The Influence of BCG Vaccine Strain on Mycobacteria-specific and Non-specific Immune Responses in a Prospective Cohort of Infants in Uganda

Overview

Journal Vaccine

Specialty Allergy & Immunology

Date 2012 Feb 4

PMID 22300718

Citations 48

Authors

Elizabeth J Anderson

Emily L Webb

Patrice A Mawa

Moses Kizza

Nancy Lyadda

Margaret Nampijja

Alison M Elliott

Affiliations

Soon will be listed here.

Abstract

Background: Globally, BCG vaccination varies in efficacy and has some non-specific protective effects. Previous studies comparing BCG strains have been small-scale, with few or no immunological outcomes and have compared TB-specific responses only. We aimed to evaluate both specific and non-specific immune responses to different strains of BCG within a large infant cohort and to evaluate further the relationship between BCG strain, scarring and cytokine responses.

Methods: Infants from the Entebbe Mother and Baby Study (ISRCTN32849447) who received BCG-Russia, BCG-Bulgaria or BCG-Denmark at birth, were analysed by BCG strain group. At one year, interferon-gamma (IFN-γ), interleukin (IL)-5, IL-13 and IL-10 responses to mycobacteria-specific antigens (crude culture filtrate proteins and antigen 85) and non-mycobacterial stimuli (tetanus toxoid and phytohaemagglutinin) were measured using ELISA. Cytokine responses, scar frequency, BCG associated adverse event frequency and mortality rates were compared across groups, with adjustments for potential confounders.

Results: Both specific and non-specific IFN-γ, IL-13 and IL-10 responses in 1341 infants differed between BCG strain groups including in response to stimulation with tetanus toxoid. BCG-Denmark immunised infants showed the highest cytokine responses. The proportion of infants who scarred differed significantly, with BCG scars occurring in 52.2%, 64.1% and 92.6% of infants immunised with BCG Russia, BCG-Bulgaria and BCG-Denmark, respectively (p<0.001). Scarred infants had higher IFN-γ and IL-13 responses to mycobacterial antigens only than infants without a scar. The BCG-Denmark group had the highest frequency of adverse events (p=0.025). Mortality differences were not significant.

Conclusions: Both specific and non-specific immune responses to the BCG vaccine differ by strain. Scarring after BCG vaccination is also strain-dependent and is associated with higher IFN-γ and IL-13 responses to mycobacterial antigens. The choice of BCG strain may be an important factor and should be evaluated when testing novel vaccine strategies that employ BCG in prime-boost sequences, or as a vector for other vaccine antigens.

Citing Articles

Effect of Bacille Calmette-Guérin vaccination on immune responses to SARS-CoV-2 and COVID-19 vaccination.

Messina N, Germano S, Chung A, van de Sandt C, Stevens N, Allen L Clin Transl Immunology. 2025; 14(1):e70023.

PMID: 39872402 PMC: 11761716. DOI: 10.1002/cti2.70023.

The effect of BCG revaccination on the response to unrelated vaccines in urban Ugandan adolescents (POPVAC C): an open-label, randomised controlled trial.

Nassuuna J, Zirimenya L, Nkurunungi G, Natukunda A, Zziwa C, Ninsiima C Lancet Glob Health. 2024; 12(11):e1849-e1859.

PMID: 39424573 PMC: 11483248. DOI: 10.1016/S2214-109X(24)00282-1.

Pediatric Tuberculosis: A Review of Evidence-Based Best Practices for Clinicians and Health Care Providers.

Moore B, Graham S, Nandakumar S, Doyle J, Maloney S Pathogens. 2024; 13(6).

PMID: 38921765 PMC: 11206390. DOI: 10.3390/pathogens13060467.

The Mycobacterium tuberculosis genome at 25 years: lessons and lingering questions.

Koleske B, Jacobs Jr W, Bishai W J Clin Invest. 2023; 133(19).

PMID: 37781921 PMC: 10541200. DOI: 10.1172/JCI173156.

Erratum: Factors influencing scar formation following Bacille Calmette-Guérin (BCG) vaccination.

Villanueva P, Crawford N, Croda M, Collopy S, Jardim B, Jardim T Heliyon. 2023; 9(6):e15821.

PMID: 37484338 PMC: 10360588. DOI: 10.1016/j.heliyon.2023.e15821.

References

Djuardi Y, Sartono E, Wibowo H, Supali T, Yazdanbakhsh M . A longitudinal study of BCG vaccination in early childhood: the development of innate and adaptive immune responses. PLoS One. 2010; 5(11):e14066. PMC: 2988815. DOI: 10.1371/journal.pone.0014066. View

McGuinness D, Bennett S, Riley E . Statistical analysis of highly skewed immune response data. J Immunol Methods. 1997; 201(1):99-114. DOI: 10.1016/s0022-1759(96)00216-5. View

Wu B, Huang C, Garcia L, de Leon A, Sifuentes Osornio J, Bobadilla-Del-Valle M . Unique gene expression profiles in infants vaccinated with different strains of Mycobacterium bovis bacille Calmette-Guerin. Infect Immun. 2007; 75(7):3658-64. PMC: 1932948. DOI: 10.1128/IAI.00244-07. View

Redford P, Murray P, OGarra A . The role of IL-10 in immune regulation during M. tuberculosis infection. Mucosal Immunol. 2011; 4(3):261-70. DOI: 10.1038/mi.2011.7. View

Roth A, Gustafson P, Nhaga A, Djana Q, Poulsen A, Garly M . BCG vaccination scar associated with better childhood survival in Guinea-Bissau. Int J Epidemiol. 2005; 34(3):540-7. DOI: 10.1093/ije/dyh392. View

Dietrich J, Doherty T . Interaction of Mycobacterium tuberculosis with the host: consequences for vaccine development. APMIS. 2009; 117(5-6):440-57. DOI: 10.1111/j.1600-0463.2009.02458.x. View

Flanagan K, Klein S, Skakkebaek N, Marriott I, Marchant A, Selin L . Sex differences in the vaccine-specific and non-targeted effects of vaccines. Vaccine. 2011; 29(13):2349-54. DOI: 10.1016/j.vaccine.2011.01.071. View

Gorak-Stolinska P, Weir R, Floyd S, Lalor M, Stenson S, Branson K . Immunogenicity of Danish-SSI 1331 BCG vaccine in the UK: comparison with Glaxo-Evans 1077 BCG vaccine. Vaccine. 2006; 24(29-30):5726-33. DOI: 10.1016/j.vaccine.2006.04.037. View

Kristensen I, Aaby P, Jensen H . Routine vaccinations and child survival: follow up study in Guinea-Bissau, West Africa. BMJ. 2000; 321(7274):1435-8. PMC: 27544. DOI: 10.1136/bmj.321.7274.1435. View

10.

Soares A, Scriba T, Joseph S, Harbacheuski R, Murray R, Gelderbloem S . Bacillus Calmette-Guérin vaccination of human newborns induces T cells with complex cytokine and phenotypic profiles. J Immunol. 2008; 180(5):3569-77. PMC: 2842001. DOI: 10.4049/jimmunol.180.5.3569. View

11.

Keller P, Bottger E, Sander P . Tuberculosis vaccine strain Mycobacterium bovis BCG Russia is a natural recA mutant. BMC Microbiol. 2008; 8:120. PMC: 2483709. DOI: 10.1186/1471-2180-8-120. View

12.

Aronson N, Santosham M, Comstock G, Howard R, Moulton L, Rhoades E . Long-term efficacy of BCG vaccine in American Indians and Alaska Natives: A 60-year follow-up study. JAMA. 2004; 291(17):2086-91. DOI: 10.1001/jama.291.17.2086. View

13.

Stensballe L, Nante E, Jensen I, Kofoed P, Poulsen A, Jensen H . Acute lower respiratory tract infections and respiratory syncytial virus in infants in Guinea-Bissau: a beneficial effect of BCG vaccination for girls community based case-control study. Vaccine. 2005; 23(10):1251-7. DOI: 10.1016/j.vaccine.2004.09.006. View

14.

Brewer T . Preventing tuberculosis with bacillus Calmette-Guérin vaccine: a meta-analysis of the literature. Clin Infect Dis. 2000; 31 Suppl 3:S64-7. DOI: 10.1086/314072. View

15.

Brosch R, Gordon S, Garnier T, Eiglmeier K, Frigui W, Valenti P . Genome plasticity of BCG and impact on vaccine efficacy. Proc Natl Acad Sci U S A. 2007; 104(13):5596-601. PMC: 1838518. DOI: 10.1073/pnas.0700869104. View

16.

Hoft D, Kemp E, Marinaro M, Cruz O, Kiyono H, McGhee J . A double-blind, placebo-controlled study of Mycobacterium-specific human immune responses induced by intradermal bacille Calmette-Guérin vaccination. J Lab Clin Med. 1999; 134(3):244-52. DOI: 10.1016/s0022-2143(99)90204-4. View

17.

Behr M, Small P . A historical and molecular phylogeny of BCG strains. Vaccine. 1999; 17(7-8):915-22. DOI: 10.1016/s0264-410x(98)00277-1. View

18.

Webb E, Mawa P, Ndibazza J, Kizito D, Namatovu A, Kyosiimire-Lugemwa J . Effect of single-dose anthelmintic treatment during pregnancy on an infant's response to immunisation and on susceptibility to infectious diseases in infancy: a randomised, double-blind, placebo-controlled trial. Lancet. 2010; 377(9759):52-62. PMC: 3018567. DOI: 10.1016/S0140-6736(10)61457-2. View

19.

Hussey G, Watkins M, Goddard E, Gottschalk S, Hughes E, Iloni K . Neonatal mycobacterial specific cytotoxic T-lymphocyte and cytokine profiles in response to distinct BCG vaccination strategies. Immunology. 2002; 105(3):314-24. PMC: 1782661. DOI: 10.1046/j.1365-2567.2002.01366.x. View

20.

Wilson M, Fineberg H, Colditz G . Geographic latitude and the efficacy of bacillus Calmette-Guérin vaccine. Clin Infect Dis. 1995; 20(4):982-91. DOI: 10.1093/clinids/20.4.982. View