Toward an Israeli mRNA Vaccine for the Plague

The Plague: Humanity’s Ancient Foe

The plague, which wiped out a large portion of Europe’s population during the Black Death in the 14th century, has haunted humanity since ancient times. The disease is caused by the bacterium Yersinia pestis, which typically spreads to humans through bites from infected rat fleas or lice. When transmitted in this way, it usually leads to bubonic plague,  in which the bacteria reach the lymph nodes, multiply, and cause painful swelling. From there, the infection can spread to the bloodstream—causing septicemic plague—or to the lungs, resulting in pneumonic plague.

Without antibiotic treatment, the mortality rate for bubonic plague ranges from 60% to 90%. The other two forms are even more lethal and are almost always fatal. Pneumonic plague is particularly dangerous because it can be transmitted directly from person to person via airborne saliva droplets, without the need for insect carriers.

Thanks to major improvements in sanitation worldwide and the development of effective antibiotics since the mid-20th century, this deadly disease has been nearly eradicated in most parts of the world. Even in the rare cases where people still contract the plague, outcomes have improved significantly, with the current mortality rate reduced to about one in ten patients. However, there is growing concern that Yersinia pestis bacteria may eventually develop resistance to antibiotics, potentially triggering a global resurgence.of the disease.

A vaccine against Yersinia pestis has been available since the late 19th century. It uses an inactivated form of the bacterium that cannot cause disease but still enables the immune system to recognize the pathogen and produce antibodies against it. However, this vaccine is primarily effective against bubonic plague  and offers limited protection against the more severe forms of the disease.

Over the past two decades, extensive efforts have been made to develop a new vaccine that provides protection against both bubonic and pneumonic plague. In 2024 alone, more than 21 different plague vaccines were in various stages of development. A team of Israeli researchers, working on an mRNA-based vaccine that provides combined protection, recently reported very high efficacy in protecting mice against pneumonic plague.

Two Molecules, One Vaccine

mRNA vaccines have gained prominence in recent years, especially for their pivotal role during the COVID-19 pandemic.  Unlike traditional vaccines—which typically introduce weakened or inactivated viruses, bacteria, or fragments of pathogens—mRNA vaccines harness the body’s own cells to produce a specific pathogen-related protein, prompting an immune response.  mRNA (messenger RNA) is a temporary copy of a DNA segment that carries instructions for making a particular protein. In the vaccine, these mRNA molecules are encased in a lipid shell that protects them until they enter target cells. Once inside, the mRNA directs the cell to produce the foreign protein and present it to the immune system, training it to recognize and respond to the actual pathogen.

Two years ago, researchers in Professor Dan Peer’s lab at Tel Aviv University, in collaboration with scientists from the Israel Institute for Biological Research in Ness Ziona, developed an mRNA vaccine targeting the F1 protein, which forms part of the outer membrane of the plague-causing bacterium Yersinia pestis. The vaccine showed high efficacy against bubonic plague in genetically engineered mice, though it had not yet been tested against the pneumonic form of the disease.

In a recent study published in the journal Advanced Science, the researchers presented the next critical step in the vaccine’s development. This time, they designed an mRNA that instructs cells to produce a different bacterial protein—part of a needle-like protein structure on the bacterial cell surface, which the bacterium uses to disrupt the body’s inflammatory response. This system is central to the bacterium’s ability to cause disease. The mRNA vaccine elicited a strong immune response against the protein and provided complete protection to mice infected with pneumonic plague.  In contrast, vaccination with the protein itself—without mRNA technology—offered only partial protection.

The researchers then combined both types of mRNA into a single vaccine. They found that the combined vaccine also provided full protection against pneumonic plague. Moreover, unlike the single-protein vaccine, which required three doses to achieve full protection, the combined vaccine conferred full protection to the mice after just two doses. Remarkably, the combined vaccine also protected mice against a bacterial strain lacking F1 proteins.

One of the key advantages of RNA vaccines is that they can be easily mass-produced. Equally important, they can be rapidly updated in response to mutations in a pathogen’s genetic material. This flexibility is especially crucial for fast-evolving viruses like SARS-CoV-2, the virus behind the COVID-19 pandemic. It is similarly valuable in combating Yersinia pestis, as some bacterial strains have acquired mutations in the protein involved in formation of the “injection needle” structure. The combined vaccine also reduces the likelihood of the bacterium evading the immune response, since the odds of simultaneous mutations occurring in both targeted proteins within the same strain are extremely low. However, this research has so far been conducted only in mice, and further studies are needed to determine whether the vaccine can trigger an effective immune response in humans and offer protection against this deadly disease.