A vaccine currently protects over 100 million infants annually from severe tuberculosis (TB), including the dangerous brain swelling it can cause in young children. However, this vaccine does not prevent adults from contracting the more prevalent pulmonary form of TB. This limitation allows TB to remain the world's deadliest infectious disease, claiming 1.25 million lives each year.
The existing TB vaccine induces a formidable immune response, as indicated by most studies. But since traditional immunity metrics fail to predict adult protection, 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 adopted a novel approach—studying how TB bacteria evade the immune system. Their genetic study in mice, recently published in npj Vaccines, reveals that TB bacteria can essentially mimic death to outlast the immune response.
npj VaccinesTB is also known by its historic name—consumption—a term reflecting the disease's slow, debilitating, and often lethal progression.
"There's an urgent need for improved prevention methods because treatment alone won't halt TCB spread," says Amanda Martinot, DVM, MPH, Ph.D., associate professor at Cummings School and co-senior author of the study.
"After antibiotics for TB were introduced over 60 years ago, cases worldwide dropped significantly. But TB resurged with the HIV epidemic and is increasingly resistant to traditional antibiotics. With few new drugs available to treat resistant tuberculosis, it's now much harder to cure."
Unlike respiratory diseases such as the flu or COVID-19 caused by viruses that frequently mutate and require constant vaccine updates, TB is caused by a genetically stable bacterium, Mycobacterium tuberculosis. Theoretically, this makes TB easily preventable with a vaccine.
For their study, the researchers used transposon insertion sequencing (TnSeq) to identify essential genes for bacterial survival in four mouse groups: one vaccinated with the current vaccine, another with an experimental vaccine showing stronger immune responses in preclinical studies, a third cured of TB through antibiotics, and finally, a control group without vaccination or infection.
While they found some promising genes for future vaccines, the bigger revelation was how certain growth-essential genes became unnecessary after vaccination or past infections.
"We were surprised to find that genes crucial for rapid bacterial growth and severe TB aren't needed as much when bacteria infect someone with an existing immune response, such as from prior vaccination or infection," says Martinot.
Instead, the research indicated that TB bacteria adapt by relying on different stress-resistant genes in a hostile environment.
"We suspect these bacteria lie dormant until the immune response weakens, whether due to waning vaccine protection, HIV, or other health conditions," says Allison Carey, assistant professor at The University of Utah and co-senior author of the study.
This understanding could guide new treatments to boost vaccine efficacy in eradicating TB when it tries to hide.
The team also discovered that different vaccines or vaccination methods influence which genes TB needs for survival, suggesting potential new combinations of vaccines plus boosters for better protection.
"TB is remarkably adept at evading the immune system," says Martinot. "It has infected humans since ancient Egypt. Further studies are necessary to outsmart TB and control this global health emergency."