Novel Vaccine Fails to Outperform BCG in Preventing Infant TB, Suggests Phase 3 Trial
USA: A phase III multicenter trial found that the investigational VPM1002 tuberculosis vaccine was not more effective than standard BCG vaccination in preventing TB infection among newborns. The trial was stopped early because far fewer QuantiFERON-TB (QFT) conversions occurred than expected—344 versus the projected 632—making it unlikely to demonstrate a meaningful benefit. The findings highlight the ongoing need for a more effective TB vaccine, particularly for infants.
The study, published in The Lancet Infectious Diseases, was conducted by Videlis Nduba of the Kenya Medical Research Institute/Center for Respiratory Disease Research (KEMRI/CRDR), Nairobi and Siaya, Kenya, and colleagues. Researchers compared VPM1002, a recombinant BCG-based vaccine, with conventional BCG vaccination to determine whether it could provide comparable or better protection against Mycobacterium tuberculosis infection during infancy.
BCG is routinely given to newborns and protects against severe childhood TB, but its effectiveness against pulmonary TB later in life and TB infection or transmission is variable. VPM1002, a recombinant BCG vaccine, had previously shown acceptable safety and immune responses in adults and South African newborns, leading to its evaluation in a phase III trial.
The double-blind, randomized, active-controlled trial was conducted at 10 main and four satellite sites across rural and urban sub-Saharan Africa. Healthy newborns aged 0–14 days with birthweights of at least 2.3 kg received a single intradermal 0.05 mL dose of VPM1002 or BCG.
Between November 9, 2020, and June 21, 2022, 6,950 infants were enrolled. After 10 withdrawals, 6,940 were randomized, including 720 infants born to mothers living with HIV. A total of 6,897 infants were vaccinated, with 3,452 receiving VPM1002 and 3,445 BCG. Median follow-up was 35 months.
The primary endpoint was new Mycobacterium tuberculosis infection, assessed through QuantiFERON-TB Gold Plus (QFT) conversion, with testing every six months from month six and additional testing when TB was suspected.
QFT conversion occurred in 184 (5.3%) infants in the VPM1002 group versus 150 (4.3%) in the BCG group. The hazard ratio was 1.23 (95% CI 0.99–1.53), indicating that VPM1002 did not meet the prespecified criterion for non-inferiority to BCG.
Key findings:
- VPM1002 did not demonstrate non-inferiority to BCG for preventing M tuberculosis infection.
- QFT conversion was reported in 5.3% of infants receiving VPM1002 versus 4.3% with BCG.
- The trial was terminated early in October 2024 because the infection rate was substantially lower than anticipated.
- Only 344 QFT conversion events occurred versus the 632 initially expected.
- Safety outcomes were broadly comparable between the two groups.
- No vaccine-related serious adverse events were reported.
The researchers noted that the lower-than-expected number of infections reduced the statistical power of the study. In addition, differences between QFT-defined infection and confirmed TB outcomes, along with greater household TB exposure in the VPM1002 group, added uncertainty to interpreting the results.
The findings highlight the difficulties of using IGRA-based infection measures as surrogate endpoints in infant TB vaccine trials and reinforce the need for improved vaccination strategies that prevent TB infection and disease in children.
Reference:
Nduba, V., Mathebula, M., Nankabirwa, V., Dempster, M., Mhimbira, F., Sabi, I., Wajja, A., Cotton, M. F., Barnabas, S., Adegnika, A. A., Kaufmann, S. H. E., Brückner, S., May, M., Höß, C. W., Revathy, M., Niranjan, V., Bhargava, A., Gupta, M., Kapse, D., . . . Niranjan, V. (2026). Comparison of VPM1002 with BCG in the prevention of tuberculosis in newborn infants: A multicentre, double-blind, randomised, phase 3, non-inferiority trial. The Lancet Infectious Diseases. https://doi.org/10.1016/S1473-3099(26)00374-9
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