A research team at Johns Hopkins Medicine is developing a nose-delivered inoculation against tuberculosis, the world’s leading cause of death from infectious disease.
The approach fuses two tuberculosis genes with the goal of directing the immune system to fight drug-tolerant bacterial survivors that can endure antibiotic treatment to spread another day.
The paper on the vaccine was published last week in the Journal of Clinical Investigation, where JH Medicine researchers were joined by colleagues from the Johns Hopkins Bloomberg School of Public Health.
TB is estimated by the World Health Organization (WHO) to be spread asymptomatically by around 2 billion people. In 2024 , WHO reported that TB was the leading cause of death from a single infectious disease.
In recent years, WHO has called for therapeutic vaccines that can be used alongside drug therapies to shorten TB treatment regimens and improve outcomes, particularly because long multidrug courses are difficult to complete, and drug-resistant TB strains continue to emerge. The vaccine described in the new Johns Hopkins study shows promise for meeting that need.
The new Johns Hopkins vaccine, says study lead author Styliani Karanika, MD, fuses two genes: relMtb and Mip3α, and is given through the nose to take advantage of 3 beneficial biological activities.
“Administered together with first-line TB drug therapy, our intranasal DNA fusion vaccine helped infected mice clear the disease bacteria faster, reduced lung inflammation, and prevented relapse after treatment ended,” says Karanika, a faculty member of the Johns Hopkins Center for Tuberculosis Research.
“The vaccine also helped the powerful TB drug combination of bedaquiline, pretomanid, and linezolid work better, suggesting it could be used with treatments against drug-resistant TB to help the body fight the disease, even hard-to-treat cases.”
Dr. Karanika explained that TB bacteria possess a gene—relMtb—that produces a protein called RelMtb—which together help the microbes survive hostile conditions such as antibiotic exposure, low oxygen, and nutrient limitation by entering a drug-tolerant persistent state.
Fusing relMtb with another gene called Mip3α produces a signal that attracts immature human dendritic cells. These cells pick up TB proteins and ‘present’ them to T cells, the immune cells that help coordinate a targeted attack on the TB bacteria.
“Finally, intranasal delivery focuses vaccination on the respiratory mucosa in the lungs where TB infection occurs, helping generate long-lasting localized T-cell immunity in the airways and lungs, along with systemic immune responses,” says Karanika.
By combining these strategies, the investigators aimed to strengthen immune activity directly in the respiratory tract, where transmission most commonly occurs.
In the mouse studies, this approach both improved the quantity and organization of dendritic and T-cells in the lungs, and generated immune responses both locally and systemically. The improved response included to two types of T-cells, CD4 (also known as helper T-cells) and CD8 (also known as killer T-cells).
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One study strongpoint was that it included tests on primates: in this case, rhesus macaques. The researchers found that their nose-delivered DNA vaccine prompted measurable TB‑focused immune responses in blood and in the airways similar to what led to lower bacterial counts in the lungs of the mice they studied.
These responses persisted for at least 6 months, suggesting durability for the vaccine’s action.
“These nonhuman primate data are encouraging because they show that the Mip3α/relMtb vaccine can generate durable, antigen-stimulated immune responses in an animal model whose immune system more closely resembles that of humans,” said Dr. Karanika. “That gives us an important translational bridge between the mouse efficacy studies and the additional preclinical work needed before human trials.”
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Readers may recoil from the notion of primate testing, but Old World Monkeys are very susceptible to TB, and in fact spread it between themselves just as we do. Research has shown that TB has been spread among humans as far back as 70,000 years, and followed our migration out of Africa and across Asia.
The authors say their findings support a broader strategy of targeting surviving TB bacteria with immunotherapy, rather than relying solely on antibiotics to eliminate actively replicating bacteria. Because DNA vaccines are relatively stable and can be manufactured efficiently, they may offer practical advantages if this approach ultimately proves effective in humans.
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