BCG Revaccination for the Prevention of Mycobacterium tuberculosis Infection

Abstract

Background: In a previous phase 2 trial, bacille Calmette-Guérin (BCG) revaccination was not shown to provide protection from primary Mycobacterium tuberculosis infection but prevented sustained M. tuberculosis infection, defined by an initial conversion on a QuantiFERON-TB (QFT) test (an interferon-γ release assay) from negative to positive, followed by two additional positive QFT tests at 3 and 6 months after the initial conversion (a secondary end point). A vaccine efficacy of 45% (95% confidence interval [CI], 6 to 68) was observed.

Methods: We performed a phase 2b, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of BCG revaccination, as compared with placebo, for the prevention of sustained QFT test conversion (primary end point) in QFT test-negative, human immunodeficiency virus (HIV)-negative adolescents. Adverse events were assessed in a secondary analysis, and immunogenicity was assessed in an exploratory analysis. Vaccine efficacy was evaluated in the modified intention-to-treat population, which included all the participants who had undergone randomization, received the BCG vaccine or placebo, and had a negative QFT test 10 weeks after receipt of BCG vaccine or placebo; the last criterion was added to exclude participants with M. tuberculosis infection around the time that the vaccine or placebo was administered. Hazard ratios and 95% confidence intervals were estimated from a stratified Cox proportional-hazards model.

Results: A total of 1836 participants underwent randomization; 918 received the BCG vaccine, and 917 received placebo. After a median 30 months of follow-up, a sustained QFT test conversion was observed in 62 of 871 participants in the BCG-vaccine group and 59 of 849 participants in the placebo group. The hazard ratio for a sustained QFT test conversion (BCG vaccine vs. placebo) was 1.04 (95% CI, 0.73 to 1.48), for a vaccine efficacy point estimate of -3.8% (95% CI, -48.3 to 27.4). Adverse events occurred more frequently in the BCG-vaccine group than in the placebo group, and most were due to injection-site reactions (pain, redness, swelling, and ulceration). BCG revaccination induced cytokine-positive type 1 helper CD4 T cells.

Conclusions: BCG revaccination in QFT-test negative, HIV-negative adolescents did not provide protection from sustained M. tuberculosis infection. (Funded by the Gates Foundation; ClinicalTrials.gov number NCT04152161.).

Figure 1:

Trial Design and CONSORT diagram A) Trial Design. Participants were randomized to placebo or BCG groups and QFT assessments were performed according to trial schedule. Participants who converted to QFT positive at Day 71 (or if missed or not feasible, at the next feasible visit) were excluded from the primary mITT efficacy analysis but were followed for safety and efficacy to end of study. Each participant was followed for safety for a minimum of 6 months after vaccination. ICF, informed consent form; PC, post conversion; QFT, QuantiFERON-TB Test B) Participant Disposition. Amongst 3653 screened individuals, 1816 were excluded from enrollment. The most common ineligibility criteria were a positive QFT test, altered laboratory values, urinalysis abnormal. Protocol deviations leading to exclusion from mITT population included IP non-compliance (3 in the BCG group) and eligibility criteria (1 in the BCG group and 3 in placebo). A total of1836 were randomized 1:1 to BCG (n=919) or placebo (n=917). IP, Investigational product; QFT, QuantiFERON-TB Test

Figure 1:

Trial Design and CONSORT diagram A) Trial Design. Participants were randomized to placebo or BCG groups and QFT assessments were performed according to trial schedule. Participants who converted to QFT positive at Day 71 (or if missed or not feasible, at the next feasible visit) were excluded from the primary mITT efficacy analysis but were followed for safety and efficacy to end of study. Each participant was followed for safety for a minimum of 6 months after vaccination. ICF, informed consent form; PC, post conversion; QFT, QuantiFERON-TB Test B) Participant Disposition. Amongst 3653 screened individuals, 1816 were excluded from enrollment. The most common ineligibility criteria were a positive QFT test, altered laboratory values, urinalysis abnormal. Protocol deviations leading to exclusion from mITT population included IP non-compliance (3 in the BCG group) and eligibility criteria (1 in the BCG group and 3 in placebo). A total of1836 were randomized 1:1 to BCG (n=919) or placebo (n=917). IP, Investigational product; QFT, QuantiFERON-TB Test

Figure 2:

Vaccine Efficacy in the mITT population. A) Cumulative event curve for sustained QFT conversion (primary efficacy endpoint) by trial visit. B) Cumulative event curve for sustained QFT conversion by calendar month. C) Cumulative event curve for initial QFT conversion by trial visit. D) Proportion of initial QFT conversions based on QFT conversion thresholds of >0.35 IU/mL. Error bars represent 95% CIs. CI, confidence intervals; mITT, modified intention-to-treat population; QFT, QuantiFERON-TB Test

Figure 2:

Vaccine Efficacy in the mITT population. A) Cumulative event curve for sustained QFT conversion (primary efficacy endpoint) by trial visit. B) Cumulative event curve for sustained QFT conversion by calendar month. C) Cumulative event curve for initial QFT conversion by trial visit. D) Proportion of initial QFT conversions based on QFT conversion thresholds of >0.35 IU/mL. Error bars represent 95% CIs. CI, confidence intervals; mITT, modified intention-to-treat population; QFT, QuantiFERON-TB Test

Figure 2:

Vaccine Efficacy in the mITT population. A) Cumulative event curve for sustained QFT conversion (primary efficacy endpoint) by trial visit. B) Cumulative event curve for sustained QFT conversion by calendar month. C) Cumulative event curve for initial QFT conversion by trial visit. D) Proportion of initial QFT conversions based on QFT conversion thresholds of >0.35 IU/mL. Error bars represent 95% CIs. CI, confidence intervals; mITT, modified intention-to-treat population; QFT, QuantiFERON-TB Test

Figure 2:

Vaccine Efficacy in the mITT population. A) Cumulative event curve for sustained QFT conversion (primary efficacy endpoint) by trial visit. B) Cumulative event curve for sustained QFT conversion by calendar month. C) Cumulative event curve for initial QFT conversion by trial visit. D) Proportion of initial QFT conversions based on QFT conversion thresholds of >0.35 IU/mL. Error bars represent 95% CIs. CI, confidence intervals; mITT, modified intention-to-treat population; QFT, QuantiFERON-TB Test

Figure 3:. Immunogenicity of BCG revaccination.

Frequencies of antigen-specific CD4 T cells expressing any combination of IFN-γ, TNF, IL-2, IL-17, and/or IL-22 after stimulation with BCG, measured by WB-ICS assay in participants receiving placebo (red) or BCG (blue). Panel A shows longitudinal responses during the first 168 days after vaccination. Lines represent medians and errors bars 95% CIs. Panel B shows area under the curve (AUC) for antigen-specific CD4 T cell response during the first 168 days after vaccination. Each dot represents an individual participant.