An investigational TB vaccine didn’t top the standard bacillus Calmette-Guérin (BCG) vaccine at preventing infections in infants, a multi-centre phase 3 trial showed, reports MedPage Today.
Among nearly 6 900 newborns in sub-Saharan Africa, QuantiFERON-TB Gold Plus (QFT) conversion, indicating Mycobacterium tuberculosis infection or exposure, occurred in 5.3% of those who received the VPM1002 vaccine compared with 4.3% of those who received the BCG vaccine, reported Sina Brückner, PhD, of Serum Life Science Europe in Hanover, Germany, and colleagues, including from several South African institutions, in Lancet Infectious Diseases.
For events meeting the first-case definition for QFT conversion in the VPM1002 group versus the BCG group, the HR was 1.23 (95% CI 0.99-1.53, P=0.057). Non-inferiority required the upper bound of the confidence interval to be less than 1.25.
The trial also delivered uncertainty about VPM1002’s relative efficacy at preventing TB disease. Among 588 participants evaluated for suspected TB disease during follow-up, 3.2% of those who received VPM1002 and 1.7% of those in the BCG group developed microbiologically confirmed or unconfirmed TB.
With fewer QFT conversions overall than predicted (344 vs 632), the investigators terminated the trial early in October 2024.
“These findings highlight the methodological challenges of using QFT-based infection endpoints in infant vaccine trials and the importance of accounting for differential tuberculosis exposure in the design and analysis of future prevention of infection trials,” Brückner and colleagues wrote.
“Given these findings, tuberculosis disease is a more appropriate endpoint in infant vaccine trials."
BCG is the only licensed TB vaccine. While it protects young children against severe TB, it delivers waning and inconsistent protection against TB disease and transmission in adolescence and adulthood.
However, as reported in MedicalBrief, another vaccine trial has shown huge promise and was described as a breakthrough vaccine for TB – the first to be introduced in more than a century. It is likely to be rolled out in South Africa soon and is expected to eliminate the disease as a public threat by 2030 as phase three trials in five countries show high promise.
The Department of Health saids at the time preparations are already under way for an expedited roll out once approval has been granted for the M72/ASOIE vaccine. See more here.
Meanwhile, VPM1002 is a recombinant BCG vaccine strain that showed similar immunogenicity to BCG, with fewer adverse injection-site events in early-phase trials.
“Finding a more effective TB vaccine than BCG is an urgent global health priority,” noted Helen McShane, PhD, of the University of Oxford in England, in an accompanying editorial. But better TB trial designs and endpoints are crucial to achieving that goal, she added.
Results from interferon-γ release assays such as QFT have been used widely as surrogate Mycobacterium tuberculosis infection markers in clinical trials.
However, the gold-standard endpoint in TB trials is microbiologically confirmed disease, a challenging metric that requires large sample sizes and long follow-up periods.
VPM1002’s relative performance was worse when measured using microbiologically confirmed disease as the endpoint. That result shows that the trial’s surrogate infection endpoint of incident QFT conversion “might not be a sufficiently robust endpoint for tuberculosis vaccine efficacy trials”, McShane wrote.
“Overall, this trial teaches us that there are no obvious short cuts in tuberculosis vaccine efficacy trials,” she noted. “We need to continue to explore viable efficacy endpoints and trial design.”
There are relatively few early-stage TB vaccine candidates and only a handful of late-stage vaccine candidates, McShane pointed out.
“As we encourage vaccine developers and funders to develop and support diverse and innovative vaccine candidates, we must in parallel work to design robust but feasible efficacy trials,” she added.
This double-blind, active-controlled trial randomised 6 940 newborns to vaccination with either VPM1002 or BCG, of whom 6 897 received shots. The trial ran from November 2020 to June 2022. Eligible infants were aged 0 to 14 days and had a birthweight of at least 2.3kg. Mothers were at least 18 years old, had no active TB, and had no household contacts with TB in the three months before study enrolment.
Median post-vaccination follow-up was 35 months, 50.3% of infants were female, median enrolment age was three days, and 95.1% of infants were black African.
The study’s primary efficacy endpoint was the occurrence of QFT conversion, indicating M. tuberculosis infection or exposure. Secondary endpoints included protective efficacy against microbiologically confirmed and unconfirmed TB disease.
Among 720 HIV-exposed, uninfected infants, 7% of those receiving VMP1002 had a QFT conversion compared with 8% of those receiving BCG. The 6,220 infants who were HIV-unexposed had a 5.1% QFT conversion rate with VPM1002 and a 3.9% rate with BCG.
Although more of the VPM1002 group had household TB exposures than the BCG group, adjustment for that increased exposure status showed similar QFT conversion rates between the two groups.
Safety profiles were similar for both vaccines. There was at least one solicited adverse event in 75% of those in the VPM1002 group versus 67% of those in the BCG group; nearly all events were mild. Rates of serious adverse events were also similar (10.7% vs 9.4%, respectively).
Study details
Comparison of VPM1002 with BCG in the prevention of TB in newborn infants: a multicentre, double-blind, randomised, phase 3, non-inferiority trial
Videlis Nduba, Matsontso Mathebula, Victoria Nankabirwa et al.
Published in The Lancet Infectious Diseases on 18 August 2026
Summary
Background
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.
Methods
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.
Findings
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.
Interpretation
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.
MedPage Today article – Novel Tuberculosis Vaccine Falls Short (Open access)
See more from MedicalBrief archives:
Century-old BCG vaccine prevents TB in children, not adults – Boston meta-analysis
Hopes pinned on major TB vaccine study launched in Paarl
Blood test predicts onset of tuberculosis in young children