BCG re-vaccination in Malawi: 30-year follow-up of a large, randomised, double-blind, placebo-controlled trial

Abstract

Background: A large, double-blind, randomised, placebo-controlled trial of repeat BCG found 49% efficacy against leprosy but no protection against tuberculosis after 6-9 years' follow-up in 1995. We report here additional follow-up, which resulted in greatly increased tuberculosis case numbers, and allowed subgroup analysis.

Methods: Nearly 47 000 individuals of all ages living in northern Malawi with a BCG vaccine scar were randomly assigned (1:1) between 1986 and 1989 to receive a second BCG or placebo. The investigators and project staff remained masked to all interventions. Enhanced passive surveillance ensured ascertainment of tuberculosis and leprosy to the end of 2018. Tuberculosis case definitions included rigorous microbiological or histological confirmation. Prespecified subgroup analyses were by tuberculosis type, age at vaccination, time since vaccination, previous tuberculin reactivity, HIV status and Mycobacterium tuberculosis lineage. The original trial is registered with ISRCTN registry, ISRCTN11311670.

Findings: In follow-up until Dec 31, 2018, 824 participants had developed tuberculosis, including 786 with pulmonary disease, of whom 383 (63%) of 607 with known HIV status were HIV positive. There was no effect of a second BCG overall (odds ratio [OR] 0·92; 95% CI 0·80-1·05), or for pulmonary (0·93; 0·81-1·07), or lymph node tuberculosis (0·60; 0·31-1·17). The OR was lower for those with known HIV-negative tuberculosis (0·77; 0·59-1·00), for those vaccinated as children (aged <5 years, 0·74; 0·41-1·35; aged 5-14 years, 0·77; 0·60-0·99), and for cases arising at least 20 years after vaccination (0·79; 0·63-1·01). There were no differences by tuberculin status at vaccination, or lineage. There was no evidence of protection against leprosy beyond 10 years after vaccination (although there have been only nine diagnostically certain cases since 1995).

Interpretation: There 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.

Funding: LEPRA, Wellcome Trust, Bill & Melinda Gates Foundation.

Figure 1

Trial profile The two columns with shaded boxes refer to the repeat BCG versus placebo comparison emphasised in this report. M leprae=Mycobacterium leprae.

Figure 2

Odds ratios of tuberculosis associated with repeated BCG among scar-positive individuals allocated either repeat BCG or placebo (intention-to-treat population for certain and probable tuberculosis) TST=tuberculin skin test. ART=antiretroviral therapy. Box areas are proportional to sample size. Subgroup analyses are for pulmonary tuberculosis, except lineage, which is based on all tuberculosis. † Interaction p value=0·30. ‡Interaction p value=0·040. §Interaction p value=0·28.

Figure 3

BCG vs placebo in scar-positive individuals, stratified by age and years since vaccination (intention-to-treat population for certain and probable pulmonary tuberculosis) p value for interaction between age group and study group by years since vaccination: <10 years, p=0·57; 10–19 years, p=0·79; ≥20 years, p=0·050.

Figure 4

BCG vs placebo in scar-positive individuals, by HIV status HIV negative (A). HIV positive (B). Intention-to-treat population for certain and probable tuberculosis. *p_interaction=0·65. † p_interaction=0·60. ‡p_interaction=0·059. §p_interaction=0·024.

Figure 5

Odds ratios of leprosy associated with repeated BCG among scar-positive individuals allocated either repeat BCG or placebo (intention-to-treat population) Note, for subgroup <5 mm one-sided 95% CI calculated (Cornfield method). *p value for interaction=0·013. † p value for interaction=0·95.