A vaccine protects more than 100 million infants each year from severe tuberculosis (TB), including the fatal brain swelling it can cause in babies and toddlers. But the vaccine doesn’t prevent adults from developing the more common form of TB that attacks the lungs. This allows TB to persist as the world’s deadliest infectious disease, killing 1.25 million people a year.

The existing vaccine for TB elicits a strong immune system reaction, according to most studies. Since standard measures of immunity don’t predict protection in adulthood, researchers at Cummings School of Veterinary Medicine at Tufts University, The University of Utah, Harvard T.H. Chan School of Public Health, and Texas A&M University took a new approach—studying how the TB bacterium evades an immune system primed to destroy it.

Their genetic study in mice, recently published in npj Vaccines, reveals that TB bacteria can essentially play dead to outlast the immune response.
TB is also known by its historic name—consumption—a term that reflects the disease’s slow, wasting, and often fatal course.

“There’s a dire need for better prevention, because treatment alone is not going to contain the spread of TB,” says Amanda Martinot, DVM, MPH, Ph.D., an associate professor at Cummings School and co-senior author of the study. “When drugs to treat TB became available more than 60 years ago, cases dramatically dropped worldwide. But TB reemerged alongside the HIV epidemic, and it is increasingly resistant to traditional antibiotics. With just a handful of newer drugs available to treat resistant tuberculosis, it’s now much harder to cure.”

While other respiratory diseases like the flu and COVID-19 are caused by viruses that mutate frequently and constantly need new vaccines, TB is caused by a very genetically stable bacterium, Mycobacterium tuberculosis. So, in theory, TB should be easily preventable by vaccine.

For their study, the research team used a tool called transposon insertion sequencing, or TnSeq, to identify which genes were essential for bacterial survival in four groups of mice. The first group of mice was vaccinated with the current vaccine, which was developed more than 100 years ago from the type of TB seen in cows. The second group was given an experimental vaccine based on the TB seen in humans, which generated a stronger immune response than the only approved vaccine in a preclinical study. The third group of mice had been exposed to TB and then cured by antibiotics. And the final, control group had never been vaccinated for or infected by TB.

The researchers expected to find key genes that TB needs to survive in vaccinated hosts, and they did uncover some potentially worth exploring for future vaccines. But the bigger surprise was which genes the bug didn’t need after vaccination or past infection.

“We were most surprised to find that certain genes that are normally important for driving rapid bacterial growth and causing serious tuberculosis infection aren’t as necessary when the bacteria infect someone who already has an immune response, either because they’ve been vaccinated or previously infected,” says Martinot.

Instead, the researchers discovered that the TB bacteria seem to switch strategies, relying on different genes that help them deal with stress and stop growing in a hostile environment.

“We suspect that the bacteria hunkers down, going quiet until the immune response weakens, whether from waning vaccine protection, HIV, or other conditions,” says Allison Carey, an assistant professor at The University of Utah and co-senior author of the study.

This knowledge could help scientists create treatments that could be given alongside vaccines to help the immune system root out TB when it tries to hide.

The team also found that different vaccines, or how they’re given, can shift which genes TB needs to stay alive. This shows that different vaccines may put different kinds of pressure on the bacteria, which could lead to new, more effective combinations of a vaccine plus booster.

“This bug is incredibly good at surviving the immune system,” says Martinot. “It’s been infecting humans since ancient Egypt. Additional studies are needed so we can finally outsmart TB and rein in the current global emergency.”

Citation: Kimra James from University of Utah is the first author. Research reported in this article was supported by the National Institutes of Health under award numbers K08AI135098 and K08 AI139339. Complete information on authors, funders, methodology, limitations, and conflicts of interest is available in the published paper.

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