OU College of Medicine Researchers Earn $6.5 Million Grant to Work Toward C. Difficile Vaccine

Potential infection with Clostridioides difficle, or C. difficile, emerges as one of the most troubling risks during a hospital stay, particularly for people taking antibiotics or those with a weakened immune system.

Hospitalized patients with C. difficile, in addition to experiencing diarrhea, fever and nausea, also face a higher risk of reinfection and more dangerous problems like sepsis and irreparable damage to the colon. Although unsuccessful thus far, efforts to develop a vaccine to protect against C. difficile continue. And now, a surge of federal funding aims to bolster the science needed to create a more effective method of preventing these infections.

Researchers at the University of Oklahoma College of Medicine recently received a significant grant from the National Institutes of Health — $6.5 million over five years — to leverage a three-part approach to better understand how C. difficile often thwarts a person’s immune system. Mark Lang, Ph.D., a Presbyterian Health Foundation Presidential Professor in the Department of Microbiology and Immunology in the OU College of Medicine, leads the work of the grant.

“Physicians see anywhere from 10 to 30 cases of C. difficile infections each month in the hospital, and it can be a major problem for patients with cancer, especially those who have had bone marrow radiation and a transplant, as well as other patients who are immune-compromised because of various conditions,” Lang said. “C. difficile can be treated, usually with an antibiotic, but that disrupts the healthy bacteria in the digestive tract and the patient is susceptible to reinfection. Each time a person is infected, the chance of reinfection is higher. We can knock C. difficile down, but we can’t knock it out.”

Researchers at the OU College of Medicine bring a wealth of experience and unique scientific methods to their three-pronged approach for better understanding C. difficile. Jimmy Ballard, Ph.D., George L. Cross Research Professor and chair of the Department of Microbiology and Immunology, leads one approach that uses the inactive C. difficile toxins that he created in his lab. Because he engineered the toxins to elicit an immune response to C. difficile, researchers can design studies that allow them to analyze the effects of the toxin during disease and following vaccination.

“The research community has gaps in knowledge about all the mechanisms by which C. difficile attacks its host, and how the bacterium affects the host’s immune response,” Lang said. “There have been several large clinical trials testing new vaccines that seemed promising, but ultimately too many people were still getting infected, and pharmaceutical companies stopped pursing the vaccines. It doesn’t matter how good a vaccine candidate is if the bacterium is doing something to limit its success.”

Lang’s contribution to the work of the grant focuses on the human immune response to C. difficile infection. In previous research, he profiled the entirety of the antibodies created in people who were infected with C. difficile and recovered. These antibodies, considered the body’s B cell “memory,” should protect against a reinfection of C. difficile, Lang said, but subsequent studies showed that the antibodies weren’t very good at remembering the bacteria when they returned, so reinfection could occur.

With funding from the new grant, Lang plans to recruit more volunteers, both healthy people and those who have recovered from a C. difficile infection, to create a more extensive profile of B cells and the antibodies they make. Somehow, C. difficile finds a way to limit a person’s immune response; understanding how immune suppression occurs marks a crucial step for developing a vaccine that prompts the body to make highly effective antibodies.

The third arm of the grant employs a different yet complementary type of research led by Maureen Cox, Ph.D., assistant professor in the Department of Microbiology and Immunology. She focuses on how the nervous system and the immune system intersect during an infection. C. difficile, like many bacteria and viruses, manipulates a person’s nervous system in various ways. Cox hypothesizes that C. difficile infections cause a profound depletion of the nerves in the gastrointestinal tract. Because the GI tract’s nerve cells play a role in fighting infection, having fewer such cells likely makes a person more susceptible to reinfection.

“Our theory is that the people who lose the density of nerves in their GI tract are the ones who are going to relapse and see if susceptibility to C. difficile increases,” Cox said. “The research community also doesn’t yet know whether people are able to recover those nerves after infection. That means that future vaccines likely need to prevent C. difficile from damaging the nerve cells.”

The NIH funding for this work, called a U19 grant, brings together a team of researchers to target their joint efforts on C. difficile infection. Although researchers have made great strides in understanding how the bacterium behaves during infection, they need much more knowledge to create a vaccine that blocks all the ways it is able to evade the immune system.

“This U19 grant is a clear recognition of Dr. Lang’s leadership in this field, and it further establishes the Department of Microbiology and Immunology as a hub for cutting-edge C. difficile research that will lead to new and effective vaccines against this serious human disease,” Ballard said.

Research reported in this press release is supported by the National Institute of Allergy and Infectious Diseases, a component of the National Institutes of Health, under the award number 1U19AI174994-01.