There is a lot to look forward to when it comes to TB vaccines

More than a dozen vaccines for tuberculosis (TB) are currently being tested in different stages of clinical trials.

We cannot end TB without new and effective vaccines. BCG (Bacille Calmette-Guerin) vaccination given to babies and young children provides consistent protection (up to 80%) against severe forms of childhood TB, such as TB meningitis but BCG is less effective against TB affecting the lungs in adults.

Treatment Action Group's 2023 Pipeline Report on TB vaccines shows us that much progress has been made: the pipeline is more robust than it ever has been, with tens of thousands of participants being recruited into Phase III trials across the globe. In 2023, some $600 million was pledged toward TB vaccine research, including $550 million from the Bill and Melinda Gates Foundation and the Wellcome Trust for a long-awaited Phase III trial of M72/AS01E slated to start in 2024. These commitments dwarf the inadequate $143 million spent on TB vaccine R&D in 2022.

Here's a summary of the TB vaccine candidates in clinical trials.

VPM1002, a genetically modified version of BCG, is injected. Macrophages take up the bacterium into a phagosome, where it produces an enzyme that causes pores to form in the phagosome membrane. This allows antigens to leak out into the cytosol and trigger an inflammasome activation, in a similar way to Mycobacterium tuberculosis (Mtb), which BCG does not do.

The Gates Medical Research Institute (Gates MRI) and Wellcome expect to open the M72/AS01E phase III trial in early 2024, ending a 5–6 year wait since positive results of an earlier phase IIb trial were published on the eve of the 2018 UN High-Level Meeting on TB. Safety and initial immunogenicity results from the MESA-TB study of M72/AS01E in PLHIV will be presented before the end of 2023. With M72/AS01E, two recombinant proteins that constitute the BCG vaccine are fused together and injected. Fusion proteins are taken up by immune cells that then display them on their surfaces to trigger an immune response against the antigens. A proprietary GlaxoSmithKline adjuvant (AS01) boosts that immune response.

A phase III trial of MTBVAC in infants continues to enroll and will soon be joined by a study of MTBVAC in adolescents and adults living with HIV, setting the stage for a larger phase IIb efficacy trial in adolescents and adults in African countries to come. Developer Biofabri has also shared plans for a phase I/II safety and immunogenicity study of MTBVAC in adults in India.

Sponsored by BioNTech, the first-ever TB vaccine constructs based on mRNA entered phase I testing in 2023. BioNTech may soon be joined by other developers working on mRNA and TB, including the mRNA Technology Transfer Hub in South Africa, Moderna/IAVI in the United States, Popvax in India, and Quratis in South Korea.

Two subunit vaccines out of Statens Serum Institute in Denmark are approaching major milestones. A phase IIb POR (prevention of recurrence) trial assessing whether H56:IC31 prevents disease recurrence in adults treated for drug-susceptible TB has completed all participant study visits and expects to report results in the first quarter of 2024. A new subunit vaccine called H107/CAF10b is expected to begin its first phase I clinical trial before the end of the year. Now 102 years old, the world’s only existing vaccine against TB, BCG, will once again make news when the Gates MRI publishes results of a phase II trial assessing whether revaccination with BCG protects adolescents against sustained MTB infection. The Gates MRI expects to share findings in early 2024. Several other groups are testing BCG revaccination in different populations, including household contacts of people with TB and preadolescents.

A positive efficacy finding in any of these vaccine candidates in a phase III trial would trigger a new set of regulatory decisions, research questions, commercial outlays, policy actions and, most importantly, community- and individual-level choices about whether to take a new TB vaccine or not.