A novel vaccination approach developed by Vanderbilt Health researchers cleared the harmful gut bacterium Clostridioides difficile (C. diff) in an animal model of infection.
An experimental vaccine administered to the mucosal lining of the colon protected against illness, death, tissue damage and infection recurrence. The findings, reported Feb. 18 in the journal Nature , represent a major step forward for vaccine development for C. diff, the leading cause of health care- and antibiotic-associated infection.
C. diff infection causes diarrhea and colitis (inflammation of the colon). There are nearly half a million C. diff infections in the U.S. each year and about 29,000 deaths, according to the Centers for Disease Control and Prevention, resulting in an estimated $4.8 billion in health care costs. People taking antibiotics; those who have had a recent hospitalization or live in a health care facility; and adults over 65 are most at risk of C. diff infection. There are limited treatments and no vaccines, and up to 30% of patients have a recurrent C. diff infection after initial treatment.
"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 D. Borden Lacy , PhD, the Edward and Nancy Fody Professor of Pathology, director of the Vanderbilt Center for Structural Biology, and corresponding author of the Nature paper.
Previous vaccine strategies for C. diff infection have targeted the bacterium's primary toxins, TcdA and TcdB, with candidate vaccines advancing to late-stage clinical trials and demonstrating protection against severe infection but not reduction of bacterial burden. These vaccines were administered by injection and induced a systemic immune response, rather than a mucosal response at the site of infection in the colon.
"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."
Lacy is co-principal investigator of VANDy-CdV (Vanderbilt Antibody and Antigen Discovery for Clostridioides difficile Vaccines), a team of over 25 multidisciplinary researchers that contributed to the current studies, which were led by graduate student Audrey Thomas.
The researchers established a novel vaccination approach to both enhance C. diff clearance and promote protection against infection symptoms. Their multivalent vaccine combined:
A selection of novel antigens present on C. diff in both its vegetative state (active, growing and toxin-producing) and spore state (dormant, resilient and responsible for transmission)
Toxins TcdA and TcdB inactivated by point mutations so that they retain native structure
An adjuvant to enhance mucosal immune responses
They compared a rectal route of administration (to mimic mucosal immunization by enema and target C. diff at its site of infection) to abdominal cavity injection (to mimic traditional parenteral immunization), and they assessed antibody and cellular immune responses.
They found that mucosal immunization, but not parenteral, cleared C. diff from the host, and that mucosal vaccination protected against illness, death, tissue damage and recurrence. Immune response indicators that correlated with protection and pathogen clearance differed based on the route of vaccine administration.
The researchers also demonstrated that mucosal vaccination provided long-term protection: Animals that were challenged with C. diff infection at 60 and 200 days after the final vaccine dose were protected against illness and death and cleared both vegetative and spore forms of C. diff.
"Our mucosal vaccine elicits sterilizing immunity (elimination of the pathogen) against acute and recurrent C. diff infection," Lacy said. "Along with decreasing disease severity, rectal administration of this vaccine reduces tissue damage caused by C. diff toxins, which is not the case for other vaccine candidates and antitoxin therapeutics.
"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."
Thomas is the first author of the Nature paper. Co-authors are F. Christopher Peritore-Galve, PhD, Alyssa Ehni, Bruno Lança, Jonathan Coggin, Eric Brady, Sandra Yoder, MT, Rebecca Shrem, Rubén Cano Rodriguez, Heather Kroh, PhD, Katherine Gibson-Corley, DVM, PhD, M. Kay Washington, MD, PhD, Danyvid Olivares-Villagómez, PhD, C. Buddy Creech, MD, MPH, Maribeth Nicholson, MD, MPH, Benjamin Spiller, PhD, and Lacy.
The research was supported by the VANDy-CdV National Institutes of Health grant (U19AI174999).
