Scientists May Be Closer to an Effective Plague Vaccine After Promising Mouse Study

Scientists have developed two experimental vaccines that completely protected mice against lethal plague infection, including pneumonic plague—the deadliest form of the disease. Although plague is often associated with medieval pandemics, the bacterium Yersinia pestis continues to circulate today and can rapidly become fatal without prompt treatment.

The study, published in Science Translational Medicine, was conducted by researchers at the University of Texas Medical Branch at Galveston. The findings offer a promising step toward new preventive strategies as concerns grow over increasing antimicrobial resistance and the limited options currently available for preventing plague.

Why Plague Remains a Global Health Concern

Plague is caused by the bacterium Yersinia pestis, which is typically transmitted through bites from infected fleas that live on rodents. In some cases, particularly with pneumonic plague, the infection can also spread between people through respiratory droplets.

Although far less common than during historical pandemics, plague has not disappeared.

Health authorities continue to report hundreds to several thousand human cases worldwide each year, most commonly in parts of Africa and in regions where people frequently come into contact with infected rodents and fleas.

The best-known form is bubonic plague, which causes swollen, painful lymph nodes known as buboes.

However, pneumonic plague, which infects the lungs, is considerably more dangerous. Without rapid antibiotic treatment, it can become fatal within three to four days and can spread directly from person to person through coughing.

Despite these ongoing risks, there is currently no plague vaccine approved by the U.S. Food and Drug Administration (FDA). The World Health Organization recommends vaccination only for selected high-risk groups, including laboratory personnel and some healthcare workers in endemic areas.

Developing a New Vaccine Strategy

The researchers developed two live-attenuated vaccine candidates known as LMA and LMP.

These vaccines use genetically weakened versions of Y. pestis that are designed to stimulate a protective immune response without causing disease.

In the study, mice first received an intramuscular injection of either LMA or LMP.

Twenty-one days later, they received a booster dose. Some animals received the same vaccine again by intramuscular injection, while others received a nasal spray using an adenovirus vector that delivered three plague antigens directly to the respiratory tract.

This strategy, known as a "prime-pull" approach, is designed to first establish systemic immunity throughout the body and then recruit immune cells to the lungs, where pneumonic plague initially takes hold.

The goal is to provide both broad immune protection and strong local defenses at the primary site of infection.

Complete Protection Against Lethal Infection

Thirty-two days after receiving the booster vaccination, researchers exposed the mice to doses of Y. pestis that would normally be fatal.

All of the unvaccinated mice died within four days.

In contrast, every vaccinated mouse survived the infection.

One week later, the researchers challenged the animals again using an even larger bacterial dose that greatly exceeded typical lethal levels.

Nearly all vaccinated groups again achieved 100% survival.

The only exception involved mice lacking a specific immune-related gene that had received only intramuscular vaccinations. In that group, survival remained high at 80%.

Laboratory analyses showed that the vaccines generated strong antibody responses in both the bloodstream and the respiratory tract.

These findings suggest that the animals were not simply surviving infection but were mounting effective immune responses capable of neutralizing the bacteria at multiple sites throughout the body.

What Comes Next

Although the results are highly encouraging, the researchers emphasize that successful experiments in mice do not guarantee similar results in humans.

Before human clinical trials can begin, the vaccines must first undergo testing in nonhuman primates to better evaluate their safety and effectiveness.

If future studies produce comparable protection, these vaccines could become valuable tools for protecting people living in plague-endemic regions and for responding rapidly during outbreaks.

The researchers also note that plague remains a potential biological threat because of its ability to spread quickly and cause severe disease. Effective vaccines could therefore serve as important components of national emergency preparedness strategies.

Future research will also explore vaccination approaches that combine rapid short-term protection with longer-lasting immunity, allowing health authorities to respond more effectively during sudden outbreaks of pneumonic plague.

Looking Ahead

The findings represent another step toward modernizing protection against one of history's deadliest infectious diseases.

As antibiotic resistance continues to increase worldwide, preventive strategies such as vaccination may become increasingly important for managing rare but potentially devastating infections.

While additional animal studies and human clinical trials remain necessary, the researchers believe these experimental vaccines demonstrate that strong protection against both bubonic and pneumonic plague may be achievable using modern vaccine technologies.