BCG Revaccination Fails to Prevent Tuberculosis Infection in Large Phase 2b Trial
核心洞察
A phase 2b randomized trial of 1,836 adolescents in South Africa found BCG revaccination provided no protection against sustained Mycobacterium tuberculosis infection, with a vaccine efficacy of -3.8%.
The study contradicts earlier promising results and represents the largest trial to date examining BCG revaccination for tuberculosis prevention in HIV (搜索)-negative adolescents.
Results align with a recent Brazilian healthcare worker study, weakening the evidence base for BCG revaccination as a tuberculosis prevention strategy.
A large-scale phase 2b trial has delivered disappointing results for BCG revaccination as a tuberculosis prevention strategy, finding no efficacy against sustained Mycobacterium tuberculosis infection in HIV (搜索)-negative adolescents. The randomized, placebo-controlled study of 1,836 participants across five South African sites contradicts earlier promising findings and raises questions about the viability of BCG revaccination for tuberculosis control.
Trial Design and Primary Findings
The double-blind trial, published in the New England Journal of Medicine, randomly allocated 918 participants to receive BCG vaccine and 917 to receive placebo. After 30 months of follow-up, sustained QuantiFERON-TB (QFT) test conversion occurred in 62 of 871 participants in the BCG group compared to 59 of 849 in the placebo group, yielding a hazard ratio of 1.04 and a vaccine efficacy point estimate of -3.8% (95% confidence interval, -48.3 to 27.4).
The primary endpoint was defined as sustained QFT conversion from negative to positive, with initial conversion at any time after randomization and remaining QFT-positive at 3- and 6-months post conversion. This stringent definition was designed to capture true tuberculosis infection rather than transient immune responses.
Safety Profile and Adverse Events
BCG revaccination demonstrated a predictable safety profile, with adverse events occurring more frequently in the vaccine group compared to placebo, primarily due to injection-site reactions. Larger scars exceeding 10mm at the BCG administration site were observed in approximately 3% of vaccinees, consistent with previous reports for the marketed BCG vaccine.
The trial enrolled participants aged 10-18 years who tested negative for both HIV (搜索) and QFT at baseline. The study was conducted at sites in Worcester, Cape Town, Mbekweni, Durban, and Johannesburg, representing diverse South African communities with varying tuberculosis transmission rates.
Contradictory Results and Geographic Considerations
These findings starkly contrast with an earlier trial that reported 45.4% vaccine efficacy for BCG revaccination in preventing sustained QFT conversion. The current study was specifically designed to confirm those promising results, with approximately three times larger sample size per treatment arm and expanded geographical coverage.
Researchers noted that the overall initial QFT conversion rate in this trial was lower than the earlier study (6.5-6.9% versus 9.9% per person-year), potentially due to COVID-19-related lockdowns and school closures in 2020 and 2021. However, site-specific vaccine efficacy at Worcester, where 92.7% of the earlier trial was conducted, remained similar to the overall results, suggesting geographical differences don't explain the contrasting outcomes.
Immunological Response and Mechanistic Insights
Despite the lack of clinical efficacy, BCG revaccination successfully induced cytokine-positive type 1 helper CD4 T cells, demonstrating immunological activity. The first 80 participants aged 10-12 years at the Worcester site were enrolled in an immunogenicity sub-cohort, where researchers evaluated BCG-specific CD4 and CD8 T cells expressing interferon-γ, tumor necrosis factor, interleukin-2, interleukin-17, and interleukin-22.
An interesting observation was the higher QFT reversion rate in the placebo arm of this trial (42%) compared to the earlier study (25%), while reversion rates in BCG groups remained comparable (44% versus 46%). Whether this difference relates to baseline characteristics, including younger participants and more diverse populations, or reduced tuberculosis exposure during COVID-19 restrictions remains unclear.
Broader Implications for Tuberculosis Prevention
The results align with a recent BCG revaccination trial in 2,000 adult healthcare workers in Brazil that also reported no vaccine efficacy against initial or sustained QFT conversion. This convergence of negative results across different populations, geographical settings, and age groups significantly weakens the evidence supporting BCG revaccination for tuberculosis infection prevention.
Alexander C. Schmidt from the Gates Medical Research Institute (搜索) and colleagues noted that while the trial doesn't allow firm conclusions about BCG revaccination efficacy for preventing tuberculosis disease, "the lack of vaccine efficacy with respect to prevention of infection probably decreases the likelihood of BCG revaccination conferring protection against disease."
Future Research Directions
The researchers emphasized that their findings don't definitively rule out potential efficacy for prevention of disease (POD), as opposed to prevention of infection (POI). A BCG revaccination trial specifically designed to assess disease prevention is currently underway in India and may provide crucial data on this endpoint.
The study employed stringent statistical criteria with 90% power and a one-sided alpha of 2.5%, requiring at least 118 sustained QFT conversion events to demonstrate vaccine efficacy. The modified intention-to-treat population included all participants who received trial treatment and were QFT-negative at day 71 or the first available post-day 71 visit.
These definitive results represent a significant setback for BCG revaccination as a tuberculosis control strategy, highlighting the challenges in developing effective interventions against one of the world's leading infectious disease killers.