In a new study, scientists tested two live-attenuated plague vaccines, LMA and LMP—weakened forms of the plague bacterium that cannot cause disease—both alone and in combination with the virus-based vaccine Ad5-YFV.

They genetically engineered the mice to completely lack a signaling protein called interferon-gamma, which plays a crucial role in activating immune cells. Despite lacking a key immune protein, the vaccines protected 80% to 100% of mice exposed to highly lethal doses of the pneumonic plague-causing Yp CO92 strain, while triggering strong antibody and immune responses in all vaccinated animals.

The strongest protection came from a two-step prime-pull strategy that paired an intramuscular injection with a nasal spray. The injection primed the immune system, while the nasal spray directed immune cells to the nose, where plague bacteria first come into contact with the body. Together, they generated strong immunity in the lungs and helped the immune system respond quickly to a second encounter with the bacteria.

The findings are published in Science Translational Medicine.

In search of plague fighters

Although plague is often associated with the bubonic plague that swept through Europe centuries ago, pneumonic plague—a severe lung infection caused by Yp—still causes outbreaks today. In Madagascar, a 2017 outbreak resulted in 2,575 cases, with 77% involving the more dangerous pneumonic form. About 9% of those infected died, while a later outbreak in 2021 saw the death rate rise to 37%.