Researchers at Johns Hopkins have engineered a nose-spray DNA vaccine that helped infected animals shed tuberculosis faster and prevented the infection from returning after drug treatment ended. The work, published in the Journal of Clinical Investigation, marks a novel approach to one of humanity's oldest and deadliest pathogens.
The experimental vaccine targets a specific vulnerability in TB bacteria: their ability to enter a dormant, drug-resistant state during antibiotic therapy. These "persister" microbes can lurk in the lungs and reignite disease weeks or months after a patient stops taking medicine. Roughly 25 percent of the global population carries latent TB infection, and the active disease kills over a million people annually, making it the leading infectious cause of death worldwide.
The Johns Hopkins team combined two genes, relMtb and Mip3α, to create the vaccine. RelMtb is a gene the TB bacterium uses to survive harsh conditions like antibiotic exposure and low oxygen. By fusing it with Mip3α, researchers created a signal that summons dendritic cells, immune sentries that identify TB proteins and alert T cells to mount a coordinated attack.
Delivery through the nose proved crucial to the strategy. "Intranasal administration focuses the vaccination directly on the respiratory mucosa where TB infection starts, generating both localized and systemic immune responses," explained Styliani Karanika, M.D., the study's lead author and an assistant professor at Johns Hopkins University School of Medicine.
In mouse studies, the vaccine strengthened immune defenses throughout the lungs, activating dendritic cells and T cells to create durable, TB-specific immune responses. When combined with standard TB drugs, vaccinated mice cleared infections faster and showed reduced lung inflammation. The vaccine also enhanced the performance of bedaquiline, pretomanid and linezolid, a powerful three-drug combination used against drug-resistant TB.
The team then tested the vaccine in rhesus macaques to bridge the gap toward human application. The nose-delivered vaccine generated measurable TB-specific immune responses in blood and airways that persisted for at least six months. However, the primate study measured immune activation only and did not challenge vaccinated animals with actual TB infection.
Karanika emphasized that additional preclinical work must precede human trials. "These nonhuman primate data give us an important translational bridge," she said. The results support a broader shift in TB treatment philosophy: using immunotherapy to eliminate persistent bacteria alongside or instead of relying solely on antibiotics to kill actively growing cells.
DNA vaccines offer practical manufacturing advantages over protein-based approaches. If future human studies confirm similar benefits, the technology could be produced efficiently and deployed widely, especially in regions where TB burden remains highest.
The work was funded by the National Institutes of Health, the Gilead HIV Research Scholar Award, the Potts Memorial Foundation, and the Johns Hopkins Tuberculosis Research Advancement Center.
Author Jessica Williams: "This vaccine doesn't replace antibiotics but could finally give the immune system a real fighting chance against the bacteria that drug therapy can't eliminate, which is what's been missing in TB treatment for decades."
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