More than 100 years after the first TB vaccine, why are we still waiting for a second?

It has been more than 100 years since the first and only tuberculosis (TB) vaccine – theBacillus Calmette–Guérin (BCG) vaccine – was used for the first time medically in 1921. With an estimated 1.6 million people dying from TB in 2021, there is an urgent need for new vaccines to help stem the never-ending pandemic.

"In order to reach the World Health Organisation (WHO)'s target of ending TB as a global health problem, we desperately need an effective and safe vaccine for use in adults and adolescents," explains Prof Frank Cobelens, Professor of Global Health at the University of Amsterdam and the Amsterdam Institute for Global Health and Development (AIGHD), Netherlands.

Despite this, for the first time since decades there are several promising new TB vaccine candidates entering phase 3 trials (efficacy testing in humans). "However, the current need for long trials implies that licensure of any of these candidates will take at least several years," says Prof Cobelens. He adds that a key issue for WHO in licensing any new TB vaccine is evidence of prevention of disease (POD) – however many of the current trials are looking at prevention of infection (POI) or prevention of recurrence (POR) in those with latent infection – which are not quite the same as POD.

Prof Cobelens highlights that, for the first time in decades there is a different platform candidate that has shown protection in adults and adolescents in a phase II trial: M72/ASO1E (an adjuvanted subunit vaccine- since the antigens alone in a subunit vaccine are insufficient to produce high immunogenicity, non-immunogenic materials known as adjuvants are typically incorporated into the vaccine formulation to improve the immune response and enhance the vaccine's efficacy). This is also important because it allows the field to identify correlates of protection. In a trial of some 3500 participants in Kenya, South Africa, and Zambia, the vaccine demonstrated 50% protection against TB infection after three years follow-up. It was also safely tested in 400 people living with HIV.

This vaccine is now going to enter a phase III trial in high-incidence settings across Africa, with an estimated 26,000 participants. It will include people never infected with TB and those with latent TB to see if they are protected from TB disease.  But as the trial will require three years for recruitment and five for follow up, it is unlikely to provide results until the start of the 2030s.

Other vaccines considered frontrunners include the Russian Vaccine GamTBVac, currently in a phase 3 trial with 7,000 participants expected to report in or around 2025. Also considered promising is the VPM1002 (live recombinant BCG), which is about report on trials on prevention of infection in babies and prevention of recurrence in adults in the next two years (delayed due to COVID pandemic)–while a further phase 3 trial, to test prevention of infection in adult household contacts of primary infected persons, is currently underway.

Another genetically modified live-attenuated vaccine, MTBVAC, has just begun a BCG-controlled phase 3 trial in babies in South Africa and Madagascar, while a phase 3 trial in BCG-vaccinated and unvaccinated adults is in its planning stages. Results from these trials are likely to be announced at the end of this decade.

"We have waited more than a century for a new effective TB vaccine, and unfortunately that wait is set to last at least several more years," concludes Prof Cobelens.  "However, there are promising new approaches that include alternative routes of delivery for BCG-vectored vaccines that will hopefully enter the development pipeline soon."