Booster Dose of Bacille Calmette-Guérin Vaccine for Tuberculosis in Low and Middle-Income Countries: A Systematic Review
Background: The Bacille Calmette-Guérin (BCG) vaccine, given as a single dose, offers variable protection against Tuberculosis (TB). It is plausible that repeat doses could improve the effectiveness of the BCG vaccine in settings where the population remain at risk of the disease.
Objective: To assess the effectiveness of BCG revaccination as a booster dose in preventing TB in Low- and Middle- Income Countries (LMICs).
Methods: We searched the electronic databases without language or publication restrictions and followed the procedures for preparing systematic reviews, including assessing the risk of bias as outlined in the Cochrane handbook. We included randomised controlled trials (RCTs) conducted in LMICs involving children and adults receiving one or more BCG vaccine doses after the primary BCG vaccination. The incidence of severe forms of TB, active TB and adverse events were the primary outcomes.
Results: Five RCTs were included in this systematic review. Revaccination with BCG probably makes little or no difference to the risk of active TB measured after five years (Relative risk (RR) 1.16, 95% CI 0.88 to 1.51; 348,083 participants; one study, moderate certainty evidence) or nine years post-revaccination (RR 0.96, 95% CI 0.82 to 1.12; 348,083 participants; one study, moderate certainty evidence). In populations with HIV co-infection, revaccination probably increases the risk of pulmonary tuberculosis compared to placebo (RR 1.74, 95% CI 1.00 to 3.01; 46,764 participants; one study, moderate certainty evidence).
Conclusion: The available evidence suggests that BCG revaccination probably makes little or no difference in preventing tuberculosis disease in LMICs.
Houben RM, Dodd PJ. The global burden of latent tuberculosis infection: a re-estimation using mathematical modelling. PLoS Med 2016; 13: e1002152. https://doi.org/10.1371/journal.pmed.1002152
World Health Organization. Tuberculosis. https://www.who.int/news-room/fact-sheets/detail/tuberculosis. 2019. (Accessed 16 March 2020).
World Health Organization. Global Tuberculosis Report 2019. https://www.who.int/tb/publications/global_report/tb19_Report_regional_global_15October2019.pdf?ua=1. 2019. (Accessed 16 March 2020).
Pawlowski A, Jansson M, Sköld M, Rottenberg ME, Källenius G. Tuberculosis and HIV co-infection. PLoS Pathog. 2012; 8(2): e1002464. https://doi.org/10.1371/journal.ppat.1002464
Chai Q, Zhang Y, Liu CH. Mycobacterium tuberculosis: An Adaptable Pathogen Associated with Multiple Human Diseases. Front Cell Infect Microbiol 2018; 8(158). https://doi.org/10.3389/fcimb.2018.00158
Bendinelli M, Friedman H, eds. Mycobacterium Tuberculosis: Interactions with the Immune System. Springer. US. 1988.
Lönnroth K, Raviglione M. The WHO's new End TB Strategy in the post-2015 era of the Sustainable Development Goals. Trans Royal Soc Trop Med Hyg 2016; 110: 148-150. https://doi.org/10.1093/trstmh/trv108
Cruz A, Starke J. Tuberculosis. Feigin and Cherry's textbook of paediatric infectious diseases. In Cherry J, Harrison G, Kaplan S, Steinbach W, Hotez P (Ed). 7th Edition. Philadelphia, PA.: Elsevier Saunders. 2014; 1335–1380.
Mansoor N, Scriba TJ, de Kock M, Tameris M, Abel B, Keyser A, et al. HIV-1 infection in infants severely impairs the immune response induced by Bacille Calmette-Guerin vaccine. J Infect Dis 2009; 199: 982-990. https://doi.org/10.1086/597304
Jeon CY, Murray MB. Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies. PLoS Med 2008; 5: e152. https://doi.org/10.1371/journal.pmed.0050152.
Dunn JJ, Starke JR, Revell PA. Laboratory diagnosis of Mycobacterium tuberculosis infection and disease in children. J Clin Microbiol 2016; 54: 1434-1441. https://doi.org/10.1128/JCM.03043-15
Dalmia N, Ramsay AJ. Prime–boost approaches to tuberculosis vaccine development. Expert Rev Vaccines 2012; 11: 1221-1233. https://doi.org/10.1586/erv.12.94
World Health Organization. BCG vaccines: WHO Position Papers - February 2018. Weekly Epidemiological Rec No. 8, 2018; 93: 73-96. (Accessed on 08 October 2020).
Roy A, Eisenhut M, Harris RJ, Rodrigues LC, Sridhar S, Habermann S, et al. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis. BMJ 2014; 349: g4643. https://doi.org/10.1136/bmj.g4643
Abubakar I, Pimpin L, Ariti C, Beynon R, Mangtani P, Sterne JA, et al. Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guérin vaccination against tuberculosis. Health Technology Assessment (Winchester, England) 2013; 17: 1. https://doi.org/10.3310/hta17370
Rakshit S, Ahmed A, Adiga V, Sundararaj BK, Sahoo PN, Kenneth J, et al. BCG revaccination boosts adaptive polyfunctional Th1/Th17 and innate effectors in IGRA+ and IGRA–Indian adults. J Clin Invest Insight 2019; 4(24). https://doi.org/10.1172/jci.insight.130540
Effa EE, Oduwole O, Schoonees A, Hohlfeld A, Durao S, Kredo T, et al. Priority setting for new systematic reviews: processes and lessons learned in three regions in Africa. BMJ Global Health. 2019; 4: e001615. http://dx.doi.org/10.1136/bmjgh-2019-001615
Oduwole O, Mwankon JP, Okebe J, Sallahdeen A, Esu BE, Effa EE, et al. Booster dose of Bacille Calmette-Guerin vaccine for tuberculosis in low- and middle-income countries. PROSPERO 2018. CRD42018095107 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42018095107
How does the World Bank classify countries? https://datahelpdesk.worldbank.org/knowledgebas
Cochrane Collaboration. Review manager (RevMan) [Computer Program]. Copenhagen: The Nordic Cochrane Centre. 2014.
Higgins JPT, Deeks JJ, Altman DG, (Editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org
Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S. Grading quality of evidence and strength of recommendations. BMJ 2004; 328: 1490. https://doi.org/10.1136/bmj.328.7454.1490GRADEproGD
GRADEpro Guideline Development Tool [Software]. McMaster University. 2015. https://gdt.gradepro.org/app/
Karonga Prevention Trial Group. Randomised controlled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevention of leprosy and tuberculosis in Malawi. The Lancet. 1996; 348: 17-24.
Fine PE, Ponnighaus JM. Background, design and prospects of the Karonga Prevention Trial, a leprosy vaccine trial in northern Malawi. Trans Royal Soc Trop Med Hyg 1988; 82: 810-817. https://doi.org/10.1016/0035-9203(88)90003-X.
Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F, Bilek N, et al. Prevention of M. tuberculosis infection with H4: IC31 vaccine or BCG revaccination. New Engl J Med 2018; 379: 138-149. https://doi.org/10.1056/NEJMoa1714021
Oliveira ES, Marinho JM, Barbosa T. Interferon-gamma production by mononuclear cells in Bacille Calmette-Guérin-revaccinated healthy volunteers predicted long-term antimycobacterial responses in a randomised controlled trial. Vaccine. 2013; 31: 3778-3782. https://doi.org/10.1016/j.vaccine.2013.04.079
Roth AE, Benn CS, Ravn H, Rodrigues A, Lisse IM, Yazdanbakhsh M, et al. Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau. BMJ 2010; 340: c671. https://doi.org/10.1136/bmj.c671
Rodrigues LC, Pereira SM, Cunha SS, Genser B, Ichihara MY, de Brito SC, et al. Effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: the BCG-REVAC cluster-randomised trial. The Lancet 2005; 366: 1290-1295. https://doi.org/10.1016/S0140-6736(05)67145-0
Bekker LG, Dintwe O, Fiore-Gartland A, Middelkoop K, Hutter J, et al. A phase 1b randomised study of the safety and immunological responses to vaccination with H4: IC31, H56: IC31, and BCG revaccination in Mycobacterium tuberculosis-uninfected adolescents in Cape Town, South Africa. EClinical Medicine 2020: 100313. https://doi.org/10.1016/j.eclinm.2020.100313
Barreto ML, Pereira SM, Pilger D, Cruz AA, Cunha SS, Sant’Anna C, et al. Evidence of an effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: second report of the BCG-REVAC cluster-randomised trial. Vaccine 2011; 29: 4875-4877. https://doi.org/10.1016/j.vaccine.2011.05.023
Dourado I, Rios MH, Pereira SM, Cunha SS, Ichihara MY, Goes JC, et al. Rates of adverse reactions to first and second doses of BCG vaccination: results of a large community trial in Brazilian schoolchildren. Int J Tuberc Lung Dis 2003; 7: 399-402.
Barreto ML, Rodrigues LC, Cunha SS, Pereira S, Hijjar MA, Ichihara MY, et al. design of the Brazilian BCG-REVAC trial against tuberculosis: a large, simple randomised community trial to evaluate the impact on tuberculosis of BCG revaccination at school age. Controlled Clin Trials 2002; 23: 540-553. https://doi.org/10.1016/S0197-2456(02)00216-7
Peleteiro TS, Oliveira ES, Conceição EL, Nascimento-Sampaio F, Alcântara-Neves NM, Mendes CM, et al. Impact of Bacille Calmette-Guérin revaccination on serum IgE levels in a randomized controlled trial. Revista da Sociedade Brasileira de Medicina Tropical 2018; 51: 94-98. https://doi.org/10.1590/0037-8682-0081-2017
Andersen A, Roth A, Jensen KJ, Erikstrup C, Lisse IM, Whittle H, et al. The immunological effect of revaccination with Bacille Calmette-Guérin vaccine at 19 months of age. Vaccine 2013; 31: 2137-2144. https://doi.org/10.1016/j.vaccine.2013.02.050
Fine P. Does giving a second BCG vaccination or adding a leprosy vaccine to BCG vaccination provide additional protection against leprosy and tuberculosis, compared with giving a single BCG vaccination? International Standard Randomised Controlled Trial Number Registry, 2019. http://www.who.int/trialsearch/Trial2.aspx?TrialID=ISRCTN11311670. Accessed 16 March 2020.
Hill P. Bacillus Calmette Guerin (BCG) vaccination/revaccination for prevention of Mycobacterium tuberculosis infection in healthcare students entering clinical training: a randomised placebo-controlled proof of principle trial (PoP BCG trial). Australian New Zealand Clinical Trials Registry, 2019. http://www.who.int/trialsearch/Trial2.aspx?TrialID=ACTRN12619001327178 Accessed 16 March 2020.
Gates MRI. BCG Revaccination of Healthy Adolescents for the Prevention of Mycobacterium Tuberculosis Sustained Infection. Clinical Trials.gov. 2019. https://clinicaltrials.gov/show/NCT04152161 Accessed 16 March 2020.
Barreto ML, Pereira SM, Ferreira AA. BCG vaccine: efficacy and indications for vaccination and revaccination. J Pediatr (Rio J) 2006; 82: S45-S54.
Dodd PJ, Gardiner E, Coghlan R, Seddon JA. Burden of childhood tuberculosis in 22 high-burden countries: a mathematical modelling study. The Lancet Global Health 2014; 2: e453-9.
Hesseling AC, Cotton MF, Jennings T, Hesseling AC, Cotton MF, Jennings T, et al. High incidence of tuberculosis among HIV-infected infants: evidence from a South African population-based study highlights the need for improved tuberculosis control strategies. Clin Infect Dis 2009; 48: 108–114
Whitaker JA. Immunisation Strategies to Span the Spectrum of Immunocompromised Adults. In: Mayo Clinic Proceedings. 2020; 95: 1530-1548.
Copyright (c) 2021 Annals of Health Research
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The articles and other materials published in the Annals of Health Research are protected by the Nigerian Copyright laws. The journal owns the copyright over every article, scientific and intellectual materials published in it. However, the journal grants all authors, users and researchers access to the materials published in the journal with the permission to copy, use and distribute the materials contained therein only for academic, scientific and non-commercial purposes.