Nasal DNA Vaccine Shows Promise Against Tuberculosis Relapse

A Johns Hopkins research team has developed a nasally delivered DNA vaccine that, in mice, helped tuberculosis drugs clear infection faster, reduced lung damage and prevented the disease from roaring back after treatment ended.

The experimental vaccine, described in a paper published in the Journal of Clinical Investigation, is designed not to prevent infection, but to treat it — working alongside antibiotics to attack tuberculosis bacteria that can linger in the body and trigger relapse.

Tuberculosis, or TB, has plagued humans for thousands of years and remains the world’s deadliest infectious disease caused by a single microbe. The World Health Organization estimates that about one-quarter of the global population carries latent TB infection. In 2024, more than 10 million people developed active TB and 1.2 million died.

Standard TB treatment requires months of multiple antibiotics. Those long regimens are hard to complete, and even when patients finish them, some bacteria can survive in a drug-tolerant state. These hardy survivors, sometimes called “persisters,” can seed relapse and fuel the spread of drug-resistant TB.

Global health agencies, including WHO, have been calling for therapeutic vaccines that could be given along with TB drugs to shorten treatment and improve outcomes. The Johns Hopkins team set out to build exactly that kind of immune boost.

Lead author Styliani Karanika, a faculty member at the Johns Hopkins Center for Tuberculosis Research and an assistant professor of medicine at the Johns Hopkins University School of Medicine, noted the new vaccine showed striking benefits in mouse studies.

“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,” Karanika said in a news release.

She explained that the experimental shot also strengthened one of the most potent drug combinations used against resistant TB.

“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,” she said.

A gene-fusion strategy

The vaccine takes an unusual approach. It is a DNA vaccine, meaning it delivers genetic instructions that cells use to make specific proteins that train the immune system. It also fuses two genes to direct the immune response toward the most stubborn TB cells, according to Karanika.

“First, TB bacteria possess a gene, rel_Mtb, that produces a protein, Rel_Mtb, to help the microbes survive hostile conditions such as antibiotic exposure, low oxygen and nutrient limitation by entering a drug-tolerant persistent state,” Karanika said.

By targeting this protein, the vaccine is aimed squarely at the bacteria most likely to survive drug treatment.

The second part of the fusion is a human gene called Mip3α, which acts like a homing signal for key immune cells.

“Fusing rel_Mtb with the Mip3α gene produces a signal that attracts immature dendritic cells — key cells that pick up TB proteins and ‘present’ them to T cells, the immune cells that help coordinate a targeted attack on the TB bacteria,” Karanika added.

The vaccine is delivered through the nose rather than by injection. That route is important because TB is spread through the air and takes hold in the lungs.

“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,” added Karanika.

In mice, this three-part strategy — targeting persister bacteria, recruiting dendritic cells and focusing on the lungs — paid off. The researchers reported increased recruitment and activation of dendritic cells in the respiratory tract, better organization of dendritic cells and T cells in lung tissue, and strong, long-lasting responses from both helper (CD4) and killer (CD8) T cells. Those immune changes were associated with faster bacterial clearance, less lung inflammation and protection against relapse after antibiotics stopped.

Early signs of durability

To see whether the same kind of immune activation could be triggered in a species closer to humans, the team tested the nose-delivered DNA vaccine in rhesus macaques. In these nonhuman primates, the vaccine generated measurable TB-focused immune responses in both blood and airways that persisted for at least six months.

The monkey study did not expose the animals to TB, so it did not test whether the vaccine could actually prevent or treat disease in that model. Instead, it was designed to answer a more basic question: Can this vaccine safely wake up and sustain the right kinds of immune responses in a primate immune system?

The answer so far is promising, according to Karanika.

“These nonhuman primate data are encouraging because they show that the Mip3α/rel_Mtb vaccine can generate durable, antigen-stimulated immune responses in an animal model whose immune system more closely resembles that of humans,” she said. “That gives us an important translational bridge between the mouse efficacy studies and the additional preclinical work needed before human trials.” 

Why it matters

The findings support a broader shift in TB research: combining antibiotics with immunotherapies that can help the body hunt down bacteria that drugs alone may miss. By going after persisters, the Johns Hopkins team hopes to reduce the risk of relapse and potentially shorten the time patients need to stay on medication.

If the approach proves safe and effective in people, it could be especially valuable in places where TB is common and health systems are stretched thin. Shorter, more effective treatment could improve adherence, lower costs and slow the spread of drug-resistant strains.

DNA vaccines also offer practical advantages. They tend to be relatively stable and can be manufactured efficiently, which could make them easier to produce and distribute in low-resource settings than some traditional vaccines.

What’s next

Despite the encouraging data, the researchers emphasize that this work is still in the preclinical stage. More animal studies are needed to refine dosing, further assess safety and test how well the vaccine performs in additional models before any human trials can begin.

The team’s work was supported by multiple grants from the National Institutes of Health and several foundation and institutional awards. Karanika and several co-authors are inventors on a patent application for the Mip3α/rel_Mtb vaccine, but the authors report no other conflicts of interest.

For now, the new intranasal DNA vaccine stands as a proof of concept that TB treatment might one day rely not only on powerful antibiotics, but also on carefully engineered immune training — delivered with a simple spray to the nose.

Source: Johns Hopkins Medicine