Comparison of VPM1002 with BCG in the prevention of tuberculosis in newborn infants: a multicentre, double-blind, randomised, phase 3, non-inferiority trial.

Abstract

Although BCG provides protection against severe forms of tuberculosis in children, its efficacy against pulmonary tuberculosis in adolescents and adults is highly variable, and it offers limited and inconsistent protection against infection and transmission. VPM1002 is a recombinant BCG vaccine that showed manageable toxicity and immunogenicity in phase 1 trials in adults and in phase 2 trials in South African newborns. We compared VPM1002 with BCG for the prevention of Mycobacterium tuberculosis infection in infants. This double-blind, randomised, active-controlled, phase 3 trial was conducted at ten main sites and four satellite sites in sub-Saharan Africa, ranging from rural to urban settings, with experience in tuberculosis trials. Healthy newborn infants, aged 0-14 days and with a birthweight of at least 2·3 kg, were randomly assigned (1:1) to receive single 0·05 mL doses of either VPM1002 or BCG, administered intradermally. Follow-up was extended from 36 months up to 48 months (due to the lower than expected event rate) or until 632 cases of M tuberculosis had accrued. The randomisation was done centrally through an interactive web response system and allocation was stratified by maternal HIV status at a 1:10 ratio, using a permuted block design with variable block sizes. Only the site personnel involved in preparation and administration of the vaccines were not masked to the trial. Mothers were aged 18 years or older, free from active tuberculosis, and without household contact with an individual with tuberculosis within the 3 months before enrolment. Neonates were excluded for any fever, acute or chronic illness, congenital malformation, substantial skin lesion or infection at the site of injection, or previous receipt of routine BCG vaccination. The primary endpoint was non-inferiority of VPM1002 versus BCG for prevention of M tuberculosis infection, defined by incident QuantiFERON-TB Gold Plus (QFT; an interferon-γ release assay [IGRA]) conversion, assessed every 6 months from month 6 until the final visit and more frequently in suspected cases of tuberculosis. In the time-to-event efficacy analysis, participants with missing event occurrence data were censored at the last timepoint for which there was no clear evidence of the event occurrence. The primary efficacy analysis was in the per-protocol population (randomly assigned, vaccinated participants with at least one post-vaccination result and no major efficacy-relevant protocol deviations) with a supportive intention-to-treat analysis of all randomly assigned participants; both were analysed as assigned. As estimates were concordant, intention-to-treat results are presented. Safety was analysed as treated in all vaccinated participants. Non-inferiority required the upper bound of the 95% CI for the hazard ratio (HR) to be less than 1·25. The trial was registered on ClinicalTrials.gov (NCT04351685) and PACTR (PACTR202007868402718) and is complete. Between Nov 9, 2020, and June 21, 2022, we enrolled 6950 infants. The trial was terminated early in October, 2024, due to a lower than expected QFT conversion rate. After the withdrawal of ten infants, 6940 were randomly assigned to treatment, including 720 infants born to mothers living with HIV and 6220 HIV-unexposed infants. Overall, 3449 male and 3491 female infants were included in the intention-to-treat population. 6897 infants received vaccination (3452 received VPM1002 and 3445 received BCG). Median follow-up was 35 months (IQR 30-38). QFT conversion occurred in 184 (5·3%) of 3471 infants in the VPM1002 group and 150 (4·3%) of 3469 infants in the BCG group. Cox proportional hazards regression analysis (VPM1002 vs BCG) revealed VPM1002 was not non-inferior to BCG, with an HR of 1·23 (95% CI 0·99-1·53). Adverse event profiles, including serious adverse events and deaths, were similar between groups; no vaccine-related serious adverse events were reported. VPM1002 did not show non-inferiority to BCG on the primary endpoint of QFT conversion. Because fewer infections occurred than expected (334 of 632 planned events, despite extending the duration to 48 months), the trial did not have sufficient statistical certainty to definitively compare the two vaccines. Moreover, discordance between the QFT surrogate and confirmed tuberculosis endpoints, approximately 33·0% higher household tuberculosis exposure in the VPM1002 group, and violation of the proportional hazards assumption when tuberculosis exposure was included as a covariate (that is, the effect of tuberculosis exposure on QFT conversion was not constant over time, precluding reliable HR estimation without penalised modelling) collectively add to this uncertainty. Both vaccines showed similar adverse event profiles. These findings highlight challenges in using IGRA-defined infection endpoints in infant vaccine trials. European and Developing Countries Clinical Trials Partnership 2 (EDCTP2) programme (RIA2016V-1645-priMe), supported by the European Union and co-funded by Deutsches Zentrum für Luft- und Raumfahrt (DLR) and the European Investment Bank (EIB).