A “butt vaccine” against C. diff-associated diarrhea

A few years ago, I learned a family secret: my grandma was enduring a years-long battle with diarrhea. Sometimes she would get it for weeks, only to be cured with antibiotics, before getting diarrhea again and continuing the cycle. As a teenager and young adult, I recognized her frequent bathroom trips, hospital stays, and the times she would double-over in pain, but I never knew why this was occurring. My grandma felt ashamed, so she never talked about her suffering with me, despite me being a diarrheal disease researcher.

Eventually, I learned that my grandma had relapsing Clostridioides difficile infection. And in a made-for-movie twist of fate, I just so happen to be a researcher working on a vaccine against Clostridioides difficile.

What is C. diff?

Clostridioides difficile, or C. diff, is a diarrheal disease primarily spread in hospital settings, and patients receiving antibiotics are most vulnerable. This is because antibiotics displace and kill healthy gut microbiota, opening an opportunistic niche in the colon for C. diff spores to proliferate. These hearty bacterial spores are expelled into the air during diarrhea, meaning they can stick to surfaces. They are also heat- and acid-tolerant, so standard disinfectant wipes and hand sanitizer do not get rid of them. C. diff spores are usually transmitted when someone touches contaminated surfaces and ingests them, either by touching their mouth or food without first washing their hands.

In the colon, C. diff creates two toxins that kill the gut lining and cause inflammation. This typically causes mild-to-severe diarrhea, like in the case of my grandma, but can worsen and even cause death. Up to 35% of C. diff patients have relapsing cases like my grandma’s, where they continually contract C. diff even after treatment. C. diff infection causes upwards of 500,000 cases, 30,000 deaths, and $5 billion in costs each year in the United States alone. While the actual numbers of cases worldwide are difficult to pinpoint due to discrepancies in reporting, the global personal and economic burden is thought to be massive. Scientists have recently prioritized preventative measures, like vaccines, against the pathogen to reduce the overall burden of C. diff.

Milestones in vaccine development

Recent clinical trials of vaccines against C. diff failed because they had either adverse side effects or were unable to prevent disease. To help accelerate C. diff vaccine development, the United States National Institutes of Health designated $7.85 million in funding over five years to vaccine research. Three groups of researchers were granted this prestigious award: those at the University of Pennsylvania, Vanderbilt University (where I am based), and the University of Oklahoma.

Last year, researchers at the University of Pennsylvania published a C. diff immunization model with messenger RNA (mRNA) technology, utilizing the same bioengineering that was popularized by COVID-19 vaccines. Their mRNA vaccine provided long-lasting protection against severe C. diff infection and death. Excitingly, their results have moved into Phase I clinical trials in the United States, spearheaded by the Nobel Laureate Dr. Drew Weissman and the biotechnology company BioNTech.

In parallel to the University of Pennsylvania group, the group I belong to at Vanderbilt University has also been making strides on a C. diff vaccine using an unorthodox approach: an enema. At work, we affectionately call this the “butt vaccine”! We aren’t doing it for the pun, though. We are aiming to target the site of C. diff infection, the colon, to obtain a better immune response than we would get with a traditional arm injection. To boost this immune response, we are using dmLT, a key vaccine ingredient provided to us by our partners at PATH. We have been able to show that the “butt vaccine” prevents death and toxin-induced tissue damage while clearing C. diff spores. Our results excitingly suggest that an enema may eliminate C. diff spores to prevent further transmission and relapsing infection, like what my grandma dealt with. Our results are currently under review for publication.

Once a viable vaccine candidate completes clinical trials, it is likely that the Food and Drug Administration (FDA) will designate it to be Fast-Tracked. This designation is given to vaccines and treatments that address unmet medical needs and accelerates their FDA approval process.

Butt wait…there’s more

An effective vaccine against C. diff, especially one that prevents transmission, is imperative to reduce the global disease burden. Yet, as with other causes of diarrhea, it remains only part of a litany of preventative measures, including proper hygiene in hospitals and clinics, handwashing with soap and hot water, and judicious, targeted antibiotic use.

Additionally, a vaccine could bolster treatment strategies to reduce healthcare burden if people do get sick. These treatments include monoclonal antibody therapies against the C. diff toxins and fecal microbiota transplantation, which replaces overgrown C. diff in the gut with healthy bacteria in another colon-centric way.

By integrating these solutions and crafting an effective C. diff vaccine, we can help ensure that people like my grandma are protected against a preventable diarrheal disease and will not have to suffer in silence.

Cover photo: An illustration of the C. diff bacterium. Credit: CDC.