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Researchers at Vanderbilt Health say they have developed a novel vaccine that cleared Clostridioides difficile (C. diff) from animal models of the infection. The development of the vaccine, reported in Nature, delivered novel vegetative and spore antigens directly to the colon to promote clearance of C. difficile and provides a potentially new strategy against the leading cause of health care—and antibiotic-associated infection.
“C. diff infection is a major public health burden in the United States and globally. A vaccine for high-risk populations could have a significant impact,” said senior author D. Borden Lacy, PhD, a professor of pathology at Vanderbilt University Medical Center.
C. difficile is a spore-forming anaerobic bacterium that causes diarrhea and colitis. In the United States alone, it causes about 500,000 cases and 29,000 deaths each year. Patients taking antibiotics, those recently hospitalized or living in healthcare facilities, and adults over 65 face highest risk of infection and as many as 30% of patients will have a recurrence of the infection after initial treatment. Currently, treatment options are limited and there are no vaccines to guard against C. diff infection.
Other strategies to develop a vaccine have focused on neutralizing the bacterium’s primary virulence factors, toxins TcdA and TcdB. These vaccine candidates, administered by injection, induced systemic immune responses and advanced to late-stage clinical trials, but while they showed the ability to protect against severe infection, these candidates did not reduce bacterial burden in the colon, an important factor for preventing transmission and recurrence.
For their research, the Vanderbilt team hypothesized that the route of immunization could determine whether vaccination achieves clearance of the pathogen at its site of infection. “Clearing the bacterium from the colon is crucial when considering C. diff spore transmission by the fecal-oral route,” Lacy said. “The 30% incidence of recurrent C. diff infection and the documented increase in community-acquired cases among otherwise healthy adults underscore the need for an immunization strategy that prioritizes C. diff clearance.”
To address this, the researchers designed a multivalent vaccine that could both enhance clearance while preventing infection symptoms. Their formulation combined novel surface antigens expressed during both vegetative and spore states, inactivated forms of TcdA and TcdB engineered by point mutations to retain native structure, and a mucosal adjuvant.
“Our strategy combined (1) selection of novel vegetative and spore antigens to promote clearance of C. difficile; (2) inactivating point mutations of the C. difficile toxin antigens that retain native structure for broad epitope recognition; (3) the double mutant of Escherichia coli heat labile toxin (dmLT) as a mucosal adjuvant; (4) a rectal route of administration that was compared against parenteral vaccination; and (5) the assessment of humoral and cellular indicators of immune responses to identify correlates of symptom reduction and clearance,” the researcher wrote in Nature.
The investigators compared rectal immunization, designed to mimic mucosal delivery by enema, with intraperitoneal injection, representing parenteral vaccination. They evaluated antibody responses, T cell responses, clinical outcomes, tissue damage and bacterial colonization burden following C. difficile challenge.
Their data showed that mucosal immunization, but not parenteral vaccination, cleared C. difficile from the host and protected against illness, death, tissue damage and recurrence. Animal models challenged 60 and 200 days after the final vaccine dose remained protected and cleared both vegetative and spore forms of the bacterium.
The durability of the response to this novel vaccine was notable. Mice vaccinated at different ages retained tissue-resident memory responses and the ability to clear infection when challenged 200 days after boosting. “The observation that mice retain TRM cell responses and the ability to clear the pathogen when challenged 200 days after boost provides a positive indication for clinical translation into older populations,” the researchers wrote, but added that an important next step will be rectal immunization trials in aged mice older than 18 months.
Looking ahead, the researchers envision the use of a rectally administered vaccine as an enema, similar to the administration methods used for fecal microbiota transplantation. “We expect this strategy to have strong translational value in the effort to develop a human vaccine for C. diff infection, as well as other gut pathogens,” Lacy said.