New mRNA Vaccine Prevents C Difficile in Mice

A new vaccine using mRNA technology protected against first-time and relapsing Clostridioides difficile infection in animal models, according to a press release from the Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
In a study published in Science, an mRNA vaccine induced robust antibody responses in mice with C difficile that allowed the mice not only to survive, but survive without significant disruption to the gut microbiota, the researchers wrote.
Overall, vaccinated mice showed higher immune response with the mRNA–lipid nanoparticle (mRNA-LNP) vaccines than with alum-adjuvanted recombinant protein vaccines. Also, serum transfer from mice with mRNA-LNPs protected them from death when injected with a lethal C difficile challenge, and all vaccinated mice were fully protected from death.
C difficile is “an incredibly challenging pathogen to treat as it lives a complex and multifaceted lifestyle in the gut,” said lead author Mohamad-Gabriel Alameh, PhD, an assistant professor in the Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, in an interview.
“Specifically, C difficile can reside as a bacterial cell that produces toxin in the complex ecosystem of the large intestine, while also forming dormant spores that are highly resistant to killing,” Alameh said. Although toxoid-based C difficile vaccines have shown promise, no C difficile vaccine is available for clinical use, leaving patients with a lengthy course of antibiotics as the leading therapeutic option, he said.
Current treatment with antibiotics also targets healthy gut bacteria, and the new vaccine was designed to target multiple aspects of C difficile without affecting the normal gut microbiota, according to the researchers.
In the current study, the mRNA vaccine protected the mice from primary and recurrent C difficile infection, and its distinctive design also preserved gastrointestinal health. “Inclusion of non-toxin cellular and spore antigens improved decolonization of toxigenic C difficile from the gastrointestinal tract,” the researchers wrote in their abstract.
The mRNA vaccine technology has more versatility than traditional vaccine designs, Alameh told Medscape Medical News. “Additionally, mRNA vaccines can easily incorporate multiple antigens into a single formulation to target multiple bacterial virulence factors simultaneously; our hypothesis was that the mRNA-LNP platform would allow us to take a holistic approach in combating this pathogen by targeting its potent toxins, the vegetative cell, and the spore,” said Alameh.
“Perhaps most excitingly and surprising, we found that the vaccine could overcome deficits in host immunity to protect animals even after infection had occurred,” said co-author Joseph Zackular, PhD, co-director of the Center for Microbial Medicine at the Children’s Hospital of Philadelphia and an assistant professor in the Department of Pathology and Laboratory Medicine, University of Pennsylvania in Philadelphia, in an interview.
Recent research has shown that the immune system does not mount a strong adaptive immune response to C difficile because of the action of the toxins; however, the current study shows that vaccination in mice after initial infection can overcome the negative effects of the toxin on adaptive immunity, said Zackular. The results suggest that the vaccine could be used for prophylaxis and to improve outcomes after infection, he added.
Clinical Implications and Next Steps
The current study shows the efficacy of multivalent mRNA-LNP vaccines to protect against complex pathogens and notably against recurrence, which is especially problematic in C difficile, Zackular told Medscape Medical News. “Most importantly, we feel that this study lays the groundwork for the ultimate eradication of this pathogen,” he said.
“We are continuing to advance our vaccine by improving immunogenicity of current antigens, discovering new and more effective antigen targets for future vaccines, and improving mucosal immunity to the mRNA-LNP vaccines,” Alameh told Medscape Medical News.
Although the current study appears to demonstrate the safety of the vaccine, more research is needed to confirm the status of the gut microbiota, he noted. “The point that the microbiota needs to be carefully accounted for is essential for all vaccines and therapeutics moving forward,” Alameh said.
The study was funded by the National Institutes of Health and supported by a BioNTech-Sponsored Research Agreement. Co-author Drew Weissman disclosed being named on patents for mRNA as a vaccine platform, and Weissman and lead author Alameh disclosed being named on patents describing the use of LNPs and lipid compositions for nucleic acid delivery and vaccination. 
 
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