andriyani, Y.

    2018-03-01

    Invasive pulmonary aspergillosis is an extraordinary rare in the immunocompetent host. Falciparum malaria contributes to high morbidity and mortality of malaria infection cases in the world. The impairments of both humoral and cellular immunity could be the reason of invasive pulmonary aspergillosis in falciparum malaria infection. Forty-nine years old patient came with fever, jaundice, pain in the right abdomen, after visiting a remote area in Africa about one month before admission. Blood films and rapid test were positive for Plasmodium falciparum. After malaria therapy in five days, consciousness was altered into somnolence and intubated with respiratory deterioration. Invasive pulmonary aspergillosis after falciparum malaria infection is life-threatening. There should be awareness of physicians of invasive pulmonary aspergillosis in falciparum malaria infection.

  10. Genetic Diversity and Protective Efficacy of the RTS,S/AS01 Malaria Vaccine

    DEFF Research Database (Denmark)

    Neafsey, Daniel E; Juraska, Michal; Bedford, Trevor

    2015-01-01

    Background The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the c......Background The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes...... protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. Results In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.......3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine...

  11. Dynamic alteration in splenic function during acute falciparum malaria

    Energy Technology Data Exchange (ETDEWEB)

    Looareesuwan, S.; Ho, M.; Wattanagoon, Y.; White, N.J.; Warrell, D.A.; Bunnag, D.; Harinasuta, T.; Wyler, D.J.

    1987-09-10

    Plasmodium-infected erythrocytes lose their normal deformability and become susceptible to splenic filtration. In animal models, this is one mechanism of antimalarial defense. To assess the effect of acute falciparum malaria on splenic filtration, we measured the clearance of heated /sup 51/Cr-labeled autologous erythrocytes in 25 patients with acute falciparum malaria and in 10 uninfected controls. Two groups of patients could be distinguished. Sixteen patients had splenomegaly, markedly accelerated clearance of the labeled erythrocytes (clearance half-time, 8.4 +/- 4.4 minutes (mean +/- SD) vs. 62.5 +/- 36.5 minutes in controls; P less than 0.001), and a lower mean hematocrit than did the patients without splenomegaly (P less than 0.001). In the nine patients without splenomegaly, clearance was normal. After institution of antimalarial chemotherapy, however, the clearance in this group accelerated to supernormal rates similar to those in the patients with splenomegaly, but without the development of detectable splenomegaly. Clearance was not significantly altered by treatment in the group with splenomegaly. Six weeks later, normal clearance rates were reestablished in most patients in both groups. We conclude that splenic clearance of labeled erythrocytes is enhanced in patients with malaria if splenomegaly is present and is enhanced only after treatment if splenomegaly is absent. Whether this enhanced splenic function applies to parasite-infected erythrocytes in patients with malaria and has any clinical benefit will require further studies.

  12. Malaria in pregnancy: the relevance of animal models for vaccine development.

    Science.gov (United States)

    Doritchamou, Justin; Teo, Andrew; Fried, Michal; Duffy, Patrick E

    2017-10-06

    Malaria during pregnancy due to Plasmodium falciparum or P. vivax is a major public health problem in endemic areas, with P. falciparum causing the greatest burden of disease. Increasing resistance of parasites and mosquitoes to existing tools, such as preventive antimalarial treatments and insecticide-treated bed nets respectively, is eroding the partial protection that they offer to pregnant women. Thus, development of effective vaccines against malaria during pregnancy is an urgent priority. Relevant animal models that recapitulate key features of the pathophysiology and immunology of malaria in pregnant women could be used to accelerate vaccine development. This review summarizes available rodent and nonhuman primate models of malaria in pregnancy, and discusses their suitability for studies of biologics intended to prevent or treat malaria in this vulnerable population.

  13. Ligasi dan Transformasi Gen MSP1 Plasmodium falciparum Penyebab Malaria di Kota Jayapura

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    Arsyam Mawardi

    2017-12-01

    MSP1 is the most antigenic and expressed protein on merozoite surface when it infects the erythrocytes of malaria patients which leads to its use for vaccine therapy design development. The ligation and transformation process of the MSP1 gene is a gene duplication attempt for producing  the same product during expression. This study aimed to clone P. falciparum MSP-1 gene from tropical malaria patients in Jayapura using pJET1.2/blunt vectors and E. coli DH5a competent cells, to get the recombinant plasmid propagation of MSP1 gene. Blood that was positive for P. falciparum was molecularly processed, starting with genomic DNA isolation and then followed by PCR amplification, ligation into pJET1.2/blunt vector, and transformation into E. coli DH5α using the heat shock transformation method. The process was ended with PCR confirmation to confirm MSP1 gene insertion. The results showed that the presence of the  MSP1 gene in pJET1.2/blunt was successfully confirmed through PCR. From a total of 10 positive colonies grown in liquid culture,  plasmid was isolated. Electropherogram result presented bands  of about 1049bp, indicating the presence of the MSP1 gene in plasmid. Hence, MSP1 gene cloning using pJET1.2/blunt cloning vector and competent cell E. coli DH5α has been successfully performed.  Key words: Heat shock, ligation, MSP-1, P. falciparum, transformation

  14. The Influence of Sub-Unit Composition and Expression System on the Functional Antibody Response in the Development of a VAR2CSA Based Plasmodium falciparum Placental Malaria Vaccine.

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    Morten A Nielsen

    Full Text Available The disease caused by Plasmodium falciparum (Pf involves different clinical manifestations that, cumulatively, kill hundreds of thousands every year. Placental malaria (PM is one such manifestation in which Pf infected erythrocytes (IE bind to chondroitin sulphate A (CSA through expression of VAR2CSA, a parasite-derived antigen. Protection against PM is mediated by antibodies that inhibit binding of IE in the placental intervillous space. VAR2CSA is a large antigen incompatible with large scale recombinant protein expression. Vaccines based on sub-units encompassing the functionally constrained receptor-binding domains may, theoretically, circumvent polymorphisms, reduce the risk of escape-mutants and induce cross-reactive antibodies. However, the sub-unit composition and small differences in the borders, may lead to exposure of novel immuno-dominant antibody epitopes that lead to non-functional antibodies, and furthermore influence the folding, stability and yield of expression. Candidate antigens from the pre-clinical development expressed in High-Five insect cells using the baculovirus expression vector system were transitioned into the Drosophila Schneider-2 cell (S2 expression-system compliant with clinical development. The functional capacity of antibodies against antigens expressed in High-Five cells or in S2 cells was equivalent. This enabled an extensive down-selection of S2 insect cell-expressed antigens primarily encompassing the minimal CSA-binding region of VAR2CSA. In general, we found differential potency of inhibitory antibodies against antigens with the same borders but of different var2csa sequences. Likewise, we found that subtle size differences in antigens of the same sequence gave varying levels of inhibitory antibodies. The study shows that induction of a functional response against recombinant subunits of the VAR2CSA antigen is unpredictable, demonstrating the need for large-scale screening in order to identify antigens

  15. New candidate vaccines against blood-stage Plasmodium falciparum malaria: prime-boost immunization regimens incorporating human and simian adenoviral vectors and poxviral vectors expressing an optimized antigen based on merozoite surface protein 1

    NARCIS (Netherlands)

    Goodman, Anna L.; Epp, C.; Moss, D.; Holder, A. A.; Wilson, J. M.; Gao, G. P.; Long, C. A.; Remarque, E. J.; Thomas, A. W.; Ammendola, V.; Colloca, S.; Dicks, M. D. J.; Biswas, S.; Seibel, D.; van Duivenvoorde, L. M.; Gilbert, S. C.; Hill, A. V. S.; Draper, S. J.

    2010-01-01

    Although merozoite surface protein 1 (MSP-1) is a leading candidate vaccine antigen for blood-stage malaria, its efficacy in clinical trials has been limited in part by antigenic polymorphism and potentially by the inability of protein-in-adjuvant vaccines to induce strong cellular immunity. Here we

  16. Vaccines for Malaria: How Close Are We?

    Science.gov (United States)

    Thera, Mahamadou A.; Plowe, Christopher V.

    2012-01-01

    Vaccines are the most powerful public health tools mankind has created, but malaria parasites are bigger, more complicated, and wilier than the viruses and bacteria that have been conquered or controlled with vaccines. Despite decades of research toward a vaccine for malaria, this goal has remained elusive. Nevertheless, recent advances justify optimism that a licensed malaria vaccine is within reach. A subunit recombinant protein vaccine that affords in the neighborhood of 50% protective efficacy against clinical malaria is in the late stages of clinical evaluation in Africa. Incremental improvements on this successful vaccine are possible and worth pursuing, but the best hope for a highly efficacious malaria vaccine that would improve prospects for malaria eradication may lie with the use of attenuated whole parasites and powerful immune-boosting adjuvants. PMID:22077719

  17. Glucose homeostasis in children with falciparum malaria: precursor supply limits gluconeogenesis and glucose production

    NARCIS (Netherlands)

    Dekker, E.; Hellerstein, M. K.; Romijn, J. A.; Neese, R. A.; Peshu, N.; Endert, E.; Marsh, K.; Sauerwein, H. P.

    1997-01-01

    To evaluate glucose kinetics in children with falciparum malaria, basal glucose production and gluconeogenesis and an estimate of the flux of the gluconeogenic precursors were measured in Kenyan children with uncomplicated falciparum malaria before (n = 11) and during infusion of alanine (1.5

  18. Antibody response dynamics to the Plasmodium falciparum conserved vaccine candidate antigen, merozoite surface protein-1 C-terminal 19kD (MSP1-19kD, in Peruvians exposed to hypoendemic malaria transmission

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    Gamboa Dionicia

    2008-09-01

    Full Text Available Abstract Background In high-transmission areas, developing immunity to symptomatic Plasmodium falciparum infections requires 2–10 years of uninterrupted exposure. Delayed malaria-immunity has been attributed to difficult-to-develop and then short-lived antibody responses. Methods In a study area with P. falciparum infections/person/year, antibody responses to the MSP1-19kD antigen were evaluated and associations with P. falciparum infections in children and adults. In months surrounding and during the malaria seasons of 2003–2004, 1,772 participants received ≥6 active visits in one study-year. Community-wide surveys were conducted at the beginning and end of each malaria season, and weekly active visits were completed for randomly-selected individuals each month. There were 79 P. falciparum infections with serum samples collected during and approximately one month before and after infection. Anti-MSP1-19kD IgG levels were measured by ELISA. Results The infection prevalence during February-July was similar in children (0.02–0.12 infections/person/month and adults (0.03–0.14 infections/person/month and was negligible in the four-month dry season. In children and adults, the seroprevalence was maintained in the beginning (children = 28.9%, adults = 61.8% versus ending malaria-season community survey (children = 26.7%, adults = 64.6%. Despite the four-month non-transmission season, the IgG levels in Plasmodium-negative adults were similar to P. falciparum-positive adults. Although children frequently responded upon infection, the transition from a negative/low level before infection to a high level during/after infection was slower in children. Adults and children IgG-positive before infection had reduced symptoms and parasite density. Conclusion Individuals in low transmission areas can rapidly develop and maintain αMSP1-19kD IgG responses for >4 months, unlike responses reported in high transmission study areas. A greater immune

  19. Thrombocytopenia in pregnant women with Plasmodium falciparum malaria in an area of unstable malaria transmission in eastern Sudan

    Directory of Open Access Journals (Sweden)

    Adam Mayyada B

    2012-08-01

    Full Text Available Abstract Background Blood platelet levels are being evaluated as predictive and prognostic indicators of the severity of malaria infections in humans. However, there are few studies on platelets and Plasmodium falciparum malaria during pregnancy. Methods A case–control study was conducted at Gadarif Hospital in Eastern Sudan, an area characterized by unstable malaria transmission. The aim of the study was to investigate thrombocytopenia in pregnant women with P. falciparum malaria (cases and healthy pregnant women (controls. Results The median (interquartile platelet counts were significantly lower in patients with malaria (N = 60 than in the controls (N = 60, 61, 000 (43,000–85,000 vs. 249,000 (204,000–300,000/μL, respectively, p P. falciparum malaria (N = 12 compared with those patients with uncomplicated P. falciparum malaria (N = 48, 68, 000 (33,000-88,000/μL vs. 61, 000 (45,000–85,000/μL, respectively, p = 0.8. While none of the control group had thrombocytopenia (platelet count p P. falciparum malaria, compared with the pregnant healthy control group, were at higher risk (OR = 10.1, 95% CI = 4.1–25.18; p  Conclusion P. falciparum malaria is associated with thrombocytopenia in pregnant women in this setting. More research is needed.

  20. [Epidemic situation and prevention and control countermeasures of imported falciparum malaria in Jiangdu District, Yangzhou City].

    Science.gov (United States)

    Zhu, Xi-Guang; She, Guang-Song

    2012-10-01

    To explore the feasible prevention and control measures for imported falciparum malaria. The epidemic situation of imported falciparum malaria and status of labor export were investigated by using the epidemic statistical method, epidemiological survey and follow-up survey. There were 46 direct network reported cases of imported falciparum malaria in Jiangdu District in 2011, and they were all export laborers to Africa, being aged from 30-49 years, Totally 28 patients of them had the history of disease in foreign countries, and 29 cases were in the same labor export services company. A total of 444 migrant labors were investigated and 24 patients were diagnosed falciparum malaria. In order to prevent and control imported falciparum malaria, we should strengthen the standard management of labor export services market and health education.

  1. Towards A Malaria Vaccine?

    Directory of Open Access Journals (Sweden)

    B S GARG

    1990-12-01

    Full Text Available The last few years have seen a marked change in the understanding of malaria mmunology.We have very little knowledge on immunity of Malaria based on experiments in humanbeings due to ethical reasons. Whatsoever our knowledge exists at present is based onexperimentas in mice and monkey. However it is clear that it is sporzoite or merozoitewhich is directly exposed to our immune system in the life cycle of Malaria parasite. On thebasis of human experiments we can draw inference that immunity to malaria is species.specific (on cross immunity, stage specific and strain specific as well acquired in the response to surface antigen and relapsed antigen although the parasite also demonstrates escape machanism to immune system.So the host system kills or elimi nate the parasite by means of (a Antbody to extracell~ular form of parasite with the help of mechanism of Block invasion, Agglutination or opsonization and/or (b Cellular machanism-either by phago-cytosis of parasite or by antibody dependent cellular cytotoxicity ABCC (? or by effects of mediators like tumor necrosis fJ.ctor (TNF in cerebaral malaria or crisis forming factor as found in sudan or by possible role of lysis mechanism.However, inspite of all these theories the parasite has been able to invade the immunesystem by virtue of its intracellular development stage specificity, sequestration in capillaries and also by its unusual characteristics of antigenic diversity and antigenic variation.

  2. Origin of the human malaria parasite Plasmodium falciparum in gorillas.

    Science.gov (United States)

    Liu, Weimin; Li, Yingying; Learn, Gerald H; Rudicell, Rebecca S; Robertson, Joel D; Keele, Brandon F; Ndjango, Jean-Bosco N; Sanz, Crickette M; Morgan, David B; Locatelli, Sabrina; Gonder, Mary K; Kranzusch, Philip J; Walsh, Peter D; Delaporte, Eric; Mpoudi-Ngole, Eitel; Georgiev, Alexander V; Muller, Martin N; Shaw, George M; Peeters, Martine; Sharp, Paul M; Rayner, Julian C; Hahn, Beatrice H

    2010-09-23

    Plasmodium falciparum is the most prevalent and lethal of the malaria parasites infecting humans, yet the origin and evolutionary history of this important pathogen remain controversial. Here we develop a single-genome amplification strategy to identify and characterize Plasmodium spp. DNA sequences in faecal samples from wild-living apes. Among nearly 3,000 specimens collected from field sites throughout central Africa, we found Plasmodium infection in chimpanzees (Pan troglodytes) and western gorillas (Gorilla gorilla), but not in eastern gorillas (Gorilla beringei) or bonobos (Pan paniscus). Ape plasmodial infections were highly prevalent, widely distributed and almost always made up of mixed parasite species. Analysis of more than 1,100 mitochondrial, apicoplast and nuclear gene sequences from chimpanzees and gorillas revealed that 99% grouped within one of six host-specific lineages representing distinct Plasmodium species within the subgenus Laverania. One of these from western gorillas comprised parasites that were nearly identical to P. falciparum. In phylogenetic analyses of full-length mitochondrial sequences, human P. falciparum formed a monophyletic lineage within the gorilla parasite radiation. These findings indicate that P. falciparum is of gorilla origin and not of chimpanzee, bonobo or ancient human origin.

  3. Malaria vaccine R&D in the Decade of Vaccines: breakthroughs, challenges and opportunities.

    Science.gov (United States)

    Birkett, Ashley J; Moorthy, Vasee S; Loucq, Christian; Chitnis, Chetan E; Kaslow, David C

    2013-04-18

    While recent progress has been made in reducing malaria mortality with other interventions, vaccines are still urgently needed to further reduce the incidence of clinical disease, including during pregnancy, and to provide "herd protection" by blocking parasite transmission. The most clinically advanced candidate, RTS,S, is presently undergoing Phase 3 evaluation in young African children across 13 clinical sites in eight African countries. In the 12-month period following vaccination, RTS,S conferred approximately 50% protection from clinical Plasmodium falciparum disease in children aged 5-17 months, and approximately 30% protection in children aged 6-12 weeks when administered in conjunction with Expanded Program for Immunization (EPI) vaccines. The development of more highly efficacious vaccines to prevent clinical disease caused by both P. falciparum and Plasmodium vivax, as well as vaccines to support elimination efforts by inducing immunity that blocks malaria parasite transmission, are priorities. Some key barriers to malaria vaccine development include: a paucity of well-characterized target immunogens and an absence of clear correlates of protection to enable vaccine development targeting all stages of the P. falciparum and P. vivax lifecycles; a limited number of safe and effective delivery systems, including adjuvants, that induce potent, long-lived protective immunity, be it by antibody, CD4+, and/or CD8+ T cell responses; and, for vaccines designed to provide "herd protection" by targeting sexual stage and/or mosquito antigens, the lack of a clear clinical and regulatory pathway to licensure using non-traditional endpoints. Recommendations to overcome these, and other key challenges, are suggested in this document. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. A Field Trial to Assess a Blood-Stage Malaria Vaccine

    Science.gov (United States)

    Thera, Mahamadou A.; Doumbo, Ogobara K.; Coulibaly, Drissa; Laurens, Matthew B.; Ouattara, Amed; Kone, Abdoulaye K.; Guindo, Ando B.; Traore, Karim; Traore, Idrissa; Kouriba, Bourema; Diallo, Dapa A.; Diarra, Issa; Daou, Modibo; Dolo, Amagana; Tolo, Youssouf; Sissoko, Mahamadou S.; Niangaly, Amadou; Sissoko, Mady; Takala-Harrison, Shannon; Lyke, Kirsten E.; Wu, Yukun; Blackwelder, William C.; Godeaux, Olivier; Vekemans, Johan; Dubois, Marie-Claude; Ballou, W. Ripley; Cohen, Joe; Thompson, Darby; Dube, Tina; Soisson, Lorraine; Diggs, Carter L.; House, Brent; Lanar, David E.; Dutta, Sheetij; Heppner, D. Gray; Plowe, Christopher V.

    2011-01-01

    BACKGROUND Blood-stage malaria vaccines are intended to prevent clinical disease. The malaria vaccine FMP2.1/AS02A, a recombinant protein based on apical membrane antigen 1 (AMA1) from the 3D7 strain of Plasmodium falciparum, has previously been shown to have immunogenicity and acceptable safety in Malian adults and children. METHODS In a double-blind, randomized trial, we immunized 400 Malian children with either the malaria vaccine or a control (rabies) vaccine and followed them for 6 months. The primary end point was clinical malaria, defined as fever and at least 2500 parasites per cubic millimeter of blood. A secondary end point was clinical malaria caused by parasites with the AMA1 DNA sequence found in the vaccine strain. RESULTS The cumulative incidence of the primary end point was 48.4% in the malaria-vaccine group and 54.4% in the control group; efficacy against the primary end point was 17.4% (hazard ratio for the primary end point, 0.83; 95% confidence interval [CI], 0.63 to 1.09; P = 0.18). Efficacy against the first and subsequent episodes of clinical malaria, as defined on the basis of various parasite-density thresholds, was approximately 20%. Efficacy against clinical malaria caused by parasites with AMA1 corresponding to that of the vaccine strain was 64.3% (hazard ratio, 0.36; 95% CI, 0.08 to 0.86; P = 0.03). Local reactions and fever after vaccination were more frequent with the malaria vaccine. CONCLUSIONS On the basis of the primary end point, the malaria vaccine did not provide significant protection against clinical malaria, but on the basis of secondary results, it may have strain-specific efficacy. If this finding is confirmed, AMA1 might be useful in a multicomponent malaria vaccine. PMID:21916638

  5. DNA Prime/Adenovirus Boost Malaria Vaccine Encoding P. falciparum CSP and AMA1 Induces Sterile Protection Associated with Cell-Mediated Immunity

    Science.gov (United States)

    2013-02-14

    Cummings2, Jack Komisar2, Awalludin Sutamihardja1¤c, Meng Shi2, Judith E. Epstein1, Santina Maiolatesi1, Donna Tosh2, Keith Limbach1, Evelina Angov2...Doolan DL, Martinez-Alier N (2006) Immune response to pre-erythrocytic stages of malaria parasites. Curr Mol Med 6: 169–185. 9. Butler NS, Schmidt NW

  6. Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria.

    Science.gov (United States)

    Jeeyapant, Atthanee; Kingston, Hugh W; Plewes, Katherine; Maude, Richard J; Hanson, Josh; Herdman, M Trent; Leopold, Stije J; Ngernseng, Thatsanun; Charunwatthana, Prakaykaew; Phu, Nguyen Hoan; Ghose, Aniruddha; Hasan, M Mahtab Uddin; Fanello, Caterina I; Faiz, Md Abul; Hien, Tran Tinh; Day, Nicholas P J; White, Nicholas J; Dondorp, Arjen M

    2017-01-01

    Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria. Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African 'AQUAMAT' trial comparing artesunate and quinine (children), and the Vietnamese 'AQ' study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the 'AQUAMAT' study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery. The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality.

  7. Protective efficacy of baculovirus dual expression system vaccine expressing Plasmodium falciparum circumsporozoite protein.

    Directory of Open Access Journals (Sweden)

    Mitsuhiro Iyori

    Full Text Available We have previously developed a new malaria vaccine delivery system based on the baculovirus dual expression system (BDES. In this system, expression of malaria antigens is driven by a dual promoter consisting of the baculovirus-derived polyhedrin and mammal-derived cytomegalovirus promoters. To test this system for its potential as a vaccine against human malaria parasites, we investigated immune responses against the newly developed BDES-based Plasmodium falciparum circumsporozoite protein vaccines (BDES-PfCSP in mice and Rhesus monkeys. Immunization of mice with BDES-PfCSP induced Th1/Th2-mixed type immune responses with high PfCSP-specific antibody (Ab titers, and provided significant protection against challenge from the bites of mosquitoes infected with a transgenic P. berghei line expressing PfCSP. Next, we evaluated the immunogenicity of the BDES-PfCSP vaccine in a rhesus monkey model. Immunization of BDES-PfCSP elicited high levels of anti-PfCSP Ab responses in individual monkeys. Moreover, the sera from the immunized monkeys remarkably blocked sporozoite invasion of HepG2 cells. Taken together with two animal models, our results indicate that this novel vaccine platform (BDES has potential clinical application as a vaccine against malaria.

  8. Secreted HSP Vaccine for Malaria Prophylaxis

    Science.gov (United States)

    2017-10-01

    AWARD NUMBER: W81XWH-13-2-0098 TITLE: Secreted HSP Vaccine for Malaria Prophylaxis PRINCIPAL INVESTIGATOR: Natasa Strbo CONTRACTING...1. REPORT DATE October 2017 2. REPORT TYPE Annual 3. DATES COVERED 09/30/16-09/29/17 4. TITLE AND SUBTITLE Secreted HSP Vaccine for Malaria...thereby stimulating an avid, antigen specific, cytotoxic CD8 T cell response. Here we developed malaria vaccine that relies on secreted gp96-Ig

  9. Artemisinin-naphthoquine for treating uncomplicated Plasmodium falciparum malaria

    Science.gov (United States)

    Isba, Rachel; Zani, Babalwa; Gathu, Michael; Sinclair, David

    2015-01-01

    Background The World Health Organization (WHO) recommends artemisinin-based combination therapy (ACT) for treating people with Plasmodium falciparum malaria. Five combinations are currently recommended, all administered over three days. Artemisinin-naphthoquine is a new combination developed in China, which is being marketed as a one-day treatment. Although shorter treatment courses may improve adherence, the WHO recommends at least three days of the short-acting artemisinin component to eliminate 90% P. falciparum parasites in the bloodstream, before leaving the longer-acting partner drug to clear the remaining parasites. Objectives To evaluate the efficacy and safety of the artemisinin-naphthoquine combination for treating adults and children with uncomplicated P. falciparum malaria. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library; MEDLINE; EMBASE; and LILACS up to January 2015. We also searched the metaRegister of Controlled Trials (mRCT) using 'malaria' and 'arte* OR dihydroarte*' as search terms. Selection criteria Randomized controlled trials comparing artemisinin-naphthoquine combinations with established WHO-recommended ACTs for the treatment of adults and children with uncomplicated malaria due to P. falciparum. Data collection and analysis Two review authors independently assessed trials for eligibility and risk of bias, and extracted data. We analysed primary outcomes in line with the WHO 'Protocol for assessing and monitoring antimalarial drug efficacy' and compared drugs using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were effects on gametocytes, haemoglobin, and adverse events. We assessed the quality of evidence using the GRADE approach. Main results Four trials, enrolling 740 adults and children, met the inclusion criteria. Artemisinin-naphthoquine was administered as a single dose (two

  10. Protective antibody and CD8+ T-cell responses to the Plasmodium falciparum circumsporozoite protein induced by a nanoparticle vaccine.

    Directory of Open Access Journals (Sweden)

    Stephen A Kaba

    Full Text Available The worldwide burden of malaria remains a major public health problem due, in part, to the lack of an effective vaccine against the Plasmodium falciparum parasite. An effective vaccine will most likely require the induction of antigen specific CD8(+ and CD4(+ T-cells as well as long-lasting antibody responses all working in concert to eliminate the infection. We report here the effective modification of a self-assembling protein nanoparticle (SAPN vaccine previously proven effective in control of a P. berghei infection in a rodent model to now present B- and T-cell epitopes of the human malaria parasite P. falciparum in a platform capable of being used in human subjects.To establish the basis for a SAPN-based vaccine, B- and CD8(+ T-cell epitopes from the P. falciparum circumsporozoite protein (PfCSP and the universal CD4 T-helper epitope PADRE were engineered into a versatile small protein (∼125 amino acids that self-assembles into a spherical nanoparticle repetitively displaying the selected epitopes. P. falciparum epitope specific immune responses were evaluated in mice using a transgenic P. berghei malaria parasite of mice expressing the human malaria full-length P. falciparum circumsporozoite protein (Tg-Pb/PfCSP. We show that SAPN constructs, delivered in saline, can induce high-titer, long-lasting (1 year protective antibody and poly-functional (IFNγ(+, IL-2(+ long-lived central memory CD8(+ T-cells. Furthermore, we demonstrated that these Ab or CD8(+ T-cells can independently provide sterile protection against a lethal challenge of the transgenic parasites.The SAPN construct induces long-lasting antibody and cellular immune responses to epitope specific sequences of the P. falciparum circumsporozoite protein (PfCSP and prevents infection in mice by a transgenic P. berghei parasite displaying the full length PfCSP.

  11. Surveillance of artemisinin and partner drug efficacy in uncomplicated Plasmodium falciparum malaria in Coastal Kenya

    OpenAIRE

    Marschallek, Maria Rebekka

    2017-01-01

    Background: Malaria remains one of the major causes of morbidity and mortality worldwide. Artemisinin-based combination therapies are used as first-line treatment in all endemic countries for uncomplicated P. falciparum malaria. artemether-lumefantrine was introduced as first-line treatment in Kenya in 2006. Since the first report of artemisinin-resistant P. falciparum malaria in 2009 on the Thai-Cambodian border, concerns about declining responsiveness to artemisinins have also been expresse...

  12. A longitudinal study of type-specific antibody responses to Plasmodium falciparum merozoite surface protein-1 in an area of unstable malaria in Sudan

    DEFF Research Database (Denmark)

    Cavanagh, D R; Elhassan, I M; Roper, C

    1998-01-01

    Merozoite surface protein-1 (MSP-1) of Plasmodium falciparum is a malaria vaccine candidate Ag. Immunity to MSP-1 has been implicated in protection against infection in animal models. However, MSP-1 is a polymorphic protein and its immune recognition by humans following infection is not well unde...

  13. Antibodies to the N-terminal block 2 of Plasmodium falciparum merozoite surface protein 1 are associated with protection against clinical malaria

    DEFF Research Database (Denmark)

    Cavanagh, David R; Dodoo, Daniel; Hviid, Lars

    2004-01-01

    to the block 2 region of MSP-1 were measured in a cohort of 280 children before the beginning of the major malaria transmission season. The cohort was then actively monitored for malaria, clinically and parasitologically, over a period of 17 months. Evidence is presented for an association between antibody...... responses to block 2 and a significantly reduced risk of subsequent clinical malaria. Furthermore, statistical survival analysis provides new information on the duration of the effect over time. The results support a conclusion that the block 2 region of MSP-1 is a target of protective immunity against P....... falciparum and, thus, a promising new candidate for the development of a malaria vaccine....

  14. The Etiology of Placental Plasmodium Falciparum Malaria in African Women.

    Science.gov (United States)

    Ofori, Michael F; Lamptey, Helena; Dickson, Emmanuel K; Kyei-Baafour, Eric; Hviid, Lars

    2018-03-22

    Plasmodium falciparum parasites causing placental malaria (PM) express the VAR2CSA type of the clonally variant antigen family PfEMP1. This enables evasion of pre-existing immunity and results in placental accumulation of infected erythrocytes (IEs). We present data on seasonal variation in levels of VAR2CSA-specific IgG and IgG specific for a PM-unrelated PfEMP1 protein among Ghanaian women at first antenatal visit. Our results indicate that PM does not require recent exposure to infected mosquitoes, in contrast to malaria in general. This has implications for the impact of insecticide-treated bed nets on PM incidence, and for antenatal care in woman with pre-existing immunity.

  15. Efficacy of chloroquine for the treatment of uncomplicated Plasmodium falciparum malaria in Honduras.

    Science.gov (United States)

    Mejia Torres, Rosa Elena; Banegas, Engels Ilich; Mendoza, Meisy; Diaz, Cesar; Bucheli, Sandra Tamara Mancero; Fontecha, Gustavo A; Alam, Md Tauqeer; Goldman, Ira; Udhayakumar, Venkatachalam; Zambrano, Jose Orlinder Nicolas

    2013-05-01

    Chloroquine (CQ) is officially used for the primary treatment of Plasmodium falciparum malaria in Honduras. In this study, the therapeutic efficacy of CQ for the treatment of uncomplicated P. falciparum malaria in the municipality of Puerto Lempira, Gracias a Dios, Honduras was evaluated using the Pan American Health Organization-World Health Organization protocol with a follow-up of 28 days. Sixty-eight patients from 6 months to 60 years of age microscopically diagnosed with uncomplicated P. falciparum malaria were included in the final analysis. All patients who were treated with CQ (25 mg/kg over 3 days) cleared parasitemia by day 3 and acquired no new P. falciparum infection within 28 days of follow-up. All the parasite samples sequenced for CQ resistance mutations (pfcrt) showed only the CQ-sensitive genotype (CVMNK). This finding shows that CQ remains highly efficacious for the treatment of uncomplicated P. falciparum malaria in Gracias a Dios, Honduras.

  16. Clinical development of a VAR2CSA-based placental malaria vaccine PAMVAC

    DEFF Research Database (Denmark)

    Gbédandé, Komi; Fievet, Nadine; Viwami, Firmine

    2017-01-01

    Background  The antigen VAR2CSA plays a pivotal role in the pathophysiology of pregnancy-associated malaria (PAM) caused by Plasmodium falciparum. A VAR2CSA-based vaccine candidate, PAMVAC, is under development by an EU-funded multi-country consortium (PlacMalVac project). As part of PAMVAC...

  17. Kinetics of B Cell responses to Plasmodium falciparum erythrocyte membrane protein 1 in Ghanaian women naturally exposed to malaria parasites

    DEFF Research Database (Denmark)

    Ampomah, Paulina; Stevenson, Liz; Ofori, Michael F

    2014-01-01

    acquisition of clinical protection takes years to develop, but it probably involves a range of immune-evasive parasite features, not least of which are PfEMP1 polymorphism and clonal variation. Parasite-induced subversion of immunological memory and expansion of "atypical" memory B cells may also contribute......Naturally acquired protective immunity to Plasmodium falciparum malaria takes years to develop. It relies mainly on Abs, particularly IgG specific for Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) proteins on the infected erythrocyte surface. It is only partially understood why...... confirmed earlier reports of high atypical memory B cell frequencies among residents of P. falciparum-endemic areas, and indicated an additional effect of pregnancy. Our study provides new knowledge regarding immunity to P. falciparum malaria and underpins efforts to develop PfEMP1-based vaccines against...

  18. Artemether-lumefantrine treatment of uncomplicated Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Kofoed, Poul-Erik

    2015-01-01

    BACKGROUND: Achieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with artemether-lumefantrine efficacy. However, the 'therapeutic' day 7 lumefantrine concentr......BACKGROUND: Achieving adequate antimalarial drug exposure is essential for curing malaria. Day 7 blood or plasma lumefantrine concentrations provide a simple measure of drug exposure that correlates well with artemether-lumefantrine efficacy. However, the 'therapeutic' day 7 lumefantrine......-lumefantrine for uncomplicated Plasmodium falciparum malaria, to define therapeutic day 7 lumefantrine concentrations and identify patient factors that substantially alter these concentrations. A systematic review of PubMed, Embase, Google Scholar, ClinicalTrials.gov and conference proceedings identified all relevant studies...... lumefantrine concentrations ≥200 ng/ml and high cure rates in most uncomplicated malaria patients. Three groups are at increased risk of treatment failure: very young children (particularly those underweight-for-age); patients with high parasitemias; and patients in very low transmission intensity areas...

  19. Comparison of functional assays used in the clinical development of a placental malaria vaccine

    DEFF Research Database (Denmark)

    Pehrson, Caroline; Heno, Kristine Klysner; Adams, Yvonne

    2017-01-01

    BACKGROUND: Malaria in pregnancy is associated with significant morbidity in pregnant women and their offspring. Plasmodium falciparum infected erythrocytes (IE) express VAR2CSA that mediates binding to chondroitin sulphate A (CSA) in the placenta. Two VAR2CSA-based vaccines for placental malaria...... conditions. Importantly the ID1-ID2a protein in a liposomal formulation, currently in a phase I trial, effectively induced antibodies that inhibited IE adhesion in placental tissue....

  20. Targeting NAD+ metabolism in the human malaria parasite Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Jessica K O'Hara

    Full Text Available Nicotinamide adenine dinucleotide (NAD+ is an essential metabolite utilized as a redox cofactor and enzyme substrate in numerous cellular processes. Elevated NAD+ levels have been observed in red blood cells infected with the malaria parasite Plasmodium falciparum, but little is known regarding how the parasite generates NAD+. Here, we employed a mass spectrometry-based metabolomic approach to confirm that P. falciparum lacks the ability to synthesize NAD+ de novo and is reliant on the uptake of exogenous niacin. We characterized several enzymes in the NAD+ pathway and demonstrate cytoplasmic localization for all except the parasite nicotinamidase, which concentrates in the nucleus. One of these enzymes, the P. falciparum nicotinate mononucleotide adenylyltransferase (PfNMNAT, is essential for NAD+ metabolism and is highly diverged from the human homolog, but genetically similar to bacterial NMNATs. Our results demonstrate the enzymatic activity of PfNMNAT in vitro and demonstrate its ability to genetically complement the closely related Escherichia coli NMNAT. Due to the similarity of PfNMNAT to the bacterial enzyme, we tested a panel of previously identified bacterial NMNAT inhibitors and synthesized and screened twenty new derivatives, which demonstrate a range of potency against live parasite culture. These results highlight the importance of the parasite NAD+ metabolic pathway and provide both novel therapeutic targets and promising lead antimalarial compounds.

  1. Plasmodium falciparum variant surface antigen expression varies between isolates causing severe and nonsevere malaria and is modified by acquired immunity

    DEFF Research Database (Denmark)

    Nielsen, Morten A; Staalsoe, Trine; Kurtzhals, Jørgen

    2002-01-01

    of immunity, as disease-causing parasites appear to be those not controlled by preexisting VSA-specific Abs. In this work we report that VSA expressed by parasites from young Ghanaian children with P. falciparum malaria were commonly and strongly recognized by plasma Abs from healthy children in the same area......, and that the VSA expression pattern is modulated by immunity. This opens the possibility of developing morbidity-reducing vaccines targeting a limited subset of common and particularly virulent VSA.......In areas of endemic parasite transmission, protective immunity to Plasmodium falciparum malaria is acquired over several years with numerous disease episodes. Acquisition of Abs to parasite-encoded variant surface Ags (VSA) on the infected erythrocyte membrane is important in the development...

  2. [Evaluation of effect of prevention and control system for imported falciparum malaria in Hanjiang District].

    Science.gov (United States)

    She, Guo-lin; Ma, Yu-Cai; Wang, Fu-biao

    2013-08-01

    To analyze the current situation of the comprehensive prevention and control system for imported falciparum malaria in Hanjiang District and evaluate its effect. According to the Management Scheme on Control of Imported Falciparum Malaria in Yangzhou City, the comprehensive prevention and control system for imported falciparum malaria was implemented, and the relevant malaria data were collected and analyzed statistically. The data included plasmodium blood test ratio of fever patients among exported labors and those returned, the ratio of laboratory-confirmed cases among all reported cases of falciparum malaria, the ratio of falciparum malaria patients who received the standard treatment within 24 hours after onset, etc from 2010 to 2012. After the implementation of the comprehensive prevention and control system, the confirmation ratio of falciparum malaria cases within 24 hours following first visit has reached 60.47%, the average time from first visit to confirmation has shortened to 1.8 d, and the average time from onset to confirmation has shortened to 3.7 d. The health education coverage ratio was 100%, the health knowledge awareness ratio was 95.56%, the ratio of patients seeking treatment on own initiative was 100%, the laboratory-confirmed ratio was 100%, and the ratio of standard treatment after malaria diagnosis was 100%. The comprehensive prevention and control system carried out by Hanjiang District has made remarkable achievements.

  3. Malaria vaccines: immunity, models and monoclonal antibodies

    DEFF Research Database (Denmark)

    Hviid, Lars; Barfod, Lea

    2008-01-01

    Although experts in the field have agreed on the malaria vaccine technology roadmap that should be followed (http://www.malariavaccineroadmap.net/), the path towards an effective malaria vaccine remains littered with intellectual and practical pot-holes. The animal models that are currently...

  4. Increased prevalence of Plasmodium falciparum malaria in Honduras, Central America Aumento de la prevalencia de malaria por Plasmodium falciparum en Honduras, Centroamerica

    Directory of Open Access Journals (Sweden)

    Carol J. Palmer

    1998-07-01

    Full Text Available We report on our investigation of a malaria outbreak in Honduras, Central America, in January 1997. We tested 202 patients with fever and chills using thin and thick blood film microscopy. Sixteen patients lived in the city and the rest lived in rural areas. A total of 95 samples (47% were positive for malaria parasites. Seventy-nine percent (63/80 of the rural patients were infected with Plasmodium vivax and 21% (17/80 were infected with P. falciparum. In the urban area, all 15 infected patients had P. vivax malaria and none showed evidence of P. falciparum. Since previous reports indicate that falciparum malaria accounts for only 2% of the overall malaria infections in Honduras, the results reported here suggest that there is a dramatic increase in falciparum malaria in the area of Honduras investigated in this study.Notificamos los resultados de un estudio de un brote de malaria que se produjo en Honduras, Centroamérica, en enero de 1997. Sometimos a examen microscópico frotis delgados y frotis gruesos de la sangre de 202 pacientes con fiebre y escalofríos. Dieciséis pacientes eran habitantes de la zona urbana y el resto de la zona rural. Un total de 95 especímenes (47% fueron positivos a parásitos de la malaria. Setenta y ocho por ciento (62/80 de los pacientes del área rural estaban infestados con Plasmodium vivax y 22% (17/80 con P. falciparum. En la zona urbana, todos los 15 pacientes que estaban infestados tenían P. vivax y en ninguno se detectó P. falciparum. Ya que según informes previos la malaria de tipo falciparum representa solamente 2% de todos los casos de malaria en Honduras, nuestros resultados sugieren que hay un gran incremento del número de casos de malaria falciparum en la zona de Honduras en que se llevó a cabo esta investigación.

  5. Transcriptional changes induced by candidate malaria vaccines and correlation with protection against malaria in a human challenge model.

    Science.gov (United States)

    Dunachie, Susanna; Berthoud, Tamara; Hill, Adrian V S; Fletcher, Helen A

    2015-09-29

    The complexity of immunity to malaria is well known, and clear correlates of protection against malaria have not been established. A better understanding of immune markers induced by candidate malaria vaccines would greatly enhance vaccine development, immunogenicity monitoring and estimation of vaccine efficacy in the field. We have previously reported complete or partial efficacy against experimental sporozoite challenge by several vaccine regimens in healthy malaria-naïve subjects in Oxford. These include a prime-boost regimen with RTS,S/AS02A and modified vaccinia virus Ankara (MVA) expressing the CSP antigen, and a DNA-prime, MVA-boost regimen expressing the ME TRAP antigens. Using samples from these trials we performed transcriptional profiling, allowing a global assessment of responses to vaccination. We used Human RefSeq8 Bead Chips from Illumina to examine gene expression using PBMC (peripheral blood mononuclear cells) from 16 human volunteers. To focus on antigen-specific changes, comparisons were made between PBMC stimulated with CSP or TRAP peptide pools and unstimulated PBMC post vaccination. We then correlated gene expression with protection against malaria in a human Plasmodium falciparum malaria challenge model. Differentially expressed genes induced by both vaccine regimens were predominantly in the IFN-γ pathway. Gene set enrichment analysis revealed antigen-specific effects on genes associated with IFN induction and proteasome modules after vaccination. Genes associated with IFN induction and antigen presentation modules were positively enriched in subjects with complete protection from malaria challenge, while genes associated with haemopoietic stem cells, regulatory monocytes and the myeloid lineage modules were negatively enriched in protected subjects. These results represent novel insights into the immune repertoires involved in malaria vaccination. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  6. Whole organism blood stage vaccines against malaria.

    Science.gov (United States)

    Stanisic, Danielle I; Good, Michael F

    2015-12-22

    Despite a century of research focused on the development and implementation of effective control strategies, infection with the malaria parasite continues to result in significant morbidity and mortality worldwide. An effective malaria vaccine is considered by many to be the definitive solution. Yet, after decades of research, we are still without a vaccine that is capable of inducing robust, long lasting protection in naturally exposed individuals. Extensive sub-unit vaccine development focused on the blood stage of the malaria parasite has thus far yielded disappointing results. There is now a renewed focus on whole parasite vaccine strategies, particularly as they may overcome some of the inherent weaknesses deemed to be associated with the sub-unit approach. This review discusses the whole parasite vaccine strategy focusing on the blood stage of the malaria parasite, with an emphasis on recent advances and challenges in the development of killed and live attenuated vaccines. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Immunoglobulin G antibody reactivity to a group A Plasmodium falciparum erythrocyte membrane protein 1 and protection from P. falciparum malaria

    DEFF Research Database (Denmark)

    Magistrado, Pamela A; Lusingu, John; Vestergaard, Lasse S

    2007-01-01

    where P. falciparum is endemic, parasites causing severe malaria and malaria in young children with limited immunity tend to express semiconserved PfEMP1 molecules encoded by group A var genes. Here we investigated antibody responses of Tanzanians who were 0 to 19 years old to PF11_0008, a group A Pf......Variant surface antigens (VSA) on the surface of Plasmodium falciparum-infected red blood cells play a major role in the pathogenesis of malaria and are key targets for acquired immunity. The best-characterized VSA belong to the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. In areas...... of antibodies to the PF11_0008 CIDR2beta domain was associated with reduced numbers of malaria episodes. These results indicate that homologues of PF11_0008 are present in P. falciparum field isolates and suggest that PF11_0008 CIDR2beta-reactive antibodies might be involved in protection against malaria...

  8. Declining concentrations of dihydroartemisinin in plasma during 5-day oral treatment with artesunate for Falciparum malaria

    NARCIS (Netherlands)

    Khanh, N. X.; de Vries, P. J.; Ha, L. D.; van Boxtel, C. J.; Koopmans, R.; Kager, P. A.

    1999-01-01

    Six patients with uncomplicated falciparum malaria received artesunate for 5 days. Plasma concentrations of artesunate and dihydroartemisinin were determined by high-performance liquid chromatography with electrochemical detection. The concentrations of dihydroartemisinin in plasma 2 h after a dose

  9. Impact of Placental Plasmodium falciparum Malaria on Pregnancy and Perinatal Outcome in Sub-Saharan Africa

    OpenAIRE

    Uneke, Chigozie J.

    2007-01-01

    Placental malaria is one of the major features of malaria during pregnancy and has been widely used as a standard indicator to characterize malaria infection in epidemiologic investigations. Although pathogenesis of placental malaria is only partially understood, placental sequestration of Plasmodium falciparum results in the accumulation of parasitized erythrocytes in the intervillous space, infiltration by inflammatory cells, and release of pro-inflammatory mediators, which cause pathologic...

  10. Transportproteiner som drug-targets hos Plasmodium falciparum. Nye perspektiver i behandlingen af malaria

    DEFF Research Database (Denmark)

    Ellekvist, Peter; Colding, Hanne

    2006-01-01

    to identify, clone and characterise a number of these transport proteins from the parasite. Since the P. falciparum transport proteins differ from their human homologues, they may provide potential drug targets in the treatment of malaria. An example of a P. falciparum transport protein which seems promising...

  11. South American Plasmodium falciparum after the malaria eradication era: clonal population expansion and survival of the fittest hybrids.

    Directory of Open Access Journals (Sweden)

    Sean M Griffing

    Full Text Available Malaria has reemerged in many regions where once it was nearly eliminated. Yet the source of these parasites, the process of repopulation, their population structure, and dynamics are ill defined. Peru was one of malaria eradication's successes, where Plasmodium falciparum was nearly eliminated for two decades. It reemerged in the 1990s. In the new era of malaria elimination, Peruvian P. falciparum is a model of malaria reinvasion. We investigated its population structure and drug resistance profiles. We hypothesized that only populations adapted to local ecological niches could expand and repopulate and originated as vestigial populations or recent introductions. We investigated the genetic structure (using microsatellites and drug resistant genotypes of 220 parasites collected from patients immediately after peak epidemic expansion (1999-2000 from seven sites across the country. The majority of parasites could be grouped into five clonal lineages by networks and AMOVA. The distribution of clonal lineages and their drug sensitivity profiles suggested geographic structure. In 2001, artesunate combination therapy was introduced in Peru. We tested 62 parasites collected in 2006-2007 for changes in genetic structure. Clonal lineages had recombined under selection for the fittest parasites. Our findings illustrate that local adaptations in the post-eradication era have contributed to clonal lineage expansion. Within the shifting confluence of drug policy and malaria incidence, populations continue to evolve through genetic outcrossing influenced by antimalarial selection pressure. Understanding the population substructure of P. falciparum has implications for vaccine, drug, and epidemiologic studies, including monitoring malaria during and after the elimination phase.

  12. Vaccine approaches to malaria control and elimination: Insights from mathematical models.

    Science.gov (United States)

    White, Michael T; Verity, Robert; Churcher, Thomas S; Ghani, Azra C

    2015-12-22

    A licensed malaria vaccine would provide a valuable new tool for malaria control and elimination efforts. Several candidate vaccines targeting different stages of the malaria parasite's lifecycle are currently under development, with one candidate, RTS,S/AS01 for the prevention of Plasmodium falciparum infection, having recently completed Phase III trials. Predicting the public health impact of a candidate malaria vaccine requires using clinical trial data to estimate the vaccine's efficacy profile--the initial efficacy following vaccination and the pattern of waning of efficacy over time. With an estimated vaccine efficacy profile, the effects of vaccination on malaria transmission can be simulated with the aid of mathematical models. Here, we provide an overview of methods for estimating the vaccine efficacy profiles of pre-erythrocytic vaccines and transmission-blocking vaccines from clinical trial data. In the case of RTS,S/AS01, model estimates from Phase II clinical trial data indicate a bi-phasic exponential profile of efficacy against infection, with efficacy waning rapidly in the first 6 months after vaccination followed by a slower rate of waning over the next 4 years. Transmission-blocking vaccines have yet to be tested in large-scale Phase II or Phase III clinical trials so we review ongoing work investigating how a clinical trial might be designed to ensure that vaccine efficacy can be estimated with sufficient statistical power. Finally, we demonstrate how parameters estimated from clinical trials can be used to predict the impact of vaccination campaigns on malaria using a mathematical model of malaria transmission. Copyright © 2015 Elsevier Ltd. All rights reserved.

  13. Mitosis in the Human Malaria Parasite Plasmodium falciparum

    Science.gov (United States)

    Gerald, Noel; Mahajan, Babita; Kumar, Sanjai

    2011-01-01

    Malaria is caused by intraerythrocytic protozoan parasites belonging to Plasmodium spp. (phylum Apicomplexa) that produce significant morbidity and mortality, mostly in developing countries. Plasmodium parasites have a complex life cycle that includes multiple stages in anopheline mosquito vectors and vertebrate hosts. During the life cycle, the parasites undergo several cycles of extreme population growth within a brief span, and this is critical for their continued transmission and a contributing factor for their pathogenesis in the host. As with other eukaryotes, successful mitosis is an essential requirement for Plasmodium reproduction; however, some aspects of Plasmodium mitosis are quite distinct and not fully understood. In this review, we will discuss the current understanding of the architecture and key events of mitosis in Plasmodium falciparum and related parasites and compare them with the traditional mitotic events described for other eukaryotes. PMID:21317311

  14. Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial.

    Science.gov (United States)

    Alonso, Pedro L; Sacarlal, Jahit; Aponte, John J; Leach, Amanda; Macete, Eusebio; Milman, Jessica; Mandomando, Inacio; Spiessens, Bart; Guinovart, Caterina; Espasa, Mateu; Bassat, Quique; Aide, Pedro; Ofori-Anyinam, Opokua; Navia, Margarita M; Corachan, Sabine; Ceuppens, Marc; Dubois, Marie-Claude; Demoitié, Marie-Ange; Dubovsky, Filip; Menéndez, Clara; Tornieporth, Nadia; Ballou, W Ripley; Thompson, Ricardo; Cohen, Joe

    Development of an effective malaria vaccine could greatly contribute to disease control. RTS,S/AS02A is a pre-erythrocytic vaccine candidate based on Plasmodium falciparum circumsporozoite surface antigen. We aimed to assess vaccine efficacy, immunogenicity, and safety in young African children. We did a double-blind, phase IIb, randomised controlled trial in Mozambique in 2022 children aged 1-4 years. The study included two cohorts of children living in two separate areas which underwent different follow-up schemes. Participants were randomly allocated three doses of either RTS,S/AS02A candidate malaria vaccine or control vaccines. The primary endpoint, determined in cohort 1 (n=1605), was time to first clinical episode of P falciparum malaria (axillary temperature > or =37.5 degrees C and P falciparum asexual parasitaemia >2500 per microL) over a 6-month surveillance period. Efficacy for prevention of new infections was determined in cohort 2 (n=417). Analysis was per protocol. 115 children in cohort 1 and 50 in cohort 2 did not receive all three doses and were excluded from the per-protocol analysis. Vaccine efficacy for the first clinical episodes was 29.9% (95% CI 11.0-44.8; p=0.004). At the end of the 6-month observation period, prevalence of P falciparum infection was 37% lower in the RTS,S/AS02A group compared with the control group (11.9% vs 18.9%; p=0.0003). Vaccine efficacy for severe malaria was 57.7% (95% CI 16.2-80.6; p=0.019). In cohort 2, vaccine efficacy for extending time to first infection was 45.0% (31.4-55.9; pRTS,S/AS02A vaccine was safe, well tolerated, and immunogenic. Our results show development of an effective vaccine against malaria is feasible.

  15. Molecular Basis of Allele-Specific Efficacy of a Blood-Stage Malaria Vaccine: Vaccine Development Implications

    Science.gov (United States)

    Ouattara, Amed; Takala-Harrison, Shannon; Thera, Mahamadou A.; Coulibaly, Drissa; Niangaly, Amadou; Saye, Renion; Tolo, Youssouf; Dutta, Sheetij; Heppner, D. Gray; Soisson, Lorraine; Diggs, Carter L.; Vekemans, Johan; Cohen, Joe; Blackwelder, William C.; Dube, Tina; Laurens, Matthew B.; Doumbo, Ogobara K.; Plowe, Christopher V.

    2013-01-01

    The disappointing efficacy of blood-stage malaria vaccines may be explained in part by allele-specific immune responses that are directed against polymorphic epitopes on blood-stage antigens. FMP2.1/AS02A, a blood-stage candidate vaccine based on apical membrane antigen 1 (AMA1) from the 3D7 strain of Plasmodium falciparum, had allele-specific efficacy against clinical malaria in a phase II trial in Malian children. We assessed the cross-protective efficacy of the malaria vaccine and inferred which polymorphic amino acid positions in AMA1 were the targets of protective allele-specific immune responses. FMP2.1/AS02A had the highest efficacy against AMA1 alleles that were identical to the 3D7 vaccine-type allele at 8 highly polymorphic amino acid positions in the cluster 1 loop (c1L) but differed from 3D7 elsewhere in the molecule. Comparison of the incidence of vaccine-type alleles before and after vaccination in the malaria vaccine and control groups and examination of the patterns of allele change at polymorphic positions in consecutive malaria episodes suggest that the highly polymorphic amino acid position 197 in c1L was the most critical determinant of allele-specific efficacy. These results indicate that a multivalent AMA1 vaccine with broad efficacy could include only a limited set of key alleles of this extremely polymorphic antigen. PMID:23204168

  16. Levels of antibody to conserved parts of Plasmodium falciparum merozoite surface protein 1 in Ghanaian children are not associated with protection from clinical malaria

    DEFF Research Database (Denmark)

    Dodoo, D; Theander, T G; Kurtzhals, J A

    1999-01-01

    The 19-kDa conserved C-terminal part of the Plasmodium falciparum merozoite surface protein 1 (PfMSP119) is a malaria vaccine candidate antigen, and human antibody responses to PfMSP119 have been associated with protection against clinical malaria. In this longitudinal study carried out in an area...... of stable but seasonal malaria transmission with an estimated parasite inoculation of about 20 infective bites/year, we monitored 266 3- to 15-year-old Ghanaian children clinically and parasitologically over a period of 18 months. Blood samples were collected at the beginning of the study before the major...

  17. A plant-produced Pfs230 vaccine candidate blocks transmission of Plasmodium falciparum.

    Science.gov (United States)

    Farrance, Christine E; Rhee, Amy; Jones, R Mark; Musiychuk, Konstantin; Shamloul, Moneim; Sharma, Satish; Mett, Vadim; Chichester, Jessica A; Streatfield, Stephen J; Roeffen, Will; van de Vegte-Bolmer, Marga; Sauerwein, Robert W; Tsuboi, Takafumi; Muratova, Olga V; Wu, Yimin; Yusibov, Vidadi

    2011-08-01

    Plasmodium falciparum is transmitted to a new host after completing its sexual cycle within a mosquito. Developing vaccines against the parasite sexual stages is a critical component in the fight against malaria. We are targeting multiple proteins of P. falciparum which are found only on the surfaces of the sexual forms of the parasite and where antibodies against these proteins have been shown to block the progression of the parasite's life cycle in the mosquito and thus block transmission to the next human host. We have successfully produced a region of the Pfs230 antigen in our plant-based transient-expression system and evaluated this vaccine candidate in an animal model. This plant-produced protein, 230CMB, is expressed at approximately 800 mg/kg in fresh whole leaf tissue and is 100% soluble. Administration of 230CMB with >90% purity induces strong immune responses in rabbits with high titers of transmission-blocking antibodies, resulting in a greater than 99% reduction in oocyst counts in the presence of complement, as determined by a standard membrane feeding assay. Our data provide a clear perspective on the clinical development of a Pfs230-based transmission-blocking malaria vaccine.

  18. Protease-associated cellular networks in malaria parasite Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Lilburn Timothy G

    2011-12-01

    Full Text Available Abstract Background Malaria continues to be one of the most severe global infectious diseases, responsible for 1-2 million deaths yearly. The rapid evolution and spread of drug resistance in parasites has led to an urgent need for the development of novel antimalarial targets. Proteases are a group of enzymes that play essential roles in parasite growth and invasion. The possibility of designing specific inhibitors for proteases makes them promising drug targets. Previously, combining a comparative genomics approach and a machine learning approach, we identified the complement of proteases (degradome in the malaria parasite Plasmodium falciparum and its sibling species 123, providing a catalog of targets for functional characterization and rational inhibitor design. Network analysis represents another route to revealing the role of proteins in the biology of parasites and we use this approach here to expand our understanding of the systems involving the proteases of P. falciparum. Results We investigated the roles of proteases in the parasite life cycle by constructing a network using protein-protein association data from the STRING database 4, and analyzing these data, in conjunction with the data from protein-protein interaction assays using the yeast 2-hybrid (Y2H system 5, blood stage microarray experiments 678, proteomics 9101112, literature text mining, and sequence homology analysis. Seventy-seven (77 out of 124 predicted proteases were associated with at least one other protein, constituting 2,431 protein-protein interactions (PPIs. These proteases appear to play diverse roles in metabolism, cell cycle regulation, invasion and infection. Their degrees of connectivity (i.e., connections to other proteins, range from one to 143. The largest protease-associated sub-network is the ubiquitin-proteasome system which is crucial for protein recycling and stress response. Proteases are also implicated in heat shock response, signal peptide

  19. Dihydroartemisinin-piperaquine for treating uncomplicated Plasmodium falciparum malaria

    Science.gov (United States)

    Zani, Babalwa; Gathu, Michael; Donegan, Sarah; Olliaro, Piero L; Sinclair, David

    2014-01-01

    Background The World Health Organization (WHO) recommends Artemisinin-based Combination Therapy (ACT) for treating uncomplicated Plasmodium falciparum malaria. This review aims to assist the decision-making of malaria control programmes by providing an overview of the relative effects of dihydroartemisinin-piperaquine (DHA-P) versus other recommended ACTs. Objectives To evaluate the effectiveness and safety of DHA-P compared to other ACTs for treating uncomplicated P. falciparum malaria in adults and children. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL) published in The Cochrane Library; MEDLINE; EMBASE; LILACS, and the metaRegister of Controlled Trials (mRCT) up to July 2013. Selection criteria Randomized controlled trials comparing a three-day course of DHA-P to a three-day course of an alternative WHO recommended ACT in uncomplicated P. falciparum malaria. Data collection and analysis Two authors independently assessed trials for eligibility and risk of bias, and extracted data. We analysed primary outcomes in line with the WHO 'Protocol for assessing and monitoring antimalarial drug efficacy’ and compared drugs using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were effects on gametocytes, haemoglobin, and adverse events. We assessed the quality of evidence using the GRADE approach. Main results We included 27 trials, enrolling 16,382 adults and children, and conducted between 2002 and 2010. Most trials excluded infants aged less than six months and pregnant women. DHA-P versus artemether-lumefantrine In Africa, over 28 days follow-up, DHA-P is superior to artemether-lumefantrine at preventing further parasitaemia (PCR-unadjusted treatment failure: RR 0.34, 95% CI 0.30 to 0.39, nine trials, 6200 participants, high quality evidence), and although PCR-adjusted treatment failure was below 5% for both ACTs, it was consistently lower

  20. N-ACETYLCYSTEINE IN SEVERE FALCIPARUM MALARIA IN THAILAND

    Science.gov (United States)

    Treeprasertsuk, Sombat; Krudsood, Srivicha; Tosukhowong, Thanawat; Maek-A-Nantawat, Wirach; Vannaphan, Suparp; Saengnetswang, Tosaporn; Looareesuwan, Sornchai; Kuhn, Walter F; Brittenham, Gary; Carroll, James

    2011-01-01

    One hundred and eight patients with severe falciparum malaria underwent a placebo controlled trial with the antioxidant, N-acetylcysteine (NAC), as an adjunctive therapy along with standard intravenous artesunate therapy. Three NAC dosage regimens were used: an intravenous loading dose of 140 mg/kg followed by 70 mg/kg every four hours intravenously for up to 18 doses (Group 1); a single intravenous loading dose followed by oral NAC in the same amount as for Group 1 (Group 2); a regimen identical to Group 1 except that oral NAC was administered after the first 24 hours (Group 3). Fifty-four patients received placebo plus artesunate. Two critically ill patients died in Group 1. No patient sustained an adverse reaction to the NAC other than vomiting, and the deaths were attributed to severe disease with multiple organ involvement. The excellent results with NAC, the lack of adverse effects, and the rationale for NAC benefit supports the need for a large, double blind trial of NAC as an adjunctive therapy for severe malaria. PMID:12971512

  1. Optimal control for Malaria disease through vaccination

    Science.gov (United States)

    Munzir, Said; Nasir, Muhammad; Ramli, Marwan

    2018-01-01

    Malaria is a disease caused by an amoeba (single-celled animal) type of plasmodium where anopheles mosquito serves as the carrier. This study examines the optimal control problem of malaria disease spread based on Aron and May (1982) SIR type models and seeks the optimal solution by minimizing the prevention of the spreading of malaria by vaccine. The aim is to investigate optimal control strategies on preventing the spread of malaria by vaccination. The problem in this research is solved using analytical approach. The analytical method uses the Pontryagin Minimum Principle with the symbolic help of MATLAB software to obtain optimal control result and to analyse the spread of malaria with vaccination control.

  2. The ¿/d T-cell response to Plasmodium falciparum malaria in a population in which malaria is endemic

    DEFF Research Database (Denmark)

    Hviid, L; Kurtzhals, J A; Dodoo, D

    1996-01-01

    Frequencies and absolute numbers of peripheral gamma/delta T cells have been reported to increase after episodes of Plasmodium falciparum malaria in adults with limited or no previous malaria exposure. In contrast, little is known about the gamma/delta T-cell response to malaria in children from...... areas where malaria is endemic, who bear the burden of malaria-related morbidity and mortality. We investigated the gamma/delta T-cell response in 19 Ghanaian children from an area of hyperendemic, seasonal malaria transmission. The children presented with cerebral malaria (n = 7), severe malarial...... anemia (n = 5), or uncomplicated malaria (n = 7) and were monitored from admission until 4 weeks later. We found no evidence of increased frequencies of gamma/delta T cells in any of the patient groups, whereas one adult expatriate studied in Ghana and three adults admitted to the hospital in Copenhagen...

  3. Status of vaccine research and development of vaccines for malaria.

    Science.gov (United States)

    Birkett, Ashley J

    2016-06-03

    Despite recent progress in reducing deaths attributable to malaria, it continues to claim approximately 500,000 lives per year and is associated with approximately 200 million infections. New tools, including safe and effective vaccines, are needed to ensure that the gains of the last 15 years are leveraged toward achieving the ultimate goal of malaria parasite eradication. In 2015, the European Medicines Agency announced the adoption of a positive opinion for the malaria vaccine candidate most advanced in development, RTS,S/AS01, which provides modest protection against clinical malaria; in early 2016, WHO recommended large-scale pilot implementations of RTS,S in settings of moderate-to-high malaria transmission. In alignment with these advancements, the community goals and preferred product characteristics for next-generation vaccines have been updated to inform the development of vaccines that are highly efficacious in preventing clinical malaria, and those needed to accelerate parasite elimination. Next-generation vaccines, targeting all stages of the parasite lifecycle, are in early-stage development with the most advanced in Phase 2 trials. Importantly, progress is being made in the definition of feasible regulatory pathways to accelerate timelines, including for vaccines designed to interrupt transmission of parasites from humans to mosquitoes. The continued absence of financially lucrative, high-income markets to drive investment in malaria vaccine development points to continued heavy reliance on public and philanthropic funding. Copyright © 2016 World Health Organization. Published by Elsevier Ltd.. All rights reserved.

  4. Quinine pharmacokinetics: ototoxic and cardiotoxic effects in healthy Caucasian subjects and in patients with falciparum malaria

    NARCIS (Netherlands)

    Claessen, F. A.; van Boxtel, C. J.; Perenboom, R. M.; Tange, R. A.; Wetsteijn, J. C.; Kager, P. A.

    1998-01-01

    To study the pharmacokinetic behaviour of quinine in Caucasians with and without malaria. Quinine-dihydrochloride was administered intravenously as a single dose of 300 mg to 12 healthy subjects and as multiple doses of 600 mg in 4 h every 8 h in 10 patients with falciparum malaria. Plasma quinine

  5. Chronic Plasmodium falciparum infections in an area of low intensity malaria transmission in the Sudan

    DEFF Research Database (Denmark)

    Hamad, A A; El Hassan, I M; El Khalifa, A A

    2000-01-01

    the October-December malaria season of 1996, 51 individuals out of a population of 420 had confirmed and treated P. falciparum malaria in the village of Daraweesh in eastern Sudan. In a cross-sectional survey carried out in December 1996, an additional 6 individuals were found to harbour a microscopically...

  6. Lung uptake of /sup 99m/Tc--sulfur colloid in falciparum malaria: case report

    Energy Technology Data Exchange (ETDEWEB)

    Ziessman, H.A.

    1976-09-01

    Increased lung uptake of /sup 99m/Tc-sulfur colloid was seen during liver scanning in a patient with falciparum malaria. This finding was due to the enhanced activity of the phagocytic cells of the reticuloendothelial system in the liver, spleen, and lung found in human and experimental malaria. Similar findings in other clinical situations and the relevant literature are reviewed.

  7. ABO blood group phenotypes and Plasmodium falciparum malaria: unlocking a pivotal mechanism

    NARCIS (Netherlands)

    Loscertales, María-Paz; Owens, Stephen; O'Donnell, James; Bunn, James; Bosch-Capblanch, Xavier; Brabin, Bernard J.

    2007-01-01

    Host susceptibility to Plasmodium falciparum infection is central for improved understanding of malaria in human populations. Red blood cell (RBC) polymorphisms have been proposed as factors associated with malaria infection or its severity, although no systematic appraisal of ABO phenotypes and

  8. European Vaccine Initiative: lessons from developing malaria vaccines.

    Science.gov (United States)

    Geels, Mark J; Imoukhuede, Egeruan B; Imbault, Nathalie; van Schooten, Harry; McWade, Terry; Troye-Blomberg, Marita; Dobbelaer, Roland; Craig, Alister G; Leroy, Odile

    2011-12-01

    For over 10 years, the European Vaccine Initiative (EVI; European Malaria Vaccine Initiative until 2009) has contributed to the development of 24 malaria candidate vaccine antigens with 13 vaccine candidates being advanced into Phase I clinical trials, two of which have been transitioned for further clinical development in sub-Saharan Africa. Since its inception the EVI organization has operated as a funding agency, but with a clear service-oriented strategy. The scientific successes and difficulties encountered during these years and how these efforts have led to standardization and harmonization in vaccine development through large-scale European consortia are discussed. In the future, the EVI will remain instrumental in the pharmaceutical and clinical development of vaccines against 'diseases of poverty' with a continued focus on malaria. EVI will continue to focus on funding and managing preclinical evaluation up to Phase I/II clinical trials and strengthening the vaccine-development infrastructure in Europe, albeit with a global orientation.

  9. Dynamics of polymorphism in a malaria vaccine antigen at a vaccine-testing site in Mali.

    Directory of Open Access Journals (Sweden)

    Shannon L Takala

    2007-03-01

    Full Text Available Malaria vaccines based on the 19-kDa region of merozoite surface protein 1 (MSP-1(19 derived from the 3D7 strain of Plasmodium falciparum are being tested in clinical trials in Africa. Knowledge of the distribution and natural dynamics of vaccine antigen polymorphisms in populations in which malaria vaccines will be tested will guide vaccine design and permit distinction between natural fluctuations in genetic diversity and vaccine-induced selection.Using pyrosequencing, six single-nucleotide polymorphisms in the nucleotide sequence encoding MSP-1(19 were genotyped from 1,363 malaria infections experienced by 100 children who participated in a prospective cohort study in Mali from 1999 to 2001. The frequencies of 14 MSP-1(19 haplotypes were compared over the course of the malaria transmission season for all three years, in three age groups, and in consecutive infections within individuals. While the frequency of individual MSP-1(19 haplotypes fluctuated, haplotypes corresponding to FVO and FUP strains of P. falciparum (MSP-1(19 haplotypes QKSNGL and EKSNGL, respectively were most prevalent during three consecutive years and in all age groups with overall prevalences of 46% (95% confidence interval [CI] 44%-49% and 36% (95% CI 34%-39%, respectively. The 3D7 haplotype had a lower overall prevalence of 16% (95% CI 14%-18%. Multiplicity of infection based on MSP-1(19 was higher at the beginning of the transmission season and in the oldest individuals (aged > or =11 y. Three MSP-1(19 haplotypes had a reduced frequency in symptomatic infections compared to asymptomatic infections. Analyses of the dynamics of MSP-1(19 polymorphisms in consecutive infections implicate three polymorphisms (at positions 1691, 1700, and 1701 as being particularly important in determining allele specificity of anti-MSP-1(19 immunity.Parasites with MSP-1(19 haplotypes different from that of the leading vaccine strain were consistently the most prevalent at a vaccine trial

  10. Unexpected fold in the circumsporozoite protein target of malaria vaccines

    Energy Technology Data Exchange (ETDEWEB)

    Doud, Michael B.; Koksal, Adem C.; Mi, Li-Zhi; Song, Gaojie; Lu, Chafen; Springer, Timothy A. (Harvard-Med)

    2012-10-09

    Circumsporozoite (CS) protein is the major surface component of Plasmodium falciparum sporozoites and is essential for host cell invasion. A vaccine containing tandem repeats, region III, and thrombospondin type-I repeat (TSR) of CS is efficacious in phase III trials but gives only a 35% reduction in severe malaria in the first year postimmunization. We solved crystal structures showing that region III and TSR fold into a single unit, an '{alpha}TSR' domain. The {alpha}TSR domain possesses a hydrophobic pocket and core, missing in TSR domains. CS binds heparin, but {alpha}TSR does not. Interestingly, polymorphic T-cell epitopes map to specialized {alpha}TSR regions. The N and C termini are unexpectedly close, providing clues for sporozoite sheath organization. Elucidation of a unique structure of a domain within CS enables rational design of next-generation subunit vaccines and functional and medicinal chemical investigation of the conserved hydrophobic pocket.

  11. P. falciparum malaria prevalence among blood donors in Bamako, Mali.

    Science.gov (United States)

    Kouriba, B; Diarra, A B; Douyon, I; Diabaté, D T; Kamissoko, F; Guitteye, H; Baby, M; Guindo, M A; Doumbo, O K

    2017-06-01

    Malaria parasite is usually transmitted to humans by Anopheles mosquitoes but it can also be transmitted through blood transfusion. Usually malaria transmission is low in African urban settings. In West Africa where the P. falciparum is the most predominant malaria species, there are limited measures to reduce the risk of blood transfusion malaria. The aim of this study was to evaluate the prevalence of P. falciparum malaria carriage among blood donors in the National Blood Center of Bamako, capital city of Mali. The study was conducted using a random sample of 946 blood donors in Bamako, Mali, from January to December 2011. Screening for malaria was performed by thick smear and rapid diagnostic test (RDT). Blood group was typed by Beth-Vincent and Simonin techniques. The frequency of malaria infection was 1.4% by thick smear and 0.8% by the RDT. The pick prevalence of P. falciparum malaria was in rainy season, indicating a probable high seasonal risk of malaria by blood transfusion, in Mali. The prevalence of P. falciparum infection was 2% among donors of group O the majority being in this group. There is a seasonal prevalence of malaria among blood donors in Bamako. A prevention strategy of transfusion malaria based on the combination of selection of blood donors through the medical interview, promoting a voluntary low-risk blood donation and screening all blood bags intended to be transfused to children under 5, pregnant women and immune-compromised patients during transmission season using thick smear will reduce the risk of transfusion malaria in Mali. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  12. Humanized HLA-DR4.RagKO.IL2RγcKO.NOD (DRAG) mice sustain the complex vertebrate life cycle of Plasmodium falciparum malaria.

    Science.gov (United States)

    Wijayalath, Wathsala; Majji, Sai; Villasante, Eileen F; Brumeanu, Teodor D; Richie, Thomas L; Casares, Sofia

    2014-09-30

    Malaria is a deadly infectious disease affecting millions of people in tropical and sub-tropical countries. Among the five species of Plasmodium parasites that infect humans, Plasmodium falciparum accounts for the highest morbidity and mortality associated with malaria. Since humans are the only natural hosts for P. falciparum, the lack of convenient animal models has hindered the understanding of disease pathogenesis and prompted the need of testing anti-malarial drugs and vaccines directly in human trials. Humanized mice hosting human cells represent new pre-clinical models for infectious diseases that affect only humans. In this study, the ability of human-immune-system humanized HLA-DR4.RagKO.IL2RγcKO.NOD (DRAG) mice to sustain infection with P. falciparum was explored. Four week-old DRAG mice were infused with HLA-matched human haematopoietic stem cells (HSC) and examined for reconstitution of human liver cells and erythrocytes. Upon challenge with infectious P. falciparum sporozoites (NF54 strain) humanized DRAG mice were examined for liver stage infection, blood stage infection, and transmission to Anopheles stephensi mosquitoes. Humanized DRAG mice reconstituted human hepatocytes, Kupffer cells, liver endothelial cells, and erythrocytes. Upon intravenous challenge with P. falciparum sporozoites, DRAG mice sustained liver to blood stage infection (average 3-5 parasites/microlitre blood) and allowed transmission to An. stephensi mosquitoes. Infected DRAG mice elicited antibody and cellular responses to the blood stage parasites and self-cured the infection by day 45 post-challenge. DRAG mice represent the first human-immune-system humanized mouse model that sustains the complex vertebrate life cycle of P. falciparum without the need of exogenous injection of human hepatocytes/erythrocytes or P. falciparum parasite adaptation. The ability of DRAG mice to elicit specific human immune responses to P. falciparum parasites may help deciphering immune correlates

  13. Comparative population structure of Plasmodium malariae and Plasmodium falciparum under different transmission settings in Malawi

    Directory of Open Access Journals (Sweden)

    Molyneux Malcolm E

    2011-02-01

    Full Text Available Abstract Background Described here is the first population genetic study of Plasmodium malariae, the causative agent of quartan malaria. Although not as deadly as Plasmodium falciparum, P. malariae is more common than previously thought, and is frequently in sympatry and co-infection with P. falciparum, making its study increasingly important. This study compares the population parameters of the two species in two districts of Malawi with different malaria transmission patterns - one seasonal, one perennial - to explore the effects of transmission on population structures. Methods Six species-specific microsatellite markers were used to analyse 257 P. malariae samples and 257 P. falciparum samples matched for age, gender and village of residence. Allele sizes were scored to within 2 bp for each locus and haplotypes were constructed from dominant alleles in multiple infections. Analysis of multiplicity of infection (MOI, population differentiation, clustering of haplotypes and linkage disequilibrium was performed for both species. Regression analyses were used to determine association of MOI measurements with clinical malaria parameters. Results Multiple-genotype infections within each species were common in both districts, accounting for 86.0% of P. falciparum and 73.2% of P. malariae infections and did not differ significantly with transmission setting. Mean MOI of P. falciparum was increased under perennial transmission compared with seasonal (3.14 vs 2.59, p = 0.008 and was greater in children compared with adults. In contrast, P. malariae mean MOI was similar between transmission settings (2.12 vs 2.11 and there was no difference between children and adults. Population differentiation showed no significant differences between villages or districts for either species. There was no evidence of geographical clustering of haplotypes. Linkage disequilibrium amongst loci was found only for P. falciparum samples from the seasonal transmission

  14. Relative Susceptibilities of ABO Blood Groups to Plasmodium falciparum Malaria in Ghana.

    Science.gov (United States)

    Afoakwah, Richmond; Aubyn, Edmond; Prah, James; Nwaefuna, Ekene Kwabena; Boampong, Johnson N

    2016-01-01

    The clinical outcome of falciparum malaria in endemic areas is influenced by erythrocyte polymorphisms including the ABO blood groups. Studies have reported association of ABO blood group to resistance, susceptibility, and severity of P. falciparum malaria infection. Individuals with blood group "A" have been found to be highly susceptible to falciparum malaria whereas blood group "O" is said to confer protection against complicated cases. We analyzed samples from 293 young children less than six years old with malaria in the Korle-Bu Teaching Hospital in Accra, Ghana. It was observed that group O was present in about 16.1% of complicated cases weighed against 40.9% of uncomplicated controls. Individuals with complicated malaria were about twice likely to be of blood groups A and B compared to group O (A versus O, OR = 1.90, 95% CI = 1.59-2.26, P Blood group O participants with complicated diseases had low parasitaemia compared to the other blood groups (P blood group O individuals a survival advantage over the other groups in complicated malaria as suggested. Participants with complicated falciparum malaria were generally anaemic and younger than those with uncomplicated disease.

  15. Plasmodium falciparum-induced severe malaria with acute kidney injury and jaundice: a case report

    Science.gov (United States)

    Baswin, A.; Siregar, M. L.; Jamil, K. F.

    2018-03-01

    P. falciparum-induced severe malaria with life-threatening complications like acute kidney injury (AKI), jaundice, cerebral malaria, severe anemia, acidosis, and acute respiratory distress syndrome (ARDS). A 31-year-old soldier man who works in Aceh Singkil, Indonesia which is an endemic malaria area presented with a paroxysm of fever, shaking chills and sweats over four days, headache, arthralgia, abdominal pain, pale, jaundice, and oliguria. Urinalysis showed hemoglobinuria. Blood examination showed hemolytic anemia, thrombocytopenia, and hyperbilirubinemia. Falciparum malaria was then confirmed by peripheral blood smear, antimalarial medications were initiated, and hemodialysis was performed for eight times. The patient’s condition and laboratory results were quickly normalized. We report a case of P. falciparum-induced severe malaria with AKI and jaundice. The present case suggests that P. falciparum may induce severe malaria with life-threatening complications, early diagnosis and treatment is important to improve the quality of life of patients. Physicians must be alert for correct diagnosis and proper management of imported tropical malaria when patients have travel history in endemic areas.

  16. Relative Susceptibilities of ABO Blood Groups to Plasmodium falciparum Malaria in Ghana

    Directory of Open Access Journals (Sweden)

    Richmond Afoakwah

    2016-01-01

    Full Text Available The clinical outcome of falciparum malaria in endemic areas is influenced by erythrocyte polymorphisms including the ABO blood groups. Studies have reported association of ABO blood group to resistance, susceptibility, and severity of P. falciparum malaria infection. Individuals with blood group “A” have been found to be highly susceptible to falciparum malaria whereas blood group “O” is said to confer protection against complicated cases. We analyzed samples from 293 young children less than six years old with malaria in the Korle-Bu Teaching Hospital in Accra, Ghana. It was observed that group O was present in about 16.1% of complicated cases weighed against 40.9% of uncomplicated controls. Individuals with complicated malaria were about twice likely to be of blood groups A and B compared to group O (A versus O, OR = 1.90, 95% CI = 1.59–2.26, P<0.0001; B versus O, OR = 1.82. 95% CI = 1.57–2.23, P<0.0001. Blood group O participants with complicated diseases had low parasitaemia compared to the other blood groups (P<0.0001. This may give blood group O individuals a survival advantage over the other groups in complicated malaria as suggested. Participants with complicated falciparum malaria were generally anaemic and younger than those with uncomplicated disease.

  17. Acute P. falciparum malaria induces a loss of CD28- T IFN-¿ producing cells

    DEFF Research Database (Denmark)

    Kemp, Kåre; Akanmori, Bartholomew D; Kurtzhals, Jørgen A L

    2002-01-01

    P. falciparum malaria is associated with increased activation among peripheral lymphocytes. In the present study, we investigated markers of susceptibility to apoptosis and expression of IFN-gamma and IL-4 by CD28-and CD28+T cells in West African children with acute P. falciparum malaria. The stu...... are sequestered away from the peripheral blood during P. falciparum malaria....

  18. Malaria case clinical profiles and Plasmodium falciparum parasite genetic diversity: a cross sectional survey at two sites of different malaria transmission intensities in Rwanda

    NARCIS (Netherlands)

    Kateera, Fredrick; Nsobya, Sam L.; Tukwasibwe, Stephen; Mens, Petra F.; Hakizimana, Emmanuel; Grobusch, Martin P.; Mutesa, Leon; Kumar, Nirbhay; van Vugt, Michele

    2016-01-01

    Malaria remains a public health challenge in sub-Saharan Africa with Plasmodium falciparum being the principal cause of malaria disease morbidity and mortality. Plasmodium falciparum virulence is attributed, in part, to its population-level genetic diversity-a characteristic that has yet to be

  19. Increasing incidence of Plasmodium knowlesi malaria following control of P. falciparum and P. vivax Malaria in Sabah, Malaysia.

    Science.gov (United States)

    William, Timothy; Rahman, Hasan A; Jelip, Jenarun; Ibrahim, Mohammad Y; Menon, Jayaram; Grigg, Matthew J; Yeo, Tsin W; Anstey, Nicholas M; Barber, Bridget E

    2013-01-01

    The simian parasite Plasmodium knowlesi is a common cause of human malaria in Malaysian Borneo and threatens the prospect of malaria elimination. However, little is known about the emergence of P. knowlesi, particularly in Sabah. We reviewed Sabah Department of Health records to investigate the trend of each malaria species over time. Reporting of microscopy-diagnosed malaria cases in Sabah is mandatory. We reviewed all available Department of Health malaria notification records from 1992-2011. Notifications of P. malariae and P. knowlesi were considered as a single group due to microscopic near-identity. From 1992-2011 total malaria notifications decreased dramatically, with P. falciparum peaking at 33,153 in 1994 and decreasing 55-fold to 605 in 2011, and P. vivax peaking at 15,857 in 1995 and decreasing 25-fold to 628 in 2011. Notifications of P. malariae/P. knowlesi also demonstrated a peak in the mid-1990s (614 in 1994) before decreasing to ≈ 100/year in the late 1990s/early 2000s. However, P. malariae/P. knowlesi notifications increased >10-fold between 2004 (n = 59) and 2011 (n = 703). In 1992 P. falciparum, P. vivax and P. malariae/P. knowlesi monoinfections accounted for 70%, 24% and 1% respectively of malaria notifications, compared to 30%, 31% and 35% in 2011. The increase in P. malariae/P. knowlesi notifications occurred state-wide, appearing to have begun in the southwest and progressed north-easterly. A significant recent increase has occurred in P. knowlesi notifications following reduced transmission of the human Plasmodium species, and this trend threatens malaria elimination. Determination of transmission dynamics and risk factors for knowlesi malaria is required to guide measures to control this rising incidence.

  20. Plasmodium falciparum erythrocyte membrane protein 1 domain cassettes 8 and 13 are associated with severe malaria in children

    DEFF Research Database (Denmark)

    Lavstsen, Thomas; Turner, Louise; Saguti, Fredy

    2012-01-01

    The clinical outcome of Plasmodium falciparum infections ranges from asymptomatic parasitemia to severe malaria syndromes associated with high mortality. The virulence of P. falciparum infections is associated with the type of P. falciparum erythrocyte membrane protein 1 (PfEMP1) expressed on the...

  1. Plasmodium falciparum associated with severe childhood malaria preferentially expresses PfEMP1 encoded by group A var genes.

    NARCIS (Netherlands)

    Jensen, A.; Magistrado, P.; Sharp, S.; Joergensen, L.; Lavstsen, T.; Chiucchiuini, A.; Salanti, A.; Vestergaard, L.S.; Lusingu, J.P.; Hermsen, R.; Sauerwein, R.W.; Christensen, J.; Nielsen, M.A.; Hviid, L.; Sutherland, C.J.; Staalsoe, T.; Theander, T.G.

    2004-01-01

    Parasite-encoded variant surface antigens (VSAs) like the var gene-encoded Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family are responsible for antigenic variation and infected red blood cell (RBC) cytoadhesion in P. falciparum malaria. Parasites causing severe malaria in

  2. Seasonal vaccination against malaria: a potential use for an imperfect malaria vaccine.

    Science.gov (United States)

    Greenwood, Brian; Dicko, Alassane; Sagara, Issaka; Zongo, Issaka; Tinto, Halidou; Cairns, Matthew; Kuepfer, Irene; Milligan, Paul; Ouedraogo, Jean-Bosco; Doumbo, Ogobara; Chandramohan, Daniel

    2017-05-02

    In many parts of the African Sahel and sub-Sahel, where malaria remains a major cause of mortality and morbidity, transmission of the infection is highly seasonal. Seasonal malaria chemoprevention (SMC), which involves administration of a full course of malaria treatment to young children at monthly intervals during the high transmission season, is proving to be an effective malaria control measure in these areas. However, SMC does not provide complete protection and it is demanding to deliver for both families and healthcare givers. Furthermore, there is a risk of the emergence in the future of resistance to the drugs, sulfadoxine-pyrimethamine and amodiaquine, that are currently being used for SMC. Substantial progress has been made in the development of malaria vaccines during the past decade and one malaria vaccine, RTS,S/AS01, has received a positive opinion from the European Medicines Authority and will soon be deployed in large-scale, pilot implementation projects in sub-Saharan Africa. A characteristic feature of this vaccine, and potentially of some of the other malaria vaccines under development, is that they provide a high level of efficacy during the period immediately after vaccination, but that this wanes rapidly, perhaps because it is difficult to develop effective immunological memory to malaria antigens in subjects exposed previously to malaria infection. A potentially effective way of using malaria vaccines with high initial efficacy but which provide only a short period of protection could be annual, mass vaccination campaigns shortly before each malaria transmission season in areas where malaria transmission is confined largely to a few months of the year.

  3. Enhancing Malaria Vaccine Development by the Naval Medical Research Center

    National Research Council Canada - National Science Library

    Hile, David

    2001-01-01

    A priority of DoD is to develop effective vaccines for preventing malaria. Developing malaria vaccines is complicated by the complexity of the parasite and of the human host's response to the infection...

  4. A phase 2b randomized, controlled trial of the efficacy of the GMZ2 malaria vaccine in African children

    DEFF Research Database (Denmark)

    Sirima, Sodiomon B; Mordmüller, Benjamin; Milligan, Paul

    2016-01-01

    BACKGROUND: GMZ2 is a recombinant protein malaria vaccine, comprising two blood-stage antigens of Plasmodium falciparum, glutamate-rich protein and merozoite surface protein 3. We assessed efficacy of GMZ2 in children in Burkina Faso, Gabon, Ghana and Uganda. METHODS: Children 12-60months old wer...

  5. Septic Shock due to Cytomegalovirus Infection in Acute Respiratory Distress Syndrome after Falciparum Malaria.

    Science.gov (United States)

    Harbarth; Meyer; Grau; Loutan; Ricou

    1997-09-01

    Incidence of falciparum malaria in developed countries has increased in recent years due to tourism to tropical countries and immigration from Asia and Africa. In Switzerland, about 250 cases of malaria were reported in 1994 to the Federal Office of Health, including three cases with fatal outcome.1 The most commonly described complications of plasmodia infection are cerebral malaria, acute renal failure, and severe anemia with disseminated intravascular coagulation. However, pulmonary involvement occurs in 3 to 10% of cases and represents the most serious complication of this infection, with a lethality of 70%.2,3 Furthermore, a pronounced general immunosuppression has been reported in malaria patients, which may predispose them to opportunistic infections.4 We report a case of Plasmodium falciparum infection complicated by severe acute respiratory distress syndrome (ARDS) with development of systemic cytomegalovirus (CMV) infection leading to death. This evolution implies a severe immune deficiency associated with malaria, as previously suggested in the literature.

  6. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria

    Science.gov (United States)

    Ariey, Frédéric; Witkowski, Benoit; Amaratunga, Chanaki; Beghain, Johann; Langlois, Anne-Claire; Khim, Nimol; Kim, Saorin; Duru, Valentine; Bouchier, Christiane; Ma, Laurence; Lim, Pharath; Leang, Rithea; Duong, Socheat; Sreng, Sokunthea; Suon, Seila; Chuor, Char Meng; Bout, Denis Mey; Ménard, Sandie; Rogers, William O.; Genton, Blaise; Fandeur, Thierry; Miotto, Olivo; Ringwald, Pascal; Le Bras, Jacques; Berry, Antoine; Barale, Jean-Christophe; Fairhurst, Rick M.; Benoit-Vical, Françoise; Mercereau-Puijalon, Odile; Ménard, Didier

    2016-01-01

    Plasmodium falciparum resistance to artemisinin derivatives in southeast Asia threatens malaria control and elimination activities worldwide. To monitor the spread of artemisinin resistance, a molecular marker is urgently needed. Here, using whole-genome sequencing of an artemisinin-resistant parasite line from Africa and clinical parasite isolates from Cambodia, we associate mutations in the PF3D7_1343700 kelch propeller domain (‘K13-propeller’) with artemisinin resistance in vitro and in vivo. Mutant K13-propeller alleles cluster in Cambodian provinces where resistance is prevalent, and the increasing frequency of a dominant mutant K13-propeller allele correlates with the recent spread of resistance in western Cambodia. Strong correlations between the presence of a mutant allele, in vitro parasite survival rates and in vivo parasite clearance rates indicate that K13-propeller mutations are important determinants of artemisinin resistance. K13-propeller polymorphism constitutes a useful molecular marker for large-scale surveillance efforts to contain artemisinin resistance in the Greater Mekong Subregion and prevent its global spread. PMID:24352242

  7. Multiplication rate variation in the human malaria parasite Plasmodium falciparum.

    Science.gov (United States)

    Murray, Lee; Stewart, Lindsay B; Tarr, Sarah J; Ahouidi, Ambroise D; Diakite, Mahamadou; Amambua-Ngwa, Alfred; Conway, David J

    2017-07-25

    It is important to understand intrinsic variation in asexual blood stage multiplication rates of the most virulent human malaria parasite, Plasmodium falciparum. Here, multiplication rates of long-term laboratory adapted parasite clones and new clinical isolates were measured, using a newly standardised assay of growth from low starting density in replicate parallel cultures with erythrocytes from multiple different donors, across multiple cycles. Multiplication rates of long-term established clones were between 7.6 and 10.5 fold per 48 hours, with clone Dd2 having a higher rate than others (clones 3D7, HB3 and D10). Parasite clone-specific growth was then analysed in co-culture assays with all possible heterologous pairwise combinations. This showed that co-culture of different parasites did not affect their replication rates, indicating that there were no suppressive interactions operating between parasites. Multiplication rates of eleven new clinical isolates were measured after a few weeks of culture, and showed a spectrum of replication rates between 2.3 and 6.0 fold per 48 hours, the entire range being lower than for the long-term laboratory adapted clones. Multiplication rate estimates remained stable over time for several isolates tested repeatedly up to three months after culture initiation, indicating considerable persistence of this important trait variation.

  8. Review Article: Vaccine for Malaria – How Far? | Oyeyinka | African ...

    African Journals Online (AJOL)

    This is a review of the progress made so far in the effort to produce a malaria vaccine. The problems that have made it impossible to get an effective vaccine for malaria are discussed. Also examined are the current efforts to produce the vaccine and the prospects for an effective vaccine in the future. Key words: Vaccine ...

  9. Combination atovaquone and proguanil hydrochloride vs. halofantrine for treatment of acute Plasmodium falciparum malaria in children.

    Science.gov (United States)

    Anabwani, G; Canfield, C J; Hutchinson, D B

    1999-05-01

    Malaria is a major cause of pediatric mortality in sub-Saharan Africa. Worldwide estimates of mortality among children with Plasmodium falciparum malaria range from 1 to 2 million deaths per year. Management of malaria is increasingly difficult because of the global spread of drug-resistant strains of P. falciparum. There is an urgent need for safe and effective new therapies to treat multidrug-resistant malaria. This open label, randomized trial compared atovaquone and proguanil hydrochloride with halofantrine for treatment of acute, uncomplicated P. falciparum malaria in children age 3 to 12 years (84 patients per group). Study drug dosages were adjusted by weight (approximately 20 and 8 mg/kg daily for three doses for atovaquone and proguanil hydrochloride and 8 mg/kg every 6 h for three doses for halofantrine). Patients were monitored by serial clinical and laboratory assessments for 28 days after starting treatment. Both regimens were effective (cure rate, 93.8% for atovaquone and proguanil hydrochloride and 90.4% for halofantrine) and produced prompt defervescence. Mean parasite clearance times were 50.2 h for halofantrine and 64.9 h for atovaquone and proguanil hydrochloride. More adverse experiences were reported in children treated with halofantrine (119) than with atovaquone and proguanil hydrochloride (73). In Kenyan children the combination of atovaquone and proguanil hydrochloride has efficacy comparable with that of halofantrine for treatment of acute uncomplicated multidrug-resistant falciparum malaria and is associated with a lower rate of adverse events.

  10. RTS,S: Toward a first landmark on the Malaria Vaccine Technology Roadmap.

    Science.gov (United States)

    Kaslow, David C; Biernaux, Sophie

    2015-12-22

    The Malaria Vaccine Technology Roadmap calls for a 2015 landmark goal of a first-generation malaria vaccine that has protective efficacy against severe disease and death, lasting longer than one year. This review focuses on product development efforts over the last five years of RTS,S, a pre-erythrocytic, recombinant subunit, adjuvanted, candidate malaria vaccine designed with this goal of a first-generation malaria vaccine in mind. RTS,S recently completed a successful pivotal Phase III safety, efficacy and immunogenicity study. Although vaccine efficacy was found to be modest, a substantial number of cases of clinical malaria were averted over a 3-4 years period, particularly in settings of significant disease burden. European regulators have subsequently adopted a positive opinion under the Article 58 procedure for an indication of active immunization of children aged 6 weeks up to 17 months against malaria caused by Plasmodium falciparum and against hepatitis B. Further evaluations of the benefit, risk, feasibility and cost-effectiveness of RTS,S are now anticipated through policy and financing reviews at the global and national levels. Copyright © 2015. Published by Elsevier Ltd.

  11. Limited variation in vaccine candidate Plasmodium falciparum Merozoite Surface Protein-6 over multiple transmission seasons

    Directory of Open Access Journals (Sweden)

    Branch OraLee H

    2010-05-01

    Full Text Available Abstract Background Plasmodium falciparum Merozoite Surface Protein-6 (PfMSP6 is a component of the complex proteinacious coat that surrounds P. falciparum merozoites. This location, and the presence of anti-PfMSP6 antibodies in P. falciparum-exposed individuals, makes PfMSP6 a potential blood stage vaccine target. However, genetic diversity has proven to be a major hurdle for vaccines targeting other blood stage P. falciparum antigens, and few endemic field studies assessing PfMSP6 gene diversity have been conducted. This study follows PfMSP6 diversity in the Peruvian Amazon from 2003 to 2006 and is the first longitudinal assessment of PfMSP6 sequence dynamics. Methods Parasite DNA was extracted from 506 distinct P. falciparum infections spanning the transmission seasons from 2003 to 2006 as part of the Malaria Immunology and Genetics in the Amazon (MIGIA cohort study near Iquitos, Peru. PfMSP6 was amplified from each sample using a nested PCR protocol, genotyped for allele class by agarose gel electrophoresis, and sequenced to detect diversity. Allele frequencies were analysed using JMP v.8.0.1.0 and correlated with clinical and epidemiological data collected as part of the MIGIA project. Results Both PfMSP6 allele classes, K1-like and 3D7-like, were detected at the study site, confirming that both are globally distributed. Allele frequencies varied significantly between transmission seasons, with 3D7-class alleles dominating and K1-class alleles nearly disappearing in 2005 and 2006. There was a significant association between allele class and village location (p-value = 0.0008, but no statistically significant association between allele class and age, sex, or symptom status. No intra-allele class sequence diversity was detected. Conclusions Both PfMSP6 allele classes are globally distributed, and this study shows that allele frequencies can fluctuate significantly between communities separated by only a few kilometres, and over time in the

  12. Rapid diagnostic tests for diagnosing uncomplicated non-falciparum or Plasmodium vivax malaria in endemic countries

    Science.gov (United States)

    Abba, Katharine; Kirkham, Amanda J; Olliaro, Piero L; Deeks, Jonathan J; Donegan, Sarah; Garner, Paul; Takwoingi, Yemisi

    2014-01-01

    Background In settings where both Plasmodium vivax and Plasmodium falciparum infection cause malaria, rapid diagnostic tests (RDTs) need to distinguish which species is causing the patients' symptoms, as different treatments are required. Older RDTs incorporated two test lines to distinguish malaria due to P. falciparum, from malaria due to any other Plasmodium species (non-falciparum). These RDTs can be classified according to which antibodies they use: Type 2 RDTs use HRP-2 (for P. falciparum) and aldolase (all species); Type 3 RDTs use HRP-2 (for P. falciparum) and pLDH (all species); Type 4 use pLDH (fromP. falciparum) and pLDH (all species). More recently, RDTs have been developed to distinguish P. vivax parasitaemia by utilizing a pLDH antibody specific to P. vivax. Objectives To assess the diagnostic accuracy of RDTs for detecting non-falciparum or P. vivax parasitaemia in people living in malaria-endemic areas who present to ambulatory healthcare facilities with symptoms suggestive of malaria, and to identify which types and brands of commercial test best detect non-falciparum and P. vivax malaria. Search methods We undertook a comprehensive search of the following databases up to 31 December 2013: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; MEDION; Science Citation Index; Web of Knowledge; African Index Medicus; LILACS; and IndMED. Selection criteria Studies comparing RDTs with a reference standard (microscopy or polymerase chain reaction) in blood samples from a random or consecutive series of patients attending ambulatory health facilities with symptoms suggestive of malaria in non-falciparum endemic areas. Data collection and analysis For each study, two review authors independently extracted a standard set of data using a tailored data extraction form. We grouped comparisons by type of RDT (defined by the combinations of antibodies used), and combined in meta-analysis where appropriate. Average sensitivities and

  13. Parasite density and the spectrum of clinical illness in falciparum malaria

    International Nuclear Information System (INIS)

    Ali, H.; Mahmood, T.; Ahmed, N.

    2008-01-01

    To determine the impact of percentage parasitemia and clinical features on morbidity and mortality in patients with P. falciparum malaria. Seventy-six adult patients of smear positive P. falciparum malaria were selected for the study. Parasite density was estimated on thin blood film and expressed as percentage of red blood cells parasitized. Patients were divided into three groups on the basis of parasite density. The data was analyzed on SPSS version 12. Results were expressed as percentages, mean and standard deviations. P-value 10%. Comparative analysis of the groups showed that pallor, impaired consciousness, jaundice or malarial hepatitis, thrombocytopenia, acute renal failure, DIC, and mortality were all strongly associated with the density of Plasmodium falciparum malaria (p=0.001). Parasite density was not related to age, gender and hepatosplenomegaly. High parasite density was associated with severe clinical illness, complications and mortality. Parasite counts of > 5% may be considered as hyperparasitaemia in this population of the world. (author)

  14. Malária por Plasmodium falciparum: estudos proteômicos Plasmodium falciparum malaria: proteomic studies

    Directory of Open Access Journals (Sweden)

    Rodrigo Siqueira-Batista

    2012-12-01

    Full Text Available A despeito dos avanços no tratamento e das campanhas de prevenção e de controle da malária nos distintos continentes nos quais a moléstia grassa, a entidade mórbida permanece com significativa relevância no mundo contemporâneo. O Plasmodium falciparum é o grande responsável pela malária grave, caracterizada por distúrbios em diferentes órgãos e sistemas, com possibilidade de evolução ao óbito. Embora incipientes, os estudos proteômicos na malária têm trazido boas perspectivas para melhor compreensão dos aspectos biológicos do Plasmodium, assim como dos mecanismos fisiopatológicos, diagnósticos, terapêuticos e profiláticos da enfermidade. Desse modo, o objetivo do presente artigo é apresentar uma breve revisão das aplicações da análise proteômica na malária por P. falciparum.Despite advances in treatment and campaigns for prevention and control of malaria on the various continents where it is still rampant, this disease remains significantly relevant to the contemporary world. Plasmodium falciparum is the organism that is mainly responsible for severe malaria, which is characterized by disturbances in different organs and systems, with possibly fatal outcomes. Although incipient, proteomic studies of malaria have yielded favorable prospects for elucidating the biological aspects of Plasmodium as well as the pathophysiological, diagnostic, prophylactic, and therapeutic mechanisms of the disease. Thus, the aim of the present article is to present a brief review of the applications of proteomic analysis in P. falciparum malaria.

  15. Temporal association of acute hepatitis A and Plasmodium falciparum malaria in children.

    Directory of Open Access Journals (Sweden)

    Peter Klein Klouwenberg

    Full Text Available BACKGROUND: In sub-Saharan Africa, Plasmodium falciparum and hepatitis A (HAV infections are common, especially in children. Co-infections with these two pathogens may therefore occur, but it is unknown if temporal clustering exists. MATERIALS AND METHODS: We studied the pattern of co-infection of P. falciparum malaria and acute HAV in Kenyan children under the age of 5 years in a cohort of children presenting with uncomplicated P. falciparum malaria. HAV status was determined during a 3-month follow-up period. DISCUSSION: Among 222 cases of uncomplicated malaria, 10 patients were anti-HAV IgM positive. The incidence of HAV infections during P. falciparum malaria was 1.7 (95% CI 0.81-3.1 infections/person-year while the cumulative incidence of HAV over the 3-month follow-up period was 0.27 (95% CI 0.14-0.50 infections/person-year. Children with or without HAV co-infections had similar mean P. falciparum asexual parasite densities at presentation (31,000/µL vs. 34,000/µL, respectively, largely exceeding the pyrogenic threshold of 2,500 parasites/µL in this population and minimizing risk of over-diagnosis of malaria as an explanation. CONCLUSION: The observed temporal association between acute HAV and P. falciparum malaria suggests that co-infections of these two hepatotrophic human pathogens may result from changes in host susceptibility. Testing this hypothesis will require larger prospective studies.

  16. Immunoglobulin G antibody reactivity to a group A Plasmodium falciparum erythrocyte membrane protein 1 and protection from P. falciparum malaria

    DEFF Research Database (Denmark)

    Magistrado, Pamela A; Lusingu, John; Vestergaard, Lasse S

    2007-01-01

    Variant surface antigens (VSA) on the surface of Plasmodium falciparum-infected red blood cells play a major role in the pathogenesis of malaria and are key targets for acquired immunity. The best-characterized VSA belong to the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. In are...

  17. Malaria vaccines: lessons from field trials

    Directory of Open Access Journals (Sweden)

    Claudio J. Struchiner

    1994-07-01

    Full Text Available Malaria vaccine candidates have already been tested and new trials are being carried out. We present a brief description of specific issues of validity that are relevant when assessing vaccine efficacy in the field and illustrate how the application of these principles might improve our interpretation of the data being gathered in actual malaria vaccine field trials. Our discussion assumes that vaccine evaluation shares the same general principles of validity with epidemiologic causal inference, i.e., the process of drawing inferences from epidemiologic data aiming at the identification of causes of diseases. Judicious exercise of these principles indicates that, for meaningful interpretation, measures of vaccine efficacy require definitions based upon arguments conditional on the amount of exposure to infection, and specification of the initial and final states in which one believes the effect of interest takes place.

  18. Serine-stretch protein (SERP) of Plasmodium falciparum corresponds to the exoantigen Ag2, a target of antibodies associated with protection against malaria

    DEFF Research Database (Denmark)

    Jakobsen, P H; Hundt, E; Hansen, Morten Bagge

    1994-01-01

    A mixture of Plasmodium falciparum exoantigens inducing lymphocyte activation and cytokine production was shown to contain the malaria vaccine candidate, the serine-stretch protein. This protein was shown serologically to correspond to Ag2, an exoantigen recognized by antibodies linked...... with protection against malaria. The glycophorin-binding protein, the histidine-rich protein II, the S-antigen, the heat shock protein 70, the ring-infected erythrocyte surface antigen, and the apical membrane antigen-1 were also shown serologically to be present in the mixture of exoantigens....

  19. Safety and immunogenicity of an AMA-1 malaria vaccine in Malian adults: results of a phase 1 randomized controlled trial.

    Directory of Open Access Journals (Sweden)

    Mahamadou A Thera

    2008-01-01

    Full Text Available The objective was to evaluate the safety, reactogenicity and immunogenicity of the AMA-1-based blood-stage malaria vaccine FMP2.1/AS02A in adults exposed to seasonal malaria.A phase 1 double blind randomized controlled dose escalation trial was conducted in Bandiagara, Mali, West Africa, a rural town with intense seasonal transmission of Plasmodium falciparum malaria. The malaria vaccine FMP2.1/AS02A is a recombinant protein (FMP2.1 based on apical membrane antigen-1 (AMA-1 from the 3D7 clone of P. falciparum, adjuvanted with AS02A. The comparator vaccine was a cell-culture rabies virus vaccine (RabAvert. Sixty healthy, malaria-experienced adults aged 18-55 y were recruited into 2 cohorts and randomized to receive either a half dose or full dose of the malaria vaccine (FMP2.1 25 microg/AS02A 0.25 mL or FMP2.1 50 microg/AS02A 0.5 mL or rabies vaccine given in 3 doses at 0, 1 and 2 mo, and were followed for 1 y. Solicited symptoms were assessed for 7 d and unsolicited symptoms for 30 d after each vaccination. Serious adverse events were assessed throughout the study. Titers of anti-AMA-1 antibodies were measured by ELISA and P. falciparum growth inhibition assays were performed on sera collected at pre- and post-vaccination time points. Transient local pain and swelling were common and more frequent in both malaria vaccine dosage groups than in the comparator group. Anti-AMA-1 antibodies increased significantly in both malaria vaccine groups, peaking at nearly 5-fold and more than 6-fold higher than baseline in the half-dose and full-dose groups, respectively.The FMP2.1/AS02A vaccine had a good safety profile, was well-tolerated, and was highly immunogenic in malaria-exposed adults. This malaria vaccine is being evaluated in Phase 1 and 2 trials in children at this site.

  20. Assessment of parental perception of malaria vaccine in Tanzania

    OpenAIRE

    Romore, Idda; Ali, Ali Mohamed; Semali, Innocent; Mshinda, Hassan; Tanner, Marcel; Abdulla, Salim

    2015-01-01

    Background Clinical trials of the RTS,S malaria vaccine have completed Phase III and the vaccine is on track for registration. Before making decisions about implementation, it is essential to prepare the ground for introducing the vaccine by assessing awareness and willingness to use malaria vaccines and to provide policy makers with evidence-based information on the best strategies to engage communities to manage the introduction of malaria vaccine in Tanzania. Methods In November 2011, as p...

  1. Development of vaccines for Plasmodium vivax malaria.

    Science.gov (United States)

    Mueller, Ivo; Shakri, Ahmad Rushdi; Chitnis, Chetan E

    2015-12-22

    Plasmodium vivax continues to cause significant morbidity outside Africa with more than 50% of malaria cases in many parts of South and South-east Asia, Pacific islands, Central and South America being attributed to P. vivax infections. The unique biology of P. vivax, including its ability to form latent hypnozoites that emerge months to years later to cause blood stage infections, early appearance of gametocytes before clinical symptoms are apparent and a shorter development cycle in the vector makes elimination of P. vivax using standard control tools difficult. The availability of an effective vaccine that provides protection and prevents transmission would be a valuable tool in efforts to eliminate P. vivax. Here, we review the latest developments related to P. vivax malaria vaccines and discuss the challenges as well as directions toward the goal of developing highly efficacious vaccines against P. vivax malaria. Copyright © 2015. Published by Elsevier Ltd.

  2. Haemoglobin variants and Plasmodium falciparum malaria in children under five years of age living in a high and seasonal malaria transmission area of Burkina Faso

    Directory of Open Access Journals (Sweden)

    Bougouma Edith C

    2012-05-01

    Full Text Available Abstract Background Genetic factors play a key role in determining resistance/susceptibility to infectious disease. Susceptibility of the human host to malaria infection has been reported to be influenced by genetic factors, which could be confounders if not taken into account in the assessment of the efficacy of interventions against malaria. This study aimed to assess the relationship between haemoglobin genotypes and malaria in children under five years in a site being characterized for future malaria vaccine trials. Methods The study population consisted of 452 children living in four rural villages. Hb genotype was determined at enrolment. Clinical malaria incidence was evaluated over a one-year period using combined active and passive surveillance. Prevalence of infection was evaluated via bi-annual cross-sectional surveys. At each follow-up visit, children received a brief clinical examination and thick and thin blood films were prepared for malaria diagnosis. A clinical malaria was defined as Plasmodium falciparum parasitaemia >2,500 parasites/μl and axillary temperature ≥37.5°C or reported fever over the previous 24 hours. Results Frequencies of Hb genotypes were 73.2% AA; 15.0% AC; 8.2% AS; 2.2% CC; 1.1% CS and 0.2% SS. Prevalence of infection at enrolment ranged from 61.9%-54.1% among AA, AC and AS children. After one year follow-up, clinical malaria incidence (95% CI (episodes per person-year was 1.9 (1.7-2.0 in AA, 1.6 (1.4-2.1 in AC, and 1.7 (1.4-2.0 in AS children. AC genotype was associated with lower incidence of clinical malaria relative to AA genotype among children aged 1–2 years [rate ratio (95% CI 0.66 (0.42-1.05] and 2–3 years [rate ratio (95% CI 0.37 (0.18-0.75]; an association of opposite direction was however apparent among children aged 3–4 years. AS genotype was associated with lower incidence of clinical malaria relative to AA genotype among children aged 2–3 years [rate ratio (95% CI 0.63 (0

  3. Genetic polymorphisms in the glutamate-rich protein of Plasmodium falciparum field isolates from a malaria-endemic area of Brazil

    Directory of Open Access Journals (Sweden)

    Lilian Rose Pratt-Riccio

    2013-06-01

    Full Text Available The genetic diversity displayed by Plasmodium falciparum, the most deadly Plasmodium species, is a significant obstacle for effective malaria vaccine development. In this study, we identified genetic polymorphisms in P. falciparum glutamate-rich protein (GLURP, which is currently being tested in clinical trials as a malaria vaccine candidate, from isolates found circulating in the Brazilian Amazon at variable transmission levels. The study was performed using samples collected in 1993 and 2008 from rural villages situated near Porto Velho, in the state of Rondônia. DNA was extracted from 126 P. falciparum-positive thick blood smears using the phenol-chloroform method and subjected to a nested polymerase chain reaction protocol with specific primers against two immunodominant regions of GLURP, R0 and R2. Only one R0 fragment and four variants of the R2 fragment were detected. No differences were observed between the two time points with regard to the frequencies of the fragment variants. Mixed infections were uncommon. Our results demonstrate conservation of GLURP-R0 and limited polymorphic variation of GLURP-R2 in P. falciparum isolates from individuals living in Porto Velho. This is an important finding, as genetic polymorphisms in B and T-cell epitopes could have implications for the immunological properties of the antigen.

  4. Identifying Residual Foci of Plasmodium falciparum Infections for Malaria Elimination: The Urban Context of Khartoum, Sudan

    OpenAIRE

    Nourein, Amal B.; Abass, Mohammed A.; Nugud, Abdel Hameed D.; El Hassan, Ibrahim; Snow, Robert W.; Noor, Abdisalan M.

    2011-01-01

    Background: Identifying the location and size of residual foci of infections is critical where malaria elimination is the primary goal. Here the spatial heterogeneity of Plasmodium falciparum infections within the urban extent of Khartoum state in Sudan is investigated using data from cross-sectional surveys undertaken from 1999 to 2008 to inform the Khartoum Malaria Free Initiative (KMFI).Methods: From 1999-2008 the KMFI undertook cross-sectional surveys of 256 clusters across 203 random sam...

  5. The ¿/d T-cell response to Plasmodium falciparum malaria in a population in which malaria is endemic

    DEFF Research Database (Denmark)

    Hviid, L; Kurtzhals, J A; Dodoo, D

    1996-01-01

    Frequencies and absolute numbers of peripheral gamma/delta T cells have been reported to increase after episodes of Plasmodium falciparum malaria in adults with limited or no previous malaria exposure. In contrast, little is known about the gamma/delta T-cell response to malaria in children from ...

  6. Correlation Between Haematological Parameters, Kidney Function Tests and Liver Function Tests in Plasmodium Falciparum and Vivax Malaria

    Directory of Open Access Journals (Sweden)

    Mitul Chhatriwala

    2017-12-01

    Full Text Available Abstract: Malaria remains a major cause of morbidity and mortality in India. Plasmodium falciparum remains the main culprit although cases with vivax malaria are on the rise. Severe malaria as defined by the WHO criteria has high rate of complications and mortality. In our study we recruited microscopy positive falciparum and vivax malaria patients. Haematological and biochemical laboratory investigations were carried out in recruited patients. Both parameters were found to be significantly derailed in falciparum cases as compared to vivax. A direct correlation has been observed between kidney function tests (serum creatinine,serum urea and direct bilirubin levels across all cases of malaria. Hence these parameters can be used to identify and monitor the progress of cases of severe malaria as significant proportion of patients fulfilled the criteria of severe malaria in the cohort.

  7. Expression, Purification and Characterization of GMZ2'.10C, a Complex Disulphide-Bonded Fusion Protein Vaccine Candidate against the Asexual and Sexual Life-Stages of the Malaria-Causing Plasmodium falciparum Parasite

    DEFF Research Database (Denmark)

    Mistarz, Ulrik H; Singh, Susheel K; Nguyen, Tam T T N

    2017-01-01

    for a multi-stage malaria vaccine that targets both transmission and asexual life-cycle stages of the parasite. METHODS: GMZ2'.10C was produced in Lactococcus lactis and purified using either an immunoaffinity purification (IP) or a conventional purification (CP) method. Protein purity and stability......-GMZ2'.10C. CP-GMZ2'.10C and IP-GMZ2'.10C both elicited a high titer of transmission blocking (TB) antibodies in rodents. The intricate disulphide-bond connectivity of C-terminus Pfs48/45 was analysed by tandem mass spectrometry and was established for GMZ2'.10C and two reference fusion proteins...

  8. Targeted Phenotypic Screening in Plasmodium falciparum and Toxoplasma gondii Reveals Novel Modes of Action of Medicines for Malaria Venture Malaria Box Molecules.

    Science.gov (United States)

    Subramanian, Gowtham; Belekar, Meenakshi A; Shukla, Anurag; Tong, Jie Xin; Sinha, Ameya; Chu, Trang T T; Kulkarni, Akshay S; Preiser, Peter R; Reddy, D Srinivasa; Tan, Kevin S W; Shanmugam, Dhanasekaran; Chandramohanadas, Rajesh

    2018-01-01

    (human malaria) and Toxoplasma gondii (human and animal toxoplasmosis). Widespread resistance to current antimalarials and the lack of a commercial vaccine necessitate novel pharmacological interventions with distinct modes of action against malaria. For toxoplasmosis, new drugs to effectively eliminate tissue-dwelling latent cysts of the parasite are needed. The Malaria Box antimalarial collection, managed and distributed by the Medicines for Malaria Venture, includes molecules of novel chemical classes with proven antimalarial efficacy. Using targeted phenotypic assays of P. falciparum and T. gondii , we have identified a subset of the Malaria Box molecules as potent inhibitors of plastid segregation and parasite invasion and egress, thereby providing early insights into their probable mode of action. Five molecules that inhibit the egress of both parasites have been identified for further mechanistic studies. Thus, the approach we have used to identify novel molecules with defined modes of action in multiple parasites can expedite the development of pan-active antiparasitic agents.

  9. Rapid diagnostic tests for diagnosing uncomplicated non-falciparum or Plasmodium vivax malaria in endemic countries.

    Science.gov (United States)

    Abba, Katharine; Kirkham, Amanda J; Olliaro, Piero L; Deeks, Jonathan J; Donegan, Sarah; Garner, Paul; Takwoingi, Yemisi

    2014-12-18

    In settings where both Plasmodium vivax and Plasmodium falciparum infection cause malaria, rapid diagnostic tests (RDTs) need to distinguish which species is causing the patients' symptoms, as different treatments are required. Older RDTs incorporated two test lines to distinguish malaria due to P. falciparum, from malaria due to any other Plasmodium species (non-falciparum). These RDTs can be classified according to which antibodies they use: Type 2 RDTs use HRP-2 (for P. falciparum) and aldolase (all species); Type 3 RDTs use HRP-2 (for P. falciparum) and pLDH (all species); Type 4 use pLDH (fromP. falciparum) and pLDH (all species).More recently, RDTs have been developed to distinguish P. vivax parasitaemia by utilizing a pLDH antibody specific to P. vivax. To assess the diagnostic accuracy of RDTs for detecting non-falciparum or P. vivax parasitaemia in people living in malaria-endemic areas who present to ambulatory healthcare facilities with symptoms suggestive of malaria, and to identify which types and brands of commercial test best detect non-falciparum and P. vivax malaria. We undertook a comprehensive search of the following databases up to 31 December 2013: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; MEDION; Science Citation Index; Web of Knowledge; African Index Medicus; LILACS; and IndMED. Studies comparing RDTs with a reference standard (microscopy or polymerase chain reaction) in blood samples from a random or consecutive series of patients attending ambulatory health facilities with symptoms suggestive of malaria in non-falciparum endemic areas. For each study, two review authors independently extracted a standard set of data using a tailored data extraction form. We grouped comparisons by type of RDT (defined by the combinations of antibodies used), and combined in meta-analysis where appropriate. Average sensitivities and specificities are presented alongside 95% confidence intervals (95% CI). We included 47 studies

  10. Cytokine balance in human malaria: does Plasmodium vivax elicit more inflammatory responses than Plasmodium falciparum?

    Directory of Open Access Journals (Sweden)

    Raquel M Gonçalves

    Full Text Available BACKGROUND: The mechanisms by which humans regulate pro- and anti-inflammatory responses on exposure to different malaria parasites remains unclear. Although Plasmodium vivax usually causes a relatively benign disease, this parasite has been suggested to elicit more host inflammation per parasitized red blood cell than P. falciparum. METHODOLOGY/PRINCIPAL FINDINGS: We measured plasma concentrations of seven cytokines and two soluble tumor necrosis factor (TNF-α receptors, and evaluated clinical and laboratory outcomes, in Brazilians with acute uncomplicated infections with P. vivax (n = 85, P. falciparum (n = 30, or both species (n = 12, and in 45 asymptomatic carriers of low-density P. vivax infection. Symptomatic vivax malaria patients, compared to those infected with P. falciparum or both species, had more intense paroxysms, but they had no clear association with a pro-inflammatory imbalance. To the contrary, these patients had higher levels of the regulatory cytokine interleukin (IL-10, which correlated positively with parasite density, and elevated IL-10/TNF-α, IL-10/interferon (IFN-γ, IL-10/IL-6 and sTNFRII/TNF-α ratios, compared to falciparum or mixed-species malaria patient groups. Vivax malaria patients had the highest levels of circulating soluble TNF-α receptor sTNFRII. Levels of regulatory cytokines returned to normal values 28 days after P. vivax clearance following chemotherapy. Finally, asymptomatic carriers of low P. vivax parasitemias had substantially lower levels of both inflammatory and regulatory cytokines than did patients with clinical malaria due to either species. CONCLUSIONS: Controlling fast-multiplying P. falciparum blood stages requires a strong inflammatory response to prevent fulminant infections, while reducing inflammation-related tissue damage with early regulatory cytokine responses may be a more cost-effective strategy in infections with the less virulent P. vivax parasite. The early induction

  11. Transfected HEK293 Cells Expressing Functional Recombinant Intercellular Adhesion Molecule 1 (ICAM-1) - A Receptor Associated with Severe Plasmodium falciparum Malaria

    DEFF Research Database (Denmark)

    Bengtsson, Anja; Joergensen, Louise; Barbati, Zachary R

    2013-01-01

    Intercellular adhesion molecule 1 (ICAM-1) is a membrane-bound glycoprotein expressed on endothelial cells and cells of the immune system. Human ICAM-1 mediates adhesion and migration of leucocytes, and is implicated in inflammatory pathologies, autoimmune diseases and in many cancer processes....... Additionally, ICAM-1 acts as receptor for pathogens like human rhinovirus and Plasmodium falciparum malaria parasites. A group of related P. falciparum erythrocyte membrane protein 1 (PfEMP1) domains, the DBLβ, mediates ICAM-1 binding of P. falciparum-infected erythrocytes. This ICAM‑1-binding phenotype has...... as vaccine candidates and go into clinical trials. Such studies require availability of functional recombinant ICAM-1 in large quantities. In this study, we compared recombinant ICAM-1 expressed in HEK293 and COS-7 cells with mouse myeloma NS0 ICAM-1 purchased from a commercial vendor in terms of protein...

  12. Vaccine candidates for malaria: what's new?

    Science.gov (United States)

    Takashima, Eizo; Morita, Masayuki; Tsuboi, Takafumi

    2016-01-01

    Although it is more than a decade since the parasite genome information was obtained, standardized novel genome-wide selection/prioritization strategies for candidacy of malaria vaccine antigens are still sought. In the quest to systematically identify candidates, it is impossible to overemphasize the usefulness of wheat germ cell-free technology in expressing quality proteins for the post-genome vaccine candidate discovery.

  13. Plasmodium falciparum: VAR2CSA expressed during pregnancy-associated malaria is partially resistant to proteolytic cleavage by trypsin

    DEFF Research Database (Denmark)

    Nielsen, Morten A; Resende, Mafalda; Alifrangis, Michael

    2007-01-01

    In areas of high Plasmodium falciparum transmission, immunity to malaria is acquired during childhood, so that adults in general are clinically immune. One exception is that first-time pregnant women are susceptible to pregnancy-associated malaria caused by accumulation of parasites in the placenta...... mediates the adhesive and antigenic phenotypes shown by parasites causing placental malaria....

  14. Patterns of protective associations differ for antibodies to P. falciparum-infected erythrocytes and merozoites in immunity against malaria in children.

    Science.gov (United States)

    Chan, Jo-Anne; Stanisic, Danielle I; Duffy, Michael F; Robinson, Leanne J; Lin, Enmoore; Kazura, James W; King, Christopher L; Siba, Peter M; Fowkes, Freya Ji; Mueller, Ivo; Beeson, James G

    2017-12-01

    Acquired antibodies play an important role in immunity to P. falciparum malaria and are typically directed towards surface antigens expressed by merozoites and infected erythrocytes (IEs). The importance of specific IE surface antigens as immune targets remains unclear. We evaluated antibodies and protective associations in two cohorts of children in Papua New Guinea. We used genetically-modified P. falciparum to evaluate the importance of PfEMP1 and a P. falciparum isolate with a virulent phenotype. Our findings suggested that PfEMP1 was the dominant target of antibodies to the IE surface, including functional antibodies that promoted opsonic phagocytosis by monocytes. Antibodies were associated with increasing age and concurrent parasitemia, and were higher among children exposed to a higher force-of-infection as determined using molecular detection. Antibodies to IE surface antigens were consistently associated with reduced risk of malaria in both younger and older children. However, protective associations for antibodies to merozoite surface antigens were only observed in older children. This suggests that antibodies to IE surface antigens, particularly PfEMP1, play an earlier role in acquired immunity to malaria, whereas greater exposure is required for protective antibodies to merozoite antigens. These findings have implications for vaccine design and serosurveillance of malaria transmission and immunity. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Population genomics diversity of Plasmodium falciparum in malaria ...

    African Journals Online (AJOL)

    Infectious Diseases and Environmental Health Research Group, Department of ... Conclusion: There is high genetic diversity in MSP – 2 and GLURP allelic families of Plasmodium falciparum isolates from Okelele. Health Centre, Ilorin, Nigeria. Keywords: Plasmodium falciparum, Merozoite Surface Protein, genetic diversity.

  16. Haemodynamic and oxygen transport response during exchange transfusion for severe falciparum malaria.

    OpenAIRE

    Beards, S. C.; Joynt, G. M.; Lipman, J.

    1994-01-01

    We describe the haemodynamic and oxygen transport response in a patient undergoing exchange transfusion for severe falciparum malaria. We found that exchange transfusion produced a significant increase in left ventricular stroke work index, systemic oxygen delivery and oxygen consumption. This potentially beneficial effect of exchange transfusion has not been reported previously.

  17. The relationship between glucose production and plasma glucose concentration in children with falciparum malaria

    NARCIS (Netherlands)

    Dekker, E.; Romijn, J. A.; Waruiru, C.; Ackermans, M. T.; Weverling, G. J.; Sauerwein, R. W.; Endert, E.; Peshu, N.; Marsh, K.; Sauerwein, H. P.

    1996-01-01

    The pathophysiology of hypoglycaemia in children with acute falciparum malaria, a frequent and serious complication, is unknown due to absence of data on glucose kinetics. We investigated the correlation between basal glucose production and plasma glucose concentration in 20 children (8 girls) with

  18. Combinations of artemisinin and quinine for uncomplicated falciparum malaria: efficacy and pharmacodynamics

    NARCIS (Netherlands)

    de Vries, P. J.; Bich, N. N.; van Thien, H.; Hung, L. N.; Anh, T. K.; Kager, P. A.; Heisterkamp, S. H.

    2000-01-01

    Combinations of artemisinin and quinine for uncomplicated falciparum malaria were studied. A total of 268 patients were randomized to 7 days of quinine at 10 mg/kg of body weight three times a day (Q) or to artemisinin at 20 mg/kg of body weight followed by 3 (AQ3) or 5 (AQ5) days of quinine.

  19. The efficacy of artemether in the treatment of Plasmodium falciparum malaria in Sudan

    DEFF Research Database (Denmark)

    Elhassan, I M; Satti, G H; Ali, A E

    1994-01-01

    The efficacy of artemether (a qinghaosu derivative) administered intramuscularly for the treatment of Plasmodium falciparum malaria was compared to quinine in an open randomized trial including 54 patients in eastern Sudan, where chloroquine resistance is common. The artemether treatment (5 d...

  20. Hypoglycemia in falciparum malaria: is fasting an unrecognized and insufficiently emphasized risk factor?

    NARCIS (Netherlands)

    Thien, Huynh V.; Kager, Piet A.; Sauerwein, Hans P.

    2006-01-01

    Hypoglycemia is a frequently encountered complication in falciparum malaria that is usually ascribed to increased glucose use and impaired glucose production caused by the inhibition of gluconeogenesis. Here, in light of recent data showing that glucose production and gluconeogenesis are often

  1. High-Dose Chloroquine for Treatment of Chloroquine-Resistant Plasmodium falciparum Malaria

    DEFF Research Database (Denmark)

    Ursing, Johan; Rombo, Lars; Bergqvist, Yngve

    2016-01-01

    to determine the in vivo efficacy of higher chloroquine concentrations against P. falciparum with resistance-conferring genotypes. METHODS:  Standard or double-dose chloroquine was given to 892 children aged malaria during 3 clinical trials (2001-2008) with ≥35 days follow...

  2. Increased levels of soluble CD30 in plasma of patients with Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Kemp, Kåre; Kurtzhals, Jørgen; Akanmori, Bartholomew D

    2002-01-01

    Levels of soluble CD30 (sCD30) in serum were elevated in patients with Plasmodium falciparum malaria but showed decline following treatment. The levels of sCD30 in serum were correlated significantly with the expression of gamma interferon by peripheral T cells. These data suggest that CD30...

  3. Malaria transmission dynamics at a site in northern Ghana proposed for testing malaria vaccines.

    Science.gov (United States)

    Appawu, Maxwell; Owusu-Agyei, Seth; Dadzie, Samuel; Asoala, Victor; Anto, Francis; Koram, Kwadwo; Rogers, William; Nkrumah, Francis; Hoffman, Stephen L; Fryauff, David J

    2004-01-01

    We studied the malaria transmission dynamics in Kassena Nankana district (KND), a site in northern Ghana proposed for testing malaria vaccines. Intensive mosquito sampling for 1 year using human landing catches in three micro-ecological sites (irrigated, lowland and rocky highland) yielded 18 228 mosquitoes. Anopheles gambiae s.l. and Anopheles funestus constituted 94.3% of the total collection with 76.8% captured from the irrigated communities. Other species collected but in relatively few numbers were Anopheles pharoensis (5.4%) and Anopheles rufipes (0.3%). Molecular analysis of 728 An. gambiae.s.l. identified Anopheles gambiae s.s. as the most dominant sibling species (97.7%) of the An. gambiae complex from the three ecological sites. Biting rates of the vectors (36.7 bites per man per night) were significantly higher (P<0.05) in the irrigated area than in the non-irrigated lowland (5.2) and rocky highlands (5.9). Plasmodium falciparum sporozoite rates of 7.2% (295/4075) and 7.1% (269/3773) were estimated for An. gambiae s.s. and An. funestus, respectively. Transmission was highly seasonal, and the heaviest transmission occurred from June to October. The intensity of transmission was higher for people in the irrigated communities than the non-irrigated ones. An overall annual entomological inoculation rate (EIR) of 418 infective bites was estimated in KND. There were micro-ecological variations in the EIRs, with values of 228 infective bites in the rocky highlands, 360 in the lowlands and 630 in the irrigated area. Approximately 60% of malaria transmission in KND occurred indoors during the second half of the night, peaking at daybreak between 04.00 and 06.00 hours. Vaccine trials could be conducted in this district, with timing dependent on the seasonal patterns and intensity of transmission taking into consideration the micro-geographical differences and vaccine trial objectives.

  4. Asymptomatic falciparum malaria and intestinal helminths co-infection among school children in Osogbo, Nigeria

    Directory of Open Access Journals (Sweden)

    Olusola Ojurongbe

    2011-01-01

    Full Text Available Background: Malaria and intestinal helminths are parasitic diseases causing high morbidity and mortality in most tropical parts of the world, where climatic conditions and sanitation practices favor their prevalence. The aim of this study was to determine the prevalence and possible impact of falciparum malaria and intestinal helminths co-infection among school children in Kajola, Osun state, Nigeria. Methods: Fresh stool and blood samples were collected from 117 primary school children age range 4-15 years. The stool samples were processed using both Kato-Katz and formol-ether concentration techniques and microscopically examined for intestinal parasitic infections. Blood was collected by finger prick to determine malaria parasitemia using thick film method; and packed cell volume (PCV was determined by hematocrit. Univariate analysis and chi-square statistical tests were used to analyze the data. Results: The prevalence of Plasmodium falciparum, intestinal helminth infections, and co-infection of malaria and helminth in the study were 25.6%, 40.2% and 4.3%, respectively. Five species of intestinal helminths were recovered from the stool samples and these were Ascaris lumbricoides (34.2%, hookworm (5.1%, Trichuris trichiura (2.6%, Diphyllobothrium latum (0.9% and Trichostrongylus species (0.9%. For the co-infection of both malaria and intestinal helminths, females (5.9% were more infected than males (2.0% but the difference was not statistically significant (p = 0.3978. Children who were infected with helminths were equally likely to be infected with malaria as children without intestinal helminths [Risk Ratio (RR = 0.7295]. Children with A. lumbricoides (RR = 1.359 were also likely to be infected with P. falciparum as compared with uninfected children. Conclusions: Asymptomatic falciparum malaria and intestinal helminth infections do co-exist without clinical symp-toms in school children in Nigeria.

  5. Extended protection capabilities of an immature dendritic-cell targeting malaria sporozoite vaccine.

    Science.gov (United States)

    Luo, Kun; Zavala, Fidel; Gordy, James; Zhang, Hong; Markham, Richard B

    2017-04-25

    Mouse studies evaluating candidate malaria vaccines have typically examined protective efficacy over the relatively short time frames of several weeks after the final of multiple immunizations. The current study examines the protective ability in a mouse model system of a novel protein vaccine construct in which the adjuvant polyinosinic polycytidilic acid (poly(I:C)) is used in combination with a vaccine in which the immature dendritic cell targeting chemokine, macrophage inflammatory protein 3 alpha (MIP3α), is fused to the circumsporozoite protein (CSP) of Plasmodium falciparum (P. falciparum). Two vaccinations, three weeks apart, elicited extraordinarily high, MIP3α-dependent antibody responses. MIP3α was able to target the vaccine to the CCR6 receptor found predominantly on immature dendritic cells and significantly enhanced the cellular influx at the vaccination site. At three and 23 weeks after the final of two immunizations, mice were challenged by intravenous injection of 5×10 3 transgenic Plasmodium berghei sporozoites expressing P. falciparum CSP, a challenge dose approximately one order of magnitude greater than that which is encountered after mosquito bite in the clinical setting. A ninety-seven percent reduction in liver sporozoite load was observed at both time points, 23 weeks being the last time point tested. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Geographical patterns of malaria transmission based on serological markers for falciparum and vivax malaria in Ratanakiri, Cambodia.

    Science.gov (United States)

    Kerkhof, Karen; Sluydts, Vincent; Heng, Somony; Kim, Saorin; Pareyn, Myrthe; Willen, Laura; Canier, Lydie; Sovannaroth, Siv; Ménard, Didier; Sochantha, Tho; Coosemans, Marc; Durnez, Lies

    2016-10-19

    Malaria transmission is highly heterogeneous, especially in low endemic countries, such as Cambodia. This results in geographical clusters of residual transmission in the dry, low transmission season, which can fuel the transmission to wider areas or populations during the wet season. A better understanding of spatial clustering of malaria can lead to a more efficient, targeted strategy to reduce malaria transmission. This study aims to evaluate the potential of the use of serological markers to define spatial patterns in malaria exposure. Blood samples collected in a community-based randomized trial performed in 98 high endemic communities in Ratanakiri province, north-eastern Cambodia, were screened with a multiplex serological assay for five serological markers (three Plasmodium falciparum and two Plasmodium vivax). The antibody half-lives range from approximately six months until more than two years. Geographical heterogeneity in malaria transmission was examined using a spatial scan statistic on serology, PCR prevalence and malaria incidence rate data. Furthermore, to identify behavioural patterns or intrinsic factors associated with malaria exposure (antibody levels), risk factor analyses were performed by using multivariable random effect logistic regression models. The serological outcomes were then compared to PCR prevalence and malaria incidence data. A total of 6502 samples from two surveys were screened in an area where the average parasite prevalence estimated by PCR among the selected villages is 3.4 %. High-risk malaria pockets were observed adjacent to the 'Tonle San River' and neighbouring Vietnam for all three sets of data (serology, PCR prevalence and malaria incidence rates). The main risk factors for all P. falciparum antigens and P. vivax MSP1.19 are age, ethnicity and staying overnight at the plot hut. It is possible to identify similar malaria pockets of higher malaria transmission together with the potential risk factors by using serology

  7. Review Article: Malaria Vaccine: The Pros and Cons | Saleh ...

    African Journals Online (AJOL)

    The key words employed were: malaria, vaccine, anopheles mosquito, insecticide treated bed-nets, pyrethroids and Plasmodium. several studies have underscored the need to develop an effective human malaria vaccine for the control and possible eradication of malaria across the globe with the view to reduce the ...

  8. Malaria vaccine: myth or reality | Ogbonna | African Journal of ...

    African Journals Online (AJOL)

    Malaria currently remains the highest killer disease nationwide despite existing control measures. Malaria vaccine would provide a more efficient means of control and prevention of this disease. The objective of this review is to present the current trends in the production of malaria vaccine thereby supporting the view that ...

  9. Combined measurement of soluble and cellular ICAM-1 among children with Plasmodium falciparum malaria in Uganda

    Directory of Open Access Journals (Sweden)

    Cserti-Gazdewich Christine M

    2010-08-01

    Full Text Available Abstract Background Intercellular adhesion molecule-1 (ICAM-1 is a cytoadhesion molecule implicated in the pathogenesis of Plasmodium falciparum malaria. Elevated levels of soluble ICAM-1 (sICAM-1 have previously been reported with increased malaria disease severity. However, studies have not yet examined both sICAM-1 concentrations and monocyte ICAM-1 expression in the same cohort of patients. To better understand the relationship of soluble and cellular ICAM-1 measurements in malaria, both monocyte ICAM-1 expression and sICAM-1 concentration were measured in children with P. falciparum infection exhibiting a spectrum of clinical severity. Methods Samples were analysed from 160 children, aged 0.5 to 10.8 years, with documented P. falciparum malaria in Kampala, Uganda. The patients belonged to one of three pre-study defined groups: uncomplicated malaria (UM, severe non-fatal malaria (SM-s, and fatal malaria (SM-f. Subset analysis was done on those with cerebral malaria (CM or severe malaria anaemia (SMA. Monocyte ICAM-1 was measured by flow cytometry. sICAM-1 was measured by enzyme immunoassay. Results Both sICAM-1 and monocyte cell-surface ICAM-1 followed a log-normal distribution. Median sICAM-1 concentrations increased with greater severity-of-illness: 279 ng/mL (UM, 462 ng/mL (SM-s, and 586 ng/mL (SM-f, p Conclusion In this cohort of children with P. falciparum malaria, sICAM-1 levels were associated with severity-of-illness. Patients with UM had higher monocyte ICAM-1 expression consistent with a role for monocyte ICAM-1 in immune clearance during non-severe malaria. Among the subsets of patients with either SMA or CM, monocyte ICAM-1 levels were higher in CM, consistent with the role of ICAM-1 as a marker of cytoadhesion. Categories of disease in pediatric malaria may exhibit specific combinations of soluble and cellular ICAM-1 expression.

  10. Influence of plasmodium Falciparum malaria on sickle cell Vaso ...

    African Journals Online (AJOL)

    . Malaria infection is thought to influence the occurrence and severity of crisis in sickle cell patients. Objective To investigate the relationship between malaria infection and vasoocclusive crisis in sickle cell disease patients. Methods In order to ...

  11. Symmetrical peripheral gangrene: A rare complication of plasmodium falciparum malaria

    OpenAIRE

    Rana, Atul; Singh, DP; Kaur, Gurdeep; Verma, SK; Mahur, Hemant

    2015-01-01

    Malaria, the most important of the parasitic diseases of humans, is transmitted in 108 countries containing 3 billion people and causes nearly 1 million deaths each year. With the re-emergence of malaria various life-threatening complications of malaria have been observed. Unarousable coma/cerebral malaria, severe normochromic, normocytic anemia, renal failure, pulmonary edema/adult respiratory distress syndrome, hypoglycemia, hypotension/shock, bleeding/disseminated intravascular coagulation...

  12. Malaria in South Sudan 4: treatment of uncomplicated P. Falciparum ...

    African Journals Online (AJOL)

    2011-05-02

    May 2, 2011 ... of malaria in Southern Sudan 2008. Ministry of Health GOSS. Southern Sudan introduces. 6. Fixed-dose Artesunate Amodiaquine. Malaria Control. Department. Note: This article is based on the powerpoint presentation 'Drug treatment of malaria' by Jane Achan. MAIN ARTICLES. PREgnAnT WOMEn AnD ...

  13. MALARIA VACCINE: MYTH OR REALITY?

    African Journals Online (AJOL)

    Femi Olaleye

    stage antigens. VACCINE DEVELOPMENT. The skill involved in development of vaccines has always been the use of a whole organism or a fraction of it. Non- ... Human vaccine trials are also reported to have been successful. (Amador et. al., 1992). Erythrocyte Stage Antigens SPF 66. This is the first synthetically produced.

  14. Optimising Controlled Human Malaria Infection Studies Using Cryopreserved P. falciparum Parasites Administered by Needle and Syringe.

    Directory of Open Access Journals (Sweden)

    Susanne H Sheehy

    Full Text Available Controlled human malaria infection (CHMI studies have become a routine tool to evaluate efficacy of candidate anti-malarial drugs and vaccines. To date, CHMI trials have mostly been conducted using the bite of infected mosquitoes, restricting the number of trial sites that can perform CHMI studies. Aseptic, cryopreserved P. falciparum sporozoites (PfSPZ Challenge provide a potentially more accurate, reproducible and practical alternative, allowing a known number of sporozoites to be administered simply by injection.We sought to assess the infectivity of PfSPZ Challenge administered in different dosing regimens to malaria-naive healthy adults (n = 18. Six participants received 2,500 sporozoites intradermally (ID, six received 2,500 sporozoites intramuscularly (IM and six received 25,000 sporozoites IM.Five out of six participants receiving 2,500 sporozoites ID, 3/6 participants receiving 2,500 sporozoites IM and 6/6 participants receiving 25,000 sporozoites IM were successfully infected. The median time to diagnosis was 13.2, 17.8 and 12.7 days for 2,500 sporozoites ID, 2,500 sporozoites IM and 25,000 sporozoites IM respectively (Kaplan Meier method; p = 0.024 log rank test.2,500 sporozoites ID and 25,000 sporozoites IM have similar infectivities. Given the dose response in infectivity seen with IM administration, further work should evaluate increasing doses of PfSPZ Challenge IM to identify a dosing regimen that reliably infects 100% of participants.ClinicalTrials.gov NCT01465048.

  15. Multilaboratory approach to preclinical evaluation of vaccine immunogens for placental malaria

    DEFF Research Database (Denmark)

    Fried, Michal; Avril, Marion; Chaturvedi, Richa

    2013-01-01

    parasites. VAR2CSA, a member of the P. falciparum EMP1 variant surface antigen family, is the leading candidate for a pregnancy malaria vaccine. Because VAR2CSA is a high-molecular-weight protein, a vaccine based on the full-length protein may not be feasible. An alternative approach has been to develop...... a vaccine targeting individual Duffy binding-like (DBL) domains. In this study, a consortium of laboratories under the Pregnancy Malaria Initiative compared the functional activity of antiadhesion antibodies elicited by different VAR2CSA domains and variants produced in prokaryotic and eukaryotic expression...... systems. Antisera were initially tested against laboratory lines of maternal parasites, and the most promising reagents were evaluated in the field against fresh placental parasite samples. Recombinant proteins expressed in Escherichia coli elicited antibody levels similar to those expressed in eukaryotic...

  16. Investigation of Hydrogen Sulfide Gas as a Treatment against P. falciparum, Murine Cerebral Malaria, and the Importance of Thiolation State in the Development of Cerebral Malaria

    DEFF Research Database (Denmark)

    Dellavalle, Brian; Staalsoe, Trine; Kurtzhals, Jørgen Anders

    2013-01-01

    Cerebral malaria (CM) is a potentially fatal cerebrovascular disease of complex pathogenesis caused by Plasmodium falciparum. Hydrogen sulfide (HS) is a physiological gas, similar to nitric oxide and carbon monoxide, involved in cellular metabolism, vascular tension, inflammation, and cell death....

  17. Immunomodulation in Plasmodium falciparum malaria: experiments in nature and their conflicting implications for potential therapeutic agents

    Science.gov (United States)

    Frosch, Anne EP; John, Chandy C

    2013-01-01

    Effective Plasmodium falciparum immunity requires a precisely timed and balanced response of inflammatory and anti-inflammatory immune regulators. These responses begin with innate immune effectors and are modulated over the course of an infection and between episodes to limit inflammation. To date, there are no effective immunomodulatory therapies for severe malaria. Some of the most potent immunomodulators are naturally occurring infections, including helminthic and chronic viral infections. This review examines malaria coinfection with these organisms, and their impact on malaria morbidity and immune responses. Overall, there is compelling evidence to suggest that chronic coinfections can modulate deleterious malaria-specific immune responses, suggesting that therapeutic agents may be effective if utilized early in infection. Examination of the mechanisms of these effects may serve as a platform to identify more targeted and effective malaria immunomodulatory therapeutics. PMID:23241191

  18. Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine among Young African Children.

    Science.gov (United States)

    Olotu, Ally; Fegan, Gregory; Wambua, Juliana; Nyangweso, George; Leach, Amanda; Lievens, Marc; Kaslow, David C; Njuguna, Patricia; Marsh, Kevin; Bejon, Philip

    2016-06-30

    The candidate malaria vaccine RTS,S/AS01 is being evaluated in order to inform a decision regarding its inclusion in routine vaccination schedules. We conducted 7 years of follow-up in children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of either the RTS,S/AS01 vaccine or a rabies (control) vaccine. The end point was clinical malaria (temperature of ≥37.5°C and infection with Plasmodium falciparum of >2500 parasites per cubic millimeter). In an analysis that was not prespecified, the malaria exposure of each child was estimated with the use of information on the prevalence of malaria among residents within a 1-km radius of the child's home. Vaccine efficacy was defined as 1 minus the hazard ratio or the incidence-rate ratio, multiplied by 100, in the RTS,S/AS01 group versus the control group. Over 7 years of follow-up, we identified 1002 episodes of clinical malaria among 223 children randomly assigned to the RTS,S/AS01 group and 992 episodes among 224 children randomly assigned to the control group. The vaccine efficacy, as assessed by negative binomial regression, was 4.4% (95% confidence interval [CI], -17.0 to 21.9; P=0.66) in the intention-to-treat analysis and 7.0% (95% CI, -14.5 to 24.6; P=0.52) in the per-protocol analysis. Vaccine efficacy waned over time (P=0.006 for the interaction between vaccination and time), including negative efficacy during the fifth year among children with higher-than-average exposure to malaria parasites (intention-to-treat analysis: -43.5%; 95% CI, -100.3 to -2.8 [P=0.03]; per-protocol analysis: -56.8%; 95% CI, -118.7 to -12.3 [P=0.008]). A three-dose vaccination with RTS,S/AS01 was initially protective against clinical malaria, but this result was offset by rebound in later years in areas with higher-than-average exposure to malaria parasites. (Funded by the PATH Malaria Vaccine Initiative and others; ClinicalTrials.gov number, NCT00872963.).

  19. Safety and immunogenicity of an AMA1 malaria vaccine in Malian children: results of a phase 1 randomized controlled trial.

    Directory of Open Access Journals (Sweden)

    Mahamadou A Thera

    2010-02-01

    Full Text Available The objective was to evaluate the safety and immunogenicity of the AMA1-based malaria vaccine FMP2.1/AS02(A in children exposed to seasonal falciparum malaria.A Phase 1 double blind randomized controlled dose escalation trial was conducted in Bandiagara, Mali, West Africa, a rural town with intense seasonal transmission of Plasmodium falciparum malaria. The malaria vaccine FMP2.1/AS02(A is a recombinant protein (FMP2.1 based on apical membrane antigen 1 (AMA1 from the 3D7 clone of P. falciparum, formulated in the Adjuvant System AS02(A. The comparator vaccine was a cell-culture rabies virus vaccine (RabAvert. One hundred healthy Malian children aged 1-6 years were recruited into 3 cohorts and randomized to receive either 10 microg FMP2.1 in 0.1 mL AS02(A, or 25 microg FMP2.1 in 0.25 mL AS02(A, or 50 microg FMP2.1 50 microg in 0.5 mL AS02(A, or rabies vaccine. Three doses of vaccine were given at 0, 1 and 2 months, and children were followed for 1 year. Solicited symptoms were assessed for 7 days and unsolicited symptoms for 30 days after each vaccination. Serious adverse events were assessed throughout the study. Transient local pain and swelling were common and more frequent in all malaria vaccine dosage groups than in the comparator group, but were acceptable to parents of participants. Levels of anti-AMA1 antibodies measured by ELISA increased significantly (at least 100-fold compared to baseline in all 3 malaria vaccine groups, and remained high during the year of follow up.The FMP2.1/AS02(A vaccine had a good safety profile, was well-tolerated, and induced high and sustained antibody levels in malaria-exposed children. This malaria vaccine is being evaluated in a Phase 2 efficacy trial in children at this site.ClinicalTrials.gov NCT00358332 [NCT00358332].

  20. Targets and Mechanisms Associated with Protection from Severe Plasmodium falciparum Malaria in Kenyan Children

    DEFF Research Database (Denmark)

    Murungi, Linda M; Sondén, Klara; Llewellyn, David

    2016-01-01

    Severe malaria (SM) is a life-threatening complication of infection with Plasmodium falciparum Epidemiological observations have long indicated that immunity against SM is acquired relatively rapidly, but prospective studies to investigate its immunological basis are logistically challenging and ...

  1. Placental Plasmodium falciparum malaria infection: Operational accuracy of HRP2 rapid diagnostic tests in a malaria endemic setting

    Directory of Open Access Journals (Sweden)

    Montague Mark

    2011-10-01

    Full Text Available Abstract Background Malaria has a negative effect on the outcome of pregnancy. Pregnant women are at high risk of severe malaria and severe haemolytic anaemia, which contribute 60-70% of foetal and perinatal losses. Peripheral blood smear microscopy under-estimates sequestered placental infections, therefore malaria rapid diagnostic tests (RDTs detecting histidine rich protein-2 antigen (HRP-2 in peripheral blood are a potential alternative. Methods HRP-2 RDTs accuracy in detecting malaria in pregnancy (MIP >28 weeks gestation and placental Plasmodium falciparum malaria (after childbirth were conducted using Giemsa microscopy and placental histopathology respectively as the reference standard. The study was conducted in Mbale Hospital, using the midwives to perform and interpret the RDT results. Discordant results samples were spot checked using PCR techniques. Results Among 433 febrile women tested, RDTs had a sensitivity of 96.8% (95% CI 92-98.8, specificity of 73.5% (95% CI 67.8-78.6, a positive predictive value (PPV of 68.0% (95% CI 61.4-73.9, and negative predictive value (NPV of 97.5% (95% CI 94.0-99.0 in detecting peripheral P. falciparum malaria during pregnancy. At delivery, in non-symptomatic women, RDTs had a 80.9% sensitivity (95% CI 57.4-93.7 and a 87.5% specificity (95%CI 80.9-92.1, PPV of 47.2% (95% CI 30.7-64.2 and NPV of 97.1% (95% CI 92.2-99.1 in detecting placental P. falciparum infections among 173 samples. At delivery, 41% of peripheral infections were detected by microscopy without concurrent placental infection. The combination of RDTs and microscopy improved the sensitivity to 90.5% and the specificity to 98.4% for detecting placental malaria infection (McNemar's X 2> 3.84. RDTs were not superior to microscopy in detecting placental infection (McNemar's X 2 Conclusion Use of HRP-2 RDTs to detect malaria in pregnancy in symptomatic women was accurate when performed by midwives. A combination of RDTs and microscopy provided

  2. Review Article: Prospect and Progress of Malaria Vaccine ...

    African Journals Online (AJOL)

    Malaria kills one child every 30 seconds in Africa. The development of a safe vaccine remains an urgent unmet need which could greatly control and even lead to the eradication of the disease. The success recorded in the recent vaccine trials have given some ray of hope that a safe and effective vaccine against malaria will ...

  3. The utility of Plasmodium berghei as a rodent model for anti-merozoite malaria vaccine assessment

    Science.gov (United States)

    Goodman, Anna L.; Forbes, Emily K.; Williams, Andrew R.; Douglas, Alexander D.; de Cassan, Simone C.; Bauza, Karolis; Biswas, Sumi; Dicks, Matthew D. J.; Llewellyn, David; Moore, Anne C.; Janse, Chris J.; Franke-Fayard, Blandine M.; Gilbert, Sarah C.; Hill, Adrian V. S.; Pleass, Richard J.; Draper, Simon J.

    2013-01-01

    Rodent malaria species Plasmodium yoelii and P. chabaudi have been widely used to validate vaccine approaches targeting blood-stage merozoite antigens. However, increasing data suggest the P. berghei rodent malaria may be able to circumvent vaccine-induced anti-merozoite responses. Here we confirm a failure to protect against P. berghei, despite successful antibody induction against leading merozoite antigens using protein-in-adjuvant or viral vectored vaccine delivery. No subunit vaccine approach showed efficacy in mice following immunization and challenge with the wild-type P. berghei strains ANKA or NK65, or against a chimeric parasite line encoding a merozoite antigen from P. falciparum. Protection was not improved in knockout mice lacking the inhibitory Fc receptor CD32b, nor against a Δsmac P. berghei parasite line with a non-sequestering phenotype. An improved understanding of the mechanisms responsible for protection, or failure of protection, against P. berghei merozoites could guide the development of an efficacious vaccine against P. falciparum. PMID:23609325

  4. Implications of the licensure of a partially efficacious malaria vaccine on evaluating second-generation vaccines.

    Science.gov (United States)

    Fowkes, Freya J I; Simpson, Julie A; Beeson, James G

    2013-10-30

    Malaria is a leading cause of morbidity and mortality, with approximately 225 million clinical episodes and >1.2 million deaths annually attributed to malaria. Development of a highly efficacious malaria vaccine will offer unparalleled possibilities for disease prevention and remains a key priority for long-term malaria control and elimination. The Malaria Vaccine Technology Roadmap's goal is to 'develop and license a first-generation malaria vaccine that has protective efficacy of more than 50%'. To date, malaria vaccine candidates have only been shown to be partially efficacious (approximately 30% to 60%). However, licensure of a partially effective vaccine will create a number of challenges for the development and progression of new, potentially more efficacious, malaria vaccines in the future. In this opinion piece we discuss the methodological, logistical and ethical issues that may impact on the feasibility and implementation of superiority, non-inferiority and equivalence trials to assess second generation malaria vaccines in the advent of the licensure of a partially efficacious malaria vaccine. Selecting which new malaria vaccines go forward, and defining appropriate methodology for assessment in logistically challenging clinical trials, is crucial. It is imperative that the scientific community considers all the issues and starts planning how second-generation malaria vaccines will advance in the advent of licensure of a partially effective vaccine.

  5. Population pharmacokinetics of orally administered mefloquine in healthy volunteers and patients with uncomplicated Plasmodium falciparum malaria.

    Science.gov (United States)

    Reuter, Stephanie E; Upton, Richard N; Evans, Allan M; Navaratnam, Visweswaran; Olliaro, Piero L

    2015-03-01

    The determination of dosing regimens for the treatment of malaria is largely empirical and thus a better understanding of the pharmacokinetic/pharmacodynamic properties of antimalarial agents is required to assess the adequacy of current treatment regimens and identify sources of suboptimal dosing that could select for drug-resistant parasites. Mefloquine is a widely used antimalarial, commonly given in combination with artesunate. Mefloquine pharmacokinetics was assessed in 24 healthy adults and 43 patients with Plasmodium falciparum malaria administered mefloquine in combination with artesunate. Population pharmacokinetic modelling was conducted using NONMEM. A two-compartment model with a single transit compartment and first-order elimination from the central compartment most adequately described mefloquine concentration-time data. The model incorporated population parameter variability for clearance (CL/F), central volume of distribution (VC/F) and absorption rate constant (KA) and identified, in addition to body weight, malaria infection as a covariate for VC/F (but not CL/F). Monte Carlo simulations predict that falciparum malaria infection is associated with a shorter elimination half-life (407 versus 566 h) and T>MIC (766 versus 893 h). This is the first known population pharmacokinetic study to show falciparum malaria to influence mefloquine disposition. Protein binding, anaemia and other factors may contribute to differences between healthy individuals and patients. As VC/F is related to the earlier portion of the concentration-time profiles, which occurs during acute malaria, and CL/F is more related to the terminal phase during convalescence after treatment, this may explain why malaria was found to be a covariate for VC/F but not CL/F. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  6. Molecular cloning of a K+ channel from the malaria parasite Plasmodium falciparum

    DEFF Research Database (Denmark)

    Ellekvist, Peter; Ricke, Christina Høier; Litman, Thomas

    2004-01-01

    concentrations of K(+) when inside the erythrocyte and low concentrations when in plasma. In the recently published genome of P. falciparum, we have identified a gene, pfkch1, encoding a potential K(+) channel, which to some extent resembles the big-conductance (BK) K(+) channel. We have cloned the approximately......In most living cells, K(+) channels are important for the generation of the membrane potential and for volume regulation. The parasite Plasmodium falciparum, which causes malignant malaria, must be able to deal with large variations in the ambient K(+) concentration: it is exposed to high...... could be a potential drug target....

  7. Influence of host factors and parasite biomass on the severity of imported Plasmodium falciparum malaria.

    Directory of Open Access Journals (Sweden)

    Nicolas Argy

    Full Text Available Imported malaria in France is characterized by various clinical manifestations observed in a heterogeneous population of patients such as travelers/expatriates and African migrants. In this population, host factors and parasite biomass associated with severe imported malaria are poorly known.From data collected by the Centre National de Référence du Paludisme, we identified epidemiological, demographic and biological features including parasite biomass and anti-plasmodial antibody levels (negative, positive and strongly positive serology associated with different disease severity groups (very severe, moderately severe, and uncomplicated malaria in 3 epidemiological groups (travelers/expatriates, first- and second-generation migrants.Age, ethnicity, absence of prior infection with P. falciparum, antibody levels, plasma PfHRP2 levels, total and circulating parasite biomass were related to severe malaria onset. Sequestered parasite biomass tended to be increased in very severe malaria, and was strongly correlated to the antibody level of the host.Prior exposure to P. falciparum is associated with high anti-plasmodial antibody levels which influence clinical presentation of imported malaria and its correlated circulating and sequestered parasite burden.

  8. Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti-circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial

    DEFF Research Database (Denmark)

    Olotu, Ally; Lusingu, John; Leach, Amanda

    2011-01-01

    RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5-17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up....

  9. Plasmodium falciparum malaria importation from Africa to China and its mortality: an analysis of driving factors

    Science.gov (United States)

    Lai, Shengjie; Wardrop, Nicola A.; Huang, Zhuojie; Bosco, Claudio; Sun, Junling; Bird, Tomas; Wesolowski, Amy; Zhou, Sheng; Zhang, Qian; Zheng, Canjun; Li, Zhongjie; Tatem, Andrew J.; Yu, Hongjie

    2016-12-01

    Plasmodium falciparum malaria importation from Africa to China is rising with increasing Chinese overseas investment and international travel. Identifying networks and drivers of this phenomenon as well as the contributors to high case-fatality rate is a growing public health concern to enable efficient response. From 2011-2015, 8653 P. falciparum cases leading to 98 deaths (11.3 per 1000 cases) were imported from 41 sub-Saharan countries into China, with most cases (91.3%) occurring in labour-related Chinese travellers. Four strongly connected groupings of origin African countries with destination Chinese provinces were identified, and the number of imported cases was significantly associated with the volume of air passengers to China (P = 0.006), parasite prevalence in Africa (P relationship with parasite importation. Risk factors for deaths from imported cases were related to the capacity of malaria diagnosis and diverse socioeconomic factors. The spatial heterogeneity uncovered, principal drivers explored, and risk factors for mortality found in the rising rates of P. falciparum malaria importation to China can serve to refine malaria elimination strategies and the management of cases, and high risk groups and regions should be targeted.

  10. Falciparum malaria associated changes in biochemical indices in children

    Directory of Open Access Journals (Sweden)

    Augusta Chinyere Nsonwu-Anyanwu

    2017-01-01

    Full Text Available Metabolic disturbances associated with fluid and electrolyte imbalance, and changes in the synthetic functions of the liver are common complications of malaria and are dependent on the degree of parasitemia. Packed cell volume (PCV, random blood glucose (RBG, total bilirubin (TB, total proteins (TP, albumin, serum electrolytes [sodium (Na+, potassium (K+, chloride (Cl-, bicarbonate (HCO3-, calcium (Ca2+, magnesium (Mg2+] and anion gap (AG were determined in fifty children with malaria aged between 1-15 years and thirty age matched apparently healthy children without malaria, using colorimetric and flame photometric methods. Data was analyzed using t-test at p < 0.05. The PCV, RBG, Na+, Mg2+, AG and TP were significantly lower and Ca2+ and TB higher in children with malaria compared to children without malaria. The serum Na+, K+, AG, TP and albumin were significantly lower and Ca2+, HCO3- and TB higher in children with severe malaria compared to those with mild malaria. Malaria and high parasite density is associated with perturbations in homeostasis of proteins and electrolytes and these may be implicated in the deleterious consequences associated with malaria in children. [J Med Allied Sci 2017; 7(1.000: 29-33

  11. Effect of acute Plasmodium falciparum malaria on reactivation and shedding of the eight human herpes viruses.

    Directory of Open Access Journals (Sweden)

    Arnaud Chêne

    Full Text Available Human herpes viruses (HHVs are widely distributed pathogens. In immuno-competent individuals their clinical outcomes are generally benign but in immuno-compromised hosts, primary infection or extensive viral reactivation can lead to critical diseases. Plasmodium falciparum malaria profoundly affects the host immune system. In this retrospective study, we evaluated the direct effect of acute P. falciparum infection on reactivation and shedding of all known human herpes viruses (HSV-1, HSV-2, VZV, EBV, CMV, HHV-6, HHV-7, HHV-8. We monitored their presence by real time PCR in plasma and saliva of Ugandan children with malaria at the day of admission to the hospital (day-0 and 14 days later (after treatment, or in children with mild infections unrelated to malaria. For each child screened in this study, at least one type of HHV was detected in the saliva. HHV-7 and HHV-6 were detected in more than 70% of the samples and CMV in approximately half. HSV-1, HSV-2, VZV and HHV-8 were detected at lower frequency. During salivary shedding the highest mean viral load was observed for HSV-1 followed by EBV, HHV-7, HHV-6, CMV and HHV-8. After anti-malarial treatment the salivary HSV-1 levels were profoundly diminished or totally cleared. Similarly, four children with malaria had high levels of circulating EBV at day-0, levels that were cleared after anti-malarial treatment confirming the association between P. falciparum infection and EBV reactivation. This study shows that acute P. falciparum infection can contribute to EBV reactivation in the blood and HSV-1 reactivation in the oral cavity. Taken together our results call for further studies investigating the potential clinical implications of HHVs reactivation in children suffering from malaria.

  12. Effect of Acute Plasmodium falciparum Malaria on Reactivation and Shedding of the Eight Human Herpes Viruses

    Science.gov (United States)

    Chêne, Arnaud; Nylén, Susanne; Donati, Daria; Bejarano, Maria Teresa; Kironde, Fred; Wahlgren, Mats; Falk, Kerstin I.

    2011-01-01

    Human herpes viruses (HHVs) are widely distributed pathogens. In immuno-competent individuals their clinical outcomes are generally benign but in immuno-compromised hosts, primary infection or extensive viral reactivation can lead to critical diseases. Plasmodium falciparum malaria profoundly affects the host immune system. In this retrospective study, we evaluated the direct effect of acute P. falciparum infection on reactivation and shedding of all known human herpes viruses (HSV-1, HSV-2, VZV, EBV, CMV, HHV-6, HHV-7, HHV-8). We monitored their presence by real time PCR in plasma and saliva of Ugandan children with malaria at the day of admission to the hospital (day-0) and 14 days later (after treatment), or in children with mild infections unrelated to malaria. For each child screened in this study, at least one type of HHV was detected in the saliva. HHV-7 and HHV-6 were detected in more than 70% of the samples and CMV in approximately half. HSV-1, HSV-2, VZV and HHV-8 were detected at lower frequency. During salivary shedding the highest mean viral load was observed for HSV-1 followed by EBV, HHV-7, HHV-6, CMV and HHV-8. After anti-malarial treatment the salivary HSV-1 levels were profoundly diminished or totally cleared. Similarly, four children with malaria had high levels of circulating EBV at day-0, levels that were cleared after anti-malarial treatment confirming the association between P. falciparum infection and EBV reactivation. This study shows that acute P. falciparum infection can contribute to EBV reactivation in the blood and HSV-1 reactivation in the oral cavity. Taken together our results call for further studies investigating the potential clinical implications of HHVs reactivation in children suffering from malaria. PMID:22039454

  13. Diagnosis ofPlasmodium falciparum Malaria in CbiIdren

    African Journals Online (AJOL)

    were tested using the ICT~Malaria P f 0 test kit as well as the conventional blood film microscopy ... fundamental role of early, rapid and precise diagnosis of malaria .... Thick and thin blood films were prepared on the same slide for each patient andlabelled. The thin film was air dried and fixed with methanol prior to staining.

  14. The epidemiology of Plasmodium vivax and Plasmodium falciparum malaria in China, 2004-2012: from intensified control to elimination.

    Science.gov (United States)

    Zhang, Qian; Lai, Shengjie; Zheng, Canjun; Zhang, Honglong; Zhou, Sheng; Hu, Wenbiao; Clements, Archie C A; Zhou, Xiao-Nong; Yang, Weizhong; Hay, Simon I; Yu, Hongjie; Li, Zhongjie

    2014-11-03

    In China, the national malaria elimination programme has been operating since 2010. This study aimed to explore the epidemiological changes in patterns of malaria in China from intensified control to elimination stages. Data on nationwide malaria cases from 2004 to 2012 were extracted from the Chinese national malaria surveillance system. The secular trend, gender and age features, seasonality, and spatial distribution by Plasmodium species were analysed. In total, 238,443 malaria cases were reported, and the proportion of Plasmodium falciparum increased drastically from population. The areas affected by Plasmodium vivax malaria shrunk, while areas affected by P. falciparum malaria expanded from 294 counties in 2004 to 600 counties in 2012. This study demonstrated that malaria has decreased dramatically in the last five years, especially since the Chinese government launched a malaria elimination programme in 2010, and areas with reported falciparum malaria cases have expanded over recent years. These findings suggest that elimination efforts should be improved to meet these changes, so as to achieve the nationwide malaria elimination goal in China in 2020.

  15. The Plasmodium falciparum transcriptome in severe malaria reveals altered expression of genes involved in important processes including surface antigen–encoding var genes

    Science.gov (United States)

    Tonkin-Hill, Gerry Q.; Trianty, Leily; Noviyanti, Rintis; Nguyen, Hanh H. T.; Sebayang, Boni F.; Lampah, Daniel A.; Marfurt, Jutta; Cobbold, Simon A.; Rambhatla, Janavi S.; McConville, Malcolm J.; Rogerson, Stephen J.; Brown, Graham V.; Day, Karen P.; Price, Ric N.; Anstey, Nicholas M.

    2018-01-01

    Within the human host, the malaria parasite Plasmodium falciparum is exposed to multiple selection pressures. The host environment changes dramatically in severe malaria, but the extent to which the parasite responds to—or is selected by—this environment remains unclear. From previous studies, the parasites that cause severe malaria appear to increase expression of a restricted but poorly defined subset of the PfEMP1 variant, surface antigens. PfEMP1s are major targets of protective immunity. Here, we used RNA sequencing (RNAseq) to analyse gene expression in 44 parasite isolates that caused severe and uncomplicated malaria in Papuan patients. The transcriptomes of 19 parasite isolates associated with severe malaria indicated that these parasites had decreased glycolysis without activation of compensatory pathways; altered chromatin structure and probably transcriptional regulation through decreased histone methylation; reduced surface expression of PfEMP1; and down-regulated expression of multiple chaperone proteins. Our RNAseq also identified novel associations between disease severity and PfEMP1 transcripts, domains, and smaller sequence segments and also confirmed all previously reported associations between expressed PfEMP1 sequences and severe disease. These findings will inform efforts to identify vaccine targets for severe malaria and also indicate how parasites adapt to—or are selected by—the host environment in severe malaria. PMID:29529020

  16. Aotus infulatus monkey is susceptible to Plasmodium falciparum infection and may constitute an alternative experimental model for malaria

    Directory of Open Access Journals (Sweden)

    Carvalho Leonardo JM

    2000-01-01

    Full Text Available Aotus is one of the WHO-recommended primate models for studies in malaria, and several species can be infected with Plasmodium falciparum or P. vivax. Here we describe the successful infection of the species A. infulatus from eastern Amazon with blood stages of P. falciparum. Both intact and splenectomized animals were susceptible to infection; the intact ones were able to keep parasitemias at lower levels for several days, but developed complications such as severe anemia; splenectomized monkeys developed higher parasitemias but no major complications. We conclude that A. infulatus is susceptible to P. falciparum infection and may represent an alternative model for studies in malaria.

  17. A phase 2b randomized, controlled trial of the efficacy of the GMZ2 malaria vaccine in African children.

    Science.gov (United States)

    Sirima, Sodiomon B; Mordmüller, Benjamin; Milligan, Paul; Ngoa, Ulysse Ateba; Kironde, Fred; Atuguba, Frank; Tiono, Alfred B; Issifou, Saadou; Kaddumukasa, Mark; Bangre, Oscar; Flach, Clare; Christiansen, Michael; Bang, Peter; Chilengi, Roma; Jepsen, Søren; Kremsner, Peter G; Theisen, Michael

    2016-08-31

    GMZ2 is a recombinant protein malaria vaccine, comprising two blood-stage antigens of Plasmodium falciparum, glutamate-rich protein and merozoite surface protein 3. We assessed efficacy of GMZ2 in children in Burkina Faso, Gabon, Ghana and Uganda. Children 12-60months old were randomized to receive three injections of either 100μg GMZ2 adjuvanted with aluminum hydroxide or a control vaccine (rabies) four weeks apart and were followed up for six months to measure the incidence of malaria defined as fever or history of fever and a parasite density ⩾5000/μL. A cohort of 1849 children were randomized, 1735 received three doses of vaccine (868 GMZ2, 867 control-vaccine). There were 641 malaria episodes in the GMZ2/Alum group and 720 in the control group. In the ATP analysis, vaccine efficacy (VE), adjusted for age and site was 14% (95% confidence interval [CI]: 3.6%, 23%, p-value=0.009). In the ITT analysis, age-adjusted VE was 11.3% (95% CI 2.5%, 19%, p-value=0.013). VE was higher in older children. In GMZ2-vaccinated children, the incidence of malaria decreased with increasing vaccine-induced anti-GMZ2 IgG concentration. There were 32 cases of severe malaria (18 in the rabies vaccine group and 14 in the GMZ2 group), VE 27% (95% CI -44%, 63%). GMZ2 is the first blood-stage malaria vaccine to be evaluated in a large multicenter trial. GMZ2 was well tolerated and immunogenic, and reduced the incidence of malaria, but efficacy would need to be substantially improved, using a more immunogenic formulation, for the vaccine to have a public health role. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Cost of treating inpatient falciparum malaria on the Thai-Myanmar border.

    Science.gov (United States)

    Kyaw, Shwe Sin; Drake, Tom; Ruangveerayuth, Ronatrai; Chierakul, Wirongrong; White, Nicholas J; Newton, Paul N; Lubell, Yoel

    2014-10-29

    Despite demonstrated benefits and World Health Organization (WHO) endorsement, parenteral artesunate is the recommended treatment for patients with severe Plasmodium falciparum malaria in only one fifth of endemic countries. One possible reason for this slow uptake is that a treatment course of parenteral artesunate is costlier than quinine and might, therefore, pose a substantial economic burden to health care systems. This analysis presents a detailed account of the resources used in treating falciparum malaria by either parenteral artesunate or quinine in a hospital on the Thai-Myanmar border. The analysis used data from four studies, with random allocation of inpatients with falciparum malaria to treatment with parenteral artesunate or quinine, conducted in Mae Sot Hospital, Thailand from 1995 to 2001. Detailed resource use data were collected during admission and unit costs from the 2008 hospital price list were applied to these. Total admission costs were broken down into five categories: 1) medication; 2) intravenous fluids; 3) disposables; 4) laboratory tests; and 5) services. While the medication costs were higher for patients treated with artesunate, total admission costs were similar in those treated with quinine, US$ 243 (95% CI: 167.5-349.7) and in those treated with artesunate US$ 190 (95% CI: 131.0-263.2) (P=0.375). For cases classified as severe malaria (59%), the total cost of admission was US$ 298 (95% CI: 203.6-438.7) in the quinine group as compared with US$ 284 (95% CI: 181.3-407) in the artesunate group (P=0.869). This analysis finds no evidence for a difference in total admission costs for malaria inpatients treated with artesunate as compared with quinine. Assuming this is generalizable to other settings, the higher cost of a course of artesunate should not be considered a barrier for its implementation in the treatment of malaria.

  19. Defining the protein interaction network of human malaria parasite Plasmodium falciparum

    KAUST Repository

    Ramaprasad, Abhinay

    2012-02-01

    Malaria, caused by the protozoan parasite Plasmodium falciparum, affects around 225. million people yearly and a huge international effort is directed towards combating this grave threat to world health and economic development. Considerable advances have been made in malaria research triggered by the sequencing of its genome in 2002, followed by several high-throughput studies defining the malaria transcriptome and proteome. A protein-protein interaction (PPI) network seeks to trace the dynamic interactions between proteins, thereby elucidating their local and global functional relationships. Experimentally derived PPI network from high-throughput methods such as yeast two hybrid (Y2H) screens are inherently noisy, but combining these independent datasets by computational methods tends to give a greater accuracy and coverage. This review aims to discuss the computational approaches used till date to construct a malaria protein interaction network and to catalog the functional predictions and biological inferences made from analysis of the PPI network. © 2011 Elsevier Inc.

  20. Transplacental Transmission of Plasmodium falciparum in a Highly Malaria Endemic Area of Burkina Faso

    Directory of Open Access Journals (Sweden)

    Alphonse Ouédraogo

    2012-01-01

    Full Text Available Malaria congenital infection constitutes a major risk in malaria endemic areas. In this study, we report the prevalence of transplacental malaria in Burkina Faso. In labour and delivery units, thick and thin blood films were made from maternal, placental, and umbilical cord blood to determine malaria infection. A total of 1,309 mother/baby pairs were recruited. Eighteen cord blood samples (1.4% contained malaria parasites (Plasmodium falciparum. Out of the 369 (28.2% women with peripheral positive parasitemia, 211 (57.2% had placental malaria and 14 (3.8% had malaria parasites in their umbilical cord blood. The umbilical cord parasitemia levels were statistically associated with the presence of maternal peripheral parasitemia (OR=9.24, ≪0.001, placental parasitemia (OR=10.74, ≪0.001, high-density peripheral parasitemia (OR=9.62, ≪0.001, and high-density placental parasitemia (OR=4.91, =0.03. In Burkina Faso, the mother-to-child transmission rate of malaria appears to be low.

  1. Chloroquine-resistant Plasmodium falciparum malaria·in the ...

    African Journals Online (AJOL)

    In addition, surgical gloves.were worn during the entire procedure to. protect both the operator and the isolates. Thick and thin blood smears were prepared from each blood sample, stained with Giemsa's solution and examined micro- scopically for the presence of P. falciparum.. Isolates were considered to be unsuitable for ...

  2. Cellulose filtration of blood from malaria patients for improving ex vivo growth of Plasmodium falciparum parasites

    DEFF Research Database (Denmark)

    Mkumbaye, Sixbert I; Minja, Daniel T R; Jespersen, Jakob S

    2017-01-01

    BACKGROUND: Establishing in vitro Plasmodium falciparum culture lines from patient parasite isolates can offer deeper understanding of geographic variations of drug sensitivity and mechanisms of malaria pathogenesis and immunity. Cellulose column filtration of blood is an inexpensive, rapid...... and effective method for the removal of host factors, such as leucocytes and platelets, significantly improving the purification of parasite DNA in a blood sample. METHODS: In this study, the effect of cellulose column filtration of venous blood on the initial in vitro growth of P. falciparum parasite isolates....... falciparum merozoite surface protein 2 genotyping was performed using nested PCR on extracted genomic DNA, and the var gene transcript levels were investigated, using quantitative PCR on extracted RNA, at admission and 4 days of culture. RESULTS: The cellulose-filtered parasites grew to higher parasitaemia...

  3. Update on the Clinical Development of Candidate Malaria Vaccines

    National Research Council Canada - National Science Library

    Ballou, W. R; Arevalo-Herrera, Myriam; Carucci, Daniel; Richie, Thomas L; Corradin, Giampietro; Diggs, Carter; Druilhe, Pierre; Giersing, Birgitte K; Saul, Allan; Heppner, D. G

    2004-01-01

    ... powerful driver for stimulating clinical development of candidate vaccines for malaria. This new way forward promises to greatly increase the likelihood of bringing a safe and effective vaccine to licensure...

  4. A fresh look at the origin of Plasmodium falciparum, the most malignant malaria agent.

    Directory of Open Access Journals (Sweden)

    Franck Prugnolle

    2011-02-01

    Full Text Available From which host did the most malignant human malaria come: birds, primates, or rodents? When did the transfer occur? Over the last half century, these have been some of the questions up for debate about the origin of Plasmodium falciparum, the most common and deadliest human malaria parasite, which is responsible for at least one million deaths every year. Recent findings bring elements in favor of a transfer from great apes, but are these evidences really solid? What are the grey areas that remain to be clarified? Here, we examine in depth these new elements and discuss how they modify our perception of the origin and evolution of P. falciparum. We also discuss the perspectives these new discoveries open.

  5. Comparison of artesunate and quinine in the treatment of Sudanese children with severe Plasmodium falciparum malaria.

    Science.gov (United States)

    Eltahir, Hatim G; Omer, Abubaker A; Mohamed, Ayoub A; Adam, Ishag

    2010-10-01

    Sixty-six children presenting to Singa hospital, Sudan with different manifestations of severe Plasmodium falciparum malaria were randomly divided into two well-matched groups (33 in each arm) to receive either intravenous artesunate 2·4 mg/kg at 0, 12, and 24 hours, then daily, or intravenous quinine 20mg/kg initially then 10mg/kg three times a day. There was no significant difference in the fever, parasite clearance, and coma resolution times. Three patients died, one in the artesunate and two in the quinine groups. One patient developed hypoglycaemia following quinine infusion. Thus, artesunate can be used for the treatment of severe falciparum malaria. Copyright © 2010 Royal Society of Tropical Medicine and Hygiene.

  6. An outbreak of Plasmodium falciparum malaria in U.S. Marines deployed to Liberia.

    Science.gov (United States)

    Whitman, Timothy J; Coyne, Philip E; Magill, Alan J; Blazes, David L; Green, Michael D; Milhous, Wilbur K; Burgess, Timothy H; Freilich, Daniel; Tasker, Sybil A; Azar, Ramzy G; Endy, Timothy P; Clagett, Christopher D; Deye, Gregory A; Shanks, G Dennis; Martin, Gregory J

    2010-08-01

    In 2003, 44 U.S. Marines were evacuated from Liberia with either confirmed or presumed Plasmodium falciparum malaria. An outbreak investigation showed that only 19 (45%) used insect repellent, 5 (12%) used permethrin-treated clothing, and none used bed netting. Adherence with weekly mefloquine (MQ) was reported by 23 (55%). However, only 4 (10%) had serum MQ levels high enough to correlate with protection (> 794 ng/mL), and 9 (22%) had evidence of steady-state kinetics (MQ carboxy metabolite/MQ > 3.79). Tablets collected from Marines met USP identity and dissolution specifications for MQ. Testing failed to identify P. falciparum isolates with MQ resistance. This outbreak resulted from under use of personal protective measures and inadequate adherence with chemophrophylaxis. It is essential that all international travelers make malaria prevention measures a priority, especially when embarking to regions of the world with high transmission intensity such as west Africa..

  7. Malaria-induced acquisition of antibodies to Plasmodium falciparum variant surface antigens

    DEFF Research Database (Denmark)

    Ofori, Michael F; Dodoo, Daniel; Staalsoe, Trine

    2002-01-01

    In areas of intense Plasmodium falciparum transmission, protective immunity is acquired during childhood in parallel with acquisition of agglutinating antibodies to parasite-encoded variant surface antigens (VSA) expressed on parasitized red blood cells. In a semi-immune child in such an area......, clinical disease is caused mainly by parasites expressing VSA not recognized by preexisting VSA-specific antibodies in that child. Such malaria episodes are known to cause an increase in agglutinating antibodies specifically recognizing VSA expressed by the parasite isolate causing the illness, whereas...... antibody responses to other parasite isolates are relatively unaffected. However, the detailed kinetics of this VSA antibody acquisition are unknown and hence were the aim of this study. We show that P. falciparum malaria in Ghanaian children generally caused a rapid and sustained increase in variant...

  8. Gibberellin biosynthetic inhibitors make human malaria parasite Plasmodium falciparum cells swell and rupture to death.

    Directory of Open Access Journals (Sweden)

    Tomoko Toyama

    Full Text Available Malaria remains as one of the most devastating infectious disease, and continues to exact an enormous toll in medical cost and days of labor lost especially in the tropics. Effective malaria control and eventual eradication remain a huge challenge, with efficacious antimalarials as important intervention/management tool. Clearly new alternative drugs that are more affordable and with fewer side effects are desirable. After preliminary in vitro assays with plant growth regulators and inhibitors, here, we focus on biosynthetic inhibitors of gibberellin, a plant hormone with many important roles in plant growth, and show their inhibitory effect on the growth of both apicomplexa, Plasmodium falciparum and Toxoplasma gondii. Treatment of P. falciparum cultures with the gibberellin biosynthetic inhibitors resulted in marked morphological changes that can be reversed to a certain degree under hyperosmotic environment. These unique observations suggest that changes in the parasite membrane permeability may explain the pleiotropic effects observed within the intracellular parasites.

  9. Non-falciparum malaria in Dakar: a confirmed case of Plasmodium ovale wallikeri infection.

    Science.gov (United States)

    Diallo, Mamadou A; Badiane, Aida S; Diongue, Khadim; Deme, Awa; Lucchi, Naomi W; Gaye, Marie; Ndiaye, Tolla; Ndiaye, Mouhamadou; Sene, Louise K; Diop, Abdoulaye; Gaye, Amy; Ndiaye, Yaye D; Samb, Diama; Yade, Mamadou S; Ndir, Omar; Udhayakumar, Venkatachalam; Ndiaye, Daouda

    2016-08-24

    Plasmodium ovale is rarely described in Senegal. A case of clinical malaria due to P. ovale wallikeri in West Central of Senegal is reported. A 34-year-old male baker in Dakar, with no significant previous medical history, was admitted to a health clinic with fever and vomiting. Fever had been lasting for 4 days with peaks every 48 h. As monospecific Plasmodium falciparum HRP-2 RDT was negative, he was treated with antibiotics. However, owing to persisting symptoms, he was referred to the emergency unit of the Youssou Mbargane Diop Hospital, Dakar, Senegal. Clinical examination found impaired general condition. All other physical examinations were normal. Laboratory tests showed anaemia (haemoglobin 11.4 g/dl), severe thrombocytopaenia (platelets 30 × 10(9)/mm(3)), leukopenia (3650/mm(3)), lymphocytopenia (650/mm(3)). Renal function was normal as indicated by creatininaemia and uraemia (11 mg/l and 0.25 g/l, respectively) and liver enzymes were slightly elevated (aspartate aminotransferase 77 UI/l and alanine aminotransferase 82 UI/l). Blood smear evaluations in Parasitology Laboratory of Aristide Le Dantec Hospital showed malaria parasites of the species P. ovale with a 0.08 % parasitaemia. Molecular confirmation was done by real time PCR targeting the 18S rRNA gene. The P. ovale infection was further analysed to species level targeting the potra gene and was identified as P. ovale wallikeri. According to the hospital's malaria treatment guidelines for severe malaria, treatment consisted of intravenous quinine at hour 0 (start of treatment) and 24 h after initial treatment, followed by artemether-lumefantrine 24 h later. A negative microscopy was noted on day 3 post-treatment and the patient reported no further symptoms. Malaria due to non-falciparum species is probably underestimated in Senegal. RDTs specific to non-falciparum species and/or pan specific RDTs should be included as tools of diagnosis to fight against malaria in Senegal. In addition

  10. VAR2CSA and protective immunity against pregnancy-associated Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Hviid, L; Salanti, A

    2007-01-01

    People living in areas with stable transmission of P. falciparum parasites acquire protective immunity to malaria over a number of years and following multiple disease episodes. Immunity acquired this way is mediated by IgG with specificity for parasite-encoded, clonally variant surface antigens...... that the selective placental accumulation of IEs that characterizes pregnancy-associated malaria (PAM) is caused by an immunologically and functionally unique subset of VSA (VSAPAM) that is only expressed by parasites infecting pregnant women, and that protective immunity to PAM is mediated by IgG with specificity...

  11. Fingerprinting the substrate specificity of M1 and M17 aminopeptidases of human malaria, Plasmodium falciparum.

    Science.gov (United States)

    Poreba, Marcin; McGowan, Sheena; Skinner-Adams, Tina S; Trenholme, Katharine R; Gardiner, Donald L; Whisstock, James C; To, Joyce; Salvesen, Guy S; Dalton, John P; Drag, Marcin

    2012-01-01

    Plasmodium falciparum, the causative agent of human malaria, expresses two aminopeptidases, PfM1AAP and PfM17LAP, critical to generating a free amino acid pool used by the intraerythrocytic stage of the parasite for proteins synthesis, growth and development. These exopeptidases are potential targets for the development of a new class of anti-malaria drugs. To define the substrate specificity of recombinant forms of these two malaria aminopeptidases we used a new library consisting of 61 fluorogenic substrates derived both from natural and unnatural amino acids. We obtained a detailed substrate fingerprint for recombinant forms of the enzymes revealing that PfM1AAP exhibits a very broad substrate tolerance, capable of efficiently hydrolyzing neutral and basic amino acids, while PfM17LAP has narrower substrate specificity and preferentially cleaves bulky, hydrophobic amino acids. The substrate library was also exploited to profile the activity of the native aminopeptidases in soluble cell lysates of P. falciparum malaria. This data showed that PfM1AAP and PfM17LAP are responsible for majority of the aminopeptidase activity in these extracts. These studies provide specific substrate and mechanistic information important for understanding the function of these aminopeptidases and could be exploited in the design of new inhibitors to specifically target these for anti-malaria treatment.

  12. Fingerprinting the substrate specificity of M1 and M17 aminopeptidases of human malaria, Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Marcin Poreba

    Full Text Available Plasmodium falciparum, the causative agent of human malaria, expresses two aminopeptidases, PfM1AAP and PfM17LAP, critical to generating a free amino acid pool used by the intraerythrocytic stage of the parasite for proteins synthesis, growth and development. These exopeptidases are potential targets for the development of a new class of anti-malaria drugs.To define the substrate specificity of recombinant forms of these two malaria aminopeptidases we used a new library consisting of 61 fluorogenic substrates derived both from natural and unnatural amino acids. We obtained a detailed substrate fingerprint for recombinant forms of the enzymes revealing that PfM1AAP exhibits a very broad substrate tolerance, capable of efficiently hydrolyzing neutral and basic amino acids, while PfM17LAP has narrower substrate specificity and preferentially cleaves bulky, hydrophobic amino acids. The substrate library was also exploited to profile the activity of the native aminopeptidases in soluble cell lysates of P. falciparum malaria.This data showed that PfM1AAP and PfM17LAP are responsible for majority of the aminopeptidase activity in these extracts. These studies provide specific substrate and mechanistic information important for understanding the function of these aminopeptidases and could be exploited in the design of new inhibitors to specifically target these for anti-malaria treatment.

  13. Report of a consultation on the optimization of clinical challenge trials for evaluation of candidate blood stage malaria vaccines, 18-19 March 2009, Bethesda, MD, USA.

    NARCIS (Netherlands)

    Moorthy, V.S.; Diggs, C.; Ferro, S.; Good, M.F.; Herrera, S.; Hill, A.V.; Imoukhuede, E.B.; Kumar, S.; Loucq, C.; Marsh, K.; Ockenhouse, C.F.; Richie, T.L.; Sauerwein, R.W.

    2009-01-01

    Development and optimization of first generation malaria vaccine candidates has been facilitated by the existence of a well-established Plasmodium falciparum clinical challenge model in which infectious sporozoites are administered to human subjects via mosquito bite. While ideal for testing

  14. Morbidity from malaria and immune responses to defined Plasmodium falciparum antigens in children with sickle cell trait in The Gambia

    DEFF Research Database (Denmark)

    Allen, S J; Bennett, S; Riley, E M

    1993-01-01

    Morbidity from Plasmodium falciparum malaria and humoral and in vitro cellular immune responses to defined malaria antigens were measured in rural Gambian children with haemoglobin phenotype AS (HbAS) and in those with a normal haemoglobin (HbAA). In a survey undertaken during the dry season, HbA...

  15. Distinct patterns of cytokine regulation in discrete clinical forms of Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Akanmori, B D; Kurtzhals, J A; Goka, B Q

    2000-01-01

    The pathogenesis of two of the most severe complications of Plasmodium falciparum malaria, cerebral malaria (CM) and severe malarial anaemia (SA) both appear to involve dysregulation of the immune system. We have measured plasma levels of TNF and its two receptors in Ghanaian children with strict...

  16. The role of reduced red cell deformability in the pathogenesis of severe falciparum malaria and its restoration by blood transfusion

    NARCIS (Netherlands)

    Dondorp, A. M.; Nyanoti, M.; Kager, P. A.; Mithwani, S.; Vreeken, J.; Marsh, K.

    2002-01-01

    As reduced red cell deformability (RCD) can contribute to derangement of the microcirculation, a central feature in the pathogenesis of severe malaria, RCD was measured with a laser diffraction technique in 232 consecutive patients with falciparum. malaria on the Kenyan coast, of whom 99 had severe

  17. Plasmodium falciparum infection in febrile Congolese children: prevalence of clinical malaria 10 years after introduction of artemisinin-combination therapies.

    Science.gov (United States)

    Etoka-Beka, Mandingha Kosso; Ntoumi, Francine; Kombo, Michael; Deibert, Julia; Poulain, Pierre; Vouvoungui, Christevy; Kobawila, Simon Charles; Koukouikila-Koussounda, Felix

    2016-12-01

    To investigate the proportion of malaria infection in febrile children consulting a paediatric hospital in Brazzaville, to determine the prevalence of submicroscopic malaria infection, to characterise Plasmodium falciparum infection and compare the prevalence of uncomplicated P. falciparum malaria according to haemoglobin profiles. Blood samples were collected from children aged <10 years with an axillary temperature ≥37.5 °C consulting the paediatric ward of Marien Ngouabi Hospital in Brazzaville. Parasite density was determined and all samples were screened for P. falciparum by nested polymerase chain reaction (PCR) using the P. falciparum msp-2 marker to detect submicroscopic infections and characterise P. falciparum infection. Sickle cell trait was screened by PCR. A total of 229 children with fever were recruited, of whom 10% were diagnosed with uncomplicated malaria and 21% with submicroscopic infection. The mean parasite density in children with uncomplicated malaria was 42 824 parasites/μl of blood. The multiplicity of infection (MOI) was 1.59 in children with uncomplicated malaria and 1.69 in children with submicroscopic infection. The mean haemoglobin level was 10.1 ± 1.7 for children with uncomplicated malaria and 12.0 ± 8.6 for children with submicroscopic infection. About 13% of the children harboured the sickle cell trait (HbAS); the rest had normal haemoglobin (HbAA). No difference in prevalence of uncomplicated malaria and submicroscopic infection, parasite density, haemoglobin level, MOI and P. falciparum genetic diversity was observed according to haemoglobin type. The low prevalence of uncomplicated malaria in febrile Congolese children indicates the necessity to investigate carefully other causes of fever. © 2016 John Wiley & Sons Ltd.

  18. Genetic Diversity of Plasmodium falciparum Populations in Malaria Declining Areas of Sabah, East Malaysia.

    Directory of Open Access Journals (Sweden)

    Mohd Ridzuan Mohd Abd Razak

    Full Text Available Malaysia has a national goal to eliminate malaria by 2020. Understanding the genetic diversity of malaria parasites in residual transmission foci can provide invaluable information which may inform the intervention strategies used to reach elimination targets. This study was conducted to determine the genetic diversity level of P. falciparum isolates in malaria residual foci areas of Sabah. Malaria active case detection was conducted in Kalabakan and Kota Marudu. All individuals in the study sites were screened for malaria infection by rapid diagnostic test. Blood from P. falciparum-infected individuals were collected on filter paper prior to DNA extraction. Genotyping was performed using merozoite surface protein-1 (MSP-1, merozoite surface protein-2 (MSP-2, glutamate rich protein (GLURP and 10 neutral microsatellite loci markers. The size of alleles, multiplicity of infection (MOI, mean number of alleles (Na, expected heterozygosity (He, linkage disequilibrium (LD and genetic differentiation (FST were determined. In Kalabakan, the MSP-1 and MSP-2 alleles were predominantly K1 and FC27 family types, respectively. The GLURP genotype VI (751-800 bp was predominant. The MOI for MSP-1 and MSP-2 were 1.65 and 1.20, respectively. The Na per microsatellite locus was 1.70. The He values for MSP-1, MSP-2, GLURP and neutral microsatellites were 0.17, 0.37, 0.70 and 0.33, respectively. In Kota Marudu, the MSP-1 and MSP-2 alleles were predominantly MAD20 and 3D7 family types, respectively. The GLURP genotype IV (651-700 bp was predominant. The MOI for both MSP-1 and MSP-2 was 1.05. The Na per microsatellite locus was 3.60. The He values for MSP-1, MSP-2, GLURP and neutral microsatellites were 0.24, 0.25, 0.69 and 0.30, respectively. A significant LD was observed in Kalabakan (0.495, p<0.01 and Kota Marudu P. falciparum populations (0.601, p<0.01. High genetic differentiation between Kalabakan and Kota Marudu P. falciparum populations was observed (FST = 0

  19. Zinc and copper levels in children with severe plasmodium falciparum malaria in an area of unstable malaria transmission in eastern Sudan

    International Nuclear Information System (INIS)

    Doka, Y. A.

    2012-08-01

    The aim of this study is to measure the levels of zinc and copper in children suffering from plasmodium falciparum malaria in an area of unstable malaria transmission in Eastern Sudan. The importance of the study emanates from the fact that this type of malaria is prevalent in a serious manner and causes many fatalities and problems. In this study the analytic statistical methodology was adopted using Atomic Absorption Spectroscopy. Subject target groups, confirmed microscopically to be infected with malaria, (severe malaria 35 samples and two control groups: 35 samples of uncomplicated malaria and 35 samples of apparently healthy). The study revealed that there is a significant increase in the level of copper for both types of malaria ( the severe and the uncomplicated) while uncomplicated malaria decreased the level of zinc significantly. The study recommended that zinc supplement could be used for the patients suffering from severe malaria. (Author)

  20. Pharmacokinetic-Pharmacodynamic Model for the Effect of l-Arginine on Endothelial Function in Patients with Moderately Severe Falciparum Malaria.

    NARCIS (Netherlands)

    Brussee, J.M.; Yeo, T.W.; Lampah, D.A.; Anstey, N.M.; Duffull, S.B.

    2016-01-01

    Impaired organ perfusion in severe falciparum malaria arises from microvascular sequestration of parasitized cells and endothelial dysfunction. Endothelial dysfunction in malaria is secondary to impaired nitric oxide (NO) bioavailability, in part due to decreased plasma concentrations of l-arginine,

  1. Assessment of parental perception of malaria vaccine in Tanzania.

    Science.gov (United States)

    Romore, Idda; Ali, Ali Mohamed; Semali, Innocent; Mshinda, Hassan; Tanner, Marcel; Abdulla, Salim

    2015-09-17

    Clinical trials of the RTS,S malaria vaccine have completed Phase III and the vaccine is on track for registration. Before making decisions about implementation, it is essential to prepare the ground for introducing the vaccine by assessing awareness and willingness to use malaria vaccines and to provide policy makers with evidence-based information on the best strategies to engage communities to manage the introduction of malaria vaccine in Tanzania. In November 2011, as part of a large cross-sectional study of all 23 regions of Tanzania (mainland Tanzania and Zanzibar) was conducted during Tanzanian Integrated Measles Campaign (IMC) survey. In this study, the variables of interests were awareness and willingness to use a malaria vaccine. The main outcome measure was willingness to use a malaria vaccine. Logistic regression was used to examine the influence of predictive factors. A representative sample of 5502 (out of 6210) women, aged 18 years or older and with children under 11 months old, was selected to participate, using random sampling probability. Awareness of the forthcoming malaria vaccine, 11.8 % of participants in mainland Tanzania responded affirmatively, compared to 3.4 % in Zanzibar (p value Tanzania (94.3 %) and Zanzibar (96.8 %) (p value = 0.0167). Although mothers had low awareness and high willingness to use malaria vaccine, still availability of malaria vaccine RTS,S will compliment other existing malaria interventions and it will be implemented through the Immunization, Vaccines and Biologicals (IVB) programme (formerly EPI). The information generated from this study can aid policy makers in planning and setting priorities for introducing and implementing the malaria vaccine.

  2. Pharmacokinetics of Mefloquine Combined with Artesunate in Children with Acute Falciparum Malaria

    Science.gov (United States)

    Price, Ric; Simpson, Julie A.; Teja-Isavatharm, Paktiya; Than, Myint Myint; Luxemburger, Christine; Gray Heppner, D.; Chongsuphajaisiddhi, Tan; Nosten, François; White, Nicholas J.

    1999-01-01

    Combining artemisinin or a derivative with mefloquine increases cure rates in falciparum malaria patients, reduces transmission, and may slow the development of resistance. The combination of artesunate, given for 3 days, and mefloquine is now the treatment of choice for uncomplicated multidrug-resistant falciparum malaria acquired on the western or eastern borders of Thailand. To optimize mefloquine administration in this combination, a prospective study of mefloquine pharmacokinetics was conducted with 120 children (4 to 15 years old) with acute uncomplicated falciparum malaria, who were divided into four age- and sex-matched groups. The patients all received artesunate (4 mg/kg of body weight/day orally for 3 days and mefloquine as either (i) a single dose (25 mg/kg) on day 2 with food, (ii) a split dose (15 mg/kg on day 2 and 10 mg/kg on day 3) with food, (iii) a single dose (25 mg/kg) on day 0 without food, or (iv) a single dose (25 mg/kg) on day 2 without food. Delaying administration of mefloquine until day 2 was associated with a mean (95% confidence interval) increase in estimated oral bioavailability of 72% (36 to 109%). On day 2 coadministration with food did not increase mefloquine absorption significantly, and there were no significant differences between patients receiving split- and single-dose administration. In combination with artesunate, mefloquine administration should be delayed until the second or third day after presentation. PMID:9925529

  3. Atovaquone and proguanil versus pyrimethamine/sulfadoxine for the treatment of acute falciparum malaria in Zambia.

    Science.gov (United States)

    Mulenga, M; Sukwa, T Y; Canfield, C J; Hutchinson, D B

    1999-05-01

    Atovaquone and proguanil hydrochloride are blood schizonticides that demonstrate in vitro synergy against drug-resistant strains of Plasmodium falciparum. When coadministered, they may therefore be effective for the treatment of malaria in regions where there is known or suspected drug resistance. In an open-label, randomized, parallel-group, clinical trial conducted in Zambia, 163 patients (age range, 14 to 54 years) with acute P falciparum malaria were randomly assigned to receive treatment with atovaquone and proguanil hydrochloride (1000 and 400 mg, respectively, administered orally at 24-hour intervals for 3 doses; n = 82) or pyrimethamine/sulfadoxine (75/1500 mg administered orally as a single dose; n = 81). Efficacy was assessed by cure rate (the percentage of patients in whom parasitemia was eliminated and did not recur during 28 days of follow-up), parasite clearance time (PCT), and fever clearance time (FCT). Safety was determined by sequential clinical and laboratory assessments over 28 days. Cure rates did not differ significantly between patients treated with atovaquone and proguanil (100%) and those treated with pyrimethamine/sulfadoxine (98.8%). Patients in the atovaquone and proguanil group had a significantly shorter FCT than patients in the pyrimethamine/sulfadoxine group (mean, 30.4 vs 44.9 hours; P proguanil was equally effective and as well tolerated as pyrimethamine/sulfadoxine for the treatment of acute, uncomplicated, drug-resistant falciparum malaria in Zambia.

  4. Perception and acceptability of malaria vaccine among maternal ...

    African Journals Online (AJOL)

    Background: Ninety percent of the world's malaria cases occur in sub-Saharan Africa. Because of challenges with ongoing malaria control strategies there is need for newer strategies such as malaria vaccine. Nigeria's immunization program has suffered series of setback in recent times due to misperception that marred its ...

  5. Long-term clinical protection from falciparum malaria is strongly associated with IgG3 antibodies to merozoite surface protein 3.

    Directory of Open Access Journals (Sweden)

    Christian Roussilhon

    2007-11-01

    Full Text Available BACKGROUND: Surrogate markers of protective immunity to malaria in humans are needed to rationalize malaria vaccine discovery and development. In an effort to identify such markers, and thereby provide a clue to the complex equation malaria vaccine development is facing, we investigated the relationship between protection acquired through exposure in the field with naturally occurring immune responses (i.e., induced by the parasite to molecules that are considered as valuable vaccine candidates. METHODS AND FINDINGS: We analyzed, under comparative conditions, the antibody responses of each of six isotypes to five leading malaria vaccine candidates in relation to protection acquired by exposure to natural challenges in 217 of the 247 inhabitants of the African village of Dielmo, Senegal (96 children and 121 older adolescents and adults. The status of susceptibility or resistance to malaria was determined by active case detection performed daily by medical doctors over 6 y from a unique follow-up study of this village. Of the 30 immune responses measured, only one, antibodies of the IgG3 isotype directed to merozoite surface protein 3 (MSP3, was strongly associated with clinical protection against malaria in all age groups, i.e., independently of age. This immunological parameter had a higher statistical significance than the sickle cell trait, the strongest factor of protection known against Plasmodium falciparum. A single determination of antibody was significantly associated with the clinical outcome over six consecutive years in children submitted to massive natural parasite challenges by mosquitoes (over three parasite inoculations per week. Finally, the target epitopes of these antibodies were found to be fully conserved. CONCLUSIONS: Since anti-MSP3 IgG3 antibodies can naturally develop along with protection against P. falciparum infection in young children, our results provide the encouraging indication that these antibodies should be

  6. Functional evaluation of malaria Pfs25 DNA vaccine by in vivo electroporation in olive baboons.

    Science.gov (United States)

    Kumar, Rajesh; Nyakundi, Ruth; Kariuki, Thomas; Ozwara, Hastings; Nyamongo, Onkoba; Mlambo, Godfree; Ellefsen, Barry; Hannaman, Drew; Kumar, Nirbhay

    2013-06-28

    Plasmodium falciparum Pfs25 antigen, expressed on the surface of zygotes and ookinetes, is one of the leading targets for the development of a malaria transmission-blocking vaccine (TBV). Our laboratory has been evaluating DNA plasmid based Pfs25 vaccine in mice and non-human primates. Previously, we established that in vivo electroporation (EP) delivery is an effective method to improve the immunogenicity of DNA vaccine encoding Pfs25 in mice. In order to optimize the in vivo EP procedure and test for its efficacy in more clinically relevant larger animal models, we employed in vivo EP to evaluate the immune response and protective efficacy of Pfs25 encoding DNA vaccine in nonhuman primates (olive baboons, Papio anubis). The results showed that at a dose of 2.5mg DNA vaccine, antibody responses were significantly enhanced with EP as compared to without EP resulting in effective transmission blocking efficiency. Similar immunogenicity enhancing effect of EP was also observed with lower doses (0.5mg and 1mg) of DNA plasmids. Further, final boosting with a single dose of recombinant Pfs25 protein resulted in dramatically enhanced antibody titers and significantly increased functional transmission blocking efficiency. Our study suggests priming with DNA vaccine via EP along with protein boost regimen as an effective method to elicit potent immunogenicity of malaria DNA vaccines in nonhuman primates and provides the basis for further evaluation in human volunteers. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Plasmodium falciparum histidine-rich protein II causes vascular leakage and exacerbates experimental cerebral malaria in mice.

    Science.gov (United States)

    Pal, Priya; Balaban, Amanda E; Diamond, Michael S; Sinnis, Photini; Klein, Robyn S; Goldberg, Daniel E

    2017-01-01

    A devastating complication of Plasmodium falciparum infection is cerebral malaria, in which vascular leakage and cerebral swelling lead to coma and often death. P. falciparum produces a protein called histidine-rich protein II (HRPII) that accumulates to high levels in the bloodstream of patients and serves as a diagnostic and prognostic marker for falciparum malaria. Using a human cerebral microvascular endothelial barrier model, we previously found that HRPII activates the endothelial cell inflammasome, resulting in decreased integrity of tight junctions and increased endothelial barrier permeability. Here, we report that intravenous administration of HRPII induced blood-brain barrier leakage in uninfected mice. Furthermore, HRPII infusion in P. berghei-infected mice increased early mortality from experimental cerebral malaria. These data support the hypothesis that HRPII is a virulence factor that contributes to cerebral malaria by compromising the integrity of the blood-brain barrier.

  8. [Establishment of early warning system of malaria in Jiangsu Province V Es- tablishment of prevention and control system of imported falciparum malaria].

    Science.gov (United States)

    Wang, Wei-ming; Zhou, Hua-yun; Liu, Yao-bao; Cao, Yuan-yuan; Cao, Jun; Gao, Qi

    2015-08-01

    To establish a system of the prevention and control of imported falciparum malaria in Jiangsu Prov- ince and provide the new scientific basis for the prevention and control of imported falciparum malaria. The data- bases for overseas labor companies and labors in Jiangsu Province were built and the health education was conducted to the overseas labors. The "1-3-7" elimination strategy was established. A weekly reporting system for malaria case details was es- tablished. A system for screening accompanies of imported malaria patients was established. At the end of 2013, the database of companies engaged in labor export was built and1 405 companies were incorporated into the database. The time interval between the symptom onset and the first health facility visit was reduced to 3.07 days in 2013. The time interval be- tween the first health facility visit to malaria diagnosis was reduced to 1.57 days in 2013. The rate of laboratory confirmation was increased to 100% in 2013, and there was a statistically significant difference among the rates of laboratory confirmation from 2009 to 2013 (χ2 = 36.35, P system of the prevention and control of imported falciparum malaria, which plays an important role in the prevention and control of overseas imported falciparum malaria.

  9. Presence of Plasmodium falciparum DNA in Plasma Does Not Predict Clinical Malaria in an HIV-1 Infected Population.

    Directory of Open Access Journals (Sweden)

    Marika Orlov

    Full Text Available HIV-1 and Plasmodium falciparum malaria cause substantial morbidity in Sub-Saharan Africa, especially as co-infecting pathogens. We examined the relationship between presence of P. falciparum DNA in plasma samples and clinical malaria as well as the impact of atazanavir, an HIV-1 protease inhibitor (PI, on P. falciparum PCR positivity.ACTG study A5175 compared two NNRTI-based regimens and one PI-based anti-retroviral (ARV regimen in antiretroviral therapy naïve participants. We performed nested PCR on plasma samples for the P. falciparum 18s rRNA gene to detect the presence of malaria DNA in 215 of the 221 participants enrolled in Blantyre and Lilongwe, Malawi. We also studied the closest sample preceding the first malaria diagnosis from 102 persons with clinical malaria and randomly selected follow up samples from 88 persons without clinical malaria.PCR positivity was observed in 18 (8% baseline samples and was not significantly associated with age, sex, screening CD4+ T-cell count, baseline HIV-1 RNA level or co-trimoxazole use within the first 8 weeks. Neither baseline PCR positivity (p = 0.45 nor PCR positivity after initiation of antiretroviral therapy (p = 1.0 were significantly associated with subsequent clinical malaria. Randomization to the PI versus NNRTI ARV regimens was not significantly associated with either PCR positivity (p = 0.5 or clinical malaria (p = 0.609. Clinical malaria was associated with a history of tuberculosis (p = 0.006 and a lower BMI (p = 0.004.P. falciparum DNA was detected in 8% of participants at baseline, but was not significantly associated with subsequent development of clinical malaria. HIV PI therapy did not decrease the prevalence of PCR positivity or incidence of clinical disease.

  10. The dog that did not bark: malaria vaccines without antibodies.

    NARCIS (Netherlands)

    Heppner, D.G.; Schwenk, R.J.; Arnot, D.; Sauerwein, R.W.; Luty, A.J.F.

    2007-01-01

    To date, the only pre-blood stage vaccine to confer protection against malaria in field trials elicits both antigen-specific antibody and T-cell responses. Recent clinical trials of new heterologous prime-boost malaria vaccine regimens using DNA, fowlpox or MVA, have chiefly elicited T-cell

  11. Proteomic Investigation of Falciparum and Vivax Malaria for Identification of Surrogate Protein Markers

    Science.gov (United States)

    Ray, Sandipan; Renu, Durairaj; Srivastava, Rajneesh; Gollapalli, Kishore; Taur, Santosh; Jhaveri, Tulip; Dhali, Snigdha; Chennareddy, Srinivasarao; Potla, Ankit; Dikshit, Jyoti Bajpai; Srikanth, Rapole; Gogtay, Nithya; Thatte, Urmila; Patankar, Swati; Srivastava, Sanjeeva

    2012-01-01

    This study was conducted to analyze alterations in the human serum proteome as a consequence of infection by malaria parasites Plasmodium falciparum and P. vivax to obtain mechanistic insights about disease pathogenesis, host immune response, and identification of potential protein markers. Serum samples from patients diagnosed with falciparum malaria (FM) (n = 20), vivax malaria (VM) (n = 17) and healthy controls (HC) (n = 20) were investigated using multiple proteomic techniques and results were validated by employing immunoassay-based approaches. Specificity of the identified malaria related serum markers was evaluated by means of analysis of leptospirosis as a febrile control (FC). Compared to HC, 30 and 31 differentially expressed and statistically significant (p<0.05) serum proteins were identified in FM and VM respectively, and almost half (46.2%) of these proteins were commonly modulated due to both of the plasmodial infections. 13 proteins were found to be differentially expressed in FM compared to VM. Functional pathway analysis involving the identified proteins revealed the modulation of different vital physiological pathways, including acute phase response signaling, chemokine and cytokine signaling, complement cascades and blood coagulation in malaria. A panel of identified proteins consists of six candidates; serum amyloid A, hemopexin, apolipoprotein E, haptoglobin, retinol-binding protein and apolipoprotein A-I was used to build statistical sample class prediction models. By employing PLS-DA and other classification methods the clinical phenotypic classes (FM, VM, FC and HC) were predicted with over 95% prediction accuracy. Individual performance of three classifier proteins; haptoglobin, apolipoprotein A-I and retinol-binding protein in diagnosis of malaria was analyzed using receiver operating characteristic (ROC) curves. The discrimination of FM, VM, FC and HC groups on the basis of differentially expressed serum proteins demonstrates

  12. Proteomic investigation of falciparum and vivax malaria for identification of surrogate protein markers.

    Directory of Open Access Journals (Sweden)

    Sandipan Ray

    Full Text Available This study was conducted to analyze alterations in the human serum proteome as a consequence of infection by malaria parasites Plasmodium falciparum and P. vivax to obtain mechanistic insights about disease pathogenesis, host immune response, and identification of potential protein markers. Serum samples from patients diagnosed with falciparum malaria (FM (n = 20, vivax malaria (VM (n = 17 and healthy controls (HC (n = 20 were investigated using multiple proteomic techniques and results were validated by employing immunoassay-based approaches. Specificity of the identified malaria related serum markers was evaluated by means of analysis of leptospirosis as a febrile control (FC. Compared to HC, 30 and 31 differentially expressed and statistically significant (p<0.05 serum proteins were identified in FM and VM respectively, and almost half (46.2% of these proteins were commonly modulated due to both of the plasmodial infections. 13 proteins were found to be differentially expressed in FM compared to VM. Functional pathway analysis involving the identified proteins revealed the modulation of different vital physiological pathways, including acute phase response signaling, chemokine and cytokine signaling, complement cascades and blood coagulation in malaria. A panel of identified proteins consists of six candidates; serum amyloid A, hemopexin, apolipoprotein E, haptoglobin, retinol-binding protein and apolipoprotein A-I was used to build statistical sample class prediction models. By employing PLS-DA and other classification methods the clinical phenotypic classes (FM, VM, FC and HC were predicted with over 95% prediction accuracy. Individual performance of three classifier proteins; haptoglobin, apolipoprotein A-I and retinol-binding protein in diagnosis of malaria was analyzed using receiver operating characteristic (ROC curves. The discrimination of FM, VM, FC and HC groups on the basis of differentially expressed serum proteins demonstrates

  13. Antigens for a Vaccine that Prevents Severe Malaria

    Science.gov (United States)

    2007-03-01

    expertise in bioinformatics. Acknowledgements We thank Tania Ewing (Health Inbox, Melbourne), Lisa Jones (ARC/NHMRC Research Network for Parasitology) and...blood cells and Plasmodium falciparum Sc ie nc e Ph ot o Li br ar y We do not have the rights to reproduce this image on the web. Comment 2038...TK, Bolla MC, Li JL, et al. Maternal Malaria and Gravidity Interact to Modify Infant Susceptibility to Malaria. PLoS Med 2005;2:e407 21. Drew DE

  14. Antibodies from malaria-exposed pregnant women recognize trypsin resistant epitopes on the surface of Plasmodium falciparum-infected erythrocytes selected for adhesion to chondroitin sulphate A

    DEFF Research Database (Denmark)

    Sharling, Lisa; Enevold, Anders; Sowa, Kordai M P

    2004-01-01

    erythrocyte surface. However, several studies have found that parasite adhesion to placental receptors can be markedly less sensitive to trypsin. This study investigates whether chondroitin sulphate A (CSA) binding parasites express trypsin-resistant variant surface antigens (VSA) that bind female....... falciparum infected erythrocytes selected for adhesion to CSA were found to express trypsin-resistant VSA that are the target of naturally acquired antibodies from pregnant women living in a malaria endemic region of Ghana. However in vitro adhesion to CSA and HA was relatively trypsin sensitive. An improved...... labelling technique for the detection of VSA expressed by CSA binding isolates has also been described. CONCLUSION: The VSA expressed by CSA binding P. falciparum isolates are currently considered potential targets for a vaccine against PAM. This study identifies discordance between the trypsin sensitivity...

  15. Progress and challenges towards the development of malaria vaccines.

    Science.gov (United States)

    Tetteh, Kevin K A; Polley, Spencer D

    2007-01-01

    The promise afforded by attenuated sporozoite vaccines in the 1970s led many researchers to believe that an efficacious malaria vaccine was an attainable medium-term goal. Over 30 years later, no licensed vaccine is currently available for public health intervention. This is despite global expenditure on research and development for malaria vaccines that is estimated to have increased from $US42 million in 1999 to $US84 million in 2004. Serious questions must therefore be asked: is this a good investment of research and public health funds, and are we really any nearer to producing a viable product for global use?Proponents of a malaria vaccine promote this technology as a viable way to combat both the current economic and humanitarian burden of malaria and the decreasing efficacy of many front-line antimalaria drug therapies. The recent successful phase IIb trial of the RTS,S/AS02A vaccine showed that the production of a subunit vaccine with significant efficacy is technically possible. The combined efforts and financial commitment of researchers, pharmaceutical companies, and not-for-profit organizations, including the Malaria Vaccines Initiative, have resulted in a significant scaling up in the number of products suitable for testing in humans. In addition, new technologies, such as genetically attenuated vaccines and the exploitation of malaria genomes, offer exciting possibilities for vaccine development. There is now a real possibility of producing a malaria vaccine licensed for public health. However, this positive outlook must be tempered with the challenges facing vaccine development and distribution. The efficacy levels seen with RTS,S/AS02A are well below those of all vaccines currently in use for public health. Furthermore, poor preclinical and clinical predictors of efficacy, allele-specific immunity, and an imperfect understanding of natural and induced immunity to malaria may yet delay (or even prevent) the development of a vaccine suitable for

  16. Artesunate-amodiaquine fixed dose combination for the treatment of Plasmodium falciparum malaria in India

    Directory of Open Access Journals (Sweden)

    Anvikar Anupkumar R

    2012-03-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT has been recommended for the treatment of falciparum malaria by the World Health Organization. Though India has already switched to ACT for treating falciparum malaria, there is need to have multiple options of alternative forms of ACT. A randomized trial was conducted to assess the safety and efficacy of the fixed dose combination of artesunate-amodiaquine (ASAQ and amodiaquine (AQ for the treatment of uncomplicated falciparum malaria for the first time in India. The study sites are located in malaria-endemic, chloroquine-resistant areas. Methods This was an open label, randomized trial conducted at two sites in India from January 2007 to January 2008. Patients between six months and 60 years of age having Plasmodium falciparum mono-infection were randomly allocated to ASAQ and AQ arms. The primary endpoint was 28-day PCR-corrected parasitological cure rate. Results Three hundred patients were enrolled at two participating centres, Ranchi, Jharkhand and Rourkela, Odisha. Two patients in AQ arm had early treatment failure while there was no early treatment failure in ASAQ arm. Late treatment failures were seen in 13 and 12 patients in ASAQ and AQ arms, respectively. The PCR-corrected cure rates in intent-to-treat population were 97.51% (94.6-99.1% in ASAQ and 88.65% (81.3-93.9% in AQ arms. In per-protocol population, they were 97.47% (94.2-99.2% and 88.30% (80-94% in ASAQ and AQ arms respectively. Seven serious adverse events (SAEs were reported in five patients, of which two were reported as related to the treatment. All SAEs resolved without sequel. Conclusion The fixed dose combination of ASAQ was found to be efficacious and safe treatment for P. falciparum malaria. Amodiaquine also showed acceptable efficacy, making it a suitable partner of artesunate. The combination could prove to be a viable option in case India opts for fixed dose combination ACT. Clinical trial registry

  17. A potential role for plasma uric acid in the endothelial pathology of Plasmodium falciparum malaria.

    Directory of Open Access Journals (Sweden)

    Neida K Mita-Mendoza

    Full Text Available BACKGROUND: Inflammatory cytokinemia and systemic activation of the microvascular endothelium are central to the pathogenesis of Plasmodium falciparum malaria. Recently, 'parasite-derived' uric acid (UA was shown to activate human immune cells in vitro, and plasma UA levels were associated with inflammatory cytokine levels and disease severity in Malian children with malaria. Since UA is associated with endothelial inflammation in non-malaria diseases, we hypothesized that elevated UA levels contribute to the endothelial pathology of P. falciparum malaria. METHODOLOGY/PRINCIPAL FINDINGS: We measured levels of UA and soluble forms of intercellular adhesion molecule-1 (sICAM-1, vascular cell adhesion molecule-1 (sVCAM-1, E-selectin (sE-Selectin, thrombomodulin (sTM, tissue factor (sTF and vascular endothelial growth factor (VEGF in the plasma of Malian children aged 0.5-17 years with uncomplicated malaria (UM, n = 487 and non-cerebral severe malaria (NCSM, n = 68. In 69 of these children, we measured these same factors once when they experienced a malaria episode and twice when they were healthy (i.e., before and after the malaria transmission season. We found that levels of UA, sICAM-1, sVCAM-1, sE-Selectin and sTM increase during a malaria episode and return to basal levels at the end of the transmission season (p<0.0001. Plasma levels of UA and these four endothelial biomarkers correlate with parasite density and disease severity. In children with UM, UA levels correlate with parasite density (r = 0.092, p = 0.043, sICAM-1 (r = 0.255, p<0.0001 and sTM (r = 0.175, p = 0.0001 levels. After adjusting for parasite density, UA levels predict sTM levels. CONCLUSIONS/SIGNIFICANCE: Elevated UA levels may contribute to malaria pathogenesis by damaging endothelium and promoting a procoagulant state. The correlation between UA levels and parasite densities suggests that parasitized erythrocytes are one possible source of excess UA. UA-induced shedding of

  18. Characterization of sporozoite surface antigens of Plasmodium falciparum, using monoclonal antibodies. Part of a coordinated programme on the preparation of irradiated vaccines against some human diseases

    International Nuclear Information System (INIS)

    Groot, M.

    1982-10-01

    Sporozoites are considered as a source of potential vaccine. Characterization of their antigens is therefore important and can be achieved by monoclonal antibodies. The purpose of this project is to study the production of monoclonal antibodies against sporozoites of P. falciparum. Various infections of mosquitoes were carried out during the period 1981-1982 to obtain antigens for the production of hybridomas. Hybridomas were produced from mice immunized through the bites of infected mosquitoes and by intravenous inoculation. The anti-sporozoite activity of the hybridomas was tested by an immunofluorescent antibody test using P. falciparum sporozoites as antigens. Positive immunofluorescence was seen in hybridoma cell lines tested with P. falciparum, whereas negative results were obtained when the cell lines were cross-reacted with other human species (P. vivax) and with a rodent malaria parasite (P. berghei)

  19. Alternative Protein Secretion in the Malaria Parasite Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Thuvaraka Thavayogarajah

    Full Text Available Plasmodium falciparum invades human red blood cells, residing in a parasitophorous vacuole (PV, with a parasitophorous vacuole membrane (PVM separating the PV from the host cell cytoplasm. Here we have investigated the role of N-myristoylation and two other N-terminal motifs, a cysteine potential S-palmitoylation site and a stretch of basic residues, as the driving force for protein targeting to the parasite plasma membrane (PPM and subsequent translocation across this membrane. Plasmodium falciparum adenylate kinase 2 (Pf AK2 contains these three motifs, and was previously proposed to be targeted beyond the parasite to the PVM, despite the absence of a signal peptide for entry into the classical secretory pathway. Biochemical and microscopy analyses of PfAK2 variants tagged with green fluorescent protein (GFP showed that these three motifs are involved in targeting the protein to the PPM and translocation across the PPM to the PV. It was shown that the N-terminal 37 amino acids of PfAK2 alone are sufficient to target and translocate GFP across the PPM. As a control we examined the N-myristoylated P. falciparum ADP-ribosylation factor 1 (PfARF1. PfARF1 was found to co-localise with a Golgi marker. To determine whether or not the putative palmitoylation and the cluster of lysine residues from the N-terminus of PfAK2 would modulate the subcellular localization of PfARF1, a chimeric fusion protein containing the N-terminus of PfARF1 and the two additional PfAK2 motifs was analysed. This chimeric protein was targeted to the PPM, but not translocated across the membrane into the PV, indicating that other features of the N-terminus of PfAK2 also play a role in the secretion process.

  20. Plasmodium falciparum malaria in children at a tertiary teaching ...

    African Journals Online (AJOL)

    raoul

    2011-09-06

    Sep 6, 2011 ... Background: ABO blood group antigens are formed by terminal glycosylation of glycoproteins and glycolipid chains present on cell surfaces. Glycosylation modulates all kinds of cell-to-cell interactions and this may be relevant in malaria pathophysiology, in which adhesion has been increasingly implicated ...

  1. Fibrinolytic activity in children with Plasmodium falciparum malaria ...

    African Journals Online (AJOL)

    Background: Malaria infection is still one of the major causes of morbidity and mortality among the under five year children in tropical Africa. Clinical and laboratory methods of assessing the risk factors for severity in order to adequately manage these children, therefore needs to be identified so that prompt and adequate ...

  2. Comparative analysis of acon- Plasmodium falciparum rapid malaria ...

    African Journals Online (AJOL)

    The study found that Acon-Pf is suitable along side microscopy in the accurate diagnosis of malaria in Enugu State. The use of Acon- Pf and thick smear tests in parallel, first collecting the Acon-Pf results, as it contributes in reading the thin smear result for confirmation of species, diagnosis and assessment of parasitaemia.

  3. The Effect of Falciparum Malaria Infection on The Platelet Count of Children in a Tertiary Hospital in Uyo, Akwa Ibom State of Nigeria

    Directory of Open Access Journals (Sweden)

    Eno-Obong Edet Utuk

    2014-06-01

    CONCLUSION: The study demonstrated a higher level of thrombocytopenia in children presenting with severe manifestations of falciparum malaria in this setting. It is therefore important to monitor the platelet counts of children presenting with severe falciparum malaria [TAF Prev Med Bull 2014; 13(3.000: 225-232

  4. Haemoglobin C and S role in acquired immunity against Plasmodium falciparum malaria.

    Directory of Open Access Journals (Sweden)

    Federica Verra

    2007-10-01

    Full Text Available A recently proposed mechanism of protection for haemoglobin C (HbC; beta6Glu-->Lys links an abnormal display of PfEMP1, an antigen involved in malaria pathogenesis, on the surface of HbC infected erythrocytes together with the observation of reduced cytoadhesion of parasitized erythrocytes and impaired rosetting in vitro. We investigated the impact of this hypothesis on the development of acquired immunity against Plasmodium falciparum variant surface antigens (VSA encoding PfEMP1 in HbC in comparison with HbA and HbS carriers of Burkina Faso. We measured: i total IgG against a single VSA, A4U, and against a panel of VSA from severe malaria cases in human sera from urban and rural areas of Burkina Faso of different haemoglobin genotypes (CC, AC, AS, SC, SS; ii total IgG against recombinant proteins of P. falciparum asexual sporozoite, blood stage antigens, and parasite schizont extract; iii total IgG against tetanus toxoid. Results showed that the reported abnormal cell-surface display of PfEMP1 on HbC infected erythrocytes observed in vitro is not associated to lower anti- PfEMP1 response in vivo. Higher immune response against the VSA panel and malaria antigens were observed in all adaptive genotypes containing at least one allelic variant HbC or HbS in the low transmission urban area whereas no differences were detected in the high transmission rural area. In both contexts the response against tetanus toxoid was not influenced by the beta-globin genotype. These findings suggest that both HbC and HbS affect the early development of naturally acquired immunity against malaria. The enhanced immune reactivity in both HbC and HbS carriers supports the hypothesis that the protection against malaria of these adaptive genotypes might be at least partially mediated by acquired immunity against malaria.

  5. Intrarectal quinine versus intravenous or intramuscular quinine for treating Plasmodium falciparum malaria.

    Science.gov (United States)

    Eisenhut, Michael; Omari, Aika A A

    2009-01-21

    In children with falciparum malaria, a proprietary quinine preparation (adjusted to make it less acidic) administered rectally may be easier to use and less painful than intramuscular or intravenous administration. However, rectal quinine may be less effective. To compare intrarectal quinine with intravenous or intramuscular quinine for treating malaria caused by Plasmodium falciparum. In May 2008, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2008, Issue 2), MEDLINE, EMBASE, LILACS, and CINAHL. We also searched conference proceedings, contacted individual researchers and a pharmaceutical company, and checked reference lists. Randomized and quasi-randomized controlled trials comparing intrarectal quinine with intramuscular and intravenous quinine for treating people with uncomplicated and severe Plasmodium falciparum malaria. We independently assessed each trial's risk of bias quality and extracted data, including adverse event data. We analysed dichotomous data using the odds ratio and continuous data using the mean difference. Ten randomized controlled trials, all involving children only (total of 1417 children), fulfilled the inclusion criteria. The same investigator was involved in nine of the trials. Seven trials compared proprietary intrarectal with intravenous quinine, and seven trials compared it with intramuscular treatment. We detected no statistically significant difference between intrarectal and intravenous or intramuscular routes for death, parasite clearance by 48 hours and seven days, parasite clearance time, fever clearance time, coma recovery time, duration of hospitalization, and time to drinking. The trials reporting on these outcomes were small, which resulted in large confidence intervals for all outcomes apart from duration of hospitalization. One large trial (898 children) reported that intrarectal was less painful than intramuscular administration. We detected no difference in the

  6. Ototoxicity of artemether/lumefantrine in the treatment of falciparum malaria: a randomized trial

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    Krause Eike

    2008-09-01

    Full Text Available Abstract Background Due to increasing drug resistance, artemisinin-based combination chemotherapy (ACT has become the first-line treatment of falciparum malaria in many endemic countries. However, irreversible ototoxicity associated with artemether/lumefantrine (AL has been reported recently and suggested to be a serious limitation in the use of ACT. The aim of the study was to compare ototoxicity, tolerability, and efficacy of ACT with that of quinine and atovaquone/proguanil in the treatment of uncomplicated falciparum malaria. Methods Ninety-seven patients in south-west Ethiopia with slide-confirmed malaria were randomly assigned to receive either artemether/lumefantrine or quinine or atovaquone/proguanil and followed-up for 90 days. Comprehensive audiovestibular testing by pure tone audiometry (PTA, transitory evoked (TE and distortion product (DP otoacoustic emissions (OAE and brain stem evoked response audiometry (BERA was done before enrolment and after seven, 28 and 90 days. Results PTA and DP-OAE levels revealed transient significant cochlear hearing loss in patients treated with quinine but not in those treated with artemether/lumefantrine or atovaquone/proguanil. TE-OAE could be elicited in all examinations, except for three patients in the Q group on day 7, who suffered a transient hearing loss greater than 30 dB. There was no evidence of drug-induced brain stem lesions by BERA measurements. Conclusion There was no detrimental effect of a standard oral regimen of artemether/lumefantrine on peripheral hearing or brainstem auditory pathways in patients with uncomplicated falciparum malaria. In contrast, transient hearing loss is common after quinine therapy and due to temporary outer hair cell dysfunction.

  7. A consultation on the optimization of controlled human malaria infection by mosquito bite for evaluation of candidate malaria vaccines.

    NARCIS (Netherlands)

    Laurens, M.B.; Duncan, C.J.; Epstein, J.E.; Hill, A.V.; Komisar, J.L.; Lyke, K.E.; Ockenhouse, C.F.; Richie, T.L.; Roestenberg, M.; Sauerwein, R.W.; Spring, M.D.; Talley, A.K.; Moorthy, V.S.

    2012-01-01

    Early clinical investigations of candidate malaria vaccines and antimalarial medications increasingly employ an established model of controlled human malaria infection (CHMI). Study results are used to guide further clinical development of vaccines and antimalarial medications as CHMI results to

  8. Resisting and tolerating P. falciparum in pregnancy under different malaria transmission intensities.

    Science.gov (United States)

    Ndam, Nicaise Tuikue; Mbuba, Emmanuel; González, Raquel; Cisteró, Pau; Kariuki, Simon; Sevene, Esperança; Rupérez, María; Fonseca, Ana Maria; Vala, Anifa; Maculuve, Sonia; Jiménez, Alfons; Quintó, Llorenç; Ouma, Peter; Ramharter, Michael; Aponte, John J; Nhacolo, Arsenio; Massougbodji, Achille; Briand, Valerie; Kremsner, Peter G; Mombo-Ngoma, Ghyslain; Desai, Meghna; Macete, Eusebio; Cot, Michel; Menéndez, Clara; Mayor, Alfredo

    2017-07-17

    Resistance and tolerance to Plasmodium falciparum can determine the progression of malaria disease. However, quantitative evidence of tolerance is still limited. We investigated variations in the adverse impact of P. falciparum infections among African pregnant women under different intensities of malaria transmission. P. falciparum at delivery was assessed by microscopy, quantitative PCR (qPCR) and placental histology in 946 HIV-uninfected and 768 HIV-infected pregnant women from Benin, Gabon, Kenya and Mozambique. Resistance was defined by the proportion of submicroscopic infections and the levels of anti-parasite antibodies quantified by Luminex, and tolerance by the relationship of pregnancy outcomes with parasite densities at delivery. P. falciparum prevalence by qPCR in peripheral and/or placental blood of HIV-uninfected Mozambican, Gabonese and Beninese women at delivery was 6% (21/340), 11% (28/257) and 41% (143/349), respectively. The proportion of peripheral submicroscopic infections was higher in Benin (83%) than in Mozambique (60%) and Gabon (55%; P = 0.033). Past or chronic placental P. falciparum infection was associated with an increased risk of preterm birth in Mozambican newborns (OR = 7.05, 95% CI 1.79 to 27.82). Microscopic infections were associated with reductions in haemoglobin levels at delivery among Mozambican women (-1.17 g/dL, 95% CI -2.09 to -0.24) as well as with larger drops in haemoglobin levels from recruitment to delivery in Mozambican (-1.66 g/dL, 95% CI -2.68 to -0.64) and Gabonese (-0.91 g/dL, 95% CI -1.79 to -0.02) women. Doubling qPCR-peripheral parasite densities in Mozambican women were associated with decreases in haemoglobin levels at delivery (-0.16 g/dL, 95% CI -0.29 to -0.02) and increases in the drop of haemoglobin levels (-0.29 g/dL, 95% CI -0.44 to -0.14). Beninese women had higher anti-parasite IgGs than Mozambican women (P < 0.001). No difference was found in the proportion of submicroscopic

  9. Epidemiologia de la malaria falciparum complicada: estudio de casos y controles en Tumaco y Turbo, Colombia, 2003 The epidemiology of complicated falciparum malaria: case and controls study in Tumaco and Turbo, Colombia, 2003

    Directory of Open Access Journals (Sweden)

    Alberto Tobón C.

    2006-09-01

    Full Text Available OBJETIVOS: Identificar aspectos del hospedero, del parásito y del ambiente asociados con ocurrencia de malaria por Plasmodium falciparum complicada. MÉTODOS: Estudio de casos y controles en pacientes de Tumaco y Turbo (Colombia aplicando los criterios de complicación de la Organización Mundial de la Salud. RESULTADOS: Entre noviembre 2002 y julio 2003 se captaron 64 casos (malaria complicada y 135 controles (malaria no complicada. Las complicaciones fueron: hiperparasitemia (40%, falla hepática (36%, síndrome dificultad respiratoria aguda (7%, falla renal (4%, trombocitopenia grave (3%, anemia grave (2%, malaria cerebral (2% e hipoglicemia grave (1%. Se encontraron como factores de riesgo para malaria falciparum complicada: a Los antecedentes de malaria falciparum durante el último año fueron menores en los casos (OR= 7.0 (1.2-43.6 P=0.019; b Mayor uso previo de antimaláricos en los casos (OR=2.2 (1.1-4.4 P=0.031 y c mayor uso de cloroquina en los casos (OR=7.4 (1.1-7.8 P=0.017. Se hallaron los alelos MAD-20 y K1 del gen msp1 y FC-27 e IC-1 del gen msp2, cuya distribución de frecuencias fue similar entre casos y controles, aunque el alelo K1 mostró una variación importante entre grupos (casos: 9.4%, controles: 3.5%. La frecuencia de "signos de peligro" fue significativamente mayor en los casos (OR= 3.3, (1.5-7.4 P=0.001. Los criterios de complicación malárica de la Organización Mundial de la Salud se comparan con otros y se discuten algunas implicaciones. CONCLUSIÓN: Se identificaron como factores de riesgo para malaria falciparum complicada, la ausencia de antecedentes de malaria falciparum en el último año y el uso de antimaláricos antes de llegar al hospital.OBJECTIVES: Aimed at identifying host and parasite aspects associated to the presence of Plasmodium falciparum complicated malaria. METHODS: Case and controls study in patients from Tumaco and Turbo (Colombia. We used the World Health Organization criteria to assess the

  10. Development of replication-deficient adenovirus malaria vaccines.

    Science.gov (United States)

    Hollingdale, Michael R; Sedegah, Martha; Limbach, Keith

    2017-03-01

    Malaria remains a major threat to endemic populations and travelers, including military personnel to these areas. A malaria vaccine is feasible, as radiation attenuated sporozoites induce nearly 100% efficacy. Areas covered: This review covers current malaria clinical trials using adenoviruses and pre-clinical research. Heterologous prime-boost regimens, including replication-deficient human adenovirus 5 (HuAd5) carrying malaria antigens, are efficacious. However, efficacy appears to be adversely affected by pre-existing anti-HuAd5 antibodies. Current strategies focus on replacing HuAd5 with rarer human adenoviruses or adenoviruses isolated from non-human primates (NHPs). The chimpanzee adenovirus ChAd63 is undergoing evaluation in clinical trials including infants in malaria-endemic areas. Key antigens have been identified and are being used alone, in combination, or with protein subunit vaccines. Gorilla adenoviruses carrying malaria antigens are also currently being evaluated in preclinical models. These replacement adenovirus vectors will be successfully used to develop vaccines against malaria, as well as other infectious diseases. Expert commentary: Simplified prime-boost single shot regimens, dry-coated live vector vaccines or silicon microneedle arrays could be developed for malaria or other vaccines. Replacement vectors with similar or superior immunogenicity have rapidly advanced, and several are now in extensive Phase 2 and beyond in malaria as well as other diseases, notably Ebola.

  11. Malaria vaccines and their potential role in the elimination of malaria

    Directory of Open Access Journals (Sweden)

    Greenwood Brian M

    2008-12-01

    Full Text Available Abstract Research on malaria vaccines is currently directed primarily towards the development of vaccines that prevent clinical malaria. Malaria elimination, now being considered seriously in some epidemiological situations, requires a different vaccine strategy, since success will depend on killing all parasites in the community in order to stop transmission completely. The feature of the life-cycles of human malarias that presents the greatest challenge to an elimination programme is the persistence of parasites as asymptomatic infections. These are an important source from which transmission to mosquitoes can occur. Consequently, an elimination strategy requires a community-based approach covering all individuals and not just those who are susceptible to clinical malaria. The progress that has been made in development of candidate malaria vaccines is reviewed. It is unlikely that many of these will have the efficacy required for complete elimination of parasites, though they may have an important role to play as part of future integrated control programmes. Vaccines for elimination must have a high level of efficacy in order to stop transmission to mosquitoes. This might be achieved with some pre-erythrocytic stage candidate vaccines or by targeting the sexual stages directly with transmission-blocking vaccines. An expanded malaria vaccine programme with such objectives is now a priority.

  12. Satisfactory safety and immunogenicity of MSP3 malaria vaccine candidate in Tanzanian children aged 12–24 months

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    Segeja Method D

    2009-07-01

    Full Text Available Abstract Background Development and deployment of an effective malaria vaccine would complement existing malaria control measures. A blood stage malaria vaccine candidate, Merozoite Surface Protein-3 (MSP3, produced as a long synthetic peptide, has been shown to be safe in non-immune and semi-immune adults. A phase Ib dose-escalating study was conducted to assess the vaccine's safety and immunogenicity in children aged 12 to 24 months in Korogwe, Tanzania (ClinicalTrials.gov number: NCT00469651. Methods This was a double-blind, randomized, controlled, dose escalation phase Ib trial, in which children were given one of two different doses of the MSP3 antigen (15 μg or 30 μg or a control vaccine (Engerix B. Children were randomly allocated either to the MSP3 candidate malaria vaccine or the control vaccine administered at a schedule of 0, 1, and 2 months. Immunization with lower and higher doses was staggered for safety reasons starting with the lower dose. The primary endpoint was safety and reactogenicity within 28 days post-vaccination. Blood samples were obtained at different time points to measure immunological responses. Results are presented up to 84 days post-vaccination. Results A total of 45 children were enrolled, 15 in each of the two MSP3 dose groups and 15 in the Engerix B group. There were no important differences in reactogenicity between the two MSP3 groups and Engerix B. Grade 3 adverse events were infrequent; only five were detected throughout the study, all of which were transient and resolved without sequelae. No serious adverse event reported was considered to be related to MSP3 vaccine. Both MSP3 dose regimens elicited strong cytophilic IgG responses (subclasses IgG1 and IgG3, the isotypes involved in the monocyte-dependant mechanism of Plasmodium falciparum parasite-killing. The titers reached are similar to those from African adults having reached a state of premunition. Furthermore, vaccination induced seroconversion in

  13. Paludismo por Plasmodium falciparum adquirido en África subsahariana Plasmodium falciparum malaria acquired in Subsaharian Africa

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    Ricardo Durlach

    2009-02-01

    Full Text Available El objetivo de este trabajo es presentar los casos de paludismo por Plasmodium falciparum ocurridos en viajeros provenientes del África tropical, atendidos en el Hospital Alemán. Se definió paludismo de origen africano como la infección adquirida en un país del África subsahariana, diagnosticado y tratado en la Argentina. El diagnóstico se realizó por la clínica y la microscopía óptica en frotis de sangre periférica coloreados con Giemsa. Se revieron las historias clínicas de 11 pacientes adultos -cinco turistas y seis marineros mercantes- no oriundos de área endémica, sin condición inmunosupresora, ni morbilidad asociada, internados entre 1993 y 2007. El rango de edad fue de 21 a 48 años; nueve hombres y dos mujeres. Los pacientes fueron clasificados retrospectivamente en malaria grave (seis o no grave (cinco según cumplieran con uno o más de los criterios de gravedad de la Organización Mundial de la Salud. Todos presentaron fiebre como signo más significativo. Como complicaciones graves se observaron casos de insuficiencia renal, epistaxis, hemoglobinuria, hipoglucemia, edema pulmonar, acidosis y coma. Tres pacientes requirieron internación en la unidad de terapia intensiva. Todos sobrevivieron y solamente tres habían recibido la quimioprofilaxis correcta antes de viajar. El tratamiento se realizó con una o más de las siguientes drogas: mefloquina, quinidina, clindamicina y cotrimoxazol.The purpose of this paper is to present the cases of malaria caused by Plasmodium falciparum in travelers coming from tropical Africa, who were treated at the Hospital Alemán (Buenos Aires. African malaria was defined as an infection acquired in any country within Africa, diagnosed and treated in Argentina. Diagnostic tools included clinical features and optic microscopy with Giemsa stained peripheral blood films. We reviewed the medical records of 11 adult patients -five tourists and six sailors- with no history of malaria

  14. Contrasting Transmission Dynamics of Co-endemic Plasmodium vivax and P. falciparum: Implications for Malaria Control and Elimination.

    Science.gov (United States)

    Noviyanti, Rintis; Coutrier, Farah; Utami, Retno A S; Trimarsanto, Hidayat; Tirta, Yusrifar K; Trianty, Leily; Kusuma, Andreas; Sutanto, Inge; Kosasih, Ayleen; Kusriastuti, Rita; Hawley, William A; Laihad, Ferdinand; Lobo, Neil; Marfurt, Jutta; Clark, Taane G; Price, Ric N; Auburn, Sarah

    2015-05-01

    Outside of Africa, P. falciparum and P. vivax usually coexist. In such co-endemic regions, successful malaria control programs have a greater impact on reducing falciparum malaria, resulting in P. vivax becoming the predominant species of infection. Adding to the challenges of elimination, the dormant liver stage complicates efforts to monitor the impact of ongoing interventions against P. vivax. We investigated molecular approaches to inform the respective transmission dynamics of P. falciparum and P. vivax and how these could help to prioritize public health interventions. Genotype data generated at 8 and 9 microsatellite loci were analysed in 168 P. falciparum and 166 P. vivax isolates, respectively, from four co-endemic sites in Indonesia (Bangka, Kalimantan, Sumba and West Timor). Measures of diversity, linkage disequilibrium (LD) and population structure were used to gauge the transmission dynamics of each species in each setting. Marked differences were observed in the diversity and population structure of P. vivax versus P. falciparum. In Bangka, Kalimantan and Timor, P. falciparum diversity was low, and LD patterns were consistent with unstable, epidemic transmission, amenable to targeted intervention. In contrast, P. vivax diversity was higher and transmission appeared more stable. Population differentiation was lower in P. vivax versus P. falciparum, suggesting that the hypnozoite reservoir might play an important role in sustaining local transmission and facilitating the spread of P. vivax infections in different endemic settings. P. vivax polyclonality varied with local endemicity, demonstrating potential utility in informing on transmission intensity in this species. Molecular approaches can provide important information on malaria transmission that is not readily available from traditional epidemiological measures. Elucidation of the transmission dynamics circulating in a given setting will have a major role in prioritising malaria control strategies

  15. Contrasting Transmission Dynamics of Co-endemic Plasmodium vivax and P. falciparum: Implications for Malaria Control and Elimination.

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    Rintis Noviyanti

    2015-05-01

    Full Text Available Outside of Africa, P. falciparum and P. vivax usually coexist. In such co-endemic regions, successful malaria control programs have a greater impact on reducing falciparum malaria, resulting in P. vivax becoming the predominant species of infection. Adding to the challenges of elimination, the dormant liver stage complicates efforts to monitor the impact of ongoing interventions against P. vivax. We investigated molecular approaches to inform the respective transmission dynamics of P. falciparum and P. vivax and how these could help to prioritize public health interventions.Genotype data generated at 8 and 9 microsatellite loci were analysed in 168 P. falciparum and 166 P. vivax isolates, respectively, from four co-endemic sites in Indonesia (Bangka, Kalimantan, Sumba and West Timor. Measures of diversity, linkage disequilibrium (LD and population structure were used to gauge the transmission dynamics of each species in each setting. Marked differences were observed in the diversity and population structure of P. vivax versus P. falciparum. In Bangka, Kalimantan and Timor, P. falciparum diversity was low, and LD patterns were consistent with unstable, epidemic transmission, amenable to targeted intervention. In contrast, P. vivax diversity was higher and transmission appeared more stable. Population differentiation was lower in P. vivax versus P. falciparum, suggesting that the hypnozoite reservoir might play an important role in sustaining local transmission and facilitating the spread of P. vivax infections in different endemic settings. P. vivax polyclonality varied with local endemicity, demonstrating potential utility in informing on transmission intensity in this species.Molecular approaches can provide important information on malaria transmission that is not readily available from traditional epidemiological measures. Elucidation of the transmission dynamics circulating in a given setting will have a major role in prioritising malaria

  16. Genetic complexity of Plasmodium falciparum in two ethnic groups of Burkina Faso with marked differences in susceptibility to malaria.

    Science.gov (United States)

    Paganotti, Giacomo M; Babiker, Hamza A; Modiano, David; Sirima, Bienvenu S; Verra, Federica; Konaté, Amadou; Ouedraogo, Andre L; Diarra, Amidou; Mackinnon, Margaret J; Coluzzi, Mario; Walliker, David

    2004-08-01

    We have characterized Plasmodium falciparum genotypes among the Mossi and Fulani sympatric ethnic groups in villages in Burkina Faso during the rainy season. Differences in clinical malaria presentation and in immune responses to malaria occur between the two groups. Asexual parasite rate, density, and gametocyte rate were higher among the Mossi than the Fulani. There was no difference in frequencies of alleles of the P. falciparum merozoite surface protein 1 (msp-1), msp-2, and glutamate-rich protein (glurp) genes among the parasites in each group. However, there were significant differences in the mean number of P. falciparum clones in the two populations, with there being more in the Mossi than in the Fulani. This effect was especially marked in older children. These differences can most probably be attributed to genetic differences in immune responsiveness to malaria between the two ethnic groups.

  17. Natural and vaccine-induced acquisition of cross-reactive IgG inhibiting ICAM-1-specific binding of a Plasmodium falciparum PfEMP1 subtype associated specifically with cerebral malaria

    DEFF Research Database (Denmark)

    Olsen, Rebecca W; Ecklu-Mensah, Gertrude; Bengtsson, Anja

    2018-01-01

    Cerebral malaria (CM) is a potentially deadly outcome of Plasmodium falciparummalaria that is precipitated by sequestration of infected erythrocytes (IEs) in the brain. The adhesion of IEs to brain endothelial cells is mediated by a subtype of parasite-encoded erythrocyte membrane protein 1 (PfEM...

  18. Successful human infection with P. falciparum using three aseptic Anopheles stephensi mosquitoes: a new model for controlled human malaria infection.

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    Matthew B Laurens

    Full Text Available Controlled human malaria infection (CHMI is a powerful method for assessing the efficacy of anti-malaria vaccines and drugs targeting pre-erythrocytic and erythrocytic stages of the parasite. CHMI has heretofore required the bites of 5 Plasmodium falciparum (Pf sporozoite (SPZ-infected mosquitoes to reliably induce Pf malaria. We reported that CHMI using the bites of 3 PfSPZ-infected mosquitoes reared aseptically in compliance with current good manufacturing practices (cGMP was successful in 6 participants. Here, we report results from a subsequent CHMI study using 3 PfSPZ-infected mosquitoes reared aseptically to validate the initial clinical trial. We also compare results of safety, tolerability, and transmission dynamics in participants undergoing CHMI using 3 PfSPZ-infected mosquitoes reared aseptically to published studies of CHMI using 5 mosquitoes. Nineteen adults aged 18-40 years were bitten by 3 Anopheles stephensi mosquitoes infected with the chloroquine-sensitive NF54 strain of Pf. All 19 participants developed malaria (100%; 12 of 19 (63% on Day 11. The mean pre-patent period was 258.3 hours (range 210.5-333.8. The geometric mean parasitemia at first diagnosis by microscopy was 9.5 parasites/µL (range 2-44. Quantitative polymerase chain reaction (qPCR detected parasites an average of 79.8 hours (range 43.8-116.7 before microscopy. The mosquitoes had a geometric mean of 37,894 PfSPZ/mosquito (range 3,500-152,200. Exposure to the bites of 3 aseptically-raised, PfSPZ-infected mosquitoes is a safe, effective procedure for CHMI in malaria-naïve adults. The aseptic model should be considered as a new standard for CHMI trials in non-endemic areas. Microscopy is the gold standard used for the diagnosis of Pf malaria after CHMI, but qPCR identifies parasites earlier. If qPCR continues to be shown to be highly specific, and can be made to be practical, rapid, and standardized, it should be considered as an alternative for diagnosis

  19. Platelet profile is associated with clinical complications in patients with vivax and falciparum malaria in Colombia

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    Edgar Leonardo Martínez-Salazar

    2014-06-01

    Full Text Available Introduction Thrombocytopenia is a common complication in malaria patients. The relationship between abnormal platelet profile and clinical status in malaria patients is unclear. In low and unstable endemic regions where vivax malaria predominates, the hematologic profiles of malaria patients and their clinical utility are poorly understood. The aim of this study was to characterize the thrombograms of malaria patients from Colombia, where Plasmodium vivax infection is common, and to explore the relationship between thrombograms and clinical status. Methods Eight hundred sixty-two malaria patients were enrolled, including 533 (61.8% patients infected with Plasmodium falciparum, 311 (36.1% patients infected with Plasmodium vivax and 18 (2.1% patients with mixed infections. Results The most frequently observed changes were low platelet count (PC and high platelet distribution width (PDW, which were observed in 65% of patients; thrombocytopenia with <50,000 platelets/µL was identified in 11% of patients. Patients with complications had lower PC and plateletcrit (PT and higher PDW values. A higher risk of thrombocytopenia was identified in patients with severe anemia, neurologic complications, pulmonary complications, liver dysfunction, renal impairment and severe hypoglycemia. The presence of thrombocytopenia (<150,000 platelets/µL was associated with a higher probability of liver dysfunction. Conclusions Young age, longer duration of illness and higher parasitemia are associated with severe thrombocytopenia. Our study showed that thrombocytopenia is related to malaria complications, especially liver dysfunction. High PDW in patients with severe malaria may explain the mechanisms of thrombocytopenia that is common in this group of patients.

  20. Opsonising antibodies to P. falciparum merozoites associated with immunity to clinical malaria.

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    Danika L Hill

    Full Text Available Naturally acquired humoral immunity to the malarial parasite Plasmodium falciparum can protect against disease, although the precise mechanisms remain unclear. Although antibody levels can be measured by ELISA, few studies have investigated functional antibody assays in relation to clinical outcomes. In this study we applied a recently developed functional assay of antibody-mediated opsonisation of merozoites, to plasma samples from a longitudinal cohort study conducted in a malaria endemic region of Papua New Guinea (PNG. Phagocytic activity was quantified by flow cytometry using a standardized and high-throughput protocol, and was subsequently evaluated for association with protection from clinical malaria and high-density parasitemia. Opsonising antibody responses were found to: i increase with age, ii be enhanced by concurrent infection, and iii correlate with protection from clinical episodes and high-density parasitemia. Stronger protective associations were observed in individuals with no detectable parasitemia at baseline. This study presents the first evidence for merozoite phagocytosis as a correlate of acquired immunity and clinical protection against P. falciparum malaria.

  1. Efficacy and safety of atovaquone/proguanil as suppressive prophylaxis for Plasmodium falciparum malaria.

    Science.gov (United States)

    Shanks, G D; Gordon, D M; Klotz, F W; Aleman, G M; Oloo, A J; Sadie, D; Scott, T R

    1998-09-01

    Currently recommended prophylactic regimens for Plasmodium falciparum malaria are associated with a high incidence of adverse events and/or suboptimal efficacy. In a double-blind, placebo-controlled, randomized clinical trial in western Kenya, adult volunteers received a treatment course of atovaquone/proguanil hydrochloride (250 mg/100 mg per tablet) to eliminate preexisting infection. Immediately thereafter, subjects were randomized to one of the three prophylactic regimens to receive one atovaquone/proguanil tablet daily (n = 68), two atovaquone/proguanil tablets daily (n = 65), or placebo (n = 65) for 10 weeks. The study endpoint for any subject was the development of parasitemia, evident on blood smear, during prophylaxis. Of the evaluable subjects, all in the low-dose (54 of 54) and high-dose (54 of 54) atovaquone/proguanil groups remained malaria-free during the 10-week prophylaxis period, in contrast to only 48% (26 of 54) in the placebo group (P proguanil prophylactic regimens were as well tolerated as placebo. Thus, atovaquone/proguanil appears to be highly efficacious and safe as prophylaxis for P. falciparum malaria.

  2. Identifying residual foci of Plasmodium falciparum infections for malaria elimination: the urban context of Khartoum, Sudan.

    Science.gov (United States)

    Nourein, Amal B; Abass, Mohammed A; Nugud, Abdel Hameed D; El Hassan, Ibrahim; Snow, Robert W; Noor, Abdisalan M

    2011-02-23

    Identifying the location and size of residual foci of infections is critical where malaria elimination is the primary goal. Here the spatial heterogeneity of Plasmodium falciparum infections within the urban extent of Khartoum state in Sudan is investigated using data from cross-sectional surveys undertaken from 1999 to 2008 to inform the Khartoum Malaria Free Initiative (KMFI). From 1999-2008 the KMFI undertook cross-sectional surveys of 256 clusters across 203 random samples of residential blocks in the urban Khartoum state in September of each year. Within sampled blocks, at least five persons, including at least one child under the age of five years, were selected from each household. Blood smears were collected from the sampled individuals to examine the presence of P. falciparum parasites. Residential blocks were mapped. Data were analysed for spatial clustering using the Bernoulli model and the significance of clusters were tested using the Kulldorff scan statistic. A total of 128,510 malaria slide examinations were undertaken during the study period. In 1999, overall prevalence was 2.5%, rising to 3.2% in 2000 and consistently staying below 1% in subsequent years. From 2006, over 90% of all surveyed clusters reported no infections. Spatial clustering of infections was present in each year but not statistically significant in the years 2001, 2002, 2004 and 2008. Spatial clusters of high infection were often located at the junction of the Blue and White Niles. Persisting foci of malaria infection in Khartoum are likely to distort wide area assessments and disproportionately affect future transmission within the city limits. Improved investments in surveillance that combines both passive and active case detection linked to a geographic information system and a more detailed analysis of the location and stability of foci should be undertaken to facilitate and track malaria elimination in the state of Khartoum.

  3. Identifying residual foci of Plasmodium falciparum infections for malaria elimination: the urban context of Khartoum, Sudan.

    Directory of Open Access Journals (Sweden)

    Amal B Nourein

    2011-02-01

    Full Text Available Identifying the location and size of residual foci of infections is critical where malaria elimination is the primary goal. Here the spatial heterogeneity of Plasmodium falciparum infections within the urban extent of Khartoum state in Sudan is investigated using data from cross-sectional surveys undertaken from 1999 to 2008 to inform the Khartoum Malaria Free Initiative (KMFI.From 1999-2008 the KMFI undertook cross-sectional surveys of 256 clusters across 203 random samples of residential blocks in the urban Khartoum state in September of each year. Within sampled blocks, at least five persons, including at least one child under the age of five years, were selected from each household. Blood smears were collected from the sampled individuals to examine the presence of P. falciparum parasites. Residential blocks were mapped. Data were analysed for spatial clustering using the Bernoulli model and the significance of clusters were tested using the Kulldorff scan statistic.A total of 128,510 malaria slide examinations were undertaken during the study period. In 1999, overall prevalence was 2.5%, rising to 3.2% in 2000 and consistently staying below 1% in subsequent years. From 2006, over 90% of all surveyed clusters reported no infections. Spatial clustering of infections was present in each year but not statistically significant in the years 2001, 2002, 2004 and 2008. Spatial clusters of high infection were often located at the junction of the Blue and White Niles.Persisting foci of malaria infection in Khartoum are likely to distort wide area assessments and disproportionately affect future transmission within the city limits. Improved investments in surveillance that combines both passive and active case detection linked to a geographic information system and a more detailed analysis of the location and stability of foci should be undertaken to facilitate and track malaria elimination in the state of Khartoum.

  4. Genetic Diversity of Plasmodium falciparum Populations in Malaria Declining Areas of Sabah, East Malaysia.

    Science.gov (United States)

    Mohd Abd Razak, Mohd Ridzuan; Sastu, Umi Rubiah; Norahmad, Nor Azrina; Abdul-Karim, Abass; Muhammad, Amirrudin; Muniandy, Prem Kumar; Jelip, Jenarun; Rundi, Christina; Imwong, Mallika; Mudin, Rose Nani; Abdullah, Noor Rain

    2016-01-01

    Malaysia has a national goal to eliminate malaria by 2020. Understanding the genetic diversity of malaria parasites in residual transmission foci can provide invaluable information which may inform the intervention strategies used to reach elimination targets. This study was conducted to determine the genetic diversity level of P. falciparum isolates in malaria residual foci areas of Sabah. Malaria active case detection was conducted in Kalabakan and Kota Marudu. All individuals in the study sites were screened for malaria infection by rapid diagnostic test. Blood from P. falciparum-infected individuals were collected on filter paper prior to DNA extraction. Genotyping was performed using merozoite surface protein-1 (MSP-1), merozoite surface protein-2 (MSP-2), glutamate rich protein (GLURP) and 10 neutral microsatellite loci markers. The size of alleles, multiplicity of infection (MOI), mean number of alleles (Na), expected heterozygosity (He), linkage disequilibrium (LD) and genetic differentiation (FST) were determined. In Kalabakan, the MSP-1 and MSP-2 alleles were predominantly K1 and FC27 family types, respectively. The GLURP genotype VI (751-800 bp) was predominant. The MOI for MSP-1 and MSP-2 were 1.65 and 1.20, respectively. The Na per microsatellite locus was 1.70. The He values for MSP-1, MSP-2, GLURP and neutral microsatellites were 0.17, 0.37, 0.70 and 0.33, respectively. In Kota Marudu, the MSP-1 and MSP-2 alleles were predominantly MAD20 and 3D7 family types, respectively. The GLURP genotype IV (651-700 bp) was predominant. The MOI for both MSP-1 and MSP-2 was 1.05. The Na per microsatellite locus was 3.60. The He values for MSP-1, MSP-2, GLURP and neutral microsatellites were 0.24, 0.25, 0.69 and 0.30, respectively. A significant LD was observed in Kalabakan (0.495, pSabah.

  5. Assessment of severe malaria in a multicenter, phase III, RTS, S/AS01 malaria candidate vaccine trial: case definition, standardization of data collection and patient care

    Directory of Open Access Journals (Sweden)

    Vekemans Johan

    2011-08-01

    Full Text Available Abstract Background An effective malaria vaccine, deployed in conjunction with other malaria interventions, is likely to substantially reduce the malaria burden. Efficacy against severe malaria will be a key driver for decisions on implementation. An initial study of an RTS, S vaccine candidate showed promising efficacy against severe malaria in children in Mozambique. Further evidence of its protective efficacy will be gained in a pivotal, multi-centre, phase III study. This paper describes the case definitions of severe malaria used in this study and the programme for standardized assessment of severe malaria according to the case definition. Methods Case definitions of severe malaria were developed from a literature review and a consensus meeting of expert consultants and the RTS, S Clinical Trial Partnership Committee, in collaboration with the World Health Organization and the Malaria Clinical Trials Alliance. The same groups, with input from an Independent Data Monitoring Committee, developed and implemented a programme for standardized data collection. The case definitions developed reflect the typical presentations of severe malaria in African hospitals. Markers of disease severity were chosen on the basis of their association with poor outcome, occurrence in a significant proportion of cases and on an ability to standardize their measurement across research centres. For the primary case definition, one or more clinical and/or laboratory markers of disease severity have to be present, four major co-morbidities (pneumonia, meningitis, bacteraemia or gastroenteritis with severe dehydration are excluded, and a Plasmodium falciparum parasite density threshold is introduced, in order to maximize the specificity of the case definition. Secondary case definitions allow inclusion of co-morbidities and/or allow for the presence of parasitaemia at any density. The programmatic implementation of standardized case assessment included a clinical

  6. Assessment of severe malaria in a multicenter, phase III, RTS, S/AS01 malaria candidate vaccine trial: case definition, standardization of data collection and patient care.

    Science.gov (United States)

    Vekemans, Johan; Marsh, Kevin; Greenwood, Brian; Leach, Amanda; Kabore, William; Soulanoudjingar, Solange; Asante, Kwaku Poku; Ansong, Daniel; Evans, Jennifer; Sacarlal, Jahit; Bejon, Philip; Kamthunzi, Portia; Salim, Nahya; Njuguna, Patricia; Hamel, Mary J; Otieno, Walter; Gesase, Samwel; Schellenberg, David

    2011-08-04

    An effective malaria vaccine, deployed in conjunction with other malaria interventions, is likely to substantially reduce the malaria burden. Efficacy against severe malaria will be a key driver for decisions on implementation. An initial study of an RTS, S vaccine candidate showed promising efficacy against severe malaria in children in Mozambique. Further evidence of its protective efficacy will be gained in a pivotal, multi-centre, phase III study. This paper describes the case definitions of severe malaria used in this study and the programme for standardized assessment of severe malaria according to the case definition. Case definitions of severe malaria were developed from a literature review and a consensus meeting of expert consultants and the RTS, S Clinical Trial Partnership Committee, in collaboration with the World Health Organization and the Malaria Clinical Trials Alliance. The same groups, with input from an Independent Data Monitoring Committee, developed and implemented a programme for standardized data collection.The case definitions developed reflect the typical presentations of severe malaria in African hospitals. Markers of disease severity were chosen on the basis of their association with poor outcome, occurrence in a significant proportion of cases and on an ability to standardize their measurement across research centres. For the primary case definition, one or more clinical and/or laboratory markers of disease severity have to be present, four major co-morbidities (pneumonia, meningitis, bacteraemia or gastroenteritis with severe dehydration) are excluded, and a Plasmodium falciparum parasite density threshold is introduced, in order to maximize the specificity of the case definition. Secondary case definitions allow inclusion of co-morbidities and/or allow for the presence of parasitaemia at any density. The programmatic implementation of standardized case assessment included a clinical algorithm for evaluating seriously sick children

  7. Mitochondrial genes support a common origin of rodent malaria parasites and Plasmodium falciparum's relatives infecting great apes

    Directory of Open Access Journals (Sweden)

    Blanquart Samuel

    2011-03-01

    Full Text Available Abstract Background Plasmodium falciparum is responsible for the most acute form of human malaria. Most recent studies demonstrate that it belongs to a monophyletic lineage specialized in the infection of great ape hosts. Several other Plasmodium species cause human malaria. They all belong to another distinct lineage of parasites which infect a wider range of primate species. All known mammalian malaria parasites appear to be monophyletic. Their clade includes the two previous distinct lineages of parasites of primates and great apes, one lineage of rodent parasites, and presumably Hepatocystis species. Plasmodium falciparum and great ape parasites are commonly thought to be the sister-group of all other mammal-infecting malaria parasites. However, some studies supported contradictory origins and found parasites of great apes to be closer to those of rodents, or to those of other primates. Results To distinguish between these mutually exclusive hypotheses on the origin of Plasmodium falciparum and its great ape infecting relatives, we performed a comprehensive phylogenetic analysis based on a data set of three mitochondrial genes from 33 to 84 malaria parasites. We showed that malarial mitochondrial genes have evolved slowly and are compositionally homogeneous. We estimated their phylogenetic relationships using Bayesian and maximum-likelihood methods. Inferred trees were checked for their robustness to the (i site selection, (ii assumptions of various probabilistic models, and (iii taxon sampling. Our results robustly support a common ancestry of rodent parasites and Plasmodium falciparum's relatives infecting great apes. Conclusions Our results refute the most common view of the origin of great ape malaria parasites, and instead demonstrate the robustness of a less well-established phylogenetic hypothesis, under which Plasmodium falciparum and its relatives infecting great apes are closely related to rodent parasites. This study sheds light

  8. Impact of pre-existing MSP142-allele specific immunity on potency of an erythrocytic Plasmodium falciparum vaccine

    Directory of Open Access Journals (Sweden)

    Bergmann-Leitner Elke S

    2012-09-01

    Full Text Available Abstract Background MSP1 is the major surface protein on merozoites and a prime candidate for a blood stage malaria vaccine. Preclinical and seroepidemiological studies have implicated antibodies to MSP1 in protection against blood stage parasitaemia and/or reduced parasite densities, respectively. Malaria endemic areas have multiple strains of Plasmodium falciparum circulating at any given time, giving rise to complex immune responses, an issue which is generally not addressed in clinical trials conducted in non-endemic areas. A lack of understanding of the effect of pre-existing immunity to heterologous parasite strains may significantly contribute to vaccine failure in the field. The purpose of this study was to model the effect of pre-existing immunity to MSP142 on the immunogenicity of blood-stage malaria vaccines based on alternative MSP1 alleles. Methods Inbred and outbred mice were immunized with various recombinant P. falciparum MSP142 proteins that represent the two major alleles of MSP142, MAD20 (3D7 and Wellcome (K1, FVO. Humoral immune responses were analysed by ELISA and LuminexTM, and functional activity of induced MSP142-specific antibodies was assessed by growth inhibition assays. T-cell responses were characterized using ex vivo ELISpot assays. Results Analysis of the immune responses induced by various immunization regimens demonstrated a strong allele-specific response at the T cell level in both inbred and outbred mice. The success of heterologous regimens depended on the degree of homology of the N-terminal p33 portion of the MSP142, likely due to the fact that most T cell epitopes reside in this part of the molecule. Analysis of humoral immune responses revealed a marked cross-reactivity between the alleles. Functional analyses showed that some of the heterologous regimens induced antibodies with improved growth inhibitory activities. Conclusion The development of a more broadly efficacious MSP1 based vaccine may be

  9. Genetic polymorphism and natural selection in the malaria parasite Plasmodium falciparum.

    OpenAIRE

    Escalante, A A; Lal, A A; Ayala, F J

    1998-01-01

    We have studied the genetic polymorphism at 10 Plasmodium falciparum loci that are considered potential targets for specific antimalarial vaccines. The polymorphism is unevenly distributed among the loci; loci encoding proteins expressed on the surface of the sporozoite or the merozoite (AMA-1, CSP, LSA-1, MSP-1, MSP-2, and MSP-3) are more polymorphic than those expressed during the sexual stages or inside the parasite (EBA-175, Pfs25, PF48/45, and RAP-1). Comparison of synonymous and nonsyno...

  10. Antibody and T-cell responses associated with experimental human malaria infection or vaccination show limited relationships.

    Science.gov (United States)

    Walker, Karen M; Okitsu, Shinji; Porter, David W; Duncan, Christopher; Amacker, Mario; Pluschke, Gerd; Cavanagh, David R; Hill, Adrian V S; Todryk, Stephen M

    2015-05-01

    This study examined specific antibody and T-cell responses associated with experimental malaria infection or malaria vaccination, in malaria-naive human volunteers within phase I/IIa vaccine trials, with a view to investigating inter-relationships between these types of response. Malaria infection was via five bites of Plasmodium falciparum-infected mosquitoes, with individuals reaching patent infection by 11-12 days, having harboured four or five blood-stage cycles before drug clearance. Infection elicited a robust antibody response against merozoite surface protein-119 , correlating with parasite load. Classical class switching was seen from an early IgM to an IgG1-dominant response of increasing affinity. Malaria-specific T-cell responses were detected in the form of interferon-γ and interleukin-4 (IL-4) ELIspot, but their magnitude did not correlate with the magnitude of antibody or its avidity, or with parasite load. Different individuals who were immunized with a virosome vaccine comprising influenza antigens combined with P. falciparum antigens, demonstrated pre-existing interferon-γ, IL-2 and IL-5 ELIspot responses against the influenza antigens, and showed boosting of anti-influenza T-cell responses only for IL-5. The large IgG1-dominated anti-parasite responses showed limited correlation with T-cell responses for magnitude or avidity, both parameters being only negatively correlated for IL-5 secretion versus anti-apical membrane antigen-1 antibody titres. Overall, these findings suggest that cognate T-cell responses across a range of magnitudes contribute towards driving potentially effective antibody responses in infection-induced and vaccine-induced immunity against malaria, and their existence during immunization is beneficial, but magnitudes are mostly not inter-related. © 2014 John Wiley & Sons Ltd.

  11. Antibodies and Plasmodium falciparum merozoites

    NARCIS (Netherlands)

    Ramasamy, R; Ramasamy, M; Yasawardena, S

    There is considerable interest in using merozoite proteins in a vaccine against falciparum malaria. Observations that antibodies to merozoite surface proteins block invasion are a basis for optimism. This article draws attention to important and varied aspects of how antibodies to Plasmodium

  12. Evidence of endothelial inflammation, T cell activation, and T cell reallocation in uncomplicated Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Elhassan, I M; Hviid, L; Satti, G

    1994-01-01

    To explain the observation that acute Plasmodium falciparum malaria is associated with a transient inability of peripheral blood cells to respond to antigenic stimulation in vitro, we have postulated the disease-induced reallocation of peripheral lymphocytes, possibly by adhesion to inflamed...... with the control donors. In addition, we found a disease-induced depletion of T cells with high expression of the LFA-1 antigen, particularly in the CD4+ subset. The results obtained provide further support for the hypothesis of T cell reallocation to inflamed endothelium in acute P. falciparum malaria....

  13. Potential impact of host immunity on malaria treatment outcome in Tanzanian children infected with Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Theander Thor G

    2007-11-01

    Full Text Available Abstract Background In malaria endemic areas children may recover from malaria after chemotherapy in spite of harbouring genotypically drug-resistant Plasmodium falciparum. This phenomenon suggests that there is a synergy between drug treatment and acquired immunity. This hypothesis was examined in an area of moderately intense transmission of P. falciparum in Tanzania during a drug trail with sulphadoxine-pyrimethamine (SP or amodiaquine (AQ. Methods One hundred children with uncomplicated malaria were treated with either SP or AQ and followed for 28 days. Mutations in parasite genes related to SP and AQ-resistance as well as human sickle cell trait and alpha-thalassaemia were determined using PCR and sequence-specific oligonucleotide probes and enzyme-linked immunosorbent assay (SSOP-ELISA, and IgG antibody responses to a panel of P. falciparum antigens were assessed and related to treatment outcome. Results Parasitological or clinical treatment failure (TF was observed in 68% and 38% of children receiving SP or AQ, respectively. In those with adequate clinical and parasitological response (ACPR compared to children with TF, and for both treatment regimens, prevalence and levels of anti-Glutamate-rich Protein (GLURP-specific IgG antibodies were significantly higher (P Conclusion These findings suggest that GLURP-specific IgG antibodies in this setting contribute to clearance of drug-resistant infections and support the hypothesis that acquired immunity enhances the clinical efficacy of drug therapy. The results should be confirmed in larger scale with greater sample size and with variation in transmission intensity.

  14. Blood stage malaria vaccine eliciting high antigen-specific antibody concentrations confers no protection to young children in Western Kenya.

    Directory of Open Access Journals (Sweden)

    Bernhards R Ogutu

    Full Text Available The antigen, falciparum malaria protein 1 (FMP1, represents the 42-kDa C-terminal fragment of merozoite surface protein-1 (MSP-1 of the 3D7 clone of P. falciparum. Formulated with AS02 (a proprietary Adjuvant System, it constitutes the FMP1/AS02 candidate malaria vaccine. We evaluated this vaccine's safety, immunogenicity, and efficacy in African children.A randomised, double-blind, Phase IIb, comparator-controlled trial.The trial was conducted in 13 field stations of one mile radii within Kombewa Division, Nyanza Province, Western Kenya, an area of holoendemic transmission of P. falciparum. We enrolled 400 children aged 12-47 months in general good health.Children were randomised in a 1ratio1 fashion to receive either FMP1/AS02 (50 microg or Rabipur(R rabies vaccine. Vaccinations were administered on a 0, 1, and 2 month schedule. The primary study endpoint was time to first clinical episode of P. falciparum malaria (temperature >/=37.5 degrees C with asexual parasitaemia of >/=50,000 parasites/microL of blood occurring between 14 days and six months after a third dose. Case detection was both active and passive. Safety and immunogenicity were evaluated for eight months after first immunisations; vaccine efficacy (VE was measured over a six-month period following third vaccinations.374 of 400 children received all three doses and completed six months of follow-up. FMP1/AS02 had a good safety profile and was well-tolerated but more reactogenic than the comparator. Geometric mean anti-MSP-1(42 antibody concentrations increased from1.3 microg/mL to 27.3 microg/mL in the FMP1/AS02 recipients, but were unchanged in controls. 97 children in the FMP1/AS02 group and 98 controls had a primary endpoint episode. Overall VE was 5.1% (95% CI: -26% to +28%; p-value = 0.7.FMP1/AS02 is not a promising candidate for further development as a monovalent malaria vaccine. Future MSP-1(42 vaccine development should focus on other formulations and antigen constructs

  15. Designing a VAR2CSA-based vaccine to prevent placental malaria.

    Science.gov (United States)

    Fried, Michal; Duffy, Patrick E

    2015-12-22

    Placental malaria (PM) due to Plasmodium falciparum is a major cause of maternal, fetal and infant mortality, but the mechanisms of pathogenesis and protective immunity are relatively well-understood for this condition, providing a path for vaccine development. P. falciparum parasites bind to chondroitin sulfate A (CSA) to sequester in the placenta, and women become resistant over 1-2 pregnancies as they acquire antibodies that block adhesion to CSA. The protein VAR2CSA, a member of the PfEMP1 variant surface antigen family, mediates parasite adhesion to CSA, and is the leading target for a vaccine to prevent PM. Obstacles to PM vaccine development include the large size (∼ 350 kD), high cysteine content, and sequence variation of VAR2CSA. A number of approaches have been taken to identify the combination of VAR2CSA domains and alleles that can induce broadly active antibodies that block adhesion of heterologous parasite isolates to CSA. This review summarizes these approaches, which have examined VAR2CSA fragments for binding activity, antigenicity with naturally acquired antibodies, and immunogenicity in animals for inducing anti-adhesion or surface-reactive antibodies. Two products are expected to enter human clinical studies in the near future based on N-terminal VAR2CSA fragments that have high binding affinity for CSA, and additional proteins preferentially expressed by placental parasites are also being examined for their potential contribution to a PM vaccine. Copyright © 2015. Published by Elsevier Ltd.

  16. Efficacy of RTS,S/AS01E Vaccine against Malaria in Children 5 to 17 Months of Age

    Science.gov (United States)

    Bejon, Philip; Lusingu, John; Olotu, Ally; Leach, Amanda; Lievens, Marc; Vekemans, Johan; Mshamu, Salum; Lang, Trudie; Gould, Jayne; Dubois, Marie-Claude; Demoitié, Marie-Ange; Stallaert, Jean-Francois; Vansadia, Preeti; Carter, Terrell; Njuguna, Patricia; Awuondo, Ken O.; Malabeja, Anangisye; Abdul, Omar; Gesase, Samwel; Mturi, Neema; Drakeley, Chris J.; Savarese, Barbara; Villafana, Tonya; Ballou, W. Ripley; Cohen, Joe; Riley, Eleanor M.; Lemnge, Martha M.; Marsh, Kevin; von Seidlein, Lorenz

    2009-01-01

    BACKGROUND Plasmodium falciparum malaria is a pressing global health problem. A previous study of the malaria vaccine RTS,S (which targets the circumsporozoite protein), given with an adjuvant system (AS02A), showed a 30% rate of protection against clinical malaria in children 1 to 4 years of age. We evaluated the efficacy of RTS,S given with a more immunogenic adjuvant system (AS01E) in children 5 to 17 months of age, a target population for vaccine licensure. METHODS We conducted a double-blind, randomized trial of RTS,S/AS01E vaccine as compared with rabies vaccine in children in Kilifi, Kenya, and Korogwe, Tanzania. The primary end point was fever with a falciparum parasitemia density of more than 2500 parasites per microliter, and the mean duration of follow-up was 7.9 months (range, 4.5 to 10.5). RESULTS A total of 894 children were randomly assigned to receive the RTS,S/AS01E vaccine or the control (rabies) vaccine. Among the 809 children who completed the study procedures according to the protocol, the cumulative number in whom clinical malaria developed was 32 of 402 assigned to receive RTS,S/AS01E and 66 of 407 assigned to receive the rabies vaccine; the adjusted efficacy rate for RTS,S/AS01E was 53% (95% confidence interval [CI], 28 to 69; P<0.001) on the basis of Cox regression. Overall, there were 38 episodes of clinical malaria among recipients of RTS,S/AS01E, as compared with 86 episodes among recipients of the rabies vaccine, with an adjusted rate of efficacy against all malarial episodes of 56% (95% CI, 31 to 72; P<0.001). All 894 children were included in the intention-to-treat analysis, which showed an unadjusted efficacy rate of 49% (95% CI, 26 to 65; P<0.001). There were fewer serious adverse events among recipients of RTS,S/AS01E, and this reduction was not only due to a difference in the number of admissions directly attributable to malaria. CONCLUSIONS RTS,S/AS01E shows promise as a candidate malaria vaccine. (ClinicalTrials.gov number, NCT

  17. Workshop report: Malaria vaccine development in Europe--preparing for the future.

    Science.gov (United States)

    Viebig, Nicola K; D'Alessio, Flavia; Draper, Simon J; Sim, B Kim Lee; Mordmüller, Benjamin; Bowyer, Paul W; Luty, Adrian J F; Jungbluth, Stefan; Chitnis, Chetan E; Hill, Adrian V S; Kremsner, Peter; Craig, Alister G; Kocken, Clemens H M; Leroy, Odile

    2015-11-17

    The deployment of a safe and effective malaria vaccine will be an important tool for the control of malaria and the reduction in malaria deaths. With the launch of the 2030 Malaria Vaccine Technology Roadmap, the malaria community has updated the goals and priorities for the development of such a vaccine and is now paving the way for a second phase of malaria vaccine development. During a workshop in Brussels in November 2014, hosted by the European Vaccine Initiative, key players from the European, North American and African malaria vaccine community discussed European strategies for future malaria vaccine development in the global context. The recommendations of the European malaria community should guide researchers, policy makers and funders of global health research and development in fulfilling the ambitious goals set in the updated Malaria Vaccine Technology Roadmap. Copyright © 2015.

  18. Neuropsychiatric manifestations after mefloquine therapy for Plasmodium falciparum malaria: comparing a retrospective and a prospective study

    DEFF Research Database (Denmark)

    Rønn, A M; Rønne-Rasmussen, J; Gøtzsche, P C

    1998-01-01

    Mefloquine has been increasingly used for treatment of chloroquine-resistant malaria since its introduction in the late 1970s. In 1987 the first case of toxic encephalopathy was published, and in 1989 the WHO initiated reporting and investigation of neuropsychiatric adverse reactions of mefloquine....... Neuropsychiatric adverse drug reactions are now well documented. We compared an open prospective 3 year study including all patients with P. falciparum treated with mefloquine with an earlier published, retrospective study on a comparable population from our department covering the period up to 1989...

  19. Quinine-resistant severe falciparum malaria effectively treated with atovaquone and proguanil hydrochloride combination therapy.

    Science.gov (United States)

    Uchiyama, Hitoji; Okamoto, Akio; Sato, Katsuaki; Yamada, Tomohiro; Murakami, Sadatsugu; Yoneda, Seiichi; Kajita, Yoshihiro; Tegoshi, Tatsuya; Arizono, Naoki

    2004-07-01

    A 22-year-old Japanese man noticed pyrexia and diarrhea after travel to Guinea. Notable physical findings included hepatosplenomegaly. Treatment with oral quinine and minocycline was started after definitive diagnosis of falciparum malaria by blood smear. Initially, parasitemia and body temperature decreased but by the third night of therapy his temperature increased to 40 degrees C with a slight increase of parasite count. When quinine treatment was changed to atovaquone/proguanil, his temperature dropped immediately and complete plasmodial elimination was confirmed on microscopic examination. Subsequent recrudescence of the disease was not observed. It was concluded that the antimalarial treatment with atovaquone/proguanil might become invaluable in Japan.

  20. Loss of cellular immune reactivity during acute Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Hviid, L; Theander, T G; Abu-Zeid, Y A

    1991-01-01

    transmission season 5 months prior to the attack, were included in the study. Lymphoproliferative responsiveness to purified soluble malarial antigens and to the unrelated antigen PPD was lost during the acute phase of the disease in most donors, but was regained during convalescence, except in four donors...... convalescence. Five donors examined by fluorescence-activated cell sorting (FACS) showed no increase in surface expression of IL-2 receptor on peripheral lymphocytes. The data indicate that acute P. falciparum malaria causes a depletion of antigen-reactive T-cells from the peripheral circulation, probably due...

  1. Implementation workshop of WHO guidelines on evaluation of malaria vaccines: Current regulatory concepts and issues related to vaccine quality, Pretoria, South Africa 07 Nov 2014.

    Science.gov (United States)

    Ho, Mei Mei; Baca-Estrada, Maria; Conrad, Christoph; Karikari-Boateng, Eric; Kang, Hye-Na

    2015-08-26

    The current World Health Organization (WHO) guidelines on the quality, safety and efficacy of recombinant malaria vaccines targeting the pre-erythrocytic and blood stages of Plasmodium falciparum were adopted by the WHO Expert Committee on Biological Standardization in 2012 to provide guidance on the quality, nonclinical and clinical aspects of recombinant malaria vaccines. A WHO workshop was organised to facilitate implementation into African (national/regional) regulatory practices, of the regulatory evaluation principles outlined in the guidelines regarding quality aspects. The workshop was used also to share knowledge and experience on regulatory topics of chemistry, manufacturing and control with a focus on vaccines through presentations and an interactive discussion using a case study approach. The basic principles and concepts of vaccine quality including consistency of production, quality control and manufacturing process were presented and discussed in the meeting. By reviewing and practicing a case study, better understanding on the relationship between consistency of production and batch release tests of an adjuvanted pre-erythrocytic recombinant malaria vaccine was reached. The case study exercise was considered very useful to understand regulatory evaluation principles of vaccines and a suggestion was made to WHO to provide such practices also through its Global Learning Opportunities for Vaccine Quality programme. Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.

  2. The role of Plasmodium falciparum variant surface antigens in protective immunity and vaccine development

    DEFF Research Database (Denmark)

    Hviid, Lars

    2010-01-01

    There is substantial immuno-epidemiological evidence that the parasite-encoded, so-called variant surface antigens (VSAs) such as PfEMP1 on the surface of infected erythrocytes (IEs) are important-in some cases probably decisive-determinants of clinical outcome of P. falciparum malaria. The evide...

  3. Does radical cure of asymptomatic Plasmodium falciparum place adults in endemic areas at increased risk of recurrent symptomatic malaria?

    Science.gov (United States)

    Owusu-Agyei, Seth; Binka, Fred; Koram, Kwadwo; Anto, Francis; Adjuik, Martin; Nkrumah, Francis; Smith, Tom

    2002-07-01

    A cohort of 197 adults in Kassena-Nankana District (northern Ghana) was radically cured of malaria parasites to study subsequent incidence of malaria infection. During the following 20 weeks of the malaria transmission season, 49% experienced clinical attacks associated with Plasmodium falciparum parasitaemia. In a group of 202 adults identically followed-up 1 year later without being treated, only 38% experienced such episodes (log-rank test for equality of survivor functions, P=0.035). Clinical attacks in radically cured individuals presented with lower parasite densities but more symptoms. Randomized studies are needed to test the hypothesis that radical cure of P. falciparum enhances the risk and severity of subsequent clinical malaria attacks.

  4. To report a case of unilateral proliferative retinopathy following noncerebral malaria with Plasmodium falciparum in Southern India

    Directory of Open Access Journals (Sweden)

    Aditya Verma

    2015-01-01

    Full Text Available The retinopathy in association with malaria fever described so far includes retinal hemorrhages, vessel changes, retinal discoloration/whitening and papilledema. Malaria retinopathy has been mostly described in severe cases, associated with Plasmodium falciparum, correlating the patho-physiology of retinal and cerebral manifestations. We report an unusual case of proliferative retinopathy as a manifestation of malaria fever, caused by P. falciparum with no cerebral involvement. The patient had features of unilateral retinal vascular occlusion with proliferative changes and vitreous hemorrhage. To the best of our knowledge, such a case has never been reported so far in the literature. This report highlights the possible occurrence of severe proliferative changes associated with malaria fever, which if diagnosed early can prevent possible blindness.

  5. Blood-stage malaria vaccines: post-genome strategies for the identification of novel vaccine candidates.

    Science.gov (United States)

    Ntege, Edward H; Takashima, Eizo; Morita, Masayuki; Nagaoka, Hikaru; Ishino, Tomoko; Tsuboi, Takafumi

    2017-08-01

    An efficacious malaria vaccine is necessary to advance the current control measures towards malaria elimination. To-date, only RTS,S/AS01, a leading pre-erythrocytic stage vaccine completed phase 3 trials, but with an efficacy of 28-36% in children, and 18-26% in infants, that waned over time. Blood-stage malaria vaccines protect against disease, and are considered effective targets for the logical design of next generation vaccines to improve the RTS,S field efficacy. Therefore, novel blood-stage vaccine candidate discovery efforts are critical, albeit with several challenges including, high polymorphisms in vaccine antigens, poor understanding of targets of naturally protective immunity, and difficulties in the expression of high AT-rich plasmodial proteins. Areas covered: PubMed ( www.ncbi.nlm.nih.gov/pubmed ) was searched to review the progress and future prospects of malaria vaccine research and development. We focused on post-genome vaccine candidate discovery, malaria vaccine development, sequence diversity, pre-clinical and clinical trials. Expert commentary: Post-genome high-throughput technologies using wheat germ cell-free protein synthesis technology and immuno-profiling with sera from malaria patients with clearly defined outcomes are highlighted to overcome current challenges of malaria vaccine candidate discovery.

  6. Malaria Vaccine Research at the Naval Medical Research Center

    National Research Council Canada - National Science Library

    Carucci, Daniel

    2001-01-01

    At a time in bioscience when many people assume that vaccines are available for most infectious diseases, it often comes as a surprise that the ancient disease, malaria, is still the most important...

  7. RTS,S/AS01 malaria vaccine and child mortality

    DEFF Research Database (Denmark)

    Aaby, Peter; Rodrigues, Amabelia; Kofoed, Poul-Erik

    2015-01-01

    Comment on Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. [Lancet. 2015]...

  8. Malaria status in Al-Hodeidah Governorate, Yemen: malariometric parasitic survey & chloroquine resistance P. falciparum local strain.

    Science.gov (United States)

    Al-Maktari, Mohamed T; Bassiouny, Hassan K; Al-Hamd, Zeinab S; Assabri, Ali M; El-Massry, Abdel Ghany; Shatat, Hanan Z

    2003-08-01

    Malaria continues to be a major public health problem in Al-Hodeidah G. A cross-sectional malariometic parasitic survey including 4000 Yemenis of various age /sex groups were enrolled in this study from 43 villages/or Harah in five selected districts representing Al-Hodeidah G. Duplicate thin and thick blood smears were stained with Giemsa's stain and examined. Out of 4000 examined slides, 646 (16.2%) were found to be malaria positive, 508 (78.6%) of them were detected through ACD, while 138 (21.4%) cases were detected by PCD. The overall parasite rate was 16.2%, a situation of prevalently mesoendemic condition. P. falciparum was the predominant species recorded (96.7%), followed by P. vivax (1.7%), the least prevalent was P. malariae (0.3%). Yemen has been considered free of ovale malaria. The recorded an indigenous case of P. ovale for the first time in Yemen should be taken into consideration for the existence of this particular Plasmodium species when surveying for malaria in the future. The present study was the first document in Yemen to compare simultaneously the in vivo and in vitro response to chloroquine among 209 of P. falciparum field isolate patients that were satisfied all criteria of WHO for the implementation of the in vivo and in vitro tests and were obtained by PCD and ACD methods. Chloroquine resistance of local strain of P. falciparum was recorded in all studied districts (Zabid, Bajil, Azohrah, Azaidiah and Al-Hodeidah city). RIII (high level of resistance) was recorded for the first time in Yemen and should be taken into consideration in the treatment of infected malaria patients. This calls for urgent revision of the current malaria treatment policy in Yemen where chloroquine is the first-line treatment of uncomplicated P. falciparum malaria.

  9. Plasmodium falciparum signal peptide peptidase cleaves malaria heat shock protein 101 (HSP101). Implications for gametocytogenesis

    International Nuclear Information System (INIS)

    Baldwin, Michael; Russo, Crystal; Li, Xuerong; Chishti, Athar H.

    2014-01-01

    Highlights: • PfSPP is an ER resident protease. • PfSPP is expressed both as a monomer and dimer. • The signal peptide of HSP101 is the first known substrate of PfSPP. • Reduced PfSPP activity may significantly affect ER homeostasis. - Abstract: Previously we described the identification of a Plasmodium falciparum signal peptide peptidase (PfSPP) functioning at the blood stage of malaria infection. Our studies also demonstrated that mammalian SPP inhibitors prevent malaria parasite growth at the late-ring/early trophozoite stage of intra-erythrocytic development. Consistent with its role in development, we tested the hypothesis that PfSPP functions at the endoplasmic reticulum of P.falciparum where it cleaves membrane-bound signal peptides generated following the enzyme activity of signal peptidase. The localization of PfSPP to the endoplasmic reticulum was confirmed by immunofluorescence microscopy and immunogold electron microscopy. Biochemical analysis indicated the existence of monomer and dimer forms of PfSPP in the parasite lysate. A comprehensive bioinformatics screen identified several candidate PfSPP substrates in the parasite genome. Using an established transfection based in vivo luminescence assay, malaria heat shock protein 101 (HSP101) was identified as a substrate of PfSPP, and partial inhibition of PfSPP correlated with the emergence of gametocytes. This finding unveils the first known substrate of PfSPP, and provides new perspectives for the function of intra-membrane proteolysis at the erythrocyte stage of malaria parasite life cycle

  10. Taste-masked quinine pamoate tablets for treatment of children with uncomplicated Plasmodium falciparum malaria.

    Science.gov (United States)

    Kayitare, E; Vervaet, C; Mehuys, E; Kayumba, P C; Ntawukulilyayo, J D; Karema, C; Bortel, Van; Remon, J P

    2010-06-15

    Children with uncomplicated malaria are generally treated with oral medication, except those unable to take oral drugs. Even though quinine has shown to be effective in treatment of African children with uncomplicated malaria its high bitterness limited the paediatric use. This study aimed to develop taste-masked quinine tablets suitable for children and offering dosing flexibility to adjust the quinine dose in function of body weight. Insoluble quinine pamoate was used to formulate fast-disintegrating tablets, using a specific tablet design (rectangular tablet which can be divided into 8 subunits) to allow dosing flexibility. The physical properties of tablets were evaluated in vitro, as well as the quinine bioavailability in healthy adults (n=18) and the efficacy for treatment of children with uncomplicated Plasmodium falciparum malaria (n=56) using a 7-day regimen of 8 mg quinine/kg. Quinine pamoate tablets complied with the pharmacopoeial requirements for mass uniformity, friability, content uniformity, breakability, disintegration and dissolution. The quinine pharmacokinetic parameters after single administration of a quinine pamoate tablet were similar to a commercially available quinine sulfate tablet. The fast decline in parasitemia (28.6%/24h), the reduction rate of fever (all children were apyretic after 72 h) and the steady state quinine plasma concentration (5.7-15.8 microg/ml) proved the efficacy of the quinine pamoate tablets against P. falciparum. Fast-dispersible and taste-masked quinine pamoate tablets improved dosing accuracy, allowed easy administration and resulted in a high efficacy during the treatment of children with uncomplicated malaria. Copyright 2010. Published by Elsevier B.V.

  11. Plasmodium falciparum signal peptide peptidase cleaves malaria heat shock protein 101 (HSP101). Implications for gametocytogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Baldwin, Michael; Russo, Crystal; Li, Xuerong [Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111 (United States); Chishti, Athar H., E-mail: athar.chishti@tufts.edu [Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA 02111 (United States); Sackler School of Graduate Biomedical Sciences, Programs in Physiology, Pharmacology, and Microbiology, Tufts University School of Medicine, Boston, MA 02111 (United States)

    2014-08-08

    Highlights: • PfSPP is an ER resident protease. • PfSPP is expressed both as a monomer and dimer. • The signal peptide of HSP101 is the first known substrate of PfSPP. • Reduced PfSPP activity may significantly affect ER homeostasis. - Abstract: Previously we described the identification of a Plasmodium falciparum signal peptide peptidase (PfSPP) functioning at the blood stage of malaria infection. Our studies also demonstrated that mammalian SPP inhibitors prevent malaria parasite growth at the late-ring/early trophozoite stage of intra-erythrocytic development. Consistent with its role in development, we tested the hypothesis that PfSPP functions at the endoplasmic reticulum of P.falciparum where it cleaves membrane-bound signal peptides generated following the enzyme activity of signal peptidase. The localization of PfSPP to the endoplasmic reticulum was confirmed by immunofluorescence microscopy and immunogold electron microscopy. Biochemical analysis indicated the existence of monomer and dimer forms of PfSPP in the parasite lysate. A comprehensive bioinformatics screen identified several candidate PfSPP substrates in the parasite genome. Using an established transfection based in vivo luminescence assay, malaria heat shock protein 101 (HSP101) was identified as a substrate of PfSPP, and partial inhibition of PfSPP correlated with the emergence of gametocytes. This finding unveils the first known substrate of PfSPP, and provides new perspectives for the function of intra-membrane proteolysis at the erythrocyte stage of malaria parasite life cycle.

  12. Experimental human challenge infections can accelerate clinical malaria vaccine development

    NARCIS (Netherlands)

    Sauerwein, R.W.; Roestenberg, M.; Moorthy, V.S.

    2011-01-01

    Malaria is one of the most frequently occurring infectious diseases worldwide, with almost 1 million deaths and an estimated 243 million clinical cases annually. Several candidate malaria vaccines have reached Phase IIb clinical trials, but results have often been disappointing. As an alternative to

  13. Cross-stage immunity for malaria vaccine development.

    Science.gov (United States)

    Nahrendorf, Wiebke; Scholzen, Anja; Sauerwein, Robert W; Langhorne, Jean

    2015-12-22

    A vaccine against malaria is urgently needed for control and eventual eradication. Different approaches are pursued to induce either sterile immunity directed against pre-erythrocytic parasites or to mimic naturally acquired immunity by controlling blood-stage parasite densities and disease severity. Pre-erythrocytic and blood-stage malaria vaccines are often seen as opposing tactics, but it is likely that they have to be combined into a multi-stage malaria vaccine to be optimally safe and effective. Since many antigenic targets are shared between liver- and blood-stage parasites, malaria vaccines have the potential to elicit cross-stage protection with immune mechanisms against both stages complementing and enhancing each other. Here we discuss evidence from pre-erythrocytic and blood-stage subunit and whole parasite vaccination approaches that show that protection against malaria is not necessarily stage-specific. Parasites arresting at late liver-stages especially, can induce powerful blood-stage immunity, and similarly exposure to blood-stage parasites can afford pre-erythrocytic immunity. The incorporation of a blood-stage component into a multi-stage malaria vaccine would hence not only combat breakthrough infections in the blood should the pre-erythrocytic component fail to induce sterile protection, but would also actively enhance the pre-erythrocytic potency of this vaccine. We therefore advocate that future studies should concentrate on the identification of cross-stage protective malaria antigens, which can empower multi-stage malaria vaccine development. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  14. RTS,S/AS01 malaria vaccine and child mortality

    DEFF Research Database (Denmark)

    Aaby, Peter; Rodrigues, Amabelia; Kofoed, Poul-Erik

    2015-01-01

    Comment on Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. [Lancet. 2015]......Comment on Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. [Lancet. 2015]...

  15. Genetic variability and population structure of Plasmodium falciparum parasite populations from different malaria ecological regions of Kenya.

    Science.gov (United States)

    Ingasia, Luicer A; Cheruiyot, Jelagat; Okoth, Sheila Akinyi; Andagalu, Ben; Kamau, Edwin

    2016-04-01

    Transmission intensity, movement of human and vector hosts, biogeographical features, and malaria control measures are some of the important factors that determine Plasmodium falciparum parasite genetic variability and population structure. Kenya has different malaria ecologies which might require different disease intervention methods. Refined parasite population genetic studies are critical for informing malaria control and elimination strategies. This study describes the genetic diversity and population structure of P. falciparum parasites from the different malaria ecological zones in Kenya. Twelve multi-locus microsatellite (MS) loci previously described were genotyped in 225 P. falciparum isolates collected between 2012 and 2013 from five sites; three in lowland endemic regions (Kisumu, Kombewa, and Malindi) and two in highland, epidemic regions (Kisii and Kericho). Parasites from the lowland endemic and highland epidemic regions of western Kenya had high genetic diversity compared to coastal lowland endemic region of Kenya [Malindi]. The Kenyan parasites had a mean genetic differentiation index (FST) of 0.072 (p=0.011). The multi-locus genetic analysis of the 12 MS revealed all the parasites had unique haplotypes. Significant linkage disequilibrium (LD) was observed in all the five parasite populations. Kisumu had the most significant index of association values (0.16; pKenya after introduction of the artemether-lumefantrine is important in refining the spread of drug resistant strains and malaria transmission for more effective control and eventual elimination of malaria in Kenya. Copyright © 2015. Published by Elsevier B.V.

  16. The detection and treatment of Plasmodium falciparum malaria: Time for change

    Directory of Open Access Journals (Sweden)

    Nosten F

    2004-01-01

    Full Text Available In most countries where malaria is endemic, P. falciparum malaria is on the rise. This is primarily due to the spread of drug-resistant strains. Drug resistance is mediated by spontaneous changes in the parasite genome that allow resistant parasites to escape the action of the drugs. The spread of drug resistance increases the transmission of malaria parasites. The consequences for the populations at risk are profound both in terms of consequences for health and economy. In order to halt the progression of drug resistance, we need to change the way antimalarials are used. As in tuberculosis and HIV/AIDS, we must use a combination of drugs for the treatment of malaria. Taking into account the pharmacokinetic and pharmacodynamic properties of the various anti-malarial agents, artemisinin-based combination therapy (ACT seems to be the best option. This strategy should be used in conjunction with early diagnosis and appropriate vector control measures to achieve reduction in the emergence and spread of drug resistance.

  17. Comparative gene expression profiling of P. falciparum malaria parasites exposed to three different histone deacetylase inhibitors.

    Directory of Open Access Journals (Sweden)

    Katherine T Andrews

    Full Text Available Histone deacetylase (HDAC inhibitors are being intensively pursued as potential new drugs for a range of diseases, including malaria. HDAC inhibitors are also important tools for the study of epigenetic mechanisms, transcriptional control, and other important cellular processes. In this study the effects of three structurally related antimalarial HDAC inhibitors on P. falciparum malaria parasite gene expression were compared. The three hydroxamate-based compounds, trichostatin A (TSA, suberoylanilide hydroxamic acid (SAHA; Vorinostat® and a 2-aminosuberic acid derivative (2-ASA-9, all caused profound transcriptional effects, with ~2-21% of genes having >2-fold altered expression following 2 h exposure to the compounds. Only two genes, alpha tubulin II and a hydrolase, were up-regulated by all three compounds after 2 h exposure in all biological replicates examined. The transcriptional changes observed after 2 h exposure to HDAC inhibitors were found to be largely transitory, with only 1-5% of genes being regulated after removing the compounds and culturing for a further 2 h. Despite some structural similarity, the three inhibitors caused quite diverse transcriptional effects, possibly reflecting subtle differences in mode of action or cellular distribution. This dataset represents an important contribution to our understanding of how HDAC inhibitors act on malaria parasites and identifies alpha tubulin II as a potential transcriptional marker of HDAC inhibition in malaria parasites that may be able to be exploited for future development of HDAC inhibitors as new antimalarial agents.

  18. Transient Loss of Protection Afforded by a Live Attenuated Non-typhoidal Salmonella Vaccine in Mice Co-infected with Malaria.

    Directory of Open Access Journals (Sweden)

    Jason P Mooney

    Full Text Available In immunocompetent individuals, non-typhoidal Salmonella serovars (NTS are associated with gastroenteritis, however, there is currently an epidemic of NTS bloodstream infections in sub-Saharan Africa. Plasmodium falciparum malaria is an important risk factor for invasive NTS bloodstream in African children. Here we investigated whether a live, attenuated Salmonella vaccine could be protective in mice, in the setting of concurrent malaria. Surprisingly, mice acutely infected with the nonlethal malaria parasite Plasmodium yoelii 17XNL exhibited a profound loss of protective immunity to NTS, but vaccine-mediated protection was restored after resolution of malaria. Absence of protective immunity during acute malaria correlated with maintenance of antibodies to NTS, but a marked reduction in effector capability of Salmonella-specific CD4 and CD8 T cells. Further, increased expression of the inhibitory molecule PD1 was identified on memory CD4 T cells induced by vaccination. Blockade of IL-10 restored protection against S. Typhimurium, without restoring CD4 T cell effector function. Simultaneous blockade of CTLA-4, LAG3, and PDL1 restored IFN-γ production by vaccine-induced memory CD4 T cells but was not sufficient to restore protection. Together, these data demonstrate that malaria parasite infection induces a temporary loss of an established adaptive immune response via multiple mechanisms, and suggest that in the setting of acute malaria, protection against NTS mediated by live vaccines may be interrupted.

  19. Features and prognosis of severe malaria caused by Plasmodium falciparum, Plasmodium vivax and mixed Plasmodium species in Papua New Guinean children.

    Directory of Open Access Journals (Sweden)

    Laurens Manning

    Full Text Available BACKGROUND: Mortality from severe pediatric falciparum malaria appears low in Oceania but Plasmodium vivax is increasingly recognized as a cause of complications and death. The features and prognosis of mixed Plasmodium species infections are poorly characterized. Detailed prospective studies that include accurate malaria diagnosis and detection of co-morbidities are lacking. METHODS AND FINDINGS: We followed 340 Papua New Guinean (PNG children with PCR-confirmed severe malaria (77.1% P. falciparum, 7.9% P. vivax, 14.7% P. falciparum/vivax hospitalized over a 3-year period. Bacterial cultures were performed to identify co-incident sepsis. Clinical management was under national guidelines. Of 262 children with severe falciparum malaria, 30.9%, 24.8% and 23.2% had impaired consciousness, severe anemia, and metabolic acidosis/hyperlactatemia, respectively. Two (0.8% presented with hypoglycemia, seven (2.7% were discharged with neurologic impairment, and one child died (0.4%. The 27 severe vivax malaria cases presented with similar phenotypic features to the falciparum malaria cases but respiratory distress was five times more common (P=0.001; one child died (3.7%. The 50 children with P. falciparum/vivax infections shared phenotypic features of mono-species infections, but were more likely to present in deep coma and had the highest mortality (8.0%; P=0.003 vs falciparum malaria. Overall, bacterial cultures were positive in only two non-fatal cases. 83.6% of the children had alpha-thalassemia trait and seven with coma/impaired consciousness had South Asian ovalocytosis (SAO. CONCLUSIONS: The low mortality from severe falciparum malaria in PNG children may reflect protective genetic factors other than alpha-thalassemia trait/SAO, good nutrition, and/or infrequent co-incident sepsis. Severe vivax malaria had similar features but severe P. falciparum/vivax infections were associated with the most severe phenotype and worst prognosis.

  20. Rapid reemergence of T cells into peripheral circulation following treatment of severe and uncomplicated Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Hviid, L; Kurtzhals, J A; Goka, B Q

    1997-01-01

    Frequencies and absolute numbers of peripheral T-cell subsets were monitored closely following acute Plasmodium falciparum malaria in 22 Ghanaian children from an area of hyperendemicity for seasonal malaria transmission. The children presented with cerebral or uncomplicated malaria (CM or UM, re...

  1. Seasonal changes in the Plasmodium falciparum population in individuals and their relationship to clinical malaria: a longitudinal study in a Sudanese village

    DEFF Research Database (Denmark)

    Roper, C; Richardson, W; Elhassan, I M

    1998-01-01

    Residents of Daraweesh village in Sudan were monitored for Plasmodium falciparum infection and malaria morbidity in 3 malaria seasons from 1993 to 1996. Malaria parasites were detected microscopically and by polymerase chain reaction (PCR) in a series of cross-sectional surveys. PCR revealed subm...

  2. The Clp Chaperones and Proteases of the Human Malaria Parasite Plasmodium falciparum

    Energy Technology Data Exchange (ETDEWEB)

    Bakkouri, Majida El; Pow, Andre; Mulichak, Anne; Cheung, Kevin L.Y.; Artz, Jennifer D.; Amani, Mehrnaz; Fell, Stuart; de Koning-Ward, Tania F.; Goodman, C. Dean; McFadden, Geoffrey I.; Ortega, Joaquin; Hui, Raymond; Houry, Walid A. (McMaster U.); (Melbourne); (Toronto); (Deakin); (HWMRI)

    2015-02-09

    The Clp chaperones and proteases play an important role in protein homeostasis in the cell. They are highly conserved across prokaryotes and found also in the mitochondria of eukaryotes and the chloroplasts of plants. They function mainly in the disaggregation, unfolding and degradation of native as well as misfolded proteins. Here, we provide a comprehensive analysis of the Clp chaperones and proteases in the human malaria parasite Plasmodium falciparum. The parasite contains four Clp ATPases, which we term PfClpB1, PfClpB2, PfClpC and PfClpM. One PfClpP, the proteolytic subunit, and one PfClpR, which is an inactive version of the protease, were also identified. Expression of all Clp chaperones and proteases was confirmed in blood-stage parasites. The proteins were localized to the apicoplast, a non-photosynthetic organelle that accommodates several important metabolic pathways in P. falciparum, with the exception of PfClpB2 (also known as Hsp101), which was found in the parasitophorous vacuole. Both PfClpP and PfClpR form mostly homoheptameric rings as observed by size-exclusion chromatography, analytical ultracentrifugation and electron microscopy. The X-ray structure of PfClpP showed the protein as a compacted tetradecamer similar to that observed for Streptococcus pneumoniae and Mycobacterium tuberculosis ClpPs. Our data suggest the presence of a ClpCRP complex in the apicoplast of P. falciparum.

  3. Population pharmacokinetics of quinine in pregnant women with uncomplicated Plasmodium falciparum malaria in Uganda.

    Science.gov (United States)

    Kloprogge, Frank; Jullien, Vincent; Piola, Patrice; Dhorda, Mehul; Muwanga, Sulaiman; Nosten, François; Day, Nicholas P J; White, Nicholas J; Guerin, Philippe J; Tarning, Joel

    2014-11-01

    Oral quinine is used for the treatment of uncomplicated malaria during pregnancy, but few pharmacokinetic data are available for this population. Previous studies have reported a substantial effect of malaria on the pharmacokinetics of quinine resulting from increased α-1-acid glycoprotein levels and decreased cytochrome P450 3A4 activity. The aim of this study was to investigate the pharmacokinetic properties of oral quinine in pregnant women with uncomplicated malaria in Uganda using a population approach. Data from 22 women in the second and third trimesters of pregnancy with uncomplicated Plasmodium falciparum malaria were analysed. Patients received quinine sulphate (10 mg of salt/kg) three times daily (0, 8 and 16 h) for 7 days. Plasma samples were collected daily and at frequent intervals after the first and last doses. A population pharmacokinetic model for quinine was developed accounting for different disposition, absorption, error and covariate models. Parasitaemia, as a time-varying covariate affecting relative bioavailability, and body temperature on admission as a covariate on elimination clearance, explained the higher exposure to quinine during acute malaria compared with the convalescent phase. Neither the estimated gestational age nor the trimester influenced the pharmacokinetic properties of quinine significantly. A population model was developed that adequately characterized quinine pharmacokinetics in pregnant Ugandan women with acute malaria. Quinine exposure was lower than previously reported in patients who were not pregnant. The measurement of free quinine concentration will be necessary to determine the therapeutic relevance of these observations. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

  4. Optimising strategies for Plasmodium falciparum malaria elimination in Cambodia: primaquine, mass drug administration and artemisinin resistance.

    Directory of Open Access Journals (Sweden)

    Richard J Maude

    Full Text Available Malaria elimination requires a variety of approaches individually optimized for different transmission settings. A recent field study in an area of low seasonal transmission in South West Cambodia demonstrated dramatic reductions in malaria parasite prevalence following both mass drug administration (MDA and high treatment coverage of symptomatic patients with artemisinin-piperaquine plus primaquine. This study employed multiple combined strategies and it was unclear what contribution each made to the reductions in malaria.A mathematical model fitted to the trial results was used to assess the effects of the various components of these interventions, design optimal elimination strategies, and explore their interactions with artemisinin resistance, which has recently been discovered in Western Cambodia. The modelling indicated that most of the initial reduction of P. falciparum malaria resulted from MDA with artemisinin-piperaquine. The subsequent continued decline and near elimination resulted mainly from high coverage with artemisinin-piperaquine treatment. Both these strategies were more effective with the addition of primaquine. MDA with artemisinin combination therapy (ACT increased the proportion of artemisinin resistant infections, although much less than treatment of symptomatic cases with ACT, and this increase was slowed by adding primaquine. Artemisinin resistance reduced the effectiveness of interventions using ACT when the prevalence of resistance was very high. The main results were robust to assumptions about primaquine action, and immunity.The key messages of these modelling results for policy makers were: high coverage with ACT treatment can produce a long-term reduction in malaria whereas the impact of MDA is generally only short-term; primaquine enhances the effect of ACT in eliminating malaria and reduces the increase in proportion of artemisinin resistant infections; parasite prevalence is a better surveillance measure for

  5. No Reduction in Hemoglobin Level in Severe Plasmodium falciparum Malaria Treated with Artesunate in Central Sudan.

    Science.gov (United States)

    Eltahir, Hatim G; Bilal, Jalal Ali; Ali, Elrazy A; Adam, Ishag

    2017-02-01

    There are few publications on anemia following artesunate treatment. To investigate the hemoglobin in patients with severe Plasmodium falciparum malaria treated with artesunate or quinine. Patients with P. falciparum (in Singa, Sudan) were treated by intravenous artesunate or quinine. Hemoglobin was measured initially, at day 14 and day 28. The mean (SD) of the age was 10.3 (10.9) years. The two groups (61 in each arm) were matched in their basic characteristics. Hypotension, convulsions, severe anemia were the main presentations. There was no significant difference in the mean (SD) hemoglobin level at the initial day, day 14 and at day 28 [11.2 (1.8), 11.3 (1.6), 11.5 (1.8), p = 0.170], respectively, in both groups. The hemoglobin did not change significantly from the baseline in any of the group separately. There was no difference in hemoglobin concentration in patients with severe malaria after treatment with either artesunate or quinine. © The Author [2016]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. Comparison of quinine and rabeprazole with quinine monotherapy in the treatment of uncomplicated falciparum malaria.

    Science.gov (United States)

    Kochar, Dhanpat K; Gupta, Vikas; Kochar, Abhishek; Acharya, Jyoti; Middha, Sheetal; Sirohi, Parminder; Kochar, Sanjay K

    2010-09-01

    This study was conducted to assess the effect of combination treatment of quinine and rabeprazole in the treatment of uncomplicated Plasmodium falciparum malaria. The study included 50 patients of uncomplicated P. falciparum malaria. Group 1 (25 patients) received quinine and placebo (Q+P) while Group 2 (25 patients) received quinine and rabeprazole (Q+R). Diagnosis was confirmed by peripheral blood film (PBF) and rapid diagnostic test (RDT). Temperature was recorded every 6 h. All patients were followed-up on Days 7, 14, 21, 28 for detailed clinical and parasitological examination. A total of 20 patients in each group completed the treatment and followed-up for 28 days. While two patients in Group 1 (Q+P) and one patient in Group 2 (Q+R) were lost in follow-up; and seven (Q+P = 4, Q+R =3) patients were withdrawn from the study. Fever clearance time (FCT) of the two groups was also almost similar (Group 1 : 2 = 52.8 : 51.3 h). No statistically significant difference was observed in early treatment failure (ETF) either of the groups. None of the patients in both the groups showed late clinical failure (LCF) or late parasitological failure (LPF). However, there was a significant difference in the parasite clearance rates of the two groups (pquinine regimen resulted in an increase in the parasite elimination rate, which may be helpful in reducing the duration of treatment and increasing patient compliance.

  7. Efficacy of sulfadoxine-pyrimethamine for the treatment of uncomplicated falciparum malaria in southern Mauritania.

    Science.gov (United States)

    Ouldabdallahi, M M; Sarr, O; Basco, L K; Lebatt, S M; Lo, B; Gaye, O

    2016-08-01

    Until 2006, the Mauritanian Ministry of Health recommended chloroquine and sulfadoxine-pyrimethamine for first- and second-line treatment of uncomplicated malaria, respectively. This study assessed the clinical efficacy of sulfadoxine-pyrimethamine in Kobeni as first-line treatment. This study included 55 patients with Plasmodium falciparum infections, who were treated with sulfadoxine-pyrimethamine and followed up for 28 days. Isolates were genotyped to distinguish between recrudescence and reinfection. Treatment success rates and survival were analysed per protocol to evaluate drug efficacy. After inclusion, 2 patients were excluded for protocol violations, and 3 patients were lost to follow-up. Of the remaining 50 patients (per protocol population), 43 (86%) had adequate clinical and parasitological responses. Of the 7 patients with treatment failure, 5 (10%) were early failures, while 2 (4%) had initially responded and had late clinical failure on day 7, associated with recrudescence. With the exception of one adult weighing 91 kg, all treatment failures occurred in children aged from 7 to 12 years. Sulfadoxine-pyrimethamine monotherapy was moderately effective but insufficiently reliable in view of the relatively high rate of early treatment failure. The high prevalence of chloroquine resistance found in earlier studies and the results of the present study on sulfadoxine-pyrimethamine justify the change in national policy and systematic use of artemisinin-based combination therapy for first-line treatment of P. falciparum malaria in Mauritania.

  8. Dihydroartemisinin-piperaquine resistance in Plasmodium falciparum malaria in Cambodia: a multisite prospective cohort study.

    Science.gov (United States)

    Amaratunga, Chanaki; Lim, Pharath; Suon, Seila; Sreng, Sokunthea; Mao, Sivanna; Sopha, Chantha; Sam, Baramey; Dek, Dalin; Try, Vorleak; Amato, Roberto; Blessborn, Daniel; Song, Lijiang; Tullo, Gregory S; Fay, Michael P; Anderson, Jennifer M; Tarning, Joel; Fairhurst, Rick M

    2016-03-01

    Artemisinin resistance in Plasmodium falciparum threatens to reduce the efficacy of artemisinin combination therapies (ACTs), thus compromising global efforts to eliminate malaria. Recent treatment failures with dihydroartemisinin-piperaquine, the current first-line ACT in Cambodia, suggest that piperaquine resistance may be emerging in this country. We explored the relation between artemisinin resistance and dihydroartemisinin-piperaquine failures, and sought to confirm the presence of piperaquine-resistant P falciparum infections in Cambodia. In this prospective cohort study, we enrolled patients aged 2-65 years with uncomplicated P falciparum malaria in three Cambodian provinces: Pursat, Preah Vihear, and Ratanakiri. Participants were given standard 3-day courses of dihydroartemisinin-piperaquine. Peripheral blood parasite densities were measured until parasites cleared and then weekly to 63 days. The primary outcome was recrudescent P falciparum parasitaemia within 63 days. We measured piperaquine plasma concentrations at baseline, 7 days, and day of recrudescence. We assessed phenotypic and genotypic markers of drug resistance in parasite isolates. The study is registered with ClinicalTrials.gov, number NCT01736319. Between Sept 4, 2012, and Dec 31, 2013, we enrolled 241 participants. In Pursat, where artemisinin resistance is entrenched, 37 (46%) of 81 patients had parasite recrudescence. In Preah Vihear, where artemisinin resistance is emerging, ten (16%) of 63 patients had recrudescence and in Ratanakiri, where artemisinin resistance is rare, one (2%) of 60 patients did. Patients with recrudescent P falciparum infections were more likely to have detectable piperaquine plasma concentrations at baseline compared with non-recrudescent patients, but did not differ significantly in age, initial parasite density, or piperaquine plasma concentrations at 7 days. Recrudescent parasites had a higher prevalence of kelch13 mutations, higher piperaquine 50% inhibitory

  9. Recent advances in recombinant protein-based malaria vaccines

    DEFF Research Database (Denmark)

    Draper, Simon J; Angov, Evelina; Horii, Toshihiro

    2015-01-01

    Plasmodium parasites are the causative agent of human malaria, and the development of a highly effective vaccine against infection, disease and transmission remains a key priority. It is widely established that multiple stages of the parasite's complex lifecycle within the human host and mosquito...... vector are susceptible to vaccine-induced antibodies. The mainstay approach to antibody induction by subunit vaccination has been the delivery of protein antigen formulated in adjuvant. Extensive efforts have been made in this endeavor with respect to malaria vaccine development, especially with regard......, with the prospects for the development of a highly effective multi-component/multi-stage/multi-antigen formulation seeming ever more likely. This review will focus on recent progress in protein vaccine design, development and/or clinical testing for a number of leading malaria antigens from the sporozoite...

  10. The Power of Malaria Vaccine Trials Using Controlled Human Malaria Infection

    NARCIS (Netherlands)

    L.E. Coffeng (Luc); C.C. Hermsen (Cornelus); R.W. Sauerwein (Robert); S.J. de Vlas (Sake)

    2017-01-01

    textabstractControlled human malaria infection (CHMI) in healthy human volunteers is an important and powerful tool in clinical malaria vaccine development. However, power calculations are essential to obtain meaningful estimates of protective efficacy, while minimizing the risk of adverse events.

  11. The Power of Malaria Vaccine Trials Using Controlled Human Malaria Infection

    NARCIS (Netherlands)

    Coffeng, L.E.; Hermsen, C.C.; Sauerwein, R.W.; Vlas, S.J. de

    2017-01-01

    Controlled human malaria infection (CHMI) in healthy human volunteers is an important and powerful tool in clinical malaria vaccine development. However, power calculations are essential to obtain meaningful estimates of protective efficacy, while minimizing the risk of adverse events. To optimize

  12. The Influence of Sub-Unit Composition and Expression System on the Functional Antibody Response in the Development of a VAR2CSA Based Plasmodium falciparum Placental Malaria Vaccine

    DEFF Research Database (Denmark)

    Nielsen, Morten A; dos Santos Marques Resende, Mafalda; de Jongh, Willem A

    2015-01-01

    of VAR2CSA, a parasite-derived antigen. Protection against PM is mediated by antibodies that inhibit binding of IE in the placental intervillous space. VAR2CSA is a large antigen incompatible with large scale recombinant protein expression. Vaccines based on sub-units encompassing the functionally...... recombinant subunits of the VAR2CSA antigen is unpredictable, demonstrating the need for large-scale screening in order to identify antigens that induce a broadly strain-transcending antibody response....

  13. Randomized comparison of mefloquine-artesunate versus quinine in the treatment of multidrug-resistant falciparum malaria in pregnancy

    NARCIS (Netherlands)

    McGready, R.; Brockman, A.; Cho, T.; Cho, D.; van Vugt, M.; Luxemburger, C.; Chongsuphajaisiddhi, T.; White, N. J.; Nosten, F.

    2000-01-01

    Since no effective malaria prevention measures have been identified for pregnant women living on the western border of Thailand, prompt diagnosis and efficient treatment are paramount, although drug resistance in Plasmodium falciparum has narrowed the treatment options. An open randomized comparison

  14. Estimated risk of placental infection and low birthweight attributable to Plasmodium falciparum malaria in Africa in 2010: a modelling study

    NARCIS (Netherlands)

    Walker, Patrick G. T.; ter Kuile, Feiko O.; Garske, Tini; Menendez, Clara; Ghani, Azra C.

    2014-01-01

    Plasmodium falciparum infection during pregnancy leads to adverse outcomes including low birthweight; however, contemporary estimates of the potential burden of malaria in pregnancy in Africa (in the absence of interventions) are poor. We aimed to estimate the need to protect pregnant women from

  15. Cytoadhesion to gC1qR through Plasmodium falciparum erythrocyte membrane protein 1 in severe malaria

    DEFF Research Database (Denmark)

    Magallón-Tejada, Ariel; Machevo, Sónia; Cisteró, Pau

    2016-01-01

    Cytoadhesion of Plasmodium falciparum infected erythrocytes to gC1qR has been associated with severe malaria, but the parasite ligand involved is currently unknown. To assess if binding to gC1qR is mediated through the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family, we analyzed...... by static binding assays and qPCR the cytoadhesion and var gene transcriptional profile of 86 P. falciparum isolates from Mozambican children with severe and uncomplicated malaria, as well as of a P. falciparum 3D7 line selected for binding to gC1qR (Pf3D7gC1qR). Transcript levels of DC8 correlated...... positively with cytoadhesion to gC1qR (rho = 0.287, P = 0.007), were higher in isolates from children with severe anemia than with uncomplicated malaria, as well as in isolates from Europeans presenting a first episode of malaria (n = 21) than Mozambican adults (n = 25), and were associated with an increased...

  16. Limited influence of haemoglobin variants on Plasmodium falciparum msp1 and msp2 alleles in symptomatic malaria

    NARCIS (Netherlands)

    Mockenhaupt, Frank P.; Ehrhardt, Stephan; Otchwemah, Rowland; Eggelte, Teunis A.; Anemana, Sylvester D.; Stark, Klaus; Bienzle, Ulrich; Kohne, Elisabeth

    2004-01-01

    Haemoglobin (Hb) S, HbC, and alpha(+)-thalassaemia confer protection from malaria. Accordingly, these traits may influence the multiplicity of infection (MOI) of Plasmodium falciparum and the presence of distinct parasite genotypes. In 840 febrile children in northern Ghana, we typed the P.

  17. A Direct from Blood Reverse Transcriptase Polymerase Chain Reaction Assay for Monitoring Falciparum Malaria Parasite Transmission in Elimination Settings

    NARCIS (Netherlands)

    Taylor, B.J.; Lanke, K.; Banman, S.L.; Morlais, I.; Morin, M.J.; Bousema, T.; Rijpma, S.R.; Yanow, S.K.

    2017-01-01

    We describe a novel one-step reverse transcriptase real-time PCR (direct RT-PCR) for Plasmodium falciparum malaria parasites that amplifies RNA targets directly from blood. We developed the assay to identify gametocyte-specific transcripts in parasites from patient blood samples, as a means of

  18. Antibody reactivities to glutamate-rich peptides of Plasmodium falciparum parasites in humans from areas of different malaria endemicity

    DEFF Research Database (Denmark)

    Jakobsen, P H; Theander, T G; Hviid, L

    1996-01-01

    Synthetic P. falciparum peptides were evaluated as tools in epidemiological investigations of malaria. Plasma IgM and IgG antibody reactivities against synthetic peptides covering sequences of glutamate-rich protein (GLURP) and acidic-basic repeat antigen (ABRA) were measured by ELISA...

  19. Qualification of standard membrane-feeding assay with Plasmodium falciparum malaria and potential improvements for future assays.

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    Kazutoyo Miura

    Full Text Available Vaccines that interrupt malaria transmission are of increasing interest and a robust functional assay to measure this activity would promote their development by providing a biologically relevant means of evaluating potential vaccine candidates. Therefore, we aimed to qualify the standard membrane-feeding assay (SMFA. The assay measures the transmission-blocking activity of antibodies by feeding cultured P. falciparum gametocytes to Anopheles mosquitoes in the presence of the test antibodies and measuring subsequent mosquito infection. The International Conference on Harmonisation (ICH Harmonised Tripartite Guideline Q2(R1 details characteristics considered in assay validation. Of these characteristics, we decided to qualify the SMFA for Precision, Linearity, Range and Specificity. The transmission-blocking 4B7 monoclonal antibody was tested over 6 feeding experiments at several concentrations to determine four suitable concentrations that were tested in triplicate in the qualification experiments (3 additional feeds to evaluate Precision, Linearity and Range. For Specificity, 4B7 was tested in the presence of normal mouse IgG. We determined intra- and inter-assay variability of % inhibition of mean oocyst intensity at each concentration of 4B7 (lower concentrations showed higher variability. We also showed that % inhibition was dependent on 4B7 concentration and the activity is specific to 4B7. Since obtaining empirical data is time-consuming, we generated a model using data from all 9 feeds and simulated the effects of different parameters on final readouts to improve the assay procedure and analytical methods for future studies. For example, we estimated the effect of number of mosquitoes dissected on variability of % inhibition, and simulated the relationship between % inhibition in oocyst intensity and % inhibition of prevalence of infected mosquitos at different mean oocysts in the control. SMFA is one of the few biological assays used in

  20. Case-control approach to identify Plasmodium falciparum polymorphisms associated with severe malaria.

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    Watcharee Chokejindachai

    Full Text Available BACKGROUND: Studies to identify phenotypically-associated polymorphisms in the Plasmodium falciparum 23 Mb genome will require a dense array of marker loci. It was considered promising to undertake initial allelic association studies to prospect for virulence polymorphisms in Thailand, as the low endemicity would allow higher levels of linkage disequilibrium (LD than would exist in more highly endemic areas. METHODOLOGY/PRINCIPAL FINDINGS: Assessment of LD was first made with 11 microsatellite loci widely dispersed in the parasite genome, and 16 microsatellite loci covering a approximately 140 kb region of chromosome 2 (an arbitrarily representative non-telomeric part of the genome, in a sample of 100 P. falciparum isolates. The dispersed loci showed minimal LD (Index of Association, I(S (A = 0.013, P = 0.10, while those on chromosome 2 showed significant LD values mostly between loci <5 kb apart. A disease association study was then performed comparing parasites in 113 severe malaria cases and 245 mild malaria controls. Genotyping was performed on almost all polymorphisms in the binding domains of three erythrocyte binding antigens (eba175, eba140 and eba181, and repeat sequence polymorphisms approximately 2 kb apart in each of three reticulocyte binding homologues (Rh1, Rh2a/b, and Rh4. Differences between cases and controls were seen for (i codons 388-90 in eba175, and (ii a repeat sequence centred on Rh1 codon 667. CONCLUSIONS/SIGNIFICANCE: Allelic association studies on P. falciparum require dense genotypic markers, even in a population of only moderate endemicity that has more extensive LD than highly endemic populations. Disease-associated polymorphisms in the eba175 and Rh1 genes encode differences in the middle of previously characterised erythrocyte binding domains, marking these for further investigation.

  1. Variant surface antigen-specific IgG and protection against clinical consequences of pregnancy-associated Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Staalsoe, Trine; Shulman, Caroline E; Bulmer, Judith N

    2004-01-01

    BACKGROUND: Pregnancy-associated malaria caused by Plasmodium falciparum adherence to chondroitin sulfate A in the placental intervillous space is a major cause of low birthweight and maternal anaemia in areas of endemic P falciparum transmission. Adhesion-blocking antibodies that specifically...... recognise parasite-encoded variant surface antigens (VSA) are associated with resistance to pregnancy-associated malaria. We looked for a possible relation between VSA-specific antibody concentrations, placental infection, and protection from low birthweight and maternal anaemia. METHODS: We used flow...... cytometry to measure VSA-specific IgG concentrations in plasma samples taken during child birth from 477 Kenyan women selected from a cohort of 910 women on the basis of HIV-1 status, gravidity, and placental histology. We measured VSA expressed by one placental P falciparum isolate and two isolates...

  2. The US President's Malaria Initiative, Plasmodium falciparum transmission and mortality: A modelling study.

    Science.gov (United States)

    Winskill, Peter; Slater, Hannah C; Griffin, Jamie T; Ghani, Azra C; Walker, Patrick G T

    2017-11-01

    Although significant progress has been made in reducing malaria transmission globally in recent years, a large number of people remain at risk and hence the gains made are fragile. Funding lags well behind amounts needed to protect all those at risk and ongoing contributions from major donors, such as the President's Malaria Initiative (PMI), are vital to maintain progress and pursue further reductions in burden. We use a mathematical modelling approach to estimate the impact of PMI investments to date in reducing malaria burden and to explore the potential negative impact on malaria burden should a proposed 44% reduction in PMI funding occur. We combined an established mathematical model of Plasmodium falciparum transmission dynamics with epidemiological, intervention, and PMI-financing data to estimate the contribution PMI has made to malaria control via funding for long-lasting insecticide treated nets (LLINs), indoor residual spraying (IRS), and artemisinin combination therapies (ACTs). We estimate that PMI has prevented 185 million (95% CrI: 138 million, 230 million) malaria cases and saved 940,049 (95% CrI: 545,228, 1.4 million) lives since 2005. If funding is maintained, PMI-funded interventions are estimated to avert a further 162 million (95% CrI: 116 million, 194 million) cases, saving a further 692,589 (95% CrI: 392,694, 955,653) lives between 2017 and 2020. With an estimate of US$94 (95% CrI: US$51, US$166) per Disability Adjusted Life Year (DALY) averted, PMI-funded interventions are highly cost-effective. We also demonstrate the further impact of this investment by reducing caseloads on health systems. If a 44% reduction in PMI funding were to occur, we predict that this loss of direct aid could result in an additional 67 million (95% CrI: 49 million, 82 million) cases and 290,649 (95% CrI: 167,208, 395,263) deaths between 2017 and 2020. We have not modelled indirect impacts of PMI funding (such as health systems strengthening) in this analysis. Our

  3. The US President's Malaria Initiative, Plasmodium falciparum transmission and mortality: A modelling study.

    Directory of Open Access Journals (Sweden)

    Peter Winskill

    2017-11-01

    Full Text Available Although significant progress has been made in reducing malaria transmission globally in recent years, a large number of people remain at risk and hence the gains made are fragile. Funding lags well behind amounts needed to protect all those at risk and ongoing contributions from major donors, such as the President's Malaria Initiative (PMI, are vital to maintain progress and pursue further reductions in burden. We use a mathematical modelling approach to estimate the impact of PMI investments to date in reducing malaria burden and to explore the potential negative impact on malaria burden should a proposed 44% reduction in PMI funding occur.We combined an established mathematical model of Plasmodium falciparum transmission dynamics with epidemiological, intervention, and PMI-financing data to estimate the contribution PMI has made to malaria control via funding for long-lasting insecticide treated nets (LLINs, indoor residual spraying (IRS, and artemisinin combination therapies (ACTs. We estimate that PMI has prevented 185 million (95% CrI: 138 million, 230 million malaria cases and saved 940,049 (95% CrI: 545,228, 1.4 million lives since 2005. If funding is maintained, PMI-funded interventions are estimated to avert a further 162 million (95% CrI: 116 million, 194 million cases, saving a further 692,589 (95% CrI: 392,694, 955,653 lives between 2017 and 2020. With an estimate of US$94 (95% CrI: US$51, US$166 per Disability Adjusted Life Year (DALY averted, PMI-funded interventions are highly cost-effective. We also demonstrate the further impact of this investment by reducing caseloads on health systems. If a 44% reduction in PMI funding were to occur, we predict that this loss of direct aid could result in an additional 67 million (95% CrI: 49 million, 82 million cases and 290,649 (95% CrI: 167,208, 395,263 deaths between 2017 and 2020. We have not modelled indirect impacts of PMI funding (such as health systems strengthening in this analysis

  4. Phase 1 study of a combination AMA1 blood stage malaria vaccine in Malian children.

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    Alassane Dicko

    2008-02-01

    Full Text Available Apical Membrane Antigen-1 (AMA1 is one of the leading blood stage malaria vaccine candidates. AMA1-C1/Alhydrogel consists of an equal mixture of recombinant AMA1 from FVO and 3D7 clones of P. falciparum, adsorbed onto Alhydrogel. A Phase 1 study in semi-immune adults in Mali showed that the vaccine was safe and immunogenic, with higher antibody responses in those who received the 80 microg dose. The aim of this study was to assess the safety and immunogenicity of this vaccine in young children in a malaria endemic area.This was a Phase 1 dose escalating study in 36 healthy children aged 2-3 years started in March 2006 in Donéguébougou, Mali. Eighteen children in the first cohort were randomized 2 ratio 1 to receive either 20 microg AMA1-C1/Alhydrogel or Haemophilus influenzae type b Hiberix vaccine. Two weeks later 18 children in the second cohort were randomized 2 ratio 1 to receive either 80 microg AMA1-C1/Alhydrogel or Haemophilus influenzae type b Hiberix vaccine. Vaccinations were administered on Days 0 and 28 and participants were examined on Days 1, 2, 3, 7, and 14 after vaccination and then about every two months. Results to Day 154 are reported in this manuscript.Of 36 volunteers enrolled, 33 received both vaccinations. There were 9 adverse events related to the vaccination in subjects who received AMA1-C1 vaccine and 7 in those who received Hiberix. All were mild to moderate. No vaccine-related serious or grade 3 adverse events were observed. There was no increase in adverse events with increasing dose of vaccine or number of immunizations. In subjects who received the test vaccine, antibodies to AMA1 increased on Day 14 and peaked at Day 42, with changes from baseline significantly different from subjects who received control vaccine.AMA-C1 vaccine is well tolerated and immunogenic in children in this endemic area although the antibody response was short lived.Clinicaltrials.gov NCT00341250.

  5. High-Throughput Testing of Antibody-Dependent Binding Inhibition of Placental Malaria Parasites

    DEFF Research Database (Denmark)

    Nielsen, Morten A; Salanti, Ali

    2015-01-01

    The particular virulence of Plasmodium falciparum manifests in diverse severe malaria syndromes as cerebral malaria, severe anemia and placental malaria. The cause of both the severity and the diversity of infection outcome, is the ability of the infected erythrocyte (IE) to bind a range......-throughput assay used in the preclinical and clinical development of a VAR2CSA based vaccine against placental malaria....

  6. Therapeutic efficacy of artemether-lumefantrine in uncomplicated falciparum malaria in India

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    Dev Vas

    2009-05-01

    Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is the treatment of choice for uncomplicated falciparum malaria. Artemether-lumefantrine (AL, a fixed dose co-formulation, has recently been approved for marketing in India, although it is not included in the National Drug Policy for treatment of malaria. Efficacy of short course regimen (4 × 4 tablets of 20 mg artemether plus 120 mg lumefantrine over 48 h was demonstrated in India in the year 2000. However, low cure rates in Thailand and better plasma lumefantrine concentration profile with a six-dose regimen over three days, led to the recommendation of higher dose globally. This is the first report on the therapeutic efficacy of the six-dose regimen of AL in Indian uncomplicated falciparum malaria patients. The data generated will help in keeping the alternative ACT ready for use in the National Programme as and when required. Methods One hundred and twenty four subjects between two and fifty-five years of age living in two highly endemic areas of the country (Assam and Orissa were enrolled for single arm, open label prospective study. The standard six-dose regimen of AL was administered over three days and was followed-up with clinical and parasitological evaluations over 28 days. Molecular markers msp-1 and msp-2 were used to differentiate the recrudescence and reinfection among the study subjects. In addition, polymorphism in pfmdr1 was also carried out in the samples obtained from patients before and after the treatment. Results The PCR corrected cure rates were high at both the sites viz. 100% (n = 53 in Assam and 98.6% (n = 71 in Orissa. The only treatment failure case on D7 was a malnourished child. The drug was well tolerated with no adverse events. Patients had pre-treatment carriage of wild type codons at positions 86 (41.7%, n = 91 and 184 (91.3%, n = 91 of pfmdr1 gene. Conclusion AL is safe and effective drug for the treatment of acute uncomplicated falciparum malaria

  7. Clinical presentation of severe malaria due plasmodiun falciparum. casecontrol study in Tumaco and Turbo (Colombia. Clínica de la malaria complicada debida a P. falciparum Estudio de casos y controles en Tumaco y Turbo (Colombia

    Directory of Open Access Journals (Sweden)

    Jaime Carmona Fonseca

    2006-04-01

    Full Text Available Background: Latin American studies on severe falciparum malaria are scarce, therefore, the pattern of complications of the region is uknown. Objectives. To identify characterize severe malaria in patients from Tumaco (Nariño and Turbo (Antioquia in Colombia. Methods. The 2000 World Health Organization criteria for complicated malaria were applied in a cases and controls study. Results. 64 cases (P falciparum complicated malaria and 135 controls (P falciparum uncomplicated malaria were included. The time of evolution of the disease (mean 5.6 days in cases and 5.9 in the controls and the frequency of most symptoms were similar in both groups (p>0.05. However, respiratory distress and jaundice was more frequent in the cases (p<0.05. The mean glycemia and creatinina values were similar in both groups; hemoglobin and platelet count were lower in the cases (p<0.05 when compared to controls. On the other hand, blood ureic nitrogen, aspartatoaminotransferase, and total and direct bilirrubin were lower in controls (p<0.05. The frequency of complications in the cases was as follows: hyperparasitaemia 48%, liver dysfunction 44%, acute respiratory distress syndrome 9%, kidney failure 6%, severe thrombocytopenia 5%, severe anemia 3%, cerebral malaria 3% and severe hipoglycemia 2%. The WHO criteria for severe malaria were compared with others and the implications are discussed. Antecedentes y problema: son muy pocos los estudios latinoamericanos sobre malaria por Plasmodium falciparum (P falciparum complicada y se requiere estudiarla para identificar un patrón propio. OBJETIVOS. Identificar las complicaciones presentes en pacientes de Tumaco (Nariño y Turbo (Antioquia en Colombia, con malaria por P falciparum. MÉTODOS. Diseño de casos y controles. Se aplicaron los criterios diagnósticos de complicación OMS-2000 (Organización Mundial de la Salud. RESULTADOS. Se captaron 64 casos (con malaria por P. falciparum complicada y 135 controles (con malaria por

  8. Cellulose filtration of blood from malaria patients for improving ex vivo growth of Plasmodium falciparum parasites.

    Science.gov (United States)

    Mkumbaye, Sixbert I; Minja, Daniel T R; Jespersen, Jakob S; Alifrangis, Michael; Kavishe, Reginald A; Mwakalinga, Steven B; Lusingu, John P; Theander, Thor G; Lavstsen, Thomas; Wang, Christian W

    2017-02-10

    Establishing in vitro Plasmodium falciparum culture lines from patient parasite isolates can offer deeper understanding of geographic variations of drug sensitivity and mechanisms of malaria pathogenesis and immunity. Cellulose column filtration of blood is an inexpensive, rapid and effective method for the removal of host factors, such as leucocytes and platelets, significantly improving the purification of parasite DNA in a blood sample. In this study, the effect of cellulose column filtration of venous blood on the initial in vitro growth of P. falciparum parasite isolates from Tanzanian children admitted to hospital was tested. The parasites were allowed to expand in culture without subcultivation until 5 days after admission or the appearance of dead parasites and parasitaemia was determined daily. To investigate whether the filtration had an effect on clonality, P. falciparum merozoite surface protein 2 genotyping was performed using nested PCR on extracted genomic DNA, and the var gene transcript levels were investigated, using quantitative PCR on extracted RNA, at admission and 4 days of culture. The cellulose-filtered parasites grew to higher parasitaemia faster than non-filtered parasites seemingly due to a higher development ratio of ring stage parasites progressing into the late stages. Cellulose filtration had no apparent effect on clonality or var gene expression; however, evident differences were observed after only 4 days of culture in both the number of clones and transcript levels of var genes compared to the time of admission. Cellulose column filtration of parasitized blood is a cheap, applicable method for improving cultivation of P. falciparum field isolates for ex vivo based assays; however, when assessing phenotype and genotype of cultured parasites, in general, assumed to represent the in vivo infection, caution is advised.

  9. Field performance of malaria rapid diagnostic test for the detection of Plasmodium falciparum infection in Odisha State, India

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    S S Sahu

    2015-01-01

    Full Text Available Background & objectives: Rapid diagnostic tests (RDTs have become an essential surveillance tool in the malaria control programme in India. The current study aimed to assess the performance of ParaHIT-f, a rapid test in diagnosis of Plasmodium falciparum infection through detecting its specific antigen, histidine rich protein 2 (PfHRP-2, in Odisha State, India. Methods: The study was undertaken in eight falciparum malaria endemic southern districts of Odisha State. Febrile patients included through active case detection, were diagnosed by Accredited Social Health Activists (ASHAs for P. falciparum infection using the RDT, ParaHIT-f. The performance of ParaHIT-f was evaluated using microscopy as the gold standard. Results: A total of 1030 febrile patients were screened by both microscopy and the RDT for P. falciparum infection. The sensitivity of ParaHIT-f was 63.6% (95% CI: 56.0-70.6 and specificity was 98.9% (95% CI: 97.9-99.5, with positive and negative predictive values (PPV and NPV of 92.6% (95% CI: 86.0-96.3 and 93.0% (95% CI: 91.0-94.5, respectively. When related to parasitaemia, the RDT sensitivity was 47.8% at the low parasitaemia of 4 to 40 parasites/µl of blood. Interpretation & conclusions: The results showed that the performance of the RDT, ParaHIT-f, was not as sensitive as microscopy in detecting true falciparum infections; a high specificity presented a low frequency of false-positive RDT results. t0 he sensitivity of ParaHIT-f was around 60 per cent. It is, therefore, essential to improve the efficiency (sensitivity of the kit so that the true falciparum infections will not be missed especially in areas where P. falciparum has been the predominant species causing cerebral malaria.

  10. Impact on malaria parasite multiplication rates in infected volunteers of the protein-in-adjuvant vaccine AMA1-C1/Alhydrogel+CPG 7909.

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    Christopher J A Duncan

    Full Text Available Inhibition of parasite growth is a major objective of blood-stage malaria vaccines. The in vitro assay of parasite growth inhibitory activity (GIA is widely used as a surrogate marker for malaria vaccine efficacy in the down-selection of candidate blood-stage vaccines. Here we report the first study to examine the relationship between in vivo Plasmodium falciparum growth rates and in vitro GIA in humans experimentally infected with blood-stage malaria.In this phase I/IIa open-label clinical trial five healthy malaria-naive volunteers were immunised with AMA1/C1-Alhydrogel+CPG 7909, and together with three unvaccinated controls were challenged by intravenous inoculation of P. falciparum infected erythrocytes.A significant correlation was observed between parasite multiplication rate in 48 hours (PMR and both vaccine-induced growth-inhibitory activity (Pearson r = -0.93 [95% CI: -1.0, -0.27] P = 0.02 and AMA1 antibody titres in the vaccine group (Pearson r = -0.93 [95% CI: -0.99, -0.25] P = 0.02. However immunisation failed to reduce overall mean PMR in the vaccine group in comparison to the controls (vaccinee 16 fold [95% CI: 12, 22], control 17 fold [CI: 0, 65] P = 0.70. Therefore no impact on pre-patent period was observed (vaccine group median 8.5 days [range 7.5-9], control group median 9 days [range 7-9].Despite the first observation in human experimental malaria infection of a significant association between vaccine-induced in vitro growth inhibitory activity and in vivo parasite multiplication rate, this did not translate into any observable clinically relevant vaccine effect in this small group of volunteers.ClinicalTrials.gov [NCT00984763].

  11. Impact on Malaria Parasite Multiplication Rates in Infected Volunteers of the Protein-in-Adjuvant Vaccine AMA1-C1/Alhydrogel+CPG 7909

    Science.gov (United States)

    Duncan, Christopher J. A.; Sheehy, Susanne H.; Ewer, Katie J.; Douglas, Alexander D.; Collins, Katharine A.; Halstead, Fenella D.; Elias, Sean C.; Lillie, Patrick J.; Rausch, Kelly; Aebig, Joan; Miura, Kazutoyo; Edwards, Nick J.; Poulton, Ian D.; Hunt-Cooke, Angela; Porter, David W.; Thompson, Fiona M.; Rowland, Ros; Draper, Simon J.; Gilbert, Sarah C.; Fay, Michael P.; Long, Carole A.; Zhu, Daming; Wu, Yimin; Martin, Laura B.; Anderson, Charles F.; Lawrie, Alison M.; Hill, Adrian V. S.; Ellis, Ruth D.

    2011-01-01

    Background Inhibition of parasite growth is a major objective of blood-stage malaria vaccines. The in vitro assay of parasite growth inhibitory activity (GIA) is widely used as a surrogate marker for malaria vaccine efficacy in the down-selection of candidate blood-stage vaccines. Here we report the first study to examine the relationship between in vivo Plasmodium falciparum growth rates and in vitro GIA in humans experimentally infected with blood-stage malaria. Methods In this phase I/IIa open-label clinical trial five healthy malaria-naive volunteers were immunised with AMA1/C1-Alhydrogel+CPG 7909, and together with three unvaccinated controls were challenged by intravenous inoculation of P. falciparum infected erythrocytes. Results A significant correlation was observed between parasite multiplication rate in 48 hours (PMR) and both vaccine-induced growth-inhibitory activity (Pearson r = −0.93 [95% CI: −1.0, −0.27] P = 0.02) and AMA1 antibody titres in the vaccine group (Pearson r = −0.93 [95% CI: −0.99, −0.25] P = 0.02). However immunisation failed to reduce overall mean PMR in the vaccine group in comparison to the controls (vaccinee 16 fold [95% CI: 12, 22], control 17 fold [CI: 0, 65] P = 0.70). Therefore no impact on pre-patent period was observed (vaccine group median 8.5 days [range 7.5–9], control group median 9 days [range 7–9]). Conclusions Despite the first observation in human experimental malaria infection of a significant association between vaccine-induced in vitro growth inhibitory activity and in vivo parasite multiplication rate, this did not translate into any observable clinically relevant vaccine effect in this small group of volunteers. Trial Registration ClinicalTrials.gov [NCT00984763] PMID:21799809

  12. Major Burden of Severe Anemia from Non-Falciparum Malaria Species in Southern Papua: A Hospital-Based Surveillance Study

    Science.gov (United States)

    Douglas, Nicholas M.; Lampah, Daniel A.; Kenangalem, Enny; Simpson, Julie A.; Poespoprodjo, Jeanne R.; Sugiarto, Paulus; Anstey, Nicholas M.; Price, Ric N.

    2013-01-01

    Background The burden of anemia attributable to non-falciparum malarias in regions with Plasmodium co-endemicity is poorly documented. We compared the hematological profile of patients with and without malaria in southern Papua, Indonesia. Methods and Findings Clinical and laboratory data were linked for all patients presenting to a referral hospital between April 2004 and December 2012. Data were available on patient demographics, malaria diagnosis, hemoglobin concentration, and clinical outcome, but other potential causes of anemia could not be identified reliably. Of 922,120 patient episodes (837,989 as outpatients and 84,131 as inpatients), a total of 219,845 (23.8%) were associated with a hemoglobin measurement, of whom 67,696 (30.8%) had malaria. Patients with P. malariae infection had the lowest hemoglobin concentration (n = 1,608, mean = 8.93 [95% CI 8.81–9.06]), followed by those with mixed species infections (n = 8,645, mean = 9.22 [95% CI 9.16–9.28]), P. falciparum (n = 37,554, mean = 9.47 [95% CI 9.44–9.50]), and P. vivax (n = 19,858, mean = 9.53 [95% CI 9.49–9.57]); p-value for all comparisons anemia (hemoglobin anemia (adjusted odds ratio [AOR] 3.25 [95% CI 2.99–3.54]); AORs for severe anaemia associated with P. falciparum, P. vivax, and P. malariae were 2.11 (95% CI 2.00–2.23), 1.87 (95% CI 1.74–2.01), and 2.18 (95% CI 1.76–2.67), respectively, panemia was attributable to non-falciparum infections compared with 15.1% (95% CI 13.9%–16.3%) for P. falciparum monoinfections. Patients with severe anemia had an increased risk of death (AOR = 5.80 [95% CI 5.17–6.50]; panemia in early infancy, mixed P. vivax/P. falciparum infections are associated with a greater hematological impairment than either species alone, and in adulthood P. malariae, although rare, is associated with the lowest hemoglobin concentration. These findings highlight the public health importance of integrated genus-wide malaria

  13. Relation between Plasmodium falciparum asymptomatic infection and malaria attacks in a cohort of Senegalese children

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    Migot-Nabias Florence

    2008-09-01

    Full Text Available Abstract Background It is important to establish whether or not the presence of malaria parasites in peripheral blood of asymptomatic individuals is a predictor of future clinical mild malaria attacks (MMA. The aim of this study was to determine how an asymptomatic positive thick blood smear could be related to the occurrence of a MMA during the nine following days. Methods The study was conducted in a cohort of 569 Senegalese children, who were investigated for Plasmodium falciparum asymptomatic carriage at two different times of the transmission season, the beginning (September and the end (November. The occurrence of MMA was investigated in asymptomatic carriers and non-carriers, every three days for nine consecutive days. Survival analysis was performed and risk estimates were calculated by Cox proportional hazards model. Results At the beginning of the transmission season, 27.8% (147/529 of the children were asymptomatic carriers (ACs and 5.4% (8/147 of MMA occurred among these, versus 1% (4/382 among non-carriers (RR = 5.32; IC = [1.56–18.15], p = 0.008. At the end of the transmission season, the frequency of asymptomatic carriers was similar to that observed at the beginning of the season (31.9%, p = 0.15, but no MMA was detected during this period. Conclusion A significant association between P. falciparum asymptomatic carriage and the occurrence of MMA at the beginning of the transmission season was demonstrated, with a five-fold increase in the risk of developing a MMA in ACs. In the context of a possible distribution of IPTc in the future, drug strategies may have dramatic consequences due to the existence of ACs (both long term and short term, as they seem to play an important role in the individual protection to malaria, in the most exposed age groups.

  14. A Controlled Trial of Mass Drug Administration to Interrupt Transmission of Multi Drug Resistant Falciparum Malaria in Cambodian Villages.

    Science.gov (United States)

    Tripura, Rupam; Peto, Thomas J; Nguon, Chea; Davoeung, Chan; Mukaka, Mavuto; Sirithiranont, Pasathorn; Dhorda, Mehul; Promnarate, Cholrawee; Imwong, Mallika; von Seidlein, Lorenz; Duanguppama, Jureeporn; Patumrat, Krittaya; Rekol, Huy; Grobusch, Martin P; Day, Nicholas P J; White, Nicholas J; Dondorp, Arjen M

    2018-03-07

    The increase in multidrug resistant Plasmodium falciparum in Southeast Asia suggests a need for acceleration of malaria elimination. We evaluated the effectiveness and safety of mass drug administrations (MDA) to interrupt malaria transmission. Four malaria-endemic villages in western Cambodia were randomized to three rounds of MDA (a three-day course of dihydroartemisinin with piperaquine-phosphate), administered in either early or at the end of the study-period. Comprehensive malaria treatment records were collected during 2014-2017. Subclinical parasite prevalence was estimated by ultra-sensitive quantitative polymerase chain reaction (uPCR) quarterly over 12 months. MDA coverage with at least one complete round was 88% (1999/2268), ≥2-rounds 73% (1645/2268), and all 3-rounds 58% (1310/2268). P.falciparum incidence in intervention and control villages was similar over the 12 months prior to the study: 39/1000 person-years vs 45/1000 person-years (p=0.50). The primary outcome, P.falciparum incidence in the 12 months after MDA, was lower in intervention villages (1.5/1,000 person-years vs 37.1/1,000 person-years; incidence rate ratio 24.5, 95%CI 3.4-177; p=0.002). Following MDA in 2016, there were no clinical falciparum malaria cases over 12 months (0/2044 person-years) in all 4 villages. After an initial decrease of P.vivax prevalence in intervention villages, P.vivaxprevalence had returned to approximately half of the baseline prevalence by 12 months, and was no longer significantly lower than in control villages. No severe adverse events were attributed to treatment. MDAs with high coverage were safe, and associated with the absence of clinical P.falciparum cases for at least one year. Registered on clinicaltrials.gov (NCT01872702).

  15. Recent developments in production and purification of malaria antigens: Harvest of Plasmodium falciparum merozoites from continuous culture*

    Science.gov (United States)

    Mrema, J. E. K.; Campbell, G. H.; Jaramillo, A. L.; Miranda, R.; Rieckmann, K. H.

    1979-01-01

    Spontaneously released merozoites were harvested from cultures in which 42-90% of the erythrocytes had been infected with mature forms of Plasmodium falciparum at the start of incubation. The mature forms had been extracted from asynchronous cultures by the use of Ficoll and Plasmagel gradients. As the mature forms consisted of both trophozoites and schizonts, merozoites were released into the culture medium over a long period of time. The synchrony of merozoite release did not appear to be improved by prior exposure of parasites to sorbitol. Over this prolonged period of incubation, the yield of merozoites was disappointingly low in cultures containing 2.5% of erythrocytes. At erythrocyte concentrations of 0.01-0.25%, 3-10 times more merozoites were released into the medium; 0.4-2.3 merozoites per initial mature form were harvested over a 15-19-hour period. In addition to merozoites, contents of the culture medium included intact erythrocytes, ghost cells, and other cellular fragments. Only intact erythrocytes were effectively removed from the medium by simple or Ficoll gradient centrifugation. Merozoite preparations that are free from host cellular material are important in the development of a human malaria vaccine. ImagesFig. 3 PMID:397009

  16. Myocardial Dysfunction: A Primary Cause of Death Due To Severe Malaria in A Plasmodium falciparum-Infected Humanized Mouse Model.

    Directory of Open Access Journals (Sweden)

    Odaro Stanley Imade

    2013-12-01

    Full Text Available Our study aimed at substantiating the recent claim of myocardial complications in severe malaria by experimentally inducing severe Plasmodium falciparum infection in a humanized mouse model employed as human surrogate.Twenty five humanized mice were inoculated with standard in vitro cultured P. falciparum and blood extracts collected from the inner cardiac muscles of infected mice that died were examined for the presence of the infectious cause of death. The therapeutic effect of quinine on 7 mice severely infected with P. falciparum was also evaluated.All the 25 humanized mice inoculated with the in vitro cultured P. falciparum revealed peripheral parasitemia with a total of 10 deaths recorded. Postmortem examination of the inner cardiac muscles of the dead mice also revealed massive sequestration of mature P. falciparum as well as significant infiltration of inflammatory cells such as lymphocytes and monocytes. Postmortem evaluation of the inner cardiac muscles of the P. falciparum-infected mice after quinine therapy showed significant decline in parasite density with no death of mice recorded.Data obtained from our study significantly corroborated the findings of myocardial dysfunction as the primary cause of death in recent case reports of humans infected with P. falciparum.

  17. Plasmodium falciparum EPCR-binding PfEMP1 expression increases with malaria disease severity and is elevated in retinopathy negative cerebral malaria

    DEFF Research Database (Denmark)

    Shabani, Estela; Hanisch, Benjamin; Opoka, Robert O.

    2017-01-01

    Background: Expression of group A and the A-like subset of group B Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is associated with severe malaria (SM). The diversity of var sequences combined with the challenges of distinct classification of patient pathologies has made studying...... the role of distinct PfEMP1 variants on malaria disease severity challenging. The application of retinopathy in the recent years has provided a further method to clinically evaluate children with cerebral malaria (CM). The question of whether children with clinical CM but no retinopathy represent...... a completely different disease process or a subgroup within the spectrum of CM remains an important question in malaria. In the current study, we use newly designed primer sets with the best coverage to date in a large cohort of children with SM to determine the role of var genes in malaria disease severity...

  18. Severe imported falciparum malaria: a cohort study in 400 critically ill adults.

    Directory of Open Access Journals (Sweden)

    Fabrice Bruneel

    Full Text Available BACKGROUND: Large studies on severe imported malaria in non-endemic industrialized countries are lacking. We sought to describe the clinical spectrum of severe imported malaria in French adults and to identify risk factors for mortality at admission to the intensive care unit. METHODOLOGY AND PRINCIPAL FINDINGS: Retrospective review of severe Plasmodium falciparum malaria episodes according to the 2000 World Health Organization definition and requiring admission to the intensive care unit. Data were collected from medical charts using standardised case-report forms, in 45 French intensive care units in 2000-2006. Risk factors for in-hospital mortality were identified by univariate and multivariate analyses. Data from 400 adults admitted to the intensive care unit were analysed, representing the largest series of severe imported malaria to date. Median age was 45 years; 60% of patients were white, 96% acquired the disease in sub-Saharan Africa, and 65% had not taken antimalarial chemoprophylaxis. Curative quinine treatment was used in 97% of patients. Intensive care unit mortality was 10.5% (42 deaths. By multivariate analysis, three variables at intensive care unit admission were independently associated with hospital death: older age (per 10-year increment, odds ratio [OR], 1.72; 95% confidence interval [95%CI], 1.28-2.32; P = 0.0004, Glasgow Coma Scale score (per 1-point decrease, OR, 1.32; 95%CI, 1.20-1.45; P<0.0001, and higher parasitemia (per 5% increment, OR, 1.41; 95%CI, 1.22-1.62; P<0.0001. CONCLUSIONS AND SIGNIFICANCE: In a large population of adults treated in a non-endemic industrialized country, severe malaria still carried a high mortality rate. Our data, including predictors of death, can probably be generalized to other non-endemic countries where high-quality healthcare is available.

  19. Retrospective study of imported falciparum malaria in French paediatric intensive care units.

    Science.gov (United States)

    Lanneaux, Justine; Dauger, Stéphane; Pham, Luu-Ly; Naudin, Jérôme; Faye, Albert; Gillet, Yves; Bosdure, Emmanuelle; Carbajal, Ricardo; Dubos, François; Vialet, Renaud; Chéron, Gérard; Angoulvant, François

    2016-11-01

    The World Health Organization (WHO) severity criteria for paediatric Plasmodium falciparum (Pf) malaria are based on studies in countries of endemic malaria. The relevance of these criteria for other countries remains unclear. We assessed the relevance of these criteria in an industrialised country. Retrospective case-control study. Eight French university hospitals, from 2006 to 2012. Children with Pf malaria admitted to paediatric intensive care units (cases: n=55) or paediatric emergency departments (controls: n=110). Descriptive analysis of WHO severity criteria and major interventions (mechanical ventilation, blood transfusion, fluid challenge, treatment of cerebral oedema, renal replacement therapy). Thresholds were set by receiver operating characteristics curve analysis. Altered consciousness (71% vs 5%), shock (24% vs 1%), renal failure (20% vs 1%), anaemia 50 µmol/L (25% vs 8%) and parasitaemia >10% (30% vs 8%) were more frequent in cases (p<0.01). All these criteria were associated with major interventions (p<0.001). Respiratory distress (six cases), and hypoglycaemia (two cases) were infrequent. Thrombocytopenia <50 000/mm 3 (46% vs 7%) and anaemia (haemoglobin concentration <70 g/L (41% vs 13%)) were more frequent in cases (p<0.0001). The WHO severity criteria for paediatric Pf malaria are relevant for countries without endemic malaria. The infrequent but severe complications also provide a timely reminder of the morbidity and mortality associated with this condition worldwide. In non-endemic countries haemoglobin <70 g/L and platelet count <50 000/mm 3 could be used as additional criteria to identify children needing high level of care. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  20. Variant surface antigen-specific IgG and protection against clinical consequences of pregnancy-associated Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Staalsoe, Trine; Shulman, Caroline E; Bulmer, Judith N

    2004-01-01

    BACKGROUND: Pregnancy-associated malaria caused by Plasmodium falciparum adherence to chondroitin sulfate A in the placental intervillous space is a major cause of low birthweight and maternal anaemia in areas of endemic P falciparum transmission. Adhesion-blocking antibodies that specifically...... recognise parasite-encoded variant surface antigens (VSA) are associated with resistance to pregnancy-associated malaria. We looked for a possible relation between VSA-specific antibody concentrations, placental infection, and protection from low birthweight and maternal anaemia. METHODS: We used flow...... selected or not selected for chondroitin sulfate A adhesiveness in-vitro. FINDINGS: Concentrations of plasma IgG specific for VSA, expressed by chondroitin sulfate A-adhering parasites (VSA in pregnancy-associated malaria or vsa-pam), increased with gravidity and were associated with placental histological...

  1. Vaccines against malaria-still a long way to go.

    Science.gov (United States)

    Matuschewski, Kai

    2017-08-01

    Several species of Plasmodium cause a broad spectrum of human disease that range from nausea and fever to severe anemia, cerebral malaria, and multiorgan failure. In malaria-endemic countries, continuous exposure to Plasmodium sporozoite inoculations and subsequent blood infections elicit only partial and short-lived immunity, which gradually develops over many years of parasite exposure and multiple clinical episodes. The ambitious goal of malaria vaccinology over the past 70 years has been to develop an immunization strategy that mounts protection superior to naturally acquired immunity. Herein, three principal concepts in evidence-based malaria vaccine development are compared. Feasible leads are typically stand-alone subunit vaccine approaches that block Plasmodium parasite life cycle progression or parasite/host interactions, and they constitute the majority of candidates in preclinical research and early clinical testing. Integrated approaches incorporate malaria antigen(s) into licensed or emerging pediatric vaccine formulations. This strategy can complement the malaria control portfolio even if the antimalarial component is only partially effective and has led to the development of the only candidate vaccine to date, namely RTS,S-AS01. Experimental whole parasite vaccine approaches have been repeatedly shown to elicit sterile and lasting protection against identical parasite strains, but mass production, proof of broad protection against different parasite strains, and routes of vaccine delivery remain significant translational road blocks. Global access to an effective and affordable malaria vaccine will critically depend on innovative translational research that builds on a better molecular understanding of Plasmodium biology and host immunity. © 2017 Federation of European Biochemical Societies.

  2. Antioxidant vitamin levels among preschool children with uncomplicated Plasmodium falciparum malaria in Sokoto, Nigeria

    Directory of Open Access Journals (Sweden)

    Aghedo FI

    2013-07-01

    Full Text Available Festus I Aghedo,1 Resqua A Shehu,2 Rabiu A Umar,2 Mohammed N Jiya,3 Osaro Erhabor4 1Department of Haematology, Usmanu Danfodiyo University Teaching Hospital, Sokoto, Nigeria; 2Department of Biochemistry, Usmanu Danfodiyo University, Sokoto, Nigeria; 3Department of Paediatrics, College of Health Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria; 4Department of Haematology, Faculty of Medical Laboratory Science, Usmanu Danfodiyo University, Sokoto, Nigeria Objective: To assess antioxidant vitamin levels among preschool children with plasmodium malarial infection. Methods: We assessed antioxidant vitamin levels by using a standard procedure in 130 malaria-parasitized preschool children. Packed cell volume and parasite density were also evaluated. Forty healthy age- and gender-matched nonparasitized children were included as controls. Results: Plasmodium falciparum was the causative species in all subjects. The mean malaria parasitemia was 4529.45 ± 1237.5/µL. The mean antioxidant concentrations for vitamins A, C, and E among plasmodium-parasitized subjects were 33.15 ± 1.79 µg/dL, 0.51 ± 0.02 mg/dL, and 0.61 ± 0.02 mg/dL, respectively. The mean concentrations of vitamins A, C, and E among the non-malaria-parasitized controls were 69.72 ± 1.71 µg/dL, 1.25 ± 0.04 mg/dL, and 1.31 ± 0.04 mg/dL respectively. We observed that the mean antioxidant concentrations of vitamins A, C, and E were significantly lower among plasmodium-parasitized subjects compared with non-parasitized controls (P = 0.01. Malaria parasitemia correlated negatively with antioxidant concentrations and packed cell volume (r = -0.736 and -0.723, P = 0.001. We observed that the higher the level of parasitemia, the lower the antioxidant concentration. Conclusion: Our study has shown that the antioxidant levels in plasmodium-parasitized children in the North-West of Nigeria are low and that the more severe the malarial infection, the lower the antioxidant level and the

  3. Mannose-binding lectin is a disease modifier in clinical malaria and may function as opsonin for Plasmodium falciparum-infected erythrocytes

    DEFF Research Database (Denmark)

    Garred, Peter; Nielsen, Morten A; Kurtzhals, Jørgen

    2003-01-01

    to the membrane of P. falciparum-infected erythrocytes, which could be inhibited by mannose, was observed. Further characterization revealed that MBL reacted with a P. falciparum glycoprotein identical to the 78-kDa glucose-regulated stress protein of P. falciparum. MBL seems to be a disease modifier in clinical...... associated with the occurrence and outcome parameters of Plasmodium falciparum malaria and asked whether MBL may function as an opsonin for P. falciparum. No difference in MBL genotype frequency was observed between infected and noninfected children or between children with cerebral malaria and/or severe......Variant alleles in the mannose-binding lectin (MBL) gene (mbl2) causing low levels of functional MBL are associated with susceptibility to different infections and are common in areas where malaria is endemic. Therefore, we investigated whether MBL variant alleles in 551 children from Ghana were...

  4. Human population, urban settlement patterns and their impact on Plasmodium falciparum malaria endemicity.

    Science.gov (United States)

    Tatem, Andrew J; Guerra, Carlos A; Kabaria, Caroline W; Noor, Abdisalan M; Hay, Simon I

    2008-10-27

    The efficient allocation of financial resources for malaria control and the optimal distribution of appropriate interventions require accurate information on the geographic distribution of malaria risk and of the human populations it affects. Low population densities in rural areas and high population densities in urban areas can influence malaria transmission substantially. Here, the Malaria Atlas Project (MAP) global database of Plasmodium falciparum parasite rate (PfPR) surveys, medical intelligence and contemporary population surfaces are utilized to explore these relationships and other issues involved in combining malaria risk maps with those of human population distribution in order to define populations at risk more accurately. First, an existing population surface was examined to determine if it was sufficiently detailed to be used reliably as a mask to identify areas of very low and very high population density as malaria free regions. Second, the potential of international travel and health guidelines (ITHGs) for identifying malaria free cities was examined. Third, the differences in PfPR values between surveys conducted in author-defined rural and urban areas were examined. Fourth, the ability of various global urban extent maps to reliably discriminate these author-based classifications of urban and rural in the PfPR database was investigated. Finally, the urban map that most accurately replicated the author-based classifications was analysed to examine the effects of urban classifications on PfPR values across the entire MAP database. Masks of zero population density excluded many non-zero PfPR surveys, indicating that the population surface was not detailed enough to define areas of zero transmission resulting from low population densities. In contrast, the ITHGs enabled the identification and mapping of 53 malaria free urban areas within endemic countries. Comparison of PfPR survey results showed significant differences between author-defined 'urban

  5. Human population, urban settlement patterns and their impact on Plasmodium falciparum malaria endemicity

    Directory of Open Access Journals (Sweden)

    Kabaria Caroline W

    2008-10-01

    Full Text Available Abstract Background The efficient allocation of financial resources for malaria control and the optimal distribution of appropriate interventions require accurate information on the geographic distribution of malaria risk and of the human populations it affects. Low population densities in rural areas and high population densities in urban areas can influence malaria transmission substantially. Here, the Malaria Atlas Project (MAP global database of Plasmodium falciparum parasite rate (PfPR surveys, medical intelligence and contemporary population surfaces are utilized to explore these relationships and other issues involved in combining malaria risk maps with those of human population distribution in order to define populations at risk more accurately. Methods First, an existing population surface was examined to determine if it was sufficiently detailed to be used reliably as a mask to identify areas of very low and very high population density as malaria free regions. Second, the potential of international travel and health guidelines (ITHGs for identifying malaria free cities was examined. Third, the differences in PfPR values between surveys conducted in author-defined rural and urban areas were examined. Fourth, the ability of various global urban extent maps to reliably discriminate these author-based classifications of urban and rural in the PfPR database was investigated. Finally, the urban map that most accurately replicated the author-based classifications was analysed to examine the effects of urban classifications on PfPR values across the entire MAP database. Results Masks of zero population density excluded many non-zero PfPR surveys, indicating that the population surface was not detailed enough to define areas of zero transmission resulting from low population densities. In contrast, the ITHGs enabled the identification and mapping of 53 malaria free urban areas within endemic countries. Comparison of PfPR survey results showed

  6. Phase 1/2a study of the malaria vaccine candidate apical membrane antigen-1 (AMA-l) administered in adjuvant system AS01B or AS02A

    NARCIS (Netherlands)

    M.D. Spring (Michele Donna); J.F. Cummings (James); C.F. Ockenhouse (Christian); S. Dutta (Shantanu); R. Reidler (Randall); E. Angov (Evelina); E. Bergmann-Leitner (Elke); V.A. Stewart (Ann); S. Bittner (Stacey); L. Juompan (Laure); M.G. Kortepeter (Mark); R. Nielsen (Robin); U. Krzych (Urszula); E. Tierney (Ev); L.A. Ware (Lisa); M. Dowler (Megan); C.C. Hermsen (Cornelus); R.W. Sauerwein (Robert); S.J. de Vlas (Sake); O. Ofori-Anyinam (Opokua); D.E. Lanar (David); J.L. Williams (Jack); K.E. Kester (Kent); K. Tucker (Kathryn); M. Shi (Meng); E. Malkin (Elissa); C. Long (Carole); C.L. Diggs (Carter); L. Soisson (Lorraine Amory); M.C. Dubois; W.R. Ballou (Ripley); J. Cohen (Joe); D.G. Heppner (Gray)

    2009-01-01

    textabstractBackground: This Phase 1/2a study evaluated the safety, immunogenicity, and efficacy of an experimental malaria vaccine comprised of the recombinant Plasmodium falciparum protein apical membrane antigen-1 (AMA-1) representing the 3D7 allele formulated with either the AS01B or AS02A

  7. Progress and prospects for blood-stage malaria vaccines.

    Science.gov (United States)

    Miura, Kazutoyo

    2016-06-01

    There have been significant decreases in malaria mortality and morbidity in the last 10-15 years, and the most advanced pre-erythrocytic malaria vaccine, RTS,S, received a positive opinion from European regulators in July 2015. However, no blood-stage vaccine has reached a phase III trial. The first part of this review summarizes the pros and cons of various assays and models that have been and will be used to predict the efficacy of blood-stage vaccines. In the second part, blood-stage vaccine candidates that showed some efficacy in human clinical trials or controlled human malaria infection models are discussed. Then, candidates under clinical investigation are described in the third part, and other novel candidates and strategies are reviewed in the last part.

  8. Plasmodium falciparum Resistance to Artemisinin Derivatives and Piperaquine: A Major Challenge for Malaria Elimination in Cambodia

    Science.gov (United States)

    Duru, Valentine; Witkowski, Benoit; Ménard, Didier

    2016-01-01

    Artemisinin-based combination therapies (ACTs) are the cornerstone of current strategies for fighting malaria. Over the last decade, ACTs have played a major role in decreasing malaria burden. However, this progress is being jeopardized by the emergence of artemisinin-resistant Plasmodium falciparum parasites. Artemisinin resistance was first detected in western Cambodia in 2008 and has since been observed in neighboring countries in southeast Asia. The problem of antimalarial drug resistance has recently worsened in Cambodia, with reports of parasites resistant to piperaquine, the latest generation of partner drug used in combination with dihydroartemisinin, leading to worrying rates of clinical treatment failure. The monitoring and the comprehension of both types of resistance are crucial to prevent the spread of multidrug-resistant parasites outside southeast Asia, and particularly to Africa, where the public health consequences would be catastrophic. To this end, new tools are required for studying the biological and molecular mechanisms underlying resistance to antimalarial drugs and for monitoring the geographic distribution of the resistant parasites. In this review, we detail the major advances in our understanding of resistance to artemisinin and piperaquine and define the challenges that the malaria community will have to face in the coming years. PMID:27928074

  9. Pharmacokinetics of oral artesunate in thai patients with uncomplicated falciparum malaria.

    Science.gov (United States)

    Karbwang, J; Na-Bangchang, K; Congpoung, K; Thanavibul, A; Harinasuta, T

    1998-01-01

    The pharmacokinetics of artesunate and its major plasma metabolite, dihydroartemisinin, were investigated in 11 Thai male patients with acute uncomplicated falciparum malaria during the acute and recovery phases. Patients were given an oral dose of 200mg artesunate (Guilin Pharmaceutical) on the first day, followed by 100mg 12 hours later, then 100mg daily for another 4 days (total dose of 700mg). All the patients showed a rapid initial response with median (range) parasite and fever clearance times of 30 (18 to 60) and 24 (4 to 94) hours, respectively; no patients showed reappearance of parasites during the 28-day follow-up period. No significant clinical adverse effects were detected in any patient. Acute phase malaria infection significantly influenced the pharmacokinetics of artesunate and its active metabolite, dihydroartemisinin. Maximum plasma drug concentration (C(max)), absorption half-life (t((1/2)a)), area under the plasma concentration-time curve from zero to the last observed time (AUC) and terminal elimination half-life (t((1/2)z)) of artesunate were decreased, while apparent total body clearance (CL/f) was increased during the acute phase, compared with the recovery phase. In addition, a decrease in the C(max) and an increase in the AUC(DHA/ARS ) ratio were found. Optimisation of therapy with oral artesunate should therefore be based on the kinetics of the drug and dihydroartemisinin in malaria patients with acute phase infection.

  10. Evidence for globally shared, cross-reacting polymorphic epitopes in the pregnancy-associated malaria vaccine candidate VAR2CSA

    DEFF Research Database (Denmark)

    Avril, Marion; Kulasekara, Bridget R; Gose, Severin O

    2008-01-01

    Pregnancy-associated malaria (PAM) is characterized by the placental sequestration of Plasmodium falciparum-infected erythrocytes (IEs) with the ability to bind to chondroitin sulfate A (CSA). VAR2CSA is a leading candidate for a pregnancy malaria vaccine, but its large size ( approximately 350 k......Da) and extensive polymorphism may pose a challenge to vaccine development. In this study, rabbits were immunized with individual VAR2CSA Duffy binding-like (DBL) domains expressed in Pichia pastoris or var2csa plasmid DNA and sera were screened on different CSA-binding parasite lines. Rabbit antibodies to three...... recombinant proteins (DBL1, DBL3, and DBL6) and four plasmid DNAs (DBL1, DBL3, DBL5, and DBL6) reacted with homologous FCR3-CSA IEs. By comparison, antibodies to the DBL4 domain were unable to react with native VAR2CSA protein unless it was first partially proteolyzed with trypsin or chymotrypsin...

  11. Malaria vaccine: WHO position paper, January 2016 - Recommendations.

    Science.gov (United States)

    2017-04-03

    This article presents the World Health Organization's (WHO) recommendations on the use of malaria vaccine excerpted from the WHO position paper on malaria vaccine published in the Weekly epidemiological Record in January 2016 [1]. The current document is the first WHO position paper on malaria vaccination and focuses primarily on the available evidence concerning the only malaria vaccine having received a positive regulation assessment from the European Medicines Agency (EMA) [2]. The position paper gives consideration to the epidemiological features of the disease and assesses the potential use of the vaccine for public health benefits. Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence, and to the evidence to recommendation table. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. This paper reflects the joint recommendation of the WHO's Strategic Advisory Group of Experts (SAGE) on immunization and the Malaria Policy Advisory Committee (MPAC). These recommendations were discussed by SAGE and MPAC at the October 2015 SAGE meeting. Evidence presented at the meeting can be accessed at http://www.who.int/immunization/sage/previous/en/index.html. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Decrease in circulating CD25(hi)Foxp3(+) regulatory T cells following vaccination with the candidate malaria vaccine RTS,S.

    Science.gov (United States)

    Parsons, Emily; Epstein, Judith; Sedegah, Martha; Villasante, Eileen; Stewart, Ann

    2016-08-31

    Regulatory T (Treg) cells have been shown in some cases to limit vaccine-specific immune responses and impact efficacy. Very little is known about the regulatory responses to the leading malaria vaccine candidate, RTS,S. The goal of this study was to begin to characterize the regulatory responses to the RTS,S vaccine. Using multi-parameter flow cytometry, we examined responses in 13 malaria naïve adult volunteers who received 2 doses of RTS,S given eight weeks apart. Five of these volunteers had previously received 3 doses of a candidate DNA-CSP vaccine, with the final dose given approximately one year prior to the first dose of the RTS,S vaccine. We found that the frequency of CD25(hi)Foxp3(+) Treg cells decreased following administration of RTS,S (p=0.0195), with no differences based on vaccine regimen. There was a concomitant decrease in CTLA-4 expression on CD25(hi)Foxp3(+) Treg cells (p=0.0093) and PD-1 levels on CD8(+) T cells (p=0.0002). Additionally, the frequency of anergic CTLA-4(+)CCR7(+) T cells decreased following vaccination. An inverse correlation was observed between the frequency of Plasmodium falciparum circumsporozoite protein (PfCSP)-specific IFN-γ and PfCSP-specific IL-10, as well as an inverse correlation between IL-10 induced by Hepatitis B surface antigen, the carrier of RTS,S, and PfCSP-specific IFN-γ, suggesting that immunity against the vaccine backbone could impact vaccine immunogenicity. These results have implications for future malaria vaccine design. Copyright © 2016. Published by Elsevier Ltd.

  13. Malaria.

    Science.gov (United States)

    Sogunro, R

    1993-01-01

    The World Health Organization (WHO) has coordinated and supported the eradication of malaria in various countries of the world since 1957. Unlike some countries in the temperate zone which have been successful in eradicating the disease, malaria remains endemic in tropical and subtropical countries. In 1969 WHO recommended that, although eradication should remain an ultimate goal, malaria control operations may form a transitional phase in countries where eradication does not appear feasible. Malaria control, however, remains an impossible goal in many countries where the disease is endemic. Plasmodium falciparum is the predominant malaria pathogen responsible for severe disease and death. It is estimated that 90% of all malaria cases worldwide occur in Africa, where the majority of people live in highly endemic or endemic prone areas. Only about 12% of the population lives in risk-free or low-risk areas. Between one-third and two-thirds of all cases of fever among children are associated with malaria, and in some parts of Africa the case-fatality rate is as high 31.9% for infants and 20.4% for children. The malaria situation in the African continent is rapidly changing due to variants of P. falciparum that are resistant to chloroquine; mosquitoes that are resistant to insecticides; movement of nonimmune individuals to endemic areas; increasing short-term travel patterns; and ecological reasons. Malaria is also appearing in previously free areas because of technological (agricultural) advances. Adult and pediatric dosages of antimalarial drugs are suggested for the treatment and prevention of P. falciparum malaria.

  14. Development of malaria vaccines that block transmission of parasites by mosquito vectors

    OpenAIRE

    Hisaeda, Hajime; Yasutomo, Koji

    2002-01-01

    Malaria is still one of the infectious diseases urgently requiring control and causes socioeconomic burdens on people residing in developing countries. Malaria vaccines are expected to control the disease. However, there is no effective vaccine available despite the intense efforts of malaria scientists. One strategy for a malaria vaccine is to prevent parasite spread by means of interfering with parasite development in mosquito vectors, which is the so-called transmission-blocking vaccine (T...

  15. An imported case of severe falciparum malaria with prolonged hemolytic anemia clinically mimicking a coinfection with babesiosis.

    Science.gov (United States)

    Na, Young Ju; Chai, Jong-Yil; Jung, Bong-Kwang; Lee, Hyun Jung; Song, Ji Young; Je, Ji Hye; Seo, Ji Hye; Park, Sung Hun; Choi, Ji Seon; Kim, Min Ja

    2014-12-01

    While imported falciparum malaria has been increasingly reported in recent years in Korea, clinicians have difficulties in making a clinical diagnosis as well as in having accessibility to effective anti-malarial agents. Here we describe an unusual case of imported falciparum malaria with severe hemolytic anemia lasting over 2 weeks, clinically mimicking a coinfection with babesiosis. A 48-year old Korean man was diagnosed with severe falciparum malaria in France after traveling to the Republic of Benin, West Africa. He received a 1-day course of intravenous artesunate and a 7-day course of Malarone (atovaquone/proguanil) with supportive hemodialysis. Coming back to Korea 5 days after discharge, he was readmitted due to recurrent fever, and further treated with Malarone for 3 days. Both the peripheral blood smears and PCR test were positive for Plasmodium falciparum. However, he had prolonged severe hemolytic anemia (Hb 5.6 g/dl). Therefore, 10 days after the hospitalization, Babesia was considered to be potentially coinfected. A 7-day course of Malarone and azithromycin was empirically started. He became afebrile within 3 days of this babesiosis treatment, and hemolytic anemia profiles began to improve at the completion of the treatment. He has remained stable since his discharge. Unexpectedly, the PCR assays failed to detect DNA of Babesia spp. from blood. In addition, during the retrospective review of the case, the artesunate-induced delayed hemolytic anemia was considered as an alternative cause of the unexplained hemolytic anemia.

  16. Ensemble modeling of the likely public health impact of a pre-erythrocytic malaria vaccine.

    Directory of Open Access Journals (Sweden)

    Thomas Smith

    2012-01-01

    Full Text Available BACKGROUND: The RTS,S malaria vaccine may soon be licensed. Models of impact of such vaccines have mainly considered deployment via the World Health Organization's Expanded Programme on Immunization (EPI in areas of stable endemic transmission of Plasmodium falciparum, and have been calibrated for such settings. Their applicability to low transmission settings is unclear. Evaluations of the efficiency of different deployment strategies in diverse settings should consider uncertainties in model structure. METHODS AND FINDINGS: An ensemble of 14 individual-based stochastic simulation models of P. falciparum dynamics, with differing assumptions about immune decay, transmission heterogeneity, and treatment access, was constructed. After fitting to an extensive library of field data, each model was used to predict the likely health benefits of RTS,S deployment, via EPI (with or without catch-up vaccinations, supplementary vaccination of school-age children, or mass vaccination every 5 y. Settings with seasonally varying transmission, with overall pre-intervention entomological inoculation rates (EIRs of two, 11, and 20 infectious bites per person per annum, were considered. Predicted benefits of EPI vaccination programs over the simulated 14-y time horizon were dependent on duration of protection. Nevertheless, EPI strategies (with an initial catch-up phase averted the most deaths per dose at the higher EIRs, although model uncertainty increased with EIR. At two infectious bites per person per annum, mass vaccination strategies substantially reduced transmission, leading to much greater health effects per dose, even at modest coverage. CONCLUSIONS: In higher transmission settings, EPI strategies will be most efficient, but vaccination additional to the EPI in targeted low transmission settings, even at modest coverage, might be more efficient than national-level vaccination of infants. The feasibility and economics of mass vaccination, and the

  17. Acute pancreatitis and subdural haematoma in a patient with severe falciparum malaria: Case report and review of literature

    Directory of Open Access Journals (Sweden)

    Sathyendra Sowmya

    2008-05-01

    Full Text Available Abstract Plasmodium falciparum infection is known to be associated with a spectrum of systemic complications ranging from mild and self-limiting to life-threatening. This case report illustrates a patient who had a protracted course in hospital due to several rare complications of falciparum malaria. A 21-year old man presented with a five-day history of high-grade fever, jaundice and abdominal pain and a two-day history of altered conscious state. A diagnosis of severe falciparum malaria was made based on the clinical presentation and a positive blood smear with parasitaemia of 45%. Despite adequate anti-malarial therapy with artesunate, the patient had persistent and worsening abdominal pain. Investigations suggested a diagnosis of acute pancreatitis, a rare association with falciparum malaria. However, in spite of supportive therapy for acute pancreatitis and a 10-day course of intravenous artesunate and oral doxycycline at recommended doses, he continued to be febrile with peripheral blood smear showing persistence of ring forms. Antimalarial therapy was, therefore, changed to quinine on the suspicion of possible artesunate resistance. On the 17th day of stay in hospital, the patient developed generalized tonic-clonic seizures. Computerized tomography of the brain showed bilateral fronto-parietal subdural haematomas that were surgically drained. His fever persisted beyond 30-days despite broad-spectrum antibiotics, quinine therapy and negative malarial smears. A possibility of drug fever was considered and all drugs were ceased. He subsequently became afebrile and was discharged on the 38th hospital admission day. Recognition of complications and appropriate management at each stage facilitated successful outcome. This report has been presented to highlight the occurrence of several rare complications of falciparum malaria in the same patient.

  18. A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model

    Science.gov (United States)

    Reuling, Isaie J; van de Schans, Lisanne A; Coffeng, Luc E; Lanke, Kjerstin; Meerstein-Kessel, Lisette; Graumans, Wouter; van Gemert, Geert-Jan; Teelen, Karina; Siebelink-Stoter, Rianne; van de Vegte-Bolmer, Marga; de Mast, Quirijn; van der Ven, André J; Ivinson, Karen; Hermsen, Cornelus C; de Vlas, Sake; Bradley, John; Collins, Katharine A; Ockenhouse, Christian F; McCarthy, James

    2018-01-01

    effect of drugs and vaccines on gametocyte dynamics, and lays the foundation for fulfilling the critical unmet need to evaluate transmission-blocking interventions against falciparum malaria for downstream selection and clinical development. Funding PATH Malaria Vaccine Initiative (MVI) PMID:29482720

  19. A randomized controlled phase Ib trial of the malaria vaccine candidate GMZ2 in African children.

    Directory of Open Access Journals (Sweden)

    Sabine Bélard

    Full Text Available GMZ2 is a fusion protein of Plasmodium falciparum merozoite surface protein 3 (MSP3 and glutamate rich protein (GLURP that mediates an immune response against the blood stage of the parasite. Two previous phase I clinical trials, one in naïve European adults and one in malaria-exposed Gabonese adults showed that GMZ2 was well tolerated and immunogenic. Here, we present data on safety and immunogenicity of GMZ2 in one to five year old Gabonese children, a target population for future malaria vaccine efficacy trials.Thirty children one to five years of age were randomized to receive three doses of either 30 µg or 100 µg of GMZ2, or rabies vaccine. GMZ2, adjuvanted in aluminum hydroxide, was administered on Days 0, 28 and 56. All participants received a full course of their respective vaccination and were followed up for one year. Both 30 µg and 100 µg GMZ2 vaccine doses were well tolerated and induced antibodies and memory B-cells against GMZ2 as well as its antigenic constituents MSP3 and GLURP. After three doses of vaccine, the geometric mean concentration of antibodies to GMZ2 was 19-fold (95%CI: 11,34 higher in the 30 µg GMZ2 group than in the rabies vaccine controls, and 16-fold (7,36 higher in the 100 µg GMZ2 group than the rabies group. Geometric mean concentration of antibodies to MSP3 was 2.7-fold (1.6,4.6 higher in the 30 µg group than in the rabies group and 3.8-fold (1.5,9.6 higher in the 100 µg group. Memory B-cells against GMZ2 developed in both GMZ2 vaccinated groups.Both 30 µg as well as 100 µg intramuscular GMZ2 are immunogenic, well tolerated, and safe in young, malaria-exposed Gabonese children. This result confirms previous findings in naïve and malaria-exposed adults and supports further clinical development of GMZ2.ClinicalTrials.gov NCT00703066.

  20. Quinine levels in patients with uncomplicated falciparum malaria in the Amazon region of Brazil.

    Science.gov (United States)

    Vieira, José Luiz Fernandes; Borges, Larissa Maria Guimarães; Nascimento, Margareth Tavares Silva; Gomes, Andreza de L S

    2008-10-01

    We examined the plasmatic concentrations of quinine in patients with uncomplicated falciparum malaria in an endemic area of the Amazon region in Brazil in a prospective clinical trial, in which a standard three-day course of oral quinine plus doxycycline was used. We measured the quinine in the plasma samples on days 0 and 3 by high performance liquid chromatography. The mean concentration of quinine was 6.04 +/-2.21 microg/mL in male patients and 5.98 +/-1.95 microg/mL in female patients. No significant differences in quinine concentration were observed between these two groups. All samples collected before starting treatment were negative for quinine. This information could help in the development of strategies for the rational use of antimalarial drugs in Brazil.

  1. Quinine levels in patients with uncomplicated falciparum malaria in the Amazon region of Brazil

    Directory of Open Access Journals (Sweden)

    José Luiz Fernandes Vieira

    Full Text Available We examined the plasmatic concentrations of quinine in patients with uncomplicated falciparum malaria in an endemic area of the Amazon region in Brazil in a prospective clinical trial, in which a standard three-day course of oral quinine plus doxycycline was used. We measured the quinine in the plasma samples on days 0 and 3by high performance liquid chromatography. The mean concentration of quinine was 6.04 ±2.21 µg/mL in male patients and 5.98 ±1.95 µg/mL in female patients. No significant differences in quinine concentration were observed between these two groups. All samples collected before starting treatment were negative for quinine. This information could help in the development of strategies for the rational use of antimalarial drugs in Brazil.

  2. Anti-JK-a Antibody in a Case of SLE Patient with Plasmodium falciparum Malaria Infection.

    Science.gov (United States)

    Datta, Suvro Sankha; Mukherjee, Somnath; Bhattacharya, Prasun; Mukherjee, Krishnendu

    2013-06-01

    A 58 year old lady presented with high grade fever, pallor, abdominal pain, loss of appetite and swelling of legs. She was subsequently diagnosed with SLE along with infection of Plasmodium falciparum malaria. She was clinically pale and advised for two units of packed red cell transfusion. One of the two units was incompatible, so only one unit was issued. Subsequently, DAT and auto control were positive. Later antibody specificity was identified, which came out to be anti JK-a. Because of recent transfusion 2 weeks back, her antigenic phenotype could not be elicited. Though we could not make out whether this antibody was the result of pregnancy or transfusion induced allo anti-JK-a or SLE induced auto anti JK-a, this antibody is highly clinically significant from transfusion point of view.

  3. Landscape and Dynamics of Transcription Initiation in the Malaria Parasite Plasmodium falciparum

    Directory of Open Access Journals (Sweden)

    Sophie H. Adjalley

    2016-03-01

    Full Text Available A comprehensive map of transcription start sites (TSSs across the highly AT-rich genome of P. falciparum would aid progress toward deciphering the molecular mechanisms that underlie the timely regulation of gene expression in this malaria parasite. Using high-throughput sequencing technologies, we generated a comprehensive atlas of transcription initiation events at single-nucleotide resolution during the parasite intra-erythrocytic developmental cycle. This detailed analysis of TSS usage enabled us to define architectural features of plasmodial promoters. We demonstrate that TSS selection and strength are constrained by local nucleotide composition. Furthermore, we provide evidence for coordinate and stage-specific TSS usage from distinct sites within the same transcription unit, thereby producing transcript isoforms, a subset of which are developmentally regulated. This work offers a framework for further investigations into the interactions between genomic sequences and regulatory factors governing the complex transcriptional program of this major human pathogen.

  4. Clindamycin plus quinine for treating uncomplicated falciparum malaria: a systematic review and meta-analysis.

    Science.gov (United States)

    Obonyo, Charles O; Juma, Elizabeth A

    2012-01-04

    Artemisinin-based combinations are recommended for treatment of uncomplicated falciparum malaria, but are costly and in limited supply. Clindamycin plus quinine is an alternative non-artemisinin-based combination recommended by World Health Organization. The efficacy and safety of clindamycin plus quinine is not known. This systematic review aims to assess the efficacy of clindamycin plus quinine versus other anti-malarial drugs in the treatment of uncomplicated falciparum malaria. All randomized controlled trials comparing clindamycin plus quinine with other anti-malarial drugs in treating uncomplicated malaria were included in this systematic review. Databases searched included: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and LILACS. Two authors independently assessed study eligibility, extracted data and assessed methodological quality. The primary outcome measure was treatment failure by day 28. Dichotomous data was compared using risk ratio (RR), in a fixed effects model. Seven trials with 929 participants were included. Clindamycin plus quinine significantly reduced the risk of day 28 treatment failure compared with quinine (RR 0.14 [95% CI 0.07 to 0.29]), quinine plus sulphadoxine-pyrimethamine (RR 0.17 [95% CI 0.06 to 0.44]), amodiaquine (RR 0.11 [95% CI 0.04 to 0.27]), or chloroquine (RR 0.11 [95% CI 0.04 to 0.29]), but had similar efficacy compared with quinine plus tetracycline (RR 0.33 [95% CI 0.01 to 8.04]), quinine plus doxycycline (RR 1.00 [95% CI 0.21 to 4.66]), artesunate plus clindamycin (RR 0.57 [95% CI 0.26 to 1.24]), or chloroquine plus clindamycin (RR 0.38 [95% CI 0.13 to 1.10]). Adverse events were similar across treatment groups but were poorly reported. The evidence on the efficacy of clindamycin plus quinine as an alternative treatment for uncomplicated malaria is inconclusive. Adequately powered trials are urgently required to compare this combination with artemisinin-based combinations.

  5. Efficacy of artesunate-amodiaquine for the treatment of acute uncomplicated falciparum malaria in southern Mauritania.

    Science.gov (United States)

    Ouldabdallahi, Mohamed; Alew, Ismail; Salem, Mohamed Salem Ould Ahmedou; Dit Dialaw Ba, Mamadou; Boukhary, Ali Ould Mohamed Salem; Khairy, Mohamed Lemine Ould; Aziz, Mohamed Boubacar Abdel; Ringwald, Pascal; Basco, Leonardo K; Niang, Saidou Doro; Lebatt, Sid Mohamed

    2014-12-16

    A regular evaluation of therapeutic efficacy in sentinel sites and a system of surveillance are required to establish treatment guidelines and adapt national anti-malarial drug policy to the rapidly changing epidemiology of drug-resistant malaria. The current anti-malarial treatment guideline in Mauritania, officially recommended since 2006, is based on artemisinin-based combination therapy. The aim of the present study was to evaluate clinical efficacy and tolerance of artesunate-amodiaquine, the first-line treatment for acute uncomplicated malaria, in Mauritanian paediatric and adult patients to validate its continued use in the country. Plasmodium falciparum-infected symptomatic patients aged > six months were enrolled in Kobeni and Timbedra in southern Mauritania in September to October 2013. Co-formulated artesunate-amodiaquine was administered at the recommended dose over three days. Patients were followed until day 28. Parasitological and clinical response was classified according to the standard 2009 World Health Organization protocol. A total of 130 patients (65 in Kobeni and 65 in Timbedra) were enrolled in the study. Seventeen patients (13.1%) were either excluded (before PCR correction) or lost to follow-up. Based on the per protocol analysis, artesunate-amodiaquine efficacy (i.e., the proportion of adequate clinical and parasitological response) was 96.6% in Kobeni and 98.2% in Timbedra before PCR correction. Late clinical failure was observed in two patients in Kobeni and one patient in Timbedra. After PCR correction, the efficacy rate in the two study sites was 98.2%. On day 3, all patients were afebrile and had negative smears. Treatment was well tolerated. Artesunate-amodiaquine is well tolerated and highly efficacious for the treatment of uncomplicated P. falciparum malaria. In the majority of patients, fever and parasitaemia were rapidly cleared before day 3. The results support the national anti-malarial drug guideline for a continued use of

  6. The Clp chaperones and proteases of the human malaria parasite Plasmodium falciparum.

    Science.gov (United States)

    El Bakkouri, Majida; Pow, Andre; Mulichak, Anne; Cheung, Kevin L Y; Artz, Jennifer D; Amani, Mehrnaz; Fell, Stuart; de Koning-Ward, Tania F; Goodman, C Dean; McFadden, Geoffrey I; Ortega, Joaquin; Hui, Raymond; Houry, Walid A

    2010-12-03

    The Clp chaperones and proteases play an important role in protein homeostasis in the cell. They are highly conserved across prokaryotes and found also in the mitochondria of eukaryotes and the chloroplasts of plants. They function mainly in the disaggregation, unfolding and degradation of native as well as misfolded proteins. Here, we provide a comprehensive analysis of the Clp chaperones and proteases in the human malaria parasite Plasmodium falciparum. The parasite contains four Clp ATPases, which we term PfClpB1, PfClpB2, PfClpC and PfClpM. One PfClpP, the proteolytic subunit, and one PfClpR, which is an inactive version of the protease, were also identified. Expression of all Clp chaperones and proteases was confirmed in blood-stage parasites. The proteins were localized to the apicoplast, a non-photosynthetic organelle that accommodates several important metabolic pathways in P. falciparum, with the exception of PfClpB2 (also known as Hsp101), which was found in the parasitophorous vacuole. Both PfClpP and PfClpR form mostly homoheptameric rings as observed by size-exclusion chromatography, analytical ultracentrifugation and electron microscopy. The X-ray structure of PfClpP showed the protein as a compacted tetradecamer similar to that observed for Streptococcus pneumoniae and Mycobacterium tuberculosis ClpPs. Our data suggest the presence of a ClpCRP complex in the apicoplast of P. falciparum. Copyright © 2010 Elsevier Ltd. All rights reserved.

  7. RTS,S vaccination is associated with serologic evidence of decreased exposure to Plasmodium falciparum liver- and blood-stage parasites.

    Science.gov (United States)

    Campo, Joe J; Aponte, John J; Skinner, Jeff; Nakajima, Rie; Molina, Douglas M; Liang, Li; Sacarlal, Jahit; Alonso, Pedro L; Crompton, Peter D; Felgner, Philip L; Dobaño, Carlota

    2015-03-01

    The leading malaria vaccine candidate, RTS,S, targets the sporozoite and liver stages of the Plasmodium falciparum life cycle, yet it provides partial protection against disease associated with the subsequent blood stage of infection. Antibodies against the vaccine target, the circumsporozoite protein, have not shown sufficient correlation with risk of clinical malaria to serve as a surrogate for protection. The mechanism by which a vaccine that targets the asymptomatic sporozoite and liver stages protects against disease caused by blood-stage parasites remains unclear. We hypothesized that vaccination with RTS,S protects from blood-stage disease by reducing the number of parasites emerging from the liver, leading to prolonged exposure to subclinical levels of blood-stage parasites that go undetected and untreated, which in turn boosts pre-existing antibody-mediated blood-stage immunity. To test this hypothesis, we compared antibody responses to 824 P. falciparum antigens by protein array in Mozambican children 6 months after receiving a full course of RTS,S (n = 291) versus comparator vaccine (n = 297) in a Phase IIb trial. Moreover, we used a nested case-control design to compare antibody responses of children who did or did not experience febrile malaria. Unexpectedly, we found that the breadth and magnitude of the antibody response to both liver and asexual blood-stage antigens was significantly lower in RTS,S vaccinees, with the exception of only four antigens, including the RTS,S circumsporozoite antigen. Contrary to our initial hypothesis, these findings suggest that RTS,S confers protection against clinical malaria by blocking sporozoite invasion of hepatocytes, thereby reducing exposure to the blood-stage parasites that cause disease. We also found that antibody profiles 6 months after vaccination did not distinguish protected and susceptible children during the subsequent 12-month follow-up period but were strongly associated with exposure. Together

  8. Rapid diagnostic tests for diagnosing uncomplicated P. falciparum malaria in endemic countries.

    Science.gov (United States)

    Abba, Katharine; Deeks, Jonathan J; Olliaro, Piero; Naing, Cho-Min; Jackson, Sally M; Takwoingi, Yemisi; Donegan, Sarah; Garner, Paul

    2011-07-06

    Rapid diagnostic tests (RDTs) for Plasmodium falciparum malaria use antibodies to detect either HRP-2 antigen or pLDH antigen, and can improve access to diagnostics in developing countries. To assess the diagnostic accuracy of RDTs for detecting P. falciparum parasitaemia in persons living in endemic areas who present to ambulatory healthcare facilities with symptoms suggestive of malaria by type and brand. We undertook a comprehensive search of the following databases: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; MEDION; Science Citation Index; Web of Knowledge; African Index Medicus; LILACS; IndMED; to January 14, 2010. Studies comparing RDTs with a reference standard (microscopy or polymerase chain reaction) in blood samples from a random or consecutive series of patients attending ambulatory health facilities with symptoms suggestive of malaria in P. falciparum endemic areas. For each study, a standard set of data was extracted independently by two authors, using a tailored data extraction form. Comparisons were grouped hierarchically by target antigen, and type and brand of RDT, and combined in meta-analysis where appropriate. We identified 74 unique studies as eligible for this review and categorized them according to the antigens they detected. Types 1 to 3 include HRP-2 (from P. falciparum) either by itself or with other antigens. Types 4 and 5 included pLDH (from P. falciparum) either by itself or with other antigens. In comparisons with microscopy, we identified 71 evaluations of Type 1 tests, eight evaluations of Type 2 tests and five evaluations of Type 3 tests. In meta-analyses, average sensitivities and specificities (95% CI) were 94.8% (93.1% to 96.1%) and 95.2% (93.2% to 96.7%) for Type 1 tests, 96.0% (94.0% to 97.3%) and 95.3% (87.3% to 98.3%) for Type 2 tests, and 99.5% (71.0% to 100.0%) and 90.6% (80.5% to 95.7%) for Type 3 tests, respectively. Overall for HRP-2, the meta-analytical average sensitivity and

  9. Population pharmacokinetics of proguanil in patients with acute P. falciparum malaria after combined therapy with atovaquone.

    Science.gov (United States)

    Hussein, Z; Eaves, C J; Hutchinson, D B; Canfield, C J

    1996-11-01

    1. The pharmacokinetics of proguanil were evaluated in patients with acute P. falciparum malaria receiving concomitantly proguanil hydrochloride and atovaquone. The population consisted of 203 Blacks, 112 Orientals and 55 Malays; 274 males and 96 females. Of the 370 patients, 114 and 256 patients were classified as 'poor' and 'extensive' metabolizers of proguanil, respectively. Body weight and age ranged between 11-110 kg and 3-65 years, respectively. 2. A one compartment model with first-order absorption and elimination was fitted to proguanil plasma concentration-time profiles, using non-linear mixed effect modelling (NONMEM). 3. Oral clearance (CLo) showed a 0.785 power relationship with body weight and was 13% higher in Orientals than Blacks and Malays and 17% lower in 'poor' than 'extensive' metabolizers. According to the mean weight of each population, the final population estimates of CLo in Blacks, Orientals and Malays who are 'extensive' metabolizers were 54.0, 61.5 and 64.3 l h-1, respectively. Age, gender and dose had no significant effects on CLo. 4. Apparent volume of distribution (V/F) showed a 0.88 power relationship with body weight. The final population estimates were 562 and 1629 l in children ( 15 years, respectively, who had a mean body weight of 22.6 and 54.8 kg, respectively. The effect of other covariates on V/F was not examined. 5. The final magnitudes of interpatient variability in CLo and V/F were relatively low at 22.5 and 17.0%, respectively. 6. Population pharmacokinetic parameter estimates in Black, Oriental and Malay patients with acute P. falciparum malaria are in good agreement with results of pharmacokinetic studies in healthy Caucasian volunteers. In view of the 30-50% residual variability in proguanil plasma concentrations, the slight effects of Orientals and 'poor' metabolizers on CLo are unlikely to be clinically significant. Hence, dose recommendation will be solely based on body weight.

  10. A focus of hyperendemic Plasmodium malariae-P. vivax with no P. falciparum in a primitive population in the Peruvian Amazon jungle.

    Science.gov (United States)

    Sulzer, A J; Cantella, R; Colichon, A; Gleason, N N; Walls, K W

    1975-01-01

    Findings in a sample population in southeastern Peru with a very high rate of malaria infection, due to Plasmodium malariae and P. vivax with apparently no P. falciparum, are described. The proportion of persons with P. malariae in this sample population, as determined by slide examination, appears to be the greatest ever reported for any area before the introduction of control measures. Although very few P. vivax were found on stained slides, results of the indirect immunofluorescence test indicated that this species was probably as prevalent as P. malariae; the absence of P. falciparum was supported by results of serologic tests. Possible reasons for this focus of malaria with no P. falciparum are discussed.

  11. Design of a Phase III cluster randomized trial to assess the efficacy and safety of a malaria transmission blocking vaccine.

    Science.gov (United States)

    Delrieu, Isabelle; Leboulleux, Didier; Ivinson, Karen; Gessner, Bradford D

    2015-03-24

    Vaccines interrupting Plasmodium falciparum malaria transmission targeting sexual, sporogonic, or mosquito-stage antigens (SSM-VIMT) are currently under development to reduce malaria transmission. An international group of malaria experts was established to evaluate the feasibility and optimal design of a Phase III cluster randomized trial (CRT) that could support regulatory review and approval of an SSM-VIMT. The consensus design is a CRT with a sentinel population randomly selected from defined inner and buffer zones in each cluster, a cluster size sufficient to assess true vaccine efficacy in the inner zone, and inclusion of ongoing assessment of vaccine impact stratified by distance of residence from the cluster edge. Trials should be conducted first in areas of moderate transmission, where SSM-VIMT impact should be greatest. Sample size estimates suggest that such a trial is feasible, and within the range of previously supported trials of malaria interventions, although substantial issues to implementation exist. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Major burden of severe anemia from non-falciparum malaria species in Southern Papua: a hospital-based surveillance study.

    Science.gov (United States)

    Douglas, Nicholas M; Lampah, Daniel A; Kenangalem, Enny; Simpson, Julie A; Poespoprodjo, Jeanne R; Sugiarto, Paulus; Anstey, Nicholas M; Price, Ric N

    2013-12-01

    The burden of anemia attributable to non-falciparum malarias in regions with Plasmodium co-endemicity is poorly documented. We compared the hematological profile of patients with and without malaria in southern Papua, Indonesia. Clinical and laboratory data were linked for all patients presenting to a referral hospital between April 2004 and December 2012. Data were available on patient demographics, malaria diagnosis, hemoglobin concentration, and clinical outcome, but other potential causes of anemia could not be identified reliably. Of 922,120 patient episodes (837,989 as outpatients and 84,131 as inpatients), a total of 219,845 (23.8%) were associated with a hemoglobin measurement, of whom 67,696 (30.8%) had malaria. Patients with P. malariae infection had the lowest hemoglobin concentration (n = 1,608, mean = 8.93 [95% CI 8.81-9.06]), followed by those with mixed species infections (n = 8,645, mean = 9.22 [95% CI 9.16-9.28]), P. falciparum (n = 37,554, mean = 9.47 [95% CI 9.44-9.50]), and P. vivax (n = 19,858, mean = 9.53 [95% CI 9.49-9.57]); p-value for all comparisons malaria, those with mixed Plasmodium infection were at greatest risk of severe anemia (adjusted odds ratio [AOR] 3.25 [95% CI 2.99-3.54]); AORs for severe anaemia associated with P. falciparum, P. vivax, and P. malariae were 2.11 (95% CI 2.00-2.23), 1.87 (95% CI 1.74-2.01), and 2.18 (95% CI 1.76-2.67), respectively, pcause of severe anemia in early infancy, mixed P. vivax/P. falciparum infections are associated with a greater hematological impairment than either species alone, and in adulthood P. malariae, although rare, is associated with the lowest hemoglobin concentration. These findings highlight the public health importance of integrated genus-wide malaria control strategies in areas of Plasmodium co-endemicity.

  13. Safety of the RTS,S/AS02A malaria vaccine in Mozambican children during a Phase IIb trial.

    Science.gov (United States)

    Sacarlal, Jahit; Aponte, John J; Aide, Pedro; Mandomando, Inácio; Bassat, Quique; Guinovart, Caterina; Leach, Amanda; Milman, Jessica; Macete, Eusebio; Espasa, Mateu; Ofori-Anyinam, Opokua; Thonnard, Joelle; Corachan, Sabine; Dubois, Marie-Claude; Lievens, Marc; Dubovsky, Filip; Ballou, W Ripley; Cohen, Joe; Alonso, Pedro L

    2008-01-10

    RTS,S/AS02A is a pre-erythrocytic vaccine candidate based on the Plasmodium falciparum circumsporozoite surface antigen and is currently the most advanced malaria vaccine candidate in development. A proof of concept phase IIb trial of the RTS,S/AS02A in Mozambican children aged 1-4 years determined a vaccine efficacy against risk of clinical malaria of 35.3% (95% CI 21.6-46.6; pRTS,S/AS02A vaccine. 2022 children that received at least one vaccine dose of RTS,S/AS02A or control vaccines were included in the intention to treat safety analysis. Vaccine safety was evaluated using active and passive follow-up. Participants were observed for at least 1h after each dose. Trained field workers visited children at home daily for the next 3 days to record solicited and unsolicited local and general symptoms. Investigators followed-up participants with severe adverse events until month 21. Overall, we recorded 1712 unsolicited adverse events after vaccination, 53% in the intervention and 47% in the control group. Most unsolicited adverse events reported with RTS,S/AS02A were self-limited, and participants recovered without sequelae. Local reactogenicity increased with the number of doses. The proportion of children experiencing serious adverse events was lower in the RTS,S/AS02A recipients compared to the control group (Engerix-Btrade mark or Prevnartrade mark and Hiberixtrade mark). Overall, these results indicate that the RTS,S/AS02A vaccine has a good safety profile and well tolerated when given in three doses to semi-immune children living in malaria-endemic areas.

  14. Reduced antibody responses against Plasmodium falciparum vaccine candidate antigens in the presence of Trichuris trichiura

    DEFF Research Database (Denmark)

    Esen, Meral; Mordmüller, Benjamin; de Salazar, Pablo Martinez

    2012-01-01

    BACKGROUND: Helminth infections are highly prevalent in the tropics and may have an effect on immune responses to vaccines due to their immunomodulatory effect. The prevalence of helminth infections in young children, the target group for malaria and most other vaccines, is high. Therefore we ass...

  15. falciparum malaria?

    African Journals Online (AJOL)

    Abstract What were first called simply false-positive. Wassermann reactions and then lupus anticoagu- lant are now known as antiphospholipid or anti- cardiolipin antibodies (ACA). These are known to cause a tendency to thrombosis and are frequently present in many neurological conditions and infections.

  16. Potential for reduction of burden and local elimination of malaria by reducing Plasmodium falciparum malaria transmission: a mathematical modelling study.

    Science.gov (United States)

    Griffin, Jamie T; Bhatt, Samir; Sinka, Marianne E; Gething, Peter W; Lynch, Michael; Patouillard, Edith; Shutes, Erin; Newman, Robert D; Alonso, Pedro; Cibulskis, Richard E; Ghani, Azra C

    2016-04-01

    Rapid declines in malaria prevalence, cases, and deaths have been achieved globally during the past 15 years because of improved access to first-line treatment and vector control. We aimed to assess the intervention coverage needed to achieve further gains over the next 15 years. We used a mathematical model of the transmission of Plasmodium falciparum malaria to explore the potential effect on case incidence and malaria mortality rates from 2015 to 2030 of five different intervention scenarios: remaining at the intervention coverage levels of 2011-13 (Sustain), for which coverage comprises vector control and access to treatment; two scenarios of increased coverage to 80% (Accelerate 1) and 90% (Accelerate 2), with a switch from quinine to injectable artesunate for management of severe disease and seasonal malaria chemoprevention where recommended for both Accelerate scenarios, and rectal artesunate for pre-referral treatment at the community level added to Accelerate 2; a near-term innovation scenario (Innovate), which included longer-lasting insecticidal nets and expansion of seasonal malaria chemoprevention; and a reduction in coverage to 2006-08 levels (Reverse). We did the model simulations at the first administrative level (ie, state or province) for the 80 countries with sustained stable malaria transmission in 2010, accounting for variations in baseline endemicity, seasonality in transmission, vector species, and existing intervention coverage. To calculate the cases and deaths averted, we compared the total number of each under the five scenarios between 2015 and 2030 with the predicted number in 2015, accounting for population growth. With an increase to 80% coverage, we predicted a reduction in case incidence of 21% (95% credible intervals [CrI] 19-29) and a reduction in mortality rates of 40% (27-61) by 2030 compared with 2015 levels. Acceleration to 90% coverage and expansion of treatment at the community level was predicted to reduce case incidence by

  17. Pfmdr1 copy number and arteminisin derivatives combination therapy failure in falciparum malaria in Cambodia

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    Wongsrichanalai Chansuda

    2009-01-01

    Full Text Available Abstract Background The combination of artesunate and mefloquine was introduced as the national first-line treatment for Plasmodium falciparum malaria in Cambodia in 2000. However, recent clinical trials performed at the Thai-Cambodian border have pointed to the declining efficacy of both artesunate-mefloquine and artemether-lumefantrine. Since pfmdr1 modulates susceptibility to mefloquine and artemisinin derivatives, the aim of this study was to assess the link between pfmdr1 copy number, in vitro susceptibility to individual drugs and treatment failure to combination therapy. Methods Blood samples were collected from P. falciparum-infected patients enrolled in two in vivo efficacy studies in north-western Cambodia: 135 patients were treated with artemether-lumefantrine (AL group in Sampovloun in 2002 and 2003, and 140 patients with artesunate-mefloquine (AM group in Sampovloun and Veal Veng in 2003 and 2004. At enrollment, the in vitro IC50 was tested and the strains were genotyped for pfmdr1 copy number by real-time PCR. Results The pfmdr1 copy number was analysed for 115 isolates in the AM group, and for 109 isolates in the AL group. Parasites with increased pfmdr1 copy number had significantly reduced in vitro susceptibility to mefloquine, lumefantrine and artesunate. There was no association between pfmdr1 polymorphisms and in vitro susceptibilities. In the patients treated with AM, the mean pfmdr1copy number was lower in subjects with adequate clinical and parasitological response compared to those who experienced late treatment failure (n = 112, p p = 0.364. The presence of three or more copies of pfmdr1 were associated with recrudescence in artesunate-mefloquine treated patients (hazard ratio (HR = 7.80 [95%CI: 2.09–29.10], N = 115, p = 0.002 but not with recrudescence in artemether-lumefantrine treated patients (HR = 1.03 [95%CI: 0.24–4.44], N = 109, p = 0.969. Conclusion This study shows that pfmdr1 copy number is a molecular

  18. A role for fetal hemoglobin and maternal immune IgG in infant resistance to Plasmodium falciparum malaria.

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    Chanaki Amaratunga

    2011-04-01

    Full Text Available In Africa, infant susceptibility to Plasmodium falciparum malaria increases substantially as fetal hemoglobin (HbF and maternal immune IgG disappear from circulation. During the first few months of life, however, resistance to malaria is evidenced by extremely low parasitemias, the absence of fever, and the almost complete lack of severe disease. This resistance has previously been attributed in part to poor parasite growth in HbF-containing red blood cells (RBCs. A specific role for maternal immune IgG in infant resistance to malaria has been hypothesized but not yet identified.We found that P. falciparum parasites invade and develop normally in fetal (cord blood, CB RBCs, which contain up to 95% HbF. However, these parasitized CB RBCs are impaired in their binding to human microvascular endothelial cells (MVECs, monocytes, and nonparasitized RBCs--cytoadherence interactions that have been implicated in the development of high parasite densities and the symptoms of malaria. Abnormal display of the parasite's cytoadherence antigen P. falciparum erythrocyte membrane protein-1 (PfEMP-1 on CB RBCs accounts for these findings and is reminiscent of that on HbC and HbS RBCs. IgG purified from the plasma of immune Malian adults almost completely abolishes the adherence of parasitized CB RBCs to MVECs.Our data suggest a model of malaria protection in which HbF and maternal IgG act cooperatively to impair the cytoadherence of parasitized RBCs in the first few months of life. In highly malarious areas of Africa, an infant's contemporaneous expression of HbC or HbS and development of an immune IgG repertoire may effectively reconstitute the waning protective effects of HbF and maternal immune IgG, thereby extending the malaria resistance of infancy into early childhood.

  19. Perturbation and proinflammatory type activation of Vd1+ gamma delta T cells in African children with Plasmodium falciparum malaria

    DEFF Research Database (Denmark)

    Hviid, L; Kurtzhals, J A; Adabayeri, V

    2001-01-01

    interferon, while fewer V delta 1(+) cells than the average proportion of all CD3(+) cells produced tumor necrosis factor alpha. No interleukin 10 production was detected among TCR-gamma delta(+) cells in general or V delta 1(+) cells in particular. Taken together, our data point to an immunoregulatory role......gamma delta T cells have variously been implicated in the protection against, and the pathogenesis of, malaria, but few studies have examined the gamma delta T-cell response to malaria in African children, who suffer the large majority of malaria-associated morbidity and mortality...... of Plasmodium falciparum malaria in Ghanaian children and they can constitute 30 to 50% of all T cells shortly after initiation of antimalarial chemotherapy. The bulk of the gamma delta T cells involved in this perturbation expressed V delta 1 and had a highly activated phenotype. Analysis of the T...

  20. Changes in lipid composition during sexual development of the malaria parasite Plasmodium falciparum.

    Science.gov (United States)

    Tran, Phuong N; Brown, Simon H J; Rug, Melanie; Ridgway, Melanie C; Mitchell, Todd W; Maier, Alexander G

    2016-02-06

    The development of differentiated sexual stages (gametocytes) within human red blood cells is essential for the propagation of the malaria parasite, since only mature gametocytes will survive in the mosquito's midgut. Hence gametocytogenesis is a pre-requisite for transmission of the disease. Physiological changes involved in sexual differentiation are still enigmatic. In particular the lipid metabolism-despite being central to cellular regulation and development-is not well explored. Here the lipid profiles of red blood cells infected with the five different sexual stages of Plasmodium falciparum were analysed by mass spectrometry and compared to those from uninfected and asexual trophozoite infected erythrocytes. Fundamental differences between erythrocytes infected with the different parasite stages were revealed. In mature gametocytes many lipids that decrease in the trophozoite and early gametocyte infected red blood cells are regained. In particular, regulators of membrane fluidity, cholesterol and sphingomyelin, increased significantly during gametocyte maturation. Neutral lipids (serving mainly as caloriometric reserves) increased from 3 % of total lipids in uninfected to 27 % in stage V gametocyte infected red blood cells. The major membrane lipid class (phospholipids) decreased during gametocyte development. The lipid profiles of infected erythrocytes are characteristic for the particular parasite life cycle and maturity stages of gametocytes. The obtained lipid profiles are crucial in revealing the lipid metabolism of malaria parasites and identifying targets to interfere with this deadly disease.

  1. Neutrophil alterations in pregnancy-associated malaria and induction of neutrophil chemotaxis by Plasmodium falciparum

    DEFF Research Database (Denmark)

    Boström, S.; Schmiegelow, C; Abu Abed, U

    2017-01-01

    Pregnancy-associated malaria (PAM) is a severe form of the disease caused by sequestration of Plasmodium falciparum-infected red blood cells (iRBCs) in the developing placenta. Pathogenesis of PAM is partially based on immunopathology, with frequent monocyte infiltration into the placenta....... Neutrophils are abundant blood cells that are essential for immune defence but may also cause inflammatory pathology. Their role in PAM remains unclear. We analysed neutrophil alterations in the context of PAM to better understand their contribution to disease development. Pregnant women exposed to Plasmodium...... falciparum had decreased numbers of circulating neutrophils. Placental-like BeWo cells stimulated with malaria parasites produced the neutrophil chemoattractant IL-8 and recruited neutrophils in a trans-well assay. Finally, immunostaining of a PAM placenta confirmed neutrophil accumulation...

  2. A Novel Virus-Like Particle Based Vaccine Platform Displaying the Placental Malaria Antigen VAR2CSA.

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    Susan Thrane

    Full Text Available Placental malaria caused by Plasmodium falciparum is a major cause of mortality and severe morbidity. Clinical testing of a soluble protein-based vaccine containing the parasite ligand, VAR2CSA, has been initiated. VAR2CSA binds to the human receptor chondroitin sulphate A (CSA and is responsible for sequestration of Plasmodium falciparum infected erythrocytes in the placenta. It is imperative that a vaccine against malaria in pregnancy, if administered to women before they become pregnant, can induce a strong and long lasting immune response. While most soluble protein-based vaccines have failed during clinical testing, virus-like particle (VLP based vaccines (e.g., the licensed human papillomavirus vaccines have demonstrated high efficacy, suggesting that the spatial assembly of the vaccine antigen is a critical parameter for inducing an optimal long-lasting protective immune response. We have developed a VLP vaccine display platform by identifying regions of the HPV16 L1 coat protein where a biotin acceptor site (AviTagTM can be inserted without compromising VLP-assembly. Subsequent biotinylation of Avi-L1 VLPs allow us to anchor monovalent streptavidin (mSA-fused proteins to the biotin, thereby obtaining a dense and repetitive VLP-display of the vaccine antigen. The mSA-VAR2CSA antigen was delivered on the Avi-L1 VLP platform and tested in C57BL/6 mice in comparison to two soluble protein-based vaccines consisting of naked VAR2CSA and mSA-VAR2CSA. The mSA-VAR2CSA Avi-L1 VLP and soluble mSA-VAR2CSA vaccines induced higher antibody titers than the soluble naked VAR2CSA vaccine after three immunizations. The VAR2CSA Avi-L1 VLP vaccine induced statistically significantly higher endpoint titres compared to the soluble mSA-VAR2CSA vaccine, after 1st and 2nd immunization; however, this difference was not statistically significant after 3rd immunization. Importantly, the VLP-VAR2CSA induced antibodies were functional in inhibiting the binding of

  3. Screening the Medicines for Malaria Venture "Malaria Box" against the Plasmodium falciparum aminopeptidases, M1, M17 and M18.

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    Alessandro Paiardini

    Full Text Available Malaria is a parasitic disease that remains a global health burden. The ability of the parasite to rapidly develop resistance to therapeutics drives an urgent need for the delivery of new drugs. The Medicines for Malaria Venture have compounds known for their antimalarial activity, but not necessarily the molecular targets. In this study, we assess the ability of the "MMV 400" compounds to inhibit the activity of three metalloaminopeptidases from Plasmodium falciparum, PfA-M1, PfA-M17 and PfM18 AAP. We have developed a multiplex assay system to allow rapid primary screening of compounds against all three metalloaminopeptidases, followed by detailed analysis of promising compounds. Our results show that there were no PfM18AAP inhibitors, whereas two moderate inhibitors of the neutral aminopeptidases PfA-M1 and PfA-M17 were identified. Further investigation through structure-activity relationship studies and molecular docking suggest that these compounds are competitive inhibitors with novel binding mechanisms, acting through either non-classical zinc coordination or independently of zinc binding altogether. Although it is unlikely that inhibition of PfA-M1 and/or PfA-M17 is the primary mechanism responsible for the antiplasmodial activity reported for these compounds, their detailed characterization, as presented in this work, pave the way for their further optimization as a novel class of dual PfA-M1/PfA-M17 inhibitors utilising non-classical zinc binding groups.

  4. Comparison of artesunate and quinine in the treatment of severe Plasmodium falciparum malaria at Kassala hospital, Sudan.

    Science.gov (United States)

    Abdallah, Tajeldin M; Elmardi, Khalid A; Elhassan, Asama H; Omer, Mona B; Elhag, Mousab S; Desogi, Mohamed A; Siddig, Mohammed F; Adam, Ishag

    2014-05-14

    There is a need to investigate the treatment (artesunate and quinine) of severe malaria, as this will influence the outcome of morbidity and the mortality of the disease. An open randomized trial conducted at Kassala, Sudan. Patients with severe P. falciparum malaria were randomly assigned to either intravenous artesunate at 2.4 mg/kg at 0, 12, and 24 hours, then daily, or intravenous quinine at a 20 mg/kg loading dose, then 10 mg/kg three times a day. Fever and parasite clearance and coma resolution time were compared between the two groups . The two groups (47 in each group) were well matched in the clinical and biochemical characteristics. Hypotension, convulsions, severe anemia, hypoglycemia, cerebral malaria, and jaundice were the predominant manifestations of severe malaria. The mean (SD) of the fever clearance (10.8 [5.5] vs. 14.0 [8.1] hours, p = 0.028) and the parasite clearance time (16.5 [6.4] vs. 21.7 [11.3] hours, p = 0.007) were significantly shorter in the artesunate-treated patients. In comatose patients, there was no difference between the two groups in coma resolution time. Following quinine infusion, ten patients developed tinnitus (p quinine, in term of parasite and fever clearance time, in the treatment of P. falciparum malaria in eastern Sudan. The study found no difference between artesunate and quinine in coma resolution time.

  5. Avances más recientes en el desarrollo de vacunas contra la malaria The most recent advances in developing vaccines against malaria

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    Lázara Rojas Rivero

    2005-02-01

    Full Text Available According to reports of the Pan American Health Organization, malaria transmission continues to occur in 21 countries of the Americas. Of the 835 million inhabitants of the Region of the Americas, 293 million live in areas with some possibility of transmission of the disease. The most advanced of the candidate vaccines that have been designed based on the sequences of the circumsporozoite protein, is one based on the RTS,S/AS02A polypeptides of Plasmodium falciparum. A test of that vaccine was conducted in Mozambique with children from 1 to 4 years old. The test proved the vaccine to be safe, well tolerated, and immunogenic, but the level of protection reached was still low. However, the advantages that the RTS,S/AS02A vaccine offers to people who live in malaria-endemic areas justifies its being tested in the Americas in order to evaluate its effectiveness in the clinical and epidemiological conditions specific to the Region.

  6. Efficacies of artesunate plus either sulfadoxine-pyrimethamine or amodiaquine, for the treatment of uncomplicated, Plasmodium falciparum malaria in eastern Sudan

    DEFF Research Database (Denmark)

    Ibrahium, A M; Kheir, M M; Osman, M E

    2007-01-01

    Artemisinin-based combination therapy (ACT) is increasingly being adopted as the first-line treatment for malaria in sub-Saharan Africa. In September-November 2005, in New Halfa, eastern Sudan, the efficacy of artesunate-sulfadoxine-pyrimethamine (AS-SP) for the treatment of uncomplicated...... of uncomplicated, P. falciparum malaria in eastern Sudan....

  7. Genetic diversity of vaccine candidate antigens in Plasmodium falciparum isolates from the Amazon basin of Peru

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    Lucas Carmen M

    2008-05-01

    Full Text Available Abstract Background Several of the intended Plasmodium falciparum vaccine candidate antigens are highly polymorphic and could render a vaccine ineffective if their antigenic sites were not represented in the vaccine. In this study, characterization of genetic variability was performed in major B and T-cell epitopes within vaccine candidate antigens in isolates of P. falciparum from Peru. Methods DNA sequencing analysis was completed on 139 isolates of P. falciparum collected from endemic areas of the Amazon basin in Loreto, Peru from years 1998 to 2006. Genetic diversity was determined in immunological important regions in circumsporozoite protein (CSP, merozoite surface protein-1 (MSP-1, apical membrane antigen-1 (AMA-1, liver stage antigen-1 (LSA-1 and thrombospondin-related anonymous protein (TRAP. Alleles identified by DNA sequencing were aligned with the vaccine strain 3D7 and DNA polymorphism analysis and FST study-year pairwise comparisons were done using the DnaSP software. Multilocus analysis (MLA was performed and average of expected heterozygosity was calculated for each loci and haplotype over time. Results Three different alleles for CSP, seven for MSP-1 Block 2, one for MSP-1 Block 17, three for AMA-1 and for LSA-1 each and one for TRAP were identified. There were 24 different haplotypes in 125 infections with complete locus typing for each gene. Conclusion Characterization of the genetic diversity in Plasmodium isolates from the Amazon Region of Peru showed that P. falciparum T and B cell epitopes in these antigens have polymorphisms more similar to India than to Africa. These findings are helpful in the formulation of a vaccine considering restricted repertoire populations.

  8. Population pharmacokinetic and pharmacodynamic properties of intramuscular quinine in Tanzanian children with severe Falciparum malaria.

    Science.gov (United States)

    Hendriksen, Ilse C E; Maiga, Deogratius; Lemnge, Martha M; Mtove, George; Gesase, Samwel; Reyburn, Hugh; Lindegardh, Niklas; Day, Nicholas P J; von Seidlein, Lorenz; Dondorp, Arjen M; Tarning, Joel; White, Nicholas J

    2013-02-01

    Although artesunate is clearly superior, parenteral quinine is still used widely for the treatment of severe malaria. A loading-dose regimen has been recommended for 30 years but is still often not used. A population pharmacokinetic study was conducted with 75 Tanzanian children aged 4 months to 8 years with severe malaria who received quinine intramuscularly; 69 patients received a loading dose of 20 mg quinine dihydrochloride (salt)/kg of body weight. Twenty-one patients had plasma quinine concentrations detectable at baseline. A zero-order absorption model with one-compartment disposition pharmacokinetics described the data adequately. Body weight was the only significant covariate and was implemented as an allometric function on clearance and volume parameters. Population pharmacokinetic parameter estimates (and percent relative standard errors [%RSE]) of elimination clearance, central volume of distribution, and duration of zero-order absorption were 0.977 liters/h (6.50%), 16.7 liters (6.39%), and 1.42 h (21.5%), respectively, for a typical patient weighing 11 kg. Quinine exposure was reduced at lower body weights after standard weight-based dosing; there was 18% less exposure over 24 h in patients weighing 5 kg than in those weighing 25 kg. Maximum plasma concentrations after the loading dose were unaffected by body weight. There was no evidence of dose-related drug toxicity with the loading dosing regimen. Intramuscular quinine is rapidly and reliably absorbed in children with severe falciparum malaria. Based on these pharmacokinetic data, a loading dose of 20 mg salt/kg is recommended, provided that no loading dose was administered within 24 h and no routine dose was administered within 12 h of admission. (This study has been registered with Current Controlled Trials under registration number ISRCTN 50258054.).

  9. Diversidad genética de Plasmodium falciparum y sus implicaciones en la epidemiología de la malaria.

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    Judy Natalia Jiménez

    2005-12-01

    Full Text Available La diversidad genética le confiere a Plasmodium falciparum la capacidad de evadir la respuesta inmune del hospedero y producir variantes resistentes a medicamentos y a vacunas, aspectos que juegan un papel importante en el establecimiento de medidas de control contra la malaria. Diferentes autores han documentado la existencia de diversas cepas o clones de P. falciparum, cuya diversidad genética se ha confirmado a través de distintos ensayos de PCR (reacción en cadena de la polimerasa. Numerosas investigaciones realizadas en poblaciones con diferente grado de transmisión de malaria han mostrado la relación existente entre la estructura de la población de P. falciparum y la epidemiología de la enfermedad. En este artículo se describen las fases del ciclo de vida en las que los eventos de recombinación originan la diversidad genética de P. falciparum, se revisan los estudios realizados sobre este aspecto en regiones con diferentes grados de endemicidad, así como sobre sus implicaciones en la adquisición de inmunidad y en el desarrollo de medidas de control.

  10. Severe Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition.

    LENUS (Irish Health Repository)

    Larkin, Deirdre

    2009-03-01

    Plasmodium falciparum infection results in adhesion of infected erythrocytes to blood vessel endothelium, and acute endothelial cell activation, together with sequestration of platelets and leucocytes. We have previously shown that patients with severe infection or fulminant cerebral malaria have significantly increased circulatory levels of the adhesive glycoprotein von Willebrand factor (VWF) and its propeptide, both of which are indices of endothelial cell activation. In this prospective study of patients from Ghana with severe (n = 20) and cerebral (n = 13) P. falciparum malaria, we demonstrate that increased plasma VWF antigen (VWF:Ag) level is associated with disproportionately increased VWF function. VWF collagen binding (VWF:CB) was significantly increased in patients with cerebral malaria and severe malaria (medians 7.6 and 7.0 IU\\/ml versus 1.9 IU\\/ml; p<0.005). This increased VWF:CB correlated with the presence of abnormal ultra-large VWF multimers in patient rather than control plasmas. Concomitant with the increase in VWF:Ag and VWF:CB was a significant persistent reduction in the activity of the VWF-specific cleaving protease ADAMTS13 (approximately 55% of normal; p<0.005). Mixing studies were performed using P. falciparum patient plasma and normal pooled plasma, in the presence or absence of exogenous recombinant ADAMTS13. These studies demonstrated that in malarial plasma, ADAMTS13 function was persistently inhibited in a time-dependent manner. Furthermore, this inhibitory effect was not associated with the presence of known inhibitors of ADAMTS13 enzymatic function (interleukin-6, free haemoglobin, factor VIII or thrombospondin-1). These novel findings suggest that severe P. falciparum infection is associated with acute endothelial cell activation, abnormal circulating ULVWF multimers, and a significant reduction in plasma ADAMTS13 function which is mediated at least in part by an unidentified inhibitor.

  11. Efficacy and safety of atovaquone/proguanil compared with mefloquine for treatment of acute Plasmodium falciparum malaria in Thailand.

    Science.gov (United States)

    Looareesuwan, S; Wilairatana, P; Chalermarut, K; Rattanapong, Y; Canfield, C J; Hutchinson, D B

    1999-04-01

    The increasing frequency of therapeutic failures in falciparum malaria underscores the need for novel, rapidly effective antimalarial drugs or drug combinations. Atovaquone and proguanil are blood schizonticides that demonstrate synergistic activity against multi-drug-resistant Plasmodium falciparum in vitro. In an open-label, randomized, controlled clinical trial conducted in Thailand, adult patients with acute P. falciparum malaria were randomly assigned to treatment with atovaquone and proguanil/hydrochloride (1,000 mg and 400 mg, respectively, administered orally at 24-hr intervals for three doses) or mefloquine (750 mg administered orally, followed 6 hr later by an additional 500-mg dose). Efficacy was assessed by cure rate (the percentage of patients in whom parasitemia was eliminated and did not recur during 28 days of follow-up), parasite clearance time (PCT), and fever clearance time (FCT). Safety was assessed by sequential clinical and laboratory assessments for 28 days. Atovaquone/proguanil was significantly more effective than mefloquine (cure rate 100% [79 of 79] vs. 86% [68 of 79]; P proguanil and mefloquine treatments did not differ with respect to PCT (mean = 65 hr versus 74 hr) or FCT (mean = 59 hr versus 51 hr). Adverse events were generally typical of malaria symptoms and each occurred in proguanil group. Transient elevations of liver enzyme levels occurred more frequently in patients treated with atovaquone/proguanil than with mefloquine, but the differences were not significant and values returned to normal by day 28 in most patients. The combination of atovaquone and proguanil was well tolerated and more effective than mefloquine in the treatment of acute uncomplicated multidrug-resistant falciparum malaria in Thailand.

  12. Dual fluorescence labeling of surface-exposed and internal proteins in erythrocytes infected with the malaria parasite Plasmodium falciparum

    DEFF Research Database (Denmark)

    Bengtsson, Dominique C; Sowa, Kordai M P; Arnot, David E

    2008-01-01

    There is a need for improved methods for in situ localization of surface proteins on Plasmodium falciparum-infected erythrocytes to help understand how these antigens are trafficked to, and positioned within, the host cell membrane. This protocol for confocal immunofluorescence microscopy combines...... is discussed here in the context of malaria parasite-infected cells, it can also be modified to visualize the membrane and intracellular distribution of surface and internal proteins in other eukaryotic cells....

  13. Plasmodium falciparum genotypes diversity in symptomatic malaria of children living in an urban and a rural setting in Burkina Faso

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    Konaté Amadou T

    2009-06-01