Versatile mRNA Vaccine Shields Mice from Lethal C. diff Infections and Recurrences

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The bacterium Clostridioides difficile, often referred to as C. diff, is notoriously challenging to deal with. Originally difficult to cultivate in the lab, it now leads to gut infections that are hard to treat. Each year, approximately half a million people in the U.S. contract C. diff, frequently in hospital settings, and even after treatment, reinfections are common.

Researchers have now developed an mRNA vaccine that protects mice from C. diff infections and prevents recurring cases. The findings, published in *Science* on October 3, suggest that this vaccine could serve as a versatile tool for targeting various C. diff strains and breaking the cycle of infection.

“This is an impressive and well-executed study,” remarked Dena Lyras, Ph.D., a microbiologist at Monash University in Melbourne, who was not involved in the research. “They’ve thoroughly investigated which antigens are crucial for eliciting a protective immune response.”

C.diff is a troublesome pathogen that capitalizes on disrupted gut microbiomes to colonize the colon and produce toxins, leading to symptoms like fever and diarrhea, and in severe cases, sepsis or death. The bacterium forms resilient spores that can survive in the environment for months or even years, withstanding even industrial washing machines.

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As reported by fiercebiotech, the challenge of developing a vaccine is compounded by the significant variability among different C. diff strains. For instance, some strains possess flagella, which aid in movement, while others do not, complicating vaccine target selection.

“Given C. diff’s highly variable surface, we sought a target that would be transiently associated with its surface yet also highly conserved,” explained Joseph Zackular, Ph.D., a microbiologist at the University of Pennsylvania. “That led us to Pro-Pro endopeptidase 1 (PPEP-1).”

PPEP-1 is an enzyme essential for C. diff’s attachment and detachment in the gut. It is present across various C. diff strains and is absent in other bacteria, which could minimize collateral damage to the gut microbiome when targeted by a vaccine.

In addition to PPEP-1, the vaccine targets two of C. diff’s toxins, TcdA and TcdB, as well as a protein specific to the protective coat of C. diff spores, known as CdeM. The research team is actively seeking additional C. diff antigens to enhance the vaccine, as mRNA vaccines allow for relatively easy incorporation of new targets.

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“We are exploring conserved molecules and identifying other secreted or internal proteins that could serve as novel vaccine targets,” said Mohamad-Gabriel Alameh, Ph.D., a biomedical engineer at Penn and the lead author of the study. Notably, Drew Weissman, M.D., Ph.D., who was awarded the Nobel Prize in 2023 for his work on mRNA vaccines, is also part of the research team.

Mice administered the four-component vaccine experienced C. diff infections but did not succumb, developing antibodies that targeted PPEP-1, indicating that their immune systems learned to combat C. diff. These mice also showed protection from severe disease upon reinfection six months later.

Analysis of the gut microbiome in the mice confirmed that this protective effect did not negatively impact their healthy gut flora.

“I believe this vaccine will be particularly valuable for individuals with recurrent infections,” Lyras stated. “Having previously suffered from the infection, vaccination could provide robust protective immunity.”

“Many patients who struggle have already experienced C. diff recently or are caught in a cycle of recurrence,” Zackular noted. “One of the promising aspects of this vaccine platform is the potential for retrospective vaccination in these patients.”

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