After decades of stalled progress, tuberculosis (TB) vaccine development is gaining momentum, with 18 candidates now in clinical development and several in or approaching late-stage trials. The pipeline includes vaccines designed to prevent TB disease in adolescents and adults, replace Bacillus Calmette-Guérin (BCG) in early-life immunization, and prevent recurrence after TB treatment.

Among the most advanced candidates is M72/AS01_E, now in a phase 3 trial involving 20,000 adolescents and adults at 54 sites worldwide. Serum Institute of India Private Limited has been selected to manufacture the vaccine if the trial supports further development and approval, addressing a key practical hurdle for a candidate that could become the first new TB vaccine in more than a century.

The only TB vaccine currently available is the BCG vaccine, which has limited efficacy beyond early childhood.

“TB is the world’s deadliest infectious disease. For too long, progress on a TB vaccine was stalled, but that is changing,” said Alemnew Dagnew, MD, MSc, MPH, head of Vaccines & Biologics Development at the Gates Medical Research Institute, which is funding the M72/AS01_E trial with Wellcome. Dagnew is leading the candidate’s clinical development.

Since most candidates are being developed outside the pharmaceutical industry, securing manufacturing capacity is an important step toward eventual rollout, he said.

Currently, the phase 3 trial of M72/AS01_E, which began in 2024, is testing whether the vaccine prevents pulmonary TB disease. In a phase 2b trial, it reduced progression to active pulmonary disease by about 50% among people infected with TB. The World Health Organization has estimated that a vaccine with this level of protection could save 8.5 million lives over 25 years.

“That would be a huge number of TB cases averted, or if it could stop TB infection from becoming TB disease, amazing,” said Anastasia Pharris, PhD, principal expert in infectious diseases at the European Centre for Disease Prevention and Control, which publishes TB surveillance reports.

Success Far From Guaranteed

Experts contacted by Medscape News Europe said M72/AS01_E could now be the front-runner, but success is not guaranteed even in phase 3.

“It is about statistics,” said Frank Cobelens, MD, PhD, professor of global health at the Amsterdam Institute for Global Health & Development in Amsterdam, Netherlands. “It is still uncertain but there are high hopes.”

One reason for caution is the wide CIs around efficacy estimates from phase 2 trials, including that of M72/AS01_E. An efficacy signal can disappear when a candidate is tested in a much larger population. In 2018, for example, a Danish study suggested that revaccinating adolescents with BCG after an initial dose at birth had approximately 50% efficacy. A larger placebo-controlled trial later found no efficacy for that or similar endpoints.

Trials can also produce unexpected findings. A study of another Danish candidate, H56:IC31, did not show a reduction in the risk for TB recurrence. “But it did find an increased risk of relapse in a sub-group of recently treated TB patients,” Cobelens said. It is unclear whether that finding reflected the vaccine itself or an immune response that vaccination could not improve. Either way, the result would be difficult to extrapolate to prevention of TB in the general population, he said.

Even when candidates fail, trials can improve the design of future studies, Cobelens said.

The broader pipeline includes Mycobacterium tuberculosis Vaccine, a genetically modified vaccine based on attenuated M tuberculosis. Developed by the University of Zaragoza, Zaragoza, Spain, in collaboration with the Pasteur Institute, France, it is in phase 2b trials and is expected to move into phase 3.

Russia’s GamTBvac recombinant subunit TB vaccine is in phase 3 trials involving 9500 volunteers and is testing prevention of active pulmonary TB.

In India, trials of VPM1002 and Immunovac in 12,000 adults across six states concluded in April that both vaccines were safe but did not show efficacy against pulmonary TB; further results are expected to be published.

Earlier in the pipeline are novel viral-vector and mRNA candidates, although the overall early-stage development remains relatively thin.

Why Europe Still Needs a TB Vaccine

Despite substantial gains from better treatment and living conditions, between 35,000 and 40,000 people are newly diagnosed with active TB in the EU each year, Pharris said. Many more cases occur across the broader European region. In 2024, 3500 people died of TB in the EU, a 17% decrease from the previous year.

TB incidence generally rises toward Eastern Europe and Central Asia. Greenland is an outlier, with the highest rate in Europe, followed by the Republic of Moldova, Romania, Ukraine, and several other Eastern European countries that report comparatively high TB rates.

TB spreads through contact with people who have active disease and can circulate in workplaces and schools, Pharris said. Outbreaks have also occurred in homeless shelters. People infected in high-burden countries outside Europe may develop active disease years later after moving to Europe.

That is why Europe still needs a TB vaccine, said Cobelens. “Look at countries like Ukraine,” he said. “It’s not just that there are higher rates of tuberculosis than in Western Europe, but that there is a lot of multidrug resistance, which makes preventive treatment much more difficult.”

Preventive treatment involves giving drugs to people with TB infection to stop progression to active disease. But some of the same drugs used for prevention, including rifampicin, may be ineffective when the infecting strain is resistant.

That is one reason the global TB community is closely awaiting results from M72/AS01_E and other vaccine trials, said Cobelens, who published a paper on the latest TB vaccine pipeline last month.

If a new vaccine is eventually approved, demand in Europe is likely to depend heavily on local TB burden.

Christophe Lange, MD, medical director at the Research Center Borstel at the Leibniz Lung Center in Borstel, Germany and founder of the Tuberculosis Network European Trials Group, said Russia has by far the largest number of TB patients in the region. “More than 50% of TB patients in Russia have drug-resistant TB. A vaccine would be one of the best options to give prevention, irrespective of the level of drug resistance,” he said.

In low-burden countries such as Italy or Germany, however, he said routine vaccination would not be a priority because the number needed to vaccinate to prevent one case would be too high.

Dagnew, Pharris, Cobelens, and Lange reported no relevant financial relationships.

Tatum Anderson is a global health journalist with almost 30 years of experience. Based in London, England, Anderson specializes in technology, public health, infectious and noncommunicable diseases, drug and vaccine development, medical research, and policy.