100 years of a tuberculosis vaccine with limited benefit

On July 18, 1921, a newborn child in Paris became the first person to receive an experimental dose of the Bacille Calmette-Guérin vaccine for tuberculosis. A century later, it’s now the most commonly used vaccine in the world. It is also still the only licensed vaccine for the disease.

To mark its 100-year anniversary, Devex spoke with Mark Feinberg, president and chief executive officer at the International Aids Vaccine Initiative, a nonprofit research organization that develops vaccines and antibodies for tuberculosis, HIV, and other emerging infectious diseases, about the vaccine.

“It has been kind of a global access success story,” he said. “The vaccine is inexpensive, it is widely available, and the existing programs for immunization of infants are pretty well established.”

But the vaccine has significant limitations, Feinberg said, and hasn’t stopped the disease from being the second-leading cause of death among infectious diseases globally in 2020, following COVID-19.

“The vaccine surely saved many people's lives, but it is far from an optimal vaccine,” he said. “TB killed half as many people as COVID did in the past year. … It's kind of remarkable how little the world has prioritized the development of a TB vaccine.”

A complicated problem

Eliminating the tuberculosis pathogen is complicated, Feinberg said. When a person is infected with Mycobacterium tuberculosis, they may or may not develop disease initially, but when the immune system is unable to clear the bacteria, they may carry that organism with them throughout their lives in a latent state. It can then be reactivated to cause disease and be transmitted to others.

While vaccines typically aim to replicate a natural immune response, there are still unknowns around what an effective natural response to TB is and around the bacteria’s ability to evade the immune system. But 90% of people who have evidence of past infection do not develop the disease, suggesting that most can mount an immune response.

Tuberculosis is similar to HIV in that people may develop disease years after infection and researchers don’t have “immunologic guideposts,” making vaccine development a challenge, Feinberg said.

While the BCG vaccine can prevent severe disease in infants, it doesn’t protect older people at risk of developing pulmonary tuberculosis, which represents the majority of the disease burden and is responsible for TB’s spread, Feinberg said. So even though a significant portion of the world’s population has been immunized with BCG, a high disease burden remains.

And while there has been significant progress in tuberculosis drug development, treatment is a long process and adherence is a problem, leading to drug resistance, Feinberg said, adding that multidrug-resistant TB treatment is expensive and difficult for the body.

Drugs and diagnostics alone will not eliminate the problem, he said. There is a need to prevent disease in people who have been exposed to Mycobacterium tuberculosis and stop infection in the first place through vaccines.

“A TB vaccine is going to be a critically important element in global TB control,” Feinberg said.

But TB vaccine research has seen inadequate investment, and commitments to significantly increase research funding have not materialized, he said.

“It's kind of remarkable, in some ways, that 100 years have gone by and vaccine development for TB has not gotten the attention that it has for a number of other diseases,” he said.

While HIV is an incredibly difficult target as well, efforts to develop an HIV vaccine have involved a high level of innovation, which has not been leveraged for TB due to lack of financial support, he said.

“There's a lot of opportunity for innovative science in the TB vaccine field that can also help us move more quickly and with greater impact,” Feinberg said.

Promising research

Nearly a century after the first TB vaccine was given, groundbreaking research in recent years — including for several vaccine candidates in late-stage clinical trials — is showing that a better vaccine is possible, Feinberg said.

One study in South Africa showed that revaccinating adolescents with BCG as a booster shot significantly reduced new TB infections. This was an important discovery, according to Feinberg, because it hints at ways to have more impact with the existing BCG vaccine. Work is ongoing to replicate and extend this research, he said.

Another study showed that two doses of the M72/AS01E vaccine candidate could reduce the development of tuberculosis with 50% efficacy in adults with latent infection. This is the first vaccine since BCG to prevent disease in people previously exposed to TB. The candidate is now moving on to phase III trials, aiming to not only replicate the original findings but explore if there are benefits for people not previously infected with TB.

Research for the MTBVAC vaccine candidate using rhesus macaques, a species of monkey, found this year that it protects better than the BCG vaccine against aerosol exposure to Mycobacterium tuberculosis. A phase III study in newborn babies is planned to start next year in several African countries.

The Statens Serum Institut's H56:IC31 protein-adjuvant vaccine candidate is being evaluated to see if it reduces recurrent disease in people who have been treated for pulmonary tuberculosis. And the vaccine candidate VPM1002 is examining the prevention of Mycobacterium tuberculosis infection in newborn babies and the prevention of recurrence in adults.

While some of these studies are expected to generate initial results over the next two to three years, several will take longer to more clearly demonstrate their effectiveness, Feinberg said. For all of these studies, examining the impact on people with HIV is crucial, since the two diseases have high levels of coinfection and more people with HIV develop TB disease. TB is the leading cause of death for people living with HIV.

Even with these developments, the pipeline for vaccines is relatively “sparse,” given the limited funding, Feinberg said.

Progress on TB vaccines will be slower than the development of a COVID-19 vaccine because the research community still has significant gaps in its understanding of what protects people against developing disease, he said. TB also takes longer to manifest than COVID-19, meaning that clinical trials require more time.

“I think it's more likely to be incremental progress, where the different vaccines that are in development will be shown to be efficacious, and they will help us better understand what the nature of protective immunity is,” Feinberg said. “Then we can build upon those insights.”