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Sample records for bcg vaccine

  1. [BCG vaccination in the world].

    Science.gov (United States)

    Toida, I

    2000-01-01

    BCG vaccination programme and BCG vaccination coverage in the world were summarized mainly based on the published informations from official organizations, such as World Health Organization (WHO), International Union Against Tuberculosis and Lung Disease (IUATLD) and Centers for Disease Control and Prevention (CDC). From this review, we can see how widely BCG has been used for the prevention of tuberculosis in the world. In most of the developing countries, especially in Africa, the Americas, and Pacific Region, BCG vaccination is carried out to newborn babies soon after birth by intradermal injection according to the recommendations from WHO, but some of the developing countries in Asia and Europe have their own modified BCG vaccination programmes. In economically developed countries, BCG vaccination programme has been established according to the tuberculosis status of each countries. Some countries have general vaccination policy, and other countries have selected vaccination policy, but there is no country where BCG vaccination is not carried out at all. Among G8 contries, as representatives of the economically developed countries, Japan, United Kingdom, France and Russian Federation have BCG general vaccination policy for the specified age group. In these 4 countries revaccination (s) of BCG are still carried out. In Germany, some provinces have general vaccination policy and some others have selected vaccination policy. In the United States of America, BCG vaccination is recommended to selected high risk infants and health care workers by CDC. There are many debates as for the efficacy and safety of BCG vaccination, and the development of new vaccine better than BCG has been actively discussed and some encouraging results in animal models have been reported from several laboratories. But, there is almost no possibility to be able to use a new vaccine in the routine practice within a couple of years. From the practical point of view, therefore, the operational

  2. Bacillus Calmette-Guerin (BCG) Vaccine

    Science.gov (United States)

    TheraCys® BCG ... TICE® BCG ... WHY is this medicine prescribed?BCG vaccine provides immunity or protection against tuberculosis (TB). The vaccine may be given to persons at high risk of developing TB. ...

  3. Lupus Vulgaris Following Bcg Vaccination

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    R K Pandhi

    1982-01-01

    Full Text Available Three cases of lupus vulgaris developing at the site of BCG vaccination are reported. All the patients had lesions starting before the age of 15 years. Clinically and histologically the lesions ′were indistinguishable from spontaneous lupus vulgarism Treatment with streptomycin and isonicotinic acid hydrazide for 1 year produced complete resolution of lesions.

  4. Tuberculosis: looking beyond BCG vaccines.

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    Mustafa Abu S

    2003-01-01

    Full Text Available Tuberculosis (TB is an infectious disease of international importance and ranks among the top 10 causes of death in the World. About one-third of the world′s population is infected with Mycobacterium tuberculosis. Every year, approximately eight million people develop active disease and two million die of TB. The currently used BCG vaccines have shown variable protective efficacies against TB in different parts of the world. Moreover, being a live vaccine, BCG can be pathogenic in immunocompromised recipients. Therefore, there is an urgent need to develop new vaccines against TB. The comparative genome analysis has revealed the existence of several M. tuberculosis-specific regions that are deleted in BCG. The work carried out to determine the immunological reactivity of proteins encoded by genes located in these regions revealed several major antigens of M. tuberculosis, including the 6 kDa early secreted antigen target (ESAT6. Immunization with ESAT6 and its peptide (aa51-70 protects mice challenged with M. tuberculosis. The protective efficacy of immunization further improves when ESAT6 is recombinantly fused with M. tuberculosis antigen 85B. In addition, ESAT6 delivered as a DNA vaccine is also protective in mice. Whether these vaccines would be safe or not cannot be speculated. The answer regarding the safety and efficacy of these vaccines has to await human trials in different parts of the world.

  5. Tuberculous spondylitis following BCG vaccination

    International Nuclear Information System (INIS)

    Mueller-Miny, H.; Bick, U.; Lengerke, H.J. von; Ritter, J.; Reiser, M.

    1990-01-01

    A case of a rare form of BCG osteomyelitis in the spine is presented. After vaccination, the disease started with a lymphadenitis. Later an abscess extended from the pelvic along the psoas muscles into the retroperitoneum. The soft tissue mass extended paraspinally and epidural involvement was also apparent. The vertebral involvement was detected by CT. The radiological findings are discussed with reference to the literature. (orig.)

  6. Improvement of Thermal Stability of BCG Vaccine

    Science.gov (United States)

    Jahanbakhsh Sefidi, Fatemeh; Kaghazian, Homan; Moradli, Gholam Ali; Hassanzadeh, Seyed Mehdi

    2017-11-01

    Thermal stability (TS) is a part of the BCG vaccine characterization by which the consistency of process in BCG vaccine production could be confirmed. To enhance the TS of the vaccine, some prevalent stabilizers in different concentrations were added to the final formulation of BCG bulk prior to Freeze-drying process. We found a formulation more effective than the current stabilizer for retaining the higher viability of lyophilized BCG vaccine produced by Pasteur Institute of Iran. In the design of experiments using Taguchi method, lactose, trehalose, glucose, dextran, and monosodium glutamate were added to the final formulation of BCG bulk prior to freeze-drying process. Viability of the samples was determined by counting the colony forming unit. Maximum signal-to-noise ratio equal to maximum TS and viability was obtained by adding lactose, dextran, and glutamate in defined concentrations. Adding the stabilizers had a significant impact on TS of BCG vaccine to meet the quality requirements.

  7. Tuberculin Reaction Among Healthy BCG Vaccinated Primary ...

    African Journals Online (AJOL)

    Objective: To assess the Mantoux test reaction pattern in healthy BCG vaccinated Primary School Children aged 6 -10 years in Nnewi, South–East Nigeria. Materials and methods:Four Primary Schools were randomly selected out of 43 government owned primary schools in the town. The entire BCG vaccinated pupils in ...

  8. Nonclinical Development of BCG Replacement Vaccine Candidates

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    Bernd Eisele

    2013-04-01

    Full Text Available The failure of current Mycobacterium bovis bacille Calmette–Guérin (BCG vaccines, given to neonates to protect against adult tuberculosis and the risk of using these live vaccines in HIV-infected infants, has emphasized the need for generating new, more efficacious and safer replacement vaccines. With the availability of genetic techniques for constructing recombinant BCG (rBCG strains containing well-defined gene deletions or insertions, new vaccine candidates are under evaluation at both the preclinical and clinical stages of development. Since most BCG vaccines in use today were evaluated in clinical trials decades ago and are produced by outdated processes, the development of new BCG vaccines offers a number of advantages that include a modern well-defined manufacturing process along with state-of-the-art evaluation of safety and efficacy in target populations. We provide a description of the preclinical development of two novel rBCGs, VPM1002 that was constructed by adding a modified hly gene coding for the protein listeriolysin O (LLO from Listeria monocytogenes and AERAS-422, which carries a modified pfoA gene coding for the protein perfringolysin O (PFO from Clostridium perfringens, and three genes from Mycobacterium tuberculosis. Novel approaches like these should be helpful in generating stable and effective rBCG vaccine candidates that can be better characterized than traditional BCG vaccines.

  9. [BCG vaccine against tuberculosis: its protective effect and vaccination policies].

    Science.gov (United States)

    Pereira, Susan M; Dantas, Odimariles Maria Souza; Ximenes, Ricardo; Barreto, Mauricio L

    2007-09-01

    The BCG vaccine has been in use since 1921, but still arouses controversy and uncertainties. The objective was to analyze the protective effect of the BCG vaccine in its first and second doses and the accompanying vaccination policies. A systematic review of the literature in both English and Spanish was carried out, covering the period 1948 to 2006, using the PubMed database. The main search terms used included BCG vaccine, BCG efficacy, BCG and tuberculosis. The studies were grouped by design, with the main results from the clinic tests, case-control studies and meta-analyses presented separately. The protective effect of the first dose of the BCG vaccine against tuberculosis in its miliary and meningeal forms is high. However, the results vary in relation to the pulmonary form of the disease, with some indicating zero effect and others levels of nearly 80%. Research is being carried out to develop new vaccines that could substitute the BCG or be used as a booster. There are evidences that the protective effect of the BCG vaccine does not increase with a second dose. In spite of its limitations and the expectation that a new tuberculosis vaccine will be developed in the future, the BCG vaccine remains an important tool in controlling the harmful effects of tuberculosis, particularly in countries with medium or high incidence levels of the disease.

  10. Effectiveness of BCG vaccination to aged mice

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    Ito Tsukasa

    2010-09-01

    Full Text Available Abstract Background The tuberculosis (TB still increases in the number of new cases, which is estimated to approach 10 million in 2010. The number of aged people has been growing all over the world. Ageing is one of risk factors in tuberculosis because of decreased immune responses in aged people. Mycobacterium bovis Bacillus Calmette Guérin (BCG is a sole vaccine currently used for TB, however, the efficacy of BCG in adults is still a matter of debate. Emerging the multidrug resistant Mycobacterium tuberculosis (MDR-TB make us to see the importance of vaccination against TB in new light. In this study, we evaluated the efficacy of BCG vaccination in aged mice. Results The Th1 responses, interferon-γ production and interleukin 2, in BCG inoculated aged mice (24-month-old were comparable to those of young mice (4- to 6-week-old. The protection activity of BCG in aged mice against Mycobacterium tuberculosis H37Rv was also the same as young mice. Conclusion These findings suggest that vaccination in aged generation is still effective for protection against tuberculosis.

  11. BCG lymphadenopathy detected in a BCG-vaccinated infant

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    A.S. Barouni

    2004-05-01

    Full Text Available Large-scale vaccination with BCG, the live attenuated strain of Mycobacterium bovis, is being adopted around the world, although sporadic complications have occurred after the procedure. Lymphadenopathy is not uncommon especially in babies under one year (0.73% of vaccinated infants, but the swelling subsides within 2 months in most cases, with no medical or surgical treatment. Brazil adopted BCG vaccination program earlier in the seventies and by 1995 more than 96% of the infant population received this immunization. We report here the occurrence of lymphadenopathy in a two-year-old child vaccinated with the Brazilian BCG strain. The diagnosis was made using a lymph node biopsy and intestinal aspirates that yielded a positive mycobacterial culture. The isolate was resistant to isoniazid, rifampicin, pyrazinamide and thiophen-2-carbonic acid hydrazide, sensitive to streptomycin, ethambutol, and p-nitrobenzoic acid, and reacted positively to cyclo-serine and negatively to niacin. The pncA gene involved in bacterial activation of pyrazinamide contains in M. bovis a point mutation that renders pyrazinamidase unable to catalyze drug activation. Therefore, this polymorphism is a good option for developing methods to differentiate M. bovis and M. tuberculosis. Taking advantage of this difference we further analyzed the isolates by single-stranded conformation polymorphism electrophoresis of DNA following PCR of the pncA gene. The isolate identity was confirmed by RFLP electrophoretic analysis of the amplified fragment following Eco065I digestion, which selectively cleaves M. tuberculosis DNA. From this result it is proposed that RFLP of pncA gene represents an alternative for differential diagnosis of M. bovis.

  12. BCG coverage and barriers to BCG vaccination in Guinea-Bissau

    DEFF Research Database (Denmark)

    Thysen, Sanne Marie; Byberg, Stine; Pedersen, Marie

    2014-01-01

    BACKGROUND: BCG vaccination is recommended at birth in low-income countries, but vaccination is often delayed. Often 20-dose vials of BCG are not opened unless at least ten children are present for vaccination ("restricted vial-opening policy"). BCG coverage is usually reported as 12-month coverage......, not disclosing the delay in vaccination. Several studies show that BCG at birth lowers neonatal mortality. We assessed BCG coverage at different ages and explored reasons for delay in BCG vaccination in rural Guinea-Bissau. METHODS: Bandim Health Project (BHP) runs a health and demographic surveillance system...... in selected intervention regions. Factors associated with delayed BCG vaccination were evaluated using logistic regression models. Coverage between intervention and control regions were evaluated in log-binomial regression models providing prevalence ratios. RESULTS: Among 3951 children born in 2010...

  13. [BCG vaccination--controversy and compromise].

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    Petrini, B

    2000-11-29

    In Sweden, BCG-vaccination is recommended to certain risk groups only, as the incidence of TB is very low. Children from high-endemic areas, as well as health care personnel, especially those working in risk areas, are the most important target groups. The efficacy of BCG vaccination has varied in different investigations, but early Nordic studies have shown approximately 80 percent protection. Vaccination prevents disseminated but not localized pulmonary disease. There are no data supporting revaccination. Today some Swedish children are vaccinated without a clear indication, due to caretakers' fear of TB. The risk of new infection is very low in Sweden today, and is for all practical purposes limited to the closest family members of affected individuals. If large numbers of refugees from high-endemic countries arrive in Sweden, the epidemiological situation must be closely monitored.

  14. BCG Vaccination: Is there light at end of the Tunnel?

    OpenAIRE

    PARTHASARATHY, A; HITT, Sharma

    2010-01-01

    The first Human BCG Vaccine was developed in 1921.Since 1960s billions of beneficiaries have received the vaccine in almost all the countries of the world .However its efficacy has been rated from 0 - 80% in several studies world over which include large randomized/controlled/case-control studies. Since 1974 BCG vaccine was included in the Expanded Program on Immunization(EPI) benefitting approx. 2 billion infants. Despite controversy BCG vaccine efficacy has been established in preventing he...

  15. Asthmatic Children And Immunological Effects Of BCG Vaccine Key words: Asthmatic children, BCG vaccine

    International Nuclear Information System (INIS)

    Saaed, A.I.

    2011-01-01

    A TH2 screwed immune response is known to play a crucial role in the pathogenesis of allergy, so, preventing the differentiation of TH cells. The TH2 cells are appeared as a logical therapeutic approach to atopic asthma. The purpose of TH1 study was to determine the possible role of BCG vaccine on asthma and whether a TH1 type immune response elicited by BCG immunization could suppress the allergic sensitization in childhood asthma. Seventy asthmatic patients (50 atopic and 20 non-atopic) and fifty healthy individuals were subjected to TH1 study. Tuberculin test was performed for all groups then subjects with positive tuberculin test were excluded. The BCG vaccine was given for all groups with assessment of TH1 and TH2 cytokine response by measuring total IgE, IL-4 (for TH2 response) and INF-γ (for TH1 response). Significant reduction in IgE and IL-4, and elevation in INF-γ were determined in group I (atopic asthma) following BCG vaccination. There was non-significant change observed in IgE and IL-4 levels of group II while significant reduction in IL-4 and significant increase in INF-γ was observed after BCG vaccine

  16. [The practice of BCG vaccination in 1930 s' China].

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    Shi, R S

    2017-07-28

    Wang Liang introduced Bacille-Calmatte-Guerin(BCG) to China in 1933 in order to prevent tuberculosis. He established a BCG laboratory and make BCG strains by himself in Chongqing, and vaccinated children around, until he was forced to stop doing it by the government in November, 1937. In 1938 Shanghai Pasteur Institute was established, and they built a BCG laboratory to promote BCG vaccination in Shanghai, and these actions were insisted during 1940s. But in 1930s the medical profession all over the world was skeptical to BCG efficacy, which impeded the promotion of BCG vaccination in China. Without the collaboration of the government and the national medical profession, tuberculosis problem in China couldn't be improved by the effort of single doctor or an institute.

  17. Localized Hyperuicbosis following BCG Vaccination

    African Journals Online (AJOL)

    \\lzgm'an jouma/of Paediatrics 2003;30:93. An eigl1t—month—0ld Turkish boy presented at theiFatih University. Pursaklar outpatient clinic with excessive hair on his left shoulder. The history was that 15 days after receiving BCGT vaccination at ...

  18. Recombinant BCG: Innovations on an old vaccine. Scope of BCG strains and strategies to improve long lasting memory

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    Adeliane C da Costa

    2014-04-01

    Full Text Available BCG (Bacille Calmette-Guérin, an attenuated vaccine derived from Mycobacterium bovis, is the current vaccine of choice against tuberculosis (TB. Despite its protection against active TB in children, BCG has failed to protect adults against TB infection and active disease development, especially in developing countries where the disease is endemic. Currently, there is a significant effort towards the development of a new TB vaccine. This review article aims to address publications on recombinant BCG (rBCG published in the last 5 years, to highlight the strategies used to develop rBCG, with a focus on the criteria used to improve immunological memory and protection compared with BCG. The literature review was done in April 2013, using the key words tuberculosis, rBCG vaccine and memory. This review discusses the BCG strains and strategies currently used for the modification of BCG, including: overexpression of M. tuberculosis (Mtb immunodominant antigens already present in BCG; gene insertion of immunodominant antigens from Mtb absent in the BCG vaccine; combination of introduction and over expression of genes that are lost during the attenuation process of BCG; BCG modifications for the induction of CD8+ T cell immune responses and cytokines expressing rBCG. Among the vaccines discussed, VPM1002, also called rBCGΔureC::hly, is currently in human clinical trials. Much progress has been made in the effort to improve BCG, with some promising candidates, but considerable work is still required to address functional long-lasting memory.

  19. Prevalence of BCG scar among BCG-vaccinated children in a ...

    African Journals Online (AJOL)

    Background: The burden of tuberculosis is high in Nigeria as in other developing countries. The administration of BCG vaccine to neonates is essential in the control of tuberculosis. A scar usually develops 6 – 8 weeks later at the site of vaccination, which can be used clinically as a proof of vaccination. Not all vaccinated ...

  20. BCG-osis after BCG vaccination in immunocompromised children: Case series and review

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    Soheila Shahmohammadi

    2014-02-01

    Full Text Available Bacillus Calmette Guerin (BCG developed by Albert Calmette and Camille Guerin in France between 1908 and 1921 contained a live attenuated strain of Mycobacterium bovis and was administered worldwide to prevent tuberculosis. BCG vaccination is also administered at birth to all the newborns in Iran. Disseminated BCG infection after BCG vaccination is rare. Here in, we report 2 new cases of disseminated BCGinfection and review 15 additional cases identified from our previous retrospective study during a 5-year period from 2005-2010. All of these reported patients were vaccinated. Impaired immunity was detected in 10 cases (59% including severe combined immunodeficiency, chronic granulomatous disease, Mendelian susceptibility to mycobacterial disease, combined variable immunodeficiency, and HIV infection. Response to therapy was poor among those patients with immune deficiencies, but the overall mortality rate was 32.3%. Disseminated BCG infection is a rare but devastating complication of vaccination. Immune-compromised children are at high risk of developing BCG related complications including regional BCG-itis or disseminated disease; BCG-osis.

  1. Invitro immune responses in children following BCG vaccination

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    Vijayalakshmi V

    2006-01-01

    Full Text Available Introduction: There is still no consensus on the efficacy of BCG vaccine in the prevention of tuberculosis. This study therefore addressed the question of the magnitude of immunity afforded by BCG, by studying the effector mechanisms of protection in children. The main objectives were to assess the degree of immunity conferred by BCG vaccine in children and to identify the most immunogenic antigen(s of BCG by conducting in-vitro studies. Materials and methods: Children in the age-group of 1 to 10 years, were categorized: (A normal, and vaccinated with BCG during the first year, n=45, (B normal, without scar and with no evident history of vaccination, n=31: and (C children admitted in the hospital with a confirmed diagnosis of tuberculosis, n=31. Fractions of BCG were obtained by lysis, sonication, separation by gel chromatography, HPLC and confirmed by SDS-PAGE. In lymphoproliferative assays PBMC were cultured and stimulated with either Concanavalin-A or Tuberculin or the fractions of BCG. Stimulation indices (SI in lymphoproliferation, CD4/CD8 cells, levels of Interferon-γ (IFN- γ in the culture supernatants were measured by ELISA. Results: The vaccinated children displayed significantly high (P< 0.05 mean values of SI in LTT, CD4/CD8 cell ratio against the unfractionated, 67kDa fraction and BCG-CF Ags. While 100% of the vaccinated children had positive lymphoproliferation indices to BCG-CF, only 8.3% of the unvaccinated children were positive. Conclusion: Some of the components of BCG induced a strong Thl cell response in children. These immunogenic antigens were present in the whole cell lysate. The use of BCG vaccine for tuberculosis is worthwhile till a new vaccine is developed.

  2. Bacille Calmette-Guérin (BCG) vaccination at birth and antibody responses to childhood vaccines

    DEFF Research Database (Denmark)

    Nissen, Thomas Nørrelykke; Birk, Nina Marie; Smits, Gaby

    2017-01-01

    Introduction BCG vaccination has been associated with beneficial non-specific effects on child health. Some immunological studies have reported heterologous effects of vaccines on antibody responses to heterologous vaccines. Within a randomised clinical trial of Bacille Calmette-Guérin (BCG......) vaccination at birth, The Danish Calmette Study, we investigated the effect of BCG at birth on the antibody response to the three routine vaccines against DiTeKiPol/Act-Hib and Prevenar 13 in a subgroup of participants. Methods Within 7 days after birth, children were randomised 1:1 to BCG vaccination...... included children (178 BCG; 122 controls), almost all children (>96%) had antibody responses above the protective levels. Overall BCG vaccination at birth did not affect the antibody level. When stratifying by ‘age at randomisation’ we found a possible inducing effect of BCG on antibodies against B...

  3. Persistence of the immune response induced by BCG vaccination

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    Blitz Rose

    2008-01-01

    Full Text Available Abstract Background Although BCG vaccination is recommended in most countries of the world, little is known of the persistence of BCG-induced immune responses. As novel TB vaccines may be given to boost the immunity induced by neonatal BCG vaccination, evidence concerning the persistence of the BCG vaccine-induced response would help inform decisions about when such boosting would be most effective. Methods A randomised control study of UK adolescents was carried out to investigate persistence of BCG immune responses. Adolescents were tested for interferon-gamma (IFN-γ response to Mycobacterium tuberculosis purified protein derivative (M.tb PPD in a whole blood assay before, 3 months, 12 months (n = 148 and 3 years (n = 19 after receiving teenage BCG vaccination or 14 years after receiving infant BCG vaccination (n = 16. Results A gradual reduction in magnitude of response was evident from 3 months to 1 year and from 1 year to 3 years following teenage vaccination, but responses 3 years after vaccination were still on average 6 times higher than before vaccination among vaccinees. Some individuals (11/86; 13% failed to make a detectable antigen-specific response three months after vaccination, or lost the response after 1 (11/86; 13% or 3 (3/19; 16% years. IFN-γ response to Ag85 was measured in a subgroup of adolescents and appeared to be better maintained with no decline from 3 to 12 months. A smaller group of adolescents were tested 14 years after receiving infant BCG vaccination and 13/16 (81% made a detectable IFN-γ response to M.tb PPD 14 years after infant vaccination as compared to 6/16 (38% matched unvaccinated controls (p = 0.012; teenagers vaccinated in infancy were 19 times more likely to make an IFN-γ response of > 500 pg/ml than unvaccinated teenagers. Conclusion BCG vaccination in infancy and adolescence induces immunological memory to mycobacterial antigens that is still present and measurable for at least 14 years in the

  4. BCG: the only available vaccine against tuberculosis: review article

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    Roghayeh Teimourpour

    2017-01-01

    Full Text Available Background: Despite advances in the vaccinology and chemotherapy in the past century, tuberculosis is still responsible for two million deaths every year. Emergence of multi-drug resistant strain and coinfection of TB-HIV make it a serious concern. Treatment and control of tuberculosis is a great health burden in every community. Active tuberculosis in children has very severe consequences especially those who are under 5-years-old, therefore vaccine indication should be taken. Bacille Calmette-Guérin (BCG is a live attenuated strain of Mycobacterium bovis that has been used for providing immunity or protection against tuberculosis (TB. In addition, BCG provides relative protection against leprosy and Buruli ulcer, it also can be used for treatment of bladder cancer. BCG is the most widely administered vaccine around the world. It has been given to over three billion individuals over the past decades. At first it was developed in 1908 at the Pasteur Institute in Lille by Albert Calmette and Camille Guérin. In fact BCG is a strain of Mycobacterium bovis that bear deletion in its genome following too long subculture in special media. Deletion in region of deletion 1 (RD1, a specific region of Mycobacterium bovis genome, has decreased pathogenicity of BCG strain. Following culture of BCG on different media since 1921 make genetic variation in the BCG strains that have specific characteristics. BCG should begin given to only immune-competent individuals and should not be administered to immunocompromised people. This vaccine is not effective in people formerly infected or sensitized with environmental mycobacteria. Previous meta-analysis studies indicate that BCG has variable range of protection from 0 to 80 percent against pulmonary TB, but is very effective against severe disseminated forms such as meningitis and miliary form of TB. Despite many research and develop new generation vaccine against TB, BCG vaccine still remains as the only

  5. Proteomic profile of culture filtrate from the Brazilian vaccine strain Mycobacterium bovis BCG Moreau compared to M. bovis BCG Pasteur

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    Degrave Wim M

    2011-04-01

    Full Text Available Abstract Background Bacille Calmette-Guerin (BCG is currently the only available vaccine against tuberculosis (TB and comprises a heterogeneous family of sub-strains with genotypic and phenotypic differences. The World Health Organization (WHO affirms that the characterization of BCG sub-strains, both on genomic and proteomic levels, is crucial for a better comprehension of the vaccine. In addition, these studies can contribute in the development of a more efficient vaccine against TB. Here, we combine two-dimensional electrophoresis (2DE and mass spectrometry to analyse the proteomic profile of culture filtrate proteins (CFPs from M. bovis BCG Moreau, the Brazilian vaccine strain, comparing it to that of BCG Pasteur. CFPs are considered of great importance given their dominant immunogenicity and role in pathogenesis, being available for interaction with host cells since early infection. Results The 2DE proteomic map of M. bovis BCG Moreau CFPs in the pH range 3 - 8 allowed the identification of 158 spots corresponding to 101 different proteins, identified by MS/MS. Comparison to BCG Pasteur highlights the great similarity between these BCG strains. However, quantitative analysis shows a higher expression of immunogenic proteins such as Rv1860 (BCG1896, Apa, Rv1926c (BCG1965c, Mpb63 and Rv1886c (BCG1923c, Ag85B in BCG Moreau when compared to BCG Pasteur, while some heat shock proteins, such as Rv0440 (BCG0479, GroEL2 and Rv0350 (BCG0389, DnaK, show the opposite pattern. Conclusions Here we report the detailed 2DE profile of CFPs from M. bovis BCG Moreau and its comparison to BCG Pasteur, identifying differences that may provide relevant information on vaccine efficacy. These findings contribute to the detailed characterization of the Brazilian vaccine strain against TB, revealing aspects that may lead to a better understanding of the factors leading to BCG's variable protective efficacy against TB.

  6. Proteomic profile of culture filtrate from the Brazilian vaccine strain Mycobacterium bovis BCG Moreau compared to M. bovis BCG Pasteur.

    Science.gov (United States)

    Berrêdo-Pinho, Marcia; Kalume, Dario E; Correa, Paloma R; Gomes, Leonardo H F; Pereira, Melissa P; da Silva, Renata F; Castello-Branco, Luiz R R; Degrave, Wim M; Mendonça-Lima, Leila

    2011-04-20

    Bacille Calmette-Guerin (BCG) is currently the only available vaccine against tuberculosis (TB) and comprises a heterogeneous family of sub-strains with genotypic and phenotypic differences. The World Health Organization (WHO) affirms that the characterization of BCG sub-strains, both on genomic and proteomic levels, is crucial for a better comprehension of the vaccine. In addition, these studies can contribute in the development of a more efficient vaccine against TB. Here, we combine two-dimensional electrophoresis (2DE) and mass spectrometry to analyse the proteomic profile of culture filtrate proteins (CFPs) from M. bovis BCG Moreau, the Brazilian vaccine strain, comparing it to that of BCG Pasteur. CFPs are considered of great importance given their dominant immunogenicity and role in pathogenesis, being available for interaction with host cells since early infection. The 2DE proteomic map of M. bovis BCG Moreau CFPs in the pH range 3-8 allowed the identification of 158 spots corresponding to 101 different proteins, identified by MS/MS. Comparison to BCG Pasteur highlights the great similarity between these BCG strains. However, quantitative analysis shows a higher expression of immunogenic proteins such as Rv1860 (BCG1896, Apa), Rv1926c (BCG1965c, Mpb63) and Rv1886c (BCG1923c, Ag85B) in BCG Moreau when compared to BCG Pasteur, while some heat shock proteins, such as Rv0440 (BCG0479, GroEL2) and Rv0350 (BCG0389, DnaK), show the opposite pattern. Here we report the detailed 2DE profile of CFPs from M. bovis BCG Moreau and its comparison to BCG Pasteur, identifying differences that may provide relevant information on vaccine efficacy. These findings contribute to the detailed characterization of the Brazilian vaccine strain against TB, revealing aspects that may lead to a better understanding of the factors leading to BCG's variable protective efficacy against TB.

  7. Multi-stage subunit vaccines against Mycobacterium tuberculosis: an alternative to the BCG vaccine or a BCG-prime boost?

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    Khademi, Farzad; Derakhshan, Mohammad; Yousefi-Avarvand, Arshid; Tafaghodi, Mohsen; Soleimanpour, Saman

    2018-01-01

    More than two billion people are latently infected with Mycobacterium tuberculosis. Most tuberculosis (TB)-subunit vaccines currently in various stages of clinical trials are designed for prevention of active TB, but not to prevent reactivation of latent TB-infection. Thus, there is an urgent need for an effective multi-stage vaccine based on early-expressed and latently-expressed antigens that prevents both acute and latent infections. Areas covered: Here, we reviewed the published pre-clinical and clinical studies of multi-stage subunit vaccines against TB, and the protective capacities of the vaccines were compared with BCG, either alone or in combination with different vaccine delivery systems/adjuvants. The results revealed that multi-stage subunit vaccines induced a wide variety of immune-responses to all forms of TB, including CD8 + T-cell-mediated cytolytic and IFN-γ responses comparable to those induced by the BCG. They could potentially be used as a booster vaccine to improve the efficacy of the BCG. Expert commentary: Multi-stage TB-vaccines could boost BCG-primed immunity, decrease bacterial loads and provide efficient protection against progressive TB-infection, especially in the latent phase. These types of vaccines administered before and after TB-infection can act as pre-exposure, post-exposure and even therapeutic vaccines. In the near future, these vaccines could provide a new generation of prime-vaccines or BCG prime-boosters.

  8. Another vaccine, another story: BCG vaccination against tuberculosis in India, 1948 to 1960.

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    Brimnes, Niels

    2011-02-01

    Through an examination of mass BCG vaccination against tuberculosis in India between 1948 and 1960 this article draws attention to the diversity of the history of vaccination. The features of vaccination campaigns often differed from those of the celebrated campaign to eradicate smallpox. Due to differences between smallpox and tuberculosis as well as between the vaccines developed against them, an analysis of BCG mass vaccination against tuberculosis seems particularly well suited for this purpose. Three points of difference are identified. First, in non-Western contexts BCG vaccination procedures were modified to a greater extent than vaccination against smallpox. Second, tuberculosis lacked the drama and urgency of smallpox and BCG vaccination campaigns suffered more from recruitment problems than did the more "heroic" smallpox eradication campaign. Third, the BCG vaccine was contested in medical circles and was much better suited than the vaccine against smallpox as a vehicle for the articulation of concerns about post-colonial modernization.

  9. The immunological effects of oral polio vaccine provided with BCG vaccine at birth

    DEFF Research Database (Denmark)

    Jensen, Kristoffer Jarlov; Karkov, Hanne Sophie; Lund, Najaaraq

    2014-01-01

    BACKGROUND: Vaccines may have non-specific effects. An observational study from Guinea-Bissau suggested that oral polio vaccine at birth (OPV0) provided with Bacillus Calmette-Guérin (BCG) vaccine was associated with down-regulation of the immune response to BCG vaccine 6 weeks later. Based...... BCG alone at birth, and subsequently randomised to have a blood sample taken at 2, 4 or 6 weeks post-randomisation. Excreted levels of cytokines (IL-2, IL-5, IL-10, TNF-α and IFN-γ) were measured from whole blood in vitro stimulations with a panel of recall vaccine antigens (BCG, PPD, OPV), mitogen...

  10. Various ultrasonographic manifestations of Bacille Calmette-Guerin (BCG) lymphadenitis in infants after BCG vaccination

    International Nuclear Information System (INIS)

    Yoon, Choon Sik; Kim, Myung Joon; Lee, Kwang Hun; Kwon, Woo Cheol; Cho, Nariya; Lee, Sung Il; Park, Kae Young; Kim, Dong Jin

    1999-01-01

    To evaluate the various ultrasonographic manifestations of BCG lymphadenitis complicated by BCG vaccination in infants. Among a total of 59 patients of BCG lymphadenitis, we retrospectively evaluated the ultrasonographic findings of five patients (seven involved areas), who were operated and confirmed by histopathology. Three cases were male and two were female and the age range is from 3 months to 9 months (mean: 5.5 months). Among five cases two had only a single lesion and three had multiple lesions, and two of those had multiple lesions at 2 separate locations. All five cases had ipsilateral supraclavicular lesions with same BCG vaccination site and two also had ipsilaeteral axillary lesions. Ultrasonography showed enlarged lymph nodes and heterogeneous hypoechoic changes suggesting internal necrosis or suppurative changes in three cases, but 1 had cystic necrotic change with fluid-fluid level and another had conglomerated mass with intermingled hyper and hypoechoic areas, which were initially suspected to be a tumorous conditions but revealed conglomerated lymph nodes on follow-up ultrasonography and MRI. BCG lymphadenitis is usually located adjacent to a BCG vaccination site, but ultrasonography can show single or multiple lymph node enlargement and various manifestations from homogeneous lymphadenitis to cystic abscess changes and even a mass-like appearance, demonstrating that the evaluation of ultrasonography should be done very carefully.

  11. Non-specific immunity of BCG vaccine: A perspective of BCG immunotherapy

    Directory of Open Access Journals (Sweden)

    Najeeha Talat Iqbal

    2014-01-01

    Full Text Available BCG is a widely used vaccine worldwide for neonates including Pakistan. BCG has more than 90% coverage through the EPI program which was introduced in 1965 in Pakistan. BCG has limited efficacy against the transmissible form of pulmonary tuberculosis in high TB endemic countries. However, BCG vaccination continues in these countries because BCG confers protection against the disseminated form of TB in children. BCG has also shown some protection against leprosy and certain forms of cancers. One reason for such nonspecific protection may be that BCG activates APCs via PAMPS that interacts with TLRs (2, 4 & 8, which initiate the inflammatory cascade thereby recruiting inflammatory cells to the site of infection and providing maturation signals for neutrophils, macrophages and dendritic cells. Such activation may be crucial for restricting the infection at the initial site. Furthermore, activation of the pro-inflammatory cascade also results in expression of adhesion molecules, co-stimulatory molecules as well as MHC class II molecule. MHC class II molecules engage CD4+ cells via the TCR receptor while the adhesion and costimulatory molecules bind to their respective receptors on CD4+ T cells for additional high affinity binding for T cell activation. Although activation of the innate arm may not provide subsequent memory, activation of T cells may introduce a certain level of memory response and therefore, may form a rational basis for BCG immunotherapy. This review, therefore, focuses on the immune activation related to both the innate and adaptive arm of the immune response that has been reported and further explores the utility of BCG immunotherapy related to non TB conditions.

  12. BCG vaccination at birth and early childhood hospitalization

    DEFF Research Database (Denmark)

    Stensballe, Lone Graff; Sørup, Signe; Aaby, Peter

    2017-01-01

    BACKGROUND: The BCG vaccine is administered to protect against tuberculosis, but studies suggest there may also be non-specific beneficial effects upon the infant immune system, reducing early non-targeted infections and atopic diseases. The present randomised trial tested the hypothesis that BCG...... vaccination at birth would reduce early childhood hospitalisation in Denmark, a high-income setting. METHODS: Pregnant women planning to give birth at three Danish hospitals were invited to participate. After parental consent, newborn children were allocated to BCG or no intervention within 7 days of age.......94). The effect was also similar in the two sexes and across study sites. The results were essentially identical in the per-protocol analysis and after adjustment for baseline characteristics. CONCLUSIONS: BCG vaccination at birth did not reduce the risk of hospitalisation for somatic acquired disease until 15...

  13. Recombinant BCG: Innovations on an Old Vaccine. Scope of BCG Strains and Strategies to Improve Long-Lasting Memory

    Science.gov (United States)

    da Costa, Adeliane Castro; Nogueira, Sarah Veloso; Kipnis, André; Junqueira-Kipnis, Ana Paula

    2014-01-01

    Bacille Calmette–Guérin (BCG), an attenuated vaccine derived from Mycobacterium bovis, is the current vaccine of choice against tuberculosis (TB). Despite its protection against active TB in children, BCG has failed to protect adults against TB infection and active disease development, especially in developing countries where the disease is endemic. Currently, there is a significant effort toward the development of a new TB vaccine. This review article aims to address publications on recombinant BCG (rBCG) published in the last 5 years, to highlight the strategies used to develop rBCG, with a focus on the criteria used to improve immunological memory and protection compared with BCG. The literature review was done in April 2013, using the key words TB, rBCG vaccine, and memory. This review discusses the BCG strains and strategies currently used for the modification of BCG, including: overexpression of Mycobacterium tuberculosis (Mtb) immunodominant antigens already present in BCG; gene insertion of immunodominant antigens from Mtb absent in the BCG vaccine; combination of introduction and overexpression of genes that are lost during the attenuation process of BCG; BCG modifications for the induction of CD8+ T-cell immune responses and cytokines expressing rBCG. Among the vaccines discussed, VPM1002, also called rBCGΔureC:hly, is currently in human clinical trials. Much progress has been made in the effort to improve BCG, with some promising candidates, but considerable work is still required to address functional long-lasting memory. PMID:24778634

  14. Foreign body granuloma caused by monosodium glutamate after BCG vaccination.

    Science.gov (United States)

    Chiu, Yao-Kun; Huang, Chao-Cheng; Jeng, Jingyueh; Shiea, Jentaie; Chen, Wei-Jen

    2006-08-01

    We describe a 7-month-old male infant with a foreign body granuloma caused by monosodium glutamate (MSG) after a Bacille Calmette-Guérin (BCG) immunization. A ridged, erythematous, indurated plaque developed over a BCG injection site on his left upper arm 1 month after the first BCG immunization. Biopsy showed multiple noncaseating foreign body granulomas without detectable mycobacteria by both Ziehl-Neelsen stain and polymerase chain reaction assay. Birefringent crystals were identified in the foreign body giant cells with polarized light microscopy. The crystals were further determined to be glutamic acid by the method of fast atom bombardment. Hence, MSG, the only composite of BCG vaccine except the bacillus, was believed to be responsible for the granulomatous foreign body reaction. On review of the literature, we could find no previous report of an adverse reaction of BCG immunization attributable to MSG (glutamic acid).

  15. Comparative Proteomic Profiling of Mycobacterium bovis and BCG Vaccine Strains

    KAUST Repository

    Gao, Ge

    2013-09-01

    BCG is the only licensed human vaccine currently available against TB. Derived from a virulent strain of M. bovis, the vaccine was thought to have struck a balance between reduced virulence and preserved immunogenicity. Nowadays, BCG vaccine strains used in different countries and vaccination programs show clear variations in their genomes and immune protective properties. The aim of this study was to characterize the proteomic profile on Mycobacterium bovis and five BCG strains Pasteur, Tokyo, Danish, Phipps and Birkhaug by Tandem Mass Tag® (TMT®)-labeling quantitative proteomic approach. In total, 420 proteins were identified and 377 of them were quantitated for their relative abundance. We reported the number and relationship of differential expressed proteins in BCG strains compared to M. bovis and investigated their functions by bioinformatics analysis. Several interesting up-regulated and down-regulated protein targets were found. The identified proteins and their quantitative expression profiles provide a basis for further understanding of the cellular biology of M. bovis and BCG vaccine strains, and hopefully would assist in the design of better anti-TB vaccine and drugs.

  16. Variable BCG efficacy in rhesus populations: Pulmonary BCG provides protection where standard intra-dermal vaccination fails.

    Science.gov (United States)

    Verreck, Frank A W; Tchilian, Elma Z; Vervenne, Richard A W; Sombroek, Claudia C; Kondova, Ivanela; Eissen, Okke A; Sommandas, Vinod; van der Werff, Nicole M; Verschoor, Ernst; Braskamp, Gerco; Bakker, Jaco; Langermans, Jan A M; Heidt, Peter J; Ottenhoff, Tom H M; van Kralingen, Klaas W; Thomas, Alan W; Beverley, Peter C L; Kocken, Clemens H M

    2017-05-01

    M.bovis BCG vaccination against tuberculosis (TB) notoriously displays variable protective efficacy in different human populations. In non-human primate studies using rhesus macaques, despite efforts to standardise the model, we have also observed variable efficacy of BCG upon subsequent experimental M. tuberculosis challenge. In the present head-to-head study, we establish that the protective efficacy of standard parenteral BCG immunisation varies among different rhesus cohorts. This provides different dynamic ranges for evaluation of investigational vaccines, opportunities for identifying possible correlates of protective immunity and for determining why parenteral BCG immunisation sometimes fails. We also show that pulmonary mucosal BCG vaccination confers reduced local pathology and improves haematological and immunological parameters post-infection in animals that are not responsive to induction of protection by standard intra-dermal BCG. These results have important implications for pulmonary TB vaccination strategies in the future. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  17. Variable Virulence and Efficacy of BCG Vaccine Strains in Mice and Correlation With Genome Polymorphisms

    Science.gov (United States)

    Zhang, Lu; Ru, Huan-wei; Chen, Fu-zeng; Jin, Chun-yan; Sun, Rui-feng; Fan, Xiao-yong; Guo, Ming; Mai, Jun-tao; Xu, Wen-xi; Lin, Qing-xia; Liu, Jun

    2016-01-01

    Bacille Calmette–Guérin (BCG), an attenuated strain of Mycobacterium bovis, is the only vaccine available for tuberculosis (TB) control. However, BCG is not an ideal vaccine and has two major limitations: BCG exhibits highly variable effectiveness against the development of TB both in pediatric and adult populations and can cause disseminated BCG disease in immunocompromised individuals. BCG comprises a number of substrains that are genetically distinct. Whether and how these genetic differences affect BCG efficacy remains largely unknown. In this study, we performed comparative analyses of the virulence and efficacy of 13 BCG strains, representing different genetic lineages, in SCID and BALB/c mice. Our results show that BCG strains of the DU2 group IV (BCG-Phipps, BCG-Frappier, BCG-Pasteur, and BCG-Tice) exhibit the highest levels of virulence, and BCG strains of the DU2 group II (BCG-Sweden, BCG-Birkhaug) are among the least virulent group. These distinct levels of virulence may be explained by strain-specific duplications and deletions of genomic DNA. There appears to be a general trend that more virulent BCG strains are also more effective in protection against Mycobacterium tuberculosis challenge. Our findings have important implications for current BCG vaccine programs and for future TB vaccine development. PMID:26643797

  18. Cutaneous necrotic ulceration due to BCG re-vaccination

    DEFF Research Database (Denmark)

    Gyldenløve, Mette; Andersen, Ase Bengård; Halkjær, Liselotte Brydensholt

    2012-01-01

    The case report describes a severe local reaction with large cutaneous necrotic ulcer following bacillus Calmette-Guérin (BCG) re-vaccination. This is a very rare adverse event, and only a few reports have been described in the literature.......The case report describes a severe local reaction with large cutaneous necrotic ulcer following bacillus Calmette-Guérin (BCG) re-vaccination. This is a very rare adverse event, and only a few reports have been described in the literature....

  19. Uptake of newly introduced universal BCG vaccination in newborns.

    LENUS (Irish Health Repository)

    Braima, O

    2012-01-31

    Universal neonatal BCG vaccination was discontinued in Cork in 1972. Following an outbreak of TB in 2 creches in the HSE South, a universal BCG vaccination program was re-introduced in October 2008. The aim of this study was to determine the vaccination process (in-hospital and community) and the in-hospital uptake of the vaccine. Following informed parental consent, babies of birth weight > 2.5 Kg were eligible for in-hospital vaccination if they were not: febrile, jaundiced on phototherapy, on antibiotics and if not born to HIV- positive mothers. Parents of babies not vaccinated in-hospital were asked to book an appointment in either of the 2 Cork community clinics. The immunisation nurse collected data on BCG vaccination, prospectively. This study examined vaccination uptakes in-hospital and community over a 6 month period (October 2008 to March 2009). There were 4018 deliveries during the study period. In-hospital consent was declined in only 16 babies (<1%) while the in-hospital vaccination uptake was 80% of total liv births. Although 635 newborns were admitted to the NICU, only 46 (8%) were vaccinated while in the NICU. At least 48% of planned community vaccination has been achieved to date. In conclusion, in-hospital consent was almost universal and vaccination uptake was satisfactory. NICU exclusion criteria accounted for a significant proportion of non-vaccination in-hospital. These criteria need to be readdressed considering that all premature babies are given other routine newborn vaccines at 2 months of age, regardless of weight.

  20. Uptake of newly introduced universal BCG vaccination in newborns.

    LENUS (Irish Health Repository)

    Braima, O

    2010-06-01

    Universal neonatal BCG vaccination was discontinued in Cork in 1972. Following an outbreak of TB in 2 creches in the HSE South, a universal BCG vaccination program was re-introduced in October 2008. The aim of this study was to determine the vaccination process (in-hospital and community) and the in-hospital uptake of the vaccine. Following informed parental consent, babies of birth weight > 2.5 Kg were eligible for in-hospital vaccination if they were not: febrile, jaundiced on phototherapy, on antibiotics and if not born to HIV- positive mothers. Parents of babies not vaccinated in-hospital were asked to book an appointment in either of the 2 Cork community clinics. The immunisation nurse collected data on BCG vaccination, prospectively. This study examined vaccination uptakes in-hospital and community over a 6 month period (October 2008 to March 2009). There were 4018 deliveries during the study period. In-hospital consent was declined in only 16 babies (<1%) while the in-hospital vaccination uptake was 80% of total liv births. Although 635 newborns were admitted to the NICU, only 46 (8%) were vaccinated while in the NICU. At least 48% of planned community vaccination has been achieved to date. In conclusion, in-hospital consent was almost universal and vaccination uptake was satisfactory. NICU exclusion criteria accounted for a significant proportion of non-vaccination in-hospital. These criteria need to be readdressed considering that all premature babies are given other routine newborn vaccines at 2 months of age, regardless of weight.

  1. BCG and BCG/DNAhsp65 vaccinations promote protective effects without deleterious consequences for experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Zorzella-Pezavento, Sofia Fernanda Gonçalves; Guerino, Clara Pires Fujiara; Chiuso-Minicucci, Fernanda; França, Thais Graziela Donegá; Ishikawa, Larissa Lumi Watanabe; Masson, Ana Paula; Silva, Célio Lopes; Sartori, Alexandrina

    2013-01-01

    A prime-boost strategy conserving BCG is considered the most promising vaccine to control tuberculosis. A boost with a DNA vaccine containing the mycobacterial gene of a heat shock protein (pVAXhsp65) after BCG priming protected mice against experimental tuberculosis. However, anti-hsp65 immunity could worsen an autoimmune disease due to molecular mimicry. In this investigation, we evaluated the effect of a previous BCG or BCG/pVAXhsp65 immunization on experimental autoimmune encephalomyelitis (EAE) development. Female Lewis rats were immunized with BCG or BCG followed by pVAXhsp65 boosters. The animals underwent EAE induction and were daily evaluated for weight loss and clinical score. They were euthanized during recovery phase to assess immune response and inflammatory infiltration at the central nervous system. Previous immunization did not aggravate or accelerate clinical score or weight loss. In addition, this procedure clearly decreased inflammation in the brain. BCG immunization modulated the host immune response by triggering a significant reduction in IL-10 and IFN-γ levels induced by myelin basic protein. These data indicated that vaccination protocols with BCG or BCG followed by boosters with pVAXhsp65 did not trigger a deleterious effect on EAE evolution.

  2. BCG and BCG/DNAhsp65 Vaccinations Promote Protective Effects without Deleterious Consequences for Experimental Autoimmune Encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Sofia Fernanda Gonçalves Zorzella-Pezavento

    2013-01-01

    Full Text Available A prime-boost strategy conserving BCG is considered the most promising vaccine to control tuberculosis. A boost with a DNA vaccine containing the mycobacterial gene of a heat shock protein (pVAXhsp65 after BCG priming protected mice against experimental tuberculosis. However, anti-hsp65 immunity could worsen an autoimmune disease due to molecular mimicry. In this investigation, we evaluated the effect of a previous BCG or BCG/pVAXhsp65 immunization on experimental autoimmune encephalomyelitis (EAE development. Female Lewis rats were immunized with BCG or BCG followed by pVAXhsp65 boosters. The animals underwent EAE induction and were daily evaluated for weight loss and clinical score. They were euthanized during recovery phase to assess immune response and inflammatory infiltration at the central nervous system. Previous immunization did not aggravate or accelerate clinical score or weight loss. In addition, this procedure clearly decreased inflammation in the brain. BCG immunization modulated the host immune response by triggering a significant reduction in IL-10 and IFN-γ levels induced by myelin basic protein. These data indicated that vaccination protocols with BCG or BCG followed by boosters with pVAXhsp65 did not trigger a deleterious effect on EAE evolution.

  3. Oral polio vaccine influences the immune response to BCG vaccination. A natural experiment.

    Science.gov (United States)

    Sartono, Erliyani; Lisse, Ida M; Terveer, Elisabeth M; van de Sande, Paula J M; Whittle, Hilton; Fisker, Ane B; Roth, Adam; Aaby, Peter; Yazdanbakhsh, Maria; Benn, Christine S

    2010-05-21

    Oral polio vaccine (OPV) is recommended to be given at birth together with BCG vaccine. While we were conducting two trials including low-birth-weight (LBW) and normal-birth-weight (NBW) infants in Guinea-Bissau, OPV was not available during some periods and therefore some infants did not receive OPV at birth, but only BCG. We investigated the effect of OPV given simultaneously with BCG at birth on the immune response to BCG vaccine. We compared the in vitro and the in vivo response to PPD in the infants who received OPV and BCG with that of infants who received BCG only. At age 6 weeks, the in vitro cytokine response to purified protein derivate (PPD) of M. Tuberculosis was reduced in LBW and NBW infants who had received OPV with BCG. In a pooled analysis receiving OPV with BCG at birth was associated with significantly lower IL-13 (p = 0.041) and IFN-gamma (p = 0.004) and a tendency for lower IL-10 (p = 0.054) in response to PPD. Furthermore, OPV was associated with reduced in vivo response to PPD at age 2 months, the prevalence ratio (PR) of having a PPD reaction being 0.75 (0.58-0.98), p = 0.033, and with a tendency for reduced likelihood of having a BCG scar (0.95 (0.91-1.00), p = 0.057)). Among children with a scar, OPV was associated with reduced scar size, the regression coefficient being -0.24 (-0.43-0.05), p = 0.012. This study is the first to address the consequences for the immune response to BCG of simultaneous administration with OPV. Worryingly, the results indicate that the common practice in low-income countries of administering OPV together with BCG at birth may down-regulate the response to BCG vaccine.

  4. Oral polio vaccine influences the immune response to BCG vaccination. A natural experiment.

    Directory of Open Access Journals (Sweden)

    Erliyani Sartono

    Full Text Available BACKGROUND: Oral polio vaccine (OPV is recommended to be given at birth together with BCG vaccine. While we were conducting two trials including low-birth-weight (LBW and normal-birth-weight (NBW infants in Guinea-Bissau, OPV was not available during some periods and therefore some infants did not receive OPV at birth, but only BCG. We investigated the effect of OPV given simultaneously with BCG at birth on the immune response to BCG vaccine. METHODS AND FINDINGS: We compared the in vitro and the in vivo response to PPD in the infants who received OPV and BCG with that of infants who received BCG only. At age 6 weeks, the in vitro cytokine response to purified protein derivate (PPD of M. Tuberculosis was reduced in LBW and NBW infants who had received OPV with BCG. In a pooled analysis receiving OPV with BCG at birth was associated with significantly lower IL-13 (p = 0.041 and IFN-gamma (p = 0.004 and a tendency for lower IL-10 (p = 0.054 in response to PPD. Furthermore, OPV was associated with reduced in vivo response to PPD at age 2 months, the prevalence ratio (PR of having a PPD reaction being 0.75 (0.58-0.98, p = 0.033, and with a tendency for reduced likelihood of having a BCG scar (0.95 (0.91-1.00, p = 0.057. Among children with a scar, OPV was associated with reduced scar size, the regression coefficient being -0.24 (-0.43-0.05, p = 0.012. CONCLUSIONS: This study is the first to address the consequences for the immune response to BCG of simultaneous administration with OPV. Worryingly, the results indicate that the common practice in low-income countries of administering OPV together with BCG at birth may down-regulate the response to BCG vaccine.

  5. Post-Vaccination disseminated BCG infection in an 8-month-old infant

    Directory of Open Access Journals (Sweden)

    fariba Tarhani

    2004-06-01

    Conclusions: Although the BCG vaccine has been in use since 1921 and its protective effect for disseminated, meningial and pulmonary tuberculosis is clear, controversy continues around its use. The most serious complication of BCG vaccine is a disseminated BCG infection that may lead to death.

  6. BCG vaccination scar associated with better childhood survival in Guinea-Bissau

    DEFF Research Database (Denmark)

    Roth, Adam Anders Edvin; Gustafson, Per; Nhaga, Alexandro

    2005-01-01

    Recent studies have suggested that Bacille Calmette-Guerin (BCG) vaccination may have a non-specific beneficial effect on infant survival and that a BCG scar may be associated with lower child mortality. No study has previously examined the influence of BCG vaccination on cause of death....

  7. Mycobacterium bovis BCG vaccine induces non-specific immune responses in Japanese flounder against Nocardia seriolae.

    Science.gov (United States)

    Kato, Goshi; Kondo, Hidehiro; Aoki, Takashi; Hirono, Ikuo

    2012-08-01

    Nocardiosis caused by Nocardia seriolae has been causing severe loss of fish production, so that an effective vaccine is urgently needed. Mycobacterium bovis BCG (BCG) is a live attenuated vaccine for tuberculosis, which is effective against various infectious diseases including nocardiosis in mammals. In this study, the protective efficacy of BCG against N. seriolae was evaluated in Japanese flounder Paralichthys olivaceus and antigen-specific immune responses induced in BCG vaccinated fish were investigated. Cumulative mortality of BCG-vaccinated fish was 21.4% whereas that of PBS-injected fish was 56.7% in N. seriolae challenge. However, gene expression level of IFN-γ was only slightly up-regulated in BCG-vaccinated fish after injection of N. seriolae antigen. In order to reveal non-specific immune responses induced by BCG vaccination, transcriptome of the kidney after BCG vaccination was investigated using oligo DNA microarray. Gene expression levels of antimicrobial peptides such as C-type and G-type lysozyme were significantly up-regulated after BCG vaccination. Consistently, BCG vaccination appeared to increase the bacteriolysis activity of the serum against Micrococcus luteus and N. seriolae. These results suggest that BCG-vaccinated Japanese flounder fight N. seriolae infection mainly by non-specific immune responses such as by the production of bacteriolytic lysozymes. Copyright © 2012 Elsevier Ltd. All rights reserved.

  8. Dendritic Cell Activity Driven by Recombinant Mycobacterium bovis BCG Producing Human IL-18, in Healthy BCG Vaccinated Adults

    Directory of Open Access Journals (Sweden)

    Piotr Szpakowski

    2015-01-01

    Full Text Available Tuberculosis remains an enormous global burden, despite wide vaccination coverage with the Bacillus Calmette-Guérin (BCG, the only vaccine available against this disease, indicating that BCG-driven immunity is insufficient to protect the human population against tuberculosis. In this study we constructed recombinant BCG producing human IL-18 (rBCGhIL-18 and investigated whether human IL-18 produced by rBCGhIL-18 modulates DC functions and enhances Th1 responses to mycobacterial antigens in humans. We found that the costimulatory CD86 and CD80 molecules were significantly upregulated on rBCGhIL-18-infected DCs, whereas the stimulation of DCs with nonrecombinant BCG was less effective. In contrast, both BCG strains decreased the DC-SIGN expression on human DCs. The rBCGhIL-18 increased IL-23, IL-10, and IP-10 production by DCs to a greater extent than nonrecombinant BCG. In a coculture system of CD4+ T cells and loaded DCs, rBCGhIL-18 favoured strong IFN-γ but also IL-10 production by naive T cells but not by memory T cells. This was much less the case for nonrecombinant BCG. Thus the expression of IL-18 by recombinant BCG increases IL-23, IP-10, and IL-10 expression by human DCs and enhances their ability to induce IFN-γ and IL-10 expression by naive T cells, without affecting the maturation phenotype of the DCs.

  9. Vitamin A supplementation and BCG vaccination at birth may affect atopy in childhood

    DEFF Research Database (Denmark)

    Kiraly, N; Benn, Christine Stabell; Biering-Sørensen, S

    2013-01-01

    Recent evidence suggests that immunogenic interventions such as vaccines and micronutrients may affect atopic sensitization and atopic disease. We aimed to determine whether neonatal BCG vaccination, vitamin A supplementation and other vaccinations affect atopy in childhood....

  10. Immune response profiles of calves following vaccination with live BCG and inactivated Mycobacterium bovis vaccine candidates.

    Directory of Open Access Journals (Sweden)

    E M D L van der Heijden

    Full Text Available Conventional control and eradication strategies for bovine tuberculosis (BTB face tremendous difficulties in developing countries; countries with wildlife reservoirs, a complex wildlife-livestock-human interface or a lack of veterinary and veterinary public health surveillance. Vaccination of cattle and other species might in some cases provide the only suitable control strategy for BTB, while in others it may supplement existing test-and-slaughter schemes. However, the use of live BCG has several limitations and the global rise of HIV/AIDS infections has furthermore warranted the exploration of inactivated vaccine preparations. The aim of this study was to compare the immune response profiles in response to parenteral vaccination with live BCG and two inactivated vaccine candidates in cattle. Twenty-four mixed breed calves (Bos taurus aged 4-6 months, were allocated to one of four groups and vaccinated sub-cutaneously with live M. bovis BCG (Danish 1331, formalin-inactivated M. bovis BCG, heat-killed M. bovis or PBS/Montanide™ (control. Interferon-γ responsiveness and antibody production were measured prior to vaccination and at weekly intervals thereafter for twelve weeks. At nine weeks post-priming, animals were skin tested using tuberculins and MTBC specific protein cocktails and subsequently challenged through intranodular injection of live M. bovis BCG. The animals in the heat-killed M. bovis group demonstrated strong and sustained cell-mediated and humoral immune responses, significantly higher than the control group in response to vaccination, which may indicate a protective immune profile. Animals in this group showed reactivity to the skin test reagents, confirming good vaccine take. Lastly, although not statistically significant, recovery of BCG after challenge was lowest in the heat-killed M. bovis group. In conclusion, the parenteral heat-killed M. bovis vaccine proved to be clearly immunogenic in cattle in the present study

  11. Neonatal BCG vaccination influences cytokine responses to Toll-like receptor ligands and heterologous antigens.

    Science.gov (United States)

    Freyne, B; Donath, S; Germano, S; Gardiner, K; Casalaz, D; Robins-Browne, R M; Amenyogbe, N; Messina, N L; Netea, M G; Flanagan, K L; Kollmann, T; Curtis, N

    2018-02-03

    Bacille Calmette-Guérin (BCG) vaccination is associated with a reduction in all-cause infant mortality in high-mortality settings. The underlying mechanisms remain uncertain but long-term modulation of the innate immune response (trained immunity) may be involved. Whole blood, collected 7 days post randomisation from 212 neonates enrolled in a randomised trial of neonatal BCG vaccination, was stimulated with killed pathogens and Toll-like receptor (TLR) ligands to interrogate cytokine responses. BCG-vaccinated infants had increased production of IL-6 in unstimulated samples and decreased production of IL-1ra, IL-6, and IL-10 and the chemokines MIP-1α, MIP-1β, MCP-1 following stimulation with peptidoglycan (TLR2) and R848 (TLR7/8). BCG-vaccinated infants also had decreased MCP-1 responses following stimulation with heterologous pathogens. Sex and maternal BCG vaccination status interacted with neonatal BCG vaccination. Neonatal BCG vaccination influences cytokine responses to TLR ligands and heterologous pathogens. This effect is characterised by decreased anti-inflammatory cytokine and chemokine responses in the context of higher levels of IL-6 in unstimulated samples. This supports the hypothesis that BCG vaccination modulates the innate immune system. Further research is warranted to determine if there is an association between these findings and the beneficial non-specific (heterologous) effects of BCG vaccine on all-cause mortality.

  12. BCG vaccination at birth and early childhood hospitalisation

    DEFF Research Database (Denmark)

    Stensballe, Lone Graff; Sørup, Signe; Aaby, Peter

    2017-01-01

    vaccination at birth would reduce early childhood hospitalisation in Denmark, a high-income setting. METHODS: Pregnant women planning to give birth at three Danish hospitals were invited to participate. After parental consent, newborn children were allocated to BCG or no intervention within 7 days of age....... Randomisation was stratified by prematurity. The primary study outcome was number of all-cause hospitalisations analysed as repeated events. Hospitalisations were identified using The Danish National Patient Register. Data were analysed by Cox proportional hazards models in intention-to-treat and per...... compared with 1003 hospitalisations among 2133 control children (mean 0.47), resulting in a HR comparing BCG versus no BCG of 1.05 (95% CI 0.93 to 1.18) (intention-to-treat analysis). The effect of BCG was the same in children born at term (1.05 (0.92 to 1.18)) and prematurely (1.07 (0.63 to 1.81), p=0...

  13. Bacille Calmette-Guerin (BCG) vaccination at birth and antibody responses to childhood vaccines. A randomised clinical trial

    NARCIS (Netherlands)

    Nissen, T.N.; Birk, N.M.; Smits, G.; Jeppesen, D.L.; Stensballe, L.G.; Netea, M.G.; Klis, F. van der; Benn, C.S.; Pryds, O.

    2017-01-01

    INTRODUCTION: BCG vaccination has been associated with beneficial non-specific effects on child health. Some immunological studies have reported heterologous effects of vaccines on antibody responses to heterologous vaccines. Within a randomised clinical trial of Bacille Calmette-Guerin (BCG)

  14. Development of a BCG challenge model for the testing of vaccine candidates against tuberculosis in cattle.

    Science.gov (United States)

    Villarreal-Ramos, Bernardo; Berg, Stefan; Chamberlain, Laura; McShane, Helen; Hewinson, R Glyn; Clifford, Derek; Vordermeier, Martin

    2014-09-29

    Vaccination is being considered as part of a sustainable strategy for the control of bovine tuberculosis (BTB) in the UK. The live attenuated Mycobacterium bovis bacillus Calmette-Guerin (BCG) has been used experimentally to vaccinate cattle against BTB. However, BCG confers partial protection against BTB and therefore, there is a need to develop improved vaccines. BTB vaccine efficacy experiments require the use of biosafety level 3 facilities which are expensive to maintain, generally oversubscribed and represent a bottle neck for the testing of vaccine candidates. One indicator of the induction of protective responses would be the ability of the host's immune response to control/kill mycobacteria. In this work we have evaluated an intranodal BCG challenge for the selection of vaccine candidates at biosafety level 2 which are capable of inducing mycobactericidal responses. To our knowledge, this is the first such report. Whilst BCG only confers partial protection, it is still the standard against which other vaccines are judged. Therefore we tested the BCG intranodal challenge in BCG (Danish strain) vaccinated cattle and showed that vaccinated cattle had lower BCG cfu counts than naïve cattle at 14 and 21 days after intranodal challenge with BCG (Tokyo strain). This model could help prioritize competing TB vaccine candidates and exploration of primary and secondary immune responses to mycobacteria. Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.

  15. Oral Polio Vaccine Influences the Immune Response to BCG Vaccination. A Natural Experiment

    DEFF Research Database (Denmark)

    Sartono, E.; Lisse, I.M.; Terveer, E.M.

    2010-01-01

    not receive OPV at birth, but only BCG. We investigated the effect of OPV given simultaneously with BCG at birth on the immune response to BCG vaccine. Methods and Findings: We compared the in vitro and the in vivo response to PPD in the infants who received OPV and BCG with that of infants who received BCG...... scar (0.95 (0.91-1.00), p = 0.057)). Among children with a scar, OPV was associated with reduced scar size, the regression coefficient being -0.24 (-0.43-0.05), p = 0.012. Conclusions: This study is the first to address the consequences for the immune response to BCG of simultaneous administration...... only. At age 6 weeks, the in vitro cytokine response to purified protein derivate (PPD) of M. Tuberculosis was reduced in LBW and NBW infants who had received OPV with BCG. In a pooled analysis receiving OPV with BCG at birth was associated with significantly lower IL-13 (p = 0.041) and IFN-gamma (p...

  16. Oral Polio Vaccine Influences the Immune Response to BCG Vaccination. A Natural Experiment

    DEFF Research Database (Denmark)

    Sartono, E.; Lisse, I.M.; Terveer, E.M.

    2010-01-01

    Background: Oral polio vaccine (OPV) is recommended to be given at birth together with BCG vaccine. While we were conducting two trials including low-birth-weight (LBW) and normal-birth-weight (NBW) infants in Guinea-Bissau, OPV was not available during some periods and therefore some infants did...

  17. Oral polio vaccine influences the immune response to BCG vaccination. A natural experiment

    DEFF Research Database (Denmark)

    Sartono, Erliyani; Lisse, Ida M; Terveer, Elisabeth M

    2010-01-01

    BACKGROUND: Oral polio vaccine (OPV) is recommended to be given at birth together with BCG vaccine. While we were conducting two trials including low-birth-weight (LBW) and normal-birth-weight (NBW) infants in Guinea-Bissau, OPV was not available during some periods and therefore some infants did...

  18. [Severe adverse reactions after vaccination with Japanese BCG vaccine: a review].

    Science.gov (United States)

    Toida, Ichiro; Nakata, Shizuko

    2007-11-01

    Japanese BCG vaccine has been admitted by the quality control of World Health Organization (WHO) as the safest BCG vaccine in the world. Even though, BCG, as a live bacterial vaccine, inevitably causes dissemination beyond vaccination site and regional lymph-nodes to various part of the body under certain special conditions. We tried to review the clinical features and immunological status of the cases in which "severe" adverse reactions had developed after vaccination with Japanese freeze-dried BCG vaccine prepared from BCG substrain Tokyo. "Severe" adverse reaction was arbitrarily defined as the adverse reactions of clinical significance developed beyond vaccination site and regional ipsilateral axillary lymph-nodes. By the extensive search of the literatures, 39 cases were identified since 1951 when vaccination with freeze-dried BCG vaccine became compulsory by the Tuberculosis Prevention Law in Japan. Incidence rate was calculated as 0.0182 cases per 100,000 vaccinations. Clinical manifestations of bone and joint were reported in 27 cases (multiple sites: 15 cases, single site: 12 cases), abnormalities in chest X-ray in 13 cases, skin manifestations in 17 cases, diseases in other sites or organs in 8 cases. Most of the cases had lesions in multiple organs. Among these 39 cases, 13 had been diagnosed to have some types of primary immunodeficiency (5 cases: chronic granulomatous disease (CGD); 4 cases: severe combined immunodeficiency (SCID); 4 cases: IFN-gamma receptor 1 deficiency). Further, unidentified defects in cellular immunity were reported in other 6 cases. Death was reported in 6 cases, but in two cases the causes of death were the infections due to different pathogens, namely, pulmonary abscess due to Staphylococcus sp. and bacteremia due to Pseudomonas aeruginosa, respectively, and in only one case death was evidenced as due to disseminated BCG infection by autopsy. All of 6 death cases had some type of immunodeficiency. Apart from fatal cases

  19. Vaccination against M. tuberculosis – what next after BCG?

    Directory of Open Access Journals (Sweden)

    Marek Fol

    2011-01-01

    Full Text Available Tuberculosis (TB still remains a huge global health problem. An increase in TB has been observed in many parts of the world, especially in poor and densely populated sub-Saharan Africa and Asia. Tuberculosis affects not only the developing countries but also the relatively wealthy regions of Europe, particularly Eastern Europe, where drug-resistant mycobacterial strains are increasingly reported.Control of tuberculosis expansion is very difficult. It requires the long-term use of anti-mycobacterial drugs. Additionally, the HIV epidemic and the phenomenon of multi-drug resistance are assumed to be responsible for the increase in TB cases. Therefore the most reasonable form of anti-TB protection seems to be effective vaccination.At the beginning of the twentieth century the BCG vaccine was introduced into general use as the first and so far the only immune protector against tuberculosis. Now it is known that this vaccine is not powerful enough and induces protection at a relatively low level. Hence ongoing research on the development of a more powerful anti-mycobacterial vaccine is still needed. Many of the new formulations are in phase II or III of clinical trials and the results are promising. The search for new vaccines involves several strategies: modified virulence-attenuated [i]Mycobacterium tuberculosis[/i] strains, recombination of attenuated M. bovis BCG bacilli, immunogenic mycobacterial proteins and DNA encoding selected proteins as well as unrelated microorganisms used as carriers of mycobacterial antigens. The wide range of concepts is extremely important because new vaccines should serve for immunization of the broadest possible population, not only healthy individuals but also those who are immunocompromised.

  20. BCG vaccine powder-laden and dissolvable microneedle arrays for lesion-free vaccination.

    Science.gov (United States)

    Chen, Fan; Yan, Qinying; Yu, Yang; Wu, Mei X

    2017-06-10

    Live attenuated Bacille Calmette-Guerin (BCG) bacillus is the only licensed vaccine for tuberculosis prevention worldwide to date. It must be delivered intradermally to be effective, which causes severe skin inflammation and sometimes, permanent scars. To minimize the side effects, we developed a novel microneedle array (MNA) that could deliver live attenuated freeze-dried BCG powder into the epidermis in a painless, lesion-free, and self-applicable fashion. The MNA was fabricated with biocompatible and dissolvable hyaluronic acid with a deep cave formed in the basal portion of each microneedle, into which BCG powder could be packaged directly. Viability of BCG vaccine packaged in the caves and the mechanical strength of the powder-laden MNA did not alter significantly before and after more than two months of storage at room temperature. Following insertion of the MNA into the skin, individual microneedle shafts melted away by interstitial fluid from the epidermis and upper dermis, exposing the powder to epidermal tissues. The powder sucked interstitial fluid, dissolved slowly, and diffused into the epidermis in a day against the interstitial fluid influx. Vaccination with BCG-MNA caused no overt skin irritation, in marked contrast to intradermal vaccination that provoked severe inflammation and bruise. While causing little skin irritation, vaccination efficacy of BCG-MNAs was comparable to that of intradermal immunization whether it was evaluated by humoral or cellular immunity. This powder-laden and dissolvable MNA represents a novel technology to sufficiently deliver live attenuated vaccine powders into the skin. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Vacina BCG contra tuberculose: efeito protetor e políticas de vacinação BCG vaccine against tuberculosis: its protective effect and vaccination policies

    Directory of Open Access Journals (Sweden)

    Susan M Pereira

    2007-09-01

    Full Text Available OBJETIVO: A vacina BCG é utilizada desde 1921, embora ainda apresente controvérsias e aspectos não esclarecidos. O objetivo do artigo foi analisar aspectos relacionados ao efeito protetor da primeira e segunda doses da vacina BCG e as políticas de vacinação adotadas. MÉTODOS: Foi realizada revisão sistemática da literatura publicada em inglês e espanhol, abrangendo o período compreendido entre 1948 e 2006, na base PubMed. Os principais descritores utilizados foram BCG vaccine, BCG efficacy, BCG e tuberculosis. Os estudos foram agrupados por tipo de desenho, apresentando-se separadamente os principais resultados de ensaios clínicos, estudos de caso-controle e metanálises. RESULTADOS: O efeito protetor da primeira dose da vacina BCG contra a tuberculose na forma miliar ou na meningite é elevado. No entanto, os resultados são discordantes em relação à forma pulmonar, variando de ausência de efeito a níveis próximos a 80%. Estão sendo conduzidas pesquisas sobre novas vacinas candidatas a substituir a BCG ou serem utilizadas como reforço. CONCLUSÕES: Há evidências de que a segunda dose da BCG não aumenta o seu efeito protetor. Apesar de seus limites e da expectativa futura de nova vacina para tuberculose, a vacina BCG mantém-se como importante instrumento no controle dos efeitos danosos da doença, sobretudo em países com taxas de incidência médias e elevadas.OBJECTIVE: The BCG vaccine has been in use since 1921, but still arouses controversy and uncertainties. The objective was to analyze the protective effect of the BCG vaccine in its first and second doses and the accompanying vaccination policies. METHODS: A systematic review of the literature in both English and Spanish was carried out, covering the period 1948 to 2006, using the PubMed database. The main search terms used included BCG vaccine, BCG efficacy, BCG and tuberculosis. The studies were grouped by design, with the main results from the clinic tests, case

  2. Ipr1 modified BCG as a novel vaccine induces stronger immunity than BCG against tuberculosis infection in mice.

    Science.gov (United States)

    Wang, Yuwei; Yang, Chun; He, Yonglin; Zhan, Xingxing; Xu, Lei

    2016-08-01

    Tuberculosis is a major challenge to global public health. However, the Bacille Calmette‑Guérin (BCG), the only vaccine available against tuberculosis, has been questioned for the low protective effect. The present study used the mouse gene intracellular pathogen resistance I (Ipr1) gene to alter the current BCG vaccine and evaluated its immunity effect against tuberculosis. This study also investigated the intrinsic relationships of Ipr1 and innate immunity. The reformed BCG (BCGi) carrying the Ipr1 gene was constructed. The mice were intranasally challenged with the M. tuberculosis H37Rv strain after vaccination with BCGi. Protection efficacy of the vaccine was assessed by the organ coefficient, bacterial load and pathological changes in the lung. The differential expression of 113 immune‑related genes between BCGi and BCG groups were detected by an oligo microarray. According to the results of organ coefficient, bacterial load and pathological changes in the organization, BCGi had been shown to have stronger protective effects against M. tuberculosis than BCG. The oligo microarray and reverse transcription‑quantitative polymerase chain reaction further revealed that the Ipr1 gene could upregulate the expression of 13 genes, including a >3‑fold increase in Toll‑like receptor (TLR)4 and 10‑fold increase in surfactant protein D (sftpd). The two genes not only participate in innate immunity against pathogens, but also are closely interrelated. Ipr1 could activate the TLR4 and sftpd signaling pathway and improve the innate immunity against tuberculosis, therefore Ipr1 modified BCG may be a candidate vaccine against M. tuberculosis.

  3. Loss of Lipid Virulence Factors Reduces the Efficacy of the BCG Vaccine

    Science.gov (United States)

    Tran, Vanessa; Ahn, Sang Kyun; Ng, Mark; Li, Ming; Liu, Jun

    2016-01-01

    Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, is the only vaccine available for tuberculosis (TB) control. BCG comprises a number of substrains that exhibit genetic and biochemical differences. Whether and how these differences affect BCG efficacy remain unknown. Compared to other BCG strains, BCG-Japan, -Moreau, and -Glaxo are defective in the production of phthiocerol dimycocerosates (PDIMs) and phenolic glycolipids (PGLs), two lipid virulence factors. To determine if the loss of PDIMs/PGLs affects BCG efficacy, we constructed a PDIM/PGL-deficient strain of BCG-Pasteur by deleting fadD28, and compared virulence, immunogenicity, and protective efficacy in animal models. SCID mouse infection experiments showed that ∆fadD28 was more attenuated than wild type (WT). The ∆fadD28 and WT strains induced equivalent levels of antigen specific IFN-γ by CD4+ and CD8+ T cells; however, ∆fadD28 was less effective against Mycobacterium tuberculosis challenge in both BALB/c mice and guinea pigs. These results indicate that the loss of PIDMs/PGLs reduces the virulence and protective efficacy of BCG. Since the loss of PDIMs/PGLs occurs naturally in a subset of BCG strains, it also suggests that these strains may have been over-attenuated, which compromises their effectiveness. Our finding has important implications for current BCG programs and future vaccine development. PMID:27357109

  4. Bacille Calmette-Guérin (BCG) vaccination at birth and antibody responses to childhood vaccines. A randomised clinical trial.

    Science.gov (United States)

    Nissen, Thomas Nørrelykke; Birk, Nina Marie; Smits, Gaby; Jeppesen, Dorthe Lisbeth; Stensballe, Lone Graff; Netea, Mihai G; van der Klis, Fiona; Benn, Christine Stabell; Pryds, Ole

    2017-04-11

    BCG vaccination has been associated with beneficial non-specific effects on child health. Some immunological studies have reported heterologous effects of vaccines on antibody responses to heterologous vaccines. Within a randomised clinical trial of Bacille Calmette-Guérin (BCG) vaccination at birth, The Danish Calmette Study, we investigated the effect of BCG at birth on the antibody response to the three routine vaccines against DiTeKiPol/Act-Hib and Prevenar 13 in a subgroup of participants. Within 7days after birth, children were randomised 1:1 to BCG vaccination or to the control group (no intervention). After three routine vaccinations given at age 3, 5 and 12months, antibodies against DiTeKiPol/Act-Hib and Prevenar 13 (Streptococcus pneumoniae serotype type 4, 6B, 9V, 14, 18C, 19F and 23F) were measured 4weeks after the third vaccine dose. Among the 300 included children (178 BCG; 122 controls), almost all children (>96%) had antibody responses above the protective levels. Overall BCG vaccination at birth did not affect the antibody level. When stratifying by 'age at randomisation' we found a possible inducing effect of BCG on antibodies against B. pertussis and all pneumococcal serotypes, when BCG was given after the first day of life. Girls had significantly higher antibody levels for Haemophilus influenza type b and pneumococcus than boys. Three routine vaccinations with DiTeKiPol/Act-Hib and Prevenar 13 induced sero-protective levels in almost all children. No overall effect of neonatal BCG vaccination was observed. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  5. Neonatal BCG vaccination is associated with enhanced T-helper 1 immune responses to heterologous infant vaccines

    Directory of Open Access Journals (Sweden)

    Daniel H. Libraty

    2014-01-01

    Full Text Available Neonatal Bacille Calmette Guérin (BCG vaccination has been reported to have beneficial effects beyond preventing infantile tuberculous meningitis and miliary disease. We hypothesized that BCG vaccine given at birth would enhance T-helper 1 (Th1 immune responses to the first vaccines given later in infancy. We conducted a nested case-control study of neonatal BCG vaccination and its heterologous Th1 immune effects in 2–3 months old infants. BCG vaccination at birth was associated with an increased frequency of interferon-γ (IFN-γ producing spot-forming cells (SFC to tetanus toxoid 2–3 months later. The frequency of IFN-γ producing SFC to polioviruses 1–3 also trended higher among infants who received BCG vaccination at birth. The frequency of IFN-γ+/tumor necrosis factor-α (TNF-α+CD45RO+CD4+ T-cells upon stimulation with phorbol myristate acetate (PMA/Ionomycin was higher in 2–3 months old infants who received BCG vaccination at birth compared to those who did not. The circulating frequency of forkhead box P3 (FoxP3+ CD45RO+ regulatory CD4+ T-cells also trended lower in these infants. Neonatal BCG vaccination is associated with heterologous Th1 immune effects 2–3 months later.

  6. Tuberculosis vaccine strain Mycobacterium bovis BCG Russia is a natural recA mutant

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    Böttger Erik C

    2008-07-01

    Full Text Available Abstract Background The current tuberculosis vaccine is a live vaccine derived from Mycobacterium bovis and attenuated by serial in vitro passaging. All vaccine substrains in use stem from one source, strain Bacille Calmette-Guérin. However, they differ in regions of genomic deletions, antigen expression levels, immunogenicity, and protective efficacy. Results As a RecA phenotype increases genetic stability and may contribute restricting the ongoing evolution of the various BCG substrains while maintaining their protective efficacy, we aimed to inactivate recA by allelic replacement in BCG vaccine strains representing different phylogenetic lineages (Pasteur, Frappier, Denmark, Russia. Homologous gene replacement was achieved successfully in three out of four strains. However, only illegitimate recombination was observed in BCG substrain Russia. Sequence analyses of recA revealed that a single nucleotide insertion in the 5' part of recA led to a translational frameshift with an early stop codon making BCG Russia a natural recA mutant. At the protein level BCG Russia failed to express RecA. Conclusion According to phylogenetic analyses BCG Russia is an ancient vaccine strain most closely related to the parental M. bovis. We hypothesize that recA inactivation in BCG Russia occurred early and is in part responsible for its high degree of genomic stability, resulting in a substrain that has less genetic alterations than other vaccine substrains with respect to M. bovis AF2122/97 wild-type.

  7. Clinical manifestations of leprosy after BCG vaccination: An observational study in Bangladesh

    NARCIS (Netherlands)

    R. Richardus (Renate); C.R. Butlin (C. Ruth); K. Alam (Khorshed); K. Kundu (Kallyan); A. Geluk (Annemieke); J.H. Richardus (Jan Hendrik)

    2015-01-01

    textabstractBackground: Although BCG is used as a vaccine against tuberculosis, it also protects against leprosy. Previous evaluation over 18 years of an intervention of two doses BCG for 3536 household contacts of leprosy patients showed that 28 (23%) out of 122 contacts diagnosed with leprosy,

  8. Revaccination of Guinea Pigs With the Live Attenuated Mycobacterium tuberculosis Vaccine MTBVAC Improves BCG's Protection Against Tuberculosis.

    Science.gov (United States)

    Clark, Simon; Lanni, Faye; Marinova, Dessislava; Rayner, Emma; Martin, Carlos; Williams, Ann

    2017-09-01

    The need for an effective vaccine against human tuberculosis has driven the development of different candidates and vaccination strategies. Novel live attenuated vaccines are being developed that promise greater safety and efficacy than BCG against tuberculosis. We combined BCG with the vaccine MTBVAC to evaluate whether the efficacy of either vaccine would be affected upon revaccination. In a well-established guinea pig model of aerosol infection with Mycobacterium tuberculosis, BCG and MTBVAC delivered via various prime-boost combinations or alone were compared. Efficacy was determined by a reduction in bacterial load 4 weeks after challenge. Efficacy data suggests MTBVAC-associated immunity is longer lasting than that of BCG when given as a single dose. Long and short intervals between BCG prime and MTBVAC boost resulted in improved efficacy in lungs, compared with BCG given alone. A shorter interval between MTBVAC prime and BCG boost resulted in improved efficacy in lungs, compared with BCG given alone. A longer interval resulted in protection equivalent to that of BCG given alone. These data indicate that, rather than boosting the waning efficacy of BCG, a vaccination schedule involving a combination of the 2 vaccines yielded stronger immunity to M. tuberculosis infection. This work supports development of MTBVAC use as a revaccination strategy to improve on the effects of BCG in vaccinated people living in tuberculosis-endemic countries. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  9. Oral vaccination with lipid-formulated BCG induces a long-lived, multifunctional CD4(+ T cell memory immune response.

    Directory of Open Access Journals (Sweden)

    Lindsay R Ancelet

    Full Text Available Oral delivery of BCG in a lipid formulation (Liporale™-BCG targets delivery of viable bacilli to the mesenteric lymph nodes and confers protection against an aerosol Mycobacterium tuberculosis challenge. The magnitude, quality and duration of the effector and memory immune response induced by Liporale™-BCG vaccination is unknown. Therefore, we compared the effector and memory CD4(+ T cell response in the spleen and lungs of mice vaccinated with Liporale™-BCG to the response induced by subcutaneous BCG vaccination. Liporale™-BCG vaccination induced a long-lived CD4(+ T cell response, evident by the detection of effector CD4(+ T cells in the lungs and a significant increase in the number of Ag85B tetramer-specific CD4(+ T cells in the spleen up to 30 weeks post vaccination. Moreover, following polyclonal stimulation, Liporale™-BCG vaccination, but not s.c. BCG vaccination, induced a significant increase in both the percentage of CD4(+ T cells in the lungs capable of producing IFNγ and the number of multifunctional CD4(+ T cells in the lungs at 30 weeks post vaccination. These results demonstrate that orally delivered Liporale™-BCG vaccine induces a long-lived multifunctional immune response, and could therefore represent a practical and effective means of delivering novel BCG-based TB vaccines.

  10. Vaccination with a BCG strain overexpressing Ag85B protects cattle against Mycobacterium bovis challenge.

    Directory of Open Access Journals (Sweden)

    Caroline Rizzi

    Full Text Available Mycobacterium bovis is the causative agent of tuberculosis in cattle but also infects other animals, including humans. Previous studies in cattle have demonstrated that the protection induced by BCG is not complete. In order to improve the protection efficacy of BCG, in this study we overexpressed Ag85B in a BCG Pasteur strain, by using an expression system based on the use of an auxotrophic strain for the leucine amino acid, and complementation with leuD. We found that vaccination of cattle with BCG overexpressing Ag85B induced higher production of IL-17 and IL-4 mRNA upon purified protein derivative (PPDB stimulation of peripheral blood mononuclear cells (PBMCs than vaccination with BCG. Moreover, the IL-17 mRNA expression after vaccination negatively correlated with disease severity resulting from a subsequent challenge with M. bovis, suggesting that this cytokine is a potential biomarker of cattle protection against bovine tuberculosis. Importantly, vaccination with the recombinant BCG vaccine protected cattle better than the wild-type BCG Pasteur.

  11. Adverse reactions to the Bacillus Calmette-Guérin (BCG) vaccine in new-born infants

    DEFF Research Database (Denmark)

    Nørrelykke Nissen, Thomas; Birk, Nina Marie; Kjærgaard, Jesper

    2016-01-01

    OBJECTIVE: To evaluate adverse reactions of the Bacillus Calmette-Guérin (BCG) Statens Serum Institut (SSI) (Danish strain 1331) used as intervention in a randomized clinical trial. DESIGN: A randomized clinical multicenter trial, The Danish Calmette Study, randomizing newborns to BCG...... and eighty four families consented to participate and 4262 children, gestational age 32 weeks and above, were randomized: 2129 to BCG vaccine and 2133 to no vaccine. None of the participants withdrew because of adverse reactions. MAIN OUTCOME AND MEASURE: Trial-registered adverse reactions after BCG...... vaccination at birth. Follow-up at 3 and 13 months by telephone interviews and clinical examinations. RESULTS: Among the 2118 BCG-vaccinated children we registered no cases of severe unexpected adverse reaction related to BCG vaccination and no cases of disseminated BCG disease. Two cases of regional...

  12. Neonatal BCG vaccination and atopic dermatitis before 13 months of age

    DEFF Research Database (Denmark)

    Thøstesen, Lisbeth Marianne; Kjaergaard, Jesper; Pihl, Gitte Thybo

    2018-01-01

    in the control group (RR=0.90 (95% confidence intervals 0.80 to 1.00)). The effect of neonatal BCG vaccination differed significantly between children with atopic predisposition (RR 0.84 (0.74 to 0.95)) and children without atopic predisposition (RR 1.09 (0.88 to 1.37)) (test of no interaction, p=0.04). Among......Studies have suggested that Bacillus Calmette-Guérin (BCG) vaccination may reduce the risk of allergic diseases, including atopic dermatitis. The Danish Calmette Study was conducted 2012-2015. Within 7 days of birth new-borns were randomised 1:1 to BCG or no BCG. Exclusion criteria were gestational...... age children in the BCG group and 495/1,952 (25.4%) children...

  13. Preclinical Development of an In Vivo BCG Challenge Model for Testing Candidate TB Vaccine Efficacy

    Science.gov (United States)

    Minassian, Angela M.; Ronan, Edward O.; Poyntz, Hazel; Hill, Adrian V. S.; McShane, Helen

    2011-01-01

    There is an urgent need for an immunological correlate of protection against tuberculosis (TB) with which to evaluate candidate TB vaccines in clinical trials. Development of a human challenge model of Mycobacterium tuberculosis (M.tb) could facilitate the detection of such correlate(s). Here we propose a novel in vivo Bacille Calmette-Guérin (BCG) challenge model using BCG immunization as a surrogate for M.tb infection. Culture and quantitative PCR methods have been developed to quantify BCG in the skin, using the mouse ear as a surrogate for human skin. Candidate TB vaccines have been evaluated for their ability to protect against a BCG skin challenge, using this model, and the results indicate that protection against a BCG skin challenge is predictive of BCG vaccine efficacy against aerosol M.tb challenge. Translation of these findings to a human BCG challenge model could enable more rapid assessment and down selection of candidate TB vaccines and ultimately the identification of an immune correlate of protection. PMID:21629699

  14. The Efficacy of the BCG Vaccine against Newly Emerging Clinical Strains of Mycobacterium tuberculosis.

    Directory of Open Access Journals (Sweden)

    Marcela Henao-Tamayo

    Full Text Available To date, most new vaccines against Mycobacterium tuberculosis, including new recombinant versions of the current BCG vaccine, have usually been screened against the laboratory strains H37Rv or Erdman. In this study we took advantage of our recent work in characterizing an increasingly large panel of newly emerging clinical isolates [from the United States or from the Western Cape region of South Africa], to determine to what extent vaccines would protect against these [mostly high virulence] strains. We show here that both BCG Pasteur and recombinant BCG Aeras-422 [used here as a good example of the new generation BCG vaccines] protected well in both mouse and guinea pig low dose aerosol infection models against the majority of clinical isolates tested. However, Aeras-422 was not effective in a long term survival assay compared to BCG Pasteur. Protection was very strongly expressed against all of the Western Cape strains tested, reinforcing our viewpoint that any attempt at boosting BCG would be very difficult to achieve statistically. This observation is discussed in the context of the growing argument made by others that the failure of a recent vaccine trial disqualifies the further use of animal models to predict vaccine efficacy. This viewpoint is in our opinion completely erroneous, and that it is the fitness of prevalent strains in the trial site area that is the centrally important factor, an issue that is not being addressed by the field.

  15. Oral vaccination of badgers (Meles meles) against tuberculosis: comparison of the protection generated by BCG vaccine strains Pasteur and Danish.

    Science.gov (United States)

    Murphy, Denise; Costello, Eamon; Aldwell, Frank E; Lesellier, Sandrine; Chambers, Mark A; Fitzsimons, Tara; Corner, Leigh A L; Gormley, Eamonn

    2014-06-01

    Vaccination of badgers by the subcutaneous, mucosal and oral routes with the Pasteur strain of Mycobacterium bovis bacille Calmette-Guérin (BCG) has resulted in significant protection against experimental infection with virulent M. bovis. However, as the BCG Danish strain is the only commercially licensed BCG vaccine for use in humans in the European Union it is the vaccine of choice for delivery to badger populations. As all oral vaccination studies in badgers were previously conducted using the BCG Pasteur strain, this study compared protection in badgers following oral vaccination with the Pasteur and the Danish strains. Groups of badgers were vaccinated orally with 10(8) colony forming units (CFU) BCG Danish 1331 (n = 7 badgers) or 10(8) CFU BCG Pasteur 1173P2 (n = 6). Another group (n = 8) served as non-vaccinated controls. At 12 weeks post-vaccination, the animals were challenged by the endobronchial route with 6 × 10(3) CFU M. bovis, and at 15 weeks post-infection, all of the badgers were euthanased. Vaccination with either BCG strain provided protection against challenge compared with controls. The vaccinated badgers had significantly fewer sites with gross pathology and significantly lower gross pathological severity scores, fewer sites with histological lesions and fewer sites of infection, significantly lower bacterial counts in the thoracic lymph node, and lower bacterial counts in the lungs than the control group. No differences were observed between either of the vaccine groups by any of the pathology and bacteriology measures. The ELISPOT analysis, measuring production of badger interferon - gamma (IFN-γ), was also similar across the vaccinated groups. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Evolution of M. bovis BCG Vaccine: Is Niacin Production Still a Valid Biomarker?

    Science.gov (United States)

    Singh, Sarman; Singh, Pragati

    2015-01-01

    BCG vaccine is usually considered to be safe though rarely serious complications have also been reported, often incriminating contamination of the seed strain with pathogenic Mycobacterium tuberculosis. In such circumstances, it becomes prudent to rule out the contamination of the vaccine seed. M. bovis BCG can be confirmed by the absence of nitrate reductase, negative niacin test, and resistance to pyrazinamide and cycloserine. Recently in India, some stocks were found to be niacin positive which led to a national controversy and closer of a vaccine production plant. This prompted us to write this review and the comparative biochemical and genotypic studies were carried out on the these contentious vaccine stocks at the Indian vaccine plant and other seeds and it was found that some BCG vaccine strains and even some strains of M. bovis with eugenic-growth characteristics mainly old laboratory strains may give a positive niacin reaction. Most probably, the repeated subcultures lead to undefined changes at the genetic level in these seed strains. These changing biological characteristics envisage reevaluation of biochemical characters of existing BCG vaccine seeds and framing of newer guidelines for manufacturing, production, safety, and effectiveness of BCG vaccine. PMID:25694828

  17. BCG Re-vaccination of Adults with Latent Mycobacterium tuberculosis Infection Induces Long-lived BCG-Reactive Natural Killer Cell Responses1

    Science.gov (United States)

    Suliman, Sara; Geldenhuys, Hennie; Johnson, John L.; Hughes, Jane E.; Smit, Erica; Murphy, Melissa; Toefy, Asma; Lerumo, Lesedi; Hopley, Christiaan; Pienaar, Bernadette; Chheng, Phalkun; Nemes, Elisa; Hoft, Daniel F.; Hanekom, Willem A.; Boom, W. Henry

    2016-01-01

    One third of the global population is estimated to be latently infected with Mycobacterium tuberculosis (M.tb). We performed a phase 1 randomized, controlled trial of isoniazid preventive therapy (IPT) before re-vaccination with Bacille Calmette-Guerin (BCG) in healthy, tuberculin skin test positive (≥15mm induration), HIV-negative, South African adults. We hypothesised that pre-clearance of latent bacilli with IPT modulates BCG immunogenicity following re-vaccination. Frequencies and co-expression of IFNγ, TNFα, IL-2, IL-17, and/or IL-22 in CD4, and IFNγ-expressing CD8, γδ T, CD3+CD56+ NKT-like and NK cells in response to BCG were measured using whole blood intracellular cytokine staining and flow cytometry. We analyzed 72 participants who were BCG re-vaccinated after IPT (n=33) or without prior IPT (n=39). IPT had little effect on frequencies or cytokine co-expression patterns of M.tb- or BCG-specific responses. Re-vaccination transiently boosted BCG-specific Th1 cytokine-expressing CD4, CD8 and γδ T cells. Despite high frequencies of IFNγ-expressing BCG-reactive CD3+CD56+ NKT-like, CD3−CD56dim and CD3−CD56hi NK cells at baseline, BCG re-vaccination boosted these responses, which remained elevated up to one year after re-vaccination. Such BCG-reactive memory NK cells were induced by BCG vaccination in infants, while in vitro IFN-γ expression by NK cells upon BCG stimulation was dependent on IL-12 and IL-18. Our data suggest that isoniazid pre-clearance of M.tb bacilli has little effect on the magnitude, persistence or functional attributes of lymphocyte responses boosted by BCG re-vaccination. Our study highlights surprising durability of BCG-boosted memory NKT-like and NK cells expressing anti-mycobacterial effector molecules, which may be novel targets for TB vaccines. PMID:27412415

  18. A Complication of BCG Vaccine: A Case of Localized Cutaneous Abscess due to Mycobacterium bovis

    Directory of Open Access Journals (Sweden)

    Nathalie Lussier

    1999-01-01

    Full Text Available The attenuated bacille Calmette-Guérin (BCG vaccine is administered to prevent tuberculosis. Complications of vaccination are uncommon. A case of cutaneous abscess due to BCG is presented in a 24-year-old woman. The abscess developed at the inoculation site four weeks after vaccination. Routine Gram stain and bacterial cultures of the pus were negative. The auramine stain was positive. Mycobacterial cultures were positive after 14 and 18 days, using the BACTEC 12B bottle and Löwenstein-Jensen media, respectively. The mycobacteria were identified as Mycobacterium bovis, vaccinal strain by high-performance liquid chromatography and DNA probe assays.

  19. Individual-level factors associated with variation in mycobacterial-specific immune response: Gender and previous BCG vaccination status.

    Science.gov (United States)

    Rhodes, Sophie J; Knight, Gwenan M; Fielding, Katherine; Scriba, Thomas J; Pathan, Ansar A; McShane, Helen; Fletcher, Helen; White, Richard G

    2016-01-01

    A more effective tuberculosis (TB) vaccine is needed to eliminate TB disease. Many new vaccine candidates enhance the immunogenicity of the existing vaccine, Bacillus Calmette-Guérin (BCG). Understanding BCG induced immune variation is key to developing a new vaccine. We aimed to establish if individual-level covariates were associated with cell-mediated immune response (interferon gamma (IFN-γ)) at vaccine trial enrolment (baseline) in a long-term retrospective analysis (LTR) and after BCG vaccination in a short-term prospective analysis (STP). Four covariates were analysed: gender, country, BCG vaccination history and monocyte/lymphocyte cell count ratio. Univariable and multivariable linear regression were conducted on IFN-γ response at baseline for LTR, and area under the curve (AUC), 24 week and peak IFN-γ response for STP. Previous BCG vaccination was strongly associated with higher IFN-γ response at baseline (LTR analysis) (p-values response (p-value = 0.1). BCG revaccination was strongly associated with a larger response increase than primary-vaccination (AUC & peak p-values 0.1). This analysis suggests that previous BCG vaccination and gender are associated with durable IFN-γ responses. Vaccine trials may need to stratify by BCG vaccination history and gender. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Tuberculin reactivity in a population of schoolchildren with high BCG vaccination coverage

    Directory of Open Access Journals (Sweden)

    Bierrenbach Ana L.

    2003-01-01

    Full Text Available OBJECTIVE: To investigate the influence of BCG vaccination or revaccination on tuberculin skin test reactivity, in order to guide the correct interpretation of this test in a setting of high neonatal BCG vaccination coverage and an increasing BCG revaccination coverage at school age. METHODS: We conducted tuberculin skin testing and BCG scar reading in 1148 children aged 7-14 years old in the city of Salvador, Bahia, Brazil. We measured the positive effect of the presence of one or two BCG scars on the proportion of tuberculin skin test results above different cut-off levels (induration sizes of > 5 mm, > 10 mm, and > 15 mm and also using several ranges of induration size (0, 1-4, 5-9, 10-14, and > 15 mm. We also measured the effects that age, gender, and the school where the child was enrolled had on these proportions. RESULTS: The proportion of tuberculin results > 10 mm was 14.2% (95% confidence interval (CI = 8.0%-20.3% for children with no BCG scar, 21.3% (95% CI = 18.5%-24.1% for children with one BCG scar, and 45.0% (95% CI = 32.0%-58.0% for children with two BCG scars. There was evidence for an increasing positive effect of the presence of one and two BCG scars on the proportion of results > 5 mm and > 10 mm. Similarly, there was evidence for an increasing positive effect of the presence of one and two scars on the proportion of tuberculin skin test results in the ranges of 5-9 mm and of 10-14 mm. The BCG scar effect on the proportion of results > 5 mm and > 10 mm did not vary with age. There was no evidence for BCG effect on the results > 15 mm. CONCLUSIONS: In Brazilian schoolchildren, BCG-induced tuberculin reactivity is indistinguishable, for results under 15 mm, from reactivity induced by Mycobacterium tuberculosis infection. BCG revaccination at school age increases the degree of BCG-induced tuberculin reactivity found among schoolchildren. This information should be taken into account in tuberculin skin test surveys intended to

  1. BCG vaccination reduces risk of tuberculosis infection in vaccinated badgers and unvaccinated badger cubs.

    Directory of Open Access Journals (Sweden)

    Stephen P Carter

    Full Text Available Wildlife is a global source of endemic and emerging infectious diseases. The control of tuberculosis (TB in cattle in Britain and Ireland is hindered by persistent infection in wild badgers (Meles meles. Vaccination with Bacillus Calmette-Guérin (BCG has been shown to reduce the severity and progression of experimentally induced TB in captive badgers. Analysis of data from a four-year clinical field study, conducted at the social group level, suggested a similar, direct protective effect of BCG in a wild badger population. Here we present new evidence from the same study identifying both a direct beneficial effect of vaccination in individual badgers and an indirect protective effect in unvaccinated cubs. We show that intramuscular injection of BCG reduced by 76% (Odds ratio = 0.24, 95% confidence interval (CI 0.11-0.52 the risk of free-living vaccinated individuals testing positive to a diagnostic test combination to detect progressive infection. A more sensitive panel of tests for the detection of infection per se identified a reduction of 54% (Odds ratio = 0.46, 95% CI 0.26-0.88 in the risk of a positive result following vaccination. In addition, we show the risk of unvaccinated badger cubs, but not adults, testing positive to an even more sensitive panel of diagnostic tests decreased significantly as the proportion of vaccinated individuals in their social group increased (Odds ratio = 0.08, 95% CI 0.01-0.76; P = 0.03. When more than a third of their social group had been vaccinated, the risk to unvaccinated cubs was reduced by 79% (Odds ratio = 0.21, 95% CI 0.05-0.81; P = 0.02.

  2. Recombinant BCG vaccines: molecular features and their influence in the expression of foreign genes.

    Science.gov (United States)

    Oliveira, Thaís Larré; Rizzi, Caroline; Dellagostin, Odir Antônio

    2017-09-01

    Recombinant Mycobacterium bovis BCG vaccines (rBCG) were first developed in the 1990s as a means of expressing antigens from multiple pathogens. This review examines the key structural factors of recombinant M. bovis that influence the expression of the heterologous antigens and the generation of genetic and functional stability in rBCG, which are crucial for inducing strong and lasting immune responses. The fundamental aim of this paper is to provide an overview of factors that affect the expression of recombinant proteins in BCG and the generation of the immune response against the target antigens, including mycobacterial promoters, location of foreign antigens, and stability of the vectors. The reporter systems that have been employed for evaluation of these molecular features in BCG are also reviewed here.

  3. Early BCG vaccine to low-birth-weight infants and the effects on growth in the first year of life

    DEFF Research Database (Denmark)

    Biering-Sørensen, Sofie; Andersen, Andreas; Ravn, Henrik

    2015-01-01

    BACKGROUND: Randomised trials have shown that early Bacille Calmette-Guérin (BCG) vaccine reduces overall neonatal and infant mortality. However, no study has examined how BCG affects growth. We investigated the effect on infant growth of early BCG vaccine given to low-birth-weight (LBW) infants...... A supplementation (VAS) or placebo. Anthropometric measurements were obtained 2, 6, and 12 months after enrolment. RESULTS: Overall there was no effect of early BCG on growth in the first year of life. The effect of early BCG on weight and mid-upper-arm circumference at 2 months tended to be beneficial among girls...... but not among boys (interaction between "early BCG" and sex: weight p = 0.03 and MUAC p = 0.04). This beneficial effect among girls was particularly seen among the largest infants weighing 2.0 kg or more at inclusion. CONCLUSION: Though BCG vaccination is not recommended to be given to LBW infants at birth...

  4. Vitamin A supplementation and BCG vaccination at birth in low birthweight neonates

    DEFF Research Database (Denmark)

    Benn, Christine Stabell; Fisker, Ane Baerent; Napirna, Bitiguida Mutna

    2010-01-01

    OBJECTIVE: To investigate the effect of vitamin A supplementation and BCG vaccination at birth in low birthweight neonates. DESIGN: Randomised, placebo controlled, two by two factorial trial. SETTING: Bissau, Guinea-Bissau. PARTICIPANTS: 1717 low birthweight neonates born at the national hospital...... months of age for infants who received vitamin A supplementation compared with those who received placebo. RESULTS: No interaction was observed between vitamin A supplementation and BCG vaccine allocation (P=0.73). Vitamin A supplementation at birth was not significantly associated with mortality......: the MRR of vitamin A supplementation compared with placebo, controlled for randomisation to "early BCG" versus "no early BCG" was 1.08 (95% CI 0.79 to 1.47). Stratification by sex revealed a significant interaction between vitamin A supplementation and sex (P=0.046), the MRR of vitamin A supplementation...

  5. Neonatal BCG-vaccination and atopic dermatitis before 13 months of age. A randomised clinical trial

    DEFF Research Database (Denmark)

    Thøstesen, Lisbeth Marianne; Kjaergaard, Jesper; Pihl, Gitte Thybo

    2017-01-01

    Studies have suggested that Bacillus Calmette-Guérin (BCG) vaccination may reduce the risk of allergic diseases, including atopic dermatitis. The Danish Calmette Study was conducted 2012-2015. Within 7 days of birth new-borns were randomised 1:1 to BCG or no BCG. Exclusion criteria were gestational...... in the control group (RR=0.90 (95% confidence intervals 0.80 to 1.00)). The effect of neonatal BCG vaccination differed significantly between children with atopic predisposition (RR 0.84 (0.74 to 0.95)) and children without atopic predisposition (RR 1.09 (0.88 to 1.37)) (test of no interaction, p=0.04). Among...

  6. Lupus vulgaris at the site of BCG vaccination: report of three cases.

    Science.gov (United States)

    Farsinejad, K; Daneshpazhooh, M; Sairafi, H; Barzegar, M; Mortazavizadeh, M

    2009-07-01

    Lupus vulgaris (LV) is a rare complication of the bacille Calmette-Guérin (BCG) vaccination, and about 65 cases of inoculation tuberculosis resembling LV have been reported in the literature. We report three cases of LV, developing many years later at the inoculation site of BCG vaccine. All three cases had a single BCG vaccination, with a LV lesion at or in the vicinity of the vaccination site, a strong positive Mantoux test, noncaseating granuloma histologically, and two of the patients had a positive PCR result for mycobacterial complex. One of the patients had an unusually delayed appearance of the LV lesion, after an interval of about 17 years, and another case was remarkable because of the large size of the lesion (210 x 110 mm).

  7. Pre-Clinical Development of BCG.HIVACAT, an Antibiotic-Free Selection Strain, for HIV-TB Pediatric Vaccine Vectored by Lysine Auxotroph of BCG

    Science.gov (United States)

    Saubi, Narcís; Mbewe-Mvula, Alice; Gea-Mallorqui, Ester; Rosario, Maximillian; Gatell, Josep Maria; Hanke, Tomáš; Joseph, Joan

    2012-01-01

    In the past, we proposed to develop a heterologous recombinant BCG prime-recombinant modified vaccinia virus Ankara (MVA) boost dual pediatric vaccine platform against transmission of breast milk HIV-1 and Mycobacterium tuberculosis (Mtb). In this study, we assembled an E. coli-mycobacterial shuttle plasmid pJH222.HIVACAT expressing HIV-1 clade A immunogen HIVA. This shuttle vector employs an antibiotic resistance-free mechanism based on Operator-Repressor Titration (ORT) system for plasmid selection and maintenance in E. coli and lysine complementation in mycobacteria. This shuttle plasmid was electroporated into parental lysine auxotroph (safer) strain of BCG to generate vaccine BCG.HIVACAT. All procedures complied with Good Laboratory Practices (GLPs). We demonstrated that the episomal plasmid pJH222.HIVACAT was stable in vivo over a 20-week period, and genetically and phenotypically characterized the BCG.HIVACAT vaccine strain. The BCG.HIVACAT vaccine in combination with MVA.HIVA induced HIV-1- and Mtb-specific interferon γ-producing T-cell responses in newborn and adult BALB/c mice. On the other hand, when adult mice were primed with BCG.HIVACAT and boosted with MVA.HIVA.85A, HIV-1-specific CD8+ T-cells producing IFN-γ, TNF-α, IL-2 and CD107a were induced. To assess the biosafety profile of BCG.HIVACAT-MVA.HIVA regimen, body mass loss of newborn mice was monitored regularly throughout the vaccination experiment and no difference was observed between the vaccinated and naïve groups of animals. Thus, we demonstrated T-cell immunogenicity of a novel, safer, GLP-compatible BCG-vectored vaccine using prototype immunogen HIVA. Second generation immunogens derived from HIV-1 as well as other major pediatric pathogens can be constructed in a similar fashion to prime protective responses soon after birth. PMID:22927933

  8. Mucosal BCG Vaccination Induces Protective Lung-Resident Memory T Cell Populations against Tuberculosis

    Science.gov (United States)

    Perdomo, Carolina; Zedler, Ulrike; Kühl, Anja A.; Lozza, Laura; Saikali, Philippe; Sander, Leif E.; Vogelzang, Alexis; Kupz, Andreas

    2016-01-01

    ABSTRACT Mycobacterium bovis Bacille Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB), yet its moderate efficacy against pulmonary TB calls for improved vaccination strategies. Mucosal BCG vaccination generates superior protection against TB in animal models; however, the mechanisms of protection remain elusive. Tissue-resident memory T (TRM) cells have been implicated in protective immune responses against viral infections, but the role of TRM cells following mycobacterial infection is unknown. Using a mouse model of TB, we compared protection and lung cellular infiltrates of parenteral and mucosal BCG vaccination. Adoptive transfer and gene expression analyses of lung airway cells were performed to determine the protective capacities and phenotypes of different memory T cell subsets. In comparison to subcutaneous vaccination, intratracheal and intranasal BCG vaccination generated T effector memory and TRM cells in the lung, as defined by surface marker phenotype. Adoptive mucosal transfer of these airway-resident memory T cells into naive mice mediated protection against TB. Whereas airway-resident memory CD4+ T cells displayed a mixture of effector and regulatory phenotype, airway-resident memory CD8+ T cells displayed prototypical TRM features. Our data demonstrate a key role for mucosal vaccination-induced airway-resident T cells in the host defense against pulmonary TB. These results have direct implications for the design of refined vaccination strategies. PMID:27879332

  9. Adverse events following immunisation with bacille Calmette-Guérin vaccination: baseline data to inform monitoring in Australia following introduction of new unregistered BCG vaccine.

    Science.gov (United States)

    Hendry, Alexandra J; Dey, Aditi; Beard, Frank H; Khandaker, Gulam; Hill, Richard; Macartney, Kristine K

    2016-12-24

    In recent years there has been a global shortage of bacille Calmette-Guérin (BCG) vaccine and, from September 2012, unregistered vaccines have needed to be used in Australia (a Danish product initially until the end of 2015, and a Polish product used in some jurisdictions from early 2016). We examined rates and types of adverse events following immunisation (AEFI) with BCG vaccine reported to the Therapeutic Goods Administration between 2009 and 2014 in children aged less than 7 years. Reporting rates of AEFI with BCG vaccine increased from 87 per 100,000 doses (registered Sanofi Pasteur product) in 2009 to 201 per 100,000 doses (unregistered Danish Statens Serum Institute product) in 2014, with Victoria having the highest rate each year. Substantial variation between jurisdictions exists, suggesting differential reporting of BCG vaccine doses administered and/or BCG vaccine-related AEFI. The most commonly reported reactions were abscess (31%), injection site reaction (27%) and lymphadenopathy/lymphadenitis (17%). This study provides baseline data on BCG vaccine safety to inform surveillance. Given the current use of unregistered vaccines in the context of vaccine supply issues, improved recording of both administered BCG vaccine doses and the reporting of BCG vaccine-related AEFI are required to facilitate close monitoring of vaccine safety.

  10. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity

    NARCIS (Netherlands)

    Arts, Rob J W; Moorlag, Simone J C F M; Novakovic, Boris; Li, Yang; Wang, Shuang-Yin; Oosting, Marije; Kumar, Vinod; Xavier, Ramnik J; Wijmenga, Cisca; Joosten, Leo A B; Reusken, Chantal B E M; Benn, Christine S; Aaby, Peter; Koopmans, Marion P; Stunnenberg, Hendrik G; van Crevel, Reinout; Netea, Mihai G

    2018-01-01

    The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections. The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide

  11. How do parents make their decision about letting their child get a BCG vaccination?

    DEFF Research Database (Denmark)

    Thybo Pihl, Gitte; Ammentorp, Jette; Schmidt Jensen, Jane

    focus for this project is parents decision making and risk evaluation. I want to investigate how parents make their decision about letting their child get a BCG vaccination and how they evaluate the risk of side effects. Method: Before the clinical trial was started, we conducted 5 focus groups......-analysis of the results shows, that some danish parents are still concerned about nondescribed and non-specific side effects, even if the BCG-vaccine has been used for over 100 years and the side effects is well-described in medical research. They express doubt about the medical descriptions of the side effects and wants...... to discuss it with a professional they trust before they can decide to let their child vaccinate with BCG or not. I will show how parents try to make their own risk evaluation on the basis of a lay epidemiology, as described by Davison, Frankel and Davey Smith (1). They use their own interpretation of cases...

  12. Extracellular forms of Mycobacterium bovis BCG in the mucosal lymphatic tissues following oral vaccination

    Directory of Open Access Journals (Sweden)

    Wenzel Czepluch

    2013-01-01

    Full Text Available Oral vaccination with BCG provides protective systemic immunity against pathogenic mycobacterial challenge. In this study, the anatomical distribution of Mycobacterium bovis BCG following oral vaccination was investigated. Replicating bacteria in the Peyer's patches and mesenteric lymph nodes were present as solitary rods or clusters of two to three bacteria, the majority of which were isolated ex vivo as extracellular forms. Only a minority were shown to be associated with typical antigen-presenting cells. Acid-fast staining of mast cell granules in lymphoid tissues revealed a potential pitfall for these analyses and may explain previous reports of acid-fast ‘coccoid’ forms of mycobacteria in tissues.

  13. Nonspecific effect of BCG vaccination at birth on early childhood infections

    DEFF Research Database (Denmark)

    Kjærgaard, Jesper; Birk, Nina Marie; Nissen, Thomas N

    2016-01-01

    BACKGROUND: Childhood infections are common and Bacillus Calmette-Guérin (BCG) vaccination at birth may prevent these via nonspecific effects. METHODS: A randomized, clinical multicenter trial. All women planning to give birth (n = 16,521) at the three study sites were invited during the recruitm......BACKGROUND: Childhood infections are common and Bacillus Calmette-Guérin (BCG) vaccination at birth may prevent these via nonspecific effects. METHODS: A randomized, clinical multicenter trial. All women planning to give birth (n = 16,521) at the three study sites were invited during...... during the first 3 mo....

  14. Engineering new mycobacterial vaccine design for HIV–TB pediatric vaccine vectored by lysine auxotroph of BCG

    Science.gov (United States)

    Saubi, Narcís; Gea-Mallorquí, Ester; Ferrer, Pau; Hurtado, Carmen; Sánchez-Úbeda, Sara; Eto, Yoshiki; Gatell, Josep M; Hanke, Tomáš; Joseph, Joan

    2014-01-01

    In this study, we have engineered a new mycobacterial vaccine design by using an antibiotic-free plasmid selection system. We assembled a novel Escherichia coli (E. coli)–mycobacterial shuttle plasmid p2auxo.HIVA, expressing the HIV-1 clade A immunogen HIVA. This shuttle vector employs an antibiotic resistance-free mechanism for plasmid selection and maintenance based on glycine complementation in E. coli and lysine complementation in mycobacteria. This plasmid was first transformed into glycine auxotroph of E. coli strain and subsequently transformed into lysine auxotroph of Mycobacterium bovis BCG strain to generate vaccine BCG.HIVA2auxo. We demonstrated that the episomal plasmid p2auxo.HIVA was stable in vivo over a 7-week period and genetically and phenotypically characterized the BCG.HIVA2auxo vaccine strain. The BCG.HIVA2auxo vaccine in combination with modified vaccinia virus Ankara (MVA). HIVA was safe and induced HIV-1 and Mycobacterium tuberculosis-specific interferon-γ-producing T-cell responses in adult BALB/c mice. Polyfunctional HIV-1-specific CD8+ T cells, which produce interferon-γ and tumor necrosis factor-α and express the degranulation marker CD107a, were induced. Thus, we engineered a novel, safer, good laboratory practice–compatible BCG-vectored vaccine using prototype immunogen HIVA. This antibiotic-free plasmid selection system based on “double” auxotrophic complementation might be a new mycobacterial vaccine platform to develop not only recombinant BCG-based vaccines expressing second generation of HIV-1 immunogens but also other major pediatric pathogens to prime protective response soon after birth. PMID:26015961

  15. Early versus late BCG vaccination in HIV-1-exposed infants in Uganda: study protocol for a randomized controlled trial.

    Science.gov (United States)

    Nankabirwa, Victoria; Tumwine, James K; Namugga, Olive; Tylleskär, Thorkild; Ndeezi, Grace; Robberstad, Bjarne; Netea, Mihai G; Sommerfelt, Halvor

    2017-03-31

    Bacillus Calmette-Guérin (BCG) vaccination may have nonspecific effects, i.e., effects on childhood morbidity and mortality that go beyond its effect on the risk of childhood tuberculosis (TB). Though the available scientific literature is mostly from observational studies, and is fraught with controversy, BCG vaccination at birth may protect infants in high-mortality populations against serious infections other than TB. Yet, other studies indicate that giving BCG later in infancy may modify immune responses to non-TB antigens and potentially enhance immunity, potentially also against tuberculosis (TB). It is unclear whether BCG vaccination very early in life offers adequate protection against TB and other infections among HIV-1-exposed children because even those who remain uninfected with HIV-1 show signs of impaired immunocompetence early in infancy. This study will compare BCG vaccination at birth with BCG vaccination at 14 weeks of age in HIV-1-exposed infants. This is an individually randomized controlled trial in 2200 HIV-1-exposed infants. The intervention is BCG vaccination within 24 h of birth while the comparator is BCG given at 14 weeks of age. The study co-primary outcomes are severe illness in the first 14 weeks of life, and production of tumor necrosis factor, interleukin (IL)-1β, IL-6 and interferon-γ in response to mycobacterial and nonmycobacterial antigens. The study is being conducted in three health centers in Uganda. A well-timed BCG vaccination could have important nonspecific effects in HIV-1-exposed infants. This trial could inform the development of appropriate timing of BCG vaccination for HIV-1-exposed infants. ClinicalTrials.gov, identifier: NCT02606526 . Registered on 12 November 2015.

  16. Non-specific effects of BCG vaccination on morbidity among children in Greenland: a population-based cohort study.

    Science.gov (United States)

    Haahr, S; Michelsen, S W; Andersson, M; Bjorn-Mortensen, K; Soborg, B; Wohlfahrt, J; Melbye, M; Koch, A

    2016-12-01

    The potential non-specific effects of BCG (Bacillus Calmette-Guérin) vaccination, with reported reduction of infectious disease morbidity among vaccinated children, in addition to the protective effect against tuberculosis (TB), are highly debated. In Greenland, BCG vaccination was introduced in 1955, but temporarily discontinued from 1991 to 1996 due to nationwide policy changes. Using the transient vaccination stop, we aimed to investigate possible non-specific effects of BCG vaccination by measuring nation-wide hospitalization rates due to infectious diseases other than TB among vaccinated and unvaccinated children. A retrospective cohort study including all children born in Greenland aged 3 months to 3 years from 1989 to 2004. A personal identification number assigned at birth allowed for follow-up through national registers. Information on hospitalization due to infectious diseases was obtained from the Greenlandic inpatient register using ICD-8 and ICD-10 codes. Participants with notified TB were censored. Incidence rate ratios (IRR) were estimated using Poisson regression. Overall, 19 363 children, hereof 66% BCG-vaccinated, were followed for 44 065 person-years and had 2069 hospitalizations due to infectious diseases. IRRs of hospitalization in BCG-vaccinated as compared with BCG-unvaccinated children were 1.07 [95% confidence interval (CI) 0.96-1.20] for infectious diseases overall, and specifically 1.10 (95% CI 0.98-1.24) for respiratory tract infections. Among BCG-vaccinated children aged 3 to 11 months, the IRR of hospitalization due to infectious diseases was 1.00 (95% CI 0.84-1.19) as compared with BCG-unvaccinated children. Our results do not support the hypothesis that neonatal BCG vaccination reduces morbidity in children caused by infectious diseases other than TB. © The Author 2016; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association

  17. [Vaccination coverage and socioeconomic determinants of BCG vaccination in children before 3 months: Results of the Elfe cohort study, 2011].

    Science.gov (United States)

    Guthmann, J-P; Ragot, M; Ben Boutieb, M; Bois, C; Dufourg, M-N; Lévy-Bruhl, D

    2016-09-01

    In 2007, French authorities changed mandatory BCG vaccination for all children into a strong recommendation to vaccinate only children considered at high risk of tuberculosis. Vaccination coverage (VC) data are insufficient in France. We estimated VC at approximately two months of age and identified socioeconomic factors associated with BCG vaccination. The Elfe study (Étude Longitudinale Française depuis l'Enfance) included a random sample of about 18 000 children born in 2011 selected at birth from 320 maternity wards from mainland France. Information was collected through questionnaires and telephone interviews conducted approximately two months after delivery. Because BCG recommendations are different in the Paris region (Île-de-France [IDF]) and outside this region, VC was estimated separately in these two regions. We estimated VC for different levels of tuberculosis risk, approached by the geographical origin of the parents. Poisson regression was performed to analyze the association between socioeconomic factors and BCG vaccination status, and results expressed by prevalence ratios (PR). CV was higher in IDF (59.5%) compared to at-risk children outside IDF (46.7%) (pchildren with two parents from a tuberculosis highly endemic country was 80.5% in IDF and 60.4% outside IDF. In the multivariable model, having one or two parents from a tuberculosis highly endemic country (PR around 1.40) or consulting a private pediatrician (PR around 1.15) or a maternal and child health (MCH) center (PR around 1.40) after leaving the maternity ward were associated with a higher VC, whereas a university educational level in mothers was associated with a lower VC (PR=0.80). In France, BCG vaccination in infants is performed early after discharge from the maternity ward. A first consultation with a pediatrician or in a MCH center is associated with better vaccination coverage. Children at higher risk are probably well identified by physicians and better vaccinated. Copyright

  18. Scar formation and tuberculin conversion following BCG vaccination in infants: A prospective cohort study

    Directory of Open Access Journals (Sweden)

    Sara S Dhanawade

    2015-01-01

    Full Text Available Background: There is considerable variation in BCG scar failure rate on available data and correlation between BCG scar and tuberculin conversion remains controversial. Through this study we aimed to determine the scar failure rate and tuberculin conversion in term infants vaccinated with BCG within the first month. Materials and Methods: A prospective cohort study was conducted among 85 consecutive infants weighing >2 kg attending the immunization clinic of a medical college hospital. Fifteen subjects who could not complete the follow up were excluded. Total of 70 cases were analyzed. All babies were administered 0.1 ml of BCG and examined at 3 months (+1 week for scar. Tuberculin test was done with 5TU PPD. An induration of >5 mm was considered positive. Statistical analysis was done using Microsoft Excel and SPSS-22. Results: Out of the 70 infants, 41 (58.6% were males. Although majority (72.9% of infants were vaccinated within 7 days, only 18 (25.7% received BCG within 48 hours of birth. Sixty-four (91.4% had a visible scar at 12 weeks post vaccination representing a scar failure rate of 8.6%. Tuberculin test was positive in 50 (71.4%. The mean ± s.d. for scar and tuberculin skin test (TST reaction size was 4.93 ± 2.01 mm and 6.01 ± 3.22 mm, respectively. The association between scar formation and tuberculin positivity was highly significant (P < 0.001. There was significant correlation between scar size and TST size (r = 0.401, P = 0.001 Conclusions: Less than 10% of infants fail to develop a scar following BCG vaccination. There is good correlation between scar positivity and tuberculin conversion.

  19. Vaccination technique, PPD reaction and BCG scarring in a cohort of children born in Guinea-Bissau 2000-2002

    DEFF Research Database (Denmark)

    Roth, Adam Anders Edvin; Sodemann, Morten; Jensen, Henrik

    2005-01-01

    =2225) of age. In a subgroup of the children the vaccination technique was monitored by direct observation of post-vaccination wheal and route of administration. Three different types of BCG vaccine supplied by the local Extended Programme on Immunization were used. At 6 months of age the rate of PPD...... reactors (>1mm) after BCG vaccination was 25% and the rate of scarring was 89%. One BCG strain was associated with fewer PPD reactors (OR=0.54 (0.31-0.91)) and BCG scars (OR=0.13 (0.05-0.37)) and larger post-vaccination wheals produced more PPD reactions (OR 1.21 (95% CI 1.02-1.43)) and BCG scars (OR 1......, low birth weight, place of residence, education and civil status of mother. We reason that vaccination technique and BCG strain are important for PPD reaction and scarring in response to BCG vaccination. Considering that these responses are associated with better infant survival, the importance...

  20. Coley's toxin and BCG vaccine in prevention and treatment of malignant melanoma in humans

    Czech Academy of Sciences Publication Activity Database

    Kučerová, Petra; Vlasáková, Jitka; Červinková, Monika

    2017-01-01

    Roč. 28, č. 3 (2017), s. 124-128 ISSN 0954-139X R&D Projects: GA MŠk(CZ) LO1609 Institutional support: RVO:67985904 Keywords : BCG vaccine * Coley´s toxin * cytokines Subject RIV: EC - Immunology OBOR OECD: Immunology

  1. The effect of BCG vaccine from protection of type 1 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Mehmet Karaci

    2012-03-01

    As a result, we concluded that if BCG is vaccine is applied at least twice and , the first dose is gives in the newborn period may exert a protective effect for the development of type I DM in children . [J Contemp Med 2012; 2(1.000: 1-8

  2. Viral Booster Vaccines Improve Mycobacterium bovis BCG-Induced Protection Against Bovine Tuberculosis

    Science.gov (United States)

    Previous work in small animal laboratory models of tuberculosis have shown that vaccination strategies based on heterologous prime-boost protocols using Mycobacterium bovis bacille Calmette-Guerin (BCG) to prime and Modified Vaccinia Ankara strain (MVA85A) or recombinant attenuated adenoviruses (Ad8...

  3. CD4 and CD8 counts of Bacillus Calmette Guerin (BCG) vaccinated ...

    African Journals Online (AJOL)

    This study examines the cellular immune factors responsible for combating infections by assessing CD4 and CD8 counts of neonates (pre and post BCG vaccination). A total of 373 blood samples were collected from neonates that visited the immunization clinics at Irrua Specialist Teaching Hospital (ISTH), Irrua and Federal ...

  4. Variation of growth in the production of the BCG vaccine and the association with the immune response. An observational study within a randomised trial

    NARCIS (Netherlands)

    Biering-Sorensen, S.; Jensen, K.J.; Aamand, S.H.; Blok, B.; Andersen, A.; Monteiro, I.; Netea, M.G.; Aaby, P.; Benn, C.S.; Haslov, K.R.

    2015-01-01

    INTRODUCTION: Bacille Calmette-Guerin (BCG) vaccine has beneficial non-specific effects on overall survival. After BCG vaccination, positive PPD response and scar formation are associated with increased survival. During a trial randomising low-birth-weight neonates to BCG at birth or the usual

  5. Effects of Bacillus Calmette-Guerin (BCG) vaccination at birth on T and B lymphocyte subsets: Results from a clinical randomized trial

    NARCIS (Netherlands)

    Birk, N.M.; Nissen, T.N.; Kjaergaard, J.; Hartling, H.J.; Thostesen, L.M.; Kofoed, P.E.; Stensballe, L.G.; Andersen, A.; Pryds, O.; Netea, M.G.; Benn, C.S.; Nielsen, S.D.; Jeppesen, D.L.

    2017-01-01

    The Bacillus Calmette-Guerin vaccine (BCG) has been associated with beneficial non-specific effects (NSEs) on infant health. Within a randomized trial on the effect of neonatal BCG on overall health, we investigated the possible immunological impact of neonatal BCG vaccination on lymphocyte subsets,

  6. BCG vaccination status of children with tuberculous meningitis and ...

    African Journals Online (AJOL)

    From 1985 to 1992, 193 children with tuberculous meningitis (TBM) with a median age of 26 months were admitted to the Department of Paediatrics and Child Health, Tygerberg Hospital. Of these children 143 (74%) were documented to have received BCG, either by reference to 'Road to Health' cards or by contact with ...

  7. BCG vaccination status of children with tuberculous meningitis and ...

    African Journals Online (AJOL)

    From 1985 to 1992, 193 children with tuberculous meningitis (TBM) with a median age of 26 months were admitted to the Department of Paediatrics and Child. Health, Tygerberg Hospital. Of these children 143 (74%) were documented to have received BCG, either by reference to 'Road to Health' cards or by contact with.

  8. Surgical management of BCG vaccine-induced regional axillary ...

    African Journals Online (AJOL)

    The age of the patient and mode of presentation, imaging findings, and results of tuberculin skin testing (Mantoux test) ... Primary surgical treatment (incisional drainage or biopsy) is therefore not considered an ideal form of management in BCG lymphadenitis because of the high fistulisation and poor wound healing, ...

  9. BCG vaccination at birth and early childhood hospitalisation: a randomised clinical multicentre trial.

    Science.gov (United States)

    Stensballe, Lone Graff; Sørup, Signe; Aaby, Peter; Benn, Christine Stabell; Greisen, Gorm; Jeppesen, Dorthe Lisbeth; Birk, Nina Marie; Kjærgaard, Jesper; Nissen, Thomas Nørrelykke; Pihl, Gitte Thybo; Thøstesen, Lisbeth Marianne; Kofoed, Poul-Erik; Pryds, Ole; Ravn, Henrik

    2017-03-01

    The BCG vaccine is administered to protect against tuberculosis, but studies suggest there may also be non-specific beneficial effects upon the infant immune system, reducing early non-targeted infections and atopic diseases. The present randomised trial tested the hypothesis that BCG vaccination at birth would reduce early childhood hospitalisation in Denmark, a high-income setting. Pregnant women planning to give birth at three Danish hospitals were invited to participate. After parental consent, newborn children were allocated to BCG or no intervention within 7 days of age. Randomisation was stratified by prematurity. The primary study outcome was number of all-cause hospitalisations analysed as repeated events. Hospitalisations were identified using The Danish National Patient Register. Data were analysed by Cox proportional hazards models in intention-to-treat and per-protocol analyses. 4184 pregnant women were randomised and their 4262 children allocated to BCG or no intervention. There was no difference in risk of hospitalisation up to 15 months of age; 2129 children randomised to BCG experienced 1047 hospitalisations with a mean of 0.49 hospitalisation per child compared with 1003 hospitalisations among 2133 control children (mean 0.47), resulting in a HR comparing BCG versus no BCG of 1.05 (95% CI 0.93 to 1.18) (intention-to-treat analysis). The effect of BCG was the same in children born at term (1.05 (0.92 to 1.18)) and prematurely (1.07 (0.63 to 1.81), p=0.94). The effect was also similar in the two sexes and across study sites. The results were essentially identical in the per-protocol analysis and after adjustment for baseline characteristics. BCG vaccination at birth did not reduce the risk of hospitalisation for somatic acquired disease until 15 months of age in this Danish study population. NCT01694108, results. 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/.

  10. Bacillus Calmette-Guérin (BCG) Vaccination in Infancy and Risk of Childhood Diabetes.

    Science.gov (United States)

    Rousseau, Marie-Claude; El-Zein, Mariam; Conus, Florence; Legault, Laurent; Parent, Marie-Elise

    2016-03-01

    A narrow time window in infancy may be relevant for the aetiology of immune-mediated type 1 diabetes. We investigated whether a non-specific immune stimulation in the first year of life, as resulting from Bacillus Calmette-Guérin (BCG) vaccination, was associated with childhood diabetes. Using data from a birth cohort assembled through linkage of administrative databases, 78,492 subjects born in 1974 were the object of the present analysis. Information was extracted from the birth, death, and BCG vaccination registries. Diabetes-related health services were obtained from administrative health databases (physician billing claims and hospitalisation data) until 1994. Subjects were classified as having diabetes according to two validated definitions: (1) ≥2 diabetes-related medical visits within 2 years or ≥1 hospitalisation for diabetes; and 2) ≥4 diabetes-related medical visits within 2 years. Cox proportional hazards regression was used to estimate adjusted hazard ratios (HR) and 95% confidence interval (CI), adjusted for potential confounders. Forty-four per cent of subjects were BCG vaccinated in the first year of life. According to the first and second definition, respectively, 293 (0.37%) and 230 (0.29%) subjects were classified as having diabetes. There was no association between BCG vaccination in the first year of life and risk of diabetes with either definition (HR(def1)  = 0.92, 95% CI 0.73, 1.17; HR(def2)  = 1.04, 95% CI 0.80, 1.37), and results did not differ by sex. Given the potentially critical importance of the exposure window and paucity of studies addressing BCG vaccination timing in relation to diabetes risk, this question deserves further investigation. © 2015 John Wiley & Sons Ltd.

  11. Variation of growth in the production of the BCG vaccine and the association with the immune response. An observational study within a randomised trial

    DEFF Research Database (Denmark)

    Biering-Sørensen, Sofie; Jensen, Kristoffer Jarlov; Aamand, Susanne Havn

    2015-01-01

    INTRODUCTION: Bacille Calmette-Guérin (BCG) vaccine has beneficial non-specific effects on overall survival. After BCG vaccination, positive PPD response and scar formation are associated with increased survival. During a trial randomising low-birth-weight neonates to BCG at birth or the usual de...... in the production of BCG vaccine may influence important immunological effects of the vaccine. TRIAL REGISTRATION: clinicaltrials.gov (NCT00625482).......INTRODUCTION: Bacille Calmette-Guérin (BCG) vaccine has beneficial non-specific effects on overall survival. After BCG vaccination, positive PPD response and scar formation are associated with increased survival. During a trial randomising low-birth-weight neonates to BCG at birth or the usual...

  12. Quality control and safety assessment of BCG vaccines in the post-genomic era

    Science.gov (United States)

    Stefanova, Tzvetelina

    2014-01-01

    A hundred and five years ago, Albert Calmette and Camille Guérin began a daunting task, which is unmatched even today, that led to the most widely used vaccine in human history. Despite a century of scientific advances, BCG (an acronym for Bacillus Calmette–Guérin) remains the only vaccine for prevention of tuberculosis. Due to the fact that the use of BCG vaccines will continue, either as a stand-alone or as a prime vaccine in prime-boost immunization strategies, the World Health Organization (WHO) has underlined the necessity for further work toward better characterization, evaluation and quality control of the BCG vaccine, taking into account recent advances in genetics and molecular biology. The potential benefit of such improved characterization could be addressed to better and easier differentiation between sub-strains used by different manufacturers. It may help to ensure consistency of production in terms of genetic stability and it may also help the clinical evaluation of new antituberculosis vaccines. Last but not least, the state-of-the-art technologies could facilitate the quality control performed by the manufacturers and by National Control Authorities as well. PMID:26019525

  13. Assessment of safety and interferon gamma responses of Mycobacterium bovis BCG vaccine in goat kids and milking goats.

    Science.gov (United States)

    Pérez de Val, Bernat; Vidal, Enric; López-Soria, Sergio; Marco, Alberto; Cervera, Zoraida; Martín, Maite; Mercader, Irene; Singh, Mahavir; Raeber, Alex; Domingo, Mariano

    2016-02-10

    Vaccination of domestic animals has emerged as an alternative long-term strategy for the control of tuberculosis (TB). A trial under field conditions was conducted in a TB-free goat herd to assess the safety of the Mycobacterium bovis BCG vaccine. Eleven kids and 10 milking goats were vaccinated with BCG. Bacterial shedding and interferon gamma (IFN-γ) responses were monitored throughout the study. Comprehensive pathological examination and mycobacterial culture of target tissues were performed. BCG vaccine strain was only isolated from the draining lymph node of the injection site of a kid euthanized at week 8 post-vaccination. The remaining animals were euthanized at week 24. Six out of 20 showed small granulomas at the injection site. BCG shedding was not detected in either faeces or in milk throughout the study. All vaccinated kids showed BCG-induced IFN-γ responses at week 8 post-vaccination. BCG vaccination of goats showed no lack of biological safety for the animals, environment and public health, and local adverse reactions were negligible. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Bacille Calmette-Guérin (BCG) vaccination at birth and antibody responses to childhood vaccines. A randomised clinical trial

    DEFF Research Database (Denmark)

    Nissen, Thomas Nørrelykke; Birk, Nina Marie; Smits, Gaby

    2017-01-01

    and all pneumococcal serotypes, when BCG was given after the first day of life. Girls had significantly higher antibody levels for Haemophilus influenza type b and pneumococcus than boys. CONCLUSIONS AND RELEVANCE: Three routine vaccinations with DiTeKiPol/Act-Hib and Prevenar 13 induced sero...

  15. Delayed BCG immunization does not alter antibody responses to EPI vaccines in HIV-exposed and -unexposed South African infants.

    Science.gov (United States)

    Hesseling, Anneke C; Blakney, Anna K; Jones, Christine E; Esser, Monika M; de Beer, Corena; Kuhn, Louise; Cotton, Mark F; Jaspan, Heather B

    2016-07-12

    Bacille Calmette-Guérin (BCG) is routinely given at birth in tuberculosis-endemic settings due to its protective effect against disseminated tuberculosis in infants. BCG is however contraindicated in HIV-infected infants. We investigated whether delaying BCG vaccination to 14 weeks of age affected vaccine-induced antibody responses to Haemophilus influenzae type b (Hib)-conjugate, pertussis, tetanus and Hepatitis B (HBV) vaccines, in HIV-exposed uninfected (HEU) and -unexposed uninfected (HUU) infants. Infants were randomized to receive BCG at birth or at 14 weeks of age. Blood was taken at 14, 24, and 52 weeks of age and analyzed for Hib, pertussis, tetanus and HBV specific antibodies. BCG was given either at birth (106 infants, 51 HEU) or at 14 weeks of age (74 infants, 50 HEU). The timing of BCG vaccination did not influence the antibody response to any antigen studied. However, in a non-randomized comparison, HEU infants had higher Hib antibody concentrations at weeks 14 and 24 (p=0.001 and BCG vaccination, was associated with antibody concentrations to Hib, pertussis, HBV and tetanus primary immunization. DOH-27-1106-1520. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period?

    Science.gov (United States)

    Aaby, Peter; Roth, Adam; Ravn, Henrik; Napirna, Bitiguida Mutna; Rodrigues, Amabelia; Lisse, Ida Maria; Stensballe, Lone; Diness, Birgitte Rode; Lausch, Karen Rokkedal; Lund, Najaaraq; Biering-Sørensen, Sofie; Whittle, Hilton; Benn, Christine Stabell

    2011-07-15

    Observational studies have suggested that BCG may have nonspecific beneficial effects on survival. Low-birth-weight (LBW) children are not given BCG at birth in Guinea-Bissau; we conducted a randomized trial of BCG at birth (early BCG) vs delayed BCG. In the period 2004-2008 we recruited 2320 LBW children in Bissau. The children were visited at home at 2, 6, and 12 months of age. With a pretrial infant mortality of 250 per 1000, we hypothesized a 25% reduction in infant mortality for LBW children. Infant mortality was only 101 per 1000 during the trial. In the primary analysis, infant mortality was reduced insignificantly by 17% (mortality rate ratio [MRR] = .83 [.63-1.08]). In secondary analyses, early BCG vaccine was safe with an MRR of .49 (.21-1.15) after 3 days and .55 (.34-.89) after 4 weeks. The reduction in neonatal mortality was mainly due to fewer cases of neonatal sepsis, respiratory infection, and fever. The impact of early BCG on infant mortality was marked for children weighing <1.5 kg (MRR = .43 [.21-.85]) who had lower coverage for diphtheria-tetanus-pertussis vaccinations. Though early BCG did not reduce infant mortality significantly, it may have a beneficial effect in the neonatal period. This could be important for public health because BCG is often delayed in low-income countries.

  17. Observational study to estimate the changes in the effectiveness of bacillus Calmette-Guérin (BCG) vaccination with time since vaccination for preventing tuberculosis in the UK.

    Science.gov (United States)

    Mangtani, Punam; Nguipdop-Djomo, Patrick; Keogh, Ruth H; Trinder, Lucy; Smith, Peter G; Fine, Paul Em; Sterne, Jonathan; Abubakar, Ibrahim; Vynnycky, Emilia; Watson, John; Elliman, David; Lipman, Marc; Rodrigues, Laura C

    2017-07-01

    Until recently, evidence that protection from the bacillus Calmette-Guérin (BCG) vaccination lasted beyond 10 years was limited. In the past few years, studies in Brazil and the USA (in Native Americans) have suggested that protection from BCG vaccination against tuberculosis (TB) in childhood can last for several decades. The UK's universal school-age BCG vaccination programme was stopped in 2005 and the programme of selective vaccination of high-risk (usually ethnic minority) infants was enhanced. To assess the duration of protection of infant and school-age BCG vaccination against TB in the UK. Two case-control studies of the duration of protection of BCG vaccination were conducted, the first on minority ethnic groups who were eligible for infant BCG vaccination 0-19 years earlier and the second on white subjects eligible for school-age BCG vaccination 10-29 years earlier. TB cases were selected from notifications to the UK national Enhanced Tuberculosis Surveillance system from 2003 to 2012. Population-based control subjects, frequency matched for age, were recruited. BCG vaccination status was established from BCG records, scar reading and BCG history. Information on potential confounders was collected using computer-assisted interviews. Vaccine effectiveness was estimated as a function of time since vaccination, using a case-cohort analysis based on Cox regression. In the infant BCG study, vaccination status was determined using vaccination records as recall was poor and concordance between records and scar reading was limited. A protective effect was seen up to 10 years following infant vaccination [BCG vaccination were adjusted for confounders, including birth cohort and ethnicity. For school-aged BCG vaccination, VE was 51% (95% CI 21% to 69%) 10-15 years after vaccination and 57% (95% CI 33% to 72%) 15-20 years after vaccination, beyond which time protection appeared to wane. Ascertainment of vaccination status was based on self-reported history and scar

  18. Comparative Tuberculosis (TB) Prevention Effectiveness in Children of Bacillus Calmette-Guérin (BCG) Vaccines from Different Sources, Kazakhstan

    Science.gov (United States)

    Favorov, Michael; Ali, Mohammad; Tursunbayeva, Aigul; Aitmagambetova, Indira; Kilgore, Paul; Ismailov, Shakhimurat; Chorba, Terence

    2012-01-01

    Background Except during a 1-year period when BCG vaccine was not routinely administered, annual coverage of infants with Bacillus Calmette-Guérin (BCG) in Kazakhstan since 2002 has exceeded 95%. BCG preparations from different sources (Japan, Serbia, and Russia) or none were used exclusively in comparable 7-month time-frames, September through March, in 4 successive years beginning in 2002. Our objective was to assess relative effectiveness of BCG immunization. Methods/Findings We compared outcomes of birth cohorts from the 4 time-frames retrospectively. Three cohorts received vaccine from one of three manufacturers exclusively, and one cohort was not vaccinated. Cohorts were followed for 3 years for notifications of clinical TB and of culture-confirmed TB, and for 21 months for TB meningitis notifications. Prevention effectiveness based on relative risk of TB incidence was calculated for each vaccinated cohort compared to the non-vaccinated cohort. Although there were differences in prevention effectiveness observed among the three BCG vaccines, all were protective. The Japanese vaccine (currently used in Kazakhstan), the Serbian vaccine, and the Russian vaccine respectively were 69%, 43%, and 22% effective with respect to clinical TB notifications, and 92%, 82%, and 51% effective with respect to culture confirmed TB. All three vaccines were >70% effective with respect to TB meningitis. Limitations Potential limitations included considerations that 1) the methodology used was retrospective, 2) multiple risk factors could have varied between cohorts and affected prevention effectiveness measures, 3) most cases were clinically diagnosed, and TB culture-positive case numbers and TB meningitis case numbers were sparse, and 4) small variations in reported population TB burden could have affected relative risk of exposure for cohorts. Conclusions/Significance All three BCG vaccines evaluated were protective against TB, and prevention effectiveness varied by

  19. Comparative tuberculosis (TB prevention effectiveness in children of Bacillus Calmette-Guérin (BCG vaccines from different sources, Kazakhstan.

    Directory of Open Access Journals (Sweden)

    Michael Favorov

    Full Text Available BACKGROUND: Except during a 1-year period when BCG vaccine was not routinely administered, annual coverage of infants with Bacillus Calmette-Guérin (BCG in Kazakhstan since 2002 has exceeded 95%. BCG preparations from different sources (Japan, Serbia, and Russia or none were used exclusively in comparable 7-month time-frames, September through March, in 4 successive years beginning in 2002. Our objective was to assess relative effectiveness of BCG immunization. METHODS/FINDINGS: We compared outcomes of birth cohorts from the 4 time-frames retrospectively. Three cohorts received vaccine from one of three manufacturers exclusively, and one cohort was not vaccinated. Cohorts were followed for 3 years for notifications of clinical TB and of culture-confirmed TB, and for 21 months for TB meningitis notifications. Prevention effectiveness based on relative risk of TB incidence was calculated for each vaccinated cohort compared to the non-vaccinated cohort. Although there were differences in prevention effectiveness observed among the three BCG vaccines, all were protective. The Japanese vaccine (currently used in Kazakhstan, the Serbian vaccine, and the Russian vaccine respectively were 69%, 43%, and 22% effective with respect to clinical TB notifications, and 92%, 82%, and 51% effective with respect to culture confirmed TB. All three vaccines were >70% effective with respect to TB meningitis. LIMITATIONS: Potential limitations included considerations that 1 the methodology used was retrospective, 2 multiple risk factors could have varied between cohorts and affected prevention effectiveness measures, 3 most cases were clinically diagnosed, and TB culture-positive case numbers and TB meningitis case numbers were sparse, and 4 small variations in reported population TB burden could have affected relative risk of exposure for cohorts. CONCLUSIONS/SIGNIFICANCE: All three BCG vaccines evaluated were protective against TB, and prevention effectiveness

  20. Comparative tuberculosis (TB) prevention effectiveness in children of Bacillus Calmette-Guérin (BCG) vaccines from different sources, Kazakhstan.

    Science.gov (United States)

    Favorov, Michael; Ali, Mohammad; Tursunbayeva, Aigul; Aitmagambetova, Indira; Kilgore, Paul; Ismailov, Shakhimurat; Chorba, Terence

    2012-01-01

    Except during a 1-year period when BCG vaccine was not routinely administered, annual coverage of infants with Bacillus Calmette-Guérin (BCG) in Kazakhstan since 2002 has exceeded 95%. BCG preparations from different sources (Japan, Serbia, and Russia) or none were used exclusively in comparable 7-month time-frames, September through March, in 4 successive years beginning in 2002. Our objective was to assess relative effectiveness of BCG immunization. We compared outcomes of birth cohorts from the 4 time-frames retrospectively. Three cohorts received vaccine from one of three manufacturers exclusively, and one cohort was not vaccinated. Cohorts were followed for 3 years for notifications of clinical TB and of culture-confirmed TB, and for 21 months for TB meningitis notifications. Prevention effectiveness based on relative risk of TB incidence was calculated for each vaccinated cohort compared to the non-vaccinated cohort. Although there were differences in prevention effectiveness observed among the three BCG vaccines, all were protective. The Japanese vaccine (currently used in Kazakhstan), the Serbian vaccine, and the Russian vaccine respectively were 69%, 43%, and 22% effective with respect to clinical TB notifications, and 92%, 82%, and 51% effective with respect to culture confirmed TB. All three vaccines were >70% effective with respect to TB meningitis. Potential limitations included considerations that 1) the methodology used was retrospective, 2) multiple risk factors could have varied between cohorts and affected prevention effectiveness measures, 3) most cases were clinically diagnosed, and TB culture-positive case numbers and TB meningitis case numbers were sparse, and 4) small variations in reported population TB burden could have affected relative risk of exposure for cohorts. All three BCG vaccines evaluated were protective against TB, and prevention effectiveness varied by manufacturer. When setting national immunization policy, consideration

  1. A lipidated peptide of Mycobacterium tuberculosis resuscitates the protective efficacy of BCG vaccine by evoking memory T cell immunity.

    Science.gov (United States)

    Rai, Pradeep K; Chodisetti, Sathi Babu; Zeng, Weiguang; Nadeem, Sajid; Maurya, Sudeep K; Pahari, Susanta; Janmeja, Ashok K; Jackson, David C; Agrewala, Javed N

    2017-10-06

    The current BCG vaccine induces only short-term protection against Mycobacterium tuberculosis (Mtb), suggesting its failure to generate long-lasting memory T cells. Previously, we have demonstrated that a self-adjuvanting peptide of Mtb (L91), successfully generated enduring memory Th1 cells. Consequently, we investigated if L91 was able to recuperate BCG potency in perpetuating the generation of memory T cells and protection against Mtb infected mice. In the present study, we evaluated the potency of a self adjuvanting Mtb peptide vaccine L91 in invigorating BCG immune response against Mtb in mice. Female BALB/c mice were immunized with BCG. Later, they were boosted twice with L91 or an antigenically irrelevant lipidated influenza virus hemagglutinin peptide (LH). Further, PBMCs obtained from BCG vaccinated healthy subjects were cultured in vitro with L91. T cell responses were determined by surface markers and intracellular cytokine staining. Secretion of cytokines was estimated in the culture supernatants (SNs) by ELISA. Compared to the BCG-vaccinated controls, L91 booster significantly enhanced the percentage of memory Th1 cells and Th17 cells and reduced the mycobacterial burden in BCG primed and L91-boosted (BCG-L91) group, even after 229 days of BCG vaccination. Further, substantial augmentation in the central (CD44 hi CD62L hi CD127 hi ) and effector memory (CD44 hi CD62L lo CD127 lo ) CD4 T cells was detected. Furthermore, greater frequency of polyfunctional Th1 cells (IFN-γ + TNF-α + ) and Th17 cells (IFN-γ + IL-17A + ) was observed. Importantly, BCG-L91 successfully prevented CD4 T cells from exhaustion by decreasing the expression of PD-1 and Tim-3. Additionally, augmentation in the frequency of Th1 cells, Th17 cells and memory CD4 T cells was observed in the PBMCs of the BCG-vaccinated healthy individuals following in vitro stimulation with L91. Our study demonstrated that L91 robustly reinvigorate BCG potency to invoke enduring protection against

  2. Overexpression of a Mycobacterium ulcerans Ag85B-EsxH Fusion Protein in Recombinant BCG Improves Experimental Buruli Ulcer Vaccine Efficacy.

    Directory of Open Access Journals (Sweden)

    Bryan E Hart

    2016-12-01

    Full Text Available Buruli ulcer (BU vaccine design faces similar challenges to those observed during development of prophylactic tuberculosis treatments. Multiple BU vaccine candidates, based upon Mycobacterium bovis BCG, altered Mycobacterium ulcerans (MU cells, recombinant MU DNA, or MU protein prime-boosts, have shown promise by conferring transient protection to mice against the pathology of MU challenge. Recently, we have shown that a recombinant BCG vaccine expressing MU-Ag85A (BCG MU-Ag85A displayed the highest level of protection to date, by significantly extending the survival time of MU challenged mice compared to BCG vaccination alone. Here we describe the generation, immunogenicity testing, and evaluation of protection conferred by a recombinant BCG strain which overexpresses a fusion of two alternative MU antigens, Ag85B and the MU ortholog of tuberculosis TB10.4, EsxH. Vaccination with BCG MU-Ag85B-EsxH induces proliferation of Ag85 specific CD4+ T cells in greater numbers than BCG or BCG MU-Ag85A and produces IFNγ+ splenocytes responsive to whole MU and recombinant antigens. In addition, anti-Ag85A and Ag85B IgG humoral responses are significantly enhanced after administration of the fusion vaccine compared to BCG or BCG MU-Ag85A. Finally, mice challenged with MU following a single subcutaneous vaccination with BCG MU-Ag85B-EsxH display significantly less bacterial burden at 6 and 12 weeks post-infection, reduced histopathological tissue damage, and significantly longer survival times compared to vaccination with either BCG or BCG MU-Ag85A. These results further support the potential of BCG as a foundation for BU vaccine design, whereby discovery and recombinant expression of novel immunogenic antigens could lead to greater anti-MU efficacy using this highly safe and ubiquitous vaccine.

  3. Overexpression of a Mycobacterium ulcerans Ag85B-EsxH Fusion Protein in Recombinant BCG Improves Experimental Buruli Ulcer Vaccine Efficacy.

    Science.gov (United States)

    Hart, Bryan E; Lee, Sunhee

    2016-12-01

    Buruli ulcer (BU) vaccine design faces similar challenges to those observed during development of prophylactic tuberculosis treatments. Multiple BU vaccine candidates, based upon Mycobacterium bovis BCG, altered Mycobacterium ulcerans (MU) cells, recombinant MU DNA, or MU protein prime-boosts, have shown promise by conferring transient protection to mice against the pathology of MU challenge. Recently, we have shown that a recombinant BCG vaccine expressing MU-Ag85A (BCG MU-Ag85A) displayed the highest level of protection to date, by significantly extending the survival time of MU challenged mice compared to BCG vaccination alone. Here we describe the generation, immunogenicity testing, and evaluation of protection conferred by a recombinant BCG strain which overexpresses a fusion of two alternative MU antigens, Ag85B and the MU ortholog of tuberculosis TB10.4, EsxH. Vaccination with BCG MU-Ag85B-EsxH induces proliferation of Ag85 specific CD4+ T cells in greater numbers than BCG or BCG MU-Ag85A and produces IFNγ+ splenocytes responsive to whole MU and recombinant antigens. In addition, anti-Ag85A and Ag85B IgG humoral responses are significantly enhanced after administration of the fusion vaccine compared to BCG or BCG MU-Ag85A. Finally, mice challenged with MU following a single subcutaneous vaccination with BCG MU-Ag85B-EsxH display significantly less bacterial burden at 6 and 12 weeks post-infection, reduced histopathological tissue damage, and significantly longer survival times compared to vaccination with either BCG or BCG MU-Ag85A. These results further support the potential of BCG as a foundation for BU vaccine design, whereby discovery and recombinant expression of novel immunogenic antigens could lead to greater anti-MU efficacy using this highly safe and ubiquitous vaccine.

  4. Overexpression of a Mycobacterium ulcerans Ag85B-EsxH Fusion Protein in Recombinant BCG Improves Experimental Buruli Ulcer Vaccine Efficacy

    Science.gov (United States)

    Hart, Bryan E.

    2016-01-01

    Buruli ulcer (BU) vaccine design faces similar challenges to those observed during development of prophylactic tuberculosis treatments. Multiple BU vaccine candidates, based upon Mycobacterium bovis BCG, altered Mycobacterium ulcerans (MU) cells, recombinant MU DNA, or MU protein prime-boosts, have shown promise by conferring transient protection to mice against the pathology of MU challenge. Recently, we have shown that a recombinant BCG vaccine expressing MU-Ag85A (BCG MU-Ag85A) displayed the highest level of protection to date, by significantly extending the survival time of MU challenged mice compared to BCG vaccination alone. Here we describe the generation, immunogenicity testing, and evaluation of protection conferred by a recombinant BCG strain which overexpresses a fusion of two alternative MU antigens, Ag85B and the MU ortholog of tuberculosis TB10.4, EsxH. Vaccination with BCG MU-Ag85B-EsxH induces proliferation of Ag85 specific CD4+ T cells in greater numbers than BCG or BCG MU-Ag85A and produces IFNγ+ splenocytes responsive to whole MU and recombinant antigens. In addition, anti-Ag85A and Ag85B IgG humoral responses are significantly enhanced after administration of the fusion vaccine compared to BCG or BCG MU-Ag85A. Finally, mice challenged with MU following a single subcutaneous vaccination with BCG MU-Ag85B-EsxH display significantly less bacterial burden at 6 and 12 weeks post-infection, reduced histopathological tissue damage, and significantly longer survival times compared to vaccination with either BCG or BCG MU-Ag85A. These results further support the potential of BCG as a foundation for BU vaccine design, whereby discovery and recombinant expression of novel immunogenic antigens could lead to greater anti-MU efficacy using this highly safe and ubiquitous vaccine. PMID:27941982

  5. Differential Adverse Event Profiles Associated with BCG as a Preventive Tuberculosis Vaccine or Therapeutic Bladder Cancer Vaccine Identified by Comparative Ontology-Based VAERS and Literature Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Jiangan Xie

    Full Text Available M. bovis strain Bacillus Calmette-Guérin (BCG has been the only licensed live attenuated vaccine against tuberculosis (TB for nearly one century and has also been approved as a therapeutic vaccine for bladder cancer treatment since 1990. During its long time usage, different adverse events (AEs have been reported. However, the AEs associated with the BCG preventive TB vaccine and therapeutic cancer vaccine have not been systematically compared. In this study, we systematically collected various BCG AE data mined from the US VAERS database and PubMed literature reports, identified statistically significant BCG-associated AEs, and ontologically classified and compared these AEs related to these two types of BCG vaccine. From 397 VAERS BCG AE case reports, we identified 64 AEs statistically significantly associated with the BCG TB vaccine and 14 AEs with the BCG cancer vaccine. Our meta-analysis of 41 peer-reviewed journal reports identified 48 AEs associated with the BCG TB vaccine and 43 AEs associated with the BCG cancer vaccine. Among all identified AEs from VAERS and literature reports, 25 AEs belong to serious AEs. The Ontology of Adverse Events (OAE-based ontological hierarchical analysis indicated that the AEs associated with the BCG TB vaccine were enriched in immune system (e.g., lymphadenopathy and lymphadenitis, skin (e.g., skin ulceration and cyanosis, and respiratory system (e.g., cough and pneumonia; in contrast, the AEs associated with the BCG cancer vaccine mainly occurred in the urinary system (e.g., dysuria, pollakiuria, and hematuria. With these distinct AE profiles detected, this study also discovered three AEs (i.e., chills, pneumonia, and C-reactive protein increased shared by the BCG TB vaccine and bladder cancer vaccine. Furthermore, our deep investigation of 24 BCG-associated death cases from VAERS identified the important effects of age, vaccine co-administration, and immunosuppressive status on the final BCG

  6. Differential Adverse Event Profiles Associated with BCG as a Preventive Tuberculosis Vaccine or Therapeutic Bladder Cancer Vaccine Identified by Comparative Ontology-Based VAERS and Literature Meta-Analysis

    Science.gov (United States)

    Xie, Jiangan; Codd, Christopher; Mo, Kevin; He, Yongqun

    2016-01-01

    M. bovis strain Bacillus Calmette–Guérin (BCG) has been the only licensed live attenuated vaccine against tuberculosis (TB) for nearly one century and has also been approved as a therapeutic vaccine for bladder cancer treatment since 1990. During its long time usage, different adverse events (AEs) have been reported. However, the AEs associated with the BCG preventive TB vaccine and therapeutic cancer vaccine have not been systematically compared. In this study, we systematically collected various BCG AE data mined from the US VAERS database and PubMed literature reports, identified statistically significant BCG-associated AEs, and ontologically classified and compared these AEs related to these two types of BCG vaccine. From 397 VAERS BCG AE case reports, we identified 64 AEs statistically significantly associated with the BCG TB vaccine and 14 AEs with the BCG cancer vaccine. Our meta-analysis of 41 peer-reviewed journal reports identified 48 AEs associated with the BCG TB vaccine and 43 AEs associated with the BCG cancer vaccine. Among all identified AEs from VAERS and literature reports, 25 AEs belong to serious AEs. The Ontology of Adverse Events (OAE)-based ontological hierarchical analysis indicated that the AEs associated with the BCG TB vaccine were enriched in immune system (e.g., lymphadenopathy and lymphadenitis), skin (e.g., skin ulceration and cyanosis), and respiratory system (e.g., cough and pneumonia); in contrast, the AEs associated with the BCG cancer vaccine mainly occurred in the urinary system (e.g., dysuria, pollakiuria, and hematuria). With these distinct AE profiles detected, this study also discovered three AEs (i.e., chills, pneumonia, and C-reactive protein increased) shared by the BCG TB vaccine and bladder cancer vaccine. Furthermore, our deep investigation of 24 BCG-associated death cases from VAERS identified the important effects of age, vaccine co-administration, and immunosuppressive status on the final BCG-associated death

  7. Effect of BCG vaccine on peritoneal endometriotic implants in a rat model of endometriosis.

    Science.gov (United States)

    Itil, Ismail Mete; Cirpan, Teksin; Akercan, Fuat; Gamaa, Akram; Kazandi, Mert; Kazandi, Ali Can; Yildiz, Pinar Solmaz; Askar, Niyazi

    2006-02-01

    To investigate the effect of Bacillus Calmette-Guerin (BCG) vaccine on peritoneal implantation of endometrial tissue in rats. Forty sexually mature virgin Wistar albino rats weighing 190-200 g were randomly assigned (double blind) to two groups. The rats in the first group were vaccinated with 0.1 mL BCG and those in the second group were injected with 0.1 mL saline into the tail, intracutaneously. All the rats underwent median laparotomy after 4 weeks of vaccination or injection. The right uterine horn was excised, and the two samples of endometrial tissue dissected from myometrium were implanted on each side of peritoneum at the 2 cm lateral line of the median laparotomy incision. The implanted peritoneal segments were excised after 8 weeks of laparotomy. The tissue samples were accepted, histologically, as endometriosis when both glands and stroma of endometrial tissue were seen in sections. Thirty-six implants from the study group and 34 implants from the control group were obtained. Ten and 23 implants were accepted as endometriosis in the study and control group, respectively. The number of endometriotic foci were significantly lower in the study group than in the control group (P = 0.01). Stimulation of the cellular immune response with BCG vaccine could exert an inhibitory effect on ectopic endometriotic implants.

  8. Is tuberculin testing before BCG vaccination necessary for children over three months of age?

    LENUS (Irish Health Repository)

    Hennessy, B

    2008-03-01

    In July 2007 Irish national policy changed such that children aged 3 months to 6 years no longer routinely require tuberculin (Mantoux) skin testing prior to BCG vaccination. Previous to that a tuberculin test was required in all children in this age group pre vaccination. While the previous policy was in place this study was conducted to assess the value of this test. The observation that children are frightened by the test (an injection into the skin) prompted the study. The author conducted a retrospective study of the results of 1,854 tuberculin tests performed as a prerequisite to BCG vaccination and found that only 0.7% of children had a positive test result (induration > 5mm). None of 107 children < 6 years of age tested positive. Those > 12 years were more likely to test positive than younger children (1.09% vs 0.4% respectively, p < 0.05). This study suggests that testing young children before BCG vaccination has a low yield of positive results and adds little to the detection of latent or active TB.

  9. Co-administration of BCG and Diphtheria-tetanus-pertussis (DTP) Vaccinations May Reduce Infant Mortality More Than the WHO-schedule of BCG First and Then DTP. A Re-analysis of Demographic Surveillance Data From Rural Bangladesh.

    Science.gov (United States)

    Aaby, Peter; Andersen, Andreas; Ravn, Henrik; Zaman, K

    2017-08-01

    WHO recommends BCG at birth and diphtheria-tetanus-pertussis (DTP)-containing vaccine at 6, 10 and 14weeks of age. However, BCG and DTP are often co-administered in low-income countries. The health implications have not been examined. We reanalysed data from Matlab, Bangladesh, to examine the influence of co-administration on mortality; 37,894 children born 1986-1999 were followed with registration of vaccinations and survival. Using Cox models, survival was analysed from 6weeks to 9months of age when measles vaccine is given; 712 children died in this age group. We calculated mortality rate ratios (MRR) for children starting the vaccination schedule with BCG-first, BCG+DTP1-first or DTP1-first. Only 17% followed the WHO-schedule with BCG-first. Mortality was 16/1000 person-years for children who initiated the vaccination schedule with BCG+DTP1 but 32/1000 and 20/1000 for children who received BCG-first or DTP-first, respectively. Compared with BCG+DTP1-first and adjusting for background factors, the BCG-first-schedule was associated with 2-fold higher mortality (MRR=1.94 (1.42-2.63)). DTP1 administered after BCG-first was associated with higher mortality than receiving DTP1 with BCG (MRR=1.78 (1.03-3.03)). Co-administration of BCG and DTP may further reduce mortality. Since all observational studies support this trend, co-administration of BCG and DTP should be tested in randomised trials. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  10. Lymph node targeting of BCG vaccines amplifies CD4 and CD8 T-cell responses and protection against Mycobacterium tuberculosis.

    Science.gov (United States)

    Waeckerle-Men, Ying; Bruffaerts, Nicolas; Liang, Yuan; Jurion, Fabienne; Sander, Peter; Kündig, Thomas M; Huygen, Kris; Johansen, Pål

    2013-02-04

    Vaccination with Mycobacterium bovis BCG provides limited protection against pulmonary tuberculosis and a risk of dissemination in immune-compromised vaccinees. For the development of new TB vaccines that stimulate strong T-cell responses a variety of strategies is being followed, especially recombinant BCG and attenuated M. tuberculosis. The objective of the current study was to test potential benefits of vaccination through direct lymph-node targeting of wildtype BCG; the recommended route of vaccination with BCG is intradermal. C57BL/6 mice were immunised with BCG by intradermal, subcutaneous or intralymphatic injections. Cellular immune responses and protection against M. tuberculosis were determined. Intralymphatic vaccination was 100-1000 times more effective in stimulating BCG-specific immune responses than intradermal or subcutaneous immunisation. Intralymphatic administration stimulated high frequencies of mycobacterium-specific lymphocytes with strong proliferating capacity and production of TNF-α, IL-2, IL-17 and, especially, IFN-γ secretion by. CD4 and CD8 T cells. Most importantly, intralymphatic vaccination with 2×10(3)CFU BCG induced sustained protection against M. tuberculosis in intratracheally challenged C57BL/6 mice, whereas subcutaneous vaccination with 2×10(5)CFU BCG conferred only a transient protection. Hence, direct administration of M. bovis BCG to lymph nodes demonstrates that efficient targeting to lymph nodes may help to overcome the efficacy problems of vaccination with BCG. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. PO and ID BCG vaccination in humans induce distinct mucosal and systemic immune responses and CD4+T cell transcriptomal molecular signatures.

    Science.gov (United States)

    Hoft, D F; Xia, M; Zhang, G L; Blazevic, A; Tennant, J; Kaplan, C; Matuschak, G; Dube, T J; Hill, H; Schlesinger, L S; Andersen, P L; Brusic, V

    2017-08-30

    Protective efficacy of Bacillus Calmette-Guérin (BCG) may be affected by the methods and routes of vaccine administration. We have studied the safety and immunogenicity of oral (PO) and/or intradermal (ID) administration of BCG in healthy human subjects. No major safety concerns were detected in the 68 healthy adults vaccinated with PO and/or ID BCG. Although both PO and ID BCG could induce systemic Th1 responses capable of IFN-γ production, ID BCG more strongly induced systemic Th1 responses. In contrast, stronger mucosal responses (TB-specific secretory IgA and bronchoalveolar lavage T cells) were induced by PO BCG vaccination. To generate preliminary data comparing the early gene signatures induced by mucosal and systemic BCG vaccination, CD4 + memory T cells were isolated from subsets of BCG vaccinated subjects pre- (Day 0) and post-vaccination (Days 7 and 56), rested or stimulated with BCG infected dendritic cells, and then studied by Illumina BeadArray transcriptomal analysis. Notably, distinct gene expression profiles were identified both on Day 7 and Day 56 comparing the PO and ID BCG vaccinated groups by GSEA analysis. Future correlation analyses between specific gene expression patterns and distinct mucosal and systemic immune responses induced will be highly informative for TB vaccine development.Mucosal Immunology advance online publication 30 August 2017; doi:10.1038/mi.2017.67.

  12. Lack of a Negative Effect of BCG-Vaccination on Child Psychomotor Development

    DEFF Research Database (Denmark)

    Kjærgaard, Jesper; Stensballe, Lone Graff; Birk, Nina Marie

    2016-01-01

    MEASURES: Psychomotor development measured using Ages and Stages Questionnaire (ASQ) completed by the parents at 12 months. Additionally, parents of premature children (gestational age Developmental assessment was available for 3453/4262 (81%). RESULTS......OBJECTIVES: To assess the non-specific effect of Bacillus Calmette-Guérin (BCG) vaccination at birth on psychomotor development. DESIGN: This is a pre-specified secondary outcome from a randomised, clinical trial. SETTING: Maternity units and paediatric wards at three university hospitals...... was -7.8 points (-20.6 to 5.0, p = 0.23), d = -0.23 (-0.62 to 0.15). CONCLUSIONS: A negative non-specific effect of BCG vaccination at birth on psychomotor development was excluded in term children. TRIAL REGISTRATION: ClinicalTrials.gov NCT01694108....

  13. Activity in mice of recombinant BCG-EgG1Y162 vaccine for Echinococcus granulosus infection.

    Science.gov (United States)

    Ma, Xiumin; Zhao, Hui; Zhang, Fengbo; Zhu, Yuejie; Peng, Shanshan; Ma, Haimei; Cao, Chunbao; Xin, Yan; Yimiti, Delixiati; Wen, Hao; Ding, Jianbing

    2016-01-01

    Cystic hydatid disease is a zoonotic parasitic disease caused by Echinococcus granulosus which is distributed worldwide. The disease is difficult to treat with surgery removal is the only cure treatment. In the high endemic areas, vaccination of humans is believed a way to protect communities from the disease. In this study we vaccinated BALB/c mice with rBCG-EgG1Y162, and then detected the level of IgG and IgE specifically against the recombinant protein by ELISA, rBCG-EgG1Y162 induced strong and specific cellular and humoral immune responses. In vitro study showed that rBCG-EgG1Y162 vaccine not only promote splenocytes proliferation but also active T cell. In addition, the rBCG-EgG1Y162 induced a protection in the mice against secondary infection of Echinococcus granulosus.

  14. rBCG Induces Strong Antigen-Specific T Cell Responses in Rhesus Macaques in a Prime-Boost Setting with an Adenovirus 35 Tuberculosis Vaccine Vector

    NARCIS (Netherlands)

    Magalhaes, Isabelle; Sizemore, Donata R.; Ahmed, Raija K.; Mueller, Stefanie; Wehlin, Lena; Scanga, Charles; Weichold, Frank; Schirru, Giulia; Pau, Maria Grazia; Goudsmit, Jaap; Kühlmann-Berenzon, Sharon; Spångberg, Mats; Andersson, Jan; Gaines, Hans; Thorstensson, Rigmor; Skeiky, Yasir A. W.; Sadoff, Jerry; Maeurer, Markus

    2008-01-01

    BACKGROUND: BCG vaccination, combined with adenoviral-delivered boosts, represents a reasonable strategy to augment, broaden and prolong immune protection against tuberculosis (TB). We tested BCG (SSI1331) (in 6 animals, delivered intradermally) and a recombinant (rBCG) AFRO-1 expressing

  15. T-cell mRNA Expression in Response to Mycobacterium bovis BCG Vaccination and Mycobacterium bovis Infection of White-tailed deer

    Science.gov (United States)

    Understanding immune responses of white-tailed deer (WTD) to infection with Mycobacterium bovis provides insight into mechanisms of pathogen control and may provide clues to development of effective vaccine strategies. WTD were vaccinated with either BCG strain Pasteur or BCG Danish. Both vaccinates...

  16. Immunogenic Properties of a BCG Adjuvanted Chitosan Nanoparticle-Based Dengue Vaccine in Human Dendritic Cells

    Science.gov (United States)

    Hunsawong, Taweewun; Sunintaboon, Panya; Warit, Saradee; Thaisomboonsuk, Butsaya; Jarman, Richard G.; Yoon, In-Kyu; Ubol, Sukathida; Fernandez, Stefan

    2015-01-01

    Dengue viruses (DENVs) are among the most rapidly and efficiently spreading arboviruses. WHO recently estimated that about half of the world’s population is now at risk for DENV infection. There is no specific treatment or vaccine available to treat or prevent DENV infections. Here, we report the development of a novel dengue nanovaccine (DNV) composed of UV-inactivated DENV-2 (UVI-DENV) and Mycobacterium bovis Bacillus Calmette-Guerin cell wall components (BCG-CWCs) loaded into chitosan nanoparticles (CS-NPs). CS-NPs were prepared by an emulsion polymerization method prior to loading of the BCG-CWCs and UVI-DENV components. Using a scanning electron microscope and a zetasizer, DNV was determined to be of spherical shape with a diameter of 372.0 ± 11.2 nm in average and cationic surface properties. The loading efficacies of BCG-CWCs and UVI-DENV into the CS-NPs and BCG-CS-NPs were up to 97.2 and 98.4%, respectively. THP-1 cellular uptake of UVI-DENV present in the DNV was higher than soluble UVI-DENV alone. DNV stimulation of immature dendritic cells (iDCs) resulted in a significantly higher expression of DCs maturation markers (CD80, CD86 and HLA-DR) and induction of various cytokine and chemokine productions than in UVI-DENV-treated iDCs, suggesting a potential use of BCG- CS-NPs as adjuvant and delivery system for dengue vaccines. PMID:26394138

  17. Immunogenic Properties of a BCG Adjuvanted Chitosan Nanoparticle-Based Dengue Vaccine in Human Dendritic Cells.

    Directory of Open Access Journals (Sweden)

    Taweewun Hunsawong

    2015-09-01

    Full Text Available Dengue viruses (DENVs are among the most rapidly and efficiently spreading arboviruses. WHO recently estimated that about half of the world's population is now at risk for DENV infection. There is no specific treatment or vaccine available to treat or prevent DENV infections. Here, we report the development of a novel dengue nanovaccine (DNV composed of UV-inactivated DENV-2 (UVI-DENV and Mycobacterium bovis Bacillus Calmette-Guerin cell wall components (BCG-CWCs loaded into chitosan nanoparticles (CS-NPs. CS-NPs were prepared by an emulsion polymerization method prior to loading of the BCG-CWCs and UVI-DENV components. Using a scanning electron microscope and a zetasizer, DNV was determined to be of spherical shape with a diameter of 372.0 ± 11.2 nm in average and cationic surface properties. The loading efficacies of BCG-CWCs and UVI-DENV into the CS-NPs and BCG-CS-NPs were up to 97.2 and 98.4%, respectively. THP-1 cellular uptake of UVI-DENV present in the DNV was higher than soluble UVI-DENV alone. DNV stimulation of immature dendritic cells (iDCs resulted in a significantly higher expression of DCs maturation markers (CD80, CD86 and HLA-DR and induction of various cytokine and chemokine productions than in UVI-DENV-treated iDCs, suggesting a potential use of BCG- CS-NPs as adjuvant and delivery system for dengue vaccines.

  18. The Effect of Oral Vaccination with Mycobacterium bovis BCG on the Development of Tuberculosis in Captive European Badgers (Meles meles).

    Science.gov (United States)

    Chambers, Mark A; Aldwell, Frank; Williams, Gareth A; Palmer, Si; Gowtage, Sonya; Ashford, Roland; Dalley, Deanna J; Davé, Dipesh; Weyer, Ute; Salguero, Francisco J; Nunez, Alejandro; Nadian, Allan K; Crawshaw, Timothy; Corner, Leigh A L; Lesellier, Sandrine

    2017-01-01

    The European badger ( Meles meles ) is a reservoir host of Mycobacterium bovis and responsible for a proportion of the tuberculosis (TB) cases seen in cattle in the United Kingdom and Republic of Ireland. An injectable preparation of the bacillus Calmette-Guérin (BCG) vaccine is licensed for use in badgers in the UK and its use forms part of the bovine TB eradication plans of England and Wales. However, there are practical limitations to the widespread application of an injectable vaccine for badgers and a research priority is the development of an oral vaccine deliverable to badgers in bait. Previous studies reported the successful vaccination of badgers with oral preparations of 10 8 colony forming units (CFU) of both Pasteur and Danish strains of BCG contained within a lipid matrix composed of triglycerides of fatty acids. Protection against TB in these studies was expressed as a reduction in the number and apparent progression of visible lesions, and reductions in the bacterial load and dissemination of infection. To reduce the cost of an oral vaccine and reduce the potential for environmental contamination with BCG, it is necessary to define the minimal efficacious dose of oral BCG for badgers. The objectives of the two studies reported here were to compare the efficacy of BCG Danish strain in a lipid matrix with unformulated BCG given orally, and to evaluate the efficacy of BCG Danish in a lipid matrix at a 10-fold lower dose than previously evaluated in badgers. In the first study, both BCG unformulated and in a lipid matrix reduced the number and apparent progression of visible lesions and the dissemination of infection from the lung. In the second study, vaccination with BCG in the lipid matrix at a 10-fold lower dose produced a similar outcome, but with greater intra-group variability than seen with the higher dose in the first study. Further research is needed before we are able to recommend a final dose of BCG for oral vaccination of badgers against TB

  19. Bacillus Calmette-Guérin (BCG) vaccine: A global assessment of demand and supply balance.

    Science.gov (United States)

    Cernuschi, Tania; Malvolti, Stefano; Nickels, Emily; Friede, Martin

    2018-01-25

    Over the past decade, several countries across all regions, income groups and procurement methods have been unable to secure sufficient BCG vaccine supply. While the frequency of stock-outs has remained rather stable, duration increased in 2014-2015 due to manufacturing issues and attracted the attention of national, regional and global immunization stakeholders. This prompted an in-depth analysis of supply and demand dynamics aiming to characterize supply risks. This analysis is unique as it provides a global picture, where previous analyses have focused on a portion of the market procuring through UN entities. Through literature review, supplier interviews, appraisal of shortages, stock-outs and historical procurement data, and through demand forecasting, this analysis shows an important increase in global capacity in 2017: supply is sufficient to meet forecasted BCG vaccine demand and possibly buffer market shocks. Nevertheless, risks remain mainly due to supply concentration and limited investment in production process improvements, as well as inflexibility in demand. Identification of these market risks will allow implementation of risk-mitigating interventions in three areas: (1) enhancing information sharing between major global health actors, countries and suppliers, (2) identifying interests and incentives to expand product registration and investment in the BCG manufacturing process, and (3) working with countries for tighter vaccine management. Copyright © 2017. Published by Elsevier Ltd.

  20. Pre-clinical toxicity and immunogenicity evaluation of a MUC1-MBP/BCG anti-tumor vaccine.

    Science.gov (United States)

    Hu, Boqi; Wang, Juan; Guo, Yingying; Chen, Tanxiu; Ni, Weihua; Yuan, Hongyan; Zhang, Nannan; Xie, Fei; Tai, Guixiang

    2016-04-01

    Mucin 1 (MUC1), as an oncogene, plays a key role in the progression and tumorigenesis of many human adenocarcinomas and is an attractive target in tumor immunotherapy. Our previous study showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific Th1-dominant immune response, simulated MUC1-specific cytotoxic T lymphocyte killing activity, and could significantly inhibit MUC1-expression B16 cells' growth in mice. To help move the vaccine into a Phase I clinical trial, in the current study, a pre-clinical toxicity and immunogenicity evaluation of the vaccine was conducted. The evaluation was comprised of a single-dose acute toxicity study in mice, repeat-dose chronic toxicity and immunogenicity studies in rats, and pilot toxicity and immunogenicity studies in cynomolgus monkeys. The results showed that treatment with the MUC1-MBP/BCG anti-tumor vaccine did not cause any organ toxicity, except for arthritis or local nodules induced by BCG in several rats. Furthermore, the vaccine significantly increased the levels of IFN-γ in rats, indicating that Th1 cells were activated. In addition, the results showed that the MUC1-MBP/BCG anti-tumor vaccine induced a MUC1-specific IgG antibody response both in rats and cynomolgus monkeys. Collectively, these data are beneficial to move the MUC1-MBP/BCG anti-tumor vaccine into a Phase I clinical trial. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Vaccination of cattle with Danish and Pasteur strains of Mycobacterium bovis BCG induce different levels of IFNgamma post-vaccination, but induce similar levels of protection against bovine tuberculosis.

    Science.gov (United States)

    Wedlock, D Neil; Denis, Michel; Vordermeier, H Martin; Hewinson, R Glyn; Buddle, Bryce M

    2007-07-15

    A number of studies have demonstrated significant protection of cattle against bovine tuberculosis following vaccination with the Pasteur strain of Mycobacterium bovis bacille Calmete-Guerin (BCG). However, it is unclear if other daughter strains of BCG are as effective, which is an important issue to resolve for a variety of regulatory compliance issues. This study compared the protective immune responses to bovine tuberculosis induced in cattle vaccinated with BCG Danish with those induced by BCG Pasteur. Groups of calves (n=10) were vaccinated with 10(6) colony forming units (CFU) BCG Pasteur prepared from a fresh liquid culture, 10(6) CFU BCG Danish prepared from a fresh liquid culture or 0.4 mg of reconstituted freeze-dried culture of BCG Danish. Another group (n=10) served as non-vaccinated controls. BCG Pasteur induced significantly higher and more sustained levels of bovine purified protein derivative (PPD)-specific gamma interferon (IFN-gamma) in whole-blood cultures following vaccination compared to either fresh culture BCG Danish or freeze-dried BCG Danish. Vaccination with a fresh culture of BCG Pasteur, fresh culture BCG Danish and freeze-dried BCG Danish gave a significant enhancement in three, four and three pathological and microbiological parameters of protection, respectively, compared to the non-vaccinated group. These results demonstrate the Danish strain of BCG is a viable alternative to BCG Pasteur for vaccination of cattle as both strains had similar efficacy and there was little difference between freshly cultured and freeze-dried formulation of BCG Danish. The results also show that post-vaccination antigen-specific IFN-gamma levels in whole blood is not always a reliable indicator of protection against a subsequent virulent challenge.

  2. Heterologous Immunological Effects of Early BCG Vaccination in Low-Birth-Weight Infants in Guinea-Bissau

    DEFF Research Database (Denmark)

    Jensen, Kristoffer Jarlov; Larsen, Nanna; Biering-Sørensen, Sofie

    2015-01-01

    -Bissau of early BCG vs the usual postponed BCG, a subgroup was bled 4 weeks after randomization. Levels of interleukin (IL)-1β, IL-5, IL-6, IL-10, IL-17, interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured from whole-blood assays stimulated with innate agonists to Toll-like receptor (TLR)-2, -4...... or -7/8, or purified protein derivative (PPD). RESULTS:  Among 467 infants, BCG significantly increased the in vitro cytokine responses to purified protein derivative of Mycobacterium tuberculosis (PPD), as expected. BCG was also associated with increased responses to heterologous innate stimulation......, particularly of the cytokines IL-1β, IL-6, TNF-α, and IFN-γ. CONCLUSION:  Four weeks after immunization, BCG-vaccinated infants have a significantly increased production of cytokines upon heterologous challenge, particularly T helper cell type 1 polarizing and typically monocyte-derived pro...

  3. The Ag85B protein of the BCG vaccine facilitates macrophage uptake but is dispensable for protection against aerosol Mycobacterium tuberculosis infection.

    Science.gov (United States)

    Prendergast, Kelly A; Counoupas, Claudio; Leotta, Lisa; Eto, Carolina; Bitter, Wilbert; Winter, Nathalie; Triccas, James A

    2016-05-17

    Defining the function and protective capacity of mycobacterial antigens is crucial for progression of tuberculosis (TB) vaccine candidates to clinical trials. The Ag85B protein is expressed by all pathogenic mycobacteria and is a component of multiple TB vaccines under evaluation in humans. In this report we examined the role of the BCG Ag85B protein in host cell interaction and vaccine-induced protection against virulent Mycobacterium tuberculosis infection. Ag85B was required for macrophage infection in vitro, as BCG deficient in Ag85B expression (BCG:(Δ85B)) was less able to infect RAW 264.7 macrophages compared to parental BCG, while an Ag85B-overexpressing BCG strain (BCG:(oex85B)) demonstrated improved uptake. A similar pattern was observed in vivo after intradermal delivery to mice, with significantly less BCG:(Δ85B) present in CD64(hi)CD11b(hi) macrophages compared to BCG or BCG:(oex85B). After vaccination of mice with BCG:(Δ85B) or parental BCG and subsequent aerosol M. tuberculosis challenge, similar numbers of activated CD4(+) and CD8(+) T cells were detected in the lungs of infected mice for both groups, suggesting the reduced macrophage uptake observed by BCG:(Δ85B) did not alter host immunity. Further, vaccination with both BCG:(Δ85B) and parental BCG resulted in a comparable reduction in pulmonary M. tuberculosis load. These data reveal an unappreciated role for Ag85B in the interaction of mycobacteria with host cells and indicates that single protective antigens are dispensable for protective immunity induced by BCG. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. The humoral immune response after BCG vaccination in humans: consequences for the serodiagnosis of tuberculosis.

    Science.gov (United States)

    Turneer, M; Van Vooren, J P; Nyabenda, J; Legros, F; Lecomte, A; Thiriaux, J; Serruys, E; Yernault, J C

    1988-07-01

    The IgM and IgG response to BCG vaccination was investigated in 75 adults, tuberculin negative before vaccination, using an enzyme-linked immunosorbent assay with purified protein derivative (PPD) as antigen. The mean optical density (OD) increased significantly (p less than 0.001) in both immunoglobulin classes. Increase in at least one class was significant in 89% of the subjects. The observed increase in anti-PPD IgG was rather small but comparable to that seen in 17 newly diagnosed tuberculosis patients with negative direct smear [mean OD (SD): 0.59 (0.38) in vaccinated and 0.70 (0.48) in patients] but significantly lower (p less than 0.001) than that seen in 31 newly diagnosed patients with positive direct smear [mean OD (SD): 1.07 (0.67)]. With 55% of sera above the upper normal limit, smear positive patients differentiated (p less than 0.001) from vaccinated subjects (20% of positive sera) whilst smear negative patients (29% of positive sera) did not. We conclude that BCG vaccination induces a definite but small increase in anti-PPD serum IgM and IgG, which is likely to interfere when interpreting serological tests for the diagnosis of tuberculosis, especially in those patients who would most benefit from an early and fast diagnosis.

  5. Complications after BCG vaccination in a big city

    Directory of Open Access Journals (Sweden)

    T. A. Sevostyanova

    2016-01-01

    Full Text Available Complications after specific prevention of tuberculosis for the last 10 years have been analyzed using the example of a big city. The frequency of severe complications (BCG-ostitis made 0.004% and the frequency of minor complications (lymphadenitis made 0.005% and cold abscesses made 0.01% per 100 000 vaccinated children. Often complications were caused by mistakes in the vaccine administration related to premature discharge from maternity hospital and administration of the vaccine in the polyclinic and also concurrent prenatal disorder. The issue of complications caused by anti-tuberculosis vaccination makes no grounds to review the policy of the primary BCG vaccination.

  6. Hypoxia induces an immunodominant target of tuberculosis specific T cells absent from common BCG vaccines.

    Directory of Open Access Journals (Sweden)

    Hannah Priyadarshini Gideon

    2010-12-01

    Full Text Available M. tuberculosis (MTB species-specific antigenic determinants of the human T cell response are important for immunodiagnosis and vaccination. As hypoxia is a stimulus in chronic tuberculosis infection, we analyzed transcriptional profiles of MTB subject to 168 hours of hypoxia to test the hypothesis that upregulation by hypoxia might result in gene products being recognized as antigens. We identified upregulation of two region of difference (RD 11 (Rv2658C and Rv2659c, and one RD2 (Rv1986 absent from commonly used BCG strains. In MTB infected persons, the IL-2 ELISpot response to Rv1986 peptides was several times greater than the corresponding IFN-γ response to the reference immunodominant ESAT-6 or CFP-10 antigens. The IL-2 response was confined to two epitopic regions containing residues 61-80 and 161-180. The biggest population of IL-2 secreting T cells was single cytokine positive central memory T cells. The IL-2 response to live MTB bacilli lacking Rv1986 was significantly lower than the response to wild type or mutant complemented with Rv1986. In addition, the IL-2 response to Rv1986 was significantly lower in HIV-TB co-infected persons than in HIV uninfected persons, and significantly increased during antiretroviral therapy. These findings demonstrate that Rv1986 is an immunodominant target of memory T cells and is therefore of relevance when considering the partial efficacy of currently used BCG vaccines and provide evidence for a clinical trial comparing BCG strains.

  7. Differential Cell Composition and Cytokine Expression Within Lymph Node Granulomas from BCG-Vaccinated and Non-vaccinated Cattle Experimentally Infected with Mycobacterium bovis.

    Science.gov (United States)

    Salguero, F J; Gibson, S; Garcia-Jimenez, W; Gough, J; Strickland, T S; Vordermeier, H M; Villarreal-Ramos, B

    2017-12-01

    Cattle vaccination against bovine tuberculosis (bTB) has been proposed as a supplementary method to help control the incidences of this disease. Bacillus Calmette-Guérin (BCG) is currently the only viable candidate vaccine for immunization of cattle against bTB, caused by Mycobacterium bovis (M. bovis). In an attempt to characterize the differences in the immune response following M. bovis infection between BCG-vaccinated and non-vaccinated animals, a combination of gross pathology, histopathology and immunohistochemical (IHC) analyses was used. BCG vaccination was found to significantly reduce the number of gross and microscopic lesions present within the lungs and lymph nodes. Additionally, the microscopically visible bacterial load of stages III and IV granulomas was reduced. IHC using cell surface markers revealed the number of CD68+ (macrophages), CD3+ (T lymphocytes) and WC1+ cells (γδ T cells) to be significantly reduced in lymph node granulomas of BCG-vaccinated animals, when compared to non-vaccinated animals. B lymphocytes (CD79a+) were significantly increased in BCG-vaccinated cattle for granulomas at stages II, III and IV. IHC staining for iNOS showed a higher expression in granulomas from BCG-vaccinated animals compared to non-vaccinated animals for all stages, being statistically significant in stages I and IV. TGFβ expression decreased alongside the granuloma development in non-vaccinated animals, whereas BCG-vaccinated animals showed a slight increase alongside lesion progression. IHC analysis of the cytokines IFN-γ and TNF-α demonstrated significantly increased expression within the lymph node granulomas of BCG-vaccinated cattle. This is suggestive of a protective role for IFN-γ and TNF-α in response to M. bovis infection. Findings shown in this study suggest that the use of BCG vaccine can reduce the number and severity of lesions, induce a different phenotypic response and increase the local expression of key cytokines related to

  8. Protection Induced by Simultaneous Subcutaneous and Endobronchial Vaccination with BCG/BCG and BCG/Adenovirus Expressing Antigen 85A against Mycobacterium bovis in Cattle.

    Science.gov (United States)

    Dean, Gillian S; Clifford, Derek; Whelan, Adam O; Tchilian, Elma Z; Beverley, Peter C L; Salguero, Francisco J; Xing, Zhou; Vordermeier, Hans M; Villarreal-Ramos, Bernardo

    2015-01-01

    The incidence of bovine tuberculosis (bTB) in the GB has been increasing since the 1980s. Immunisation, alongside current control measures, has been proposed as a sustainable measure to control bTB. Immunisation with Mycobacterium bovis bacillus Calmette-Guerin (BCG) has been shown to protect against bTB. Furthermore, much experimental data indicates that pulmonary local immunity is important for protection against respiratory infections including Mycobacterium tuberculosis and that pulmonary immunisation is highly effective. Here, we evaluated protection against M. bovis, the main causative agent of bTB, conferred by BCG delivered subcutaneously, endobronchially or by the new strategy of simultaneous immunisation by both routes. We also tested simultaneous subcutaneous immunisation with BCG and endobronchial delivery of a recombinant type 5 adenovirus expressing mycobacterial antigen 85A. There was significantly reduced visible pathology in animals receiving the simultaneous BCG/BCG or BCG/Ad85 treatment compared to naïve controls. Furthermore, there were significantly fewer advanced microscopic granulomata in animals receiving BCG/Ad85A compared to naive controls. Thus, combining local and systemic immunisation limits the development of pathology, which in turn could decrease bTB transmission.

  9. Protection Induced by Simultaneous Subcutaneous and Endobronchial Vaccination with BCG/BCG and BCG/Adenovirus Expressing Antigen 85A against Mycobacterium bovis in Cattle.

    Directory of Open Access Journals (Sweden)

    Gillian S Dean

    Full Text Available The incidence of bovine tuberculosis (bTB in the GB has been increasing since the 1980s. Immunisation, alongside current control measures, has been proposed as a sustainable measure to control bTB. Immunisation with Mycobacterium bovis bacillus Calmette-Guerin (BCG has been shown to protect against bTB. Furthermore, much experimental data indicates that pulmonary local immunity is important for protection against respiratory infections including Mycobacterium tuberculosis and that pulmonary immunisation is highly effective. Here, we evaluated protection against M. bovis, the main causative agent of bTB, conferred by BCG delivered subcutaneously, endobronchially or by the new strategy of simultaneous immunisation by both routes. We also tested simultaneous subcutaneous immunisation with BCG and endobronchial delivery of a recombinant type 5 adenovirus expressing mycobacterial antigen 85A. There was significantly reduced visible pathology in animals receiving the simultaneous BCG/BCG or BCG/Ad85 treatment compared to naïve controls. Furthermore, there were significantly fewer advanced microscopic granulomata in animals receiving BCG/Ad85A compared to naive controls. Thus, combining local and systemic immunisation limits the development of pathology, which in turn could decrease bTB transmission.

  10. Deletion of nuoG from the Vaccine Candidate Mycobacterium bovis BCG ΔureC::hly Improves Protection against Tuberculosis

    Science.gov (United States)

    Gengenbacher, Martin; Nieuwenhuizen, Natalie; Vogelzang, Alexis; Liu, Haipeng; Kaiser, Peggy; Schuerer, Stefanie; Lazar, Doris; Wagner, Ina; Mollenkopf, Hans-Joachim

    2016-01-01

    ABSTRACT The current tuberculosis (TB) vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), provides insufficient protection against pulmonary TB. Previously, we generated a listeriolysin-expressing recombinant BCG strain, which to date has successfully completed phase I and phase IIa clinical trials. In an attempt to further improve efficacy, we deleted the antiapoptotic virulence gene nuoG, encoding NADH dehydrogenase 1 subunit G, from BCG ΔureC::hly. In vitro, deletion of nuoG unexpectedly led to strongly increased recruitment of the autophagosome marker LC3 to the engulfed vaccine, suggesting that nuoG also affects xenophagic pathways. In mice, BCG ΔureC::hly ΔnuoG vaccination was safer than BCG and improved protection over that of parental BCG ΔureC::hly, significantly reducing TB load in murine lungs, ameliorating pulmonary pathology, and enhancing immune responses. Transcriptome analysis of draining lymph nodes after vaccination with either BCG ΔureC::hly or BCG ΔureC::hly ΔnuoG demonstrated earlier and stronger induction of immune responses than that with BCG SSI and suggested upregulation of inflammasome activation and interferon-induced GTPases. In summary, BCG ΔureC::hly ΔnuoG is a promising next-generation TB vaccine candidate with excellent efficacy and safety. PMID:27222470

  11. Effects of Bacillus Calmette-Guérin (BCG) vaccination at birth on T and B lymphocyte subsets

    DEFF Research Database (Denmark)

    Birk, Nina Marie; Nissen, Thomas Nørrelykke; Kjærgaard, Jesper

    2017-01-01

    , determined by flow cytometry. In 118 infants blood samples were obtained 4 (±2) days post randomization to BCG vaccination or no intervention, and at 3 and 13 months of age. No effects of BCG were found at 4 days. However, BCG increased proportions of effector memory cells at 3 months (Geometric mean ratio......The Bacillus Calmette-Guérin vaccine (BCG) has been associated with beneficial non-specific effects (NSEs) on infant health. Within a randomized trial on the effect of neonatal BCG on overall health, we investigated the possible immunological impact of neonatal BCG vaccination on lymphocyte subsets...... (GMR) 1.62, 95% confidence interval (CI) (1.20-2.21), p = 0.002 for CD4(+) T cells and GMR 1.69, 95% CI (1.06-2.70), p = 0.03 for CD8(+) T cells), and reduced proportions of late differentiated CD4(+) T cells (GMR = 0.62, 95% CI (0.38-1.00), p = 0.05) and apoptotic CD4(+) T cells at 13 months (GMR = 0...

  12. Identification of surrogates and correlates of protection in protective immunity against Mycobacterium bovis infection induced in neonatal calves by vaccination with M. bovis BCG Pasteur and M. bovis BCG Danish.

    Science.gov (United States)

    Hope, J C; Thom, M L; McAulay, M; Mead, E; Vordermeier, H M; Clifford, D; Hewinson, R G; Villarreal-Ramos, B

    2011-03-01

    Vaccination of neonatal calves with Mycobacterium bovis bacillus Calmette-Guérin (BCG) induces a significant degree of protection against infection with virulent M. bovis, the causative agent of bovine tuberculosis (bTB). We compared two strains of BCG, Pasteur and Danish, in order to confirm that the current European human vaccine strain (BCG Danish) induced protective immunity in calves, and we assessed immune responses to determine correlates of protection that could assist future vaccine evaluation in cattle. Both vaccine strains induced antigen (purified protein derivate [PPD])-specific gamma interferon (IFN-γ) in whole-blood cultures. These responses were not significantly different for BCG Pasteur and BCG Danish and peaked at week 2 to 4 postvaccination. Vaccination with either BCG Danish or BCG Pasteur induced significant protection against bTB, with reductions in both lesion score and bacteriological burden evident in both groups of vaccinated calves compared with nonvaccinated control calves. Measurement of IFN-γ-expressing T lymphocytes postvaccination and postchallenge revealed both correlates and surrogates of protective efficacy. The frequency of central memory T lymphocytes present at 12 weeks postvaccination (at the time of M. bovis challenge) correlated significantly with protection. Conversely, the number of IFN-γ-expressing effector T cells present after M. bovis challenge was correlated with disease. These results demonstrate that vaccination of neonatal calves with either BCG Pasteur or BCG Danish induces protective immune responses against TB. In addition, we show that measurement of antigen-specific T lymphocyte populations may provide a reliable means for identifying protective vaccine candidates.

  13. Randomized trial of BCG vaccination at birth to low-birth-weight children

    DEFF Research Database (Denmark)

    Aaby, Peter; Roth, Adam Anders Edvin; Ravn, Henrik

    2011-01-01

    Observational studies have suggested that BCG may have nonspecific beneficial effects on survival. Low-birth-weight (LBW) children are not given BCG at birth in Guinea-Bissau; we conducted a randomized trial of BCG at birth (early BCG) vs delayed BCG....

  14. Boosting BCG-primed responses with a subunit Apa vaccine during the waning phase improves immunity and imparts protection against Mycobacterium tuberculosis.

    Science.gov (United States)

    Nandakumar, Subhadra; Kannanganat, Sunil; Dobos, Karen M; Lucas, Megan; Spencer, John S; Amara, Rama Rao; Plikaytis, Bonnie B; Posey, James E; Sable, Suraj B

    2016-05-13

    Heterologous prime-boosting has emerged as a powerful vaccination approach against tuberculosis. However, optimal timing to boost BCG-immunity using subunit vaccines remains unclear in clinical trials. Here, we followed the adhesin Apa-specific T-cell responses in BCG-primed mice and investigated its BCG-booster potential. The Apa-specific T-cell response peaked 32-52 weeks after parenteral or mucosal BCG-priming but waned significantly by 78 weeks. A subunit-Apa-boost during the contraction-phase of BCG-response had a greater effect on the magnitude and functional quality of specific cellular and humoral responses compared to a boost at the peak of BCG-response. The cellular response increased following mucosal BCG-prime-Apa-subunit-boost strategy compared to Apa-subunit-prime-BCG-boost approach. However, parenteral BCG-prime-Apa-subunit-boost by a homologous route was the most effective strategy in-terms of enhancing specific T-cell responses during waning in the lung and spleen. Two Apa-boosters markedly improved waning BCG-immunity and significantly reduced Mycobacterium tuberculosis burdens post-challenge. Our results highlight the challenges of optimization of prime-boost regimens in mice where BCG drives persistent immune-activation and suggest that boosting with a heterologous vaccine may be ideal once the specific persisting effector responses are contracted. Our results have important implications for design of prime-boost regimens against tuberculosis in humans.

  15. Boosting BCG-primed responses with a subunit Apa vaccine during the waning phase improves immunity and imparts protection against Mycobacterium tuberculosis

    Science.gov (United States)

    Nandakumar, Subhadra; Kannanganat, Sunil; Dobos, Karen M.; Lucas, Megan; Spencer, John S.; Amara, Rama Rao; Plikaytis, Bonnie B.; Posey, James E.; Sable, Suraj B.

    2016-01-01

    Heterologous prime–boosting has emerged as a powerful vaccination approach against tuberculosis. However, optimal timing to boost BCG-immunity using subunit vaccines remains unclear in clinical trials. Here, we followed the adhesin Apa-specific T-cell responses in BCG-primed mice and investigated its BCG-booster potential. The Apa-specific T-cell response peaked 32–52 weeks after parenteral or mucosal BCG-priming but waned significantly by 78 weeks. A subunit-Apa-boost during the contraction-phase of BCG-response had a greater effect on the magnitude and functional quality of specific cellular and humoral responses compared to a boost at the peak of BCG-response. The cellular response increased following mucosal BCG-prime–Apa-subunit-boost strategy compared to Apa-subunit-prime–BCG-boost approach. However, parenteral BCG-prime–Apa-subunit-boost by a homologous route was the most effective strategy in-terms of enhancing specific T-cell responses during waning in the lung and spleen. Two Apa-boosters markedly improved waning BCG-immunity and significantly reduced Mycobacterium tuberculosis burdens post-challenge. Our results highlight the challenges of optimization of prime–boost regimens in mice where BCG drives persistent immune-activation and suggest that boosting with a heterologous vaccine may be ideal once the specific persisting effector responses are contracted. Our results have important implications for design of prime–boost regimens against tuberculosis in humans. PMID:27173443

  16. The Type of Growth Medium Affects the Presence of a Mycobacterial Capsule and Is Associated With Differences in Protective Efficacy of BCG Vaccination Against Mycobacterium tuberculosis

    OpenAIRE

    Prados-Rosales, Rafael; Carreño, Leandro J.; Weinrick, Brian; Batista-Gonzalez, Ana; Glatman-Freedman, Aarona; Xu, Jiayong; Chan, John; Jacobs, William R.; Porcelli, Steven A.; Casadevall, Arturo

    2016-01-01

    Background. Bacillus Calmette-Guerin (BCG) vaccine is widely used for the prevention of tuberculosis, despite limited efficacy. Most immunological studies of BCG or Mycobacterium tuberculosis strains grow bacteria in the presence of detergent, which also strips the mycobacterial capsule. The impact of the capsule on vaccine efficacy has not been explored.

  17. Children with lymphadenitis associated with Bacillus Calmette-Guérin (BCG) vaccination do not experience more infections when compared with BCG-vaccinated children without lymphadenitis: a three years paired-cohort in Mexico.

    Science.gov (United States)

    Chacon-Cruz, Enrique; Arellano-Estrada, Jorge Luis; Lopatynsky-Reyes, Erika; Alvelais-Palacios, Jorge; Becka, Chandra

    2017-08-01

    Vaccination against tuberculosis with live-attenuated Bacillus Calmette-Guérin (BCG) is widely used even though its effectiveness is controversial. BCG-lymphadenitis (BCG-LA) is its most common complication. Some studies have proposed that BCG-LA can be associated with primary immunodeficiencies (PIs). This study's aim is to see whether patients who developed BCG-LA (named as 'LA') developed more infections than BCG-vaccinated children without BCG-LA (named as 'NON-LA'). From January 2009 to April 2014, 31 LA children were seen at the outpatient clinic of the General Hospital of Tijuana, Mexico. Among them, 22 (70.97%), 5 (16.13%) and 4 (12.9%) had axillary, supraclavicular, or both BCG-LA, respectively. No treatment was given and complications were not seen. Per LA subject, a NON-LA not >1 month of age difference and same gender was paired and followed for 3 years to look for ambulatory infections (AINFs), acute otitis media (AOM) and hospitalizations. Surveillance per patient was performed by phone monthly, and they were seen at the clinic every 4 months. All patients were HIV-negative and had no family history of PI. Statistical analyses used were relative risk (RR) with confidence intervals (CI), t test for independent variables and z test. In total 62 subjects were enrolled: 31 LA paired with 31 NON-LA. Between them, there were no differences in age, day care attendance and breastfeeding. There were no differences in the total number of AINF per patient (LA: 18.61 avg. ± 5.03 SD versus NON-LA: 18.19 avg. ± 4.17 SD, RR = 1.06, 95% CI = 0.33-0.66), AOM total episodes (LA: 30 versus NON-LA: 26, RR = 0.87, 95% CI = 0.31-0.68) and hospitalizations (LA: 5 versus NON-LA: 4, RR = 1, 95% CI = 0.25-0.74). This cohort strongly suggests that BCG-LA in healthy children is not associated with more episodes of AINF and hospitalizations, when paired and compared with children BCG-vaccinated without BCG-LA.

  18. [Examination of protein MPB 70 properties in BCG substrains used for the production of Polish antituberculosis vaccines].

    Science.gov (United States)

    Janaszek, W; Wysokińska, T; Aleksandrowicz, J

    1998-01-01

    The aim of the study was examination of MPB70 protein production by different BCG substrains and testing this protein as reagent in allergenic skin test on BCG vaccinated guinea pigs. Three BCG substrains: Danish 1331 (D), Japanese 172 (J) and Polish BCG Moreau (P) were used for the study. The protein MPB70 received from dr Nagai from Osaka University was used as reference preparation. It has been shown that MPB70 protein of molecular weight about 21,500 Da was present only in BCG Moreau (P) and Japanese (J) substrains. In immunoblotting test monoclonal antibodies reacted additionally with 43,000 Da protein in all tested substrains. We suspect that the detected additional molecule was a dimer of MPB70 protein. The development of skin reactions to MPB70 protein was seen in guinea pigs vaccinated with J and P substrains. The peak of alergy to MPB70 protein was observed 9 weeks after vaccination. In sera of vaccinated animals antibodies against MPB70 protein were detected by ELISA method. The possibility of using MPB70 protein for diagnostic purpose is discussed.

  19. [Our experience with 1 mg BCG vaccine instillation in T1 stage cancer of the bladder].

    Science.gov (United States)

    Rivera, P; Orio, M; Hinostroza, J; Venegas, P; Pastor, P; Gorena, M; Lagos, M; Pinochet, R

    1999-10-01

    We studied 67 patients with bladder cancer in stage T1, with terminated BCG treatment and in pursuit. No stage Ta neither carcinoma in situ was included. The protocol was: beginning of treatment upon retiring vesical catheter, instilation of 1 mg of liofilized BCG vaccine (16 x 10(6) bacilles) in 40-50 ml of intravesical saline solution. A weekly instilation during the first month. An instilation each 15 days during the second and third month and one monthly until complete 12 months of treatment. Also was carried out an study of T lymphocites and cytokines. The average followup of the 67 patients treated was 51.3 months. 17 patients relapses (25.4%). A 33% were grade 3 and 27% grade 2. Like complications there was a case of inguinal TBC adenititis, 2 TBC prostatitis, 2 TBC cistitis and 5 cases of slight disuric syndrome. The study of subpopulations of lymphocites in peripheral blood demonstrated a significant increase of CD3 and CD4/CD8 ratio. The interleukin 2 measurement in serum also increased significantly after the BCG instilations. Our protocol gets similar results to the higher doses, but with minimal complications diminishing the relapses of the tumors in stage T1. A monthly maintenance dose would help to maintain immunity.

  20. A booster vaccine expressing a latency-associated antigen augments BCG induced immunity and confers enhanced protection against tuberculosis.

    Directory of Open Access Journals (Sweden)

    Bappaditya Dey

    Full Text Available BACKGROUND: In spite of a consistent protection against tuberculosis (TB in children, Mycobacterium bovis Bacille Calmette-Guerin (BCG fails to provide adequate protection against the disease in adults as well as against reactivation of latent infections or exogenous reinfections. It has been speculated that failure to generate adequate memory T cell response, elicitation of inadequate immune response against latency-associated antigens and inability to impart long-term immunity against M. tuberculosis infections are some of the key factors responsible for the limited efficiency of BCG in controlling TB. METHODS/PRINCIPAL FINDINGS: In this study, we evaluated the ability of a DNA vaccine expressing α-crystallin--a key latency antigen of M. tuberculosis to boost the BCG induced immunity. 'BCG prime-DNA boost' regimen (B/D confers robust protection in guinea pigs along with a reduced pathology in comparison to BCG vaccination (1.37 log(10 and 1.96 log(10 fewer bacilli in lungs and spleen, respectively; p<0.01. In addition, B/D regimen also confers enhanced protection in mice. Further, we show that B/D immunization in mice results in a heightened frequency of PPD and antigen specific multi-functional CD4 T cells (3(+ simultaneously producing interferon (IFNγ, tumor necrosis factor (TNFα and interleukin (IL2. CONCLUSIONS/SIGNIFICANCE: These results clearly indicate the superiority of α-crystallin based B/D regimen over BCG. Our study, also demonstrates that protection against TB is predictable by an increased frequency of 3(+ Th1 cells with superior effector functions. We anticipate that this study would significantly contribute towards the development of superior booster vaccines for BCG vaccinated individuals. In addition, this regimen can also be expected to reduce the risk of developing active TB due to reactivation of latent infection.

  1. Lactococcus lactis carrying a DNA vaccine coding for the ESAT-6 antigen increases IL-17 cytokine secretion and boosts the BCG vaccine immune response.

    Science.gov (United States)

    Pereira, V B; da Cunha, V P; Preisser, T M; Souza, B M; Turk, M Z; De Castro, C P; Azevedo, M S P; Miyoshi, A

    2017-06-01

    A regimen utilizing Bacille Calmette-Guerin (BCG) and another vaccine system as a booster may represent a promising strategy for the development of an efficient tuberculosis vaccine for adults. In a previous work, we confirmed the ability of Lactococcus lactis fibronectin-binding protein A (FnBPA+) (pValac:ESAT-6), a live mucosal DNA vaccine, to produce a specific immune response in mice after oral immunization. In this study, we examined the immunogenicity of this strain as a booster for the BCG vaccine in mice. After immunization, cytokine and immunoglobulin profiles were measured. The BCG prime L. lactis FnBPA+ (pValac:ESAT-6) boost group was the most responsive group, with a significant increase in splenic pro-inflammatory cytokines IL-17, IFN-γ, IL-6 and TNF-α compared with the negative control. Based on the results obtained here, we demonstrated that L. lactis FnBPA+ (pValac:ESAT-6) was able to increase the BCG vaccine general immune response. This work is of great scientific and social importance because it represents the first step towards the development of a booster to the BCG vaccine using L. lactis as a DNA delivery system. © 2017 The Society for Applied Microbiology.

  2. An update on vaccines for tuberculosis - there is more to it than just waning of BCG efficacy with time.

    Science.gov (United States)

    Romano, Marta; Huygen, Kris

    2012-12-01

    Apart from better diagnostics and new anti-microbial drugs, an effective vaccine for tuberculosis is urgently needed to halt this poverty-related disease, afflicting millions of people worldwide. After a general introduction on the global threat of tuberculosis, the pros and cons of the existing M. bovis BCG vaccine are discussed. As the correlates of protection against tuberculosis remain largely unknown, new findings in biomarker research are described. Next, an update on the ongoing Phase I and Phase II clinical trials is given. Finally, some of the most promising novel pre-clinical developments using live attenuated vaccines, sub-unit vaccines, prime-boost strategies, and new vaccination routes are discussed. The field has made considerable progress and 12 vaccine candidates have now actually entered Phase I or Phase IIa and IIb clinical trials. It is argued that the variable protection conferred by the existing BCG vaccine against reactivation of latent TB is caused not only by waning of its efficacy with time but also by its weak induction of MHC class I restricted responses. Prime-boost strategies based on the actual BCG vaccine may not be sufficient to overcome this hurdle. The use of plasmid DNA vaccination might offer a solution.

  3. Vaccination with Mycobacterium bovis BCG strains Danish and Pasteur in white-tailed deer (Odocoileus virginianus) experimentally challenged with Mycobacterium bovis.

    Science.gov (United States)

    Palmer, M V; Thacker, T C; Waters, W R

    2009-06-01

    Wildlife reservoirs of Mycobacterium bovis represent serious obstacles to the eradication of tuberculosis in domestic livestock and the cause for many faltering bovine tuberculosis eradication programmes. One approach in dealing with wildlife reservoirs of disease is to interrupt inter-species and intraspecies transmission through vaccination of deer or cattle. To evaluate the efficacy of BCG vaccination in white-tailed deer, 35 deer were assigned to one of three groups; one s.c. dose of 10(7) CFU of M. bovis BCG Pasteur (n = 12); 1 s.c. dose of 10(7) CFU of M. bovis BCG Danish (n = 11); or unvaccinated deer (n = 12). After vaccination, deer were inoculated intratonsilarly with virulent M. bovis. Lesion severity scores of the medial retropharyngeal lymph node, as well as all lymph nodes combined, were reduced in vaccinated deer compared to unvaccinated deer. BCG Danish vaccinated deer had no late stage granulomas characterized by coalescent caseonecrotic granulomas containing numerous acid-fast bacilli compared to BCG Pasteur vaccinated or unvaccinated deer where such lesions were present. Both BCG strains were isolated as late as 250 days after vaccination from deer that were vaccinated but not challenged. In white-tailed deer, BCG provides protection against challenge with virulent M. bovis. Issues related to vaccine persistence, safety and shedding remain to be further investigated.

  4. Cellular Immunity Confers Transient Protection in Experimental Buruli Ulcer following BCG or Mycolactone-Negative Mycobacterium ulcerans Vaccination

    Science.gov (United States)

    Fraga, Alexandra G.; Martins, Teresa G.; Torrado, Egídio; Huygen, Kris; Portaels, Françoise; Silva, Manuel T.; Castro, António G.; Pedrosa, Jorge

    2012-01-01

    Background Buruli ulcer (BU) is an emerging infectious disease caused by Mycobacterium ulcerans that can result in extensive necrotizing cutaneous lesions due to the cytotoxic exotoxin mycolactone. There is no specific vaccine against BU but reports show some degree of cross-reactive protection conferred by M. bovis BCG immunization. Alternatively, an M. ulcerans-specific immunization could be a better preventive strategy. Methodology/Principal Findings In this study, we used the mouse model to characterize the histological and cytokine profiles triggered by vaccination with either BCG or mycolactone-negative M. ulcerans, followed by footpad infection with virulent M. ulcerans. We observed that BCG vaccination significantly delayed the onset of M. ulcerans growth and footpad swelling through the induction of an earlier and sustained IFN-γ T cell response in the draining lymph node (DLN). BCG vaccination also resulted in cell-mediated immunity (CMI) in M. ulcerans-infected footpads, given the predominance of a chronic mononuclear infiltrate positive for iNOS, as well as increased and sustained levels of IFN-γ and TNF. No significant IL-4, IL-17 or IL-10 responses were detected in the footpad or the DLN, in either infected or vaccinated mice. Despite this protective Th1 response, BCG vaccination did not avoid the later progression of M. ulcerans infection, regardless of challenge dose. Immunization with mycolactone-deficient M. ulcerans also significantly delayed the progression of footpad infection, swelling and ulceration, but ultimately M. ulcerans pathogenic mechanisms prevailed. Conclusions/Significance The delay in the emergence of pathology observed in vaccinated mice emphasizes the relevance of protective Th1 recall responses against M. ulcerans. In future studies it will be important to determine how the transient CMI induced by vaccination is compromised. PMID:22413022

  5. Cellular immunity confers transient protection in experimental Buruli ulcer following BCG or mycolactone-negative Mycobacterium ulcerans vaccination.

    Directory of Open Access Journals (Sweden)

    Alexandra G Fraga

    Full Text Available BACKGROUND: Buruli ulcer (BU is an emerging infectious disease caused by Mycobacterium ulcerans that can result in extensive necrotizing cutaneous lesions due to the cytotoxic exotoxin mycolactone. There is no specific vaccine against BU but reports show some degree of cross-reactive protection conferred by M. bovis BCG immunization. Alternatively, an M. ulcerans-specific immunization could be a better preventive strategy. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we used the mouse model to characterize the histological and cytokine profiles triggered by vaccination with either BCG or mycolactone-negative M. ulcerans, followed by footpad infection with virulent M. ulcerans. We observed that BCG vaccination significantly delayed the onset of M. ulcerans growth and footpad swelling through the induction of an earlier and sustained IFN-γ T cell response in the draining lymph node (DLN. BCG vaccination also resulted in cell-mediated immunity (CMI in M. ulcerans-infected footpads, given the predominance of a chronic mononuclear infiltrate positive for iNOS, as well as increased and sustained levels of IFN-γ and TNF. No significant IL-4, IL-17 or IL-10 responses were detected in the footpad or the DLN, in either infected or vaccinated mice. Despite this protective Th1 response, BCG vaccination did not avoid the later progression of M. ulcerans infection, regardless of challenge dose. Immunization with mycolactone-deficient M. ulcerans also significantly delayed the progression of footpad infection, swelling and ulceration, but ultimately M. ulcerans pathogenic mechanisms prevailed. CONCLUSIONS/SIGNIFICANCE: The delay in the emergence of pathology observed in vaccinated mice emphasizes the relevance of protective Th1 recall responses against M. ulcerans. In future studies it will be important to determine how the transient CMI induced by vaccination is compromised.

  6. The patterns of in vitro cell-death and inflammatory cytokines induced by distinct BCG vaccine strains are differentially induced in human mononuclear cells.

    Science.gov (United States)

    Ponte, C; Hacker, M; Moraes, M; Castello-Branco, L; Silva, F; Antas, P

    2018-01-02

    Tuberculosis (TB) remains among the world's leading cause of mortality. For its control, studies of TB vaccines are needed. Since live-attenuated Mycobacterium bovis bacillus Calmette-Guérin (BCG) is the only TB vaccine currently in use, studies on the protective role of BCG are required. In this study, we analyzed host cells purified directly from whole blood of human immunodeficiency virus (HIV)-negative volunteers, comprising adult healthy donors (HD) and neonates (umbilical cord bloods, UCB), with the aim to directly compare in vitro immune responses with distinct BCG strains in human mononuclear cells. The Moreau, Pasteur, and Danish BCG strains were used to infect mononuclear cells in vitro for 48 h; bacilli viability and cell-death were subsequently detected by flow cytometry. In addition, cell culture supernatants were used in cytokine detection assays. Overall, the Moreau BCG strain induced higher levels of apoptosis than the Pasteur and Danish BCG strains in both the HD and UCB groups (p-value BCG infection. The Moreau BCG strain, exclusively, induced Th1 cytokines at the highest levels in cells from adults (p-value BCG strains, whereas TGF-β1 levels were reduced significantly (p-value BCG vaccine. As expected, eight out of 22 pro-inflammatory cytokines were secreted at significant levels (p-value BCG-infected cell cultures, in the HD group only. When analyzing these results, we excluded confounding factors related to storage and viability of the BCG strains used. These findings suggest that Moreau BCG is a more potent immunostimulating agent than the Pasteur and Danish BCG strains. Clinical trials will be needed to confirm these findings.

  7. Effectiveness and cost-effectiveness of first BCG vaccination against tuberculosis in school-age children without previous tuberculin test (BCG-REVAC trial): a cluster-randomised trial.

    Science.gov (United States)

    Pereira, Susan M; Barreto, Mauricio L; Pilger, Daniel; Cruz, Alvaro A; Sant'Anna, Clemax; Hijjar, Miguel A; Ichihara, Maria Y; Santos, Andreia C; Genser, Bernd; Rodrigues, Laura C

    2012-04-01

    Neonatal BCG vaccination is part of routine vaccination schedules in many developing countries; vaccination at school age has not been assessed in trials in low-income and middle-income countries. Catch-up BCG vaccination of school-age children who missed neonatal BCG vaccination could be indicated if it confers protection and is cost-effective. We did a cluster-randomised trial (BCG REVAC) to estimate the effectiveness (efficacy given in routine settings) of school-age vaccination. We assessed the effectiveness of BCG vaccination in school-age children (aged 7-14 years) with unknown tuberculin status who did not receive neonatal BCG vaccination (subpopulation of the BCG REVAC cluster-randomised trial), between July, 1997, and June, 2006, in Salvador, Brazil, and between January, 1999, and December, 2007, in Manaus, Brazil. 763 schools were randomly assigned into BCG vaccination group or a not-vaccinated control group. Neither allocation nor intervention was concealed. Incidence of tuberculosis was the primary outcome. Cases were identified via the Brazilian Tuberculosis Control Programme. Study staff were masked to vaccination status when identified cases were linked to the study population. We estimated cost-effectiveness in Salvador by comparison of the cost for vaccination to prevent one case of tuberculosis (censored at 9 years) with the average cost of treating one case of tuberculosis. Analysis of all included children was by intention to treat. For calculation of the incidence rate we used generalised estimating equations and correlated observations over time. We randomly assigned 20,622 children from 385 schools to the BCG vaccination group and 18,507 children from 365 schools to the control group. The crude incidence of tuberculosis was 54·9 (95% CI 45·3-66·7) per 100,000 person-years in the BCG vaccination group and 72·7 (62·8-86·8) per 100,000 person-years in the control group. The overall vaccine effectiveness of a first BCG vaccination at school

  8. Long-Lasting Effects of BCG Vaccination on Both Heterologous Th1/Th17 Responses and Innate Trained Immunity

    DEFF Research Database (Denmark)

    Kleinnijenhuis, Johanneke; Quintin, Jessica; Preijers, Frank

    2013-01-01

    '. In the present study we assessed whether BCG was able to induce long-lasting effects on both trained immunity and heterologous T helper 1 (Th1) and Th17 immune responses 1 year after vaccination. The production of TNFα and IL-1β to mycobacteria or unrelated pathogens was higher after 2 weeks and 3 months...... in proinflammatory cytokine production after stimulation with the TLR4 ligand lipopolysaccharide. The heterologous production of Th1 (IFN-γ) and Th17 (IL-17 and IL-22) immune responses to nonmycobacterial stimulation remained strongly elevated even 1 year after BCG vaccination. In conclusion, BCG induces sustained...... changes in the immune system associated with a nonspecific response to infections both at the level of innate trained immunity and at the level of heterologous Th1/Th17 responses. © 2013 S. Karger AG, Basel....

  9. Another vaccine, another story: BCG vaccination against tuberculosis in India, 1948 to 1960 Outra vacina, outra história: a vacinação de BCG contra tuberculose na Índia, 1948 a 1960

    Directory of Open Access Journals (Sweden)

    Niels Brimnes

    2011-02-01

    Full Text Available Through an examination of mass BCG vaccination against tuberculosis in India between 1948 and 1960 this article draws attention to the diversity of the history of vaccination. The features of vaccination campaigns often differed from those of the celebrated campaign to eradicate smallpox. Due to differences between smallpox and tuberculosis as well as between the vaccines developed against them, an analysis of BCG mass vaccination against tuberculosis seems particularly well suited for this purpose. Three points of difference are identified. First, in non-Western contexts BCG vaccination procedures were modified to a greater extent than vaccination against smallpox. Second, tuberculosis lacked the drama and urgency of smallpox and BCG vaccination campaigns suffered more from recruitment problems than did the more "heroic" smallpox eradication campaign. Third, the BCG vaccine was contested in medical circles and was much better suited than the vaccine against smallpox as a vehicle for the articulation of concerns about post-colonial modernization.Através da observação da vacinação em massa de BCG contra a tuberculose na Índia durante os anos de 1948 a 1960, este artigo chama a atenção para a diversidade da história da vacinação. As características das campanhas de vacinação geralmente diferem daquelas celebradas nas campanhas para erradicação da varíola. Devido às diferenças entre a varíola e a turberculose, assim como entre as vacinas desenvolvidas para combater essas doenças, uma análise da vacinação em massa de BCG contra a turberculose parece especialmente bem situada para essa proposta. Três pontos de diferença foram identificados. O primeiro é que em contextos não ocidentais os procedimentos da vacinação de BCG foram modificados em uma extensão maior do que a vacinação contra a varíola. Em segundo lugar, a tuberculose não tinha o drama e a urgência da varíola, e as campanhas de vacinação de BCG

  10. Early versus late BCG vaccination in HIV-1-exposed infants in Uganda: study protocol for a randomized controlled trial

    NARCIS (Netherlands)

    Nankabirwa, V.; Tumwine, J.K.; Namugga, O.; Tylleskar, T.; Ndeezi, G.; Robberstad, B.; Netea, M.G.; Sommerfelt, H.

    2017-01-01

    BACKGROUND: Bacillus Calmette-Guerin (BCG) vaccination may have nonspecific effects, i.e., effects on childhood morbidity and mortality that go beyond its effect on the risk of childhood tuberculosis (TB). Though the available scientific literature is mostly from observational studies, and is

  11. Effect of 50,000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau

    DEFF Research Database (Denmark)

    Benn, Christine Stabell; Diness, Birgitte Rode; Roth, Adam

    2008-01-01

    OBJECTIVE: To investigate the effect of high dose vitamin A supplementation given with BCG vaccine at birth in an African setting with high infant mortality. DESIGN: Randomised placebo controlled trial. Setting Bandim Health Project's demographic surveillance system in Guinea-Bissau, covering app...

  12. The HyVac4 subunit vaccine efficiently boosts BCG-primed anti-mycobacterial protective immunity.

    Directory of Open Access Journals (Sweden)

    Rolf Billeskov

    Full Text Available BACKGROUND: The current vaccine against tuberculosis (TB, BCG, has failed to control TB worldwide and the protective efficacy is moreover limited to 10-15 years. A vaccine that could efficiently boost a BCG-induced immune response and thus prolong protective immunity would therefore have a significant impact on the global TB-burden. METHODS/FINDINGS: In the present study we show that the fusion protein HyVac4 (H4, consisting of the mycobacterial antigens Ag85B and TB10.4, given in the adjuvant IC31® or DDA/MPL effectively boosted and prolonged immunity induced by BCG, leading to improved protection against infection with virulent M. tuberculosis (M.tb. Increased protection correlated with an increased percentage of TB10.4 specific IFNγ/TNFα/IL-2 or TNFα/IL-2 producing CD4 T cells at the site of infection. Moreover, this vaccine strategy did not compromise the use of ESAT-6 as an accurate correlate of disease development/vaccine efficacy. Indeed both CD4 and CD8 ESAT-6 specific T cells showed significant correlation with bacterial levels. CONCLUSIONS/SIGNIFICANCE: H4-IC31® can efficiently boost BCG-primed immunity leading to an increased protective anti-M.tb immune response dominated by IFNγ/TNFα/IL-2 or TNFα/IL2 producing CD4 T cells. H4 in the CD4 T cell inducing adjuvant IC31® is presently in clinical trials.

  13. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis.

    Science.gov (United States)

    Roy, A; Eisenhut, M; Harris, R J; Rodrigues, L C; Sridhar, S; Habermann, S; Snell, L; Mangtani, P; Adetifa, I; Lalvani, A; Abubakar, I

    2014-08-05

    To determine whether BCG vaccination protects against Mycobacterium tuberculosis infection as assessed by interferon γ release assays (IGRA) in children. Systematic review and meta-analysis. Searches of electronic databases 1950 to November 2013, checking of reference lists, hand searching of journals, and contact with experts. Community congregate settings and households. Vaccinated and unvaccinated children aged under 16 with known recent exposure to patients with pulmonary tuberculosis. Children were screened for infection with M tuberculosis with interferon γ release assays. Study results relating to diagnostic accuracy were extracted and risk estimates were combined with random effects meta-analysis. The primary analysis included 14 studies and 3855 participants. The estimated overall risk ratio was 0.81 (95% confidence interval 0.71 to 0.92), indicating a protective efficacy of 19% against infection among vaccinated children after exposure compared with unvaccinated children. The observed protection was similar when estimated with the two types of interferon γ release assays (ELISpot or QuantiFERON). Restriction of the analysis to the six studies (n=1745) with information on progression to active tuberculosis at the time of screening showed protection against infection of 27% (risk ratio 0.73, 0.61 to 0.87) compared with 71% (0.29, 0.15 to 0.58) against active tuberculosis. Among those infected, protection against progression to disease was 58% (0.42, 0.23 to 0.77). BCG protects against M tuberculosis infection as well as progression from infection to disease.Trial registration PROSPERO registration No CRD42011001698 (www.crd.york.ac.uk/prospero/). © Roy et al 2014.

  14. A Mycobacterium bovis BCG-Naked DNA Prime-Boost Vaccination Strategy Induced CD4+ and CD8+ T-Cell Response against Mycobacterium tuberculosis Immunogens

    Directory of Open Access Journals (Sweden)

    Miao Lu

    2014-01-01

    Full Text Available Mycobacterium tuberculosis infection is still a major global public health problem. Presently the only tuberculosis (TB vaccine available is Bacille Calmette-Guérin (BCG, although it fails to adequately protect against pulmonary TB in adults. To solve this problem, the development of a new effective vaccine is urgently desired. BCG-prime DNA-booster vaccinations strategy has been shown to induce greater protection against tuberculosis (TB than BCG alone. Some studies have demonstrated that the two genes (Rv1769 and Rv1772 are excellent T-cell antigens and could induce T-cell immune responses. In this research, we built BCG-C or BCG-P prime-recombination plasmid PcDNA3.1-Rv1769 or PcDNA3.1-Rv1772 boost vaccinations strategy to immunize BALB/c mice and evaluated its immunogenicity. The data suggests that the BCG-C+3.1-72 strategy could elicit the most long-lasting and strongest Th1-type cellular immune responses and the BCG-C+3.1-69 strategy could induce the high level CD8+ T-cell response at certain time points. These findings support the ideas that the prime-boost strategy as a combination of vaccines may be better than a single vaccine for protection against tuberculosis.

  15. Effectiveness of Routine BCG Vaccination on Buruli Ulcer Disease: A Case-Control Study in the Democratic Republic of Congo, Ghana and Togo

    Science.gov (United States)

    Phillips, Richard Odame; Phanzu, Delphin Mavinga; Beissner, Marcus; Badziklou, Kossi; Luzolo, Elysée Kalundieko; Sarfo, Fred Stephen; Halatoko, Wemboo Afiwa; Amoako, Yaw; Frimpong, Michael; Kabiru, Abass Mohammed; Piten, Ebekalisai; Maman, Issaka; Bidjada, Bawimodom; Koba, Adjaho; Awoussi, Koffi Somenou; Kobara, Basile; Nitschke, Jörg; Wiedemann, Franz Xaver; Kere, Abiba Banla; Adjei, Ohene; Löscher, Thomas; Fleischer, Bernhard; Bretzel, Gisela; Herbinger, Karl-Heinz

    2015-01-01

    Background The only available vaccine that could be potentially beneficial against mycobacterial diseases contains live attenuated bovine tuberculosis bacillus (Mycobacterium bovis) also called Bacillus Calmette-Guérin (BCG). Even though the BCG vaccine is still widely used, results on its effectiveness in preventing mycobacterial diseases are partially contradictory, especially regarding Buruli Ulcer Disease (BUD). The aim of this case-control study is to evaluate the possible protective effect of BCG vaccination on BUD. Methodology The present study was performed in three different countries and sites where BUD is endemic: in the Democratic Republic of the Congo, Ghana, and Togo from 2010 through 2013. The large study population was comprised of 401 cases with laboratory confirmed BUD and 826 controls, mostly family members or neighbors. Principal Findings After stratification by the three countries, two sexes and four age groups, no significant correlation was found between the presence of BCG scar and BUD status of individuals. Multivariate analysis has shown that the independent variables country (p = 0.31), sex (p = 0.24), age (p = 0.96), and presence of a BCG scar (p = 0.07) did not significantly influence the development of BUD category I or category II/III. Furthermore, the status of BCG vaccination was also not significantly related to duration of BUD or time to healing of lesions. Conclusions In our study, we did not observe significant evidence of a protective effect of routine BCG vaccination on the risk of developing either BUD or severe forms of BUD. Since accurate data on BCG strains used in these three countries were not available, no final conclusion can be drawn on the effectiveness of BCG strain in protecting against BUD. As has been suggested for tuberculosis and leprosy, well-designed prospective studies on different existing BCG vaccine strains are needed also for BUD. PMID:25569674

  16. Effects of Bacillus Calmette-Guérin (BCG) vaccination at birth on T and B lymphocyte subsets: Results from a clinical randomized trial.

    Science.gov (United States)

    Birk, Nina Marie; Nissen, Thomas Nørrelykke; Kjærgaard, Jesper; Hartling, Hans Jacob; Thøstesen, Lisbeth Marianne; Kofoed, Poul-Erik; Stensballe, Lone Graff; Andersen, Andreas; Pryds, Ole; Netea, Mihai G; Benn, Christine Stabell; Nielsen, Susanne Dam; Jeppesen, Dorthe Lisbeth

    2017-09-29

    The Bacillus Calmette-Guérin vaccine (BCG) has been associated with beneficial non-specific effects (NSEs) on infant health. Within a randomized trial on the effect of neonatal BCG on overall health, we investigated the possible immunological impact of neonatal BCG vaccination on lymphocyte subsets, determined by flow cytometry. In 118 infants blood samples were obtained 4 (±2) days post randomization to BCG vaccination or no intervention, and at 3 and 13 months of age. No effects of BCG were found at 4 days. However, BCG increased proportions of effector memory cells at 3 months (Geometric mean ratio (GMR) 1.62, 95% confidence interval (CI) (1.20-2.21), p = 0.002 for CD4 + T cells and GMR 1.69, 95% CI (1.06-2.70), p = 0.03 for CD8 + T cells), and reduced proportions of late differentiated CD4 + T cells (GMR = 0.62, 95% CI (0.38-1.00), p = 0.05) and apoptotic CD4 + T cells at 13 months (GMR = 0.55, 95% CI (0.32-0.92), p = 0.03). In conclusion, limited overall impact of neonatal BCG vaccination on lymphocyte subsets was found in healthy Danish infants within the first 13 months of life. This is in line with the limited clinical effects of BCG observed in our setting.

  17. Heterologous Immunological Effects of Early BCG Vaccination in Low-Birth-Weight Infants in Guinea-Bissau: A Randomized-controlled Trial

    NARCIS (Netherlands)

    Jensen, K.J.; Larsen, N.; Biering-Sorensen, S.; Andersen, A.; Eriksen, H.B.; Monteiro, I.; Hougaard, D.; Aaby, P.; Netea, M.G.; Flanagan, K.L.; Benn, C.S.

    2015-01-01

    BACKGROUND: Bacillus Calmette-Guerin (BCG) seems to have beneficial nonspecific effects; early BCG vaccination of low-birth-weight (LBW) newborns reduces neonatal mortality by >40% due to prevention of primarily septicemia and pneumonia. METHODS: Within a randomized trial in LBW infants in

  18. Bacillus Calmette-Guérin (BCG) vaccination patterns in the province of Québec, Canada, 1956-1974.

    Science.gov (United States)

    Rousseau, Marie-Claude; Conus, Florence; Kâ, Khady; El-Zein, Mariam; Parent, Marie-Élise; Menzies, Dick

    2017-08-24

    In the province of Québec, Canada, the Bacillus Calmette-Guérin (BCG) vaccine was offered to newborns and school-age children from the 1950s to mid-1970s in an organized tuberculosis prevention program. We aimed to describe the annual rates of skin test administration, proportion of skin tests that were positive, and rates of BCG vaccination from 1956 to 1974 according to age, sex, and administrative region. For rates, numerators were extracted from the Québec BCG Vaccination Registry whereas population denominators were obtained from the Canadian Census and governmental publications. Time trends were assessed with linear regression. A total of 2,755,336 skin tests and 2,531,366 BCG vaccinations were administered. Yearly rates of skin tests, routinely administered before vaccination among all except newborns, were highest among children aged 5-9 (9.3 per 100) and 10-14years (7.9 per 100). The proportion of positive skin tests varied greatly by age, ranging from 10.2% among children BCG vaccination. Our results confirm that the targeted groups, newborns and school-age children, were preferentially reached. Socioeconomic, demographic, and organizational factors may explain regional differences in immunization rates. Beyond presenting a historical context for this vaccination campaign, our findings are relevant to contemporary uses of the Québec BCG Vaccination Registry in epidemiological research. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  19. The impact of BCG vaccination on tuberculin skin test responses in children is age dependent: evidence to be considered when screening children for tuberculosis infection.

    Science.gov (United States)

    Seddon, James A; Paton, James; Nademi, Zohreh; Keane, Denis; Williams, Bhanu; Williams, Amanda; Welch, Steven B; Liebeschutz, Sue; Riddell, Anna; Bernatoniene, Jolanta; Patel, Sanjay; Martinez-Alier, Nuria; McMaster, Paddy; Kampmann, Beate

    2016-10-01

    Following exposure to TB, contacts are screened to target preventive treatment at those at high risk of developing TB. The UK has recently revised its recommendations for screening and now advises a 5 mm tuberculin skin test (TST) cut-off irrespective of age or BCG status. We sought to evaluate the impact of BCG on TST responses in UK children exposed to TB and the performance of different TST cut-offs to predict interferon γ release assay (IGRA) positivity. Children vaccination on TST positivity was evaluated in IGRA-negative children, as was the performance of different TST cut-offs to predict IGRA positivity. Of 422 children recruited (median age 69 months; IQR: 32-113 months), 300 (71%) had been vaccinated with BCG. BCG vaccination affected the TST response in IGRA-negative children less than 5 years old but not in older children. A 5 mm TST cut-off demonstrated good sensitivity and specificity in BCG-unvaccinated children, and an excellent negative predictive value but was associated with low specificity (62.7%; 95% CI 56.1% to 69.0%) in BCG-vaccinated children. For BCG-vaccinated children, a 10 mm cut-off provided a high negative predictive value (97.7%; 95% CI 94.2% to 99.4%) with the positive predictive value increasing with increasing age of the child. BCG vaccination had little impact on TST size in children over 5 years of age. The revised TST cut-off recommended in the recent revision to the UK TB guidelines demonstrates good sensitivity but is associated with impaired specificity in BCG-vaccinated children. 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. The Impact of Transcriptomics on the Fight against Tuberculosis: Focus on Biomarkers, BCG Vaccination, and Immunotherapy

    Directory of Open Access Journals (Sweden)

    Carlos Rodrigo Zárate-Bladés

    2011-01-01

    Full Text Available In 1882 Robert Koch identified Mycobacterium tuberculosis as the causative agent of tuberculosis (TB, a disease as ancient as humanity. Although there has been more than 125 years of scientific effort aimed at understanding the disease, serious problems in TB persist that contribute to the estimated 1/3 of the world population infected with this pathogen. Nonetheless, during the first decade of the 21st century, there were new advances in the fight against TB. The development of high-throughput technologies is one of the major contributors to this advance, because it allows for a global vision of the biological phenomenon. This paper analyzes how transcriptomics are supporting the translation of basic research into therapies by resolving three key issues in the fight against TB: (a the discovery of biomarkers, (b the explanation of the variability of protection conferred by BCG vaccination, and (c the development of new immunotherapeutic strategies to treat TB.

  1. Comparison of Karl Fischer titrimetric and gravimetric methods for determination of moisture content in BCG vaccine.

    Science.gov (United States)

    Shi, M; Klegerman, M E; Groves, M J

    1989-01-01

    A model 447 Coulomatic K-F titrimeter was used to determine the water content of seventeen lots of freeze-dried Tice-substrain BCG vaccine. The results were compared with corresponding moisture contents determined by a standard gravimetric method at the time of manufacture. The advantages of the titrimetric method include simplicity, rapidity, convenience, sensitivity, reproducibility and specificity, whereas the gravimetric method is tedious and time-consuming. Although moisture content determined by the K-F titrimeter tended to be higher than that determined by the gravimetric method, the results correlated significantly (r = 0.882, P less than 10(-5]. Alteration of national and international regulations to permit use of the K-F titrimeter is recommended.

  2. The Type of Growth Medium Affects the Presence of a Mycobacterial Capsule and Is Associated With Differences in Protective Efficacy of BCG Vaccination Against Mycobacterium tuberculosis.

    Science.gov (United States)

    Prados-Rosales, Rafael; Carreño, Leandro J; Weinrick, Brian; Batista-Gonzalez, Ana; Glatman-Freedman, Aarona; Xu, Jiayong; Chan, John; Jacobs, William R; Porcelli, Steven A; Casadevall, Arturo

    2016-08-01

    Bacillus Calmette-Guerin (BCG) vaccine is widely used for the prevention of tuberculosis, despite limited efficacy. Most immunological studies of BCG or Mycobacterium tuberculosis strains grow bacteria in the presence of detergent, which also strips the mycobacterial capsule. The impact of the capsule on vaccine efficacy has not been explored. We tested the influence of detergent in cultures of BCG and M. tuberculosis strains on the outcome of vaccination experiments on mice and transcriptional responses on M. tuberculosis  Vaccination of mice with encapsulated BCG promoted a more potent immune response relative to vaccination with unencapsulated BCG, including higher polysaccharide-specific capsule antibody titers, higher interferon γ and interleukin 17 splenic responses, and more multifunctional CD4(+) T cells. These differences correlated with variability in the bacterial burden in lung and spleen of mice infected with encapsulated or unencapsulated M. tuberculosis The combination of vaccination and challenge with encapsulated strains resulted in the greatest protection efficacy. The transcriptome of encapsulated M. tuberculosis was similar to that of starvation, hypoxia, stationary phase, or nonreplicating persistence. The presence of detergent in growth media and a capsule on BCG were associated with differences in the outcome of vaccination, implying that these are important variables in immunological studies. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  3. Effect of deworming on human T cell responses to mycobacterial antigens in helminth-exposed individuals before and after bacille Calmette-Guérin (BCG) vaccination

    DEFF Research Database (Denmark)

    Elias, D; Wolday, D; Akuffo, H

    2001-01-01

    The protective efficacy of BCG vaccination against pulmonary tuberculosis (TB) is highly variable in different populations. The reason remains to be elucidated. This study aims to investigate the possible effect of intestinal helminths on the immune response to PPD in naturally immunized or BCG-vaccinated...... tuberculin skin test-negative in both groups were BCG vaccinated and later on tested for PPD-specific responses. Albendazole induced elimination/or reduction in intestinal worms resulting in a significant improvement in T cell proliferation and in interferon-gamma production by peripheral blood mononuclear...... cells (PBMC) stimulated with PPD. Moreover, BCG vaccination significantly improved PPD-specific immune responses in the treated group but not in the placebo group. The differences in the in vivo skin test responses were not significant. The data show that cellular immune responses to PPD are reduced...

  4. A family history of serious complications due to BCG vaccination is a tool for the early diagnosis of severe primary immunodeficiency.

    Science.gov (United States)

    Roxo-Junior, Pérsio; Silva, Jorgete; Andrea, Mauro; Oliveira, Larissa; Ramalho, Fernando; Bezerra, Thiago; Nunes, Altacílio A

    2013-09-10

    Severe Combined Immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency (PID). Complications of BCG vaccination, especially disseminated infection and its most severe forms, are known to occur in immunodeficient patients, particularly in SCID. A carefully taken family history before BCG injection as well as delaying vaccination if PID is suspected could be a simple and effective method to avoid inappropriate vaccination of an immunodeficient child in some cases until the prospect of newborn screening for SCID has been fully developed. We describe a patient with a very early diagnosis of SCID, which was suspected on the basis of the previous death of two siblings younger than one year due to severe complications secondary to the BCG vaccine. We suggest that a family history of severe or fatal reactions to BCG should be included as a warning sign for an early diagnosis of SCID.

  5. Genomic expression catalogue of a global collection of BCG vaccine strains show evidence for highly diverged metabolic and cell-wall adaptations

    KAUST Repository

    Abdallah, Abdallah

    2015-10-21

    Although Bacillus Calmette-Guérin (BCG) vaccines against tuberculosis have been available for more than 90 years, their effectiveness has been hindered by variable protective efficacy and a lack of lasting memory responses. One factor contributing to this variability may be the diversity of the BCG strains that are used around the world, in part from genomic changes accumulated during vaccine production and their resulting differences in gene expression. We have compared the genomes and transcriptomes of a global collection of fourteen of the most widely used BCG strains at single base-pair resolution. We have also used quantitative proteomics to identify key differences in expression of proteins across five representative BCG strains of the four tandem duplication (DU) groups. We provide a comprehensive map of single nucleotide polymorphisms (SNPs), copy number variation and insertions and deletions (indels) across fourteen BCG strains. Genome-wide SNP characterization allowed the construction of a new and robust phylogenic genealogy of BCG strains. Transcriptional and proteomic profiling revealed a metabolic remodeling in BCG strains that may be reflected by altered immunogenicity and possibly vaccine efficacy. Together, these integrated-omic data represent the most comprehensive catalogue of genetic variation across a global collection of BCG strains.

  6. Genomic expression catalogue of a global collection of BCG vaccine strains show evidence for highly diverged metabolic and cell-wall adaptations

    Science.gov (United States)

    Abdallah, Abdallah M.; Hill-Cawthorne, Grant A.; Otto, Thomas D.; Coll, Francesc; Guerra-Assunção, José Afonso; Gao, Ge; Naeem, Raeece; Ansari, Hifzur; Malas, Tareq B.; Adroub, Sabir A.; Verboom, Theo; Ummels, Roy; Zhang, Huoming; Panigrahi, Aswini Kumar; McNerney, Ruth; Brosch, Roland; Clark, Taane G.; Behr, Marcel A.; Bitter, Wilbert; Pain, Arnab

    2015-01-01

    Although Bacillus Calmette-Guérin (BCG) vaccines against tuberculosis have been available for more than 90 years, their effectiveness has been hindered by variable protective efficacy and a lack of lasting memory responses. One factor contributing to this variability may be the diversity of the BCG strains that are used around the world, in part from genomic changes accumulated during vaccine production and their resulting differences in gene expression. We have compared the genomes and transcriptomes of a global collection of fourteen of the most widely used BCG strains at single base-pair resolution. We have also used quantitative proteomics to identify key differences in expression of proteins across five representative BCG strains of the four tandem duplication (DU) groups. We provide a comprehensive map of single nucleotide polymorphisms (SNPs), copy number variation and insertions and deletions (indels) across fourteen BCG strains. Genome-wide SNP characterization allowed the construction of a new and robust phylogenic genealogy of BCG strains. Transcriptional and proteomic profiling revealed a metabolic remodeling in BCG strains that may be reflected by altered immunogenicity and possibly vaccine efficacy. Together, these integrated-omic data represent the most comprehensive catalogue of genetic variation across a global collection of BCG strains. PMID:26487098

  7. Improving the Immunogenicity of the Mycobacterium bovis BCG Vaccine by Non-Genetic Bacterial Surface Decoration Using the Avidin-Biotin System.

    Directory of Open Access Journals (Sweden)

    Ting-Yu Angela Liao

    Full Text Available Current strategies to improve the current BCG vaccine attempt to over-express genes encoding specific M. tuberculosis (Mtb antigens and/or regulators of antigen presentation function, which indeed have the potential to reshape BCG in many ways. However, these approaches often face serious difficulties, in particular the efficiency and stability of gene expression via nucleic acid complementation and safety concerns associated with the introduction of exogenous DNA. As an alternative, we developed a novel non-genetic approach for rapid and efficient display of exogenous proteins on bacterial cell surface. The technology involves expression of proteins of interest in fusion with a mutant version of monomeric avidin that has the feature of reversible binding to biotin. Fusion proteins are then used to decorate the surface of biotinylated BCG. Surface coating of BCG with recombinant proteins was highly reproducible and stable. It also resisted to the freeze-drying shock routinely used in manufacturing conventional BCG. Modifications of BCG surface did not affect its growth in culture media neither its survival within the host cell. Macrophages phagocytized coated BCG bacteria, which efficiently delivered their surface cargo of avidin fusion proteins to MHC class I and class II antigen presentation compartments. Thereafter, chimeric proteins corresponding to a surrogate antigen derived from ovalbumin and the Mtb specific ESAT6 antigen were generated and tested for immunogenicity in vaccinated mice. We found that BCG displaying ovalbumin antigen induces an immune response with a magnitude similar to that induced by BCG genetically expressing the same surrogate antigen. We also found that BCG decorated with Mtb specific antigen ESAT6 successfully induces the expansion of specific T cell responses. This novel technology, therefore, represents a practical and effective alternative to DNA-based gene expression for upgrading the current BCG vaccine.

  8. Improving the Immunogenicity of the Mycobacterium bovis BCG Vaccine by Non-Genetic Bacterial Surface Decoration Using the Avidin-Biotin System

    Science.gov (United States)

    Liao, Ting-Yu Angela; Lau, Alice; Joseph, Sunil; Hytönen, Vesa; Hmama, Zakaria

    2015-01-01

    Current strategies to improve the current BCG vaccine attempt to over-express genes encoding specific M. tuberculosis (Mtb) antigens and/or regulators of antigen presentation function, which indeed have the potential to reshape BCG in many ways. However, these approaches often face serious difficulties, in particular the efficiency and stability of gene expression via nucleic acid complementation and safety concerns associated with the introduction of exogenous DNA. As an alternative, we developed a novel non-genetic approach for rapid and efficient display of exogenous proteins on bacterial cell surface. The technology involves expression of proteins of interest in fusion with a mutant version of monomeric avidin that has the feature of reversible binding to biotin. Fusion proteins are then used to decorate the surface of biotinylated BCG. Surface coating of BCG with recombinant proteins was highly reproducible and stable. It also resisted to the freeze-drying shock routinely used in manufacturing conventional BCG. Modifications of BCG surface did not affect its growth in culture media neither its survival within the host cell. Macrophages phagocytized coated BCG bacteria, which efficiently delivered their surface cargo of avidin fusion proteins to MHC class I and class II antigen presentation compartments. Thereafter, chimeric proteins corresponding to a surrogate antigen derived from ovalbumin and the Mtb specific ESAT6 antigen were generated and tested for immunogenicity in vaccinated mice. We found that BCG displaying ovalbumin antigen induces an immune response with a magnitude similar to that induced by BCG genetically expressing the same surrogate antigen. We also found that BCG decorated with Mtb specific antigen ESAT6 successfully induces the expansion of specific T cell responses. This novel technology, therefore, represents a practical and effective alternative to DNA-based gene expression for upgrading the current BCG vaccine. PMID:26716832

  9. The effect of high-dose vitamin A supplementation administered with BCG vaccine at birth may be modified by subsequent DTP vaccination

    DEFF Research Database (Denmark)

    Benn, Christine Stabell; Rodrigues, Amabelia; Yazdanbakhsh, Maria

    2009-01-01

    Unexpectedly, we found no overall beneficial effect on mortality in a randomised trial of vitamin A supplementation (VAS) or placebo administered with BCG vaccine at birth in Guinea-Bissau. We conducted an explorative analysis to examine whether subsequent diphtheria-tetanus-pertussis (DTP...

  10. Non-clinical efficacy and safety of HyVac4:IC31 vaccine administered in a BCG prime-boost regimen.

    Science.gov (United States)

    Skeiky, Yasir A W; Dietrich, Jes; Lasco, Todd M; Stagliano, Katherine; Dheenadhayalan, Veerabadran; Goetz, Margaret Ann; Cantarero, Luis; Basaraba, Randall J; Bang, Peter; Kromann, Ingrid; McMclain, J Bruce; Sadoff, Jerald C; Andersen, Peter

    2010-01-22

    Despite the extensive success with the introduction of M. bovis Bacille Calmette-Guérin (BCG), tuberculosis (TB) remains a major global epidemic infecting between 8 and 9 million people annually with an estimated 1.7 million deaths each year. However, because of its demonstrated effectiveness against some of the most severe forms of childhood TB, it is now realized that BCG vaccination of newborns is unlikely to be replaced. Therefore, BCG or an improved BCG will continue to be used as a prime TB vaccine and there is a need to develop effective boost vaccines that would enhance and prolong the protective immunity induced by BCG prime immunization. We report on a heterologous booster approach using two highly immunogenic TB antigens comprising Ag85B and TB10.4 (HyVac4) delivered as a fusion molecule and formulated in the proprietary adjuvant IC31. This vaccine was found to be immunogenic and demonstrated greater protection in the more stringent guinea pig model of pulmonary tuberculosis than BCG alone when used in a prime/boost regimen. Significant difference in lung involvement was observed for all animals in the HyVac4 boosted group compared to BCG alone regardless of time to death or sacrifice. A vaccine toxicology study of the HyVac4:IC31 regimen was performed and it was judged safe to advance the vaccine into clinical trials. Therefore, all non-clinical data supports the suitability of HyVac4 as a safe, immunogenic, and effective vaccination in a prime-boost regimen with BCG.

  11. [The long controversy over anti-tuberculosis vaccination in Canada: the Calmette-Guerin bacillus (BCG), 1925-1975].

    Science.gov (United States)

    Malissard, P

    1998-01-01

    The focus of this article is the history of Canada's reception of Bacillus Calmette-Guerin (BCG), an anti-tuberculosis vaccine which has almost constantly been plagued with controversy. The article examines this vaccine NRCC sponsored introduction in 1925, which led to the creation of the Associate Committee on Tuberculosis Research, a committee almost unique for its acrimonious debates. It also analyzes the interests at stakes in the ultimate rejection of the BCG by the federal Department of Agriculture veterinary services and, with the exception of Quebec and Newfoundland, by almost all public health authorities in Canada. Based on sources never taped before, this paper sheds a light on the multiple ramifications of a little known episode of the Canadian public health history.

  12. Neonatal BCG vaccination has no effect on recurrent wheeze in the first year of life: A randomized clinical trial.

    Science.gov (United States)

    Thøstesen, Lisbeth Marianne; Stensballe, Lone Graff; Pihl, Gitte Thybo; Kjærgaard, Jesper; Birk, Nina Marie; Nissen, Thomas Nørrelykke; Jensen, Aksel Karl Georg; Aaby, Peter; Olesen, Annette Wind; Jeppesen, Dorthe Lisbeth; Benn, Christine Stabell; Kofoed, Poul-Erik

    2017-12-01

    Recurrent wheeze (RW) is frequent in childhood. Studies have suggested that BCG vaccination can have nonspecific effects, reducing general nontuberculosis morbidity, including respiratory tract infections and atopic diseases. The mechanisms behind these nonspecific effects of BCG are not fully understood, but a shift from a T H 2 to a T H 1 response has been suggested as a possible explanation. We hypothesized that BCG at birth would reduce the cumulative incidence of RW during the first year of life. The Danish Calmette Study is a multicenter randomized trial conducted from 2012-2015 at 3 Danish hospitals. The 4262 newborns of 4184 included mothers were randomized 1:1 to BCG (SSI strain 1331) or to a no-intervention control group within 7 days of birth; siblings were randomized together as one randomization unit. Exclusion criteria were gestational age of less than 32 weeks, birth weight of less than 1000 g, known immunodeficiency, or no Danish-speaking parent. Information was collected through telephone interviews and clinical examinations at 3 and 13 months of age; data collectors were blind to randomization group. RW was defined in several ways, with the main definition being physician-diagnosed and medically treated RW up to 13 months of age. By 13 months, 211 (10.0%) of 2100 children in the BCG group and 195 (9.4%) of 2071 children in the control group had received a diagnosis of RW from a medical doctor and received antiasthma treatment (relative risk, 1.07; 95% CI, 0.89-1.28). Supplementary analyses were made, including an analysis of baseline risk factors for development of RW. Neonatal BCG had no effect on the development of RW before 13 months of age. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  13. The effect of zinc supplementation during pregnancy on immune response to Hib and BCG vaccines in Bangladesh.

    Science.gov (United States)

    Osendarp, Saskia J M; Fuchs, George J; van Raaij, Joop M A; Mahmud, Hasan; Tofail, Fahmida; Black, Robert E; Prabhakar, Hari; Santosham, Mathuram

    2006-10-01

    An essential role for zinc in development of the fetal immune system has been documented. However, the effect of antenatal zinc supplementation on infants' postnatal immune response to vaccinations is unknown. The objective of this study was to evaluate the effect of zinc supplementation during pregnancy on immune response to the Bacillus Calmette-Guerin (BCG) vaccine and the Haemophilus influenzae type b (Hib) component of the combined diphtheria, tetanus toxoid and pertussis (DTP)-Haemophilus influenzae type-b (Hib)- conjugate vaccine in poor Bangladeshi infants. We immunized 405 infants whose mothers were supplemented daily with 30 mg elemental zinc or placebo beginning at 12-16 weeks gestation with the standard BCG vaccine at birth. A subcohort of 203 infants were in addition immunized at 1-month intervals with three doses of DTP-Hib vaccine starting at 9 weeks of age. The delayed hypersensitivity (PPD) skin test was performed in 345 infants at 24 weeks of age. Hib polysaccharide (PRP) antibodies were assessed for 91 infants at 4 and 24 weeks of age. In infants born with low birth weight (LBW) a lower proportion of negative responses to PPD skin test were observed in the zinc (66.2%) compared to placebo (78.5%) group (p = 0.07). No differences were observed in normal birth weight infants. There were no differences in proportion of infants above the protective thresholds for anti-PRP antibodies between zinc (81%) and placebo (89%) group. Geometric mean PRP antibody titres at 4 and 24 weeks of age were not different between groups. Zinc supplementation during pregnancy did not enhance immune response to Hib-conjugate vaccine but there was a suggestion of improved delayed hypersensitivity immune responses to BCG-vaccine in Bangladeshi LBW infants.

  14. Poly(I:C)-Encapsulating Nanoparticles Enhance Innate Immune Responses to the Tuberculosis Vaccine Bacille Calmette-Guérin (BCG) via Synergistic Activation of Innate Immune Receptors.

    Science.gov (United States)

    Speth, Martin T; Repnik, Urska; Müller, Elisabeth; Spanier, Julia; Kalinke, Ulrich; Corthay, Alexandre; Griffiths, Gareth

    2017-11-06

    The attenuated live vaccine strain bacille Calmette-Guérin (BCG) is currently the only available vaccine against tuberculosis (TB), but is largely ineffective against adult pulmonary TB, the most common disease form. This is in part due to BCG's ability to interfere with the host innate immune response, a feature that might be targeted to enhance the potency of this vaccine. Here, we investigated the ability of chitosan-based nanoparticles (pIC-NPs) containing polyinosinic-polycytidylic acid (poly(I:C)), an inducer of innate immunity via Toll-like receptor 3 (TLR3), to enhance the immunogenicity of BCG in mouse bone marrow derived macrophages (BMDM) in vitro. Incorporation of poly(I:C) into NPs protected it against degradation by ribonucleases and increased its uptake by mouse BMDM. Whereas soluble poly(I:C) was ineffective, pIC-NPs strongly enhanced the proinflammatory immune response of BCG-infected macrophages in a synergistic fashion, as evident by increased production of cytokines and induction of nitric oxide synthesis. Using macrophages from mice deficient in key signaling molecules involved in the pathogen recognition response, we identified combined activation of MyD88- and TRIF-dependent TLR signaling pathways to be essential for the synergistic effect between BCG and NP. Moreover, synergy was strongly dependent on the order of the two stimuli, with TLR activation by BCG functioning as the priming event for the subsequent pIC-NP stimulus, which acted through an auto-/paracrine type I interferon (IFN) feedback loop. Our results provide a foundation for a promising new approach to enhance BCG-vaccine immunogenicity by costimulation with NPs. They also contribute to a molecular understanding of the observed synergistic interaction between the pIC-NPs and BCG vaccine.

  15. Oral vaccination of white-tailed deer (Odocoileus virginianus with Mycobacterium bovis Bacillus Calmette-Guerin (BCG.

    Directory of Open Access Journals (Sweden)

    Mitchell V Palmer

    Full Text Available Wildlife reservoirs of Mycobacterium bovis represent serious obstacles to the eradication of tuberculosis from livestock, particularly cattle. In Michigan, USA tuberculous white-tailed deer transmit M. bovis to other deer and cattle. One approach in dealing with this wildlife reservoir is to vaccinate deer, thus interfering with the intraspecies and interspecies transmission cycles. Thirty-three white-tailed deer were assigned to one of two groups; oral vaccination with 1 × 10(8 colony-forming units of M. bovis BCG Danish (n = 17; and non-vaccinated (n = 16. One hundred eleven days after vaccination deer were infected intratonsilarly with 300 colony-forming units of virulent M. bovis. At examination, 150 days after challenge, BCG vaccinated deer had fewer gross and microscopic lesions, fewer tissues from which M. bovis could be isolated, and fewer late stage granulomas with extensive liquefactive necrosis. Fewer lesions, especially those of a highly necrotic nature should decrease the potential for dissemination of M. bovis within the host and transmission to other susceptible hosts.

  16. Vitamin A supplementation and BCG vaccination at birth may affect atopy in childhood: long-term follow-up of a randomized controlled trial.

    Science.gov (United States)

    Kiraly, N; Benn, C S; Biering-Sørensen, S; Rodrigues, A; Jensen, K J; Ravn, H; Allen, K J; Aaby, P

    2013-09-01

    Recent evidence suggests that immunogenic interventions such as vaccines and micronutrients may affect atopic sensitization and atopic disease. We aimed to determine whether neonatal BCG vaccination, vitamin A supplementation and other vaccinations affect atopy in childhood. In Guinea-Bissau, low-birthweight infants were randomized to early (intervention) or delayed (usual policy) BCG. A subgroup was also randomly assigned vitamin A supplementation or placebo in a two-by-two factorial design. Participants were followed up at age 3-9 years. The main outcome was atopy defined as skin prick test reaction ≥3 mm. Secondary outcomes were symptoms of eczema, asthma and food allergy. Two hundred eighty-one children had valid skin prick tests performed, and 14% (39/281) were atopic. There was no significant difference in atopy between the early and delayed BCG groups (OR, 0.71; 95% CI, 0.34-1.47). Atopy was significantly reduced in children who had responded to BCG with a scar (OR, 0.42; 0.19-0.94). Vitamin A supplementation was associated with increased atopy (OR, 2.88; 1.26-6.58), especially in those who received simultaneous BCG (5.99; 1.99-18.1, P = 0.09 for interaction between vitamin A supplementation and BCG). Early vs delayed BCG was not associated with symptoms of atopic disease, but vitamin A supplementation increased odds of wheeze within the past 12 months (OR, 2.45; 1.20-4.96). There were no statistically significant effects of early vs delayed BCG on atopy or symptoms of atopic disease. Having a BCG scar was associated with reduced atopy, whereas neonatal vitamin A supplementation was associated with increased atopy. Clinicaltrials.gov NCT 01420705. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Subunit Vaccines Consisting of Antigens from Dormant and Replicating Bacteria Show Promising Therapeutic Effect against Mycobacterium Bovis BCG Latent Infection.

    Science.gov (United States)

    Li, F; Kang, H; Li, J; Zhang, D; Zhang, Y; Dannenberg, A M; Liu, X; Niu, H; Ma, L; Tang, R; Han, X; Gan, C; Ma, X; Tan, J; Zhu, B

    2017-06-01

    To screen effective antigens as therapeutic subunit vaccines against Mycobacterium latent infection, we did bioinformatics analysis and literature review to identify effective antigens and evaluated the immunogenicity of five antigens highly expressed in dormant bacteria, which included Rv2031c (HspX), Rv2626c (Hrp1), Rv2007c (FdxA), Rv1738 and Rv3130c. Then, several fusion proteins such as Rv2007c-Rv2626c (F6), Rv2031c-Rv1738-Rv1733c (H83), ESAT6-Rv1738-Rv2626c (LT40), ESAT6-Ag85B-MPT64 -Mtb8.4 (EAMM), and EAMM-Rv2626c (LT70) were constructed and their therapeutic effects were evaluated in pulmonary Mycobacterium bovis Bacilli Calmette-Guérin (BCG) - latently infected rabbit or mouse models. The results showed that EAMM and F6 plus H83 had therapeutic effect against BCG latent infection in the rabbit model, respectively, and that the combination of EAMM with F6 plus H83 significantly reduced the bacterial load. In addition, the fusion proteins LT40 and LT70 consisting of multistage antigens showed promising therapeutic effects in the mouse model. We conclude that subunit vaccines consisting of both latency and replicating-associated antigens show promising therapeutic effects in BCG latent infection animal models. © 2017 The Foundation for the Scandinavian Journal of Immunology.

  18. Molecular Characterization of Heterologous HIV-1gp120 Gene Expression Disruption in Mycobacterium bovis BCG Host Strain: A Critical Issue for Engineering Mycobacterial Based-Vaccine Vectors

    Directory of Open Access Journals (Sweden)

    Joan Joseph

    2010-01-01

    Full Text Available Mycobacterium bovis Bacillus Calmette-Guérin (BCG as a live vector of recombinant bacterial vaccine is a promising system to be used. In this study, we evaluate the disrupted expression of heterologous HIV-1gp120 gene in BCG Pasteur host strain using replicative vectors pMV261 and pJH222. pJH222 carries a lysine complementing gene in BCG lysine auxotrophs. The HIV-1 gp120 gene expression was regulated by BCG hsp60 promoter (in plasmid pMV261 and Mycobacteria spp. α-antigen promoter (in plasmid pJH222. Among 14 rBCG:HIV-1gp120 (pMV261 colonies screened, 12 showed a partial deletion and two showed a complete deletion. However, deletion was not observed in all 10 rBCG:HIV-1gp120 (pJH222 colonies screened. In this study, we demonstrated that E. coli/Mycobacterial expression vectors bearing a weak promoter and lysine complementing gene in a recombinant lysine auxotroph of BCG could prevent genetic rearrangements and disruption of HIV 1gp120 gene expression, a key issue for engineering Mycobacterial based vaccine vectors.

  19. Naive helper T cells from BCG-vaccinated volunteers produce IFN-gamma and IL-5 to mycobacterial antigen-pulsed dendritic cells.

    Directory of Open Access Journals (Sweden)

    JoĂŤl Pestel

    2008-06-01

    Full Text Available Mycobacterium bovis bacillus Calmette-GuĂŠrin (BCG is a live vaccine that has been used in routine vaccination against tuberculosis for nearly 80 years. However, its efficacy is controversial. The failure of BCG vaccination may be at least partially explained by the induction of poor or inappropriate host responses. Dendritic cells (DCs are likely to play a key role in the induction of immune response to mycobacteria by polarizing the reactivity of T lymphocytes toward a Th1 profile, contributing to the generation of protective cellular immunity against mycobacteria. In this study we aimed to investigate the production of Th1 and Th2 cytokines by naive CD4+ T cells to mycobacterial antigen-pulsed DCs in the group of young, healthy BCG vaccinated volunteers. The response of naive helper T cells was compared with the response of total blood lymphocytes. Our present results clearly showed that circulating naive CD45RA+CD4+ lymphocytes from BCG-vaccinated subjects can become effector helper cells producing IFN-gamma and IL-5 under the stimulation by autologous dendritic cells presenting mycobacterial protein antigen-PPD or infected with live M. bovis BCG bacilli.

  20. Deep sequencing analysis of the heterogeneity of seed and commercial lots of the bacillus Calmette-Guérin (BCG) tuberculosis vaccine substrain Tokyo-172

    Science.gov (United States)

    Wada, Takayuki; Maruyama, Fumito; Iwamoto, Tomotada; Maeda, Shinji; Yamamoto, Taro; Nakagawa, Ichiro; Yamamoto, Saburo; Ohara, Naoya

    2015-01-01

    BCG, only vaccine available to prevent tuberculosis, was established in the early 20th century by prolonged passaging of a virulent clinical strain of Mycobacterium bovis. BCG Tokyo-172, originally distributed within Japan in 1924, is one of the currently used reference substrains for the vaccine. Recently, this substrain was reported to contain two spontaneously arising, heterogeneous subpopulations (Types I and II). The proportions of the subpopulations changed over time in both distributed seed lots and commercial lots. To maintain the homogeneity of live vaccines, such variations and subpopulational mutations in lots should be restrained and monitored. We incorporated deep sequencing techniques to validate such heterogeneity in lots of the BCG Tokyo-172 substrain without cloning. By bioinformatics analysis, we not only detected the two subpopulations but also detected two intrinsic variations within these populations. The intrinsic variants could be isolated from respective lots as colonies cultured on plate media, suggesting analyses incorporating deep sequencing techniques are powerful, valid tools to detect mutations in live bacterial vaccine lots. Our data showed that spontaneous mutations in BCG vaccines could be easily monitored by deep sequencing without direct isolation of variants, revealing the complex heterogeneity of BCG Tokyo-172 and its daughter lots currently in use. PMID:26635118

  1. Effect of vaccine dose on the safety and immunogenicity of a candidate TB vaccine, MVA85A, in BCG vaccinated UK adults.

    Science.gov (United States)

    Pathan, Ansar A; Minassian, Angela M; Sander, Clare R; Rowland, Rosalind; Porter, David W; Poulton, Ian D; Hill, Adrian V S; Fletcher, Helen A; McShane, Helen

    2012-08-17

    A non-randomised, open-label, Phase I safety and immunogenicity dose-finding study to assess the safety and immunogenicity of the candidate TB vaccine Modified Vaccinia virus Ankara expressing Antigen 85A (MVA85A) from Mycobacterium tuberculosis (MTB) in healthy adult volunteers previously vaccinated with BCG. Healthy BCG-vaccinated volunteers were vaccinated with either 1×10(7) or 1×10(8)PFU of MVA85A. All adverse events were documented and antigen specific T cell responses were measured using an ex vivo IFN-γ ELISPOT assay. Safety and immunogenicity were compared between the 2 dose groups and with a previous trial in which a dose of 5×10(7)PFU MVA85A had been administered. There were no serious adverse events recorded following administration of either 1×10(7) or 1×10(8)PFU of MVA85A. Systemic adverse events were more frequently reported following administration of 1×10(8)PFU of MVA85A when compared to either 5×10(7) or 1×10(7)PFU of MVA85A but were mild or moderate in severity and resolved completely within 7 days of immunisation. Antigen specific T cell responses as measured by the IFN-γ ELISPOT were significantly higher following immunisation in adults receiving 1×10(8)PFU compared to the 5×10(7) and 1×10(7) doses. Additionally, a broader range of Ag85A epitopes are detected following 1×10(8)PFU of MVA85A. A higher dose of 1×10(8)PFU of MVA85A is well-tolerated, increases the frequency of IFN-γ secreting T cells detected following immunisation and broadens the range of Ag85A epitopes detected. Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. The effect of current Schistosoma mansoni infection on the immunogenicity of a candidate TB vaccine, MVA85A, in BCG-vaccinated adolescents: An open-label trial.

    Directory of Open Access Journals (Sweden)

    Anne Wajja

    2017-05-01

    Full Text Available Helminth infection may affect vaccine immunogenicity and efficacy. Adolescents, a target population for tuberculosis booster vaccines, often have a high helminth burden. We investigated effects of Schistosoma mansoni (Sm on the immunogenicity and safety of MVA85A, a model candidate tuberculosis vaccine, in BCG-vaccinated Ugandan adolescents.In this phase II open label trial we enrolled 36 healthy, previously BCG-vaccinated adolescents, 18 with no helminth infection detected, 18 with Sm only. The primary outcome was immunogenicity measured by Ag85A-specific interferon gamma ELISpot assay. Tuberculosis and schistosome-specific responses were also assessed by whole-blood stimulation and multiplex cytokine assay, and by antibody ELISAs.Ag85A-specific cellular responses increased significantly following immunisation but with no differences between the two groups. Sm infection was associated with higher pre-immunisation Ag85A-specific IgG4 but with no change in antibody levels following immunisation. There were no serious adverse events. Most reactogenicity events were of mild or moderate severity and resolved quickly.The significant Ag85A-specific T cell responses and lack of difference between Sm-infected and uninfected participants is encouraging for tuberculosis vaccine development. The implications of pre-existing Ag85A-specific IgG4 antibodies for protective immunity against tuberculosis among those infected with Sm are not known. MVA85A was safe in this population.ClinicalTrials.gov NCT02178748.

  3. Impact of PGL-I seropositivity on the protective effect of BCG vaccination among leprosy contacts: a cohort study.

    Directory of Open Access Journals (Sweden)

    Nádia C Düppre

    Full Text Available BACKGROUND: Contacts of leprosy patients are at increased risk of developing leprosy and need to be targeted for early diagnosis. Seropositivity to the phenolic glycolipid I (PGL-I antigen of Mycobacterium leprae has been used to identify contacts who have an increased risk of developing leprosy. In the present study, we studied the effect of seropositivity in patient contacts, on the risk of developing leprosy, stratified by Bacille Calmette Guerin (BCG vaccination after index case diagnosis. METHODOLOGY/PRINCIPAL FINDINGS: Leprosy contacts were examined as part of the surveillance programme of the Oswaldo Cruz Institute Leprosy Outpatient Clinic in Rio de Janeiro. Demographic, social, epidemiological and clinical data were collected. The presence of IgM antibodies to PGL-I in sera and BCG vaccination status at the time of index case diagnosis were evaluated in 2,135 contacts. During follow-up, 60 (2.8%; 60/2,135 leprosy cases were diagnosed: 41 among the 1,793 PGL-I-negative contacts and 19 among the 342 PGL-I-positive contacts. Among PGL-I-positive contacts, BCG vaccination after index case diagnosis increased the adjusted rate of developing clinical manifestations of leprosy (Adjusted Rate Ratio (aRR = 4.1; 95% CI: 1.8-8.2 compared with the PGL-I-positive unvaccinated contacts (aRR = 3.2; 95% CI: 1.2-8.1. The incidence density was highest during the first year of follow-up for the PGL-I-positive vaccinated contacts. However, all of those contacts developed PB leprosy, whereas most MB cases (4/6 occurred in PGL-I-positive unvaccinated contacts. CONCLUSION: Contact examination combined with PGL-I testing and BCG vaccination remain important strategies for leprosy control. The finding that rates of leprosy cases were highest among seropositive contacts justifies targeting this specific group for close monitoring. Furthermore, it is recommended that PGL-I-positive contacts and contacts with a high familial bacteriological index

  4. Sendai Virus Mucosal Vaccination Establishes Lung-Resident Memory CD8 T Cell Immunity and Boosts BCG-Primed Protection against TB in Mice.

    Science.gov (United States)

    Hu, Zhidong; Wong, Ka-Wing; Zhao, Hui-Min; Wen, Han-Li; Ji, Ping; Ma, Hui; Wu, Kang; Lu, Shui-Hua; Li, Feng; Li, Zhong-Ming; Shu, Tsugumine; Xu, Jian-Qing; Lowrie, Douglas B; Fan, Xiao-Yong

    2017-05-03

    Accumulating evidence has shown the protective role of CD8 + T cells in vaccine-induced immunity against Mycobacterium tuberculosis (Mtb) despite controversy over their role in natural immunity. However, the current vaccine BCG is unable to induce sufficient CD8 + T cell responses, especially in the lung. Sendai virus, a respiratory RNA virus, is here engineered firstly as a novel recombinant anti-TB vaccine (SeV85AB) that encodes Mtb immuno-dominant antigens, Ag85A and Ag85B. A single mucosal vaccination elicited potent antigen-specific T cell responses and a degree of protection against Mtb challenge similar to the effect of BCG in mice. Depletion of CD8 + T cells abrogated the protective immunity afforded by SeV85AB vaccination. Interestingly, only SeV85AB vaccination induced high levels of lung-resident memory CD8 + T (T RM ) cells, and this led to a rapid and strong recall of antigen-specific CD8 + T cell responses against Mtb challenge infection. Furthermore, when used in a BCG prime-SeV85AB boost strategy, SeV85AB vaccine significantly enhanced protection above that seen after BCG vaccination alone. Our findings suggest that CD8 + T RM cells that arise in lungs responding to this mucosal vaccination might help to protect against TB, and SeV85AB holds notable promise to improve BCG's protective efficacy in a prime-boost immunization regimen. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  5. BCG status in children with tuberculosis: A multicenter study in ...

    African Journals Online (AJOL)

    Background: Bacille Calmette.Guerin (BCG) vaccine has been in use since 1921, yet childhood TB is still very prevalent in Nigeria. Since BCG efficacy depends in part on appropriate vaccine utilization, this study was designed to investigate the current practice of BCG administration through determination of BCG status.

  6. Successive Intramuscular Boosting with IFN-Alpha Protects Mycobacterium bovis BCG-Vaccinated Mice against M. lepraemurium Infection

    Directory of Open Access Journals (Sweden)

    G. G. Guerrero

    2015-01-01

    Full Text Available Leprosy caused by Mycobacterium leprae primarily affects the skin and peripheral nerves. As a human infectious disease, it is still a significant health and economic burden on developing countries. Although multidrug therapy is reducing the number of active cases to approximately 0.5 million, the number of cases per year is not declining. Therefore, alternative host-directed strategies should be addressed to improve treatment efficacy and outcome. In this work, using murine leprosy as a model, a very similar granulomatous skin lesion to human leprosy, we have found that successive IFN-alpha boosting protects BCG-vaccinated mice against M. lepraemurium infection. No difference in the seric isotype and all IgG subclasses measured, neither in the TH1 nor in the TH2 type cytokine production, was seen. However, an enhanced iNOS/NO production in BCG-vaccinated/i.m. IFN-alpha boosted mice was observed. The data provided in this study suggest a promising use for IFN-alpha boosting as a new prophylactic alternative to be explored in human leprosy by targeting host innate cell response.

  7. Interruption of persistent exposure to leprosy combined or not with recent BCG vaccination enhances the response to Mycobacterium leprae specific antigens.

    Science.gov (United States)

    de Carvalho, Fernanda Marques; Rodrigues, Luciana Silva; Duppre, Nádia Cristina; Alvim, Iris Maria Peixoto; Ribeiro-Alves, Marcelo; Pinheiro, Roberta Olmo; Sarno, Euzenir Nunes; Pessolani, Maria Cristina Vidal; Pereira, Geraldo Moura Batista

    2017-05-01

    Household contacts of multibacillary leprosy patients (HCMB) constitute the group of individuals at the highest risk of developing leprosy. Early diagnosis and treatment of their index cases combined with Bacille Calmette-Guerin (BCG) immunization remain important strategies adopted in Brazil to prevent HCMB from evolving into active disease. In the present study, we assessed the impact of these measures on the immune response to Mycobacterium leprae in HCMB. Peripheral blood mononuclear cells (PBMC) from HCMB (n = 16) were obtained at the beginning of leprosy index case treatment (T0). At this time point, contacts were vaccinated (n = 13) or not (n = 3) in accordance with their infancy history of BCG vaccination and PBMCs were recollected at least 6 months later (T1). As expected, a significant increase in memory CD4 and CD8 T cell frequencies responsive to M. leprae whole-cell sonicate was observed in most contacts. Of note, higher frequencies of CD4+ T cells that recognize M. leprae specific epitopes were also detected. Moreover, increased production of the inflammatory mediators IL1-β, IL-6, IL-17, TNF, IFN-γ, MIP1-β, and MCP-1 was found at T1. Interestingly, the increment in these parameters was observed even in those contacts that were not BCG vaccinated at T0. This result reinforces the hypothesis that the continuous exposure of HCMB to live M. leprae down regulates the specific cellular immune response against the pathogen. Moreover, our data suggest that BCG vaccination of HCMB induces activation of T cell clones, likely through "trained immunity", that recognize M. leprae specific antigens not shared with BCG as an additional protective mechanism besides the expected boost in cell-mediated immunity by BCG homologues of M. leprae antigens.

  8. Neonatal BCG vaccination has no effect on recurrent wheeze in the first year of life

    DEFF Research Database (Denmark)

    Thøstesen, Lisbeth Marianne; Stensballe, Lone Graff; Pihl, Gitte Thybo

    2017-01-01

    are not fully understood, but a shift from a TH2 to a TH1 response has been suggested as a possible explanation. Objective: We hypothesized that BCG at birth would reduce the cumulative incidence of RW during the first year of life. Methods: The Danish Calmette Study is a multicenter randomized trial conducted...... (relative risk, 1.07; 95% CI, 0.89-1.28). Supplementary analyses were made, including an analysis of baseline risk factors for development of RW. Conclusion: Neonatal BCG had no effect on the development of RW before 13 months of age....

  9. Fecal volatile organic compound profiles from white-tailed deer (Odocoileus virginianus) as indicators of Mycobacterium bovis exposure or Mycobacterium bovis bacille Calmette-Guerin (BCG) vaccination

    Science.gov (United States)

    White-tailed deer (Odocoileus virginianus) serve as a reservoir for bovine tuberculosis, caused by Mycobacterium bovis, and can be a source of infection in cattle. Vaccination with M. bovis bacille Calmette-Guerin (BCG) is being considered for management of bovine tuberculosis in deer. Presently, no...

  10. Immunotherapy with autologous tumor cell-BCG vaccine in patients with colon cancer: a prospective study of medical and economic benefits

    NARCIS (Netherlands)

    Uyl-de Groot, C. A.; Vermorken, J. B.; Hanna, M. G.; Verboom, P.; Groot, M. T.; Bonsel, G. J.; Meijer, C. J. L. M.; Pinedo, H. M.

    2005-01-01

    We have completed a multicenter, randomized controlled phase III clinical trial in Stages II and III colon cancer patients with active specific immunotherapy (ASI) using autologous tumor cells with an immunomodulating adjuvant bacillus Callmette-Guerin (BCG) vaccine (OncoVAX (R)) in an adjuvant

  11. Effect of 50 000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau: randomised placebo controlled trial

    DEFF Research Database (Denmark)

    Diness, B.R.; Roth, A.; Nante, E.

    2008-01-01

    Objective To investigate the effect of high dose vitamin A supplementation given with BCG vaccine at birth in an African setting with high infant mortality. Design Randomised placebo controlled trial. Setting Bandim Health Project's demographic surveillance system in Guinea-Bissau, covering appro...

  12. Effect of vitamin A supplementation with BCG vaccine at birth on vitamin A status at 6 wk and 4 mo of age

    DEFF Research Database (Denmark)

    Fisker, Ane B; Lisse, Ida M; Aaby, Peter

    2007-01-01

    BACKGROUND: The effect of vitamin A supplementation (VAS) at birth on subsequent vitamin A status has not been studied. OBJECTIVE: The objective was to study the effect of 50,000 IU vitamin A administered with BCG vaccine at birth on vitamin A status in both sexes. DESIGN: Within a randomized pla...

  13. Family history of immigration from a tuberculosis endemic country and low family income are associated with a higher BCG vaccination coverage in Ile-de-France region, France.

    Science.gov (United States)

    Guthmann, Jean-Paul; Chauvin, Pierre; Le Strat, Yann; Soler, Marion; Fonteneau, Laure; Lévy-Bruhl, Daniel

    2013-11-19

    After withdrawal of multipuncture BCG device from the French market in January 2006, vaccination coverage (VC) with the intradermal device has dropped and since remained sub-optimal in Ile-de-France, the only region of mainland France where BCG is recommended to all children. We conducted a cross-sectional study to identify socio-economic factors associated with BCG VC in children of Paris metropolitan area born after January 2006. Two-stage random sampling was used to include 425 children up to 5 years old from Paris and its suburbs. Information was collected through face-to-face interviews and vaccination status confirmed by a vaccination document. Poisson regression analyzed the association between VC and potential determinants. VC of children from families with the lowest incomes (first quartile of family income/consumption unit (CU) (immigration, regardless of family income, are correctly identified as being at high risk of tuberculosis and properly vaccinated with BCG in this area. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Cyclic di-AMP-mediated interaction between Mycobacterium tuberculosis ΔcnpB and macrophages implicates a novel strategy for improving BCG vaccination.

    Science.gov (United States)

    Zhang, Yang; Yang, Jun; Bai, Guangchun

    2018-01-31

    Cyclic di-AMP (c-di-AMP) has been shown to play an important role in bacterial physiology and pathogen-host interactions. We previously reported that deletion of the sole c-di-AMP phosphodiesterase-encoding gene (cnpB) in Mycobacterium tuberculosis (Mtb) led to significant virulence attenuation. In this study, we found that ΔcnpB of M. bovis BCG (BCG) was unable to secrete c-di-AMP, which differs from Mtb ΔcnpB. We infected bone marrow-derived macrophages (BMDMs) with c-di-AMP-associated mutants generated from both Mtb and BCG. Our results showed that upon infection with Mtb ΔcnpB, BMDMs of WT mice secreted a large amount of interferon-β (IFN-β) post-infection similarly as we reported previously. In contrast, the response was less pronounced with BMDMs isolated from cGAS-/- mice and was nearly abolished with BMDMs prepared from STING-/- mice. Deletion of the region of difference 1 (RD1) locus in Mtb ΔcnpB did not alter the c-di-AMP secretion of ΔcnpB but eliminated the IFN-β production in the infected cells. In contrast, neither BCG ΔcnpB nor a recombinant BCG ΔcnpB with a pRD1 cosmid induced a type I interferon response. Interestingly, multiple studies have demonstrated that type I IFN enhances BCG's immunity. Thus, amending BCG based on our findings might improve BCG vaccination. © FEMS 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  15. The Effect of 50 000 IU Vitamin A with BCG Vaccine at Birth on Growth in the First Year of Life

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    Ane Bærent Fisker

    2011-01-01

    Neonatal VAS had no effect on anthropometric measures at 12 months, but may interact sex differentially with routine vaccines. While BCG was the most recent vaccine, neonatal VAS benefitted growth (difference in weight-for-length z-score (dWFL: 0.31(95% CI: 0.03–0.59. While DTP was the most recent vaccine, VAS tended to affect growth adversely in girls (dWFL = −0.21 (−0.48–0.06. After measles vaccine (MV there was no overall effect of neonatal VAS. The VAS effect differed significantly between the BCG and DTP windows (P=0.03, and the difference was borderline significant between the DTP and MV windows for girls (P=0.09.

  16. Neonatal BCG vaccination has no effect on recurrent wheeze in the first year of life

    DEFF Research Database (Denmark)

    Thøstesen, Lisbeth Marianne; Stensballe, Lone Graff; Pihl, Gitte Thybo

    2017-01-01

    are not fully understood, but a shift from a TH2 to a TH1 response has been suggested as a possible explanation. Objective: We hypothesized that BCG at birth would reduce the cumulative incidence of RW during the first year of life. Methods: The Danish Calmette Study is a multicenter randomized trial conducted...

  17. rBCG induces strong antigen-specific T cell responses in rhesus macaques in a prime-boost setting with an adenovirus 35 tuberculosis vaccine vector.

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    Isabelle Magalhaes

    Full Text Available BACKGROUND: BCG vaccination, combined with adenoviral-delivered boosts, represents a reasonable strategy to augment, broaden and prolong immune protection against tuberculosis (TB. We tested BCG (SSI1331 (in 6 animals, delivered intradermally and a recombinant (rBCG AFRO-1 expressing perfringolysin (in 6 animals followed by two boosts (delivered intramuscullary with non-replicating adenovirus 35 (rAd35 expressing a fusion protein composed of Ag85A, Ag85B and TB10.4, for the capacity to induce antigen-specific cellular immune responses in rhesus macaques (Macaca mulatta. Control animals received diluent (3 animals. METHODS AND FINDINGS: Cellular immune responses were analyzed longitudinally (12 blood draws for each animal using intracellular cytokine staining (TNF-alpha, IL-2 and IFN-gamma, T cell proliferation was measured in CD4(+, CD8alpha/beta(+, and CD8alpha/alpha(+ T cell subsets and IFN-gamma production was tested in 7 day PBMC cultures (whole blood cell assay, WBA using Ag85A, Ag85B, TB10.4 recombinant proteins, PPD or BCG as stimuli. Animals primed with AFRO-1 showed i increased Ag85B-specific IFN-gamma production in the WBA assay (median >400 pg/ml for 6 animals one week after the first boost with adenoviral-delivered TB-antigens as compared to animals primed with BCG (<200 pg/ml, ii stronger T cell proliferation in the CD8alpha/alpha(+ T cell subset (proliferative index 17% as compared to BCG-primed animals (proliferative index 5% in CD8alpha/alpha(+ T cells. Polyfunctional T cells, defined by IFN-gamma, TNF-alpha and IL-2 production were detected in 2/6 animals primed with AFRO-1 directed against Ag85A/b and TB10.4; 4/6 animals primed with BCG showed a Ag85A/b responses, yet only a single animal exhibited Ag85A/b and TB10.4 reactivity. CONCLUSION: AFRO-1 induces qualitatively and quantitatively different cellular immune responses as compared with BCG in rhesus macaques. Increased IFN-gamma-responses and antigen-specific T cell

  18. The expression of ferritin, lactoferrin, transferrin receptor and solute carrier family 11A1 in the host response to BCG-vaccination and Mycobacterium tuberculosis challenge.

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    Thom, R E; Elmore, M J; Williams, A; Andrews, S C; Drobniewski, F; Marsh, P D; Tree, J A

    2012-05-02

    Iron is an essential cofactor for both mycobacterial growth during infection and for a successful protective immune response by the host. The immune response partly depends on the regulation of iron by the host, including the tight control of expression of the iron-storage protein, ferritin. BCG vaccination can protect against disease following Mycobacterium tuberculosis infection, but the mechanisms of protection remain unclear. To further explore these mechanisms, splenocytes from BCG-vaccinated guinea pigs were stimulated ex vivo with purified protein derivative from M. tuberculosis and a significant down-regulation of ferritin light- and heavy-chain was measured by reverse-transcription quantitative-PCR (P≤0.05 and ≤0.01, respectively). The mechanisms of this down-regulation were shown to involve TNFα and nitric oxide. A more in depth analysis of the mRNA expression profiles, including genes involved in iron metabolism, was performed using a guinea pig specific immunological microarray following ex vivo infection with M. tuberculosis of splenocytes from BCG-vaccinated and naïve guinea pigs. M. tuberculosis infection induced a pro-inflammatory response in splenocytes from both groups, resulting in down-regulation of ferritin (P≤0.05). In addition, lactoferrin (P≤0.002), transferrin receptor (P≤0.05) and solute carrier family 11A1 (P≤0.05), were only significantly down-regulated after infection of the splenocytes from BCG-vaccinated animals. The results show that expression of iron-metabolism genes is tightly regulated as part of the host response to M. tuberculosis infection and that BCG-vaccination enhances the ability of the host to mount an iron-restriction response which may in turn help to combat invasion by mycobacteria. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Impact of the BCG vaccination policy on tuberculous meningitis in children under 6 years in metropolitan France between 2000 and 2011.

    Science.gov (United States)

    Van Bui, T; Lévy-Bruhl, D; Che, D; Antoine, D; Jarlier, V; Robert, J

    2015-03-19

    In France, Bacillus Calmette–Guérin (BCG) vaccination by multipuncture device was withdrawn in 2006. In 2007, universal mandatory BCG vaccination was replaced by vaccination of high-risk children. To evaluate the impact of these changes on tuberculous meningitis (TBM) epidemiology, data on culture-positive and culture-negative (or unknown microbiological result) TBM in ≤5 years olds were collected from 2000–2011. Ten culture-positive and 17 culture-negative TBM cases were identified, with an annual incidence rate ranging from 0.16 to 0.66 cases per 10 million inhabitants. The average annual numbers of TBM cases were 2.7 and 1.8 from 2000–2005 and 2006–2011, respectively. In Ile-de-France where all children are considered at risk, the overall incidence rates were 1.14 and 0.29 per million for the two periods. In other regions where only at-risk children are vaccinated since 2007, rates were 0.30 and 0.47, respectively. None of these differences were significant. Annual incidence rates for each one year age group cohort were comparable before and after changes. Childhood TBM remains rare in France. No increase in incidence was observed after changes in BCG vaccination strategy. Ongoing surveillance should be maintained, as a slight increase in TBM in the coming years remains possible, in the context of suboptimal vaccination coverage of high-risk children.

  20. Adverse reactions to the Bacillus Calmette-Guérin (BCG) vaccine in new-born infants-an evaluation of the Danish strain 1331 SSI in a randomized clinical trial.

    Science.gov (United States)

    Nissen, Thomas Nørrelykke; Birk, Nina Marie; Kjærgaard, Jesper; Thøstesen, Lisbeth Marianne; Pihl, Gitte Thybo; Hoffmann, Thomas; Jeppesen, Dorthe Lisbeth; Kofoed, Poul-Erik; Greisen, Gorm; Benn, Christine Stabell; Aaby, Peter; Pryds, Ole; Stensballe, Lone Graff

    2016-05-11

    To evaluate adverse reactions of the Bacillus Calmette-Guérin (BCG) Statens Serum Institut (SSI) (Danish strain 1331) used as intervention in a randomized clinical trial. A randomized clinical multicenter trial, The Danish Calmette Study, randomizing newborns to BCG or no intervention. Follow-up until 13 months of age. Pediatric and maternity wards at three Danish university hospitals. All women planning to give birth at the three study sites (n=16,521) during the recruitment period were invited to participate in the study. Four thousand one hundred and eighty four families consented to participate and 4262 children, gestational age 32 weeks and above, were randomized: 2129 to BCG vaccine and 2133 to no vaccine. None of the participants withdrew because of adverse reactions. Trial-registered adverse reactions after BCG vaccination at birth. Follow-up at 3 and 13 months by telephone interviews and clinical examinations. Among the 2118 BCG-vaccinated children we registered no cases of severe unexpected adverse reaction related to BCG vaccination and no cases of disseminated BCG disease. Two cases of regional lymphadenitis were hospitalized and thus classified as serious adverse reactions related to BCG. The most severe adverse reactions were 10 cases of suppurative lymphadenitis. This was nearly a fivefold increase compared to what was expected based on the summary of product characteristics of the vaccine. All cases were treated conservatively and recovered. Six of 10 (60%) families of children experiencing suppurative lymphadenitis compared to 117/2071 (6%) of those with no lymphadenitis indicated that the vaccine had more adverse effects than expected (p-value <0.001). BCG vaccination was associated with only mild morbidity and no mortality. A higher incidence of suppurative lymphadenitis than expected was observed. All children were treated conservatively without sequelae or complications. Trial registration number NCT01694108 at www

  1. Prova tuberculínica, BCG oral e infecção tuberculosa em crianças menores de 5 anos Tuberculin test, oral BCG vaccine, and tuberculosis infection among children under five years of age

    Directory of Open Access Journals (Sweden)

    Marialda Höfling de Pádua Dias

    1978-12-01

    vaccination and positivation to the tuberculin test in the two age groups was studied, thus obtaining information about the previous oral BCG vaccination. Likewise, in 575 children under one year of age and 1113 children one to four years of age, a positive relationship between the previous oral administration of BCG and the positivation to the tuberculin test was found. In analyzing the relationship between the number of doses of previous oral BCG administration and the results of the tuberculin test by the Goodman method, it was found that the proportion of children who had taken three or more doses of BCG by oral administration and showed strong reaction to the tuberculin test is significantly greater than that observed for the non-reactors, a fact which does not hold true for the one to four age group. For the children who had taken one or two doses there was no significant statistical difference.

  2. MVA.85A boosting of BCG and an attenuated, phoP deficient M. tuberculosis vaccine both show protective efficacy against tuberculosis in rhesus macaques.

    Directory of Open Access Journals (Sweden)

    Frank A W Verreck

    Full Text Available Continuous high global tuberculosis (TB mortality rates and variable vaccine efficacy of Mycobacterium bovis Bacille Calmette-Guérin (BCG motivate the search for better vaccine regimes. Relevant models are required to downselect the most promising vaccines entering clinical efficacy testing and to identify correlates of protection.Here, we evaluated immunogenicity and protection against Mycobacterium tuberculosis in rhesus monkeys with two novel strategies: BCG boosted by modified vaccinia virus Ankara expressing antigen 85A (MVA.85A, and attenuated M. tuberculosis with a disrupted phoP gene (SO2 as a single-dose vaccine. Both strategies were well tolerated, and immunogenic as evidenced by induction of specific IFNgamma responses. Antigen 85A-specific IFNgamma secretion was specifically increased by MVA.85A boosting. Importantly, both MVA.85A and SO2 treatment significantly reduced pathology and chest X-ray scores upon infectious challenge with M. tuberculosis Erdman strain. MVA.85A and SO2 treatment also showed reduced average lung bacterial counts (1.0 and 1.2 log respectively, compared with 0.4 log for BCG and significant protective effect by reduction in C-reactive protein levels, body weight loss, and decrease of erythrocyte-associated hematologic parameters (MCV, MCH, Hb, Ht as markers of inflammatory infection, all relative to non-vaccinated controls. Lymphocyte stimulation revealed Ag85A-induced IFNgamma levels post-infection as the strongest immunocorrelate for protection (spearman's rho: -0.60.Both the BCG/MVA.85A prime-boost regime and the novel live attenuated, phoP deficient TB vaccine candidate SO2 showed significant protective efficacy by various parameters in rhesus macaques. Considering the phylogenetic relationship between macaque and man and the similarity in manifestations of TB disease, these data support further development of these primary and combination TB vaccine candidates.

  3. Tuberculosis contact investigation with a new, specific blood test in a low-incidence population containing a high proportion of BCG-vaccinated persons

    Directory of Open Access Journals (Sweden)

    Meywald-Walter K

    2006-05-01

    Full Text Available Abstract Background BCG-vaccination can confound tuberculin skin test (TST reactions in the diagnosis of latent tuberculosis infection. Methods We compared the TST with a Mycobacterium tuberculosis specific whole blood interferon-gamma assay (QuantiFERON®-TB-Gold In Tube; QFT-G during ongoing investigations among close contacts of sputum smear positive source cases in Hamburg, Germany. Results During a 6-month period, 309 contacts (mean age 28.5 ± 10.5 years from a total of 15 source cases underwent both TST and QFT-G testing. Of those, 157 (50.8% had received BCG vaccination and 84 (27.2% had migrated to Germany from a total of 25 different high prevalence countries (i.e. >20 cases/100,000. For the TST, the positive response rate was 44.3% (137/309, whilst only 31 (10% showed a positive QFT-G result. The overall agreement between the TST and the QFT-G was low (κ = 0.2, with 95% CI 0.14.-0.23, and positive TST reactions were closely associated with prior BCG vaccination (OR 24.7; 95% CI 11.7–52.5. In contrast, there was good agreement between TST and QFT-G in non-vaccinated persons (κ = 0.58, with 95% CI 0.4–0.68, increasing to 0.68 (95% CI 0.46–0.81, if a 10-mm cut off for the TST was used instead of the standard 5 mm recommended in Germany. Conclusion The QFT-G assay was unaffected by BCG vaccination status, unlike the TST. In close contacts who were BCG-vaccinated, the QFT-G assay appeared to be a more specific indicator of latent tuberculosis infection than the TST, and similarly sensitive in unvaccinated contacts. In BCG-vaccinated close contacts, measurement of IFN-gamma responses of lymphocytes stimulated with M. tuberculosis-specific antigen should be recommended as a basis for the decision on whether to perform subsequent chest X-ray examinations or to start treatment for latent tuberculosis infection.

  4. Relation between BCG vaccine scar and an interferon-gamma release assay in immigrant children with "positive" tuberculin skin test (≥10 mm).

    Science.gov (United States)

    Gudjónsdóttir, Margret Johansson; Kötz, Karsten; Nielsen, Ruth Stangebye; Wilmar, Philip; Olausson, Sofia; Wallmyr, Daniel; Trollfors, Birger

    2016-10-06

    Immigrants from countries with high incidence of tuberculosis (TB) are usually offered screening when they arrive to low incidence countries. The tuberculin skin test (TST) is often used. The interferon gamma release assays (IGRAs) are more specific and not affected by BCG vaccination. The aims of this study were 1. To see if there if there is a correlation between a positive IGRA (QFT) and presence of a BCG scar in children with TST ≥10 mm, 2. To compare the TST diameter with QFT result, 3. To see if chest X-ray can be omitted in QFT negative children despite TST ≥10 mm. 762 healthy children/adolescents (median age 14 years) arriving to Gothenburg and surroundings with TST ≥10 mm were tested with QFT. A total of 163/492 (33 %) children with BCG scar had positive QFT, whereas 205/270 (76 %) without BCG scar had positive QFT (p BCG scar. Among the QFT positive children 25/368 had chest X-ray changes compared to 2/393 among the QFT negative children (p BCG vaccination had an effect on the TST diameter so an IGRA is recommended to diagnose latent TB. Using only TST for screening of latent TB would lead to overdiagnosis. The TST diameter was larger in QFT positive than in QFT negative children but could not predict QFT in the individual patient. Chest X ray contributes little to the diagnosis of TB in QFT negative children but can not be omitted because of late seroconversion of QFT in some patients. Not applicable.

  5. BCG vaccination in southern rural Mozambique: an overview of coverage and its determinants based on data from the demographic and health surveillance system in the district of Manhiça.

    Science.gov (United States)

    Marbán-Castro, Elena; Sacoor, Charfudin; Nhacolo, Ariel; Augusto, Orvalho; Jamisse, Edgar; López-Varela, Elisa; Casellas, Aina; Aponte, John J; Bassat, Quique; Sigauque, Betuel; Macete, Eusebio; Garcia-Basteiro, Alberto L

    2018-02-13

    Over the past four decades, the World Health Organization established the Expanded Programme on Immunization (EPI) to foster universal access to all relevant vaccines for all children at risk. The success of this program has been undeniable, but requires periodic monitoring to ensure that coverage rates remain high. The aim of this study was to measure the BCG vaccination coverage in Manhiça district, a high TB burden rural area of Southern Mozambique and to investigate factors that may be associated with BCG vaccination. We used data from the Health and Demographic Surveillance System (HDSS) run by the Manhiça Health Research Centre (CISM) in the district of Manhiça. A questionnaire was added in the annual HDSS round visits to retrospectively collect the vaccination history of children under the age of 3 years. Vaccinations are registered in the National Health Cards which are universally distributed at birth. This information was collected for children born from 2011 to 2014. Data on whether a child was vaccinated for BCG were collected from these National Health Cards and/or BCG scar assessment. A total of 10,875 number of children were eligible for the study and 7903 presented the health card. BCG coverage was 97.4% for children holding a health card. A BCG-compatible scar was observed in 99.0% of all children and in 99.6% of children with recorded BCG in the card. A total of 93.4% of children had been vaccinated with BCG within their first 28 days of life. None of the factors analysed were found to be associated with lack of BCG vaccination except for living in the municipality of Maluana compared to living in the municipality of Manhiça; (OR = 1.89, 95% CI: 1.18-3.00). Coverage for other EPI vaccines during the first year of life was similarly high, but decreased for subsequent doses. BCG coverage is high and timely administered. Almost all vaccinated infants develop scar, which is a useful proxy for monitoring BCG vaccine implementation.

  6. Valor preditivo do teste tuberculínico padronizado em crianças vacinadas com BCG The predictive value of the standard tuberculin test in BCG-vaccinated children

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    Gilberto Ribeiro Arantes

    1992-08-01

    Full Text Available A aplicabilidade do teste tuberculínico em crianças menores de 5 anos vacinadas com BCG é assunto controvertido. Visando contribuir para esclarecê-lo foi analisado o valor preditivo positivo do teste tuberculínico padronizado em população sob elevada cobertura vacinal e baixa prevalência de infecção tuberculosa. A partir da proporção de reatores fortes em lactentes e escolares vacinados e não vacinados, foram calculadas a razão de declínio da alergia tuberculínica nos vacinados e a razão de crescimento nos não vacinados, o que possibilitou a estimativa dos respectivos valores nas idades intermediárias. A expectativa de falsos-positivos (FP foi então calculada por diferença. Conhecidas a sensibilidade e a especificidade do teste (E=1-FP, a cobertura BCG e a prevalência de infecção, os valores preditivos (para a infecção tuberculosa foram: 1,52%, 4,22%, 8,26%, 14,86% e 23,00%, do primeiro ao quinto ano de vida. Nessas condições, a probabilidade de uma reação forte ser devida ao BCG é grande, especialmente nos dois primeiros anos, o que reduz a aplicabilidade clínica e epidemiológica do teste.The applicability of tuberculin test in children under five years of age, BCG-vaccinated during their first year of life, is a controversial matter. With a view to clarifying the subject the predictive positive value of the test in a region of high BCG coverage and low prevalence of tuberculous infection was analysed. From the proportion of strong reactors among infants and school-age children, vaccinated and not unvaccinated, the declining rate of BCG induced allergy and the increment rate of naturally acquired tuberculin sensitivity between the first and the seventh years of life were calculated. Those calculations allowed for the estimation of the respective values for the intermediate ages. The numbers of false positives to be expected were calculated by difference. Knowing the sensibility and the especificity (1 - FP of

  7. Preclinical development of BCG.HIVA2auxo.int, harboring an integrative expression vector, for a HIV-TB Pediatric vaccine. Enhancement of stability and specific HIV-1 T-cell immunity.

    Science.gov (United States)

    Mahant, Aakash; Saubi, Narcís; Eto, Yoshiki; Guitart, Núria; Gatell, Josep Ma; Hanke, Tomáš; Joseph, Joan

    2017-08-03

    One of the critical issues that should be addressed in the development of a BCG-based HIV vaccine is genetic plasmid stability. Therefore, to address this issue we have considered using integrative vectors and the auxotrophic mutant of BCG complemented with a plasmid carrying a wild-type complementing gene. In this study, we have constructed an integrative E. coli-mycobacterial shuttle plasmid, p2auxo.HIVA int , expressing the HIV-1 clade A immunogen HIVA. This shuttle vector uses an antibiotic resistance-free mechanism for plasmid selection and maintenance. It was first transformed into a glycine auxotrophic E. coli strain and subsequently transformed into a lysine auxotrophic Mycobacterium bovis BCG strain to generate the vaccine BCG.HIVA 2auxo.int . Presence of the HIVA gene sequence and protein expression was confirmed. We demonstrated that the in vitro stability of the integrative plasmid p2auxo.HIVA int was increased 4-fold, as compared with the BCG strain harboring the episomal plasmid, and was genetically and phenotypically characterized. The BCG.HIVA 2auxo.int vaccine in combination with modified vaccinia virus Ankara (MVA).HIVA was found to be safe and induced HIV-1 and Mycobacterium tuberculosis-specific interferon-γ-producing T-cell responses in adult BALB/c mice. We have engineered a more stable and immunogenic BCG-vectored vaccine using the prototype immunogen HIVA. Thus, the use of integrative expression vectors and the antibiotic-free plasmid selection system based on "double" auxotrophic complementation are likely to improve the mycobacterial vaccine stability in vivo and immunogenicity to develop not only recombinant BCG-based vaccines expressing second generation of HIV-1 immunogens but also other major pediatric pathogens to prime protective responses shortly following birth.

  8. Characterization of immune response to killed leishmania major promastigotes plus BCG vaccine in Sudanese volunteers: a double-blind placebo controlled study

    International Nuclear Information System (INIS)

    Sati, Iman Nasr Eldin

    1996-12-01

    This work was examined whether intradermal immunization of healthy adult Sudanese volunteers with killed leishmania major (KLM) promastigotes plus BCG would induce antigen-specific T cell responses. Only healthy Sudanese volunteers with negative reactivity to leishmania skin test and with ≤20 mm induration of reactivity to purified protein derivative (PPD) were included in the trial. Group (A) (n=3): received a single dose (0.1ml) at a concentration of 10 mg protein of a whole cell component of KLM promastigotes/ml BCG, group (B) (n=12): received as a single dose of viable attenuated BCG alone (0.1 ml) at a concentration of 1 mg protein/ml diluent, group (C) (n=11): received the vaccine diluent only (Placebo) (o.1 ml). Study subjects were tested for their immunological and clinical responses before intervention, . Following vaccination 65% of group (A) subjects converted in their reactivity to leishmanin skin testing,non of the BCG vaccinated subjects converted in leishmanin skin test and only one subject of group (C) became leishmanin positive. Levels of Interferon-gamma (IFN-γ), interleukin-5 (IL-5) and interleukin-10 (IL-10) were measured by a double sandwich enzyme-linked immunosorbent assay (ELISA). A vaccine was considered as a positive responder in terms of cytokine production when the level of the produced cytokine was equal to the 80th percentile of the levels produced by the volunteers in the placebo group. 92% of the group vaccinated with KLM=BCG had circulating T cells. No significant of IL-5 or Il-10 was reported in any of the volunteers in the three group. Levels of anti l eishmania specific IgG were measured by ELISA in optical densities. Volunteers with mean antibody titre above the cut-off point (mean=3X standard deviation) were considered to have positive scores. Accordingly after vaccination 7.69% one volunteers in group (A) had a positive antibody response corresponding to 0% in the other two groups. No serious side effects were reported

  9. Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses.

    Science.gov (United States)

    Dowling, David J; Scott, Evan A; Scheid, Annette; Bergelson, Ilana; Joshi, Sweta; Pietrasanta, Carlo; Brightman, Spencer; Sanchez-Schmitz, Guzman; Van Haren, Simon D; Ninković, Jana; Kats, Dina; Guiducci, Cristiana; de Titta, Alexandre; Bonner, Daniel K; Hirosue, Sachiko; Swartz, Melody A; Hubbell, Jeffrey A; Levy, Ofer

    2017-11-01

    Newborns display distinct immune responses, leaving them vulnerable to infections and impairing immunization. Targeting newborn dendritic cells (DCs), which integrate vaccine signals into adaptive immune responses, might enable development of age-specific vaccine formulations to overcome suboptimal immunization. Small-molecule imidazoquinoline Toll-like receptor (TLR) 8 agonists robustly activate newborn DCs but can result in reactogenicity when delivered in soluble form. We used rational engineering and age- and species-specific modeling to construct and characterize polymer nanocarriers encapsulating a TLR8 agonist, allowing direct intracellular release after selective uptake by DCs. Chemically similar but morphologically distinct nanocarriers comprised of amphiphilic block copolymers were engineered for targeted uptake by murine DCs in vivo, and a range of TLR8 agonist-encapsulating polymersome formulations were then synthesized. Novel 96-well in vitro assays using neonatal human monocyte-derived DCs and humanized TLR8 mouse bone marrow-derived DCs enabled benchmarking of the TLR8 agonist-encapsulating polymersome formulations against conventional adjuvants and licensed vaccines, including live attenuated BCG vaccine. Immunogenicity of the TLR8 agonist adjuvanted antigen 85B (Ag85B)/peptide 25-loaded BCG-mimicking nanoparticle formulation was evaluated in vivo by using humanized TLR8 neonatal mice. Although alum-adjuvanted vaccines induced modest costimulatory molecule expression, limited T H -polarizing cytokine production, and significant cell death, BCG induced a robust adult-like maturation profile of neonatal DCs. Remarkably, TLR8 agonist polymersomes induced not only newborn DC maturation profiles similar to those induced by BCG but also stronger IL-12p70 production. On subcutaneous injection to neonatal mice, the TLR8 agonist-adjuvanted Ag85B peptide 25 formulation was comparable with BCG in inducing Ag85B-specific CD4 + T-cell numbers. TLR8 agonist

  10. 'Fight TB with BCG': mass vaccination campaigns in the British Caribbean, 1951-6.

    Science.gov (United States)

    Altink, Henrice

    2014-10-01

    Based on a wide range of primary materials, including WHO reports and Colonial Office correspondence, this article examines the UNICEF/WHO-funded mass BCG campaigns that were carried out in seven Caribbean colonies between 1951 and 1956. It explores the reasons behind them, their nature and aftermath and also compares them to those in other non-European countries and discusses them within a context of decolonisation. In doing so, it not only adds to the scholarship on TB in non-European contexts, which had tended to focus on Africa and Asia, but also to the relatively new field of Caribbean medical history and the rapidly expanding body of work on international health, which has paid scant attention to the Anglophone Caribbean and the pre-independence period.

  11. A single dose of a DNA vaccine encoding apa coencapsulated with 6,6'-trehalose dimycolate in microspheres confers long-term protection against tuberculosis in Mycobacterium bovis BCG-primed mice.

    Science.gov (United States)

    Carlétti, Dyego; Morais da Fonseca, Denise; Gembre, Ana Flávia; Masson, Ana Paula; Weijenborg Campos, Lívia; Leite, Luciana C C; Rodrigues Pires, Andréa; Lannes-Vieira, Joseli; Lopes Silva, Célio; Bonato, Vânia Luiza Deperon; Horn, Cynthia

    2013-08-01

    Mycobacterium bovis BCG prime DNA (Mycobacterium tuberculosis genes)-booster vaccinations have been shown to induce greater protection against tuberculosis (TB) than BCG alone. This heterologous prime-boost strategy is perhaps the most realistic vaccination for the future of TB infection control, especially in countries where TB is endemic. Moreover, a prime-boost regimen using biodegradable microspheres seems to be a promising immunization to stimulate a long-lasting immune response. The alanine proline antigen (Apa) is a highly immunogenic glycoprotein secreted by M. tuberculosis. This study investigated the immune protection of Apa DNA vaccine against intratracheal M. tuberculosis challenge in mice on the basis of a heterologous prime-boost regimen. BALB/c mice were subcutaneously primed with BCG and intramuscularly boosted with a single dose of plasmid carrying apa and 6,6'-trehalose dimycolate (TDM) adjuvant, coencapsulated in microspheres (BCG-APA), and were evaluated 30 and 70 days after challenge. This prime-boost strategy (BCG-APA) resulted in a significant reduction in the bacterial load in the lungs, thus leading to better preservation of the lung parenchyma, 70 days postinfection compared to BCG vaccinated mice. The profound effect of this heterologous prime-boost regimen in the experimental model supports its development as a feasible strategy for prevention of TB.

  12. The Effect of 50 000 IU Vitamin A with BCG Vaccine at Birth on Growth in the First Year of Life

    Science.gov (United States)

    Fisker, Ane Bærent; Benn, Christine Stabell; Diness, Birgitte Rode; Martins, Cesario; Rodrigues, Amabelia; Aaby, Peter; Bibby, Bo Martin

    2011-01-01

    Vitamin A supplements may interact with diphtheria-tetanus-pertussis (DTP) vaccine causing increased female mortality. In a randomised trial of neonatal vitamin A supplementation (VAS), we examined growth during the first year of life in 808 children, pursuing the hypothesis that a negative interaction between VAS and DTP in girls would be reflected in growth. Length and weight were measured at 6 weekly visits and WHO-growth-reference z-scores derived. Neonatal VAS had no effect on anthropometric measures at 12 months, but may interact sex differentially with routine vaccines. While BCG was the most recent vaccine, neonatal VAS benefitted growth (difference in weight-for-length z-score (dWFL: 0.31(95% CI: 0.03–0.59)). While DTP was the most recent vaccine, VAS tended to affect growth adversely in girls (dWFL = −0.21 (−0.48–0.06)). After measles vaccine (MV) there was no overall effect of neonatal VAS. The VAS effect differed significantly between the BCG and DTP windows (P = 0.03), and the difference was borderline significant between the DTP and MV windows for girls (P = 0.09). PMID:21912559

  13. Mycobacterium tuberculosis PPD-induced immune biomarkers measurable in vitro following BCG vaccination of UK adolescents by multiplex bead array and intracellular cytokine staining

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    Worth Andrew

    2010-07-01

    Full Text Available Abstract Background The vaccine efficacy reported following Mycobacterium bovis Bacillus Calmette Guerin (BCG administration to UK adolescents is 77% and defining the cellular immune response in this group can inform us as to the nature of effective immunity against tuberculosis. The aim of this study was to identify which cytokines and lymphocyte populations characterise the peripheral blood cellular immune response following BCG vaccination. Results Diluted blood from before and after vaccination was stimulated with Mycobacterium tuberculosis purified protein derivative for 6 days, after which soluble biomarkers in supernatants were assayed by multiplex bead array. Ten out of twenty biomarkers measured were significantly increased (p Mycobacterium tuberculosis purified protein derivative stimulation of PBMC samples from the 12 month group revealed that IFNγ expression was detectable in CD4 and CD8 T-cells and natural killer cells. Polyfunctional flow cytometry analysis demonstrated that cells expressing IFNγ alone formed the majority in each subpopulation of cells. Only in CD4 T-cells and NK cells were there a notable proportion of responding cells of a different phenotype and these were single positive, TNFα producers. No significant expression of the cytokines IL-2, IL-17 or IL-10 was seen in any population of cells. Conclusions The broad array of biomarker responses detected by multiplex bead array suggests that BCG vaccination is capable, in this setting, of inducing a complex immune phenotype. Although polyfunctional T-cells have been proposed to play a role in protective immunity, they were not present in vaccinated adolescents who, based on earlier epidemiological studies, should have developed protection against pulmonary tuberculosis. This may be due to the later sampling time point available for testing or on the kinetics of the assays used.

  14. Effect of 50,000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau: randomised placebo controlled trial.

    Science.gov (United States)

    Benn, Christine Stabell; Diness, Birgitte Rode; Roth, Adam; Nante, Ernesto; Fisker, Ane Baerent; Lisse, Ida Maria; Yazdanbakhsh, Maria; Whittle, Hilton; Rodrigues, Amabelia; Aaby, Peter

    2008-06-21

    To investigate the effect of high dose vitamin A supplementation given with BCG vaccine at birth in an African setting with high infant mortality. Randomised placebo controlled trial. Setting Bandim Health Project's demographic surveillance system in Guinea-Bissau, covering approximately 90,000 inhabitants. Participants 4345 infants due to receive BCG. Infants were randomised to 50,000 IU vitamin A or placebo and followed until age 12 months. Mortality rate ratios. 174 children died during follow-up (mortality=47/1000 person-years). Vitamin A supplementation was not significantly associated with mortality; the mortality rate ratio was 1.07 (95% confidence interval 0.79 to 1.44). The effect was 1.00 (0.65 to 1.56) during the first four months and 1.13 (0.75 to 1.68) from 4 to 12 months of age. The mortality rate ratio in boys was 0.84 (0.55 to 1.27) compared with 1.39 (0.90 to 2.14) in girls (P for interaction=0.10). An explorative analysis revealed a strong interaction between vitamin A and season of administration. Vitamin A supplementation given with BCG vaccine at birth had no significant benefit in this African setting. Although little doubt exists that vitamin A supplementation reduces mortality in older children, a global recommendation of supplementation for all newborn infants may not contribute to better survival. Clinical trials NCT00168597.

  15. Effect of 50 000 IU vitamin A given with BCG vaccine on mortality in infants in Guinea-Bissau: randomised placebo controlled trial

    DEFF Research Database (Denmark)

    Diness, B.R.; Roth, A.; Nante, E.

    2008-01-01

    Objective To investigate the effect of high dose vitamin A supplementation given with BCG vaccine at birth in an African setting with high infant mortality. Design Randomised placebo controlled trial. Setting Bandim Health Project's demographic surveillance system in Guinea-Bissau, covering...... approximately 90 000 inhabitants. Participants 4345 infants due to receive BCG. Intervention Infants were randomised to 50 000 IU vitamin A or placebo and followed until age 12 months. Main outcome measure Mortality rate ratios. Results 174 children died during follow-up (mortality=47/ 1000 person......-years). Vitamin A supplementation was not significantly associated with mortality; the mortality rate ratio was 1.07 (95% confidence interval 0.79 to 1.44). The effect was 1.00 (0.65 to 1.56) during the first four months and 1.13 (0.75 to 1.68) from 4 to 12 months of age. The mortality rate ratio in boys was 0...

  16. Evolution and Strain Variation in BCG

    KAUST Repository

    Abdallah, Abdallah

    2017-11-07

    BCG vaccines were derived by in vitro passage, during the years 1908–1921, at the Pasteur Institute of Lille. Following the distribution of stocks of BCG to vaccine production laboratories around the world, it was only a few decades before different BCG producers recognized that there were variants of BCG, likely due to different passaging conditions in the different laboratories. This ultimately led to the lyophilization of stable BCG products in the 1950s and 1960s, but not before considerable evolution of the different BCG strains had taken place. The application of contemporary research methodologies has now revealed genomic, transcriptomic and proteomic differences between BCG strains. These molecular differences in part account for phenotypic differences in vitro between BCG strains, such as their variable secretion of antigenic proteins. Yet, the relevance of BCG variability for immunization policy remains elusive. In this chapter we present an overview of what is known about BCG evolution and its resulting strain variability, and provide some speculation as to the potential relevance for a vaccine given to over 100 million newborns each year.

  17. Evolution and Strain Variation in BCG.

    Science.gov (United States)

    Abdallah, Abdallah M; Behr, Marcel A

    2017-01-01

    BCG vaccines were derived by in vitro passage, during the years 1908-1921, at the Pasteur Institute of Lille. Following the distribution of stocks of BCG to vaccine production laboratories around the world, it was only a few decades before different BCG producers recognized that there were variants of BCG, likely due to different passaging conditions in the different laboratories. This ultimately led to the lyophilization of stable BCG products in the 1950s and 1960s, but not before considerable evolution of the different BCG strains had taken place. The application of contemporary research methodologies has now revealed genomic, transcriptomic and proteomic differences between BCG strains. These molecular differences in part account for phenotypic differences in vitro between BCG strains, such as their variable secretion of antigenic proteins. Yet, the relevance of BCG variability for immunization policy remains elusive. In this chapter we present an overview of what is known about BCG evolution and its resulting strain variability, and provide some speculation as to the potential relevance for a vaccine given to over 100 million newborns each year.

  18. Immunological Links to Nonspecific Effects of DTwP and BCG Vaccines on Infant Mortality

    DEFF Research Database (Denmark)

    Claesson, Mogens Helweg

    2011-01-01

    A number of mainly observational studies suggest that many African females below the age of one year die each year from the nonspecific effects of vaccination with diphtheria-tetanus toxoids and killed (whole-cell) Bordetella pertussis (DTwP). In contrast, similar studies suggest that many African...

  19. Lack of BCG vaccination and other risk factors for bacteraemia in severely malnourished children with pneumonia.

    Science.gov (United States)

    Chisti, M J; Salam, M A; Ahmed, T; Shahid, A S M S B; Shahunja, K M; Faruque, A S G; Bardhan, P K; Hossain, M I; Islam, M M; Das, S K; Huq, S; Shahrin, L; Huq, E; Chowdhury, F; Ashraf, H

    2015-03-01

    We sought to examine the factors associated with bacteraemia and their outcome in children with pneumonia and severe acute malnutrition (SAM). All SAM children of either sex, aged 0-59 months, admitted to the Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh with radiologically confirmed pneumonia from April 2011 to July 2012 were enrolled (n = 405). Comparison was made between pneumonic SAM children with (cases = 18), and without (controls = 387) bacteraemia. The death rate was significantly higher in cases than controls (28% vs. 8%, P vaccination (odds ratio 7·39, 95% confidence interval 1·67-32·73, P vaccination which may provide benefit beyond its primary purpose.

  20. Ultrasonographic features of BCG lymphadenitis

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    Kim, Do Youn; Lee, Sun Wha; Hwang, Ji Young [College of Medicine, Ewha Womans University, Seoul (Korea, Republic of)

    2005-07-15

    To evaluate the ultrasonographic findings of BCG lymphadenitis complicated by BCG vaccination in children. Ultrasonography was performed for 22 cases of BCG lymphadenitis in 21 patients who were diagnosed by clinical (n=10) or pathological (n=11) examinations. Their age ranged from 4 months to 3 years (mean age; 14 months). We retrospectively analyzed the ultrasonographic findings for location, multiplicity, size, shape, margin, echogenecity, posterior enhancement, calcifications, inner anechoic portion and Doppler pattern of the BCG lymphadenitis. The BCG lymphadenitis was found at the axillary area in 15 cases (68%) and at the supraclavicular area in 7 cases (32%). There were ten cases (45%) of solitary lesion and 12 cases (55%) of multiple conglomerated lesions. The maximum diameter ranged from about 0.9 cm to 3.2 cm. The BCG lymphadenitis showed as round (82%), well defined (86%), or heterogeneous hypoechoic (68%) lesions with posterior enhancement (78%). Calcifications were found in 6 cases (27%) and 5 cases (83%) had been vaccinated more than 5 months ago. There were eccentric inner anechoic portions in 16 cases (73%), which were pathologically confirmed as having caseating necrosis. There were increased Doppler flow patterns in 15 cases (68%); 4 cases (18%) were of the central type, 6 cases (27%) were of the peripheral type and 5 cases (23%) were of mixed type. BCG lymphadenitis is frequently located at the axillary area adjacent to a vaccination site. The ultrasonographic findings of BCG lymphadenitis are well-defined, round, heterogeneously hypoechoic lesions with posterior enhancement, calcifications and inner eccentric anechoic portion.

  1. Ultrasonographic features of BCG lymphadenitis

    International Nuclear Information System (INIS)

    Kim, Do Youn; Lee, Sun Wha; Hwang, Ji Young

    2005-01-01

    To evaluate the ultrasonographic findings of BCG lymphadenitis complicated by BCG vaccination in children. Ultrasonography was performed for 22 cases of BCG lymphadenitis in 21 patients who were diagnosed by clinical (n=10) or pathological (n=11) examinations. Their age ranged from 4 months to 3 years (mean age; 14 months). We retrospectively analyzed the ultrasonographic findings for location, multiplicity, size, shape, margin, echogenecity, posterior enhancement, calcifications, inner anechoic portion and Doppler pattern of the BCG lymphadenitis. The BCG lymphadenitis was found at the axillary area in 15 cases (68%) and at the supraclavicular area in 7 cases (32%). There were ten cases (45%) of solitary lesion and 12 cases (55%) of multiple conglomerated lesions. The maximum diameter ranged from about 0.9 cm to 3.2 cm. The BCG lymphadenitis showed as round (82%), well defined (86%), or heterogeneous hypoechoic (68%) lesions with posterior enhancement (78%). Calcifications were found in 6 cases (27%) and 5 cases (83%) had been vaccinated more than 5 months ago. There were eccentric inner anechoic portions in 16 cases (73%), which were pathologically confirmed as having caseating necrosis. There were increased Doppler flow patterns in 15 cases (68%); 4 cases (18%) were of the central type, 6 cases (27%) were of the peripheral type and 5 cases (23%) were of mixed type. BCG lymphadenitis is frequently located at the axillary area adjacent to a vaccination site. The ultrasonographic findings of BCG lymphadenitis are well-defined, round, heterogeneously hypoechoic lesions with posterior enhancement, calcifications and inner eccentric anechoic portion

  2. Estimativa do risco de infecção tuberculosa em populações vacinadas pelo BCG Determining the risk of tuberculosis infection in BCG-vaccinated populations

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    Gilberto Ribeiro Arantes

    1992-04-01

    Full Text Available A revacinação de escolares com BCG, capaz de restaurar a alergia remanescente de vacinação realizada nos primeiros meses de vida, porém incapaz de modificar a alergia devida à infecção pelo M. tuberculosis, possibilitaria a quantificação da parcela dessa população infectada pelo bacilo de Koch. Foi desenvolvida pesquisa com o objetivo de avaliar a aplicabilidade desses pressupostos na estimativa do risco de infecção tuberculosa em áreas sob elevada cobertura com BCG. A população de estudo foi constituída por escolares com 6 a 9 anos de idade freqüentando escolas municipais da zona leste da cidade de São Paulo, durante o primeiro semestre letivo de 1988. De 11.455 vacinados, apenas 7.470 foram submetidos ao teste tuberculínico, revacinados em seguida e retestados dez semanas depois. Destes, 3.314 tinham sido vacinados no primeiro trimestre de vida com meia dose e os demais 4.156 receberam dose plena acima dessa idade (75% no primeiro ano de vida, 20% no segundo e 5% no terceiro. A contagem dos infectados, pelo confronto dos resultados pré e pós vacinais em tabelas de correlação, foi realizada segundo os critérios do método original e modificação introduzida pelos autores, separadamente para os vacinados no primeiro trimestre de vida e após essa idade. O risco de infecção foi, respectivamente, 0,35% e 0,37% com o critério original e 0,45% e 0,49% com o modificado. O referencial médio disponível para a área estudada, estimado por outros métodos, foi 0,55%. As diferenças entre critérios e idades e destes com o referencial não foram significantes (P > 0,05. Os resultados sugerem que o método é aplicável para a estimativa do risco de infecção tuberculosa na idade escolar, em vacinados com BCG no primeiro ano de vida, com dose plena de vacina.The revaccination of schoolchildren can restore the residual allergy induced by vaccination in the first years of life but can not modify the allergy resulting from a

  3. Necrotizing Ulcer After BCG Vaccination in a Girl With Leukocyte-adhesion Deficiency Type 1.

    Science.gov (United States)

    Kurosawa, Hidemitsu; Mizukami, Tomoyuki; Nunoi, Hiroyuki; Kato, Masaya; Sato, Yuya; Okuya, Mayuko; Fukushima, Keitaro; Katsuyama, Yoshihiko; Arisaka, Osamu

    2018-01-01

    Leukocyte-adhesion deficiency-1 is a recessively inherited disorder associated with recurrent bacterial infections, severe periodontitis, peripheral leukocytosis, and impaired wound healing. We diagnosed moderate-type leukocyte-adhesion deficiency-1 in a 7-year-old girl who developed a necrotizing ulcer after Bacillus Calmette-Guerin vaccination. The patient showed moderate expression of CD18 in neutrophils with a homozygous splice mutation with c.41_c.58+2dup20 of ITGB2 and experienced recurrent severe infections complicated with systemic lupus erythematosus. She received hematopoietic stem cell transplantation from a matched elder brother with heterozygous mutation of ITGB2, and has since remained free of infection and systemic lupus erythematosus symptoms without immunosuppression therapy.

  4. Protective effect of Bacillus Calmette-Guerin (BCG) vaccination in children with extra-pulmonary tuberculosis, but not the pulmonary disease. A case-control study in Rosario, Argentina.

    Science.gov (United States)

    Bonifachich, Elena; Chort, Monica; Astigarraga, Ana; Diaz, Nora; Brunet, Beatriz; Pezzotto, Stella Maris; Bottasso, Oscar

    2006-04-05

    A hospital-based case-control study was carried out at the Vilela Children's Hospital in Rosario, Argentina, to measure the protection conferred by BCG vaccination against tuberculosis (TB). The study included 148 newly diagnosed cases of TB (75 males and 73 females, mean age 3.34+/-2.97 years, S.D.), 134 of them with pulmonary TB and 14 cases with extra-pulmonary disease. Controls (425 males and 357 females, 3.39+/-2.98 years) were selected randomly among children who attended to the Hospital showing, neither respiratory diseases nor any other infectious illnesses. Information on BCG vaccination history was assessed from scars or immunisation records. All participants were negative to human immunodeficiency virus and belonged to the lower and upper-lower socioeconomic status, being similar in place of residence and ethnic characteristics. Rate of vaccinated children was 92.6% of cases and 94.5% of controls (3.4 and 3.9% of them without scars, respectively). Regarding the total cases, the protective association between BCG and TB was statistically insignificant, as was for the pulmonary form. Among cases with extra-pulmonary disease, vaccine effectiveness attained significance [79% (95% CI=26-94)], no matter their age, sex or nutritional status. BCG vaccination exerted a beneficial role in extra-pulmonary TB, even in children not seriously undernourished.

  5. BCG protects against tuberculosis irrespective of HIV status

    DEFF Research Database (Denmark)

    Faurholt-Jepsen, Daniel; Range, Nyagosya; PrayGod, George

    2013-01-01

    While BCG vaccine protects against severe tuberculosis (TB) in children, its effect against adult TB is questionable. Furthermore, it is not known if HIV co-infection modifies the effect of BCG. Among 352 pairs of Tanzanian TB cases and matched controls, the BCG scar was associated with a reduced...

  6. Effect of vitamin A supplementation with BCG vaccine at birth on vitamin A status at 6 wk and 4 mo of age

    DEFF Research Database (Denmark)

    Fisker, Ane B; Lisse, Ida M; Aaby, Peter

    2007-01-01

    concentrations indicated vitamin A deficiency in 32% of the children at age 6 wk and in 16% at age 4 mo. VAS was not associated with higher RBP concentrations overall or in either sex. However, the effect of VAS varied with maternal education (P for interaction = 0.004): At age 6 wk, VAS was associated......BACKGROUND: The effect of vitamin A supplementation (VAS) at birth on subsequent vitamin A status has not been studied. OBJECTIVE: The objective was to study the effect of 50,000 IU vitamin A administered with BCG vaccine at birth on vitamin A status in both sexes. DESIGN: Within a randomized...... with higher (9%; 95% CI: 2, 17%) RBP concentrations in children of noneducated mothers but not in children of educated mothers. Overall, RBP concentrations increased between 6 wk and 4 mo of age. The increase correlated inversely with the number of diphtheria-tetanus-pertussis (DTP) vaccines received...

  7. Autophagy Controls BCG-Induced Trained Immunity and the Response to Intravesical BCG Therapy for Bladder Cancer

    NARCIS (Netherlands)

    Buffen, Kathrin; Oosting, Marije; Quintin, Jessica; Ng, Aylwin; Kleinnijenhuis, Johanneke; Magadi Gopalaiah, Vinod Kumar; van de Vosse, Esther; Wijmenga, Cisca; van Crevel, Reinout; Oosterwijk, Egbert; Grotenhuis, Anne J.; Vermeulen, Sita H.; Kiemeney, Lambertus A.; van de Veerdonk, Frank L.; Chamilos, Georgios; Xavier, Ramnik J.; van der Meer, Jos W. M.; Netea, Mihai G.; Joosten, Leo A. B.

    2014-01-01

    The anti-tuberculosis-vaccine Bacillus Calmette-Guerin (BCG) is the most widely used vaccine in the world. In addition to its effects against tuberculosis, BCG vaccination also induces non-specific beneficial effects against certain forms of malignancy and against infections with unrelated

  8. Different effects of BCG strains - A natural experiment evaluating the impact of the Danish and the Russian BCG strains on morbidity and scar formation in Guinea-Bissau.

    Science.gov (United States)

    Frankel, H; Byberg, S; Bjerregaard-Andersen, M; Martins, C L; Aaby, P; Benn, C S; Fisker, A B

    2016-08-31

    Different Bacillus Calmette-Guerin (BCG) vaccine strains may have different non-specific effects. We assessed the effect of two BCG strains (Danish and Russian) on childhood morbidity and BCG scarification in Guinea-Bissau. During 2011-2013, infants in the Bandim Health Project's urban study area received the Danish or Russian BCG in a natural experiment. Health center consultations were registered at point of care and scar status and size at age 4½ months. We assessed the effect of strain on consultation rates between vaccination and age 45days in Cox proportional hazards models. Scar prevalence and size were compared using binomial regression and ranksum tests. Among 1206 children, 18% received Danish BCG (n=215) and 82% Russian BCG (n=991). The adjusted hazard ratio (aHR) for consultations was 0.94 (95% CI 0.60-1.46) for Danish BCG compared with Russian BCG. Girls vaccinated with Danish BCG tended to have lower consultation rates compared with girls vaccinated with Russian BCG (aHR 0.56 (0.25-1.24)), whereas the effect was opposite for boys (aHR 1.24 (0.74-2.11)), p=0.09. Children vaccinated with Danish BCG were more likely to develop a scar (97%) than children vaccinated with Russian BCG (87%), the relative risk (RR) being 1.11 (1.06-1.16). The effect was stronger in girls, and BCG scar size was larger among infants vaccinated with the Danish strain. BCG strain influences scar prevalence and scar size, and may have sex differential effects on morbidity. BCG strains are currently used interchangeably, but BCG scarring has been linked to subsequent survival. Hence, more research into the health effects of different BCG strains is warranted. Small adjustments of BCG production could potentially lower childhood morbidity and mortality at low cost. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Increased TNF-alpha/IFN-gamma/IL-2 and decreased TNF-alpha/IFN-gamma production by central memory T cells are associated with protective responses against bovine tuberculosis following BCG vaccination

    Directory of Open Access Journals (Sweden)

    Mayara Fernanda Maggioli

    2016-10-01

    Full Text Available Central memory T cells (Tcm and polyfunctional CD4 T cell responses contribute to vaccine-elicited protection with both human and bovine tuberculosis (TB; however, their combined role in protective immunity to TB is unclear. To address this question, we evaluated polyfunctional cytokine responses by CD4 T cell effector / memory populations from bacille Calmette Guerin (BCG vaccinated and non-vaccinated calves prior to and after aerosol challenge with virulent Mycobacterium bovis. Polyfunctional cytokine expression patterns in the response by Tcm, effector memory, and effector T cell subsets were similar between BCG-vaccinated and M. bovis-infected calves; only differing in magnitude (i.e., infected > vaccinated. BCG vaccination, however, did alter the kinetics of the ensuing response to virulent M. bovis infection. Early after challenge (three weeks post-infection, non-vaccinates had greater antigen-specific IFN-γ/TNF-α and lesser IFN-γ/TNF-α/IL-2 responses by Tcm cells than did vaccinated animals. Importantly, these differences were also associated with mycobacterial burden upon necropsy. Polyfunctional responses to ESAT-6:CFP10 (antigens not synthesized by BCG strains were detected in memory subsets, as well as in effector cells, as early as three weeks after challenge. These findings suggest that cell fate divergence may occur early after antigen priming in the response to bovine TB and that memory and effector T cells may expand concurrently during the initial phase of the immune response. In summary, robust IFN-γ/TNF-α response by Tcm cells is associated with greater mycobacterial burden while IFN-γ/TNF-α/IL-2 response by Tcm cells are indicative of a protective response to bovine TB.

  10. MicroRNA expression profiling of PPD-B stimulated PBMC from M. bovis-challenged unvaccinated and BCG vaccinated cattle.

    Science.gov (United States)

    Golby, P; Villarreal-Ramos, B; Dean, G; Jones, G J; Vordermeier, M

    2014-10-07

    There is an urgent need to identify additional diagnostic biomarkers for bovine TB to complement existing read-out systems such as interferon-gamma and for predictive markers of vaccine efficacy to accelerate vaccine development. To evaluate the potential of miRNAs as such biomarkers, we have analysed their expression in bovine PPD stimulated PBMC isolated from unvaccinated and BCG vaccinated cattle before and following Mycobacterium bovis (M. bovis) infection. Using a bovine microRNA microarray, miR-155 was found to show a significant up-regulation in expression in early (week 2) and late (week 11) M. bovis post-infection samples from unvaccinated cattle, while in BCG vaccinated cattle up-regulation was observed only in late post-infection samples. No differential expression of miR-155 was observed in pre-infection samples from unvaccinated and vaccinated cattle. These observations suggest that miR-155 could be exploited as a marker distinguishing vaccinated from infected animals (DIVA). Analysis by TaqMan RT-PCR, verified the up-regulation of miR-155 in unvaccinated cattle post-infection. Significant correlation was found between the degree of pathology and miR-155 induction in the experimentally infected cattle, suggesting miR-155 is a biomarker of disease development and/or severity. Induction of miR155 expression in cattle sourced from farms with confirmed bTB that tested positive in the tuberculin skin or interferon-gamma blood test was found to be significantly higher in cattle presenting with more advanced pathology (defined by the presence of visible TB lesions) compared to infected cattle without visible pathology and thus likely to be of lower infectivity than those with more advanced disease. In conclusion, our data indicate that miR-155 has potential both as a diagnostic and prognostic biomarker that could be used to identify animals with advanced pathology and as a DIVA test read-out. Its role in the immune biology of bovine TB will also be discussed

  11. BCG and Kawasaki disease in Mexico and Japan.

    Science.gov (United States)

    Gamez-Gonzalez, Luisa Berenise; Hamada, Hiromichi; Llamas-Guillen, Beatriz Adriana; Ruiz-Fernandez, Miguel; Yamazaki-Nakashimada, Marco

    2017-05-04

    Dr. Tomisaku Kawasaki was the first to describe BCG reactivation in Kawasaki Disease (K D ), and this sign is present in about 30-50% of K D patients. It is a very specific early sign of the disease and although it has been recognized for decades, its pathophysiology continues to be an enigma. Recently, Yamada et al. reported a severe BCG reaction with tuberculid in 2 Japanese K D patients. We present 2 cases with K D and severe BCG reaction, one from Japan and the other from Mexico and review the policies of administration of BCG in both countries. The BCG vaccine has a worldwide coverage of 88%. Differences in BCG strains and methods of administration may influence BCG reactions in K D . The BCG reaction in the inoculation site may represent the most useful sign in K D .

  12. Lack of a Negative Effect of BCG-Vaccination on Child Psychomotor Development: Results from the Danish Calmette Study - A Randomised Clinical Trial.

    Science.gov (United States)

    Kjærgaard, Jesper; Stensballe, Lone Graff; Birk, Nina Marie; Nissen, Thomas Nørrelykke; Foss, Kim Thestrup; Thøstesen, Lisbeth Marianne; Pihl, Gitte Thybo; Andersen, Andreas; Kofoed, Poul-Erik; Pryds, Ole; Greisen, Gorm

    2016-01-01

    To assess the non-specific effect of Bacillus Calmette-Guérin (BCG) vaccination at birth on psychomotor development. This is a pre-specified secondary outcome from a randomised, clinical trial. Maternity units and paediatric wards at three university hospitals in Denmark. Children born at gestational age (GA) 32 weeks and above. All women planning to give birth at the three sites were invited during the recruitment period. Out of 4262 randomised children, 144 were premature (GA Psychomotor development measured using Ages and Stages Questionnaire (ASQ) completed by the parents at 12 months. Additionally, parents of premature children (gestational age psychomotor development was excluded in term children. ClinicalTrials.gov NCT01694108.

  13. Safety and immunogenicity of an inactivated whole cell tuberculosis vaccine booster in adults primed with BCG: A randomized, controlled trial of DAR-901.

    Directory of Open Access Journals (Sweden)

    C Fordham von Reyn

    Full Text Available Development of a tuberculosis vaccine to boost BCG is a major international health priority. SRL172, an inactivated whole cell booster derived from a non-tuberculous mycobacterium, is the only new vaccine against tuberculosis to have demonstrated efficacy in a Phase 3 trial. In the present study we sought to determine if a three-dose series of DAR-901 manufactured from the SRL172 master cell bank by a new, scalable method was safe and immunogenic.We performed a single site, randomized, double-blind, controlled, Phase 1 dose escalation trial of DAR-901 at Dartmouth-Hitchcock Medical Center in the United States. Healthy adult subjects age 18-65 with prior BCG immunization and a negative interferon-gamma release assay (IGRA were enrolled in cohorts of 16 subjects and randomized to three injections of DAR-901 (n = 10 per cohort, or saline placebo (n = 3 per cohort, or two injections of saline followed by an injection of BCG (n = 3 per cohort; 1-8 x 106 CFU. Three successive cohorts were enrolled representing DAR-901 at 0.1, 0.3, and 1 mg per dose. Randomization was performed centrally and treatments were masked from staff and volunteers. Subsequent open label cohorts of HIV-negative/IGRA-positive subjects (n = 5 and HIV-positive subjects (n = 6 received three doses of 1 mg DAR-901. All subjects received three immunizations at 0, 2 and 4 months administered as 0.1 mL injections over the deltoid muscle alternating between right and left arms. The primary outcomes were safety and immunogenicity. Subjects were followed for 6 months after dose 3 for safety and had phlebotomy performed for safety studies and immune assays before and after each injection. Immune assays using peripheral blood mononuclear cells included cell-mediated IFN-γ responses to DAR-901 lysate and to Mycobacterium tuberculosis (MTB lysate; serum antibody to M. tuberculosis lipoarabinomannan was assayed by ELISA.DAR-901 had an acceptable safety profile and was well-tolerated at all

  14. High-sensitive and rapid detection of Mycobacterium tuberculosis infection by IFN-γ release assay among HIV-infected individuals in BCG-vaccinated area

    Directory of Open Access Journals (Sweden)

    Jiang Weimin

    2009-05-01

    Full Text Available Abstract Background An accurate test for Mycobacterium tuberculosis infection is urgently needed in immunosuppressed populations. The aim of this study was to investigate the diagnostic power of enzyme-linked immunospot (ELISPOT-based IFN-γ release assay in detecting active and latent tuberculosis in HIV-infected population in bacillus Calmette-Guerin (BCG-vaccinated area. A total of 100 HIV-infected individuals including 32 active tuberculosis patients were recruited. An ELISPOT-based IFN-γ release assay, T-SPOT.TB, was used to evaluate the M. tuberculosis ESAT-6 and CFP-10 specific IFN-γ response. Tuberculin skin test (TST was performed for all recruited subjects. Results The subjects were divided into group HIV+ATB (HIV-infected individuals with active tuberculosis, n = 32, group HIV+LTB (HIV-infected individuals with positive results of T-SPOT.TB assay, n = 46 and group HIV only (HIV-infected individuals with negative results of T-SPOT.TB assay and without evidence of tuberculosis infection, n = 22. In group HIV+ATB and HIV+LTB, T-SPOT.TB positive rate in subjects with TST P 85% in patients with TB treatment for less than 1 month and CD4+ T cells ≥200/μl, while for patients treated for more than 3 months and CD4+ T cells Conclusion ELISPOT-based IFN-γ release assay is more sensitive and rapid for the diagnosis of TB infection in Chinese HIV-infected individuals with history of BCG vaccination, and could be an effective tool for guiding preventive treatment with isoniazid in latently infected people and for TB control in China.

  15. Integração das atividades de vacinação pelo BCG intradérmico nos programas gerais de imunização das unidades sanitárias Integration of intradermic BCG vaccination in general public health immunization programmes

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    Roberto Brólio

    1976-03-01

    Full Text Available A imunização pelo BCG constitui um recurso operacional de grande alcance nos países em desenvolvimento, onde é elevada a incidência da tuberculose. Os conhecimentos adquiridos nos últimos cinco anos, em nosso meio, permitem elaborar programas para a aplicação do BCG, por via intradérmica, em extensão útil epidemiologicamente, sem o teste tuberculínico prévio. É analisada a experiência da integração da vacinação pelo BCG intradérmico no programa geral de imunização do Centro de Saúde "Geraldo de Paula Souza", da Faculdade de Saúde Pública da USP. As suas conclusões são favoráveis à viabilidade do método, permitindo ampla cobertura de imunização anti-tuberculose da população, desde os primeiros meses de vida.Immunization by BCG is of great effect in developing countries where the incidence of tuberculosis is high. The knowledge that has been acquired in our environment in the last five years has made possible the organization of programmes for BCG intradermic immunization, to a useful epidemiological extent, without a prior tuberculin test. The practice of the integration of intradermic BCG vaccination in the general immunization programmes of the "Geraldo de Paula Souza" Health Unit of S. Paulo University School of Public Health was analysed and the conclusion was favourable as to the viability of the method, which allows a large-scale anti-tuberculosis immunization of the population right from the very first months of life.

  16. Sex-differential effects on mortality of BCG and diphtheria-tetanus-pertussis vaccines in a rural area with high vaccination coverage

    DEFF Research Database (Denmark)

    Aaby, Peter; Nielsen, Jens; Benn, Christine S

    2016-01-01

    BACKGROUND: Diphtheria-tetanus-pertussis (DTP) may be associated with increased female mortality; the effect of co-administration with BCG is not known. METHODS: Between 1989 and 1997, we examined female and male mortality rates in rural Senegal where 7824 infants received the first dose of DTP...

  17. Features of General Reactive Potential of the Body in Infants with BCG lymphadenitis

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    A.I. Bobrovitskaia

    2014-11-01

    Conclusions. When using BCG vaccine of Russian production, there is far less significant overload of blood flow by products of intoxication and inflammation, more pronounced body’s ability to respond to antigenic stimulus generalization and no risk of infection, especially in infants, compared with Danish BCG vaccine. For vaccination of infants against tuberculosis, it is advisable to use more refined, with high immunogenicity and less reactogenic BCG vaccine of Russian production. Despite the presence of complications when using BCG vaccine, protection of the body from the development of generalized forms of tuberculosis in young children is possible by vaccination in the neonatal period.

  18. Reaction of the BCG Scar in the Acute Phase of Kawasaki Disease in Mexican Children.

    Science.gov (United States)

    Garrido-García, Luis Martín; Castillo-Moguel, Ariel; Vázquez-Rivera, Mirella; Cravioto, Patricia; Fernando, Galván

    2017-10-01

    Kawasaki disease (KD) is an acute self-limited systemic vasculitis that primarily affects children BCG) inoculation site has been reported as a common finding in patients with KD where BCG vaccination is mandatory. The purpose of this study was to evaluate the frequency of reactivation of the BCG in Mexican children diagnosed with KD. A retrospective study of all patients diagnosed with KD from August 1, 1995, to August 31, 2015, at our Institution was performed. The clinical profile, laboratory results, treatment used and coronary artery abnormalities in the BCG reactive and the BCG nonreactive groups were analyzed and compared. We included 399 patients with KD. Ninety-seven (24.3%) had BCG reaction at the inoculation site. The BCG(+) group was younger than the BCG(-) group (P BCG(+) group compared with 65 (21.52%) in the BCG(-) group without statistical significance. The BCG+ group developed coronary artery aneurysms in 37 cases and the BCG(-) group developed coronary artery aneurysms in 111 cases without statistical significance. Multivariate analysis showed that younger age at diagnosis was the only variable associated with a reaction at the BCG inoculation site in patients with KD. In Mexico, a country with a National BCG Vaccination Program and a low incidence of KD, reaction at the BCG inoculation site could be a useful diagnostic sign of KD.

  19. A single, low dose of a cGMP recombinant BCG vaccine elicits protective T cell immunity against the human respiratory syncytial virus infection and prevents lung pathology in mice.

    Science.gov (United States)

    Céspedes, Pablo F; Rey-Jurado, Emma; Espinoza, Janyra A; Rivera, Claudia A; Canedo-Marroquín, Gisela; Bueno, Susan M; Kalergis, Alexis M

    2017-02-01

    Human respiratory syncytial virus (hRSV) is a major health burden worldwide, causing the majority of hospitalizations in children under two years old due to bronchiolitis and pneumonia. HRSV causes year-to-year outbreaks of disease, which also affects the elderly and immunocompromised adults. Furthermore, both hRSV morbidity and epidemics are explained by a consistently high rate of re-infections that take place throughout the patient life. Although significant efforts have been invested worldwide, currently there are no licensed vaccines to prevent hRSV infection. Here, we describe that a recombinant Bacillus Calmette-Guerin (BCG) vaccine expressing the nucleoprotein (N) of hRSV formulated under current good manufacture practices (cGMP rBCG-N-hRSV) confers protective immunity to the virus in mice. Our results show that a single dose of the GMP rBCG-N-hRSV vaccine retains its capacity to protect mice against a challenge with a disease-causing infection of 1×10 7 plaque-forming units (PFUs) of the hRSV A2 clinical strain 13018-8. Compared to unimmunized infected controls, vaccinated mice displayed reduced weight loss and less infiltration of neutrophils within the airways, as well as reduced viral loads in bronchoalveolar lavages, parameters that are characteristic of hRSV infection in mice. Also, ex vivo re-stimulation of splenic T cells at 28days post-immunization activated a repertoire of T cells secreting IFN-γ and IL-17, which further suggest that the rBCG-N-hRSV vaccine induced a mixed, CD8 + and CD4 + T cell response capable of both restraining viral spread and preventing damage of the lungs. All these features support the notion that rBCG-N-hRSV is a promising candidate vaccine to be used in humans to prevent the disease caused by hRSV in the susceptible population. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. Different effects of BCG strains - A natural experiment evaluating the impact of the Danish and the Russian BCG strains on morbidity and scar formation in Guinea-Bissau

    DEFF Research Database (Denmark)

    Frankel, H; Byberg, S; Andersen, Morten Bjerregaard

    2016-01-01

    BACKGROUND: Different Bacillus Calmette-Guerin (BCG) vaccine strains may have different non-specific effects. We assessed the effect of two BCG strains (Danish and Russian) on childhood morbidity and BCG scarification in Guinea-Bissau. METHODS: During 2011-2013, infants in the Bandim Health Project......'s urban study area received the Danish or Russian BCG in a natural experiment. Health center consultations were registered at point of care and scar status and size at age 4½ months. We assessed the effect of strain on consultation rates between vaccination and age 45days in Cox proportional hazards...... models. Scar prevalence and size were compared using binomial regression and ranksum tests. RESULTS: Among 1206 children, 18% received Danish BCG (n=215) and 82% Russian BCG (n=991). The adjusted hazard ratio (aHR) for consultations was 0.94 (95% CI 0.60-1.46) for Danish BCG compared with Russian BCG...

  1. STUDY OF BCG SCAR AND SERUM ADA LEVELS IN INFANTS

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    Harishchandra Venkata Yanamandala

    2017-11-01

    Full Text Available BACKGROUND In developing countries, in both adults and children, tuberculosis is an important cause of morbidity and mortality. In 1993, it is declared as the first infectious disease by global health emergency.1 According to WHO report globally, there were an estimated 9.27 million ancient cases of TB in 2009. The cases reported were 8.3 million, the children covered an estimated percentage of 11 and it ranged from 3-25 percent.2 BCG vaccination was advocated for prevention of tuberculosis in children. The aim of the study is to estimate serum ADA levels in newborns before BCG vaccination, serum ADA levels in children with and without BCG scar, after receiving BCG vaccination, serum ADA levels in children without BCG vaccination and to find significance of serum ADA levels in BCG vaccinated children by comparing the above groups. MATERIALS AND METHODS This study was conducted at the Department of Paediatrics, Gitam Institute of Medical Sciences and Research Institute, October 2015 to September 2016. Babies who were in postnatal ward and infants of age of 12 weeks attending for BCG vaccination were included in the study. The total numbers of infants studied were 150. RESULTS In our study, out of 120 children included in the study before BCG vaccination comprising group-1, 61% were males and 39% were females. Out of 120 children received BCG vaccination, only 100 came for follow up comprising group-2, of which 67 (67% were males and 33 (33% were females. 15 children who did not receive BCG vaccination at 12 weeks of age were included in group 3 out of which 11 (73.33% were males and 4 (26.67% were females. Mean ADA levels at the age of 12 weeks in group-2 who were vaccinated at birth were 30.89 ± 5.27 U/L compared to mean ADA levels at the age of 12 weeks in group-3, which was 15.47 ± 1.85 U/L. This shows significant rise in mean ADA levels at 12 weeks of age in those who were vaccinated at birth comprising group-2 compared to their mean ADA

  2. Short Communication: Age at BCG administration during routine ...

    African Journals Online (AJOL)

    In Nigeria, as part of the National Programme on Immunization (NPI), BCG should be given at birth. A survey of the ages at which mothers bring their children for BCG vaccination showed that only 22% of children receive their BCG within the first 3 days of life and 36.2% within the first 7 days of life. The place of birth and ...

  3. Tuberculin skin reactivity after neonatal BCG vaccination in preterm infants in Minas Gerais, Brazil, 2001-2002 Reactividad cutánea a la tuberculina tras la vacunación con BCG de neonatos prematuros en Minas Gerais, Brasil, 2001-2002

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    Paulo Camargos

    2006-06-01

    Full Text Available OBJECTIVES: The efficacy of BCG vaccination in preterm babies is unknown, and available data on conversion rates to tuberculin in this age group are scarce and controversial. This study assessed the tuberculin response in preterm infants after BCG vaccination. METHODS: This randomized cohort study was carried out at the Neonatal Department, University Hospital, Federal University of Minas Gerais in Brazil during 2001 and 2002. The BCG vaccine was administered at birth to 65 full-term (control and 40 preterm newborns. All of them were tested with 5 tuberculin units of purified protein derivative-S approximately 3 months after vaccination. RESULTS: A typical BCG scar was verified in 96.9% of the control group and in 90.0% of the preterm infants (P = 0.19. Indurations > 5 mm in diameter were recorded in 87.7% of the full-term and 67.5% of the preterm infants (P = 0.02. Indurations > 10 mm were recorded in 70.8% of the full-term and 42.5% of the preterm infants (P = 0.007. For indurations > 5 mm the upper and the lower limits of the 95% confidence interval for the difference between proportions were 8.5% to 31.8%, and for indurations > 10 mm these limits were 18.0% to 38.4%. No adverse reactions were observed in the study population. CONCLUSION: BCG vaccination could be recommended for preterm infants upon discharge from the neonatal unit to reduce morbidity and mortality in infants at risk for tuberculous infection, and to increase BCG vaccination coverage rates, especially in countries with high prevalence rates of tuberculosis.OBJETIVOS: Se desconoce la eficacia de la vacunación con Bacilo de Calmette-Guérin (BCG en neonatos prematuros, y los datos que existen acerca de la proporción de casos de conversión tuberculínica en este grupo de edad son pocos y cuestionables. En este estudio se evaluó la respuesta a la prueba de tuberculina de neonatos prematuros tras la vacunación con BCG. MÉTODOS: Este estudio de cohorte aleatorizado se llev

  4. Deletion of zmp1 improves Mycobacterium bovis BCG-mediated protection in a guinea pig model of tuberculosis.

    Science.gov (United States)

    Sander, Peter; Clark, Simon; Petrera, Agnese; Vilaplana, Cristina; Meuli, Michael; Selchow, Petra; Zelmer, Andrea; Mohanan, Deepa; Andreu, Nuria; Rayner, Emma; Dal Molin, Michael; Bancroft, Gregory J; Johansen, Pål; Cardona, Pere-Joan; Williams, Ann; Böttger, Erik C

    2015-03-10

    Having demonstrated previously that deletion of zinc metalloprotease zmp1 in Mycobacterium bovis BCG increased immunogenicity of BCG vaccines, we here investigated the protective efficacy of BCG zmp1 deletion mutants in a guinea pig model of tuberculosis infection. zmp1 deletion mutants of BCG provided enhanced protection by reducing the bacterial load of tubercle bacilli in the lungs of infected guinea pigs. The increased efficacy of BCG due to zmp1 deletion was demonstrated in both BCG Pasteur and BCG Denmark indicating that the improved protection by zmp1 deletion is independent from the BCG sub-strain. In addition, unmarked BCG Δzmp1 mutant strains showed a better safety profile in a CB-17 SCID mouse survival model than the parental BCG strains. Together, these results support the further development of BCG Δzmp1 for use in clinical trials. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Determinants of BCG scarification among children in rural Guinea-Bissau: A prospective cohort study.

    Science.gov (United States)

    Funch, Katarina M; Thysen, Sanne M; Rodrigues, Amabelia; Martins, Cesario L; Aaby, Peter; Benn, Christine S; Fisker, Ane B

    2018-01-02

    Bacillus Calmette-Guérin (BCG) vaccination may have beneficial non-specific effects on child survival, the effects being stronger for children developing a scar. In a prospective cohort study, we examined determinants for not developing a BCG scar within 6 months of vaccination. Bandim Health Project (BHP) runs a Health and Demographic Surveillance System site in rural Guinea-Bissau. BHP provides BCG at monthly visits. We studied determinants for not developing a BCG scar using binomial regression models to obtain relative risks (RR). From May 2012 until October 2014, BHP nurses vaccinated 2415 infants with BCG. We assessed BCG scar between 6 and 12 months of age for 2156 (89%) of these children and 2115 (98%) had developed a scar. In comparison, among 785 children BCG vaccinated elsewhere, 622 (79%) had a scar, the RR of not having a scar being 10.91 (7.52-15.85) compared with children vaccinated by BHP. Among children vaccinated by BHP, those receiving the Russian BCG strain were more likely not to develop a scar (RR = 2.98 (1.52-5.81)) compared with children receiving Danish BCG strain. Children with no post-injection wheal or a wheal BCG scar development while nutritional status and socioeconomic status were not. Scarring rate may therefore be a better indicator of vaccination programme performance than coverage.

  6. INTRAVESICULAR IMMUNOTHERAPY WITH BCG VACCINE AND INTERFERON-αα2B FOR NON-INVASIVE CARCINOMA OF THE URINARY BLADDER: RESULTS OF PROSPECTIVE RANDOMIZED STUDY

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    A. A. Minich

    2009-01-01

    Full Text Available Background: Both bacillus Calmette-Gue’rin (BCG and interferon-alpha (IFN-α are active against urinary bladder cancer. In this studywe evaluate the therapeutic efficacy and toxicity of combined intravesical BCG plus IFN-α for treating non-invasive bladder cancer.Subjects and methods: A total of 149 patients (mean age 63.2 years were enrolled for the study. The inclusion criteria were histologically verifiednon-invasive transitional cell carcinoma with intermediate and high risks of recurrence and progression. After transurethral tumor resection, all thepatients were randomized in three groups. Group 1 (n=60 was treated with a 6-week course of BCG, 125 mg, starting 14 to 21 days after TUR, Group2 (n=60 patients received 6-week instillations of BCG, 125 mg, plus IFN-α, 6 million units, Group 3 patients (n = 29 had 4-month courses ofintravesical IFN-α, 6 million units, twice daily during 3 consecutive days. A response was assessed by cystoscopy every 3 months after treatment.Results: A median follow-up of 30.9 months revealed recurrences in 26 (43.3% patients in the BCG group, 8 (13.3% patients in the BCG + IFN-αgroup and 18 (62.1% patients in the IFN-α group. Progression to muscle invasion occurred in 12% and 7% in Groups 1 and 3, respectively, withno progression in Group 2 patients. Three-year relapse-free survival was higher in the BCG+IFN group (78.5% versus 62.6 and 40.2% in theBCG and IFN-α groups, respectively. There was no significant difference between the BCG groups in relapse-free survival. Monotherapy withIFN-α showed a significantly lower response rate than did BCG therapies (p = 0.007. Adverse reactions were observed in 25, 116, and 6.9% ofpatients from Groups 1, 2 and 3, respectively. Toxicity-related withdrawal and treatment delay were similar in both BCG groups. Comparison ofthe rate of adverse reactions revealed a significant difference between the BCG + IFN-α and BCG groups (p = 0.025. The respective rates ofmoderate

  7. INTRAVESICULAR IMMUNOTHERAPY WITH BCG VACCINE AND INTERFERON-αα2B FOR NON-INVASIVE CARCINOMA OF THE URINARY BLADDER: RESULTS OF PROSPECTIVE RANDOMIZED STUDY

    Directory of Open Access Journals (Sweden)

    A. A. Minich

    2014-07-01

    Full Text Available Background: Both bacillus Calmette-Gue’rin (BCG and interferon-alpha (IFN-α are active against urinary bladder cancer. In this studywe evaluate the therapeutic efficacy and toxicity of combined intravesical BCG plus IFN-α for treating non-invasive bladder cancer.Subjects and methods: A total of 149 patients (mean age 63.2 years were enrolled for the study. The inclusion criteria were histologically verifiednon-invasive transitional cell carcinoma with intermediate and high risks of recurrence and progression. After transurethral tumor resection, all thepatients were randomized in three groups. Group 1 (n=60 was treated with a 6-week course of BCG, 125 mg, starting 14 to 21 days after TUR, Group2 (n=60 patients received 6-week instillations of BCG, 125 mg, plus IFN-α, 6 million units, Group 3 patients (n = 29 had 4-month courses ofintravesical IFN-α, 6 million units, twice daily during 3 consecutive days. A response was assessed by cystoscopy every 3 months after treatment.Results: A median follow-up of 30.9 months revealed recurrences in 26 (43.3% patients in the BCG group, 8 (13.3% patients in the BCG + IFN-αgroup and 18 (62.1% patients in the IFN-α group. Progression to muscle invasion occurred in 12% and 7% in Groups 1 and 3, respectively, withno progression in Group 2 patients. Three-year relapse-free survival was higher in the BCG+IFN group (78.5% versus 62.6 and 40.2% in theBCG and IFN-α groups, respectively. There was no significant difference between the BCG groups in relapse-free survival. Monotherapy withIFN-α showed a significantly lower response rate than did BCG therapies (p = 0.007. Adverse reactions were observed in 25, 116, and 6.9% ofpatients from Groups 1, 2 and 3, respectively. Toxicity-related withdrawal and treatment delay were similar in both BCG groups. Comparison ofthe rate of adverse reactions revealed a significant difference between the BCG + IFN-α and BCG groups (p = 0.025. The respective rates ofmoderate

  8. Polyfunctional cytokine production by central memory T cells from cattle in response to Mycobacterium bovis infection and BCG vaccination

    Science.gov (United States)

    Polyfunctional T cells simultaneously produce IFN-gamma, IL-2 and TNF-alpha and play relevant roles in several chronic infections, including TB. Mycobacterium bovis infection of cattle elicits ex vivo polyfunctional T cell responses. Vaccine-elicited IFN-gamma Tcm (CD4 plus CD45RO plus CCR7 plus) re...

  9. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity

    DEFF Research Database (Denmark)

    Arts, Rob J W; Moorlag, Simone J C F M; Novakovic, Boris

    2018-01-01

    -wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain. Epigenetic reprogramming was accompanied by functional changes indicative of trained immunity. Reduction of viremia was highly correlated with the upregulation of IL-1β...

  10. The effect of zinc supplementation during pregnancy on immune response to Hib and BCG vaccines in Bangladesh

    NARCIS (Netherlands)

    Osendarp, S.J.M.; Fuchs, G.J.; Raaij, van J.M.A.; Mahmud, H.; Tofail, F.; Black, R.E.; Prabhakar, H.; Santosham, M.

    2006-01-01

    An essential role for zinc in development of the fetal immune system has been documented. However, the effect of antenatal zinc supplementation on infants' postnatal immune response to vaccinations is unknown. The objective of this study was to evaluate the effect of zinc supplementation during

  11. Genomic and proteomic analyses of Mycobacterium bovis BCG Mexico 1931 reveal a diverse immunogenic repertoire against tuberculosis infection.

    Science.gov (United States)

    Orduña, Patricia; Cevallos, Miguel A; de León, Samuel Ponce; Arvizu, Adriana; Hernández-González, Ismael L; Mendoza-Hernández, Guillermo; López-Vidal, Yolanda

    2011-10-08

    Studies of Mycobacterium bovis BCG strains used in different countries and vaccination programs show clear variations in the genomes and immune protective properties of BCG strains. The aim of this study was to characterise the genomic and immune proteomic profile of the BCG 1931 strain used in Mexico. BCG Mexico 1931 has a circular chromosome of 4,350,386 bp with a G+C content and numbers of genes and pseudogenes similar to those of BCG Tokyo and BCG Pasteur. BCG Mexico 1931 lacks Region of Difference 1 (RD1), RD2 and N-RD18 and one copy of IS6110, indicating that BCG Mexico 1931 belongs to DU2 group IV within the BCG vaccine genealogy. In addition, this strain contains three new RDs, which are 53 (RDMex01), 655 (RDMex02) and 2,847 bp (REDMex03) long, and 55 single-nucleotide polymorphisms representing non-synonymous mutations compared to BCG Pasteur and BCG Tokyo. In a comparative proteomic analysis, the BCG Mexico 1931, Danish, Phipps and Tokyo strains showed 812, 794, 791 and 701 protein spots, respectively. The same analysis showed that BCG Mexico 1931 shares 62% of its protein spots with the BCG Danish strain, 61% with the BCG Phipps strain and only 48% with the BCG Tokyo strain. Thirty-nine reactive spots were detected in BCG Mexico 1931 using sera from subjects with active tuberculosis infections and positive tuberculin skin tests. BCG Mexico 1931 has a smaller genome than the BCG Pasteur and BCG Tokyo strains. Two specific deletions in BCG Mexico 1931 are described (RDMex02 and RDMex03). The loss of RDMex02 (fadD23) is associated with enhanced macrophage binding and RDMex03 contains genes that may be involved in regulatory pathways. We also describe new antigenic proteins for the first time.

  12. Genomic and proteomic analyses of Mycobacterium bovis BCG Mexico 1931 reveal a diverse immunogenic repertoire against tuberculosis infection

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    López-Vidal Yolanda

    2011-10-01

    Full Text Available Abstract Background Studies of Mycobacterium bovis BCG strains used in different countries and vaccination programs show clear variations in the genomes and immune protective properties of BCG strains. The aim of this study was to characterise the genomic and immune proteomic profile of the BCG 1931 strain used in Mexico. Results BCG Mexico 1931 has a circular chromosome of 4,350,386 bp with a G+C content and numbers of genes and pseudogenes similar to those of BCG Tokyo and BCG Pasteur. BCG Mexico 1931 lacks Region of Difference 1 (RD1, RD2 and N-RD18 and one copy of IS6110, indicating that BCG Mexico 1931 belongs to DU2 group IV within the BCG vaccine genealogy. In addition, this strain contains three new RDs, which are 53 (RDMex01, 655 (RDMex02 and 2,847 bp (REDMex03 long, and 55 single-nucleotide polymorphisms representing non-synonymous mutations compared to BCG Pasteur and BCG Tokyo. In a comparative proteomic analysis, the BCG Mexico 1931, Danish, Phipps and Tokyo strains showed 812, 794, 791 and 701 protein spots, respectively. The same analysis showed that BCG Mexico 1931 shares 62% of its protein spots with the BCG Danish strain, 61% with the BCG Phipps strain and only 48% with the BCG Tokyo strain. Thirty-nine reactive spots were detected in BCG Mexico 1931 using sera from subjects with active tuberculosis infections and positive tuberculin skin tests. Conclusions BCG Mexico 1931 has a smaller genome than the BCG Pasteur and BCG Tokyo strains. Two specific deletions in BCG Mexico 1931 are described (RDMex02 and RDMex03. The loss of RDMex02 (fadD23 is associated with enhanced macrophage binding and RDMex03 contains genes that may be involved in regulatory pathways. We also describe new antigenic proteins for the first time.

  13. Mothers' informational needs when deciding to have their newborn infant vaccinated with BCG. A Mixed-methods design

    DEFF Research Database (Denmark)

    Pihl, Gitte Thybo; Ammentorp, Jette; Johannessen, Helle

    2018-01-01

    . The telephone consultation ensured the mothers' understanding by tailoring and deriving meaning from the information to her special needs. Moreover, it helped the mothers gain an overview of risks and benefits and inspired confidence. These findings indicate that the telephone consultation improved health......OBJECTIVE: To explore the informational needs of mothers with different levels of education in order to improve counselling about vaccination. METHODS: In the setting of a large vaccination trial, mothers' assessments and yield of written information in combination with telephone consultations were...... evaluated in a survey. Furthermore, searching strategies for additional information were investigated. Mothers' perspectives on informational needs were explored in focus group discussions. RESULTS: Out of 2025 mothers, 95% felt well-informed. Of the 4% not feeling well-informed, there were significantly...

  14. "Lay epidemiology": an important factor in Danish parents' decision of whether to allow their child to receive a BCG vaccination

    DEFF Research Database (Denmark)

    Thybo Pihl, Gitte; Johannessen, Helle; Ammentorp, Jette

    2017-01-01

    Forældre anvender lægmandsepidemiologi i et forsøg på at foretage en individuel risikovurdering for deres barn, når de skal opveje fordele og ulemper ved en vaccine. Holdninger og overbevisninger om årsager til sygdom og bivirkninger i forældrenes familie og netværk har betydning for deres...

  15. Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer.

    Directory of Open Access Journals (Sweden)

    Kathrin Buffen

    2014-10-01

    Full Text Available The anti-tuberculosis-vaccine Bacillus Calmette-Guérin (BCG is the most widely used vaccine in the world. In addition to its effects against tuberculosis, BCG vaccination also induces non-specific beneficial effects against certain forms of malignancy and against infections with unrelated pathogens. It has been recently proposed that the non-specific effects of BCG are mediated through epigenetic reprogramming of monocytes, a process called trained immunity. In the present study we demonstrate that autophagy contributes to trained immunity induced by BCG. Pharmacologic inhibition of autophagy blocked trained immunity induced in vitro by stimuli such as β-glucans or BCG. Single nucleotide polymorphisms (SNPs in the autophagy genes ATG2B (rs3759601 and ATG5 (rs2245214 influenced both the in vitro and in vivo training effect of BCG upon restimulation with unrelated bacterial or fungal stimuli. Furthermore, pharmacologic or genetic inhibition of autophagy blocked epigenetic reprogramming of monocytes at the level of H3K4 trimethylation. Finally, we demonstrate that rs3759601 in ATG2B correlates with progression and recurrence of bladder cancer after BCG intravesical instillation therapy. These findings identify a key role of autophagy for the nonspecific protective effects of BCG.

  16. Sex-differential effect on infant mortality of oral polio vaccine administered with BCG at birth in Guinea-Bissau. A natural experiment.

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    Christine Stabell Benn

    Full Text Available The policy to provide oral polio vaccine (OPV at birth was introduced in low-income countries to increase coverage. The effect of OPV at birth on overall child mortality was never studied. During a trial of vitamin A supplementation (VAS at birth in Guinea-Bissau, OPV was not available during several periods. We took advantage of this "natural experiment" to test the effect on mortality of receiving OPV at birth.Between 2002 and 2004, the VAS trial randomised normal-birth-weight infants to 50,000 IU VAS or placebo administered with BCG. Provision of OPV at birth was not part of the trial, but we noted whether the infants received OPV or not. OPV was missing during several periods in 2004. We used Cox proportional hazards models to compute mortality rate ratios (MRR of children who had received or not received OPV at birth.A total of 962 (22.1% of the 4345 enrolled children did not receive OPV at birth; 179 children died within the first year of life. Missing OPV at birth was associated with a tendency for decreased mortality (adjusted MRR = 0.69 (95% CI = 0.46-1.03, the effect being similar among recipients of VAS and placebo. There was a highly significant interaction between OPV at birth and sex (p = 0.006. Not receiving OPV at birth was associated with a weak tendency for increased mortality in girls (1.14 (0.70-1.89 but significantly decreased mortality in boys (0.35 (0.18-0.71.In our study OPV at birth had a sex-differential effect on mortality. Poliovirus is almost eradicated and OPV at birth contributes little to herd immunity. A randomised study of the effect of OPV at birth on overall mortality in both sexes is warranted.

  17. BCG-induced trained immunity in NK cells: Role for non-specific protection to infection.

    Science.gov (United States)

    Kleinnijenhuis, Johanneke; Quintin, Jessica; Preijers, Frank; Joosten, Leo A B; Jacobs, Cor; Xavier, Ramnik J; van der Meer, Jos W M; van Crevel, Reinout; Netea, Mihai G

    2014-12-01

    Adaptive features of innate immunity, also termed 'trained immunity', have recently been shown to characterize monocytes of BCG vaccinated healthy volunteers. Trained immunity leads to increased cytokine production in response to non-related pathogens via epigenetic reprogramming of monocytes. Recently, memory-like properties were also observed in NK cells during viral infections, but it is unknown if memory properties of NK cells contribute to trained immunity due to BCG vaccination. BCG vaccination of healthy volunteers increased proinflammatory cytokine production following ex vivo stimulation of NK cells with mycobacteria and other unrelated pathogens up until at least three months after vaccination. In addition, in a murine model of disseminated candidiasis, BCG vaccination led to an increased survival in SCID mice, which was partially dependent on NK cells. These findings suggest that NK cells may contribute to the non-specific (heterologous) beneficial effects of BCG vaccination. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Successful Handling of Disseminated BCG Disease in a Child with Severe Combined Immunodeficiency

    Directory of Open Access Journals (Sweden)

    Sílvia Bacalhau

    2011-01-01

    Full Text Available In high-burden countries, Mycobacterium bovis Bacillus Calmette-Guérin (BCG vaccine is administered in newborn to prevent severe Mycobacterium tuberculosis infection. Because life-threatening disseminated BCG disease may occur in children with primary immunodeficiency, vaccination strategy against tuberculosis should be redefined in non-high-burden countries. We report the case of a patient with X-linked severe combined immunodeficiency (SCID who developed disseminated BCG disease, highlighting the specific strategies adopted.

  19. Successful Handling of Disseminated BCG Disease in a Child with Severe Combined Immunodeficiency

    OpenAIRE

    Bacalhau, S; Freitas, C; Valente, R; Barata, D; Neves, C; Schäfer, K; Lubatschofski, A; Schulz, A; Farela Neves, J

    2011-01-01

    In high-burden countries, Mycobacterium bovis Bacillus Calmette-Guérin (BCG) vaccine is administered in newborn to prevent severe Mycobacterium tuberculosis infection. Because life-threatening disseminated BCG disease may occur in children with primary immunodeficiency, vaccination strategy against tuberculosis should be redefined in non-high-burden countries. We report the case of a patient with X-linked severe combined immunodeficiency (SCID) who developed disseminated BCG disease, highligh...

  20. Double-Blind Randomized Efficacy Field Trial of Alum Precipi¬tated Autoclaved Leishmania major (Alum-ALM Vaccine Mixed With BCG Plus Imiquimod Vs. Placebo Control Group

    Directory of Open Access Journals (Sweden)

    Mohammad BARATI

    2015-10-01

    Full Text Available Background: Canine visceral leishmaniasis (CVL is not only an emerging veterinary concern but also a public health threat in endemic areas. The aim of this study was to assess the efficacy, immunogenicity and safety of two doses of aluminum hydroxide (alum precipitated Leishmania major (Alum-ALM mixed with BCG plus imiquimod against CVL.Methods: A total of 560 ownership dogs were serologically tested and 234 healthy dogs with no clinical signs of CVL, no anti-Leishmania antibodies and negative leish­manin skin test were selected and double-blind randomly injected intradermally either with 0.1 ml Alum-ALM (200µg protein mixed with BCG (2 × 106 CFUs plus imiquimod (121 dogs or with 0.1 ml of normal saline (113 dogs.Results: The follow-up examinations showed that there was no side effect associated with the vaccination except one case. Strong skin test conversion were seen in vac­cinated group (30.3% compared to the control group (6.6% at 22-24 weeks after the booster injection (p<0.001. The seroconversion was 16.3% (18/110 in vaccinated group and 26.4% (28/106 in control group after two transmission cycles but the differ­ence was not significant (P=0.095. The efficacy rate based on seroconversion was 40.4 %.Conclusion: Two injections of Alum-ALM mixed with BCG and imiquimod is safe, although decreases the seroconversion rate of CVL, but the overall efficacy was low.

  1. Tuberculous meningitis in children: a review of clinical, laboratory, epidemiological, and therapeutic aspects and of the usefulness of BCG vaccination Meningitis tuberculosa en niños: una revisión de aspectos clínicos, de laboratorio, epidemiológicos y terapéuticos y de la utilidad de la vacunación con BCG

    Directory of Open Access Journals (Sweden)

    José William Cornejo Ochoa

    2010-08-01

    Full Text Available

    Tuberculous meningitis is the most frequent extrapulmonary form of tuberculosis in underdeveloped countries, among them Colombia. It is associated with high rates of morbidity and mortality. In this article a review is presented of the following aspects of the disease: clinical, epidemiological, therapeutic, prophylactic by means of BCG vaccination, laboratory diagnosis, and tomographic findings.

    La tuberculosis meníngea (MTB es la enfermedad tuberculosa extrapulmonar más frecuente en los países del tercer mundo, incluida Colombia, y tiene tasas altas de morbilidad y mortalidad. En este artículo se presenta una revisión de la literatura sobre los siguientes aspectos de la enfermedad: clínicos, epidemiológicos, de laboratorio, tomográficos, terapéuticos y de prevención con la vacuna BCG.

  2. BCG protects toddlers during a tuberculosis outbreak.

    LENUS (Irish Health Repository)

    Gaensbauer, J T

    2009-05-01

    In 2007, an outbreak of tuberculosis occurred in a toddler population attending two child care centres in Cork, Ireland. Of 268 children exposed, 18 were eventually diagnosed with active tuberculosis. We present the initial clinical and radiographic characteristics of the active disease group. Mantoux testing was positive in only 66% of cases. All cases were either pulmonary or involved hilar adenopathy on chest radiograph; there were no cases of disseminated disease or meningitis. 24% of the exposed children had been previously vaccinated with BCG, and no case of active disease was found in this group (p = 0.016), suggesting a profound protective effect of BCG in this population. Our experience provides evidence supporting a protective effect of BCG against pulmonary disease in young children.

  3. BCG and Adverse Events in the Context of Leprosy

    Directory of Open Access Journals (Sweden)

    Renate Richardus

    2018-04-01

    Full Text Available BackgroundNotwithstanding its beneficial immunoprophylactic outcomes regarding leprosy and childhood TB, BCG vaccination may cause adverse events, particularly of the skin. However, this local hyper-immune reactivity cannot be predicted before vaccination, nor is its association with protection against leprosy known. In this study we investigated the occurrence of adverse events after BCG (revaccination in contacts of leprosy patients and analyzed whether the concomitant systemic anti-mycobacterial immunity was associated with these skin manifestations.MethodsWithin a randomized controlled BCG vaccination trial in Bangladesh, 14,828 contacts of newly diagnosed leprosy patients received BCG vaccination between 2012 and 2017 and were examined for adverse events 8 to 12 weeks post-vaccination. From a selection of vaccinated contacts, venous blood was obtained at follow-up examination and stimulated with Mycobacterium leprae (M. leprae antigens in overnight whole-blood assays (WBA. M. leprae phenolic glycolipid-I-specific antibodies and 32 cytokines were determined in WBAs of 13 individuals with and 13 individuals without adverse events after vaccination.ResultsOut of the 14,828 contacts who received BCG vaccination, 50 (0.34% presented with adverse events, mainly (80% consisting of skin ulcers. Based on the presence of BCG scars, 30 of these contacts (60% had received BCG in this study as a booster vaccination. Similar to the pathological T-cell immunity observed for tuberculoid leprosy patients, contacts with adverse events at the site of BCG vaccination showed elevated IFN-γ levels in response to M. leprae-specific proteins in WBA. However, decreased levels of sCD40L in serum and GRO (CXCL1 in response to M. leprae simultaneously indicated less T-cell regulation in these individuals, potentially causing uncontrolled T-cell immunity damaging the skin.ConclusionSkin complications after BCG vaccination present surrogate markers for protective

  4. Long-term in vitro and in vivo effects of γ-irradiated BCG on innate and adaptive immunity

    DEFF Research Database (Denmark)

    Arts, Rob J W; Blok, Bastiaan A; Aaby, Peter

    2015-01-01

    but not in immunocompromised hosts, as it is a live, attenuated vaccine. Therefore, we assessed whether killed γBCG has similar potentiating effects. In an in vitro model of trained immunity, human monocytes were incubated with γBCG for 24 h and restimulated after 6 d. Cytokine production and the role of pattern recognition...... were less strong than those induced by live BCG. γBCG vaccination in volunteers had only minimal effects on innate immunity, whereas a significant increase in heterologous Th1/Th17 immunity was observed. Our results indicate that γBCG induces long-term training of innate immunity in vitro. In vivo, γ......BCG vaccination is associated with a reduced mortality from nonmycobacterial infections. This is likely to be mediated by a combination of innate-immune memory ("trained immunity") and heterologous effects on adaptive immunity. As such, BCG could be used to boost host immunity...

  5. Hubungan antara Pembentukan Scar Vaksin BCG dan Kejadian Infeksi Tuberkulosis

    Directory of Open Access Journals (Sweden)

    Fajriah Rosandali

    2016-08-01

    Full Text Available AbstrakTuberkulosis adalah penyakit menular yang disebabkan oleh kuman Mycobacterium tuberculosis. Orang dewasa yang menderita tuberkulosis sangat mudah menularkan kuman TB kepada orang disekitarnya terutama pada anak-anak. Salah satu cara pencegahan penyakit tuberkulosis adalah pemberian imunisasi BCG pada saat bayi baru lahir. Scar vaksin BCG dapat terbentuk setelah penyuntikan, kadang Scar tidak terbentuk setelah penyuntikan. Tujuan penelitian ini adalah menentukan hubungan antara pembentukan Scar vaksin BCG dan kejadian infeksi tuberkulosis. Penelitian ini menggunakan desain cross sectional dengan jumlah subjek sebanyak 80 orang. Pengambilan data berupa melakukan pengamatan terhadap Scar pada lengan atas serta wawancara kepada responden dengan menggunakan pedoman wawancara. Kemudian data ditabulasi dalam bentuk persentase dan dianalisis dengan uji chi-square . Hasil penelitian menunjukan bahwa responden yang terbanyak adalah perempuan dan usia yang terbanyak 35-44 tahun. Terdapat hubungan yang bermakna antara pembentukan Scar  vaksin BCG dengan kejadian infeksi tuberkulosis (p < 0,05. Disimpulkan bahwa terdapat pengaruh antara pembentukan Scar vaksin BCG terhadap kejadian infeksi tuberkulosis.Kata kunci: tuberkulosis, vaksin BCG, Scar. AbstractTuberculosis is an infectious disease caused by Mycobacterium tuberculosis with the number of sufferers tend to increase every years. Adults who suffer  tuberculosis is very easy to spread it to around, especially to children. One of the way to prevent tuberculosis is immunization of BCG vaccine which given since infant. The Scar of BCG vaccine can formed after injection or not. The objective of this study was to determine the relation of BCG vaccine Scar formation on  the incidence of tuberculosis infection.This research used a cross sectional design with 80 total subjects. The data was collected by observations of the scar on the upper arm while interviewed  respondents using interview guide

  6. BCG revaccination does not protect against leprosy in the Brazilian Amazon: a cluster randomised trial.

    Directory of Open Access Journals (Sweden)

    Sérgio S Cunha

    2008-02-01

    Full Text Available Although BCG has been found to impart protection against leprosy in many populations, the utility of repeat or booster BCG vaccinations is still unclear. When a policy of giving a second BCG dose to school children in Brazil was introduced, a trial was conducted to assess its impact against tuberculosis, and a leprosy component was then undertaken in parallel.to estimate the protection against leprosy imparted by a second dose of BCG given to schoolchildren.This is a cluster randomised community trial, with 6 years and 8 months of follow-up.City of Manaus, Amazon region, a leprosy-endemic area in Brazil.99,770 school children with neonatal BCG (aged 7-14 years at baseline, of whom 42,662 were in the intervention arm (revaccination.BCG given by intradermal injection.Leprosy (all clinical forms.The incidence rate ratio of leprosy in the intervention over the control arm within the follow-up, in schoolchildren with neonatal BCG, controlled for potential confounders and adjusted for clustering, was 0.99 (95% confidence interval: 0.68 to 1.45.There was no evidence of protection conferred by the second dose of BCG vaccination in school children against leprosy during the trial follow-up. These results point to a need to consider the effectiveness of the current policy of BCG vaccination of contacts of leprosy cases in Brazilian Amazon region.

  7. Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial

    DEFF Research Database (Denmark)

    Biering-Sørensen, Sofie; Aaby, Peter; Lund, Najaaraq

    2017-01-01

    Background. BCG vaccine may reduce overall mortality by increasing resistance to nontuberculosis infections. In 2 randomized trials in Guinea-Bissau of early BCG-Denmark (Statens Serum Institut) given to low-weight (LW) neonates (... ratios (MRRs). We had prespecified an analysis censoring follow-up at oral poliovirus vaccine campaigns. Results. Early administration of BCG-Denmark was associated with a nonsignificant reduction in neonatal mortality rate (MRR, 0.70; 95% confidence interval [CI], .47–1.04) and a 34% reduction (0.......66; .44–1.00) when censoring for oral poliovirus vaccine campaigns. There was no reduction in mortality rate for noninfectious diseases, but a 43% reduction in infectious disease mortality rate (MRR, 0.57; 95% CI, .35–.93). A meta-analysis of 3 BCG trials showed that early BCG-Denmark reduced mortality...

  8. A review of the literature on the economics of vaccination against TB

    NARCIS (Netherlands)

    Tu, H.A.; Vu, H.D.; Rozenbaum, M.H.; Woerdenbag, H.J.; Postma, M.J.

    The BCG vaccine was introduced in 1921 and remains the only licensed vaccine for the prevention of TB worldwide. Despite its extensive use, the BCG vaccine lacks the ability to fully control the TB-endemic and -pandemic situations. The BCG vaccine is most effective in preventing pediatric TB, in

  9. Recombinant BCG Expressing ESX-1 of Mycobacterium marinum Combines Low Virulence with Cytosolic Immune Signaling and Improved TB Protection

    NARCIS (Netherlands)

    Gröschel, Matthias I.; Sayes, Fadel; Shin, Sung Jae; Frigui, Wafa; Pawlik, Alexandre; Orgeur, Mickael; Canetti, Robin; Honore, Nadine; Simeone, Roxane; van der Werf, Tjip S.; Bitter, Wilbert; Cho, Sang-Nae; Majlessi, Laleh; Brosch, Roland

    2017-01-01

    Recent insights into the mechanisms by which Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is recognized by cytosolic nucleotide sensors have opened new avenues for rational vaccine design. The only licensed anti-tuberculosis vaccine, Mycobacteriumbovis BCG, provides limited

  10. Long-term in vitro and in vivo effects of γ-irradiated BCG on innate and adaptive immunity.

    Science.gov (United States)

    Arts, Rob J W; Blok, Bastiaan A; Aaby, Peter; Joosten, Leo A B; de Jong, Dirk; van der Meer, Jos W M; Benn, Christine Stabell; van Crevel, Reinout; Netea, Mihai G

    2015-12-01

    BCG vaccination is associated with a reduced mortality from nonmycobacterial infections. This is likely to be mediated by a combination of innate-immune memory ("trained immunity") and heterologous effects on adaptive immunity. As such, BCG could be used to boost host immunity but not in immunocompromised hosts, as it is a live, attenuated vaccine. Therefore, we assessed whether killed γBCG has similar potentiating effects. In an in vitro model of trained immunity, human monocytes were incubated with γBCG for 24 h and restimulated after 6 d. Cytokine production and the role of pattern recognition receptors and histone methylation markers were assessed. The in vivo effects of γBCG vaccination were studied in a proof-of-principle trial in 15 healthy volunteers. γBCG induced trained immunity in vitro via the NOD2 receptor pathway and up-regulation of H3K4me3 histone methylation. However, these effects were less strong than those induced by live BCG. γBCG vaccination in volunteers had only minimal effects on innate immunity, whereas a significant increase in heterologous Th1/Th17 immunity was observed. Our results indicate that γBCG induces long-term training of innate immunity in vitro. In vivo, γBCG induces mainly heterologous effects on the adaptive-immune system, whereas effects on innate cytokine production are limited. © Society for Leukocyte Biology.

  11. Cytochemical and biological properties of Mycobacterium bovis BCG.

    Science.gov (United States)

    Slosárek, M

    1977-01-01

    It was the aim of the present communication to find a simple test for a reliable discrimination of Mycobacterium bovis BCG from Mycobacterium tuberculosis. A total of 26 BCG strains, out of them 10 Czechoslovak strains (2 lyophilized cultures of BCG of different batch, 6 strains isolated from abscesses of children after BCG-vaccination and 2 strains from fatal cases after BCG-vaccination) and 16 strains obtained from foreign laboratories, were used. Of the tested characteristics a combination of 3 tests, sensitivity to 1 microgram of 2-thiophene carbonylhydrazide (TCH), activity of 3 acylamidases (urease, nicotinamidase and pyrazinamidase) and a quantitative nitrate test, was found to be most advantageous. The Czechoslovak strains of Mycobacterium bovis BCG were fully sensitive to TCH, of the 3 acylamidases mentioned above only urease was positive and nitrate was reduced only little or not at all. On the other hand, strains of Mycobacterium tuberculosis were always resistant to TCH, had positive urease, nicotinamidase and pyrazinamidase and reduced nitrate very intensively.

  12. BCG and protection against inflammatory and auto-immune diseases.

    Science.gov (United States)

    Kowalewicz-Kulbat, Magdalena; Locht, Camille

    2017-07-01

    Bacillus Calmette-Guérin (BCG) is the only available vaccine against tuberculosis. Although its protective efficacy against pulmonary tuberculosis is still under debate, it provides protection against other mycobacterial diseases. BCG is also an effective therapy against superficial bladder cancer and potentially decreases overall childhood mortality. Areas covered: The purpose of this paper is to provide a state-of-the-art summary of the beneficial effects of BCG in inflammatory and auto-immune diseases. As a strong inducer of Th1 type immunity, BCG has been reported to protect against atopic conditions, such as allergic asthma, a Th2-driven disorder. Its protective effect has been well documented in mice, but still awaits definitive evidence in humans. Similarly, murine studies have shown a protective effect of BCG against auto-immune diseases, such as multiple sclerosis and insulin-dependent diabetes, but studies in humans have come to conflicting conclusions. Expert commentary: Studies in mice have shown a beneficial effect of the BCG vaccine against allergic asthma, multiple sclerosis and diabetes. However, the understanding of its mechanism is still fragmentary and requires further in depth research. Some observational or intervention studies in humans have also suggested a beneficial effect, but definitive evidence for this requires confirmation in carefully conducted prospective studies.

  13. Estudo sobre a evolução do risco de infecção tuberculosa em área com elevada cobertura por BCG The trend in the risk of tuberculous infection in an area with wide coverage with BCG vaccination

    Directory of Open Access Journals (Sweden)

    Gilberto Ribeiro Arantes

    1985-04-01

    Full Text Available A partir da prevalência de infecção tuberculosa em escolares com 7 anos de idade, calculou-se a taxa de redução do risco anual de infecção na cidade de São Paulo (Brasil, entre 1974 e 1982. Nesse período o declínio médio foi de 5% ao ano. Nas 59 escolas municipais pesquisadas não houve correlação entre a cobertura de vacinação BCG e a prevalência de infecção natural em não-vacinados, à idade estudada. A alergia tuberculínica no grupo de crianças vacinadas, que recebeu a vacina em alguma idade anterior entre o 1° e o 6° ano de vida, revelou-se 2,5 vezes mais intensa do que a alergia no grupo de mesma idade (7 anos, não vacinado previamente. Foram feitos comentários quanto à impropriedade do material utilizado com vistas ao cálculo do verdadeiro valor do risco de infecção tuberculosa na área em questão.The estimation of the risk of tuberculous infection from prevalence data obtained at school-age, in 1974 and in 1982, permitted the determination of the relevant trend in the city of S. Paulo, Brazil, between those years. The risk of infection decreased, on average, by 5% annually during the period. There was no evidence of any association between the proportions of vaccinated children and that of infected children among those unvaccinated, in the 59 schools studied. Tuberculin sensitivity in 7 years old school-children, vaccinated with BCG at any age between the 1st and the 6th year of life was 2.5 times more intense than that in unvaccinaetd children of the same age. With regard to the calculation of the true value of the risk of tuberculous infection, commentaries about the unrealiability of the available data were made.

  14. Immunotherapy with BCG cell wall plus irradiated tumor cells

    Energy Technology Data Exchange (ETDEWEB)

    Mizukuro, Tomoyuki (Kyoto Prefectural Univ. of Medicine (Japan))

    1983-04-01

    Two different fibrosarcomas (MCB-I, MCB-II) were induced by methylcholcholanthrene in syngeneic Balb/C mice were used. The tumor cells irradiated with 5,000 to 30,000 rads did not growth in mice on 30 days after inoculation. The viable tumor cells were challenged intradermally to mice on 7 days after inoculation of the tumor cells irradiated with 5,000 to 30,000 rads. The challenged tumor cells were all rejected at 30 days after inoculation. Mice were challenged with 5 x 10/sup 5/ viable tumor cells on 7 days after inoculation of 10/sup 3/ to 10/sup 8/ irradiated tumor cells. Mice pretreated with 10/sup 5/ or 10/sup 6/ irradiated tumor cells rejected the tumor cells completely. The viable tumor cells were challenged to mice on 7 days after inoculation of BCG-CW emulsion plus 10/sup 6/ irradiated tumor cells. 0, 50, 100, 200, and 400 mu g of BCG-CW emulsion were mixed in 10/sup 6/ irradiated tumor cells. Optimal dosage of BCG-CW emulsion was 50 or 100 mu g. BCG-CW emulsion plus irradiated tumor cells were injected subcutaneously to the mice after tumor cells inoculation. Three injections of the vaccine significantly suppressed the tumor outgrowth, but not one or two injections in no-treated mice. However, in the mice pretreated with BCG-CW emulsion, the tumor growth was significantly suppressed by one or two injections of the vaccine. Especially, the three injections of the vaccine significantly suppressed the tumor growth and the 25% of the mice were completely cured. The effect of the vaccine was almost the same grade by contralateral or ipsilateral treatment. The irradiated MCB-II tumor cells plus BCG-CW emulsion were not effective to the MCB-1 tumor bearing mice, suggesting the anti-tumor effect of this vaccine was immunologically specific.

  15. BCG-loaded chitosan microparticles: interaction with macrophages and preliminary in vivo studies.

    Science.gov (United States)

    Caetano, Liliana Aranha; Figueiredo, Lara; Almeida, António J; Gonçalves, L M D

    2017-03-01

    The aim of this study was to develop a novel BCG-loaded chitosan vaccine with high association efficiency which can afford efficient interaction with APC and elicit local and Th1-type-specific immune response after intranasal administration. Chitosan-suspended BCG and BCG-loaded chitosan-alginate microparticles were prepared by ionotropic gelation. Interaction with APC was evaluated by fluorescence microscopy using rBCG-GFP. Specific immune responses were evaluated following intranasal immunisation of mice. Cellular uptake was approximately two-fold higher for chitosan-suspended BCG. A single dose of BCG-loaded microparticles or chitosan-suspended BCG by intranasal route improved Th1-type response compared with subcutaneous BCG. Chitosan-suspended BCG originated the highest mucosal response in the lungs by intranasal route. These positive results indicate that the proposed approach of whole live BCG microencapsulation in chitosan-alginate for intranasal immunisation was successful in allowing efficient interaction with APC, while improving the cellular immune response, which is of interest for local immunisation against tuberculosis.

  16. Commonly administered BCG strains including an evolutionarily early strain and evolutionarily late strains of disparate genealogy induce comparable protective immunity against tuberculosis.

    Science.gov (United States)

    Horwitz, Marcus A; Harth, Günter; Dillon, Barbara Jane; Maslesa-Galić, Sasa

    2009-01-14

    BCG has been administered to over 4 billion persons worldwide, but its efficacy in preventing tuberculosis in adults has been highly variable. One hypothesis for its variability is that different strains of BCG vary in protective efficacy, and moreover, that evolutionarily early strains are more efficacious than the more attenuated evolutionarily late strains, which lack region of deletion 2. To examine this hypothesis, we tested six widely used BCG strains--the evolutionarily early strain BCG Japanese, two evolutionarily late strains in DU2 Group III (BCG Danish and Glaxo), and three evolutionarily late strains in DU2 Group IV (BCG Connaught, Pasteur, and Tice)--in the guinea pig model of pulmonary tuberculosis. With the exception of BCG Glaxo, which had relatively poor efficacy, we found no substantial differences in efficacy between the early strain and the late strains, and only small differences in efficacy among late strains. BCG Tice was the most efficacious BCG vaccine, with significantly fewer Mycobacterium tuberculosis in the lung and spleen than BCG Danish and BCG Japanese, although absolute differences in the organ burden of M. tuberculosis among these three vaccines were small (Pasteur were not significantly different. rBCG30, a recombinant BCG Tice vaccine overexpressing the M. tuberculosis 30 kDa major secretory protein (Antigen 85B), was more potent than any BCG vaccine (P < 0.0001 for differences in organ burden). Our study shows that late strains are not less potent than an early strain and argues against strain differences as a major factor in the variability of outcomes in BCG vaccine trials.

  17. Non-tuberculous mycobacteria have diverse effects on BCG efficacy against Mycobacterium tuberculosis☆

    Science.gov (United States)

    Poyntz, Hazel C.; Stylianou, Elena; Griffiths, Kristin L.; Marsay, Leanne; Checkley, Anna M.; McShane, Helen

    2014-01-01

    Summary The efficacy of Bacillus Calmette-Guerin (BCG) vaccination in protection against pulmonary tuberculosis (TB) is highly variable between populations. One possible explanation for this variability is increased exposure of certain populations to non-tuberculous mycobacteria (NTM). This study used a murine model to determine the effect that exposure to NTM after BCG vaccination had on the efficacy of BCG against aerosol Mycobacterium tuberculosis challenge. The effects of administering live Mycobacterium avium (MA) by an oral route and killed MA by a systemic route on BCG-induced protection were evaluated. CD4+ and CD8+ T cell responses were profiled to define the immunological mechanisms underlying any effect on BCG efficacy. BCG efficacy was enhanced by exposure to killed MA administered by a systemic route; T helper 1 and T helper 17 responses were associated with increased protection. BCG efficacy was reduced by exposure to live MA administered by the oral route; T helper 2 cells were associated with reduced protection. These findings demonstrate that exposure to NTM can induce opposite effects on BCG efficacy depending on route of exposure and viability of NTM. A reproducible model of NTM exposure would be valuable in the evaluation of novel TB vaccine candidates. PMID:24572168

  18. Rapid Protective Effects of Early BCG on Neonatal Mortality Among Low Birth Weight Boys: Observations From Randomized Trials.

    Science.gov (United States)

    Biering-Sørensen, Sofie; Jensen, Kristoffer Jarlov; Monterio, Ivan; Ravn, Henrik; Aaby, Peter; Benn, Christine Stabell

    2018-02-14

    Three randomized trials (RCTs) in low-weight (BCG) vaccine nonspecifically reduces all-cause mortality in the neonatal period. Using data from 3 RCTs of early BCG (n = 6583) we examined potential sex differences in the timing of the mortality reduction in the neonatal period, presenting metaestimates of the main outcome mortality rate ratios (MRR) for BCG-vaccinated and controls. Among controls, boys had a particularly high mortality during the first week after randomization: male-female MRR 2.71 (95% CI, 1.70-4.50). During the first week, BCG had a marked beneficial effect for boys, reducing mortality 3-fold (MRR [BCG/no BCG] = 0.36 [0.20-0.67]). In weeks 2-4 the effect waned for boys (MRR = 0.91 [0.51-1.69]). In girls, the pattern was opposite with a limited effect in the first week (MRR = 0.85 [0.46-1.54]), but a significant reduction in weeks 2-4 (MRR = 0.56 [0.31-1.00]). This was consistent in all 3 trials. Verbal autopsies linked early benefit to fewer sepsis-related deaths among BCG-vaccinated boys. The marked reduction in mortality in the days after BCG vaccination in boys emphasizes the importance of providing BCG soon after birth. ClinicalTrials.gov (NCT00146302) and ClinicalTrials.gov (NCT00625482).

  19. Adaptive immunity in the colostrum-deprived calf: Response to early vaccination with Mycobacterium bovis, strain Bacille Calmette Guerin (BCG) and ovalbumin

    Science.gov (United States)

    Responses of the newborn calf to vaccination are variable and frequently characterized by marginal antibody (Ab) responses. The present study evaluated effects of colostrum ingestion on the adaptive immune response of the preruminant calf to early vaccination. Colostrum-fed (CF) and colostrum-depriv...

  20. Immunometabolic Pathways in BCG-Induced Trained Immunity

    NARCIS (Netherlands)

    Arts, R.J.; Carvalho, A.; Rocca, C. La; Palma, C.; Rodrigues, F.; Silvestre, R.; Kleinnijenhuis, J.; Lachmandas, E.; Goncalves, L.G.; Belinha, A.; Cunha, C.; Oosting, M.; Joosten, L.A.; Matarese, G.; Crevel, R. van; Netea, M.G.

    2016-01-01

    The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity.

  1. Diffuse bony involvement in disseminated BCG disease in a patient ...

    African Journals Online (AJOL)

    BCG (bacille Calmette-Guérin) vaccination is carried out worldwide to prevent tuberculosis. It is considered to be very effective and has an excellent safety profile, but complications do occur. These may range from erythema and abscess at the site of inoculation to extensive disseminated disease including regional and ...

  2. Recombinant BCG Expressing Mycobacterium ulcerans Ag85A Imparts Enhanced Protection against Experimental Buruli ulcer.

    Science.gov (United States)

    Hart, Bryan E; Hale, Laura P; Lee, Sunhee

    2015-09-01

    Buruli ulcer, an emerging tropical disease caused by Mycobacterium ulcerans (MU), is characterized by disfiguring skin necrosis and high morbidity. Relatively little is understood about the mode of transmission, pathogenesis, or host immune responses to MU infection. Due to significant reduction in quality of life for patients with extensive tissue scarring, and that a disproportionately high percentage of those affected are disadvantaged children, a Buruli ulcer vaccine would be greatly beneficial to the worldwide community. Previous studies have shown that mice inoculated with either M. bovis bacille Calmette-Guérin (BCG) or a DNA vaccine encoding the M. ulcerans mycolyl transferase, Ag85A (MU-Ag85A), are transiently protected against pathology caused by intradermal challenge with MU. Building upon this principle, we have generated quality-controlled, live-recombinant strains of BCG and M. smegmatis which express the immunodominant MU Ag85A. Priming with rBCG MU-Ag85A followed by an M. smegmatis MU-Ag85A boost strongly induced murine antigen-specific CD4+ T cells and elicited functional IFNγ-producing splenocytes which recognized MU-Ag85A peptide and whole M. ulcerans better than a BCG prime-boost vaccination. Strikingly, mice vaccinated with a single subcutaneous dose of BCG MU-Ag85A or prime-boost displayed significantly enhanced survival, reduced tissue pathology, and lower bacterial load compared to mice vaccinated with BCG. Importantly, this level of superior protection against experimental Buruli ulcer compared to BCG has not previously been achieved. These results suggest that use of BCG as a recombinant vehicle expressing MU antigens represents an effective Buruli ulcer vaccine strategy and warrants further antigen discovery to improve vaccine efficacy.

  3. Recombinant BCG Expressing Mycobacterium ulcerans Ag85A Imparts Enhanced Protection against Experimental Buruli ulcer

    Science.gov (United States)

    Hart, Bryan E.; Hale, Laura P.; Lee, Sunhee

    2015-01-01

    Buruli ulcer, an emerging tropical disease caused by Mycobacterium ulcerans (MU), is characterized by disfiguring skin necrosis and high morbidity. Relatively little is understood about the mode of transmission, pathogenesis, or host immune responses to MU infection. Due to significant reduction in quality of life for patients with extensive tissue scarring, and that a disproportionately high percentage of those affected are disadvantaged children, a Buruli ulcer vaccine would be greatly beneficial to the worldwide community. Previous studies have shown that mice inoculated with either M. bovis bacille Calmette–Guérin (BCG) or a DNA vaccine encoding the M. ulcerans mycolyl transferase, Ag85A (MU-Ag85A), are transiently protected against pathology caused by intradermal challenge with MU. Building upon this principle, we have generated quality-controlled, live-recombinant strains of BCG and M. smegmatis which express the immunodominant MU Ag85A. Priming with rBCG MU-Ag85A followed by an M. smegmatis MU-Ag85A boost strongly induced murine antigen-specific CD4+ T cells and elicited functional IFNγ-producing splenocytes which recognized MU-Ag85A peptide and whole M. ulcerans better than a BCG prime-boost vaccination. Strikingly, mice vaccinated with a single subcutaneous dose of BCG MU-Ag85A or prime-boost displayed significantly enhanced survival, reduced tissue pathology, and lower bacterial load compared to mice vaccinated with BCG. Importantly, this level of superior protection against experimental Buruli ulcer compared to BCG has not previously been achieved. These results suggest that use of BCG as a recombinant vehicle expressing MU antigens represents an effective Buruli ulcer vaccine strategy and warrants further antigen discovery to improve vaccine efficacy. PMID:26393347

  4. Duas epidemias de tuberculose em crianças menores de três anos de idade, vacinadas com BCG oral, numa creche do município de São Paulo, Brasil Two epidemics of tuberculosis in children under three years of age vaccinated with oral BCG in a day-nursery in S. Paulo county, Brazil

    Directory of Open Access Journals (Sweden)

    Roberto Brólio

    1974-09-01

    Full Text Available São descritas duas epidemias de tuberculose em crianças menores de 3 anos de idade vacinadas com BCG oral, ocorridas numa creche para crianças menores de 5 anos de idade, no município de São Paulo, nos anos de 1967 e 1969. Em 1967 havia no estabelecimento 96 crianças, inicialmente não reatoras ao teste tuberculínico padronizado (PPD, Rt-23, 2 UT. Foram encontrados 19 reatores, sendo 12 reatores fortes (63,2% e 7 reatores fracos (36,8% e imagens radiológicas indicativas de anormalidade pulmonar em 15 crianças ou 78,9% dos reatores. Em 1969 havia no estabelecimento mais 62 crianças não reatoras, que foram acompanhadas separadamente em relação ao grupo de 1967, embora convivessem no mesmo ambiente. Foram encontrados 36 reatores à tuberculina, sendo 29 reatores fortes (80,5% e 7 reatores fracos (19,5% e imagens radiológicas indicativas de anormalidade pulmonar em 11 crianças, ou 30,5% dos reatores. Nesse mesmo ano houve viragem tuberculínica em mais 7 crianças pertencentes ao grupo de não reatores de 1967, sendo 5 reatores fortes e 2 reatores fracos. Nas duas epidemias, as viragens tuberculínicas e as alterações radiológicas pulmonares foram constatadas apenas nas crianças menores de 3 anos de idade, em sua maioria vacinadas previamente com 3 doses de BCG oral, com intervalo de uma semana entre uma dose e outra. A fonte de infecção foi um operário que trabalhou no estabelecimento durante aproximadamente dois meses em 1967 e um mês em 1969, nos locais onde eram mantidas as crianças menores de 3 anos de idade. A vacina administrada por esse método não parece ter influenciado nas conversões tuberculínicas e no desenvolvimento de imunidade específica.Two epidemics of tuberculosis in children under three years of age vaccinated with oral BCG, in the year of 1967 and 1969, in a day-nursery in S. Paulo borough, are here described. In 1967 there were 96 children in the place, at first non-reactors, to the standard

  5. Peptide microarray-based characterization of antibody responses to host proteins after bacille Calmette–Guérin vaccination

    Directory of Open Access Journals (Sweden)

    Davide Valentini

    2017-03-01

    Conclusions: BCG vaccination modifies the host’s immune landscape after 56 days, but this imprint changes over time. This may influence the establishment of immunological memory in BCG-vaccinated individuals.

  6. Low Dose BCG Infection as a Model for Macrophage Activation Maintaining Cell Viability

    Directory of Open Access Journals (Sweden)

    Leslie Chávez-Galán

    2016-01-01

    Full Text Available Mycobacterium bovis BCG, the current vaccine against tuberculosis, is ingested by macrophages promoting the development of effector functions including cell death and microbicidal mechanisms. Despite accumulating reports on M. tuberculosis, mechanisms of BCG/macrophage interaction remain relatively undefined. In vivo, few bacilli are sufficient to establish a mycobacterial infection; however, in vitro studies systematically use high mycobacterium doses. In this study, we analyze macrophage/BCG interactions and microenvironment upon infection with low BCG doses and propose an in vitro model to study cell activation without affecting viability. We show that RAW macrophages infected with BCG at MOI 1 activated higher and sustained levels of proinflammatory cytokines and transcription factors while MOI 0.1 was more efficient for early stimulation of IL-1β, MCP-1, and KC. Both BCG infection doses induced iNOS and NO in a dose-dependent manner and maintained nuclear and mitochondrial structures. Microenvironment generated by MOI 1 induced macrophage proliferation but not MOI 0.1 infection. In conclusion, BCG infection at low dose is an efficient in vitro model to study macrophage/BCG interactions that maintains macrophage viability and mitochondrial structures. This represents a novel model that can be applied to BCG research fields including mycobacterial infections, cancer immunotherapy, and prevention of autoimmunity and allergies.

  7. BCG stimulated dendritic cells induce an interleukin-10 producing T-cell population with no T helper 1 or T helper 2 bias in vitro

    DEFF Research Database (Denmark)

    Madura Larsen, Jeppe; Benn, Christine Stabell; Fillie, Yvonne

    2007-01-01

    Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine has been associated with beneficial effects on overall childhood mortality in low-income countries; this cannot be explained merely by the prevention of tuberculosis (TB) deaths. The beneficial effects of BCG vaccine could be the result o...

  8. Immunometabolic Pathways in BCG-Induced Trained Immunity.

    Science.gov (United States)

    Arts, Rob J W; Carvalho, Agostinho; La Rocca, Claudia; Palma, Carla; Rodrigues, Fernando; Silvestre, Ricardo; Kleinnijenhuis, Johanneke; Lachmandas, Ekta; Gonçalves, Luís G; Belinha, Ana; Cunha, Cristina; Oosting, Marije; Joosten, Leo A B; Matarese, Giuseppe; van Crevel, Reinout; Netea, Mihai G

    2016-12-06

    The protective effects of the tuberculosis vaccine Bacillus Calmette-Guerin (BCG) on unrelated infections are thought to be mediated by long-term metabolic changes and chromatin remodeling through histone modifications in innate immune cells such as monocytes, a process termed trained immunity. Here, we show that BCG induction of trained immunity in monocytes is accompanied by a strong increase in glycolysis and, to a lesser extent, glutamine metabolism, both in an in-vitro model and after vaccination of mice and humans. Pharmacological and genetic modulation of rate-limiting glycolysis enzymes inhibits trained immunity, changes that are reflected by the effects on the histone marks (H3K4me3 and H3K9me3) underlying BCG-induced trained immunity. These data demonstrate that a shift of the glucose metabolism toward glycolysis is crucial for the induction of the histone modifications and functional changes underlying BCG-induced trained immunity. The identification of these pathways may be a first step toward vaccines that combine immunological and metabolic stimulation. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  9. Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau.

    Science.gov (United States)

    Roth, Adam Edvin; Benn, Christine Stabell; Ravn, Henrik; Rodrigues, Amabelia; Lisse, Ida Maria; Yazdanbakhsh, Maria; Whittle, Hilton; Aaby, Peter

    2010-03-15

    To determine whether BCG revaccination at 19 months of age reduces overall child mortality. Randomised trial, with follow-up to age 5. A health project in Bissau, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area with 90 000 inhabitants. 2871 children aged 19 months to 5 years with low or no reactivity to tuberculin and who were not severely sick on the day of enrollment. BCG vaccination or no vaccination (control). Hazard ratios for mortality. 77 children died during follow-up. Compared with controls, the BCG revaccinated children had a hazard ratio of 1.20 (95% confidence interval 0.77 to 1.89). Two hundred and fifty children were admitted to hospital for the first time between enrollment and the end of the study, with an incidence rate ratio for BCG revaccinated children versus controls of 1.04 (0.81 to 1.33). The trial was stopped prematurely because of a cluster of deaths in the BCG arm of the study. This increase in mortality occurred at a time when many children had received missing vaccinations or vitamin A or iron supplementation; the hazard ratio for BCG revaccinated children compared with controls was 2.69 (1.05 to 6.88) in the period after these campaigns. Throughout the trial, the effect of BCG revaccination on mortality was significantly different (P=0.006) in children who had received diphtheria-tetanus-pertussis (DTP) booster vaccination before enrollment (hazard ratio 0.36, 0.13 to 0.99) and children who had not received the booster before enrollment (1.78, 1.04 to 3.04). There was no overall beneficial effect of being revaccinated with BCG. The effect of BCG revaccination on mortality might depend on other health interventions. Trial registration Clinical Trials ICA4-CT-2002-10053-REVAC.

  10. Long-term in vitro and in vivo effects of gamma-irradiated BCG on innate and adaptive immunity

    NARCIS (Netherlands)

    Arts, R.J.W.; Blok, B.A.; Aaby, P.; Joosten, L.A.B.; Jong, D.J. de; Meer, J.W.M. van der; Benn, C.S.; Crevel, R. van; Netea, M.G.

    2015-01-01

    BCG vaccination is associated with a reduced mortality from nonmycobacterial infections. This is likely to be mediated by a combination of innate-immune memory ("trained immunity") and heterologous effects on adaptive immunity. As such, BCG could be used to boost host immunity but not in

  11. Evaluation of Granulysin and Perforin as Candidate Biomarkers for Protection Following Vaccination with Mycobacterium bovis BCG or M. bovisDeltaRD1

    Science.gov (United States)

    Tuberculosis remains a major health problem worldwide. Cell mediated immunity based on a Th1 response plays an important role in the outcome of the disease. Measurements of immune responsiveness after TB vaccination include the standard skin test, IFN gamma-based diagnostic assays and T cell prolif...

  12. Vaccination with Mycobacterium bovis BCG Strains Danish and Pasteur in White-tailed Deer (Odocoileus virginianus) Experimentally Challenged with Mycobacterium bovis

    Science.gov (United States)

    Wildlife reservoirs of Mycobacterium bovis represent serious obstacles to the eradication of tuberculosis in domestic livestock. The cause for many faltering eradication programs is the presence of wildlife reservoirs of M. bovis. One approach in dealing with this wildlife reservoir is to vaccinate ...

  13. The Effect of 50 000 IU Vitamin A with BCG Vaccine at Birth on Growth in the First Year of Life

    DEFF Research Database (Denmark)

    Fisker, Ane Bærent; Benn, Christine Stabell; Diness, Birgitte Rode

    2011-01-01

    Vitamin A supplements may interact with diphtheria-tetanus-pertussis (DTP) vaccine causing increased female mortality. In a randomised trial of neonatal vitamin A supplementation (VAS), we examined growth during the first year of life in 808 children, pursuing the hypothesis that a negative...

  14. Effect of vitamin A supplementation with BCG vaccine at birth on vitamin A status at 6 wk and 4 mo of age

    DEFF Research Database (Denmark)

    Fisker, Ane B; Lisse, Ida M; Aaby, Peter

    2007-01-01

    with higher (9%; 95% CI: 2, 17%) RBP concentrations in children of noneducated mothers but not in children of educated mothers. Overall, RBP concentrations increased between 6 wk and 4 mo of age. The increase correlated inversely with the number of diphtheria-tetanus-pertussis (DTP) vaccines received...

  15. Disseminated Bacillus Calmette-Guérin (BCG) infections in infants with immunodeficiency.

    Science.gov (United States)

    Al-Hammadi, Suleiman; Alsuwaidi, Ahmed R; Alshamsi, Eman T; Ghatasheh, Ghassan A; Souid, Abdul-Kader

    2017-05-05

    The Bacillus Calmette-Guérin (BCG) preparations are live-attenuated derivatives of Mycobacterium bovis. These products are used to vaccinate infants at birth, a practice that may result in a disseminated infection in those patients who have an unidentified immunodeficiency. Patients who were immunized at birth with BCG and who developed a disseminated infection are reported here to emphasize the importance of taking an extensive medical history before ‎giving the BCG vaccine. Patient 1 has a sibling who had familial hemophagocytic lymphohistiocytosis. Patient 2 has a severe immunodeficiency with profound lymphopenia. Patient 3 has a sibling who had a disseminated BCG infection. Patient 4 has two siblings with an immunodeficiency disorder; one sibling passed away in infancy and one is receiving regular immunoglobulin infusions. Patient 5 has profound lymphopenia and his brother had cytomegalovirus (CMV) pneumonitis and passed away in infancy. These unfortunate events could have been avoided by compiling the relevant clinical and laboratory information. These cases also underscore the importance of a strict adherence to the BCG vaccine policies. Local and international registries that estimate the birth prevalence of primary immune deficiencies are needed prior to implementing universal BCG vaccination administration.

  16. Formulation of a mmaA4 gene deletion mutant of Mycobacterium bovis BCG in cationic liposomes significantly enhances protection against tuberculosis.

    Directory of Open Access Journals (Sweden)

    Steven C Derrick

    Full Text Available A new vaccination strategy is urgently needed for improved control of the global tuberculosis (TB epidemic. Using a mouse aerosol Mycobacterium tuberculosis challenge model, we investigated the protective efficacy of a mmaA4 gene deletion mutant of Mycobacterium bovis BCG (ΔmmaA4BCG formulated in dimethyl dioctadecyl ammonium bromide (DDA - D(+ trehalose 6,6 dibenenate (TDB (DDA/TDB adjuvant. In previous studies, deletion of the mmaA4 gene was shown to reduce the suppression of IL-12 production often seen after mycobacterial infections. While the non-adjuvanted ΔmmaA4BCG strain did not protect mice substantially better than conventional BCG against a tuberculous challenge in four protection experiments, the protective responses induced by the ΔmmaA4BCG vaccine formulated in DDA/TDB adjuvant was consistently increased relative to nonadjuvanted BCG controls. Furthermore, the ΔmmaA4BCG-DDA/TDB vaccine induced significantly higher frequencies of multifunctional (MFT CD4 T cells expressing both IFNγ and TNFα (double positive or IFNγ, TNFα and IL-2 (triple positive than CD4 T cells derived from mice vaccinated with BCG. These MFT cells were characterized by having higher IFNγ and TNFα median fluorescence intensity (MFI values than monofunctional CD4 T cells. Interestingly, both BCG/adjuvant and ΔmmaA4BCG/adjuvant formulations induced significantly higher frequencies of CD4 T cells expressing TNFα and IL-2 than nonadjuvanted BCG or ΔmmaA4BCG vaccines indicating that BCG/adjuvant mixtures may be more effective at inducing central memory T cells. Importantly, when either conventional BCG or the mutant were formulated in adjuvant and administered to SCID mice or immunocompromised mice depleted of IFNγ, significantly lower vaccine-derived mycobacterial CFU were detected relative to immunodeficient mice injected with non-adjuvanted BCG. Overall, these data suggest that immunization with the ΔmmaA4BCG/adjuvant formulation may be an effective

  17. Sex-differential effect on infant mortality of oral polio vaccine administered with BCG at birth in Guinea-Bissau. A natural experiment

    DEFF Research Database (Denmark)

    Benn, Christine Stabell; Fisker, Ane Baerent; Rodrigues, Amabelia

    2008-01-01

    BACKGROUND: The policy to provide oral polio vaccine (OPV) at birth was introduced in low-income countries to increase coverage. The effect of OPV at birth on overall child mortality was never studied. During a trial of vitamin A supplementation (VAS) at birth in Guinea-Bissau, OPV was not availa......-differential effect on mortality. Poliovirus is almost eradicated and OPV at birth contributes little to herd immunity. A randomised study of the effect of OPV at birth on overall mortality in both sexes is warranted.......BACKGROUND: The policy to provide oral polio vaccine (OPV) at birth was introduced in low-income countries to increase coverage. The effect of OPV at birth on overall child mortality was never studied. During a trial of vitamin A supplementation (VAS) at birth in Guinea-Bissau, OPV...

  18. Evaluation of Immunogenicity and Protective Efficacy Elicited by Mycobacterium bovis BCG Overexpressing Ag85A Protein against Mycobacterium tuberculosis Aerosol Infection.

    Science.gov (United States)

    Xu, Zheng Zhong; Chen, Xiang; Hu, Ting; Meng, Chuang; Wang, Xiao Bo; Rao, Yan; Zhang, Xiao Ming; Yin, Yue Lan; Pan, Zhi Ming; Jiao, Xin An

    2016-01-01

    Mycobacterium bovis bacillus Calmette-Guérin (BCG) is currently the only vaccine available for preventing tuberculosis (TB), however, BCG has varying success in preventing pulmonary TB. In this study, a recombinant BCG (rBCG::Ag85A) strain overexpressing the immunodominant Ag85A antigen was constructed, and its immunogenicity and protective efficacy were evaluated. Our results indicated that the Ag85A protein was successfully overexpressed in rBCG::Ag85A, and the Ag85A peptide-MHC complexes on draining lymph node dendritic cells of C57BL/6 mice infected with rBCG::Ag85A were detectable 4 h post-infection. The C57BL/6 mice infected with this strain had stronger antigen-specific interferon-gamma (IFN-γ) responses and higher antibody titers than those immunized with BCG, and the protective experiments showed that rBCG::Ag85A can enhance protection against Mycobacterium tuberculosis (M. tuberculosis) H37Rv infection compared to the BCG vaccine alone. Our results demonstrate the potential of rBCG::Ag85A as a candidate vaccine against TB.

  19. Recombinant BCG Expressing ESX-1 of Mycobacterium marinum Combines Low Virulence with Cytosolic Immune Signaling and Improved TB Protection.

    Science.gov (United States)

    Gröschel, Matthias I; Sayes, Fadel; Shin, Sung Jae; Frigui, Wafa; Pawlik, Alexandre; Orgeur, Mickael; Canetti, Robin; Honoré, Nadine; Simeone, Roxane; van der Werf, Tjip S; Bitter, Wilbert; Cho, Sang-Nae; Majlessi, Laleh; Brosch, Roland

    2017-03-14

    Recent insights into the mechanisms by which Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is recognized by cytosolic nucleotide sensors have opened new avenues for rational vaccine design. The only licensed anti-tuberculosis vaccine, Mycobacterium bovis BCG, provides limited protection. A feature of BCG is the partial deletion of the ESX-1 type VII secretion system, which governs phagosomal rupture and cytosolic pattern recognition, key intracellular phenotypes linked to increased immune signaling. Here, by heterologously expressing the esx-1 region of Mycobacterium marinum in BCG, we engineered a low-virulence, ESX-1-proficient, recombinant BCG (BCG::ESX-1 Mmar ) that induces the cGas/STING/TBK1/IRF-3/type I interferon axis and enhances AIM2 and NLRP3 inflammasome activity, resulting in both higher proportions of CD8 + T cell effectors against mycobacterial antigens shared with BCG and polyfunctional CD4 + Th1 cells specific to ESX-1 antigens. Importantly, independent mouse vaccination models show that BCG::ESX-1 Mmar confers superior protection relative to parental BCG against challenges with highly virulent M. tuberculosis. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  20. Neonatal BCG has no effect on allergic sensitization and suspected food allergy until 13 months.

    Science.gov (United States)

    Thøstesen, Lisbeth Marianne; Kjaer, Henrik Fomsgaard; Pihl, Gitte Thybo; Nissen, Thomas Nørrelykke; Birk, Nina Marie; Kjaergaard, Jesper; Jensen, Aksel Karl Georg; Aaby, Peter; Olesen, Annette Wind; Stensballe, Lone Graff; Jeppesen, Dorthe Lisbeth; Benn, Christine Stabell; Kofoed, Poul-Erik

    2017-09-01

    Vaccination with Bacillus Calmette-Guérin (BCG) is used in many countries as protection against tuberculosis. Studies have suggested that BCG may also have non-specific effects, reducing non-tuberculosis mortality, morbidity, and atopic manifestations. In this study, we evaluated the effect of neonatal BCG vaccination on allergic sensitization and suspected food allergy at 13 months of age. The Danish Calmette Study was conducted from 2012 to 2015 at three Danish hospitals. Within 7 days of birth, the 4262 newborns of 4184 included mothers were randomized 1:1 to BCG or to a no-intervention control group. Exclusion criteria were gestational age BCG group and 6.1% (126/2061) of the control group suspected food allergy, resulting in a risk ratio comparing BCG-vaccinated children with control children of 0.91 (95% CI 0.71-1.16). Among 1370 blood samples, sensitization (Phadiatop Infant >0.35 kUA/L) was found in 55 of 743 (7.4%) children in the BCG group and 50 of 627 (8.0%) of the control group (risk ratio 0.94 [0.65-1.36]). In this randomized clinical trial, neonatal BCG had no significant effect on suspected food allergy or on sensitization at 13 months of age. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

  1. Murine Splenic Natural Killer Cells Do Not Develop Immunological Memory after Re-Encounter with Mycobacterium bovis BCG

    Science.gov (United States)

    Kawahara, Mamoru; Hasegawa, Nozomi; Takaku, Hiroshi

    2016-01-01

    Several lines of evidence have recently suggested that natural killer (NK) cells develop immunological memory against viral infections. However, there is no apparent evidence that NK cells acquire specific memory against Mycobacterium bovis bacillus Calmette—Guérin (BCG), the only currently licensed vaccine for preventing tuberculosis. In the present study, we investigated whether murine splenic NK cells can be activated by BCG in a dendritic cell (DC)-independent or -dependent manner, and furthermore examined whether these NK cells acquire specific memory following BCG vaccination. NK cells isolated from spleens of BCG-immunized mice produced interferon (IFN)γ through direct BCG stimulation in the absence of antigen-presenting cells; however, NK cells from control animals similarly directly responded to BCG, and the response level was not statistically significant between the immunized and the naïve NK cells. When purified NK cells that had been exposed to BCG were cocultured with RAW murine macrophages infected with BCG, the antibacterial activity of the macrophages was strongly enhanced; however, its level was similar to that by naïve NK cells, which had not been exposed to BCG. When splenocytes harvested from BCG-immunized mice were stimulated with purified protein derivative (PPD) derived from Mycobacterium tuberculosis, a specific IFNγ response was clearly observed, mainly attributed to NK cells and memory CD4+ T cells. To investigate whether these NK cells as well as the T cells are activated by cell−cell interaction with DCs presenting mycobacterial antigens, NK cells isolated from BCG-immunized mice were cocultured with splenocytes harvested from naïve mice in the presence of PPD stimulation. However, no IFNγ response was found in the NK cells. These results suggest that murine splenic NK cells do not develop BCG-specific immunological memory in either a DC-independent or -dependent manner. PMID:26999357

  2. Rapid Protective Effects of Early BCG on Neonatal Mortality Among Low Birth Weight Boys: Observations From Randomized Trials

    DEFF Research Database (Denmark)

    Biering-Sorensen, Sofie; Jensen, Kristoffer Jarlov; Monterio, Ivan

    2018-01-01

    Background. Three randomized trials (RCTs) in low-weight (....46–1.54]), but a significant reduction in weeks 2–4 (MRR = 0.56 [0.31–1.00]). This was consistent in all 3 trials. Verbal autopsies linked early benefit to fewer sepsis-related deaths among BCG-vaccinated boys. Discussion. The marked reduction in mortality in the days after BCG vaccination in boys emphasizes the importance...... of providing BCG soon after birth. Trial registration numbers: ClinicalTrials.gov (NCT00146302) and ClinicalTrials.gov (NCT00625482)....

  3. The value of counting BCG scars for interpretation of tuberculin skin tests in a tuberculosis hyperendemic shanty-town, Peru

    Science.gov (United States)

    Saito, M.; Bautista, C. T.; Gilman, R. H.; Bowering, A.; Levy, M. Z.; Evans, C. A.

    2010-01-01

    SUMMARY SETTING The tuberculin skin test (TST) is widely used as a diagnostic or screening test for Mycobacterium tuberculosis infection and disease. A peri-urban shanty-town in the desert hills of south Lima, Peru, highly endemic for tuberculosis, and where bacille Calmette-Guérin (BCG) vaccine had been given in multiple doses until 1995. OBJECTIVE To analyze the effect of multiple BCG vaccines on TST in a community-based setting. DESIGN Point-prevalence survey of TST reactions of 572 people aged 6–26 years from 255 households. TST reactions were compared to the observed number of BCG scars and other potential risk factors (age, living with a TST-positive person, and contact with active tuberculosis). RESULT People with two or more scars had significantly larger reactions, even after adjusting for potential risk factors. The adjusted population attributable fraction of being TST-positive and having two or more BCG scars was 26%. CONCLUSION There is no demonstrated benefit of repeat BCG vaccination. We therefore recommend that physicians take into consideration the number of BCG scars when interpreting the TST and that programs give no more than one BCG vaccination. PMID:15260275

  4. Factors determining whether the parents accept BCG immunization of the new-born child in a high-income country

    DEFF Research Database (Denmark)

    Thybo Pihl, Gitte; Ammentorp, Jette; Kofoed, Poul-Erik

    Introduction: A large prospective randomised clinical trial in Denmark is planned to test the hypothesis that compared to non-BCG-vaccinated infants, infants who are BCG vaccinated at birth experience less hospitalisations, use less antibiotics, and develop less atopic disease in early childhood.......' Connors 'Decisional Conflict scale' to compare decisional conflicts for the parents that accept BCG vaccination and parents who do not accept the BCG vaccination of their newborn child.......Introduction: A large prospective randomised clinical trial in Denmark is planned to test the hypothesis that compared to non-BCG-vaccinated infants, infants who are BCG vaccinated at birth experience less hospitalisations, use less antibiotics, and develop less atopic disease in early childhood....... My focus for this project is decision making. Method: During the next year all parents planning to give birth at Kolding Hospital will be offered inclusion in the study . In the 2nd/3rd trimester they will receive a letter with information on the study and afterward the local Ph...

  5. The BCGΔBCG1419c strain, which produces more pellicle in vitro, improves control of chronic tuberculosis in vivo.

    Science.gov (United States)

    Pedroza-Roldán, César; Guapillo, Carolina; Barrios-Payán, Jorge; Mata-Espinosa, Dulce; Aceves-Sánchez, Michel de Jesús; Marquina-Castillo, Brenda; Hernández-Pando, Rogelio; Flores-Valdez, Mario Alberto

    2016-09-14

    Mycobacterium tuberculosis (Mtb) has been a threat to humans since ancient times, and it is the main causative agent of tuberculosis (TB). Until today, the only licensed vaccine against Mtb is the live attenuated M. bovis Bacillus Calmette-Guérin (BCG), which has variable levels of protection against the pulmonary form of infection. The quest for a new vaccine is a priority given the rise of multidrug-resistant Mtb around the world, as well as the tremendous burden imposed by latent TB. The objective of this study was to evaluate the immunogenicity and capacity of protection of a modified BCG strain (BCGΔBCG1419c) lacking the c-di-GMP phosphodiesterase gene BCG1419c, in diverse mice models. In a previous report, we have shown that BCGΔBCG1419c was capable of increasing biofilm production and after intravenous infection of immunocompetent mice; this strain persisted longer in lungs than parental BCG Pasteur. This led us to hypothesize that BCGΔBCG1419c might therefore possess some advantage as vaccine candidate. Our results in this report indicate that compared to conventional BCG, vaccination with BCGΔBCG1419c induced a better activation of specific T-lymphocytes population, was equally effective in preventing weight loss despite being used at lower dose, reduced tissue damage (pneumonic scores), increased local IFNγ(+) T cells, and diminished bacterial burden in lungs of BALB/c mice infected intratracheally with high dose Mtb H37Rv to induce progressive TB. Moreover, vaccination with BCGΔBCG1419c improved resistance to reactivation after immunosuppression induced by corticosterone in a murine model of chronic infection similar to latent TB. Furthermore, despite showing increased persistence in immunocompetent mice, BCGΔBCG1419c was as attenuated as parental BCG in nude mice. To our knowledge, this is the first demonstration that a modified BCG vaccine candidate with increased pellicle/biofilm production has the capacity to protect against Mtb challenge in

  6. Heterologous boosting with recombinant VSV-846 in BCG-primed mice confers improved protection against Mycobacterium infection.

    Science.gov (United States)

    Zhang, Ming; Dong, Chunsheng; Xiong, Sidong

    2017-04-03

    Tuberculosis (TB) remains a major health problem worldwide, and the development of effective vaccines is urgently needed. Vaccination strategies based on heterologous prime-boost protocols using Mycobacterium bovis bacillus Calmette-Guérin (BCG) as primer and modified vaccinia virus Ankara strain expressing the mycobacterial antigen Ag85A (MVA85A) as booster may increase the protective efficacy of BCG. In addition, vaccination with the recombinant viral vaccine vesicular stomatitis virus (VSV)-846 (Rv3615c, Mtb10.4, and Rv2660c) can elicit a remarkable T-cell-mediated immune response and provide an effective long-term protection after the BCG challenge. In this study, we used VSV-846 to boost BCG and evaluated its immunogenicity in BALB/c mice. In this prime-boost approach, boosting with VSV-846 significantly enhanced IFN-γ CD4 T cell responses, which are crucial for anti-TB immune responses. Moreover, VSV-846 boosting significantly reduced pathology compared with mock vaccination, and decreased the bacterial loads in lung tissues compared with BCG or VSV-846 vaccination alone. The analysis of vaccine-induced immunity identified that polyfunctional T cells might contribute to the enhanced protection by VSV-846 boosting. This study proved that viral booster VSV-846 in mice improved the protection against mycobacteria infection, which could be helpful in designing an efficient vaccination strategy against TB in humans.

  7. Evaluation of immunogenicity and protective efficacy elicited by Mycobacterium bovis BCG overexpressing Ag85A protein against Mycobacterium tuberculosis aerosol infection

    Directory of Open Access Journals (Sweden)

    Zheng Zhong Xu

    2016-01-01

    Full Text Available Mycobacterium bovis bacillus Calmette-Guérin (BCG is currently the only vaccine available against tuberculosis (TB, however, it has various levels of efficacy for preventing pulmonary TB. In this study, a recombinant BCG (rBCG::Ag85A strain overexpressing the immunodominant Ag85A antigen was constructed, and its immunogenicity and protective efficacy were evaluated. The results showed that the Ag85A protein was successfully overexpressed in rBCG::Ag85A, the Ag85A peptide–MHC complexes on draining lymph node dendritic cells of C57BL/6 mice infected with rBCG were detectable 4 h post-infection. The C57BL/6 mice infected with this strain had stronger antigen-specific interferon-gamma (IFN-γ responses and higher antibody titers than those immunized with BCG, and the protective experiments showed that the rBCG::Ag85A can provide higher but not significantly protective efficacy against Mycobacterium tuberculosis (M. tuberculosis H37Rv infection compared with BCG vaccine. Therefore, our results demonstrated the potential of rBCG::Ag85A as a vaccine candidate against TB.

  8. Rapid protective effects of early BCG on neonatal mortality among low birth weight boys

    DEFF Research Database (Denmark)

    Biering-Sørensen, Sofie; Jensen, Kristoffer Jarlov; Monterio, Ivan

    2018-01-01

    .85 (0.46-1.54)), but a significant reduction in weeks 2-4 (MRR=0.56 (0.31-1.00)). This pattern was consistent in all three trials. The verbal autopsies linked the early benefit to fewer sepsis-related deaths among BCG-vaccinated boys. Discussion: The marked reduction in mortality in the first few days......Background: Three randomised trials (RCTs) in low-weight (LW, vaccine non-specifically reduces all-cause mortality in the neonatal period. Methods: Using data from three RCTs of early BCG (N=6,583) we examined potential sex......-differences in the timing of the mortality reduction in the neonatal period, presenting meta-estimates of the main outcome mortality rate ratios (MRR) for BCG-vaccinated and controls. Results: Among controls, boys had a particularly high mortality during the first week after randomisation, the male-female MRR being 2...

  9. Active Mycobacterium Infection Due to Intramuscular BCG Administration Following Multi-Steps Medication Errors

    Directory of Open Access Journals (Sweden)

    MohammadReza Rafati

    2015-10-01

    Full Text Available Bacillus Calmette-Guérin (BCG is indicated for treatment of primary or relapsing flat urothelial cell carcinoma in situ (CIS of the urinary bladder. Disseminated infectious complications occasionally occur due to BCG as a vaccine and intravesical therapy.  Intramuscular (IM or Intravenous (IV administrations of BCG are rare medication errors which are more probable to produce systemic infections. This report presents 13 years old case that several steps medication errors occurred consequently from physician handwriting, pharmacy dispensing, nursing administration and patient family. The physician wrote βHCG instead of HCG in the prescription. βHCG was read as BCG by the pharmacy staff and 6 vials of intravesical BCG were administered IM twice a week for 3 consecutive weeks. The patient experienced fever and chills after each injection, but he was admitted 2 months after first IM administration of BCG with fever and pancytopenia. Unfortunately four month after using drug, during second admission duo to cellulitis at the sites of BCG injection the physicians diagnosed the medication error. Using handwritten prescription and inappropriate abbreviations, spending inadequate time for taking a brief medical history in pharmacy, lack of verifying name, dose and wrote before medication administration and lack of considering medication error as an important differential diagnosis had roles to occur this multi-steps medication error.

  10. BCG-associated heterologous immunity, a historical perspective: experimental models and immunological mechanisms.

    Science.gov (United States)

    Freyne, Bridget; Marchant, Arnaud; Curtis, Nigel

    2015-01-01

    Randomized controlled trials indicate that bacille Calmette-Guerin (BCG) has beneficial heterologous ('non-specific') effects on mortality in high mortality settings. These findings have stimulated interest in understanding the immunological mechanisms underlying these effects in the hope of harnessing them to reduce all-cause mortality. This line of investigation is especially important in light of BCG being discontinued in some countries as the prevalence of TB falls. Stopping routine BCG in this situation may have the unintended consequence of depriving children of the beneficial immune modulating effects of this vaccine. BCG has been recognized as a potent immunomodulator for decades. This review details experimental studies involving BCG and any heterologous antigen that aimed to interrogate potential immunological mechanisms. To provide a historical perspective, the evidence is presented chronologically. The lines of immunological enquiry can be seen to mirror the evolution of our understanding of cell-mediated immunity and its components. As new clinical trials to investigate the heterologous effects of BCG are undertaken, an understanding of the history of BCG-induced immunity against heterologous antigens may provide information on immunological pathways worthy of further interrogation using modern immunological methods. © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  11. Tuberculin-purified protein derivative-, MPT-64-, and ESAT-6-stimulated gamma interferon responses in medical students before and after Mycobacterium bovis BCG vaccination and in patients with tuberculosis

    DEFF Research Database (Denmark)

    Johnson, P D; Stuart, R L; Grayson, M L

    1999-01-01

    of QIFN in medical students before and after BCG immunization was assessed, and sensitivity in patients with tuberculosis was assessed. Antigens were PPD derived from M. tuberculosis and two M. tuberculosis-specific proteins, ESAT-6 and MPT-64. Of 60 medical students, all of whom had 0-mm tuberculin skin......-gamma responses in the medical students were negative prior to and after BCG immunization. For patients with active tuberculosis, 12 of 19 (63%) were positive by PPD QIFN, 11 of 19 (58%) were positive by ESAT-6 QIFN, and 0 of 12 were positive by MPT-64 QIFN. In conclusion, PPD QIFN was negative in 97% of a low...

  12. Loss of BCG Viability Adversely Affects the Direct Response of Urothelial Carcinoma Cells to BCG Exposure

    Science.gov (United States)

    Shah, Gopitkumar; Zhang, Guangjian; Chen, Fanghong; Cao, YanLi; Kalyanaraman, Balaraman; See, William

    2018-01-01

    INTRODUCTION The attenuated mycobacterium Bacille Calmette Guerin (BCG) is widely utilized as intravesical “immunotherapy” for the treatment of non-muscle invasive urothelial carcinoma. Previous studies have demonstrated that in both the laboratory and clinical setting, BCG viability is a variable that correlates with anti-tumor efficacy. This study evaluated how loss of BCG viability impacted a number of molecular and phenotypic intermediate endpoints that characterize, and/or contribute to, the direct effect of BCG on Urothelial carcinoma (UC) cells. MATERIALS AND METHODS Two human UC cell lines were used to study the effect of loss of BCG viability on the tumor cell response to BCG. The cellular response to BCG rendered non-viable by heat killing (hk) was compared to the response to viable BCG. The response endpoints evaluated included the induction of oxidative stress, activation of intracellular signaling pathways, gene transactivation, and phenotypic changes. RESULTS Loss of viability resulted in a quantitative decrease in the tumor cell response, relative to viable BCG, for all of the measured endpoints. The decrease in response varied by cell line, ranging from 15% to 100% of the response to viable BCG. While quantitatively different, non-viable BCG continued to induce responses that were qualitatively similar to BCG relative to untreated controls. CONCLUSIONS BCG viability is an important variable influencing the direct tumor cell response to BCG. Although the magnitude of it effects are attenuated, hkBCG remains active for the induction of BCG responsive biologic endpoints. PMID:24035882

  13. Systemic BCG-osis following intravesical BCG instillation for bladder carcinoma.

    Science.gov (United States)

    Liaw, Frank; Tan, Yan Yu; Hendry, David

    2017-10-01

    Intravesical instillation of Bacillus Calmette-Guérin (BCG) has been shown to be an effective form of immunotherapy for bladder cancer. This case report describes a patient who develops systemic BCG-osis following intravesical BCG instillation and demonstrates the importance of being aware of more severe complications associated with BCG immunotherapy.

  14. Boosting BCG with inert spores improves immunogenicity and induces specific IL-17 responses in a murine model of bovine tuberculosis.

    Science.gov (United States)

    Garcia-Pelayo, M Carmen; Kaveh, Daryan A; Sibly, Laura; Webb, Paul R; Bull, Naomi C; Cutting, Simon M; Hogarth, Philip J

    2016-05-01

    Tuberculosis (TB) remains a global pandemic, in both animals and man, and novel vaccines are urgently required. Heterologous prime-boost of BCG represents a promising strategy for improved TB vaccines, with respiratory delivery the most efficacious to date. Such an approach may be an ideal vaccination strategy against bovine TB (bTB), but respiratory vaccination presents a technical challenge in cattle. Inert bacterial spores represent an attractive vaccine vehicle. Therefore we evaluated whether parenterally administered spores are efficacious when used as a BCG boost in a murine model of immunity against Mycobacterium bovis. Here we report the use of heat-killed, TB10.4 adsorbed, Bacillus subtilis spores delivered via subcutaneous injection to boost immunity primed by BCG. We demonstrate that this approach improves the immunogenicity of BCG. Interestingly, this associated with substantial boosting of IL-17 responses; considered to be important in protective immunity against TB. These data demonstrate that parenteral delivery of spores represents a promising vaccine vehicle for boosting BCG, and identifies potential for optimisation for use as a vaccine for bovine TB. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

  15. Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau

    DEFF Research Database (Denmark)

    Roth, A.E.; Benn, Christine Stabell; Ravn, H.

    2010-01-01

    Objective To determine whether BCG revaccination at 19 months of age reduces overall child mortality. Design Randomised trial, with follow-up to age 5. Setting A health project in Bissau, Guinea-Bissau, which maintains a health and demographic surveillance system in an urban area with 90 000...... ratio 0.36, 0.13 to 0.99) and children who had not received the booster before enrolment (1.78, 1.04 to 3.04). Conclusions There was no overall beneficial effect of being revaccinated with BCG. The effect of BCG revaccination on mortality might depend on other health interventions...... children compared with controls was 2.69 (1.05 to 6.88) in the period after these campaigns. Throughout the trial, the effect of BCG revaccination on mortality was significantly different (P=0.006) in children who had received diphtheria-tetanus-pertussis (DTP) booster vaccination before enrolment (hazard...

  16. Extraction and localization by electron microscopy of an immunosuppressor fraction from Mycobacterium bovis Bacillus Calmette-Guérin (BCG).

    Science.gov (United States)

    Hiu, I J

    1990-03-01

    BCG has been used all over the world to immunize against tuberculosis. Nevertheless in certain areas (South India) BCG vaccines failed to show any protective efficacy. Furthermore immunosuppressive cell populations have been reported in experimental mycobacterial infection in mice. The present work reports the localization and isolation of an immunosuppressor fraction from BCG. This lipid fraction called WDB inhibited the skin reactivity of delayed-type hypersensitivity (DTH) to the test antigen CEWA (crystalline egg white albumin) in guinea pigs and depressed the production of immune antibody to SRBC (sheep red blood cells) in mice. WDB is a glycolipid with an approximate mol.wt. of 62,000. By electron microscopy, WDB was located among the BCG extracellular metabolic products (ECMP) surrounding the BCG cell wall.

  17. Studies of monocytopoiesis in patients with malignant disease and after imunostimulation with BCG, using /sup 3/H-thymidine as a DNA-label

    Energy Technology Data Exchange (ETDEWEB)

    Schmitt, E.; Meuret, G.; Waldermann, F.; Hoffmann, G.

    1982-04-01

    Monocytopoiesis and blood monocytes were investigated in patients with Hodgkin's disease, non-Hodgkin lymphomas, mycosis fungoides, breast cancer or melanoma. The investigation was carried out before surgery and just before each application of BCG. Monocyte production was increased in untreated patients. Postoperative prophylactic BCG-vaccination gave rise to increased proliferation activity. However monocyte production returned to normal between the 4th and 6th month of BCG immunotherapy. These results indicate that monocytopoiesis is stimulated by human tumors. BCG immunostimulation is able to increase proliferation activity during the first month of treatment only.

  18. [Disseminated BCG infection revealing X-linked severe combined immunodeficiency].

    Science.gov (United States)

    Marchand, I; Mahé, E; Clérici, T; Saiag, P; Chevallier, B

    2008-01-01

    Live attenuated Bacillus Calmette-Guérin (BCG) vaccine is rarely responsible for disseminated infection. We report a case of X-linked severe combined immunodeficiency (SCID) revealed by a disseminated skin infection. A 4-month-old baby was hospitalized for prolonged gastroenteritis. He was in poor general condition, with prolonged fever, oral and gluteal candidiasis and purple nodules associated with ulceration of the BCG scar. The absence of a thymus, T-cells and NK-cells, and the presence of nonfunctional B-lymphocytes led to a diagnosis of SCID. Biopsies of nodules revealed a dermal infiltrate without necrosis. A Ziehl-Neelson stain was highly positive and the culture grew Mycobacterium bovis. Treatment consisted of a four-drug antibiotic regimen directed against M. bovis combined with gamma interferon, immunoglobulins and antibiotic prophylaxis by cotrimoxazole and was followed by a haploid-identical bone marrow transplant without rejection at six months. The early death of the child's maternal uncle from sepsis suggested X-linked transmission, which was subsequently confirmed by genetic analysis. BCG vaccination can cause serious infections in immunocompromised subjects. Skin involvement is extremely rare but may be the first sign of SCID, of which the X-linked form is the most common and corresponds to a variety of mutations in the gene coding for the gamma chain common to several interleukin receptors. Genetic counselling is essential to identify female carriers and allow early antenatal diagnosis. Bone marrow transplantation is the only treatment.

  19. Recombinant HBHA Boosting Effect on BCG-Induced Immunity against Mycobacterium tuberculosis Infection

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    G. G. Guerrero

    2011-01-01

    Full Text Available Heterologous prime-boost regimens are effective strategies to promote long-term memory and strong cellular Th1 responses to Mycobacterium tuberculosis, when BCG is used in the priming step. Subcutaneous or intranasal boosting of BCG-vaccinated newborn mice with native heparin-binding haemagglutinin (nHBHA significantly enhances protection against M. tuberculosis. However, nHBHA is characterized by a complex methylation pattern in its C-terminal domain, which is important for protective immunogenicity in primary vaccination. In this study we addressed the question whether boosting with recombinant, non-methylated HBHA (rHBHA produced in Escherichia coli may enhance protection of BCG-primed newborn mice. We found that while subcutaneous rHBHA boosting enhanced protection of BCG-primed mice against intranasal M. tuberculosis infection both in spleen and lungs, enhanced protection against aerosol infection was only seen in the spleen (0.72 logs; P<0.05 but not in the lungs. Thus, in BCG-primed mice the methylation of the C-terminal domain of HBHA is dispensable for the induction of enhanced protection in the lungs against intranasal but not aerosol infection, whereas it enhances protection in the spleen in both challenge models. This report thus provides evidence that rHBHA may be considered as a booster vaccine against disseminated tuberculosis.

  20. Enhanced and enduring protection against tuberculosis by recombinant BCG-Ag85C and its association with modulation of cytokine profile in lung.

    Directory of Open Access Journals (Sweden)

    Ruchi Jain

    Full Text Available BACKGROUND: The variable efficacy (0-80% of Mycobacterium bovis Bacille Calmette Guréin (BCG vaccine against adult tuberculosis (TB necessitates development of alternative vaccine candidates. Development of recombinant BCG (rBCG over-expressing promising immunodominant antigens of M. tuberculosis represents one of the potential approaches for the development of vaccines against TB. METHODS/PRINCIPAL FINDINGS: A recombinant strain of BCG - rBCG85C, over expressing the antigen 85C, a secretory immuno-dominant protein of M. tuberculosis, was evaluated for its protective efficacy in guinea pigs against M. tuberculosis challenge by aerosol route. Immunization with rBCG85C resulted in a substantial reduction in the lung (1.87 log(10, p<0.01 and spleen (2.36 log(10, p<0.001 bacillary load with a commensurate reduction in pathological damage, when compared to the animals immunized with the parent BCG strain at 10 weeks post-infection. rBCG85C continued to provide superior protection over BCG even when post-challenge period was prolonged to 16 weeks. The cytokine profile of pulmonary granulomas revealed that the superior protection imparted by rBCG85C was associated with the reduced levels of pro-inflammatory cytokines - interleukin (IL-12, interferon (IFN-gamma, tumor necrosis factor (TNF-alpha, moderate levels of anti-inflammatory cytokine - transforming growth factor (TGF-beta along with up-regulation of inducible nitric oxide synthase (iNOS. In addition, the rBCG85C vaccine induced modulation of the cytokine levels was found to be associated with reduced fibrosis and antigen load accompanied by the restoration of normal lung architecture. CONCLUSIONS/SIGNIFICANCE: These results clearly indicate the superiority of rBCG85C over BCG as a promising prophylactic vaccine against TB. The enduring protection observed in this study gives enough reason to postulate that if an open-ended study is carried out with low dose of infection, rBCG85C vaccine in all

  1. The Glycosylated Rv1860 Protein of Mycobacterium tuberculosis Inhibits Dendritic Cell Mediated TH1 and TH17 Polarization of T Cells and Abrogates Protective Immunity Conferred by BCG

    Science.gov (United States)

    Satchidanandam, Vijaya; Kumar, Naveen; Jumani, Rajiv S.; Challu, Vijay; Elangovan, Shobha; Khan, Naseem A.

    2014-01-01

    We previously reported interferon gamma secretion by human CD4+ and CD8+ T cells in response to recombinant E. coli-expressed Rv1860 protein of Mycobacterium tuberculosis (MTB) as well as protection of guinea pigs against a challenge with virulent MTB following prime-boost immunization with DNA vaccine and poxvirus expressing Rv1860. In contrast, a Statens Serum Institute Mycobacterium bovis BCG (BCG-SSI) recombinant expressing MTB Rv1860 (BCG-TB1860) showed loss of protective ability compared to the parent BCG strain expressing the control GFP protein (BCG-GFP). Since Rv1860 is a secreted mannosylated protein of MTB and BCG, we investigated the effect of BCG-TB1860 on innate immunity. Relative to BCG-GFP, BCG-TB1860 effected a significant near total reduction both in secretion of cytokines IL-2, IL-12p40, IL-12p70, TNF-α, IL-6 and IL-10, and up regulation of co-stimulatory molecules MHC-II, CD40, CD54, CD80 and CD86 by infected bone marrow derived dendritic cells (BMDC), while leaving secreted levels of TGF-β unchanged. These effects were mimicked by BCG-TB1860His which carried a 6-Histidine tag at the C-terminus of Rv1860, killed sonicated preparations of BCG-TB1860 and purified H37Rv-derived Rv1860 glycoprotein added to BCG-GFP, but not by E. coli-expressed recombinant Rv1860. Most importantly, BMDC exposed to BCG-TB1860 failed to polarize allogeneic as well as syngeneic T cells to secrete IFN-γ and IL-17 relative to BCG-GFP. Splenocytes from mice infected with BCG-SSI showed significantly less proliferation and secretion of IL-2, IFN-γ and IL-17, but secreted higher levels of IL-10 in response to in vitro restimulation with BCG-TB1860 compared to BCG-GFP. Spleens from mice infected with BCG-TB1860 also harboured significantly fewer DC expressing MHC-II, IL-12, IL-2 and TNF-α compared to mice infected with BCG-GFP. Glycoproteins of MTB, through their deleterious effects on DC may thus contribute to suppress the generation of a TH1- and TH17-dominated

  2. Neonatal BCG has no effect on allergic sensitization and suspected food allergy until 13 months

    DEFF Research Database (Denmark)

    Thøstesen, Lisbeth Marianne; Kjaer, Henrik Fomsgaard; Pihl, Gitte Thybo

    2017-01-01

    the effect of neonatal BCG vaccination on allergic sensitization and suspected food allergy at 13 months of age. METHODS: The Danish Calmette Study was conducted from 2012 to 2015 at three Danish hospitals. Within 7 days of birth, the 4262 newborns of 4184 included mothers were randomized 1:1 to BCG...... sampling at 13 months of age. RESULTS: By 13 months of age, the parents and/or general practitioners of 5.6% (117/2089) of the children in the BCG group and 6.1% (126/2061) of the control group suspected food allergy, resulting in a risk ratio comparing BCG-vaccinated children with control children of 0...... effect on suspected food allergy or on sensitization at 13 months of age....

  3. BCG (Bacille Calmette-Guerin) Vaccine

    Science.gov (United States)

    ... Studies Consortium Research Projects Publications TB Trials Consortium Study Descriptions Background Behavioral & Social Science Research Infection Control TB in Specific Populations African-American Community Stop TB in the African-American ...

  4. Vacuna contra la tuberculosis BCG: Eficacia y efectos adversos

    Directory of Open Access Journals (Sweden)

    Quezada-Andrade, Steven

    2015-12-01

    Full Text Available TB is the second leading cause of death from an infectious agent, disease caused by Mycobacterium tuberculosis. It allowed the creation of a vaccine officially launched in 1924 and known as Bacillus Calmette-Guerin (BCG used since then. However, there has been extensive research on its effectiveness and other related factors have shown an imbalance. Several countries recommend the use of this vaccine in infants, but in the case of Ecuador has failed to suggest its application, although there are no data regarding the efficacy of the vaccine in that country. Other studies show that the knowledge of people about the disease is destitute, thus allowing this could spread more quickly because the infected person does not know the type of symptoms that generates Tuberculosis. This article aims to identify the current status of the efficiency and safety of BCG through review and analysis of collected items related to the use of the vaccine and its effectiveness in the research population.

  5. Tuberculin-purified protein derivative-, MPT-64-, and ESAT-6-stimulated gamma interferon responses in medical students before and after Mycobacterium bovis BCG vaccination and in patients with tuberculosis

    DEFF Research Database (Denmark)

    Johnson, P D; Stuart, R L; Grayson, M L

    1999-01-01

    -gamma responses in the medical students were negative prior to and after BCG immunization. For patients with active tuberculosis, 12 of 19 (63%) were positive by PPD QIFN, 11 of 19 (58%) were positive by ESAT-6 QIFN, and 0 of 12 were positive by MPT-64 QIFN. In conclusion, PPD QIFN was negative in 97% of a low...... of QIFN in medical students before and after BCG immunization was assessed, and sensitivity in patients with tuberculosis was assessed. Antigens were PPD derived from M. tuberculosis and two M. tuberculosis-specific proteins, ESAT-6 and MPT-64. Of 60 medical students, all of whom had 0-mm tuberculin skin...... tests (TSTs) at study entry, 58 (97%) were initially classified as negative for M. tuberculosis infection by PPD QIFN. Five months after BCG immunization, 7 of 54 students (13%) had a TST result of >/=10 mm and 11 of 54 students (20%) tested positive by PPD QIFN. ESAT-6- and MPT-64-stimulated IFN...

  6. Vaccines and multiple sclerosis

    DEFF Research Database (Denmark)

    Mailand, Mia Topsøe; Frederiksen, Jette Lautrup

    2017-01-01

    on the database PubMed. The study found no change in risk of developing multiple sclerosis (MS) after vaccination against hepatitis B virus, human papillomavirus, seasonal influenza, measles-mumps-rubella, variola, tetanus, Bacillus Calmette-Guérin (BCG), polio, or diphtheria. No change in risk of relapse...... was found for influenza. Further research is needed for the potential therapeutic use of the BCG vaccine in patients in risk of developing MS and for the preventive potential of the tetanus and diphtheria vaccine....

  7. Deletion of BCG Hip1 protease enhances dendritic cell and CD4 T cell responses.

    Science.gov (United States)

    Bizzell, Erica; Sia, Jonathan Kevin; Quezada, Melanie; Enriquez, Ana; Georgieva, Maria; Rengarajan, Jyothi

    2017-12-28

    Dendritic cells (DCs) play a key role in the generation of CD4 T cell responses to pathogens. Mycobacterium tuberculosis (Mtb) harbors immune evasion mechanisms that impair DC responses and prevent optimal CD4 T cell immunity. The vaccine strain Mycobacterium bovis Bacille Calmette-Guérin (BCG) shares many of the immune evasion proteins utilized by Mtb, but the role of these proteins in DC and T cell responses elicited by BCG is poorly understood. We previously reported that the Mtb serine protease, Hip1, promotes sub-optimal DC responses during infection. Here, we tested the hypothesis that BCG Hip1 modulates DC functions and prevents optimal antigen-specific CD4 T cell responses that limit the immunogenicity of BCG. We generated a strain of BCG lacking hip1 (BCGΔhip1) and show that it has superior capacity to induce DC maturation and cytokine production compared with the parental BCG. Furthermore, BCGΔhip1-infected DCs were more effective at driving the production of IFN-γ and IL-17 from antigen-specific CD4 T cells in vitro. Mucosal transfer of BCGΔhip1-infected DCs into mouse lungs induced robust CD4 T cell activation in vivo and generated antigen-specific polyfunctional CD4 T cell responses in the lungs. Importantly, BCGΔhip1-infected DCs enhanced control of pulmonary bacterial burden following Mtb aerosol challenge compared with the transfer of BCG-infected DCs. These results reveal that BCG employs Hip1 to impair DC activation, leading to attenuated lung CD4 T cell responses with limited capacity to control Mtb burden after challenge. ©2017 Society for Leukocyte Biology.

  8. Review: New Vaccine Against Tuberculosis: Current Developments and Future Challenges

    Science.gov (United States)

    Liu, Jun

    2009-04-01

    Tuberculosis (TB) continues to be a global health threat. BCG was developed as an attenuated live vaccine for tuberculosis control nearly a century ago. Despite being the most widely used vaccine in human history, BCG is not an ideal vaccine and has two major limitations: its poor efficacy against adult pulmonary TB and its disconcerting safety in immunocompromised individuals. A safer and more effective TB vaccine is urgently needed. This review article discusses current strategies to develop the next generation of TB vaccines to replace BCG. While some progresses have been made in the past decade, significant challenges lie ahead.

  9. Clinical features and outcome of eleven patients with disseminated Bacille Calmette-Guerin (BCG) infection

    International Nuclear Information System (INIS)

    Al-Arishi, Haider M.; Frayha, Husn H.; Qari, Hussni Y.; Al-Rayes, H.; Tufenkeji, Haysam T.; Harfi, H.

    1996-01-01

    Disseminated BCG infection is a very rare complication of BCG vaccination. This study presents 11 patients with such complication. The underlying disease in eight of the 11 patients was primary immunodeficiency. Seven of these had severe combined immune deficiency (SCID) and one had isolated T-cell defect. Of the three remaining patients, one was healthy, one was diagnosed with mucocutaneous candidiasis and the third was diagnosed with leukocytoclastic vasculitis. Cutaneous nodular lesion, persistent fever, hepatosplenomegaly and pulmonary symptoms were common presenting features. All but one patient received antituberculous treatment. Four of 11 patients died because of extensive BCG disease. Three of these had SCID and one had T-cell deficiency. Patients with SCID who survived had bone marrow transplantation in addition to antituberculous chemotherapy. We conclude that a family history of immunodeficiency should be sought and if suggestive, BCG vaccine should be deferred until the immune status of the baby is clarified. In addition, early diagnosis is important for successful outcome. Bone marrow transplant on an emergency basis is the treatment of choice in patients with SCID and disseminated BCG infection, as immune reconstitution is essential to control infection in these patients. (author)

  10. Expression of Cathepsin S in BCG converts it into a pro-apoptotic and highly immunogenic strain.

    Science.gov (United States)

    Lau, Alice; Singh, Vijender; Soualhine, Hafid; Hmama, Zakaria

    2017-04-11

    BCG vaccine, introduced almost 100years ago, is the only option to prevent TB disease. It effectively protects newborns from meningeal TB but fails to prevent adult pulmonary TB. TB kills 1.3million people annually in areas where BCG vaccination is widely practiced. Thus, more effective TB vaccines are urgently needed. Others and we have shown that BCG mimics features of virulent M. tuberculosis, in particular attenuation of essential macrophage functions such as phagosome maturation and antigen presentation. One of these studies revealed that defect in antigen presentation is largely due to down-regulation of the cysteine protease Cathepsin S (CatS), which prevents MHC II molecule maturation and proper antigen peptide loading. Recent studies also suggested a potential role for cysteine proteases in the regulation of apoptosis, a key cellular process used by the macrophage to (i) contain and process ingested bacteria and (ii) facilitate cross-talk antigen presentation between the macrophage and dendritic cells. To reverse the phenotype of vaccine-mediated macrophage attenuation, we engineered a novel BCG strain that expresses and secretes active CatS (rBCG-CatS) to examine its pro-apoptotic properties in vitro, and subsequently, immunogenicity in mice. Transcriptomic profiling of macrophages infected with rBCG-CatS, but not BCG, revealed upregulation of key pro-apoptotic genes and downregulation of anti-apoptotic genes, which were further confirmed by RT-qPCR analyses of expression of selected genes. Macrophages infected with rBCG-CatS undergo apoptosis as indicated by increased levels of annexin V staining and intracellular caspase-3 cleavage. Consistent with these findings, mice vaccinated with rBCG-CatS showed increased antigen-specific CD4 + T-cell responses, as well as enhanced cytokine production and proliferation in CD4 + upon ex vivo re-stimulation. Collectively, this study shows that a pro-apoptotic BCG strain alleviates adverse traits of the wild

  11. Development of BCG Scar and Subsequent Morbidity and Mortality in Rural Guinea-Bissau.

    Science.gov (United States)

    Storgaard, Line; Rodrigues, Amabelia; Martins, Cesario; Nielsen, Bibi Uhre; Ravn, Henrik; Benn, Christine Stabell; Aaby, Peter; Fisker, Ane Bærent

    2015-09-15

    Previous studies have found that BCG vaccination has nonspecific beneficial effects on child survival, especially among children who developed a BCG scar. These studies have mostly been done in settings with a high scar frequency. In rural Guinea-Bissau, many children do not develop a scar; we tested the hypothesis that among BCG-vaccinated children, a vaccination scar was associated with lower mortality and fewer hospital admissions. During 2009-2011, children Health Project's demographic surveillance system had their scar status assessed at semiannual visits. We compared mortality and hospital admission rates of scar-positive and scar-negative BCG-vaccinated children during 6 months of follow-up in Cox proportional hazards models. Among 15 911 BCG-vaccinated children, only 52% had a scar. There were 106 non-injury-related deaths among scar-positive children and 137 among scar-negative children. The mortality rate ratio (MRR) was 0.74 (95% confidence interval [CI], .56-.96) overall; 0.48 (95% CI, .26-.90) in infancy, 0.69 (95% CI, .45-1.05) in the second year of life, and 0.89 (95% CI, .61-1.31) in the third-fifth year of life. The association between scar positivity and lower mortality differed significantly by cause of death and was strongest for respiratory infections (MRR, 0.20 [95% CI, .07-.55]). There were 99 hospital admissions among scar-positive children and 125 admissions among scar-negative children, resulting in an incidence rate ratio of 0.74 (95% CI, .60-.92). Among BCG-vaccinated children in a setting with low scar prevalence, having a scar is associated with lower mortality and morbidity. BCG scar prevalence may be an important marker of vaccination program quality. © The Author 2015. 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.

  12. Rational design of diagnostic and vaccination strategies for tuberculosis

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    Sibele Borsuk

    Full Text Available The development of diagnostic tests which can readily differentiate between vaccinated and tuberculosis-infected individuals is crucial for the wider utilization of bacillus Calmette-Guérin (BCG as vaccine in humans and animals. BCG_0092 is an antigen that elicits specific delayed type hypersensitivity reactions similar in size and morphological aspects to that elicited by purified protein derivative, in both animals and humans infected with the tubercle bacilli. We carried out bioinformatics analyses of the BCG_0092 and designed a diagnostic test by using the predicted MHC class I epitopes. In addition, we performed a knockout of this gene by homologous recombination in the BCG vaccine strain to allow differentiation of vaccinated from infected individuals. For that, the flanking sequences of the target gene (BCG_0092were cloned into a suicide vector. Spontaneous double crossovers, which result in wild type revertants or knockouts were selected using SacB. BCG_0092 is present only in members of the Mycobacterium tuberculosis complex. Eight predicted MHC class I epitopes with potential for immunological diagnosis were defined, allowing the design of a specific diagnostic test. The strategy used to delete the (BCG_0092 gene from BCG was successful. The knockout genotype was confirmed by PCR and by Southern blot. The mutant BCG strain has the potential of inducing protection against tuberculosis without interfering with the diagnostic test based on the use of selected epitopes from BCG_0092.

  13. Vaccination against tuberculosis.

    Science.gov (United States)

    Martin, Carlos; Aguilo, Nacho; Gonzalo-Asensio, Jesús

    2018-04-04

    BCG (Bacille Calmette-Guérin) vaccination is included in the immunization schedule for tuberculosis endemic countries with a global coverage at birth close to 90% worldwide. BCG was attenuated from Mycobacterium bovis almost a century ago, and provides a strong protection against disseminated forms of the disease, though very limited against pulmonary forms of tuberculosis, responsible for transmission. Novel prophylactic tuberculosis vaccines are in clinical development either to replace BCG or to improve its protection against respiratory forms of the disease. There are limitations understanding the immunological responses involved and the precise type of long-lived immunity that new vaccines need to induce. MTBVAC is the first and only tuberculosis vaccine candidate based on live-attenuated Mycobacterium tuberculosis in clinical evaluation. MTBVAC clinical development plans to target tuberculosis prevention in newborns, as a BCG replacement strategy, and as secondary objective to be tested in adolescents and adults previous vaccinated with BCG. Copyright © 2018 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  14. Mitsuda's reactions: induced by BCG in the normal Rhesus ("Macacca mulatta"

    Directory of Open Access Journals (Sweden)

    M. J. Pereira Filho

    1955-12-01

    Full Text Available The reversals of Mitsuda's reactions induced by BCG have been objected to based on the possiblem interference of other determination causes of the phenomenon: tuberculous primo-infections, communicants of unsuspected leprosy, revearsals due to other causes, such as anti-diphteric and anti-tetanic vaccination, etc. In order to study the problem, we have used Rhesus monkeys (Macaca mulatta, which were reared in isolation, in an attempt to avoid the referred to interferences. Prior to the experiments, all animals were tested and found negative to radiograph, tuberculin and lepromin tests and were then submitted to the application of BCG vaccine (from 1 to 3 days old, in different doses and by different via. At different times, after the application of BCG, they were again submitted to the radiographic, tuberculin and lepromin tests. In the tables I to IV the experiences were summarised. From the experiments, the following conclusions were reached: 1 - From 12 Rhesus that received BCG 11 showed reversals of the Mitsuda reaction (91.7%. 2 - These reverseals took place both in tests effected shortly after BCG (from 6 days to 2 months, and tests effected much later (from 7 to 12 months after BCG. 3 - Some differences were found in the results, according to the dosis and the application via of the BCG. a - The testicular and peritonela via (0,02g were the only that determined strong positive Mitsuda's reactions (+++. b - By oral via, animals that received high dosis (0.6g and 1.2 g, there resulted uniform and regular reversals, even though of low intensity (+; but from those who got small doses (0.2 g. one showed no reversals in all tests, and the other presented reversals in the 2nd and 3rd tests only, also with low positivity (+. 4 In the 2nd and 3rd Mitsuda's reactions in the same animals, positivity was always precocious (generally within 48 hours, one getting the impression that there occurs a sensibilization of the animal body by the antigen with

  15. Tuberculin reaction and BCG scar

    DEFF Research Database (Denmark)

    Timmermann, Clara Amalie Gade; Biering-Sørensen, Sofie; Aaby, Peter

    2015-01-01

    rate ratio (MRR) comparing children with a BCG scar with those without was 0.42 (95% CI = 0.19; 0.93). There was a similar tendency for TST positivity: MRR = 0.47 (95% CI = 0.14; 1.54). For LBW children who had both a positive TST reaction and a scar, the MRR was 0.22 (95% CI = 0.05; 0.87). For NBW...

  16. Evitar o efeito da vacinação BCG na detecção de infecção por Mycobacterium tuberculosis com um teste sanguíneo Avoiding the effect of BCG vaccination in detecting Mycobacterium tuberculosis infection with a blood test

    OpenAIRE

    R. Diel; M Ernst; G Doscher; L Visuri-Karbe; U Greinert; S Niemann; A Nienhaus; C Lange

    2007-01-01

    O risco de progressão da infecção por Mycobacterium tuberculosis para tuberculose-doença é sobretudo elevado nos primeiros anos após a infecção, estimando-se que 50% dos casos de tuberculose-infecção desenvolvem doença nos dois anos seguintes. A investigação precoce dos contactos baseia-se neste facto, e o teste cutâneo de tuberculina tem sido largamente utilizado como a prova de rastreio, apesar da sua limitação na população vacinada com BCG, nas reacções cruzadas com micobactérias não tuber...

  17. Positive impact of rescheduling Bacillus Calmette-Gu?rin vaccination on vaccinations at birth

    OpenAIRE

    Oberoi, Simmi; Amarjit, Singh; Avneet, Randhawa; Neha, Chaudhary; Patnaik, Siriesha

    2017-01-01

    Context: Inimitable among the trio of recommended immunizations administered to newborns at delivery centers of institutions is hepatitis B. While it is necessary for hepatitis B to be given within 24 hours of birth, the same cannot be said for Bacillus Calmette-Guérin (BCG) and zero-dose oral polio vaccine (OPV). Objective: To assess the impact of rescheduling of BCG vaccination from the current twice weekly to daily to cover newborn vaccinations at the Government Medical College, Patial...

  18. Priming with a recombinant pantothenate auxotroph of Mycobacterium bovis BCG and boosting with MVA elicits HIV-1 Gag specific CD8+ T cells.

    Directory of Open Access Journals (Sweden)

    Rosamund Chapman

    Full Text Available A safe and effective HIV vaccine is required to significantly reduce the number of people becoming infected with HIV each year. In this study wild type Mycobacterium bovis BCG Pasteur and an attenuated pantothenate auxotroph strain (BCGΔpanCD that is safe in SCID mice, have been compared as vaccine vectors for HIV-1 subtype C Gag. Genetically stable vaccines BCG[pHS400] (BCG-Gag and BCGΔpanCD[pHS400] (BCGpan-Gag were generated using the Pasteur strain of BCG, and a panothenate auxotroph of Pasteur respectively. Stability was achieved by the use of a codon optimised gag gene and deletion of the hsp60-lysA promoter-gene cassette from the episomal vector pCB119. In this vector expression of gag is driven by the mtrA promoter and the Gag protein is fused to the Mycobacterium tuberculosis 19 kDa signal sequence. Both BCG-Gag and BCGpan-Gag primed the immune system of BALB/c mice for a boost with a recombinant modified vaccinia virus Ankara expressing Gag (MVA-Gag. After the boost high frequencies of predominantly Gag-specific CD8(+ T cells were detected when BCGpan-Gag was the prime in contrast to induction of predominantly Gag-specific CD4(+ T cells when priming with BCG-Gag. The differing Gag-specific T-cell phenotype elicited by the prime-boost regimens may be related to the reduced inflammation observed with the pantothenate auxotroph strain compared to the parent strain. These features make BCGpan-Gag a more desirable HIV vaccine candidate than BCG-Gag. Although no Gag-specific cells could be detected after vaccination of BALB/c mice with either recombinant BCG vaccine alone, BCGpan-Gag protected mice against a surrogate vaccinia virus challenge.

  19. Health-Care Associated Mycobacterium bovis-BCG Infection in Cancer Patients without prior BCG Instillation.

    Science.gov (United States)

    Meije, Y; Martínez-Montauti, J; Caylà, J A; Loureiro, J; Ortega, L; Clemente, M; Sanz, X; Ricart, M; Santomà, M J; Coll, P; Sierra, M; Calsina, M; Vaqué, M; Ruiz-Camps, I; López-Sánchez, C; Montes, M; Ayestarán, A; Carratalà, J; Orcau, A

    2017-05-29

    Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, is widely used as adjunctive therapy for superficial bladder cancer. Intravesical administration of BCG has been associated with systemic infection. Disseminated infection due to M. bovis is otherwise uncommon. After identification of three patients with health-care associated BCG infection (HCBCGI) who had never received intravesical BCG administration, an epidemiologic study was performed. All patients with HCBCGI in the Barcelona tuberculosis (TB) program were reviewed from January 1, 2005 to December 31, 2015 searching for infections caused by M. bovis-BCG. Patients with HCBCGI who had not received intravesical BCG instillation were selected and the source of infection was investigated. Nine oncology patients with infection caused by M. bovis-BCG were studied. All had permanent central venous catheters. Catheter maintenance was performed at four different outpatient clinics in the same room in which other patients underwent BCG instillations for bladder cancer without required biological precautions. All patients developed pulmonary TB, either alone or with extrapulmonary disease. Catheter-related infection was considered the mechanism of acquisition based on the epidemiologic association and positive catheter cultures for BCG in patients in whom mycobacterial cultures were performed. Physicians should be alerted to the possibility of TB due to nosocomially acquired, catheter-related infections with M. bovis-BCG in patients with indwelling catheters. This problem may be more common than expected in centers providing BCG therapy for bladder cancer without adequate precautions.

  20. Bacillus Calmette-Guérin vaccination at birth and in vitro cytokine responses to non-specific stimulation

    DEFF Research Database (Denmark)

    Nissen, T N; Birk, N M; Blok, B A

    2018-01-01

    mean concentrations of IL-1β, TNF-α, IL-6 (24 h stimulation) and IFN-γ, IL-10, IL-17, IL-22 (96 h stimulation) in response to in vitro stimulation with RPMI, LPS, PHA, Escherichia coli, Streptococcus pneumoniae, Candida albicans and BCG were compared among BCG vaccinated children and controls. BCG...

  1. Estimativa da prevalência de infecção tuberculosa em escolares vacinados com BCG, por meio de método de Bhattacharya The determination of the prevalence of tuberculosis infection among school-children vaccinated by Bhattacharya's method

    Directory of Open Access Journals (Sweden)

    Gilberto Ribeiro Arantes

    1991-04-01

    Full Text Available Em populações muito afetadas por reações tuberculínicas inespecíficas, o teste tuberculínico padronizado, via de regra, superestima a infecção tuberculosa. A bem sucedida aplicação do método de Bhattacharya (método gráfico para a decomposição de uma distribuição de freqüências em componentes normais na análise de resultados do teste em população contaminada por infecçõcs atípicas sugeriu seu uso nos resultados obtidos cm populações vacinadas com BCG. Assim, na análise dos resultados de dois inquéritos tuberculínicos realizados na cidade de São Paulo, SP (Brasil, em 1982 (escolares vacinados entre o segundo e o sexto ano de vida, e em 1988 (escolares vacinados no primeiro ano de vida, foi possível a caracterização e quantificação da componente normal devida à infecção natural em cada uma das misturas. Na população de 1982 o diâmetro médio das reações foi de 17,40 mm com desvio padrão 3,72 mm, e a proporção de infectados foi de 7,71% contra 4,85% nos não vacinados; na população de 1988, o diâmetro médio foi 17,00 mm com desvio padrão 4,67 mm, e a proporção de infectados foi de 4,14% contra 4,48% nos não vacinados. Concluiu-se que o método permite estimar a prevalência da infecção tuberculosa em populações com alta cobertura vacinal, desde que a vacina tenha sido aplicada no primeiro ano de vida.The sucessful application of Bhattacharya's method ( decomposition of frequency distribution into normal components by a grafic method in the analysis of the results of tuberculin test performed on a population sensitized by "anonymous" strains of mycobacteria, suggested the possibility of its application to two samples of BCG vacinated school-children, living in the city of S. Paulo (Brazil. One of the sample groups, vaccinated between the second and seventh years of life, was surveyed in 1982 and the other, vaccinated during the first year of life, was surveyed in 1988. In both populations it

  2. The novel tuberculosis vaccine, AERAS-402, induces robust and polyfunctional CD4+ and CD8+ T cells in adults

    NARCIS (Netherlands)

    Abel, Brian; Tameris, Michele; Mansoor, Nazma; Gelderbloem, Sebastian; Hughes, Jane; Abrahams, Deborah; Makhethe, Lebohang; Erasmus, Mzwandile; de Kock, Marwou; van der Merwe, Linda; Hawkridge, Anthony; Veldsman, Ashley; Hatherill, Mark; Schirru, Giulia; Pau, Maria Grazia; Hendriks, Jenny; Weverling, Gerrit Jan; Goudsmit, Jaap; Sizemore, Donata; McClain, J. Bruce; Goetz, Margaret; Gearhart, Jacqueline; Mahomed, Hassan; Hussey, Gregory D.; Sadoff, Jerald C.; Hanekom, Willem A.

    2010-01-01

    RATIONALE: AERAS-402 is a novel tuberculosis vaccine designed to boost immunity primed by bacillus Calmette-Guérin (BCG), the only licensed vaccine. OBJECTIVES: We investigated the safety and immunogenicity of AERAS-402 in healthy Mycobacterium tuberculosis-uninfected BCG-vaccinated adults from a

  3. BCG-mediated protection against Mycobacterium ulcerans infection in the mouse.

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    Paul J Converse

    2011-03-01

    Full Text Available Vaccination with Mycobacterium bovis bacille Calmette-Guérin (BCG is widely used to reduce the risk of childhood tuberculosis and has been reported to have efficacy against two other mycobacterial diseases, leprosy and Buruli ulcer caused by M. ulcerans (Mu. Studies in experimental models have also shown some efficacy against infection caused by Mu. In mice, most studies use the C57BL/6 strain that is known to develop good cell-mediated protective immunity. We hypothesized that there may be differences in vaccination efficacy between C57BL/6 and the less resistant BALB/c strain.We evaluated BCG vaccine efficacy against challenge with ∼3×10(5M. ulcerans in the right hind footpad using three strains: initially, the Australian type strain, designated Mu1617, then, a Malaysian strain, Mu1615, and a recent Ghanaian isolate, Mu1059. The latter two strains both produce mycolactone while the Australian strain has lost that capacity. CFU of both BCG and Mu and splenocyte cytokine production were determined at intervals after infection. Time to footpad swelling was assessed weekly.BCG injection induced visible scars in 95.5% of BALB/c mice but only 43.4% of C57BL/6 mice. BCG persisted at higher levels in spleens of BALB/c than C57BL/6 mice. Vaccination delayed swelling and reduced Mu CFU in BALB/c mice, regardless of challenge strain. However, vaccination was only protective against Mu1615 and Mu1617 in C57BL/6 mice. Possible correlates of the better protection of BALB/c mice included 1 the near universal development of BCG scars in these mice compared to less frequent and smaller scars observed in C57BL/6 mice and 2 the induction of sustained cytokine, e.g., IL17, production as detected in the spleens of BALB/c mice whereas cytokine production was significantly reduced, e.g., IL17, or transient, e.g., Ifnγ, in the spleens of C57BL/6 mice.The efficacy of BCG against M. ulcerans, in particular, and possibly mycobacteria in general, may vary due to

  4. Vaccination coverage and out-of-sequence vaccinations in rural Guinea-Bissau

    DEFF Research Database (Denmark)

    Hornshøj, Linda; Benn, Christine Stabell; Fernandes, Manuel

    2012-01-01

    OBJECTIVE: The WHO aims for 90% coverage of the Expanded Program on Immunization (EPI), which in Guinea-Bissau included BCG vaccine at birth, three doses of diphtheria-tetanus-pertussis vaccine (DTP) and oral polio vaccine (OPV) at 6, 10 and 14 weeks and measles vaccine (MV) at 9 months when...

  5. Next-Generation Vaccines Based on Bacille Calmette-Guérin.

    Science.gov (United States)

    Nieuwenhuizen, Natalie E; Kaufmann, Stefan H E

    2018-01-01

    Tuberculosis (TB), caused by the intracellular bacterium Mycobacterium tuberculosis (Mtb), remains a major health threat. A live, attenuated mycobacterium known as Bacille Calmette-Guérin (BCG), derived from the causative agent of cattle TB, Mycobacterium bovis , has been in clinical use as a vaccine for 90 years. The current incidence of TB demonstrates that BCG fails to protect sufficiently against pulmonary TB, the major disease manifestation and source of dissemination. The protective efficacy of BCG is on average 50% but varies substantially with geographical location and is poorer in those with previous exposure to mycobacteria. BCG can also cause adverse reactions in immunocompromised individuals. However, BCG has contributed to reduced infant TB mortality by protecting against extrapulmonary TB. In addition, BCG has been associated with reduced general childhood mortality by stimulating immune responses. In order to improve the efficacy of BCG, two major strategies have been employed. The first involves the development of recombinant live mycobacterial vaccines with improved efficacy and safety. The second strategy is to boost BCG with subunit vaccines containing Mtb antigens. This article reviews recombinant BCG strains that have been tested against TB in animal models. This includes BCG strains that have been engineered to induce increased immune responses by the insertion of genes for Mtb antigens, mammalian cytokines, or host resistance factors, the insertion of bacterial toxin-derived adjuvants, and the manipulation of bacterial genes in order to increase antigen presentation and immune activation. Subunit vaccines for boosting BCG are also briefly discussed.

  6. Anti-tumour research of recombinant BCG using BZLF1 and hGM-CSF fusion genes.

    Science.gov (United States)

    Xue, Qing-Jie; Li, Yun-Qing; Yang, Chun-Qing; Chen, Ting; Li, Xiu-Zhen; Cheng, Baohua; Wang, Chun-Mei

    2017-03-14

    The random primer Oligo(dT) 15 was used in RT-PCR to obtain cDNA from the human granulocyte macrophage colony stimulating factor (hGM-CSF) gene and the Epstein-Barr virus (EBV) gene BZLF1. Then, the sequence splicing overlap extension method was used to obtain a GCBF fusion gene containing a linker sequence that encoded the polypeptide (Gly 4 Ser) 3 . The GCBF fusion gene was inserted into pMV261, which was then transformed into competent E. coli DH5 alpha cells, and positive cells were selected based on kanamycin resistance on LB plates. The recombinant plasmid pMVBZLF1 was extracted from E. coli, and BCG (Bacillus Calmette-Guérin) was transformed into competent cells. According to the RT-PCR results, the target genes hGM-CSF and BZLF1 were 461bp and 788bp in size, which was in agreement with the expected values. Construction of the recombinant plasmid by double enzyme digestion, amplification, sequencing and Western blotting confirmed that the GCBF fusion gene (1204bp) was correctly inserted into pMV261, successfully transformed into BCG competent cells, and properly expressed. After mice were injected with rBCG (recombinant BCG), antibody levels were detected using ELISA, and spleen cells were obtained and the killing rates of specific CTLs by rBCG were detected using a CTL assay kit. Then, the influence of rBCG on tumour cells was analysed in C57BL/6 mice. We found that rBCG-secreting cytokines hybridized with hGM-CSF and BZLF1 antibodies and that the rBCG vaccine stimulated antibody production in C57BL/6 mice. The specific cytotoxic effects of the spleen cells from the rBCG group on EB virus-positive tumour cells was significantly different from the cytotoxic effects of the control group cells (P<0.01). CD8 + T and CD4 + T lymphocytes were detected in the tumour tissues of the rBCG group mice by flow cytometry, indicating that CD8 + T and CD4 + T lymphocytes infiltrated into the tumour tissue in the mice. Morphological observations of the tumour sections from

  7. Systemic BCG immunization induces persistent lung mucosal multifunctional CD4 T(EM cells which expand following virulent mycobacterial challenge.

    Directory of Open Access Journals (Sweden)

    Daryan A Kaveh

    Full Text Available To more closely understand the mechanisms of how BCG vaccination confers immunity would help to rationally design improved tuberculosis vaccines that are urgently required. Given the established central role of CD4 T cells in BCG induced immunity, we sought to characterise the generation of memory CD4 T cell responses to BCG vaccination and M. bovis infection in a murine challenge model. We demonstrate that a single systemic BCG vaccination induces distinct systemic and mucosal populations of T effector memory (T(EM cells in vaccinated mice. These CD4+CD44(hiCD62L(loCD27⁻ T cells concomitantly produce IFN-γ and TNF-α, or IFN-γ, IL-2 and TNF-α and have a higher cytokine median fluorescence intensity MFI or 'quality of response' than single cytokine producing cells. These cells are maintained for long periods (>16 months in BCG protected mice, maintaining a vaccine-specific functionality. Following virulent mycobacterial challenge, these cells underwent significant expansion in the lungs and are, therefore, strongly associated with protection against M. bovis challenge. Our data demonstrate that a persistent mucosal population of T(EM cells can be induced by parenteral immunization, a feature only previously associated with mucosal immunization routes; and that these multifunctional T(EM cells are strongly associated with protection. We propose that these cells mediate protective immunity, and that vaccines designed to increase the number of relevant antigen-specific T(EM in the lung may represent a new generation of TB vaccines.

  8. Resposta de testes de hipersensibilidade tardia utilizando PPD e outros antígenos em crianças e adolescentes saudáveis e infectados pelo HIV-1 e vacinados com BCG Delayed-type hypersensitivity skin test responses to PPD and other antigens among BCG-vaccinated HIV-1-infected and healthy children and adolescents

    Directory of Open Access Journals (Sweden)

    Natalia Moriya Xavier da Costa

    2011-10-01

    Full Text Available INTRODUÇÃO: A contagem de células CD4+ representa marcador da resposta imune celular em pacientes infectados pelo HIV-1. Testes cutâneos de hipersensibilidade tardia (DTH podem ser empregados para avaliar in vivo respostas celulares a antígenos comuns. MÉTODOS: DTH para derivado proteico purificado de tuberculina (PPD, esporotriquina, tricofitina, candidina e estreptoquinase/estreptodornase foram realizados. Foram testados crianças/adolescentes infectados pelo HIV-1 (n=36 e indivíduos saudáveis (n=56, soronegativos para HIV-1/HIV-2 pareados por sexo-idade, todos com cicatriz vacinal por BCG. Teste exato de Fisher foi aplicado (pINTRODUCTION: Among HIV-1-infected patients, CD4+ T cell counts are well-established markers of cell-mediated immunity. Delayed-type hypersensitivity (DTH skin tests can be used to evaluate in vivo cell-mediated immunity to common antigens. METHODS: DTH responses to tuberculin purified protein derivative (PPD, sporotrichin, trichophytin, candidin and streptokinase/streptodornase antigens were assessed. Thirty-six HIV-1-infected children/adolescents and 56 age- and sex-matched HIV-1/HIV-2-seronegative participants were tested. All participants had a BCG scar. Fisher's exact test was used to evaluate significant differences between groups (p<0.05. RESULTS: The main characteristics of the HIV-1 patients were as follows: median age 8.1 years; 20/36 were males; 35 were vertical transmission cases; 34 were AIDS cases under antiretroviral therapy; median viral load = 3.04 log10 copies/ml; median CD4+ T cell count = 701 cells/μl. A total of 25% (9/36 and 87.5% (49/56 of HIV-1-infected and healthy participants, respectively, displayed DTH reactivity to at least one antigen (p<0.001. Among HIV-1-infected participants, reactivity to candidin predominated (8/36, 22.2%, while PPD positivity prevailed among healthy participants (40/56, 71.4%. PPD reactivity in the HIV-1-positive group was 8.3% (p<0.01. The median PPD

  9. M2-Polarized Macrophages Compose Lupus Vulgaris Arising from a Bacillus Calmette-Guérin Vaccination Site

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    Yota Sato

    2016-07-01

    Full Text Available Since bacillus Calmette-Guérin (BCG is an attenuated strain of Mycobacterium bovis, lupus vulgaris (LV is reported as one of the rare complications after BCG vaccination, correlating with immunosuppression in the lesional skin. In this report, we describe a case of LV arising from the BCG vaccination site 22 years after vaccination. Interestingly, in the present case, granuloma cells were composed of M2-polarized macrophages. Our case might explain the contribution of M2-polarized macrophages to the biology of LV arising from a BCG vaccination site.

  10. M2-Polarized Macrophages Compose Lupus Vulgaris Arising from a Bacillus Calmette-Guérin Vaccination Site.

    Science.gov (United States)

    Sato, Yota; Fujimura, Taku; Furudate, Sadanori; Kakizaki, Aya; Iizawa, Osamu; Aiba, Setsuya

    2016-01-01

    Since bacillus Calmette-Guérin (BCG) is an attenuated strain of Mycobacterium bovis , lupus vulgaris (LV) is reported as one of the rare complications after BCG vaccination, correlating with immunosuppression in the lesional skin. In this report, we describe a case of LV arising from the BCG vaccination site 22 years after vaccination. Interestingly, in the present case, granuloma cells were composed of M2-polarized macrophages. Our case might explain the contribution of M2-polarized macrophages to the biology of LV arising from a BCG vaccination site.

  11. Attrition of T-Cell Functions and Simultaneous Upregulation of Inhibitory Markers Correspond with the Waning of BCG-Induced Protection against Tuberculosis in Mice

    Science.gov (United States)

    Nandakumar, Subhadra; Kannanganat, Sunil; Posey, James E.; Amara, Rama Rao; Sable, Suraj B.

    2014-01-01

    Mycobacterium bovis bacille Calmette-Guérin (BCG) is the most widely used live attenuated vaccine. However, the correlates of protection and waning of its immunity against tuberculosis is poorly understood. In this study, we correlated the longitudinal changes in the magnitude and functional quality of CD4+ and CD8+ T-cell response over a period of two years after mucosal or parenteral BCG vaccination with the strength of protection against Mycobacterium tuberculosis in mice. The BCG vaccination-induced CD4+ and CD8+ T cells exhibited comparable response kinetics but distinct functional attributes in-terms of IFN-γ, IL-2 and TNF-α co-production and CD62L memory marker expression. Despite a near life-long BCG persistence and the induction of enduring CD4+ T-cell responses characterized by IFN-γ and/or TNF-α production with comparable protection, the protective efficacy waned regardless of the route of vaccination. The progressive decline in the multifactorial functional abilities of CD4+ and CD8+ T cells in-terms of type-1 cytokine production, proliferation and cytolytic potential corresponded with the waning of protection against M. tuberculosis infection. In addition, simultaneous increase in the dysfunctional and terminally-differentiated T cells expressing CTLA-4, KLRG-1 and IL-10 during the contraction phase of BCG-induced response coincided with the loss of protection. Our results question the empirical development of BCG-booster vaccines and emphasize the pursuit of strategies that maintain superior T-cell functional capacity. Furthermore, our results underscore the importance of understanding the comprehensive functional dynamics of antigen-specific T-cell responses in addition to cytokine polyfunctionality in BCG-vaccinated hosts while optimizing novel vaccination strategies against tuberculosis. PMID:25419982

  12. Revaccination of cattle with bacille Calmette-Guérin two years after first vaccination when immunity has waned, boosted protection against challenge with Mycobacterium bovis.

    Science.gov (United States)

    Parlane, Natalie A; Shu, Dairu; Subharat, Supatsak; Wedlock, D Neil; Rehm, Bernd H A; de Lisle, Geoffrey W; Buddle, Bryce M

    2014-01-01

    In both humans and animals, controversy exists concerning the duration of protection induced by BCG vaccine against tuberculosis (TB) and whether revaccination enhances protection. A long-term study was undertaken to determine whether BCG-vaccinated calves would be protected against challenge with Mycobacterium bovis 2½ years after vaccination and to determine the effect of revaccination after 2 years. Seventy-nine calves were divided into five groups (n = 15-17 calves/group) with four of the groups vaccinated subcutaneously with 105 CFU of BCG Danish at 2-4 weeks of age and the fifth group serving as non-vaccinated controls. Three of the four BCG-vaccinated groups were revaccinated 2 years after the initial vaccination. One BCG-vaccinated group was revaccinated with BCG. A second group was vaccinated subcutaneously with a TB protein vaccine consisting of biopolyester particles (Biobeads) displaying two mycobacterial proteins, ESAT-6 and Antigen 85A, mixed with an adjuvant. A third group was vaccinated with TB proteins from M. bovis culture filtrate, mixed with an adjuvant. Twenty-three weeks after the BCG revaccination, all animals were challenged endotracheally with virulent M. bovis and a further 13 weeks later, animals were killed and necropsied to determine protection against TB. The BCG-vaccinated animals produced positive tuberculin caudal fold intradermal (15 of 62 animals) and IFN-γ TB test responses (six of 62 animals) at 6 months after vaccination, but not at subsequent time-points compared to the non-vaccinated animals. Calves receiving a single vaccination with BCG vaccine 2½ years prior to challenge were not protected against TB, while those revaccinated with BCG 2 years after the initial vaccination displayed significant reductions in lung and pulmonary lymph node lesion scores compared to the non-vaccinated animals. In contrast, no reduction in lesion scores was observed in the animals revaccinated with the TB protein vaccines with their immune

  13. ESAT-6 and HspX improve the effectiveness of BCG to induce human dendritic cells-dependent Th1 and NK cells activation.

    Directory of Open Access Journals (Sweden)

    Laura Marongiu

    Full Text Available The limited efficacy of the BCG vaccine against tuberculosis is partly due to the missing expression of immunogenic proteins. We analyzed whether the addition to BCG of ESAT-6 and HspX, two Mycobacterium tuberculosis (Mtb antigens, could enhance its capacity to activate human dendritic cells (DCs. BCG showed a weak ability to induce DC maturation, cytokine release, and CD4(+ lymphocytes and NK cells activation. The addition of ESAT-6 or HspX alone to BCG-stimulated DC did not improve these processes, whereas their simultaneous addition enhanced BCG-dependent DC maturation and cytokine release, as well as the ability of BCG-treated DCs to stimulate IFN-γ release and CD69 expression by CD4(+ lymphocytes and NK cells. Addition of TLR2-blocking antibody decreased IL-12 release by BCG-stimulated DCs incubated with ESAT-6 and HspX, as well as IFN-γ secretion by CD4(+ lymphocytes co-cultured with these cells. Moreover, HspX and ESAT-6 improved the capacity of BCG-treated DCs to induce the expression of memory phenotype marker CD45RO in naïve CD4(+ T cells. Our results indicate that ESAT-6 and HspX cooperation enables BCG-treated human DCs to induce T lymphocyte and NK cell-mediated immune responses through TLR2-dependent IL-12 secretion. Therefore ESAT-6 and HspX represent good candidates for improving the effectiveness of BCG vaccination.

  14. BCG immune activation reduces growth and angiogenesis in an in vitro model of head and neck squamous cell carcinoma.

    Science.gov (United States)

    Sánchez-Rodríguez, Carolina; Cruces, Keyliz Peraza; Riestra Ayora, Juan; Martín-Sanz, Eduardo; Sanz-Fernández, Ricardo

    2017-11-07

    Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent cancers worldwide and is associated with poor survival and significant treatment morbidity. The immune profile in patients with HNSCC is immunosuppressive and presents cytokine-mediated adaptive immune responses, triggered apoptosis of T cells, and alterations in antigen processing machinery. Bacille Calmette-Guerin (BCG) immunotherapy has been used successfully as a treatment for several types of cancer. In the present study, we sought to determine the antitumor effect of soluble mediators from peripheral blood mononuclear immune cells (PBMCs) activated with BCG vaccine in a three-dimensional coculture model of HNSCC growth using FaDu hypopharynx carcinoma squamous cells. BCG activation of PBMCs led to an increase in CD4+ and CD8+ lymphocyte subsets concomitant with an elevation in the levels of the antitumor cytokines IL-6, TNF-α and IFN-γ, and a EGFR in FaDu cells. In addition, coculture with BCG-activated PBMCs reduced FaDu proliferation and increased cytotoxicity and apoptosis in parallel with an increase in caspase-3 activity and p53 expression. Finally, conditioned medium from BCG-activated PBMCs reduced the levels of the angiogenic factors vascular endothelial growth factor and angiopoietin-2 produced by human aortic endothelial cells (HAECs), and inhibited their proliferation and differentiation into capillary-like structures. Taken together, these results demonstrate that BCG vaccination induces antitumor responses in an HNSCC in vitro model and suggest that the BCG vaccine could be an effective alternative therapy for the treatment of HNSCC. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Evitar o efeito da vacinação BCG na detecção de infecção por Mycobacterium tuberculosis com um teste sanguíneo Avoiding the effect of BCG vaccination in detecting Mycobacterium tuberculosis infection with a blood test

    Directory of Open Access Journals (Sweden)

    R. Diel

    2007-01-01

    Full Text Available O risco de progressão da infecção por Mycobacterium tuberculosis para tuberculose-doença é sobretudo elevado nos primeiros anos após a infecção, estimando-se que 50% dos casos de tuberculose-infecção desenvolvem doença nos dois anos seguintes. A investigação precoce dos contactos baseia-se neste facto, e o teste cutâneo de tuberculina tem sido largamente utilizado como a prova de rastreio, apesar da sua limitação na população vacinada com BCG, nas reacções cruzadas com micobactérias não tuberculosas e na anergia cutânea em grupos específicos. Nos presentes estudos avalia-se a maior especificidade (no primeiro e a maior sensibilidade (no segundo de um novo teste sanguíneo na detecção de tuberculose- infecção. Este teste laboratorial feito em uma única amostra de sangue do doente baseia-se na libertação de gama-interferão das células T CD4 do indivíduo infectado quando expostas a antigenes micobacterianos. A libertação de interferão é fortemente estimulada por antigenes do Mycobacterium tuberculosis ausentes no M. bovis e na grande maioria das restantes micobactérias - conferindo especificidade ao teste. Estes antigenes ESAT-6/ CFP10 (early secretory antigenic target 6/ culture filtrated protein 10 reagem com o sangue do indivíduo infectado, levando à libertação de gama-interferão medido pelos métodos ELISA ou ELISPOT, dependendo do fabricante, respectivamente - Quantiferon Gold; Cellestis Limited, Austrália; e T-Spot.TB, Oxford Immunotec, UK. No primeiro estudo referenciado, 369 pessoas da academia de Polícia alemã foram avaliadas para o risco de tuberculose-infecção após o contacto com militar a quem foi diagnosticada tuberculose pulmonar com presença de bacilos ácido-alcool resistentes 3+ em exames de expectoração, com posterior cultura positiva para Mycobacterium tuberculosis. Foi efectuado teste de Mantoux a todos os contactos, e aos que apresentavam o teste positivo (induração = 5mm

  16. Bladder Cancer Immunotherapy: BCG and Beyond

    Directory of Open Access Journals (Sweden)

    Eric J. Askeland

    2012-01-01

    Full Text Available Mycobacterium bovis bacillus Calmette-Guérin (BCG has become the predominant conservative treatment for nonmuscle invasive bladder cancer. Its mechanism of action continues to be defined but has been shown to involve a T helper type 1 (Th1 immunomodulatory response. While BCG treatment is the current standard of care, a significant proportion of patients fails or do not tolerate treatment. Therefore, many efforts have been made to identify other intravesical and immunomodulating therapeutics to use alone or in conjunction with BCG. This paper reviews the progress of basic science and clinical experience with several immunotherapeutic agents including IFN-α, IL-2, IL-12, and IL-10.

  17. Non-specific Effects of Vaccines and Stunting: Timing May Be Essential

    NARCIS (Netherlands)

    Berendsen, M.L.T.; Smits, J.P.J.M.; Netea, M.G.; Ven, A.J.A.M. van der

    2016-01-01

    BACKGROUND - Bacillus Calmette-Guérin (BCG) vaccination possesses effects on health beyond its target disease, the so called “non-specific effects”. We evaluate these effects, as well as the effect of timing of BCG and other vaccinations, on stunting in Sub-Saharan African (SSA) children under

  18. Non-specific Effects of Vaccines and Stunting: Timing May Be Essential

    NARCIS (Netherlands)

    Berendsen, M.L.; Smits, J.; Netea, M.G.; Ven, A. van der

    2016-01-01

    BACKGROUND: Bacillus Calmette-Guerin (BCG) vaccination possesses effects on health beyond its target disease, the so called "non-specific effects". We evaluate these effects, as well as the effect of timing of BCG and other vaccinations, on stunting in Sub-Saharan African (SSA) children under five.

  19. Low birth weight infants and Calmette-Guérin bacillus vaccination at birth

    DEFF Research Database (Denmark)

    Roth, Adam Anders Edvin; Jensen, Henrik; Garly, May-Lill

    2004-01-01

    In developing countries, low birth weight (LBW) children are often not vaccinated with Calmette-Guérin bacillus (BCG) at birth. Recent studies have suggested that BCG may have a nonspecific beneficial effect on infant mortality. We evaluated the consequences of not vaccinating LBW children at birth...

  20. Bacillus Calmette-Guérin vaccine- induced lupus vulgaris in a child.

    Science.gov (United States)

    Najem, Nabeel M; Zadeh, Valid Bagher; Al-Abdulrazzaq, Adel H; Al-Otaibi, Sultan R; Kadyan, S; Joneja, Munish

    2009-12-01

    Lupus vulgaris (LV) is a rare form of cutaneous mycobacterial infection in children. Most cases follow hematogenous or lymphatic seeding, and more rarely from exposure to bacillus Calmette- Guérin (BCG) vaccine. We report a child that received BCG vaccination and developed LV 2 months later.

  1. Maternal BCG scar is associated with increased infant proinflammatory immune responses.

    Science.gov (United States)

    Mawa, Patrice Akusa; Webb, Emily L; Filali-Mouhim, Abdelali; Nkurunungi, Gyaviira; Sekaly, Rafick-Pierre; Lule, Swaib Abubaker; Prentice, Sarah; Nash, Stephen; Dockrell, Hazel M; Elliott, Alison M; Cose, Stephen

    2017-01-05

    Prenatal exposures such as infections and immunisation may influence infant responses. We had an opportunity to undertake an analysis of innate responses in infants within the context of a study investigating the effects of maternal mycobacterial exposures and infection on BCG vaccine-induced responses in Ugandan infants. Maternal and cord blood samples from 29 mother-infant pairs were stimulated with innate stimuli for 24h and cytokines and chemokines in supernatants were measured using the Luminex® assay. The associations between maternal latent Mycobacterium tuberculosis infection (LTBI), maternal BCG scar (adjusted for each other's effect) and infant responses were examined using linear regression. Principal Component Analysis (PCA) was used to assess patterns of cytokine and chemokine responses. Gene expression profiles for pathways associated with maternal LTBI and with maternal BCG scar were examined using samples collected at one (n=42) and six (n=51) weeks after BCG immunisation using microarray. Maternal LTBI was positively associated with infant IP-10 responses with an adjusted geometric mean ratio (aGMR) [95% confidence interval (CI)] of 5.10 [1.21, 21.48]. Maternal BCG scar showed strong and consistent associations with IFN-γ (aGMR 2.69 [1.15, 6.17]), IL-12p70 (1.95 [1.10, 3.55]), IL-10 (1.82 [1.07, 3.09]), VEGF (3.55 [1.07, 11.48]) and IP-10 (6.76 [1.17, 38.02]). Further assessment of the associations using PCA showed no differences for maternal LTBI, but maternal BCG scar was associated with higher scores for principal component (PC) 1 (median level of scores: 1.44 in scar-positive versus -0.94 in scar-negative, p=0.020) in the infants. PC1 represented a controlled proinflammatory response. Interferon and inflammation response pathways were up-regulated in infants of mothers with LTBI at six weeks, and in infants of mothers with a BCG scar at one and six weeks after BCG immunisation. Maternal BCG scar had a stronger association with infant

  2. A review of the literature on the economics of vaccination against TB.

    Science.gov (United States)

    Tu, Hong-Anh T; Vu, Hoa D; Rozenbaum, Mark H; Woerdenbag, Herman J; Postma, Maarten J

    2012-03-01

    The BCG vaccine was introduced in 1921 and remains the only licensed vaccine for the prevention of TB worldwide. Despite its extensive use, the BCG vaccine lacks the ability to fully control the TB-endemic and -pandemic situations. The BCG vaccine is most effective in preventing pediatric TB, in particular, miliary TB and tuberculous meningitis. However, it has a limited effect in preventing pulmonary TB, which occurs more frequently in adults. BCG vaccination has now been implemented in more than 157 countries worldwide. For various countries, the benefits of vaccination are only limited and potentially not cost effective. The International Union Against Tuberculosis and Lung Diseases had set the criteria for discontinuation of BCG vaccination in 1994. This decision, however, was not based on economic considerations. Many developed countries have met the criteria set by the International Union Against Tuberculosis and Lung Disease and stopped universal BCG vaccination. For developing countries, the BCG vaccine is still an effective intervention in protecting young children from TB infection. A lot of effort has been spent on R&D of new TB vaccines, the first of which are expected to be available within 5-7 years from now. Novel TB vaccines are expected to be better and more effective than the current BCG vaccine and should provide a viable strategy in controlling TB morbidity and mortality. In this review, the aim is to explore economic evaluations that have been carried out for vaccination against TB worldwide. In addition to epidemiological evidence, economic evidence can play a crucial role in supporting the governments of countries in making proper public health decisions on BCG vaccination policies, in particular, to implement, continue, or discontinue.

  3. Bacillus Calmette-Guérin (BCG) complications associated with primary immunodeficiency diseases

    Science.gov (United States)

    Norouzi, Sayna; Aghamohammadi, Asghar; Mamishi, Setareh; Rosenzweig, Sergio D.; Rezaei, Nima

    2016-01-01

    Summary Primary immunodeficiency diseases (PIDs) are a group of inherited disorders, characterized by defects of the immune system predisposing individuals to variety of manifestations, including recurrent infections and unusual vaccine complications. There are a number of PIDs prone to Bacillus Calmette-Guérin (BCG) complications. This review presents an update on our understanding about the BCGosis-susceptible PIDs, including severe combined immunodeficiency, chronic granulomatous disease, and Mendelian susceptibility to mycobacterial diseases. PMID:22430715

  4. Spinal tuberculosis with severe neurological symptoms as a complication of intravesical BCG therapy for carcinoma of the bladder.

    Science.gov (United States)

    Białecki, Jerzy; Nowak-Misiak, Mirosława; Rąpała, Kazimierz; Marczyński, Wojciech; Suchodolski, Gracjan; Truszczyńska, Aleksandra

    2016-01-01

    Non-invasive bladder cancer is effectively treated with intravesical BCG therapy. The administration of the BCG vaccine is to destroy the neoplastic lesion or prevent further recurrences. The activity of the vaccine involves boosting the immune system through the stimulation of the inflammation in the bladder. Adverse reactions after this immunotherapy are rare. The aim of the study was to present complications in the form of spinal tuberculosis and serious neurological symptoms that occurred during intravesical BCG immunotherapy for carcinoma of the bladder. The manuscript also describes a method for neurosurgical spinal cord decompression of the thoracic spine. In the first patient, aged 66, after intravesical BCG therapy for bladder carcinoma, back pain and spastic paralysis of the lower limbs were observed. The MRI and CT revealed destruction of the intervertebral disc and vertebral endplates Th11-Th12. Mycobacterium tuberculosis complex bacilli were cultured from the material obtained by puncture aspiration. In the second patient, aged 35 years, during intravesical BCG immunotherapy for carcinoma of the bladder, girdle thoracic spine pain was observed. The MRI and CT of the spine showed visible lesions characteristic of tuberculosis. Immobilization in a plaster corset and implementation of antituberculous treatment resulted in quick relief of the pain and healing of the tuberculosis focus in the spine. The cases described in the work are the first documented reports in the Polish literature of spinal tuberculosis which occurred as a complication of intravesical administration of bacilli Calmette-Guérin. The diagnosis was based on the finding of BCG vaccine bacillus with molecular methods or PCR. Full antimycobacterial treatment was implemented. Copyright © 2015 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  5. The immunological effect of revaccination with Bacille Calmette-Guérin vaccine at 19 months of age

    DEFF Research Database (Denmark)

    Andersen, Andreas; Roth, Adam; Jensen, Kristoffer Jarlov

    2013-01-01

    Bacille Calmette-Guérin (BCG) vaccination has important non-specific immune effects. In a randomized trial in Guinea-Bissau, BCG revaccination was associated with significantly increased survival in children who received diphtheria-tetanus-pertussis (DTP)-booster vaccine before enrolment and in c...

  6. Tuberculosis case finding for vaccine trials in young children in high-incidence settings: a randomised trial

    NARCIS (Netherlands)

    Moyo, S.; Verver, S.; Hawkridge, A.; Geiter, L.; Hatherill, M.; Workman, L.; Ontong, C.; Msemburi, W.; Tameris, M.; Geldenhuys, H.; Mulenga, H.; Snowden, M. A.; Hanekom, W. A.; Hussey, G.; Mahomed, H.

    2012-01-01

    SETTING: A high tuberculosis (TB) burden rural area in South Africa. OBJECTIVE: To compare TB case yield and disease profile among bacille Calmette-Guerin (BCG) vaccinated children using two case-finding strategies from birth until 2 years of age. DESIGN: BCG-vaccinated infants were enrolled within

  7. Increased TNF-alpha/IFN-gamma/IL-2 and decreased TNF-alpha/IFN-gamma production by central memory T cells are associated with protective responses against bovine tuberculosis following BCG vaccination

    Science.gov (United States)

    Central memory T cells (Tcm’s) and polyfunctional CD4 T responses contribute to vaccine-elicited protection with both human and bovine tuberculosis (TB); however, their combined role in protective immunity to TB is unclear. To address this question, we evaluated polyfunctional cytokine responses by ...

  8. Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial

    DEFF Research Database (Denmark)

    Biering-Sørensen, Sofie; Aaby, Peter; Lund, Najaaraq

    2017-01-01

    -Denmark” (intervention group; n = 2083) or “control” (local policy for LW and no BCG-Denmark; n = 2089) at discharge from the maternity ward or at first contact with the health center. The infants were randomized (1:1) without blinding in blocks of 24. Data was analyzed in Cox hazards models providing mortality rate...... ratios (MRRs). We had prespecified an analysis censoring follow-up at oral poliovirus vaccine campaigns. Results. Early administration of BCG-Denmark was associated with a nonsignificant reduction in neonatal mortality rate (MRR, 0.70; 95% confidence interval [CI], .47–1.04) and a 34% reduction (0...... by 38% (MRR, 0.62; 95% CI, .46–.83) within the neonatal period and 16% (0.84; .71–1.00) by age 12 months.ConclusionEarly administration of BCG-Denmark in LW infants is associated with major reductions in mortality rate. It is important that all LW infants receive early BCG in areas with high neonatal...

  9. Enhanced expression of PD-L1 and IFN-γ on dendritic cells is associated with BCG-induced Th2 inhibition.

    Science.gov (United States)

    Gouveia, A C C; Braga, F G; Mota, M; Silva, F M C; Brugiolo, A S S; Oliveira, E E; Ayupe, M C; Teixeira, H C; Ferreira, A P

    2017-11-01

    Accumulating evidence indicates that the exposure to Mycobacterium bovis bacillus Calmette-Guérin (BCG) prevents the development of allergy and the airway dendritic cells (DCs) may be involved in this protective effect. However, studies to better characterize the specific interactions between BCG and DCs and their role in this mycobacteria-mediated Th2 cell suppression are still ongoing. This study aimed to evaluate the effect of the neonatal BCG vaccination in the innate immune response in a mouse model of ovalbumin (OVA)-induced airway inflammation. BCG treated neonatal BALB/c mice were sensitized and challenged with aerosolized OVA. Twenty-four hours after the last challenge, samples were collected for analysis. The intranasal BCG treatment inhibited the allergic Th2-response by decreasing the allergen-induced eosinophilic inflammation, EPO activity, CCL11, IL-25, TSLP, IL-4 and IL-5 lung levels, and serum levels of IgE. Mycobacteria treatment increased lung levels of IL-10 and TGF-β, and the TLR2 and TLR4 expressions by pulmonary CD11c + CD103 + CD8α + DCs. Additionally an enhanced expression of PD-L1 was observed besides an increased production of IFN-γ by these cells. These results indicated that neonatal BCG vaccination inhibits key features of allergic airway inflammation, probably by promoting T regulatory immune response via an enhanced expression of TLR2, TLR4 and PD-L1 on DCs. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Vaccines and multiple sclerosis

    DEFF Research Database (Denmark)

    Frederiksen, J. L.; Topsøe Mailand, M.

    2017-01-01

    An association between certain vaccinations and onset or relapse of multiple sclerosis (MS) has been debated. Based on PubMed, we made a thorough literature review and included all relevant studies, 51 on MS and 15 on optic neuritis (ON). Case studies were excluded. With the exception of a live...... vaccine against yellow fever, vaccinations appear safe in untreated patients with MS and ON. However, most studies were underpowered, and small risks cannot be excluded. One study of BCG vaccination after the first demyelinating event showed even a reduced risk of developing MS. Further studies are needed...

  11. Immunotherapy of murine bladder cancer by irradiated tumor vaccine

    Energy Technology Data Exchange (ETDEWEB)

    Lamm, D.L.; Riggs, D.R.; DeHaven, J.I.; Bryner, R.W. (West Virginia Univ. School of Medicine, Morgantown (USA))

    1991-01-01

    This investigation explored the efficacy of irradiated autologous mouse bladder tumor (Ir-MBT2) as an active specific immunotherapeutic agent and as adjuvant therapy with Bacillus Calmette-Guerin (BCG) against a subcutaneously transplanted murine bladder tumor. Tumor incidence was significantly reduced in groups receiving BCG (27%, p less than 0.005) or Ir-MBT2 with BCG (53%, p less than 0.025), compared to control (93%). Survival was significantly improved in groups treated with BCG (100%, p less than 0.005), 10(5) Ir-MBT2 with BCG (53%, p less than 0.01), or 10(7) Ir-MBT2 with BCG (47%, p less than 0.025) compared with control (13%). Surprisingly, Ir-MBT2 consistently reduced the efficacy of BCG alone. Ir-MBT2 alone (10(7)) appeared to enhance tumor growth. Autologous irradiated bladder tumor vaccine, alone or in combination with BCG, displayed no immunotherapeutic advantage. The use of irradiated tumor cell vaccine for bladder cancer therapy may reduce the results achievable with BCG alone.

  12. Original Article Failure of Bacillus Calmette Guerin (BCG) Therapy ...

    African Journals Online (AJOL)

    Administrator

    -up, 6 (3.8%) stopped BCG due to side-effects and were subsequently treated with intravesical chemotherapy, while another 5 (3.1%) died during BCG therapy ... patients with impaired renal function. Hematuria was the most common clinical.

  13. Current status of new tuberculosis vaccine in children.

    Science.gov (United States)

    Pang, Yu; Zhao, Aihua; Cohen, Chad; Kang, Wanli; Lu, Jie; Wang, Guozhi; Zhao, Yanlin; Zheng, Suhua

    2016-04-02

    Pediatric tuberculosis contributes significantly to the burden of TB disease worldwide. In order to achieve the goal of eliminating TB by 2050, an effective TB vaccine is urgently needed to prevent TB transmission in children. BCG vaccination can protect children from the severe types of TB such as TB meningitis and miliary TB, while its efficacy against pediatric pulmonary TB ranged from no protection to very high protection. In recent decades, multiple new vaccine candidates have been developed, and shown encouraging safety and immunogenicity in the preclinical experiments. However, the limited data on protective efficacy in infants evaluated by clinical trials has been disappointing, an example being MVA85A. To date, no vaccine has been shown to be clinically safer and more effective than the presently licensed BCG vaccine. Hence, before a new vaccine is developed with more promising efficacy, we must reconsider how to better use the current BCG vaccine to maximize its effectiveness in children.

  14. The association between Bacillus Calmette-Guérin vaccination (1331 SSI) skin reaction and subsequent scar development in infants

    DEFF Research Database (Denmark)

    Birk, Nina Marie; Nissen, Thomas Nørrelykke; Ladekarl, Monica

    2017-01-01

    of vaccination technique for scarring in a high income setting, by assessing the associations between the post injection reaction, the wheal size, and the probability of developing a scar, and scar size. METHODS: This study was nested within a clinical multicenter study randomizing 4262 infants to either BCG...... vaccination (BCG 1331 SSI) or no intervention. In this substudy, including 492 vaccinated infants, the immediate post BCG vaccination reaction was registered as either wheal (a raised, blanched papule at the injection site), bulge (a palpable element at the injection site), or no reaction. The presence...... or absence of a BCG scar and the size the scar was measured at 13 months of age. RESULTS: Of 492 infants included, 87% had a wheal after vaccination, 11% had a bulge, and 2% had no reaction. The mean wheal size was 3.8 mm (95% confidence interval 3.7-3.9). Overall, 95% (442/466, 26 lost to follow-up) of BCG...

  15. Adverse reactions to the Bacillus Calmette-Guérin (BCG) vaccine in new-born infants-an evaluation of the Danish strain 1331 SSI in a randomized clinical trial

    DEFF Research Database (Denmark)

    Nissen, Thomas Nørrelykke; Birk, Nina Marie; Kjærgaard, Jesper

    2016-01-01

    or no intervention. Follow-up until 13 months of age. SETTING: Pediatric and maternity wards at three Danish university hospitals. PARTICIPANTS: All women planning to give birth at the three study sites (n=16,521) during the recruitment period were invited to participate in the study. Four thousand one hundred...... cases were treated conservatively and recovered. Six of 10 (60%) families of children experiencing suppurative lymphadenitis compared to 117/2071 (6%) of those with no lymphadenitis indicated that the vaccine had more adverse effects than expected (p-value ... vaccination was associated with only mild morbidity and no mortality. A higher incidence of suppurative lymphadenitis than expected was observed. All children were treated conservatively without sequelae or complications. TRIAL REGISTRATION: Trial registration number NCT01694108 at www.clinicaltrials.gov....

  16. HIV-1 Subtype C Mosaic Gag Expressed by BCG and MVA Elicits Persistent Effector T Cell Responses in a Prime-Boost Regimen in Mice.

    Directory of Open Access Journals (Sweden)

    Tsungai Ivai Jongwe

    Full Text Available Over 90% of HIV/AIDS positive individuals in sub-Saharan Africa are infected with highly heterogeneous HIV-1 subtype C (HIV-1C viruses. One of the best ways to reduce the burden of this disease is the development of an affordable and effective prophylactic vaccine. Mosaic immunogens are computationally designed to overcome the hurdle of HIV diversity by maximizing the expression of potential T cell epitopes. Mycobacterium bovis BCG ΔpanCD auxotroph and modified vaccinia Ankara (MVA vaccines expressing HIV-1C mosaic Gag (GagM were tested in a prime-boost regimen to demonstrate immunogenicity in a mouse study. The BCG-GagM vaccine was stable and persisted 11.5 weeks post vaccination in BALB/c mice. Priming with BCG-GagM and boosting with MVA-GagM elicited higher Gag-specific IFN-γ ELISPOT responses than the BCG-GagM only and MVA-GagM only homologous vaccination regimens. The heterologous vaccination also generated a more balanced and persistent CD4+ and CD8+ T cell Gag-specific IFN-γ ELISPOT response with a predominant effector memory phenotype. A Th1 bias was induced by the vaccines as determined by the predominant secretion of IFN-γ, TNF-α, and IL-2. This study shows that a low dose of MVA (104 pfu can effectively boost a BCG prime expressing the same mosaic immunogen, generating strong, cellular immune responses against Gag in mice. Our data warrants further evaluation in non-human primates. A low dose vaccine would be an advantage in the resource limited countries of sub-Saharan Africa and India (where the predominating virus is HIV-1 subtype C.

  17. A case of infectious endocarditis due to BCG

    Directory of Open Access Journals (Sweden)

    Alice Fournier

    2015-06-01

    Full Text Available The occurrence of bacillus Calmette–Guérin (BCG disease following instillation for bladder cancer is commonly documented. The intravesical administration of BCG is generally safe, but may present severe complications. A fatal case of native aortic valve infectious endocarditis with septicemia due to BCG in a patient treated with intravesical instillation is reported herein.

  18. Oral bacillus Calmette-Guérin vaccine against tuberculosis: why not?

    Directory of Open Access Journals (Sweden)

    Renata Monteiro-Maia

    2014-09-01

    Full Text Available The bacillus Calmette-Guérin (BCG vaccine is the only licensed vaccine for human use against tuberculosis (TB. Although controversy exists about its efficacy, the BCG vaccine is able to protect newborns and children against disseminated forms of TB, but fails to protect adults against active forms of TB. In the last few years, interest in the mucosal delivery route for the vaccine has been increasing owing to its increased capacity to induce protective immune responses both in the mucosal and the systemic immune compartments. Here, we show the importance of this route of vaccination in newly developed vaccines, especially for vaccines against TB.

  19. Lipoproteins of slow-growing Mycobacteria carry three fatty acids and are N-acylated by apolipoprotein N-acyltransferase BCG_2070c.

    Science.gov (United States)

    Brülle, Juliane K; Tschumi, Andreas; Sander, Peter

    2013-10-05

    Lipoproteins are virulence factors of Mycobacterium tuberculosis. Bacterial lipoproteins are modified by the consecutive action of preprolipoprotein diacylglyceryl transferase (Lgt), prolipoprotein signal peptidase (LspA) and apolipoprotein N- acyltransferase (Lnt) leading to the formation of mature triacylated lipoproteins. Lnt homologues are found in Gram-negative and high GC-rich Gram-positive, but not in low GC-rich Gram-positive bacteria, although N-acylation is observed. In fast-growing Mycobacterium smegmatis, the molecular structure of the lipid modification of lipoproteins was resolved recently as a diacylglyceryl residue carrying ester-bound palmitic acid and ester-bound tuberculostearic acid and an additional amide-bound palmitic acid. We exploit the vaccine strain Mycobacterium bovis BCG as model organism to investigate lipoprotein modifications in slow-growing mycobacteria. Using Escherichia coli Lnt as a query in BLASTp search, we identified BCG_2070c and BCG_2279c as putative lnt genes in M. bovis BCG. Lipoproteins LprF, LpqH, LpqL and LppX were expressed in M. bovis BCG and BCG_2070c lnt knock-out mutant and lipid modifications were analyzed at molecular level by matrix-assisted laser desorption ionization time-of-flight/time-of-flight analysis. Lipoprotein N-acylation was observed in wildtype but not in BCG_2070c mutants. Lipoprotein N- acylation with palmitoyl and tuberculostearyl residues was observed. Lipoproteins are triacylated in slow-growing mycobacteria. BCG_2070c encodes a functional Lnt in M. bovis BCG. We identified mycobacteria-specific tuberculostearic acid as further substrate for N-acylation in slow-growing mycobacteria.

  20. Vaccinations

    Science.gov (United States)

    ... will not work well for all pets. Your veterinarian will determine a vaccination schedule most appropriate for ... programs, but in some instances may help your veterinarian determine if your pet has a reasonable expectation ...

  1. BCG-induced interleukin-6 upregulation and BCG internalization in well and poorly differentiated human bladder cancer cell lines

    NARCIS (Netherlands)

    Bevers, R. F.; de Boer, E. C.; Kurth, K. H.; Schamhart, D. H.

    1998-01-01

    Intravesical bacillus Calmette-Guerin (BCG) is a successful therapy for superficial bladder cancer. However, the working mechanism of BCG after intravesical instillation is not completely understood. A functional role of urothelial (tumor) cells in the initiation of the BCG-induced immune reaction

  2. Alternative BCG delivery strategies improve protection against Mycobacterium tuberculosis in non-human primates: Protection associated with mycobacterial antigen-specific CD4 effector memory T-cell populations.

    Science.gov (United States)

    Sharpe, S; White, A; Sarfas, C; Sibley, L; Gleeson, F; McIntyre, A; Basaraba, R; Clark, S; Hall, G; Rayner, E; Williams, A; Marsh, P D; Dennis, M

    2016-12-01

    Intradermal (ID) BCG injection provides incomplete protection against TB in humans and experimental models. Alternative BCG vaccination strategies may improve protection in model species, including rhesus macaques. This study compares the immunogenicity and efficacy of BCG administered by ID and intravenous (IV) injection, or as an intratracheal mucosal boost (ID + IT), against aerosol challenge with Mycobacterium tuberculosis Erdman strain. Disease pathology was significantly reduced, and survival improved, by each BCG vaccination strategy, relative to unvaccinated animals. However, IV induced protection surpassed that achieved by all other routes, providing an opportunity to explore protective immunological mechanisms using antigen-specific IFN-γ ELISpot and polychromatic flow cytometry assays. IFN-γ spot forming units and multifunctional CD4 T-cell frequencies increased significantly following each vaccination regimen and were greatest following IV immunisation. Vaccine-induced multifunctional CD4 T-cells producing IFN-γ and TNF-α were associated with reduced disease pathology following subsequent M.tb challenge; however, high frequencies of this population following M.tb infection correlated with increased pathology. Cytokine producing T-cells primarily occupied the CD4 transitional effector memory phenotype, implicating this population as central to the mycobacterial response, potentially contributing to the stringent control observed in IV vaccinated animals. This study demonstrates the protective efficacy of IV BCG vaccination in rhesus macaques, offering a valuable tool for the interrogation of immunological mechanisms and potential correlates of protection. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

  3. Adverse Reactions Due to the Bacillus Calmette-Guerin Vaccine: Twenty Tunisian Cases.

    Science.gov (United States)

    Sellami, Khadija; Amouri, Meriem; Kmiha, Sana; Bahloul, Emna; Aloulou, Hajer; Sfaihi, Lamia; Guirat, R; Mseddi, Madiha; Kamoun, T; Hachicha, Mongia; Turki, Hamida

    2018-01-01

    Bacillus Calmette-Guérin (BCG) vaccine is a widely used vaccine. Management of local BCG complications differs between clinicians, and the optimal approach remains unclear. We aim to describe the epidemiological, clinical and therapeutic aspects of the BCG vaccine side effects in Sfax. This was a retrospective study of all the cases of BCG vaccine adverse reactions recorded in the Dermatology and Paediatrics Departments of Hedi Chaker University Hospital of Sfax over a period of 10 years (2005-2015). Twenty cases of BCG adverse reactions were notified during the study period. Actually, 80% of the patients presented local adverse reactions. The outcome was good in all the followed patients. The rate of disseminated BCG disease was 20%. Biological tests of immunity showed a primary immunodeficiency in three cases, whereas the outcome was fatal in two cases. BCG vaccine adverse reactions range from mild to severe. However, the management of benign local reactions remains unclear. Disseminated BCG disease must alert clinicians to the possibility of a primary immunodeficiency.

  4. Adverse reactions due to the bacillus Calmette-Guerin vaccine: Twenty Tunisian cases

    Directory of Open Access Journals (Sweden)

    Khadija Sellami

    2018-01-01

    Full Text Available Background: Bacillus Calmette-Guérin (BCG vaccine is a widely used vaccine. Management of local BCG complications differs between clinicians, and the optimal approach remains unclear. Aims: We aim to describe the epidemiological, clinical and therapeutic aspects of the BCG vaccine side effects in Sfax. Patients and Methods: This was a retrospective study of all the cases of BCG vaccine adverse reactions recorded in the Dermatology and Paediatrics Departments of Hedi Chaker University Hospital of Sfax over a period of 10 years (2005–2015. Results: Twenty cases of BCG adverse reactions were notified during the study period. Actually, 80% of the patients presented local adverse reactions. The outcome was good in all the followed patients. The rate of disseminated BCG disease was 20%. Biological tests of immunity showed a primary immunodeficiency in three cases, whereas the outcome was fatal in two cases. Conclusion: BCG vaccine adverse reactions range from mild to severe. However, the management of benign local reactions remains unclear. Disseminated BCG disease must alert clinicians to the possibility of a primary immunodeficiency.

  5. Novel GMO-Based Vaccines against Tuberculosis: State of the Art and Biosafety Considerations

    Science.gov (United States)

    Leunda, Amaya; Baldo, Aline; Goossens, Martine; Huygen, Kris; Herman, Philippe; Romano, Marta

    2014-01-01

    Novel efficient vaccines are needed to control tuberculosis (TB), a major cause of morbidity and mortality worldwide. Several TB vaccine candidates are currently in clinical and preclinical development. They fall into two categories, the one of candidates designed as a replacement of the Bacille Calmette Guérin (BCG) to be administered to infants and the one of sub-unit vaccines designed as booster vaccines. The latter are designed as vaccines that will be administered to individuals already vaccinated with BCG (or in the future with a BCG replacement vaccine). In this review we provide up to date information on novel tuberculosis (TB) vaccines in development focusing on the risk assessment of candidates composed of genetically modified organisms (GMO) which are currently evaluated in clinical trials. Indeed, these vaccines administered to volunteers raise biosafety concerns with respect to human health and the environment that need to be assessed and managed. PMID:26344627

  6. Novel GMO-Based Vaccines against Tuberculosis: State of the Art and Biosafety Considerations

    Directory of Open Access Journals (Sweden)

    Amaya Leunda

    2014-06-01

    Full Text Available Novel efficient vaccines are needed to control tuberculosis (TB, a major cause of morbidity and mortality worldwide. Several TB vaccine candidates are currently in clinical and preclinical development. They fall into two categories, the one of candidates designed as a replacement of the Bacille Calmette Guérin (BCG to be administered to infants and the one of sub-unit vaccines designed as booster vaccines. The latter are designed as vaccines that will be administered to individuals already vaccinated with BCG (or in the future with a BCG replacement vaccine. In this review we provide up to date information on novel tuberculosis (TB vaccines in development focusing on the risk assessment of candidates composed of genetically modified organisms (GMO which are currently evaluated in clinical trials. Indeed, these vaccines administered to volunteers raise biosafety concerns with respect to human health and the environment that need to be assessed and managed.

  7. Novel GMO-Based Vaccines against Tuberculosis: State of the Art and Biosafety Considerations.

    Science.gov (United States)

    Leunda, Amaya; Baldo, Aline; Goossens, Martine; Huygen, Kris; Herman, Philippe; Romano, Marta

    2014-06-16

    Novel efficient vaccines are needed to control tuberculosis (TB), a major cause of morbidity and mortality worldwide. Several TB vaccine candidates are currently in clinical and preclinical development. They fall into two categories, the one of candidates designed as a replacement of the Bacille Calmette Guérin (BCG) to be administered to infants and the one of sub-unit vaccines designed as booster vaccines. The latter are designed as vaccines that will be administered to individuals already vaccinated with BCG (or in the future with a BCG replacement vaccine). In this review we provide up to date information on novel tuberculosis (TB) vaccines in development focusing on the risk assessment of candidates composed of genetically modified organisms (GMO) which are currently evaluated in clinical trials. Indeed, these vaccines administered to volunteers raise biosafety concerns with respect to human health and the environment that need to be assessed and managed.

  8. Increased B and T Cell Responses in M. bovis Bacille Calmette-Guérin Vaccinated Pigs Co-Immunized with Plasmid DNA Encoding a Prototype Tuberculosis Antigen

    DEFF Research Database (Denmark)

    Bruffaerts, Nicolas; Pedersen, Lasse Eggers; Vandermeulen, Gaëlle

    2015-01-01

    two regions with strong predicted SLA-1*0401/SLA-1*0801 binding affinity, was promiscuously recognized by 6/6 animals vaccinated with the BCG-pAg85A combination. Our study provides a proof of concept in a large mammalian species, for a new Th1 and CD8+ targeting tuberculosis vaccine, based on BCG...

  9. Age at BCG administration during routine immunization.

    African Journals Online (AJOL)

    Age at BCG administration during routine immunization. R.D. Wammanda , M.J. Gambo and I. Abdulkadir. Department of Paediatrics,. Ahmadu Bello University Teaching Hospital,. Zaria. Correspondence to: Dr.R.D. Wammanda. Email: wammanda@yahoo.com. Summary. In Nigeria, as part of the National Programme on ...

  10. Osteomielitis esternal y escrofuloderma por vacuna BCG.

    Directory of Open Access Journals (Sweden)

    Ivohne Fernanda Corrales

    2003-06-01

    Full Text Available La vacuna BCG se ha usado en todo el mundo desde principios del siglo XX para la prevención de la tuberculosis. Se describe el caso de una niña de 13 meses de edad, previamente sana, que consultó por una masa esternal. El estudio radiológico mostró erosión perióstica. La lesión fue resecada y en la histopatología se encontró una reacción inflamatoria crónica con granulomas caseificantes con compromiso óseo y cutáneo. Se realizó una amplificación por PCR con iniciadores específicos de Mycobacterium tuberculosis del ADN obtenido a partir del tejido incluido en parafina, cuyo resultado fue negativo. Los antecedentes de vacunación con BCG, la aparición de este tipo de granulomas y la ausencia de ADN de M. tuberculosis en el tejido resecado apoyan el diagnóstico de osteomielitis esternal y escrofuloderma por BCG. La osteomielitis es una complicación infrecuente de la vacunación por BCG, que puede presentarse especialmente en pacientes inmunosuprimidos. La evolución clínica de la paciente no ha demostrado ninguna forma de inmunodeficiencia.

  11. Recognition and Treatment of BCG Failure in Bladder Cancer

    Directory of Open Access Journals (Sweden)

    Andrew J. Lightfoot

    2011-01-01

    Full Text Available Patients with high-grade Ta, T1, or carcinoma in situ non–muscle-invasive bladder cancer (NMIBC are at high risk for recurrence and, more importantly, progression. Thus, both the American Urological Association and European Association of Urology recommend initial intravesical treatment with bacillus Calmette-Guerin(BCG followed by maintenance therapy for a minimum of 1 year. The complete response rate to BCG therapy in patients with high-risk NMIBC can be as high as ∼80%; however, most patients with high-risk disease suffer from recurrence. BCG failure can be further characterized into BCG refractory, BCG resistant, BCG relapsing, and BCG intolerant. Current recommendations include one further course of BCG or cystectomy. In patients who continue to fail conservative treatment and who refuse surgical therapy or are not surgical candidates, treatment options become even more complicated. In this setting, treatment options are limited and include repeat BCG treatment, an alternate immunotherapy regimen, chemotherapy, or device-assisted therapy. To date, however, further research is necessary for all secondary treatment options in order to determine which might be the most efficacious. All conservative treatments should be considered investigational. Currently, cystectomy remains the standard of care for high-risk patients who have failed BCG therapy.

  12. The Effect of Oral Polio Vaccine at Birth on Infant Mortality

    DEFF Research Database (Denmark)

    Lund, Najaaraq; Andersen, Andreas; Hansen, Anna Sofie K

    2015-01-01

    of 7012 healthy normal-birth-weight neonates were randomized to BCG only (intervention group) or OPV0 with BCG (usual practice). All children were to receive OPV with pentavalent vaccine (diphtheria, tetanus, pertussis, Haemophilus influenzae type b, and hepatitis B) at 6, 10, and 14 weeks of age. Seven...

  13. Effect of milk fermentation by kefir grains and selected single strains of lactic acid bacteria on the survival of Mycobacterium bovis BCG.

    Science.gov (United States)

    Macuamule, C L S; Wiid, I J; van Helden, P D; Tanner, M; Witthuhn, R C

    2016-01-18

    Mycobacterium bovis that causes Bovine tuberculosis (BTB) can be transmitted to humans thought consumption of raw and raw fermented milk products from diseased animals. Lactic acid bacteria (LAB) used in popular traditional milk products in Africa produce anti-microbial compounds that inhibit some pathogenic and spoilage bacteria. M. bovis BCG is an attenuated non-pathogenic vaccine strain of M. bovis and the aim of the study was to determine the effect of the fermentation process on the survival of M. bovis BCG in milk. M. bovis BCG at concentrations of 6 log CFU/ml was added to products of kefir fermentation. The survival of M. bovis BCG was monitored at 12-h intervals for 72 h by enumerating viable cells on Middlebrook 7H10 agar plates enriched with 2% BD BACTEC PANTA™. M. bovis BCG was increasingly reduced in sterile kefir that was fermented for a period of 24h and longer. In the milk fermented with kefir grains, Lactobacillus paracasei subsp. paracasei or Lactobacillus casei, the viability of M. bovis BCG was reduced by 0.4 logs after 24h and by 2 logs after 48 h of fermentation. No viable M. bovis BCG was detected after 60 h of fermentation. Results from this study show that long term fermentation under certain conditions may have the potential to inactivate M. bovis BCG present in the milk. However, to ensure safety of fermented milk in Africa, fermentation should be combined with other hurdle technologies such as boiling and milk pasteurisation. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Rodent malaria: BCG-induced protection and immunosuppression

    International Nuclear Information System (INIS)

    Smrkovski, L.L.; Strickland, G.T.

    1978-01-01

    One dose of 10 7 viable units of Mycobacterium bovis, strain BCG, protected a significant number of Swiss mice from a primary challenge with 10 4 thoracic sporozoites of Plasmodium berghei. Immunization with irradiated sporozoites induced greater protection than that observed in BCG-treated animals. Mice treated with BCG and surviving a primary sporozoite challenge were not protected from rechallenge, whereas mice immunized with irradiated sporozoites and surviving initial challenge of sporozoites were solidly immune to further challenge. Immunizing mice with BCG and irradiated sporozoites simulataneously resulted in a synergistic effect of increased protection against a primary challenge of sporozoites only if the two immunogens were administered on the same day and if the mice were challenged 1 to 3 days later. Mice given BCG and irradiated sporozoites and surviving a primary challenge of sporozoites were unable to survive rechallenge. BCG given to mice previously immunized with irradiated sporozoites suppressed their protective immunity against sporozoite challenge

  15. Immunization with Bacillus Calmette-Guérin (BCG) alleviates neuroinflammation and cognitive deficits in APP/PS1 mice via the recruitment of inflammation-resolving monocytes to the brain.

    Science.gov (United States)

    Zuo, Zejie; Qi, Fangfang; Yang, Junhua; Wang, Xiao; Wu, Yingying; Wen, Yaru; Yuan, Qunfang; Zou, Juntao; Guo, Kaihua; Yao, Zhi Bin

    2017-05-01

    The immune system plays a crucial role in the progression of Alzheimer's disease (AD). Recently, immune-dependent cascade induced by systemic immune activation has been verified to play a beneficial role in AD mouse models. Here, we tested whether Bacillus Calmette-Guérin (BCG) immunization alters AD pathology and cognitive dysfunction in APP/PS1 AD mouse model, and with 4Aβ1-15 vaccination as positive control. It was found that BCG treatment reversed the cognitive decline to the extent observed in 4Aβ1-15 group, but did not reduce the β-amyloid (Aβ) burden in the brain. Then, we demonstrated the enhanced recruitment of inflammation-resolving monocytes across the choroid plexus and perivascular spaces to cerebral sites of plaque pathology in APP/PS1 mice immunized with BCG. Furthermore, elevated splenocyte Foxp3 + regulatory T cell levels in the control APP/PS1 mice were down-regulated back to the wild-type (WT) levels by BCG treatment but not 4Aβ1-15 vaccination. In addition, BCG treatment induced the production of more circulating interferon (IFN)-γ than the controls and 4Aβ1-15 vaccination. Though the similar reductions in brain levels of pro-inflammatory cytokines were observed in the BCG and 4Aβ1-15 groups compared to the controls, only BCG had the great effect in upregulating cerebral anti-inflammatory cytokine levels as well as elevating the expression of neurotrophic factors in the brain of APP/PS1 mice. Thus, it is suggested that BCG exerts a beneficial immunomodulatory effect in APP/PS1 mice through mitigation of systemic immune suppression, induction of IFN-γ response and alleviation of the neuroinflammatory response. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Molecular analysis of Mycobacterium isolates from patients with BCG-induced lymphadenitis

    Directory of Open Access Journals (Sweden)

    Farahnoosh Doustdar

    2015-01-01

    Conclusion: As all of the strains isolated from the patients were confirmed as M. bovis BCG strain Pasteur, the other possible factors causing BCG complications, including BCG overdose, faulty intradermal technique, and disturbance of cellular immunity, must be considered.

  17. BCG lowers plasma cholesterol levels and delays atherosclerotic lesion progression in mice

    NARCIS (Netherlands)

    Dam, A.D. van; Bekkering, S.; Crasborn, M.; Beek, L. van der; Berg, S.M. van den; Vrieling, F.; Joosten, S.A.; Harmelen, V. van; Winther, M.P. de; Lutjohann, D.; Lutgens, E.; Boon, M.R.; Riksen, N.P.; Rensen, P.C.; Berbee, J.F.

    2016-01-01

    BACKGROUND AND AIMS: Bacille-Calmette-Guerin (BCG), prepared from attenuated live Mycobacterium bovis, modulates atherosclerosis development as currently explained by immunomodulatory mechanisms. However, whether BCG is pro- or anti-atherogenic remains inconclusive as the effect of BCG on

  18. Tuberculin reaction, BCG scar, and lower female mortality

    DEFF Research Database (Denmark)

    Roth, Adam Anders Edvin; Sodemann, Morten; Jensen, Henrik

    2006-01-01

    Recent studies have suggested that bacille Calmette-Guérin (BCG) immunization may have a nonspecific beneficial effect on infant survival and that the effect may be more pronounced among girls. In a prospective birth cohort, we examine whether a positive tuberculin skin test and BCG scar...... in response to BCG immunization were related to better overall survival in Guinea-Bissau and, if so, whether the effect was sex-specific....

  19. The efficacy of BCG TICE and BCG Connaught in a cohort of 2,099 patients with T1G3 non-muscle-invasive bladder cancer

    NARCIS (Netherlands)

    Witjes, J.A.; Dalbagni, G.; Karnes, R.J.; Shariat, S.; Joniau, S.; Palou, J.; Serretta, V.; Larre, S.; Stasi, S. Di; Colombo, R.; Babjuk, M.; Malmstrom, P.U.; Malats, N.; Irani, J.; Baniel, J.; Cai, T.; Cha, E.; Ardelt, P.; Varkarakis, J.; Bartoletti, R.; Spahn, M.; Pisano, F.; Gontero, P.; Sylvester, R.

    2016-01-01

    BACKGROUND: Potential differences in efficacy of different bacillus Calmette-Guerin (BCG) strains are of importance for daily practice, especially in the era of BCG shortage. OBJECTIVE: To retrospectively compare the outcome with BCG Connaught and BCG TICE in a large study cohort of pT1 high-grade

  20. Bacille Calmette-Guérin-vaccination kan muligvis sænke den generelle sygelighed hos børn

    DEFF Research Database (Denmark)

    Nissen, Thomas Nørrelykke; Thøstesen, Lisbeth Marianne; Birk, Nina Marie

    2014-01-01

    For almost 100 years the bacille Calmette-Guérin (BCG) vaccine has been the primary prophylaxis of tuberculosis (TB). Recent studies suggest that reintroduction of the vaccine might be beneficial from a general child health perspective. Studies from West-Africa report that BCG vaccination at birth...... reduces child mortality and morbidity. We recently started "The Calmette Study" in Denmark to conduct a randomised clinical trial and collect firm evidence of the suggested hypothesis, that BCG vaccination at birth has beneficial unspecific effect on child health also in a high-income TB low...

  1. A New Rabbit-Skin Model to Evaluate Protective Efficacy of Tuberculosis Vaccines.

    Science.gov (United States)

    Chen, Huiyu; Liu, Xun; Ma, Xingming; Wang, Qian; Yang, Guang; Niu, Hongxia; Li, Shuaixiang; He, Bingzheng; He, Shanshan; Dannenberg, Arthur M; Zhu, Bingdong; Zhang, Ying

    2017-01-01

    Background: BCG protection is suboptimal and there is significant interest to develop new tuberculosis (TB) vaccines. However, there are significant limitations of the current vaccine evaluation systems in the mouse model. Here, we developed a BCG-challenge rabbit skin model as a new way to evaluate the protective efficacy of selected TB subunit vaccine candidates. Methods: Rabbits were immunized with subunit vaccines, including EAMM (ESAT6-Ag85B-MPT64 -Mtb8.4), MH (Mtb10.4-HspX), and LT70 (ESAT6-Ag85B-MPT64 -Mtb8.4-Rv2626c) three times subcutaneously every 3-weeks and challenged with the attenuated Mycobacterium bovis BCG intradermally 6-weeks after last immunization. The immune response induced by the vaccine candidates was measured, the histopathology induced by the BCG challenge was studied, and the number of bacilli in the liquefied caseum was determined. Results: The subunit vaccines generated high antigen-specific IgG antibodies and fastened the liquefaction and healing process, and significantly reduced the viable BCG load. The subunit vaccine LT70 and EAMM-MH reduced BCG bacterial load in comparison to proteins EAMM, MH, Rv2626c, and also BCG itself. The Koch phenomena induced by the LT70 and combination of EAMM-MH were the same as that produced by BCG itself and were more rapid than those induced by the other proteins and the saline controls. Conclusions: The subunit vaccines LT70 and the combination of EAMM-MH showed promising protective efficacy as expected in the rabbit skin model, which can serve as a visual and convenient new model for evaluating TB vaccines.

  2. Neonatal vaccination of low birthweight infants in Ghana.

    Science.gov (United States)

    O'Leary, Maureen; Edmond, Karen; Floyd, Sian; Hurt, Lisa; Shannon, Caitlin; Thomas, Gyan; Newton, Sam; Kirkwood, Betty; Thomas, Sara

    2017-02-01

    Global vaccination policy advocates for identifying and targeting groups who are underserved by vaccination to increase equity and uptake. We investigated whether birth weight and other factors are determinants of neonatal BCG vaccination in order to identify infants underserved by vaccination. We used logistic regression to calculate adjusted ORs (AORs) for the association between birth weight (categorised as non-low birth weight (NLBW) (≥2.50 kg) and low birth weight (LBW) (2-2.49 kg, 1.50-1.99 kg and vaccination with BCG at the end of the neonatal period (0-27 days). We assessed whether this association varied by place of delivery and infant illness. We calculated how BCG timing and uptake would improve by ensuring the vaccination of all facility-born infants prior to discharge. There was a strong dose-response relationship between LBW and not receiving BCG in the neonatal period (p-trendvaccination 1.6 times (AOR 1.64; 95% CI 1.30 to 2.08), and those weighing vaccination (p-interaction all >0.19). Facility-born infants were vaccinated at a mean of 6 days, suggesting that they were not vaccinated in the facility at birth but were referred for vaccination. LBW is a risk factor for neonatal under-vaccination, even for facility-born infants. Ensuring vaccination at facility births would substantively improve timing and equitable BCG vaccination. 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/.

  3. Difference in TB10.4 T-cell epitope recognition following immunization with recombinant TB10.4, BCG or infection with Mycobacterium tuberculosis

    DEFF Research Database (Denmark)

    Billeskov, Rolf; Grandal, Michael V; Poulsen, Christian

    2010-01-01

    Most novel vaccines against infectious diseases are based on recombinant Ag; however, only few studies have compared Ag-specific immune responses induced by natural infection with that induced by the same Ag in a recombinant form. Here, we studied the epitope recognition pattern of the tuberculosis...... vaccine Ag, TB10.4, in a recombinant form, or when expressed by the pathogen Mycobacterium tuberculosis (M.tb), or by the current anti-tuberculosis vaccine, Mycobacterium bovis BCG. We showed that BCG and M.tb induced a similar CD4(+) T-cell specific TB10.4 epitope-pattern, which differed completely from...... that induced by recombinant TB10.4. This difference was not due to post-translational modifications of TB10.4 or because TB10.4 is secreted from BCG and M.tb as a complex with Rv0287. In addition, BCG and TB10.4/CAF01 were both taken up by DC and macrophages in vivo, and in vitro uptake experiments revealed...

  4. Asociación entre tuberculosis infantil grave e inmunización previa con BCG en un hospital de referencia nacional, Perú 1990-2000 Association between severe tuberculosis in children and previous BCG immunization in a national referral Hospital, Peru 1990-2000

    Directory of Open Access Journals (Sweden)

    Félix Llanos-Tejada

    2012-03-01

    Full Text Available El objetivo del estudio fue determinar la asociación entre la inmunización con BCG y tuberculosis grave (TB. Se realizó un estudio retrospectivo, se incluyó fichas de pacientes atendidos en el servicio de neumología del Instituto Nacional de Salud del Niño de Perú, entre los años 1990-2000. Se revisaron un total de 2106 casos de TB entre los que había 259 casos graves (TB miliar o meningoencefalitis por TB. Del total, 497 casos no tenían antecedente de inmunización con BCG; 202 tenían TB grave y 295 TB no grave (OR= 0,05; IC 95%= 0,03-0,07. En conclusión, los niños con diagnóstico de TB y que han sido inmunizados con BCG, tienen 94% menos riesgo de desarrollar TB grave, en comparación a los niños con diagnóstico no inmunizados con BCG.The objective of the study was to determine the association between BCG immunization and severe tuberculosis (TB. We performed a retrospective study, including medical records from patients of the pneumology department at the National Children’s Institute in Peru, between the years 1990-2000. A total of 2106 TB cases were reviewed, from them 259 patients were severe (miliary TB or meningoencephalitic TB. From all, 497 cases did not have history of BCG vaccination, 202 had severe TB and 295 non-severe TB (OR = 0.05, 95% CI = 0.03 to 0.07. In conclusion, children diagnosed with TB and who have been immunized with BCG, has 94% lower risk of developing severe TB, compared to children with TB non-immunized with BCG.

  5. Immunization of Mice by BCG Formulated HCV Core Protein Elicited Higher Th1-Oriented Responses Compared to Pluronic-F127 Copolymer

    Science.gov (United States)

    Yazdanian, Maryam; Memarnejadian, Arash; Mahdavi, Mehdi; Sadat, Seyed Mehdi; Motevali, Fatemeh; Vahabpour, Rouhollah; Khanahmad, Hossein; Siadat, Seyed Davar; Aghasadeghi, Mohammad Reza; Roohvand, Farzin

    2013-01-01

    Background A supreme vaccine for Hepatitis C virus (HCV) infection should elicit strong Th1-oriented cellular responses. In the absence of a Th1-specific adjuvant, immunizations by protein antigens generally induce Th2-type and weak cellular responses. Objectives To evaluate the adjuvant effect of BCG in comparison with nonionic copolymer-Pluronic F127 (F127) as a classic adjuvant in the formulation of HCV core protein (HCVcp) as a candidate vaccine for induction of Th1 immune responses. Materials and Methods Expression of N-terminally His-Tagged HCVcp (1-122) by pIVEX2.4a-core vector harboring the corresponding gene under the control of arabinose-inducible (araBAD) promoter was achieved in BL21-AI strain of E.coli and purified through application of nitrilotriacetic acid (Ni-NTA) chromatography. Mice were immunized subcutaneously (s.c.) in base of the tail with 100 μl of immunogen (F127+HCVcp or BCG+HCVcp; 5 μgHCVcp/mouse/dose) or control formulations (PBS, BCG, F127) at weeks 0, 3, 6. Total and subtypes of IgG, as well as cellular immune responses (Proliferation, In vivo CTL and IFN-γ/IL-4 ELISpot assays against a strong and dominant H2-d restricted, CD8+-epitopic peptide, core 39-48; RRGPRLGVRA of HCVcp) were compared in each group of immunized animals. Results Expression and purification of core protein around the expected size (21 kDa) was confirmed by Western blotting. The HCVcp + BCG vaccinated mice showed significantly higher lymphocyte proliferation and IFN-γ production but lower levels of cell lysis (45% versus 62% in CTL assay) than the HCVcp+F127 immunized animals. “Besides, total anti-core IgG and IgG1 levels were significantly higher in HCVcp + F127 immunized mice as compared to HCVcp + BCG vaccinated animals, indicating relatively higher efficacy of F127 for the stimulation of humoral and Th2-oriented immune responses”. Conclusions Results showed that HCVcp + BCG induced a moderate CTL and mixed Th1/Th2 immune responses with higher levels of

  6. Mycobacterium bovis endophthalmitis from BCG immunotherapy for bladder cancer

    NARCIS (Netherlands)

    Gerbrandy, S. J. F.; Schreuders, L. C.; de Smet, M. D.

    2008-01-01

    BACKGROUND: We report a patient who developed BCG endophthalmitis after BCG immunotherapy for bladder cancer. Comparison of this case with 2 other reported cases reveals a similar pattern of elderly, debilitated and immunocompromised patients with poor response to systemic antituberculous therapy in

  7. Murine model of BCG lung infection: Dynamics of lymphocyte ...

    Indian Academy of Sciences (India)

    Unknown

    pulmonary BCG infection. Few T cells in tracheal LN of BCG infected mice produce IFNγ, suggesting that maturational changes associated with migration to the lungs or residence in the lungs enhance the capability of some T cells to produce this cytokine. [Saxena R K, Weissman D, Simpson J and Lewis D M 2002 Murine ...

  8. Revaccination of cattle with bacille Calmette-Guérin two years after first vaccination when immunity has waned, boosted protection against challenge with Mycobacterium bovis.

    Directory of Open Access Journals (Sweden)

    Natalie A Parlane

    Full Text Available In both humans and animals, controversy exists concerning the duration of protection induced by BCG vaccine against tuberculosis (TB and whether revaccination enhances protection. A long-term study was undertaken to determine whether BCG-vaccinated calves would be protected against challenge with Mycobacterium bovis 2½ years after vaccination and to determine the effect of revaccination after 2 years. Seventy-nine calves were divided into five groups (n = 15-17 calves/group with four of the groups vaccinated subcutaneously with 105 CFU of BCG Danish at 2-4 weeks of age and the fifth group serving as non-vaccinated controls. Three of the four BCG-vaccinated groups were revaccinated 2 years after the initial vaccination. One BCG-vaccinated group was revaccinated with BCG. A second group was vaccinated subcutaneously with a TB protein vaccine consisting of biopolyester particles (Biobeads displaying two mycobacterial proteins, ESAT-6 and Antigen 85A, mixed with an adjuvant. A third group was vaccinated with TB proteins from M. bovis culture filtrate, mixed with an adjuvant. Twenty-three weeks after the BCG revaccination, all animals were challenged endotracheally with virulent M. bovis and a further 13 weeks later, animals were killed and necropsied to determine protection against TB. The BCG-vaccinated animals produced positive tuberculin caudal fold intradermal (15 of 62 animals and IFN-γ TB test responses (six of 62 animals at 6 months after vaccination, but not at subsequent time-points compared to the non-vaccinated animals. Calves receiving a single vaccination with BCG vaccine 2½ years prior to challenge were not protected against TB, while those revaccinated with BCG 2 years after the initial vaccination displayed significant reductions in lung and pulmonary lymph node lesion scores compared to the non-vaccinated animals. In contrast, no reduction in lesion scores was observed in the animals revaccinated with the TB protein vaccines with

  9. Natural killer cell cytokine response to M. bovis BCG Is associated with inhibited proliferation, increased apoptosis and ultimate depletion of NKp44(+CD56(bright cells.

    Directory of Open Access Journals (Sweden)

    Damien Portevin

    Full Text Available Mycobacterium bovis BCG, a live attenuated strain of M. bovis initially developed as a vaccine against tuberculosis, is also used as an adjuvant for immunotherapy of cancers and for treatment of parasitic infections. The underlying mechanisms are thought to rely on its immunomodulatory properties including the recruitment of natural killer (NK cells. In that context, we aimed to study the impact of M. bovis BCG on NK cell functions. We looked at cytotoxicity, cytokine production, proliferation and cell survival of purified human NK cells following exposure to single live particles of mycobacteria. We found that M. bovis BCG mediates apoptosis of NK cells only in the context of IL-2 stimulation during which CD56(bright NK cells are releasing IFN-γ in response to mycobacteria. We found that the presence of mycobacteria prevented the IL-2 induced proliferation and surface expression of NKp44 receptor by the CD56(bright population. In summary, we observed that M. bovis BCG is modulating the functions of CD56(bright NK cells to drive this subset to produce IFN-γ before subsequent programmed cell death. Therefore, IFN-γ production by CD56(bright cells constitutes the main effector mechanism of NK cells that would contribute to the benefits observed for M. bovis BCG as an immunotherapeutic agent.

  10. Natural killer cell cytokine response to M. bovis BCG Is associated with inhibited proliferation, increased apoptosis and ultimate depletion of NKp44(+)CD56(bright) cells.

    Science.gov (United States)

    Portevin, Damien; Young, Douglas

    2013-01-01

    Mycobacterium bovis BCG, a live attenuated strain of M. bovis initially developed as a vaccine against tuberculosis, is also used as an adjuvant for immunotherapy of cancers and for treatment of parasitic infections. The underlying mechanisms are thought to rely on its immunomodulatory properties including the recruitment of natural killer (NK) cells. In that context, we aimed to study the impact of M. bovis BCG on NK cell functions. We looked at cytotoxicity, cytokine production, proliferation and cell survival of purified human NK cells following exposure to single live particles of mycobacteria. We found that M. bovis BCG mediates apoptosis of NK cells only in the context of IL-2 stimulation during which CD56(bright) NK cells are releasing IFN-γ in response to mycobacteria. We found that the presence of mycobacteria prevented the IL-2 induced proliferation and surface expression of NKp44 receptor by the CD56(bright) population. In summary, we observed that M. bovis BCG is modulating the functions of CD56(bright) NK cells to drive this subset to produce IFN-γ before subsequent programmed cell death. Therefore, IFN-γ production by CD56(bright) cells constitutes the main effector mechanism of NK cells that would contribute to the benefits observed for M. bovis BCG as an immunotherapeutic agent.

  11. Efficacy of a vaccine formula against tuberculosis in cattle.

    Directory of Open Access Journals (Sweden)

    Germinal J Canto Alarcon

    Full Text Available "Test-and-slaughter" has been successful in industrialized countries to control and eradicate tuberculosis from cattle; however, this strategy is too expensive for developing nations, where the prevalence is especially high. Vaccination with the Calmette-Guérin (BCG strain has been shown to protect against the development of lesions in vaccinated animals: mouse, cattle and wildlife species. In this study, the immune response and the pathology of vaccinated (BCG-prime and BCG prime-CFP-boosted and unvaccinated (controls calves were evaluated under experimental settings. A 10(6 CFU dose of the BCG strain was inoculated subcutaneously on the neck to two groups of ten animas each. Thirty days after vaccination, one of the vaccinated groups was boosted with an M. bovis culture filtrate protein (CFP. Three months after vaccination, the three groups of animals were challenged with 5×10(5 CFU via intranasal by aerosol with a field strain of M. bovis. The immune response was monitored throughout the study. Protection was assessed based on immune response (IFN-g release prechallenge, presence of visible lesions in lymph nodes and lungs at slaughter, and presence of bacilli in lymph nodes and lung samples in histological analysis. Vaccinated cattle, either with the BCG alone or with BCG and boosted with CFP showed higher IFN-g response, fewer lesions, and fewer bacilli per lesion than unvaccinated controls after challenge. Animals with low levels of IFN-g postvaccine-prechallenge showed more lesions than animals with high levels. Results from this study support the argument that vaccination could be incorporated into control programs to reduce the incidence of TB in cattle in countries with high prevalence.

  12. Central memory CD4+ T cells are responsible for the recombinant Bacillus Calmette-Guérin ΔureC::hly vaccine's superior protection against tuberculosis.

    Science.gov (United States)

    Vogelzang, Alexis; Perdomo, Carolina; Zedler, Ulrike; Kuhlmann, Stefanie; Hurwitz, Robert; Gengenbacher, Martin; Kaufmann, Stefan H E

    2014-12-15

    Bacillus Calmette-Guérin (BCG) has been used for vaccination against tuberculosis for nearly a century. Here, we analyze immunity induced by a live tuberculosis vaccine candidate, recombinant BCG ΔureC::hly vaccine (rBCG), with proven preclinical and clinical safety and immunogenicity. We pursue in-depth analysis of the endogenous mycobacteria-specific CD4(+) T-cell population, comparing the more efficacious rBCG with canonical BCG to determine which T-cell memory responses are prerequisites for superior protection against tuberculosis. rBCG induced higher numbers and proportions of antigen-specific memory CD4(+) T cells than BCG, with a CXCR5(+)CCR7(+) phenotype and low expression of the effector transcription factors T-bet and Bcl-6. We found that the superior protection of rBCG, compared with BCG, correlated with higher proportions and numbers of these central memory T cells and of T follicular helper cells associated with specific antibody responses. Adoptive transfer of mycobacteria-specific central memory T cells validated their critical role in protection against pulmonary tuberculosis. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

  13. Bacillus Calmette-Guérin Vaccination Using a Microneedle Patch

    Science.gov (United States)

    Hiraishi, Yasuhiro; Nandakumar, Subhadra; Choi, Seong-O; Lee, Jeong Woo; Kim, Yeu-Chun; Posey, James E.; Sable, Suraj B.; Prausnitz, Mark R.

    2011-01-01

    Tuberculosis (TB) caused by Mycobacterium tuberculosis continues to be a leading cause of mortality among bacterial diseases, and the bacillus Calmette-Guerin (BCG) is the only licensed vaccine for human use against this disease. TB prevention and control would benefit from an improved method of BCG vaccination that simplifies logistics and eliminates dangers posed by hypodermic needles without compromising immunogenicity. Here, we report the design and engineering of a BCG-coated microneedle vaccine patch for a simple and improved intradermal delivery of the vaccine. The microneedle vaccine patch induced a robust cell-mediated immune response in both the lungs and spleen of guinea pigs. The response was comparable to the traditional hypodermic needle based intradermal BCG vaccination and was characterized by a strong antigen specific lymphocyte proliferation and IFN-γ levels with high frequencies of CD4+IFN-γ+, CD4+TNF-α+ and CD4+IFN-γ+TNF-α+ T cells. The BCG-coated microneedle vaccine patch was highly immunogenic in guinea pigs and supports further exploration of this new technology as a simpler, safer, and compliant vaccination that could facilitate increased coverage, especially in developing countries that lack adequate healthcare infrastructure. PMID:21277407

  14. Síndrome de reconstitución inmune por BCG en niños tratados por VIH Immune reconstitution syndrome due to BCG in HIV-treated children

    Directory of Open Access Journals (Sweden)

    Edwin Miranda-Choque

    2012-12-01

    Full Text Available El objetivo del estudio fue describir el perfil clínico del síndrome de reconstitución inmune por Mycobacterium bovis Bacillus Calmette-Guérin (SIRI-BCG en niños con infección VIH que reciben tratamiento antirretroviral de gran actividad (TARGA en el Instituto Nacional de Salud del Niño de Lima, Perú. Se realizó un estudio de serie de casos, que incluyó ocho niños con SIRI-BCG, definido como la presencia de linfadenopatía regional o inflamación en sitio de inoculación de BCG con disminución de al menos un logaritmo en la carga viral o mejoría inmunológica. Todos los pacientes tenían estadio SIDA (C3. La mediana de edad de inicio del TARGA fue de 7,2 meses y el evento se produjo entre 3 a 11 semanas luego de haberlo iniciado. En siete casos se produjo adenitis axilar. Al comparar con el grupo sin SIRI-BCG se encontró asociación significativa con la edad de inicio del TARGA de un año, estado de inmunodepresión severa, y carga viral incrementada. Se concluye que el SIRI-BCG está relacionado con una rápida progresión clínica de la infección VIH/SIDA de trasmisión vertical, estadio de inmunosupresión severa, y carga viral alta al momento del inicio del TARGA.The objective of this study is to describe the clinical profile of the immune reconstitution syndrome due to Mycobacterium bovis Bacillus Calmette-Guérin (IRS-BCG in children with HIV infection who receive highly active antiretroviral treatment (HAART at Instituto Nacional de Salud del Niño de Lima (National Children’s Health Institute of Lima, Peru. A case study was conducted, including 8 children with IRS-BCG, defined as the presence of regional lymphadenopathy or inflammation on the BCG vaccination site with at least one less logarithm in the viral load or immune improvement. All patients had AIDS (C3. The starting median age in HAART was 7.2 months and the event occurred 3 to 11 weeks after the treatment was started. 7 cases showed axillary adenitis. When

  15. BCG Induced Necrosis of the Entire Bladder Urothelium

    Directory of Open Access Journals (Sweden)

    Malte Krönig

    2015-09-01

    Full Text Available Instillation therapy with attenuated tuberculosis bacteria (BCG can significantly reduce rates of recurrence of non-muscle invasive bladder cancer. Local and systemic side effects such as dysuria, irritative voiding symptoms or partial bladder contracture and systemic inflammation were reported. A 75 year-old male patient with recurrent non muscle invasive bladder cancer developed necrosis of the entire bladder urothelium more than six years after BCG instillation immunotherapy. The resulting irritative voiding symptoms and low bladder capacity required radical cystectomy. BCG instillation can cause severe side effects, which develop gradually and eventually need radical surgical therapy such as cystectomy without tumor recurrence.

  16. Immune response elicited by two rBCG strains devoid of genes involved in c-di-GMP metabolism affect protection versus challenge with M. tuberculosis strains of different virulence.

    Science.gov (United States)

    Segura-Cerda, Cristian Alfredo; Aceves-Sánchez, Michel de Jesús; Marquina-Castillo, Brenda; Mata-Espinoza, Dulce; Barrios-Payán, Jorge; Vega-Domínguez, Perla Jazmín; Pedroza-Roldán, César; Bravo-Madrigal, Jorge; Vallejo-Cardona, Alba Adriana; Hernández-Pando, Rogelio; Flores-Valdez, Mario Alberto

    2018-04-12

    Pellicles, a type of biofilm, have gathered a renewed interest in the field of tuberculosis as a structure that mimics some characteristics occurring during M. tuberculosis infection, such as antibiotic recalcitrance and chronicity of infection, and as a source of antigens for humoral response in infected guinea pigs. In other bacteria, it has been well documented that the second messenger c-di-GMP modulates the transition from planktonic cells to biofilm formation. In this work, we used the live vaccine Mycobacterium bovis BCG to determine whether deletion of genes involved in c-di-GMP metabolism would affect interaction with macrophages, capacity to induce immune response in a murine cell line and mice, and how the protein profile was modified when grown as surface pellicles. We found that deletion of the BCG1419c (Delta c-di-GMP phosphodiesterase, ΔPDE) gene, or deletion of the BCG1416c (Delta c-di-GMP diguanylate cyclase, ΔDGC) gene, altered production of TNF-α, IL-6, and IL-1β, in murine macrophages, and resulted in attenuation in intra-macrophage replication. Moreover, in addition to the improved immunogenicity of the BCGΔBCG1419c mutant already reported, deletion of the BCG1416c gene leads to increased T CD4 + and T CD8 + activation. This correlated with protection versus lethality in mice infected with the highly virulent M. tuberculosis 5186 afforded by vaccination with all the tested BCG strains, and controlled the growth of the mildly virulent M. tuberculosis H37Rv in lungs by vaccination with BCGΔBCG1419c during chronic late infection from 4 to 6 months after challenge. Furthermore, when grown as surface pellicles, a condition used to manufacture BCG vaccine, in comparison to BCG wild type, both rBCGs changed expression of antigenic proteins such as DnaK, HbhA, PstS2, 35KDa antigen, GroEL2, as well as AcpM, a protein involved in synthesis of mycolic acids, molecules relevant to modulate inflammatory responses. Copyright © 2018 Elsevier Ltd. All

  17. Human T cell responses induced by vaccination with Mycobacterium bovis bacillus Calmette-Guérin

    DEFF Research Database (Denmark)

    Ravn, P; Boesen, H; Pedersen, B K

    1997-01-01

    Many aspects of the widely used bacillus Calmette-Guérin (BCG) vaccine against tuberculosis are still the subject of controversy. There is a huge variation in efficacy from one clinical trial to another and no relationship between vaccine-induced skin test conversion and subsequent protection. We...... have studied in vitro cell-mediated immune responses primed by BCG vaccination in 22 healthy Danish donors with different levels of in vitro purified protein derivative (PPD) reactivity before vaccination. The study demonstrated a markedly different development of reactivity to mycobacterial Ags...... depending on the prevaccination sensitivity to PPD. Previously sensitized donors mounted a potent and highly accelerated recall response within the first week of BCG vaccination. Nonsensitized donors, in contrast, exhibited a gradually increasing responsiveness to mycobacterial Ags, reaching maximal levels...

  18. THE ABELL 85 BCG: A NUCLEATED, CORELESS GALAXY

    Energy Technology Data Exchange (ETDEWEB)

    Madrid, Juan P. [Gemini Observatory, Southern Operations Center, Colina El Pino s/n, La Serena (Chile); Donzelli, Carlos J. [Instituto de Astronomía Teórica y Experimental, CONICET-UNC, Laprida 922, Córdoba (Argentina)

    2016-03-01

    New high-resolution r-band imaging of the brightest cluster galaxy (BCG) in Abell 85 (Holm 15A) was obtained using the Gemini Multi Object Spectrograph. These data were taken with the aim of deriving an accurate surface brightness profile of the BCG of Abell 85, in particular, its central region. The new Gemini data show clear evidence of a previously unreported nuclear emission that is evident as a distinct light excess in the central kiloparsec of the surface brightness profile. We find that the light profile is never flat nor does it present a downward trend toward the center of the galaxy. That is, the new Gemini data show a different physical reality from the featureless, “evacuated core” recently claimed for the Abell 85 BCG. After trying different models, we find that the surface brightness profile of the BCG of Abell 85 is best fit by a double Sérsic model.

  19. Disseminated BCG infection in a patient with severe combined immunodeficiency

    International Nuclear Information System (INIS)

    Han, Tae Il; Kim, In One; Kim, Woo Sun; Yeon, Kyung Mo

    2000-01-01

    Disseminated mycobacterial infection after bacillus Calmette-Guerin (BCG) accination is a very rare disorder, occurring mostly in patients with immunologic eficiency. We report a case of disseminated BCG infection in a 16-month-old girl with severe combined immunodeficiency. Plain radiographs showed multiple osteolytic lesions in the femora, tibiae, humerus, and phalanges. Abdominal sonography and CT scanning revealed multiple nodules in the spleen, and portocaval lymphadenopathy

  20. Disseminated BCG infection in a patient with severe combined immunodeficiency

    Energy Technology Data Exchange (ETDEWEB)

    Han, Tae Il [Eulji University School of Medicine, Taejon (Korea, Republic of); Kim, In One; Kim, Woo Sun; Yeon, Kyung Mo [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2000-06-01

    Disseminated mycobacterial infection after bacillus Calmette-Guerin (BCG) accination is a very rare disorder, occurring mostly in patients with immunologic eficiency. We report a case of disseminated BCG infection in a 16-month-old girl with severe combined immunodeficiency. Plain radiographs showed multiple osteolytic lesions in the femora, tibiae, humerus, and phalanges. Abdominal sonography and CT scanning revealed multiple nodules in the spleen, and portocaval lymphadenopathy.

  1. [Disseminated BCG infection in patients with urinary bladder carcinoma].

    Science.gov (United States)

    Korać, Milos; Milosević, Branko; Lavadinović, Lidija; Janjić, Aleksandar; Brmbolić, Branko

    2009-01-01

    Bacillus Calmette-Guërin--a live, attenuated strain of Mycobacterium bovis has been used in immunotherapy of patients with superficial urinary bladder carcinoma. Some patients develop complications after intravesical instillation of BCG: high temperature followed by hematuria or granulomatous prostatits, epidydimoorchitis, urethral obstruction, and less than 1% have a systemic disease followed by dissemination of bacteria into other organs. A 50-year-old man underwent transurethral resection of a bladder tumor. One month after the operation BCG intravesical installations were administered for three weeks. After the fourth installation, our patient developed high fever, fatigue, vomiting, dark urine, light stools, and jaundice. On admission he was jaundiced with a high fever, enlarged liver and spleen and laboratory findings which included high erythrocyte sedimentation rate, pancytopenia, elevated liver enzymes, especially alkaline phosphatase and aminotranspherases. The bone-marrow biopsy showed granulomatous inflamation suggesting mycobacterial spread in the bone marrow, liver and spleen and sepsis. The patient was initially treated with antituberculous therapy, but his state did not improve until corticosteroids were added to the antituberculous treatment regimen. Although dissemination of BCG is a rare complication of intravesical BCG treatment of the bladder carcinoma, it may result in prolonged fever and granulomatous inflamation of the liver, spleen, lungs, bone marrow and BCG sepsis. Antituberclous agents in combination with corticosteroids comprise the treatment of choice for disseminated BCG infection.

  2. Vaccination Timeliness in Children Under India's Universal Immunization Program.

    Science.gov (United States)

    Shrivastwa, Nijika; Gillespie, Brenda W; Lepkowski, James M; Boulton, Matthew L

    2016-09-01

    India has the highest number of deaths among children younger than 5 years of age globally; the majority are from vaccine preventable diseases. Untimely vaccination unnecessarily prolongs susceptibility to disease and contributes to the burden of childhood morbidity and mortality, yet there is scarce literature on vaccination delays. The aim of this study is to characterize the timeliness of childhood vaccinations administered under India's routine immunization program using a novel application of an existing statistical methodology. This study utilized the district level household and facility survey data, 2008 from India using vaccination data from children with and without immunization cards. Turnbull estimator of the cumulative distribution function was used to estimate the probability of vaccination at each age. Timeliness of Bacille Calmette-Guerin (BCG), all 3 doses of diphtheria, pertussis and tetanus vaccine (DPT) and measles-containing vaccine (MCV) were considered for this analysis. Vaccination data on 268,553 children who were 0-60 months of age were analyzed; timely administration of BCG, DPT3 and MCV occurred in 31%, 19% and 34% of children, respectively. The estimated vaccination probability plateaued for DPT and BCG around the age of 24 months, whereas MCV uptake increased another 5% after 24 months of age. The 5-year coverage of BCG, DPT3 and MCV in Indian children was 87%, 63% and 76%, respectively. Lack of timely administration of key childhood vaccines, especially DPT3 and MCV, remains a major challenge in India and likely contributes to the significant burden of vaccine preventable disease-related morbidity and mortality in children.

  3. The contribution of non-conventional T cells and NK cells in the mycobacterial-specific IFNγ response in Bacille Calmette-Guerin (BCG-immunized infants.

    Directory of Open Access Journals (Sweden)

    Christel Zufferey

    Full Text Available BACKGROUND: The Mycobacterium bovis Bacille Calmette-Guérin (BCG vaccine is given to >120 million infants each year worldwide. Most studies investigating the immune response to BCG have focused on adaptive immunity. However the importance of TCR-gamma/delta (γδ T cells and NK cells in the mycobacterial-specific immune response is of increasing interest. METHODS: Participants in four age-groups were BCG-immunized. Ten weeks later, in vitro BCG-stimulated blood was analyzed for NK and T cell markers, and intracellular IFNgamma (IFNγ by flow cytometry. Total functional IFNγ response was calculated using integrated median fluorescence intensity (iMFI. RESULTS: In infants and children, CD4 and CD4-CD8- (double-negative (DN T cells were the main IFNγ-expressing cells representing 43-56% and 27-37% of total CD3+ IFNγ+ T cells respectively. The iMFI was higher in DN T cells compared to CD4 T cells in all age groups, with the greatest differences seen in infants immunized at birth (p=0.002 or 2 months of age (p<0.0001. When NK cells were included in the analysis, they accounted for the majority of total IFNγ-expressing cells and, together with DN Vδ2 γδ T cells, had the highest iMFI in infants immunized at birth or 2 months of age. CONCLUSION: In addition to CD4 T cells, NK cells and DN T cells, including Vδ2 γδ T cells, are the key populations producing IFNγ in response to BCG immunization in infants and children. This suggests that innate immunity and unconventional T cells play a greater role in the mycobacterial immune response than previously recognized and should be considered in the design and assessment of novel tuberculosis vaccines.

  4. Systemic BCG-Osis as a Rare Side Effect of Intravesical BCG Treatment for Superficial Bladder Cancer

    Directory of Open Access Journals (Sweden)

    S. Lukacs

    2013-01-01

    Full Text Available Intravesical Bacilli Calmette-Guérin (BCG immunotherapy is a commonly used treatment for superficial bladder cancer. Although the treatment is well tolerated in 95% of cases, life-threatening side effects including BCG sepsis can occur. This report describes the case of an 82-year-old man with a background of lung disease. He developed septic shock and type two respiratory failure after receiving the sixth installation of intravesical BCG (TICE strain immunotherapy for recurrent bladder Transitional Cell Carcinoma in situ. Despite the early initiation of broad spectrum antibiotics (tazocin and gentamicin, he remained pyrexial. There was a rapid deterioration, and on the second day of his admission, he developed type two respiratory failure secondary to Acute Respiratory Distress Syndrome (ARDS prompting transfer to Intensive Care for Bilevel Positive Airway Pressure (BiPAP Ventilation. The blood cultures taken before the induction of antibiotics results were negative. Increasing clinical suspicion of systemic BCG-osis prompted the initiation of antituberculosis therapy (ethambutol, isoniazid rifampicin and steroids. Following six days of BiPAP and anti-tuberculosis therapy in ITU, his condition started to improve. Following a prolonged hospital stay he was discharged on long term ethambutol therapy. BCG-osis is a well-known though rare side effect of intravesical BCG therapy. We would like to highlight the importance of having a low threshold for starting anti-TB treatment.

  5. Sex differences in the effect of vaccines on the risk of hospitalization due to measles in Guinea-bissau

    DEFF Research Database (Denmark)

    Aaby, Peter; Martins, Cesario; Bale, Carlito

    2010-01-01

    Routine immunizations have non-specific and sex-differential effects on childhood mortality and morbidity in low-income countries; BCG and measles vaccine (MV) may reduce and diphtheria-tetanus-pertussis vaccine (DTP) may increase the mortality of girls relative to boys.......Routine immunizations have non-specific and sex-differential effects on childhood mortality and morbidity in low-income countries; BCG and measles vaccine (MV) may reduce and diphtheria-tetanus-pertussis vaccine (DTP) may increase the mortality of girls relative to boys....

  6. The efficacy of BCG TICE and BCG Connaught in a cohort of 2,099 patients with T1G3 non-muscle-invasive bladder cancer.

    Science.gov (United States)

    Witjes, J Alfred; Dalbagni, Guido; Karnes, Robert J; Shariat, Shahrokh; Joniau, Steven; Palou, Joan; Serretta, Vincenzo; Larré, Stéphane; di Stasi, Savino; Colombo, Renzo; Babjuk, Marek; Malmström, Per-Uno; Malats, Nuria; Irani, Jacques; Baniel, Jack; Cai, Tommaso; Cha, Eugene; Ardelt, Peter; Varkarakis, John; Bartoletti, Riccardo; Spahn, Martin; Pisano, Francesca; Gontero, Paolo; Sylvester, Richard

    2016-11-01

    Potential differences in efficacy of different bacillus Calmette-Guérin (BCG) strains are of importance for daily practice, especially in the era of BCG shortage. To retrospectively compare the outcome with BCG Connaught and BCG TICE in a large study cohort of pT1 high-grade non-muscle-invasive bladder cancer patients. Individual patient data were collected for 2,451 patients with primary T1G3 tumors from 23 centers who were treated with BCG for the first time between 1990 and 2011. Using Cox multivariable regression and adjusting for the most important prognostic factors in this nonrandomized comparison, BCG Connaught and TICE were compared for time to recurrence, progression, and the duration of cancer specific survival and overall survival. Information on the BCG strain was available for 2,099 patients: 957 on Connaught and 1,142 on TICE. Overall, 765 (36%) patients received some form of maintenance BCG, 560 (59%) on Connaught and 205 (18%) on TICE. Without maintenance, Connaught was more effective than TICE only for the time to first recurrence (hazard ratio [HR] = 1.48; 95% CI: 1.20-1.82; PBCG significantly reduced the risk of recurrence, progression and death, both overall, and disease specific, for TICE, but not for Connaught. We found that BCG Connaught results in a lower recurrence rate as compared with BCG TICE when no maintenance is used. However, the opposite is true when maintenance is given. As there is currently a BCG shortage, information on the efficacy of different BCG strains is important. In this nonrandomized retrospective comparison in over 2,000 patients, we found that BCG Connaught reduces the recurrence rate compared to BCG TICE when no maintenance is used, but the opposite is true when maintenance is given. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Infant vaccination timing: Beyond traditional coverage metrics for maximizing impact of vaccine programs, an example from southern Nepal.

    Science.gov (United States)

    Hughes, Michelle M; Katz, Joanne; Englund, Janet A; Khatry, Subarna K; Shrestha, Laxman; LeClerq, Steven C; Steinhoff, Mark; Tielsch, James M

    2016-02-10

    Immunization programs currently measure coverage by assessing the proportion of children 12-24 months who have been immunized but this does not address the important question of when the scheduled vaccines were administered. Data capturing the timing of vaccination in first 6 months, when severe disease is most likely to occur, are limited. To estimate the time to Bacillus Calmette-Guérin (BCG) (recommended at birth), diphtheria-tetanus-pertussis-H, influenza b-hepatitis B (DTP-Hib-HepB), and oral polio vaccine (OPV) (recommended at 6, 10, and 14 weeks) vaccinations and risk factors for vaccination delay in infants vaccination were visited weekly at home from birth through age 6 months to ascertain if any vaccinations had been given in the prior week. Infant, maternal, and household characteristics were recorded. BCG, DTP-Hib-HepB, and OPV vaccination coverage at 4 and 6 months was estimated. Time to vaccination was estimated through Kaplan-Meier curves; Cox-proportional hazards models were used to examine risk factors for delay for the first vaccine. The median age of BCG, first OPV and DTP-Hib-HepB receipt was 22, 21, and 18 weeks, respectively. Almost half of infants received no BCG by age 6 months. Only 8% and 7% of infants had received three doses of OPV and DTP-Hib-HepB, respectively, by age 6 months. A significant delay in receipt of infant vaccines was found in a prospective, population-based, cohort in southern Nepal despite traditional coverage metrics being high. Immunization programs should consider measuring time to receipt relative to the official schedule in order to maximize benefits for disease control and child health. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. Spinocellulært karcinom opstået ved cikatrice efter Calmette-vaccination

    DEFF Research Database (Denmark)

    Nielsen, Rikke Maria; Andersen, F.; Salskov-Iversen, Maria Luise

    2014-01-01

    Marjolin's ulcer is an aggressive squamous cell carcinoma (SCC) found in chronically inflamed skin. SCC has been reported in smallpox vaccination sites, whereas basal cell carcinomas are more common in scar after bacille Calmette-Guerin (BCG) vaccination. A 72-year-old man presented with a chronic...... ulcer at the site of his childhood BCG vaccination. At the time of examination, a 3 x 1.5 cm fleshy and secreting ulcer was found on the shoulder. Biopsy revealed SCC, and the tumour was surgically removed. In conclusion, chronic ulcers, especially those originating in chronically inflamed skin, should...

  9. Ultraviolet susceptibility of BCG and virulent tubercle bacilli

    International Nuclear Information System (INIS)

    Riley, R.L.; Knight, M.; Middlebrook, G.

    1976-01-01

    To test the effectiveness of irradiating the upper air of a room with ultraviolet light at reducing the concentration of airborne tubercle bacilli, the susceptibility to the germicidal effects of ultraviolet light, Z, was determined for various mycobacteria. Virulent tubercle bacilli and bacille Calmette-Guerin (BCG) were susceptible to ultraviolet radiation, whereas Mycobacterium phlei had 10 times their resistance (Z, approximately one-tenth that for M. tuberculosis). The effectiveness against BCG of upper air ultraviolet irradiation in a room was tested directly by nebulizing BCG into the air of the room and monitoring its rate of disappearance. With one 17-watt fixture operating, the rate of disappearance increased 6-fold; with 2 fixtures operating (46 watts total), the rate of disappearance increased 9-fold. This implies that under steady-state conditions, the concentrations of airborne organisms with ultraviolet light(s) on would have been one-sixth and one-ninth, respectively. The increase in rate of decay of the airborne organism using 1 fixture was equivalent to 10 air changes per hour, whereas that using 2 fixtures was approximately 25 air changes per hour (range: 18 to 33 air changes per hour). These increments are less than those reported previously for Serratia marcescens, because the Z value for BCG is approximately one-seventh that for serratia. These findings with BCG are believed to be directly applicable to virulent tubercle bacilli

  10. Vaccination in elite athletes.

    Science.gov (United States)

    Gärtner, Barbara C; Meyer, Tim

    2014-10-01

    Public health vaccination guidelines cannot be easily transferred to elite athletes. An enhanced benefit from preventing even mild diseases is obvious but stronger interference from otherwise minor side effects has to be considered as well. Thus, special vaccination guidelines for adult elite athletes are required. In most of them, protection should be strived for against tetanus, diphtheria, pertussis, influenza, hepatitis A, hepatitis B, measles, mumps and varicella. When living or traveling to endemic areas, the athletes should be immune against tick-borne encephalitis, yellow fever, Japanese encephalitis, poliomyelitis, typhoid fever, and meningococcal disease. Vaccination against pneumococci and Haemophilus influenzae type b is only relevant in athletes with certain underlying disorders. Rubella and papillomavirus vaccination might be considered after an individual risk-benefit analysis. Other vaccinations such as cholera, rabies, herpes zoster, and Bacille Calmette-Guérin (BCG) cannot be universally recommended for athletes at present. Only for a very few diseases, a determination of antibody titers is reasonable to avoid unnecessary vaccinations or to control efficacy of an individual's vaccination (especially for measles, mumps, rubella, varicella, hepatitis B and, partly, hepatitis A). Vaccinations should be scheduled in a way that possible side effects are least likely to occur in periods of competition. Typically, vaccinations are well tolerated by elite athletes, and resulting antibody titers are not different from the general population. Side effects might be reduced by an optimal selection of vaccines and an appropriate technique of administration. Very few discipline-specific considerations apply to an athlete's vaccination schedule mainly from the competition and training pattern as well as from the typical geographical distribution of competitive sites.

  11. Does oral polio vaccine have non-specific effects on all-cause mortality?

    DEFF Research Database (Denmark)

    Aaby, Peter; Andersen, Andreas; Martins, Cesário L

    2016-01-01

    BACKGROUND: BCG and measles vaccine (MV) may have beneficial non-specific effects (NSEs). If an unplanned intervention with a vaccine (a natural experiment) modifies the estimated effect in a randomised controlled trial (RCT), this suggests NSEs. We used this approach to test NSEs of triple oral...

  12. Bacillus Calmette-Guérin (BCG) Treatment Failures with Non-Muscle Invasive Bladder Cancer: A Data-Driven Definition for BCG Unresponsive Disease.

    Science.gov (United States)

    Steinberg, Ryan L; Thomas, Lewis J; Mott, Sarah L; O'Donnell, Michael A

    2016-04-27

    Objective: To create the first data-driven definition for those unlikely to benefit from further BCG treatment. Materials and Methods: The database created for the Phase 2 BCG-Interferon- α 2B (IFN) study was queried and BCG failure patients were identified ( n  = 334). Full study protocols have previously been published. Separate models were constructed for analysis of patients with any CIS (pure or concomitant) and pure papillary disease. Variables considered included age, gender, stage, grade, tumor size and focality (for papillary only), number of prior BCG courses, and prior BCG failure interval. Results: Patients with recurrent CIS within 6 months of their most recent prior BCG course (HR 2.56, p  disease within 6 months (HR 1.82, p  = 0.02), ≥2 BCG failures (HR 1.54, p  = 0.03), and multifocal disease (HR 2.05, p  disease remained disease free in 38% of cases (24-51% 95% CI) at 2 years with low rates of progression. Conclusions: Patients who fail two courses of BCG with either persistent or recurrent multifocal papillary disease within 6 months or CIS within 12 months of their prior BCG should be considered BCG unresponsive. Recurrent T1 disease respond reasonably well to another course with low progression rates but further investigation is warranted.

  13. BCG lowers plasma cholesterol levels and delays atherosclerotic lesion progression in mice

    NARCIS (Netherlands)

    van Dam, Andrea D.; Bekkering, Siroon; Crasborn, Malou; van Beek, Lianne; van den Berg, Susan M.; Vrieling, Frank; Joosten, Simone A.; van Harmelen, Vanessa; de Winther, Menno P. J.; Lütjohann, Dieter; Lutgens, Esther; Boon, Mariëtte R.; Riksen, Niels P.; Rensen, Patrick C. N.; Berbée, Jimmy F. P.

    2016-01-01

    Bacille-Calmette-Guérin (BCG), prepared from attenuated live Mycobacterium bovis, modulates atherosclerosis development as currently explained by immunomodulatory mechanisms. However, whether BCG is pro- or anti-atherogenic remains inconclusive as the effect of BCG on cholesterol metabolism, the

  14. Inhibition of natural killer cell-mediated cytotoxicity by lipids extracted from Mycobacterium bovis BCG

    NARCIS (Netherlands)

    Roozemond, R. C.; Halperin, M.; Das, P. K.

    1985-01-01

    Several studies have demonstrated an augmentation of natural killer (NK) cell-mediated cytotoxicity by various adjuvants including BCG. Inhibitory effects of BCG have also been reported, particularly for relatively high doses. Because the cell wall of Mycobacterium bovis BCG contains a high

  15. Positive impact of rescheduling Bacillus Calmette-Guérin vaccination on vaccinations at birth.

    Science.gov (United States)

    Oberoi, Simmi; Amarjit, Singh; Avneet, Randhawa; Neha, Chaudhary; Patnaik, Siriesha

    2017-01-01

    Inimitable among the trio of recommended immunizations administered to newborns at delivery centers of institutions is hepatitis B. While it is necessary for hepatitis B to be given within 24 hours of birth, the same cannot be said for Bacillus Calmette-Guérin (BCG) and zero-dose oral polio vaccine (OPV). To assess the impact of rescheduling of BCG vaccination from the current twice weekly to daily to cover newborn vaccinations at the Government Medical College, Patiala, India. Until 2015, the delivery of BCG vaccine was restricted to twice a week, but from the year 2015, the schedule was changed from twice weekly to daily. Records for the 2 years, 2014 and 2015, were obtained, i.e., before and after the change. Data on 7065 babies born from January 2014 to December 2015 were statistically analyzed for the coverage of birth dose of hepatitis B, BCG, and OPV using Microsoft Excel. Chi-square test was applied, and p vaccine wastage increased from 21.5% to 26.2%, the difference found to be statistically insignificant. Modification in the delivery of immunization service from twice a week to daily has had a good impact on the vaccination of newborns though the goal of achieving the ideal 100% coverage is yet to be reached. Apart from the immunization of newborns, improving parental awareness, better coordination between immunization staff and maternal health staff, improved communication, and clear delineation of responsibility and answerability in the immunization service delivery will have a good impact on the vaccination of newborns.

  16. Progress and challenges in TB vaccine development.

    Science.gov (United States)

    Voss, Gerald; Casimiro, Danilo; Neyrolles, Olivier; Williams, Ann; Kaufmann, Stefan H E; McShane, Helen; Hatherill, Mark; Fletcher, Helen A

    2018-01-01

    The Bacille Calmette Guerin (BCG) vaccine can provide decades of protection against tuberculosis (TB) disease, and although imperfect, BCG is proof that vaccine mediated protection against TB is a possibility. A new TB vaccine is, therefore, an inevitability; the question is how long will it take us to get there? We have made substantial progress in the development of vaccine platforms, in the identification of antigens and of immune correlates of risk of TB disease. We have also standardized animal models to enable head-to-head comparison and selection of candidate TB vaccines for further development.  To extend our understanding of the safety and immunogenicity of TB vaccines we have performed experimental medicine studies to explore route of administration and have begun to develop controlled human infection models. Driven by a desire to reduce the length and cost of human efficacy trials we have applied novel approaches to later stage clinical development, exploring alternative clinical endpoints to prevention of disease outcomes. Here, global leaders in TB vaccine development discuss the progress made and the challenges that remain. What emerges is that, despite scientific progress, few vaccine candidates have entered clinical trials in the last 5 years and few vaccines in clinical trials have progressed to efficacy trials. Crucially, we have undervalued the knowledge gained from our "failed" trials and fostered a culture of risk aversion that has limited new funding for clinical TB vaccine development. The unintended consequence of this abundance of caution is lack of diversity of new TB vaccine candidates and stagnation of the clinical pipeline. We have a variety of new vaccine platform technologies, mycobacterial antigens and animal and human models.  However, we will not encourage progression of vaccine candidates into clinical trials unless we evaluate and embrace risk in pursuit of vaccine development.

  17. A brief history of vaccines & vaccination in India

    Science.gov (United States)

    Lahariya, Chandrakant

    2014-01-01

    The challenges faced in delivering lifesaving vaccines to the targeted beneficiaries need to be addressed from the existing knowledge and learning from the past. This review documents the history of vaccines and vaccination in India with an objective to derive lessons for policy direction to expand the benefits of vaccination in the country. A brief historical perspective on smallpox disease and preventive efforts since antiquity is followed by an overview of 19th century efforts to replace variolation by vaccination, setting up of a few vaccine institutes, cholera vaccine trial and the discovery of plague vaccine. The early twentieth century witnessed the challenges in expansion of smallpox vaccination, typhoid vaccine trial in Indian army personnel, and setting up of vaccine institutes in almost each of the then Indian States. In the post-independence period, the BCG vaccine laboratory and other national institutes were established; a number of private vaccine manufacturers came up, besides the continuation of smallpox eradication effort till the country became smallpox free in 1977. The Expanded Programme of Immunization (EPI) (1978) and then Universal Immunization Programme (UIP) (1985) were launched in India. The intervening events since UIP till India being declared non-endemic for poliomyelitis in 2012 have been described. Though the preventive efforts from diseases were practiced in India, the reluctance, opposition and a slow acceptance of vaccination have been the characteristic of vaccination history in the country. The operational challenges keep the coverage inequitable in the country. The lessons from the past events have been analysed and interpreted to guide immunization efforts. PMID:24927336

  18. A brief history of vaccines & vaccination in India

    Directory of Open Access Journals (Sweden)

    Chandrakant Lahariya

    2014-01-01

    Full Text Available The challenges faced in delivering lifesaving vaccines to the targeted beneficiaries need to be addressed from the existing knowledge and learning from the past. This review documents the history of vaccines and vaccination in India with an objective to derive lessons for policy direction to expand the benefits of vaccination in the country. A brief historical perspective on smallpox disease and preventive efforts since antiquity is followed by an overview of 19 th century efforts to replace variolation by vaccination, setting up of a few vaccine institutes, cholera vaccine trial and the discovery of plague vaccine. The early twentieth century witnessed the challenges in expansion of smallpox vaccination, typhoid vaccine trial in Indian army personnel, and setting up of vaccine institutes in almost each of the then Indian States. In the post-independence period, the BCG vaccine laboratory and other national institutes were established; a number of private vaccine manufacturers came up, besides the continuation of smallpox eradication effort till the country became smallpox free in 1977. The Expanded Programme of Immunization (EPI (1978 and then Universal Immunization Programme (UIP (1985 were launched in India. The intervening events since UIP till India being declared non-endemic for poliomyelitis in 2012 have been described. Though the preventive efforts from diseases were practiced in India, the reluctance, opposition and a slow acceptance of vaccination have been the characteristic of vaccination history in the country. The operational challenges keep the coverage inequitable in the country. The lessons from the past events have been analysed and interpreted to guide immunization efforts.

  19. Protein energy malnutrition during vaccination has limited influence on vaccine efficacy but abolishes immunity if administered during Mycobacterium tuberculosis infection

    DEFF Research Database (Denmark)

    Hoang, Truc; Agger, Else Marie; Cassidy, Joseph P

    2015-01-01

    blocked the protection afforded by the H56-CAF01 subunit vaccine, and this was associated with a very substantial loss of the interleukin-2-positive memory CD4 T cells promoted by this vaccine. Similarly, PEM during the vaccination phase markedly reduced the H56-CAF01 vaccine response, influencing all...... of Mycobacterium tuberculosis, as well as increased pathology, in both Mycobacterium bovis BCG-vaccinated and unvaccinated animals. PEM did not change the overall numbers of CD4 T cells in BCG-vaccinated animals but resulted in an almost complete loss of antigen-specific cytokine production. Furthermore......, there was a change in cytokine expression characterized by a gradual loss of multifunctional antigen-specific CD4 T cells and an increased proportion of effector cells expressing gamma interferon and tumor necrosis factor alpha (IFN-γ(+) TNF-α(+) and IFN-γ(+) cells). PEM during M. tuberculosis infection completely...

  20. Improving Mycobacterium bovis bacillus Calmette-Guèrin as a vaccine delivery vector for viral antigens by incorporation of glycolipid activators of NKT cells.

    Directory of Open Access Journals (Sweden)

    Manjunatha M Venkataswamy

    Full Text Available Recombinant Mycobacterium bovis bacillus Calmette-Guèrin (rBCG has been explored as a vector for vaccines against HIV because of its ability to induce long lasting humoral and cell mediated immune responses. To maximize the potential for rBCG vaccines to induce effective immunity against HIV, various strategies are being employed to improve its ability to prime CD8+ T cells, which play an important role in the control of HIV infections. In this study we adopted a previously described approach of incorporating glycolipids that activate CD1d-restricted natural killer T (NKT cells to enhance priming of CD8+ T cells by rBCG strains expressing an SIV Gag antigen (rBCG-SIV gag. We found that the incorporation of the synthetic NKT activating glycolipid α-galactosylceramide (α-GC into rBCG-SIV gag significantly enhanced CD8+ T cell responses against an immunodominant Gag epitope, compared to responses primed by unmodified rBCG-SIV gag. The abilities of structural analogues of α-GC to enhance CD8+ T cell responses to rBCG were compared in both wild type and partially humanized mice that express human CD1d molecules in place of mouse CD1d. These studies identified an α-GC analogue known as 7DW8-5, which has previously been used successfully as an adjuvant in non-human primates, as a promising compound for enhancing immunogenicity of antigens delivered by rBCG.vectors. Our findings support the incorporation of synthetic glycolipid activators of NKT cells as a novel approach to enhance the immunogenicity of rBCG-vectored antigens for induction of CD8+ T cell responses. The glycolipid adjuvant 7DW8-5 may be a promising candidate for advancing to non-human primate and human clinical studies for the development of HIV vaccines based on rBCG vectors.