mRNA Vaccine Shows Potential for C difficile Infections

Joseph Zackular, PhD, an assistant professor at the Children's Hospital of Philadelphia and the University of Pennsylvania, is leading research on Clostridioides difficile (C difficile) and the development of an mRNA vaccine. His recent work has shown promise in reducing mortality and improving outcomes for infections caused by this bacterium.

In our recent interview, Zackular discussed how his team used animal models, including mice and non-human primates, to test the vaccine's safety, immunogenicity, and efficacy. C difficile has long posed a major public health threat due to its ability to form spores that survive harsh environments, making treatment difficult. Zackular believes the mRNA vaccine could help address this persistent infection, especially for patients with recurrent cases.

The current study builds on promising results from animal models, including mice, where the vaccine showed encouraging efficacy. When asked about the transition from animal to human trials, Zackular emphasized the importance of animal models in understanding immune response, vaccine efficacy, and safety.

“To start with, animal models that recapitulate what we see in humans, so that we can study the immune response, the efficacy of, you know, treatments like vaccines, you know. So ultimately, thinking about safety, thinking about immunogenicity, thinking about the effectiveness of these strategies for taking on a challenging infection like C difficile," Zackular explained. He further noted that while animal models are valuable, the ultimate goal is to bring these therapies, particularly vaccines, to human trials.

"Our work in animal models was by design using physiologically relevant concentrations of these mRNA vaccines that would be safe for humans, validated by the work done with the COVID-19 vaccines. What we’re working towards now is using other animal models, like hamsters and non-human primates, to assess immunogenicity and safety, and ultimately bring this to phase one clinical trials to evaluate efficacy and safety in humans,” he said.

Zackular is hopeful that results from animal models will be replicated in humans, providing an important tool for addressing C difficile infections.

Addressing C Diff's Complex Life Cycle

C difficile is known for its ability to oscillate between a vegetative cell state and a dormant spore form, making it extremely difficult to eliminate. The pathogen's lifecycle, which includes toxin production and spore formation, complicates treatment and prevention efforts.

"C difficile is a really challenging and uniquely challenging pathogen for us to take on. It lives a really complex life cycle, and so, C difficile is a vegetative cell, so a bacterium that produces two really potent toxins that cause disease, but C difficile also makes a spore, and this spore is really, really hard to kill and survive outside of the body, but even when it’s inside the body, it can be really challenging for antibiotics to kill, can be challenging for our own immune systems to kill," Zackular explained.

Despite these challenges, the vaccine developed in his lab has shown the potential to reduce the severity of disease. While it has not yet prevented the initial colonization of C difficile in animal models, the vaccine significantly reduced mortality and improved outcomes.

“The goal would be to prevent all C difficile from being able to colonize and cause infection, but that’s challenging. It's an organism that lives in this relatively hard-to-get-to part of our body, the lumen of the gut, and it doesn’t invade. And so being able to prevent it from colonizing, of course, can be challenging,” Zackular said.

In studies with a highly virulent strain of C difficile, the vaccine prevented 100% of mortality in mice, which is a remarkable outcome. “What we found is that we aren’t able to prevent the initial colonization and outgrowth of this pathogen. However, we are able to find that we can dramatically stunt the pathogenicity and the disease that's caused by this really problematic infection,” he added.

This vaccine uses the mRNA platform, which has already proven successful in COVID-19 vaccines. Zackular's team has developed a tetravalent vaccine targeting both toxins responsible for C difficile’s harmful effects and the bacterial cell and spores.

“This mRNA vaccine platform allows us to create multivalent vaccines very readily. And so what we’re able to do in this paper was make a tetravalent vaccine that targets both of the really important toxins that cause disease with C difficile, but also target the cell itself as well as the spore,” Zackular explained.

The research represents a promising proof of principle that mRNA vaccines could be effective in preventing C difficile disease. Looking forward, the team hopes to further refine the vaccine, targeting more virulence factors and potentially preventing initial infection or promoting quicker bacterial clearance.

“Ultimately, in the future, we’re hopeful that we can add even more targets against the cell, against the spore, against other virulence factors that might allow us to prevent initial infection, or at least clear even quicker,” Zackular said.

Stay tuned for part 2 of our interview where we discussed the complexities of C difficile infections, often recurrent due to antibiotic-induced disruption of the gut microbiome and more.