A novel tuberculosis (TB) vaccine candidate failed to match the standard bacillus Calmette-Guerin (BCG) vaccine in preventing TB infections in newborns, according to the results of a phase 3 trial published last week in The Lancet Infectious Diseases.
The double-blind, randomized trial, conducted at 14 sites in sub-Saharan Africa, enrolled healthy newborns to receive a single dose of either BCG or VPM1002, a genetically modified recombinant BCG vaccine. The primary end point was to show non-inferiority of VPM1002 compared with BCG in prevention of Mycobacterium tuberculosis infection, defined as QuantiFERON-TB Gold Plus (QFT) conversion.
Introduced in 1921, BCG is the only licensed vaccine for TB prevention. While it protects young children against severe forms of TB disease and is widely used in national immunization programs, its efficacy wanes over time, and it provides limited protection against TB disease and transmission in adolescents and adults.
Because of the limitations of the BCG vaccine, the World Health Organization has prioritized development of new TB vaccines. VPM1002, developed by Serum Institute of India, is one of 17 vaccine candidates in the pipeline for the disease, which sickened an estimated 10.7 million people and killed 1.2 million globally in 2024.
“There is an urgent need for new tuberculosis vaccines that not only have a good adverse event profile and are effective across all age groups, but are also scalable and sustainably produced to address the growing global burden of tuberculosis, including extrapulmonary tuberculosis,” the international team of investigators wrote.
Trial highlights methodology challenges
VPM1002, however, fell short of meeting the non-inferiority criteria established for the trial.
Overall, 6,897 newborns from five countries (Gabon, Kenya, South Africa, Tanzania, and Uganda) were enrolled and vaccinated from November 9, 2020, through June 21, 2002, with 3,452 receiving VPM1002 and 3,445 receiving the BCG vaccine. After a median follow-up of 35 months, QFT conversion—a change from a negative TB test to a positive result—occurred in 5.3% of infants in VPM1002 group and 4.3% of those in the BCG group.
The hazard ratio was 1.23, but the upper bounds of the confidence interval, which was 1.53, needed to be less than 1.25. VPM1002 also failed to meet non-inferiority for other end points, including microbiologically confirmed TB.
“The results favoured BCG over VPM1002 across the efficacy endpoints: there were more QFT conversion events (184 vs 150), more participants with confirmed tuberculosis (18 vs six), more participants with unconfirmed tuberculosis (92 vs 53), and more sustained QFT conversions (44 vs 33) in the VPM1002 group than in the BCG group,” the study authors wrote.
Safety profiles were similar for the two vaccines.
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.
Because fewer infections occurred than expected (334 QFT conversions versus the 632 required), the investigators say the trial did not have sufficient statistical certainty to definitively compare the two vaccines or support a definitive conclusion of VPM1002 inferiority. The trial was terminated early in October 2024, following review by the data safety monitoring board.
The authors say the results highlight the methodologic challenges of using QFT-based infection as an end point in infant TB vaccine trials, rather than TB disease. While prevention of infection is epidemiologically meaningful, they note, “tuberculosis disease is a more appropriate endpoint in infant vaccine trials.”
But evaluating a vaccine’s ability to prevent TB disease in infants requires larger populations and more follow-up time. In an accompanying commentary, Helen McShane, PhD, a professor of vaccinology at the University of Oxford, says the results show “there are no obvious short cuts in tuberculosis vaccine efficacy trials.”
“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 wrote. “It would be a tragedy for the more than 3,000 people who will die every day from tuberculosis if the failure of these first-generation vaccine candidates stops us trying harder.”
