Follow-up of a BCG trial after 30 years: what lessons have we learned?

The need for tuberculosis control through vaccination remains a global priority. The efficacy of BCG given to neonates to prevent tuberculosis meningitis and miliary tuberculosis is well known.1Trunz BB Fine P Dye C Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness.Lancet. 2006; 367: 1173-1180Summary Full Text Full Text PDF PubMed Scopus (752) Google Scholar In addition, BCG close to birth protects against other infectious diseases in the first 6 weeks of life.2Prentice S Nassanga B Webb EL et al.BCG-induced non-specific effects on heterologous infectious disease in Ugandan neonates: an investigator-blind randomised controlled trial.Lancet Infect Dis. 2021; 21: 993-1003Summary Full Text Full Text PDF PubMed Scopus (35) Google Scholar As vaccines able to prevent pulmonary tuberculosis in children and adults remain elusive and are being actively studied, there is much interest in whether repeat BCG immunisation can fulfil this role. In The Lancet Global Health, Judith Glynn and colleagues report on the 30-year outcome of the Karonga trial for tuberculosis prevention. Repeat BCG was compared with placebo in participants with BCG scars.3Glynn JR Fielding K Mzembe T et al.BCG re-vaccination in Malawi: 30-year follow-up of a large, randomised, double-blind, placebo-controlled trial.Lancet Glob Health. 2021; 9: e1453-e1459Summary Full Text Full Text PDF Scopus (2) Google Scholar The original trial, done in northern Malawi, was a randomised placebo-controlled trial of first or repeat BCG vaccination with or without killed Mycobacterium leprae for prevention of tuberculosis and leprosy and recruited over 120 000 participants. Recruitment began in 1986 and the first outcomes were reported in 1996.4Karonga Prevention Trial GroupRandomised controlled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevention of leprosy and tuberculosis in Malawi.Lancet. 1996; 348: 17-24Summary Full Text Full Text PDF PubMed Scopus (352) Google Scholar Follow-up was through both active and enhanced passive surveillance, with those with suspected tuberculosis or leprosy being seen by project staff who were masked to randomisation strategy. Both a first and second BCG vaccine were highly effective for preventing leprosy but not tuberculosis. Of 376 cases of confirmed or probable pulmonary tuberculosis and 24 of confirmed lymph node tuberculosis, the rate of confirmed pulmonary disease was actually higher after second BCG (incidence rate ratio 1·74 [1·00–3·03], p=0·05) than for placebo, attributable to those living with HIV.4Karonga Prevention Trial GroupRandomised controlled trial of single BCG, repeated BCG, or combined BCG and killed Mycobacterium leprae vaccine for prevention of leprosy and tuberculosis in Malawi.Lancet. 1996; 348: 17-24Summary Full Text Full Text PDF PubMed Scopus (352) Google Scholar In the current 30-year follow-up, over 46 000 participants yielded 824 cases of certain or probable tuberculosis. With more tuberculosis cases identified, the investigators showed no harm after a second BCG vaccination and evidence for modest protection in adults without HIV, especially if the second immunisation was in childhood. As BCG is more effective further away from the equator,5Mangtani P Abubakar I Ariti C et al.Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials.Clin Infect Dis. 2014; 58: 470-480Crossref PubMed Scopus (502) Google Scholar Black and colleagues6Black GF Weir RE Floyd S et al.BCG-induced increase in interferon-gamma response to mycobacterial antigens and efficacy of BCG vaccination in Malawi and the UK: two randomised controlled studies.Lancet. 2002; 359: 1393-1401Summary Full Text Full Text PDF PubMed Scopus (254) Google Scholar compared adolescents from the Karonga trial study and the UK for baseline interferon γ and tuberculin skin test and subsequent response to BCG. Higher baseline responses were found in Malawi but a better response to BCG was found in the UK, supporting the hypothesis that higher exposure to other mycobacteria in Malawi adversely affects protection afforded by BCG.6Black GF Weir RE Floyd S et al.BCG-induced increase in interferon-gamma response to mycobacterial antigens and efficacy of BCG vaccination in Malawi and the UK: two randomised controlled studies.Lancet. 2002; 359: 1393-1401Summary Full Text Full Text PDF PubMed Scopus (254) Google Scholar These findings support the finding that repeat BCG offers more protection for children who are likely to be less exposed to other mycobacteria than adults in the 30-year follow-up of the Karonga trial. Another issue is whether the high HIV prevalence of 12% in the district7White RG Vynnycky E Glynn JR et al.HIV epidemic trend and antiretroviral treatment need in Karonga District, Malawi.Epidemiol Infect. 2007; 135: 922-932Crossref PubMed Scopus (27) Google Scholar could have masked the overall benefit seen in HIV-negative participants. 63% of tuberculosis cases were HIV-positive, with almost 97% of cases having pulmonary tuberculosis. Mangtani and colleagues, in a systematic review, meta-analysis, and meta-regression of studies evaluating a single BCG immunisation, apart from showing more protection in trials done further from the equator, also showed protection against pulmonary tuberculosis. BCG strain was unimportant.5Mangtani P Abubakar I Ariti C et al.Protection by BCG vaccine against tuberculosis: a systematic review of randomized controlled trials.Clin Infect Dis. 2014; 58: 470-480Crossref PubMed Scopus (502) Google Scholar More recently, De Gijsel and von Reyn reviewed evidence from prospective and retrospective BCG trials in which follow-up was between 2 and 50 years, also suggesting protective efficacy against pulmonary tuberculosis in adults.8de Gijsel D von Reyn CF A breath of fresh air: BCG prevents adult pulmonary tuberculosis.Int J Infect Dis. 2019; 80S: S6-S8Summary Full Text Full Text PDF PubMed Scopus (12) Google Scholar One of these was a 60-year follow-up of a BCG trial in Native Americans who were between 1 month and 20 years of age, had normal chest radiographs, and were tuberculin skin test negative at baseline. Participants received either BCG or saline and were unaware of their intervention. Prospective follow-up after 11 years (1937–48) showed a protective efficacy of 80% against pulmonary tuberculosis. Follow-up continued through medical record review and after a record of 60 years, still showed efficacy of 52% (95% CI 27–69), with females more protected than males.9Aronson NE Santosham M Comstock GW et al.Long-term efficacy of BCG vaccine in American Indians and Alaska Natives: a 60-year follow-up study.JAMA. 2004; 291: 2086-2091Crossref PubMed Scopus (242) Google Scholar Although randomised, prospective clinical trials are essential for establishing the efficacy of interventions, follow-up is often too short and is limited by costs and logistics. Fitzpatrick and colleagues did a scoping review of 113 intervention trials that were extended by record linkage after the formal trials had been completed.10Fitzpatrick T Perrier L Shakik S et al.Assessment of long-term follow-up of randomized trial participants by linkage to routinely collected data: a scoping review and analysis.JAMA Netw Open. 2018; 1e186019Crossref PubMed Scopus (21) Google Scholar They showed that both benefits and harms could extend beyond trial completion. They recommend that researchers routinely request permission from trial participants to study long-term intervention effects after the trial is complete. This advice seems especially relevant for vaccines aiming to prevent tuberculosis. Despite the data supporting a protective effect from BCG and widespread neonatal BCG immunisation, tuberculosis is a global health priority and a major cause of morbidity and mortality. The field of tuberculosis vaccinology is progressing with many new candidates being studied.11Schrager LK Harris RC Vekemans J Research and development of new tuberculosis vaccines: a review.F1000 Res. 2018; 71732Crossref PubMed Scopus (25) Google Scholar Long-term outcomes from well-conducted trials such as the Karonga Prevention trial, are worth pursuing and give added depth to the field. As BCG is already widely used, reimmunisation in children should be seriously reconsidered. Also, because of variability in different regions, individualised approaches should be contemplated. We declare no competing interests. BCG re-vaccination in Malawi: 30-year follow-up of a large, randomised, double-blind, placebo-controlled trialThere was no evidence that repeat BCG vaccination provides appreciable protection against overall tuberculosis in this rural African population with a high prevalence of HIV. Subgroup effects should not be overinterpreted given the multiple analyses done. However, the evidence for modest protection against HIV-negative tuberculosis, and for a delayed benefit in those vaccinated as children, is consistent with other observations in the literature. Full-Text PDF Open Access