C. difficile is a bacterium that can cause infection with symptoms ranging from diarrhea to deadly colon damage. It spreads quickly via its hard-to-kill spores and commonly infects vulnerable populations, including the elderly, children, those taking antibiotics, and often, patients in hospitals or nursing homes. The bug is also persistent: 30 to 40% of those diagnosed with a C. difficile infection will likely get it again. There are currently no C. difficile vaccines available, and the main treatment for the infection is a lengthy course of antibiotics. However, because antibiotics also target beneficial bacteria in the gut microbiome, C. difficile often takes advantage of their absence, releasing toxins in the colon that allow C. difficile to prosper.

“Our approach was to create a multivalent mRNA vaccine that would attack multiple aspects of C. diff’s complex lifestyle simultaneously without affecting the normal microbiota,” said co-first author Mohamad-Gabriel Alameh, PhD, an assistant professor of Pathology and Laboratory Medicine at Penn and a senior principal scientist at Children’s Hospital of Philadelphia. “Antibiotics are not always an effective means of successfully treating really tough pathogens like C. diff, and we have only begun to scratch the surface of the full potential of mRNA vaccines for a host of infectious diseases.”

“Where most vaccines are spurring one’s immune system to create specific antibodies, mRNA vaccines were a perfect candidate for a C. difficile vaccine because they can be easily packaged up to elicit the immune system to do more than one thing to protect against a bacteria, virus, or fungus,” said study author and Nobel Laureate Drew Weissman, MD, PhD, the Roberts Family Professor in Vaccine Research at Penn whose work laid the foundation for the world’s first mRNA vaccines.

“C. diff can persist in multiple forms in the gut, including in biofilms and as an incredibly hardy spore, making it uniquely difficult to treat,” said Joseph P. Zackular, PhD, co-director of the Center for Microbial Medicine at CHOP and an assistant professor of Pathology and Laboratory Medicine Penn. “This work represents how collaboration between vaccine researchers and basic scientists can transform new discoveries into potential therapeutics faster than ever before.”

Researchers used the mRNA-LNP vaccine platform, the same platform that gave us the highly effective mRNA COVID-19 vaccines. While many mRNA vaccines being studied are for viruses, this pioneering technology has broader applications than other vaccine designs, like inactivated vaccines. A successful C. difficile vaccine would mark a turning point in C. diff therapeutics research which has struggled to make breakthroughs for this challenging pathogen. Previous vaccines, including a non-mRNA vaccine that was in clinical trials in 2022, did not meet the research threshold to be released to market. “mRNA-LNP vaccines have given us a new tool to take on complex bacterial infections, like C. diff, that are only becoming more of a problem with the rise of antimicrobial resistance” said Alexa Semon, co-first author of this study and a PhD candidate at Penn.

This research adds to the growing field of mRNA research in Philadelphia.. Penn has designed mRNA vaccines to prevent Lyme disease, norovirus, and herpes simplex virus 2. Penn is also studying how mRNA can treat sickle cell disease, deadly food allergies, and even cancer among other diseases. CHOP is developing novel ionizable lipids and biomaterials for vaccine and gene therapy applications in perinatal and pediatric medicine, expanding on the successes of the mRNA-LNP platform, studying mRNA vaccines and therapeutics that can be used to treat glycogen storage disease type 1a (GSD1a) and Isolated Methylmalonic Acidemia, as well as continued research into various difficult-to-treat forms of cancer and bacterial infection.