Researchers at VUMC have developed a novel vaccine that successfully eliminates the harmful gut bacterium Clostridioides difficile in mice. When delivered to the mucosal lining of the colon, the experimental vaccine protects against severe illness, death, tissue damage and recurring infection. The findings, published Feb. 18 in the journal “Nature”, mark a major advancement for vaccine development for C. diff.
C. diff is a bacterial infection that causes diarrhea and inflammation of the colon. According to the National Foundation for Infectious Diseases, the United States sees nearly 500,000 cases each year, leading to approximately 30,000 deaths and an estimated $4.8 billion in annual health care costs. The people at highest risk include those taking antibiotics, individuals recently hospitalized or living in health care facilities and adults over 65. Treatment options remain limited, and there is currently no vaccine to treat the infection.
Audrey Thomas (PhD ‘26), primary author of the recent publication, discussed the vaccine research process and the precautions taken to ensure the success of the study.
“One thing I had to adapt to was the dedication and resilience necessary to achieve the experiments in the timely manner in which I had planned them. My mouse experiments are at least 10 days straight of monitoring, and having multiple experiments stacked up simultaneously or back-to-back was necessary to achieve what we did. I worked most weekends in 2025, as well as long days. I even dreamt about my experiments,” Thomas said.
As for next steps, Thomas laid out the lab’s future focuses for potential vaccine implementation.
“We’re working on improvements right now. The biggest limitation is Toxin B (TCDB), which is the main ecologic agent of C. diff infection in disease and pathology. We protected significantly against death, weight loss and epithelial damage — everything that TCDB would cause. However, we didn’t see any sort of changes humorally or any sort of antibody production against TCDB,” Thomas said. “I think we really need to focus in what our lab is doing, [which] is focusing on engineering a better TCDB response so that we can actually target the main driver of disease.”
Professor Borden Lacy, principal investigator, detailed previous trials that have left a gap in treatment options for C. diff.
“I have worked on C. diff for 15 to 20 years, and it’s a huge clinical problem in the United States and other countries. There are about 500,000 infections each year and 30,000 deaths in the United States alone,” Lacy said. “There were two major pharmaceutical companies that took vaccines into clinical trials, but both of those trials failed. That prompted the field and the NIH [to] really want to prioritize novel approaches for vaccines, and we realized here that we had a team that would be able to tackle it in a new way that could be responsive.”
Lacy also explained the unique approach that the vaccine utilized compared to previous vaccine trials.
“One step that was critical was giving the vaccine rectally, as opposed to giving it intraperitoneally. The idea is you are delivering the antigens directly to the site where you want the immune response to occur, rather than injecting it into the bloodstream and hoping that it travels to the right place,” Lacy said. “Our paper shows how, if we do the intraperitoneal injection, it protects against symptoms, but it does not clear the bug. It is only the rectal [administration] that leads to clearance of the bacteria.”
Lacy explained the next steps needed before the vaccine may be introduced into a clinical setting.
“One of the big [challenges] now is reducing it down to something simpler. We weren’t concerned about that in this study, but now that we have something that works, we can start to take things away and still have the vaccine work just as well,” Lacy said.
Lacy also elaborated on considerations of the projected patient population.
“Elderly people and people who will be taking antibiotics within the healthcare system are at high risk for C. diff. People could consider getting vaccinated prior to planned hospitalization stays and/or entry into long-term care facilities,” Lacy said. “If you want to develop molecules that you’re going to be putting into people, every single one of those molecules is going to have to be made at a large scale and go through a lot of quality control and scrutiny.”
Junior Miranda Lynch, research assistant in the Lacy Lab, shared her excitement about seeing the research being published.
“I was thrilled to see the publication in ‘Nature’, especially given how challenging C. diff infections are to prevent and treat. [In science] you have setbacks and challenges, but to be able to see Audrey and the team push through those and see all of those 6 a.m. mornings coming to fruition, it’s super exciting. They found something that’ll make a big difference in the treatment of the C. diff infection and moving forward in the field,” Lynch said.
Lynch also shared her personal connection to the C. diff infection and her motivation to research it further in the Lacy Lab.
“I gravitated toward the Lacy Lab when I came to Vanderbilt because my sister contracted CDI during a hospital procedure. I’ve seen the patient side of CDI and how unpleasant it can be, and I wanted to have the opportunity to contribute to future treatments,” Lynch said. “Beyond the personal aspect, C. diff is just an interesting bacterium because it sits at the intersection of microbiology, immunology and host-pathogen interactions.”
Lynch also expanded on the research’s future implications in the longer term.
“A C. diff vaccine could significantly reduce the incidence of primary infections and, importantly, recurrent infections, which are a major clinical challenge. That would mean fewer hospitalizations, less reliance on broad-spectrum antibiotics, which disrupt the gut microbiota and lower healthcare costs. Because CDI disproportionately affects older adults and hospitalized patients, the public health impact could be substantial,” Lynch said.
