Researchers at The University of Texas Medical Branch (UTMB) have developed experimental plague vaccines that fully protected mice against pneumonic plague, one of the deadliest forms of the disease, even when the animals lacked an immune system protein long believed to be essential for fighting bacterial infections.
The findings, published in Science Translational Medicine, challenge decades of assumptions about how immunity to plague works and could help guide the development of more effective vaccines against the highly lethal disease.
Pneumonic plague is a severe lung infection caused by Yersinia pestis, the same bacterium responsible for the Black Death. Although rare today, plague continues to occur in parts of the world, and the World Health Organization considers Yersinia pestis a priority pathogen because of its epidemic and pandemic potential and growing concerns over antibiotic-resistant strains.
“Our findings show these vaccines generate a remarkably broad immune response,” said senior investigator Ashok Chopra, PhD, CSc, a professor and John S. Dunn Distinguished Chair in Global Health in the Department of Microbiology and Immunology at UTMB. “Even without interferon-gamma, which has long been considered one of the immune system's most important antibacterial defenses, vaccinated animals remained protected from lethal pneumonic plague.
”The research evaluated two live attenuated plague vaccines developed at UTMB, both individually and in combination with a virus-based vaccine carrying three plague antigens," said Dr. Jian Sha, an assistant professor in the same department. "The vaccines were tested in both normal mice and mice genetically engineered to lack interferon-gamma (IFN-γ), a signaling protein that helps coordinate immune responses to many bacterial infections."
After vaccination, the animals were exposed toYersinia pestis, the bacterium that causes pneumonic plague. Nearly all vaccinated mice survived, including those without IFN-γ. Researchers also temporarily blocked IFN-γ in vaccinated normal mice immediately before infection and found that the vaccines continued to provide complete protection.
“The immune system has multiple ways to recognize and fight infection,” said first author Emily Hendrix, PhD, who was Chopra’s PhD student and later a postdoctoral fellow in the Department of Microbiology and Immunology at UTMB and is now a postdoctoral fellow at Seattle Children’s Hospital. “These vaccines appear to activate several of those pathways at once, producing strong antibody responses, long-lasting immune memory, and protective immunity in the lungs, where pneumonic plague attacks.”
The combination vaccination strategy produced particularly strong immune responses in lung tissue, an important finding because pneumonic plague spreads rapidly through the respiratory system and can be fatal within days if untreated.
The researchers also demonstrated protection against several strains of Yersinia pestis, including strains lacking one of the bacterial proteins targeted by earlier vaccine approaches. That broader protection could prove valuable as scientists continue searching for vaccines capable of protecting against naturally occurring strains as well as potential engineered variants.
Although sporadic plague cases are not uncommon in the United States and Yersinia pestis is a biothreat agent, outbreaks with high fatality rates continue to occur in parts of Africa, Asia, and the Americas. No plague vaccine is currently approved by the U.S. Food and Drug Administration.
The researchers caution that the findings are based on animal studies, and additional research will be needed before the vaccines can be tested in humans.
Additional researchers involved in this study: Paul Kilgore, PhD; Blake Neil, PhD; and Atul Verma, PhD, from the UTMB Department of Microbiology and Immunology; and Heidi Spratt, PhD, from the UTMB School of Public and Population Health.