Researchers at the Johns Hopkins School of Medicine and the Johns Hopkins Bloomberg School of Public Health have developed an experimental DNA vaccine to treat tuberculosis (TB) that is administered through the nose. The vaccine is designed to help the immune system identify and attack drug-resistant tuberculosis bacteria known as “persisters,” which can withstand long-term antibiotic treatment and later cause a relapse of the disease.
The survey results are clinical research journal.
Tuberculosis has plagued humanity for at least 6,000 years and remains one of the world’s deadliest infectious diseases. According to the World Health Organization (WHO), about a quarter of the world’s population, or about 2 billion people, carry latent tuberculosis infection without symptoms. In 2024, more than 10 million people will develop active tuberculosis and 1.2 million will die from tuberculosis, making it the leading cause of death from a single infectious pathogen.
New approaches needed for tuberculosis treatment
WHO emphasizes the need for therapeutic vaccines that can complement existing drug treatments. Such a vaccine could shorten long-term treatment regimens and improve outcomes, especially when patients have difficulty completing multidrug therapy and drug-resistant forms of tuberculosis remain prevalent.
New research results from Johns Hopkins University suggest that this vaccine approach could help address these challenges.
“Our intranasal DNA fusion vaccine, administered in conjunction with first-line tuberculosis drug therapy, helped to clear the pathogen from infected mice faster, reduce lung inflammation, and prevent relapse after treatment ended,” said study lead author Stigliani Karanica, MD, a faculty member at the Johns Hopkins Tuberculosis Research Center and assistant professor at the Johns Hopkins School of Medicine. “This vaccine also helps increase the effectiveness of a combination of powerful tuberculosis drugs – bedaquiline, pretomanid and linezolid, suggesting that it may be used in combination with drugs to fight drug-resistant tuberculosis to help the body fight this disease, even in hard-to-treat cases.”
How an experimental tuberculosis vaccine works
The vaccine combines two genes, relMtb and Mip3α, and is administered through the nose to exploit several biological mechanisms that may enhance immunity against tuberculosis, Karanika said.
“First, Mycobacterium tuberculosis has the gene relMtb, which produces the protein RelMtb, which allows the microorganism to enter a state of persistent drug resistance and survive harsh conditions such as exposure to antibiotics, hypoxia, and nutrient restriction,” she says. “Fusing the relMtb and Mip3α genes generates a signal that attracts immature dendritic cells, which are the key cells that pick up tuberculosis proteins and ‘present’ them to T cells, immune cells that help coordinate targeted attacks against the tubercle bacillus.”
The vaccine is also designed to target immune activity where TB infection begins.
“Finally, intranasal delivery helps focus vaccination on the respiratory mucosa of the lungs, where tuberculosis infection occurs, and generates long-lasting local T-cell immunity in the airways and lungs, along with a systemic immune response,” says Professor Karanika.
Strong immune response in animal studies
By combining these mechanisms, the researchers attempted to boost immune defense directly within the airways. In mouse experiments, the vaccine increased dendritic cell recruitment and activation, improved the organization of dendritic cells and T cells within lung tissue, and generated durable T cell responses from CD4 (also known as helper T cells) and CD8 (also known as killer T cells) locally and systemically upon antigen stimulation.
The research team also evaluated the vaccine in rhesus monkeys. The nasally delivered DNA vaccine generated a measurable tuberculosis-specific immune response in both the bloodstream and respiratory tract. These responses were similar to those associated with reduced bacterial levels in the lungs of vaccinated mice.
Researchers observed that the immune response lasted for at least six months, suggesting the vaccine may provide durable protection. However, Karanika points out that the primate study only assessed immune activation and did not test how the animals would respond to an actual tuberculosis infection.
He said additional research will be needed before the vaccine can advance to human clinical trials.
“These non-human primate data are encouraging as they show that the Mip3α/relMtb vaccine is able to generate durable immune responses upon antigen stimulation in animal models where the immune system is more similar to that of humans,” says Professor Karanika. “This provides an important bridge between efficacy studies in mice and the additional preclinical studies needed before clinical trials in humans.”
Immunotherapy for patients with persistent tuberculosis
The researchers believe the results support a broader treatment strategy that focuses on eliminating persistent Mycobacterium tuberculosis through immunotherapy, rather than relying solely on antibiotics to kill actively multiplying bacteria.
Because DNA vaccines are generally stable and can be produced efficiently, this approach could have practical benefits if future studies demonstrate similar benefits in humans.
In addition to Karanika, the Johns Hopkins research team includes Tianying Wang, Addis Irma, Jenny Ruelas Castillo, James Gordy, Hannah Bailey, Darla Quijada, and Kay. They included Trinh Fessler, Rokeya Tasneen, Elisa M. Rouse Salcido, Farah Shamma, Harley Harris, Fenjixing Chen, Rowan Bates, Heamey Tong, and Jacob Meza. Yangchen Li, Alannah Taylor, Jean Zheng, Jiaqi Zhang, Theodoros Karantanos, Amanda Maxwell, Eric Nuerberger, J. David Peske, Richard Markham, and Petros Karacousis.
Federal funding for this research came from National Institutes of Health grants R01AI148710, K24AI143447, P30AI18436, K08AI174959 and P30CA006973.
Additional support was provided by the Gilead HIV Research Scholar Award, the Johns Hopkins Tuberculosis Research Advancement Center Developmental Award, the Johns Hopkins University AIDS Research Center HIV/AIDS Developmental Award, the Willow Craft Foundation Award, the Johns Hopkins University Clinical Scientist Award, and the Potts Memorial Foundation.
Karanika, Gordy, Markham, Karakousis are the inventors of patent PCT/US2023/065584 for the Mip3α/relMtb vaccine. The authors reported no conflicts of interest.
