Caleb was a healthy 4-year-old boy when, in 2014, he developed frequent episodes of watery diarrhea and intense intestinal pain.
Rushed to a community hospital, Caleb was transferred the next day to Monroe Carell Jr. Children’s Hospital at Vanderbilt. There he was diagnosed with C. diff, a bacterial infection of the colon for which treatment options are limited.
Caleb endured repeated bouts of brutal diarrhea and abdominal pain for six months before receiving a fecal microbiota transplant (FMT). The transfer of fecal material from a healthy donor replenished his colon with beneficial microbes that normally ward off C. diff infection. Since then, they’ve held the bacterium in check.
Now 15, Caleb is an honors student, plays alto sax in his high school’s marching band, and participates in Scouts and karate. But he’s developed irritable bowel syndrome, his mother said. Ingesting carbonated beverages or anything with bubbles will trigger paroxysms of piercing abdominal pain.
Unfortunately, treatment options for the estimated 20,000 children — and the more than 500,000 adults — who are diagnosed annually with C. diff infections are not much better today than they were in 2014.
“We’re in a tough place,” said Maribeth Nicholson, MD, MPH, a pediatric gastroenterologist and associate professor of Pediatrics at Monroe Carell who treated Caleb in 2014. Treatments that replenish friendly microbes or stimulate immunity against inflammatory toxins released by C. diff have recently become unavailable.
“We’re stuck with just treating kids with more antibiotics,” Nicholson said. Unfortunately, antibiotics kill the good bacteria along with the bad, increasing the likelihood of recurrent C. diff infections.
“These kids will have four, five, six episodes of C. diff in a row,” she said. “There’s really not a lot to offer them.”
The promise of research
But there is hope. In a research lab across the Vanderbilt Health campus from Monroe Carell, Borden Lacy, PhD, and her colleagues are working on potential vaccines, therapeutic antibodies and — most recently — nanobodies, to prevent and treat infections by the bacterium known by its scientific name as Clostridioides difficile.
Lacy holds the Edward and Nancy Fody Chair in Pathology, is a professor in the departments of Pathology, Microbiology & Immunology and Biochemistry, and directs the Center for Structural Biology.
A major goal of her research is to understand how toxins produced by C. diff — TcdA, TcdB and, by some bacterial strains, CDT — help the bacterium gain a foothold in the gut, evade the body’s immune defenses, and resist efforts to eradicate infection.
C. diff toxins invade epithelial cells that make up the protective lining of the colon and immune cells. This triggers a complex cascade of cellular events that result in inflammation (colitis), disruption of the epithelial barrier, leakage of fluid into the colon, and diarrhea — hallmark features of C. diff infection.
In older adults or patients who are immunocompromised, severe C. diff infections can lead to extensive inflammation (fulminant or pseudomembranous colitis), bloody diarrhea, toxic (enlarged) megacolon, bowel perforation, sepsis and death. In the United States, C. diff infections kill an estimated 12,800 people every year.
The incidence of C. diff infections in the hospital has been declining in recent years, thanks largely to efforts that limit the overuse of antibiotics. But the bacterium is persistent, and community-acquired C. diff infections remain a stubborn public health challenge.
It didn’t help that last year the pharmaceutical giant Merck stopped producing Zinplava, the first (and so far, the only) human monoclonal antibody approved by the Food and Drug Administration to prevent recurrent C. diff infections by neutralizing the TcdB toxin.
In addition, OpenBiome, the nation’s largest provider of FMT products, suspended distribution at the end of 2024 in response to a change in FDA regulations. Vaccine candidates targeting C. diff and its toxins have entered clinical trials, but so far none has blocked infections by the bacterium.
Lacy is determined to change this picture. Since 2011, her research has been funded continuously by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, and her team has published more than 40 scientific papers on C. diff and its toxins.
Adding to the tool kit
In 2023, the NIAID awarded a five-year, $7.86-million grant to Vanderbilt Health to establish “VANDy-CdV,” an antibody and antigen discovery program for C. diff vaccines. Its goal is to identify toxin subunits and novel cell surface antigens that, when combined, will enable durable immune protection against infection and its consequences.
VANDy-CdV investigators recently reported in the journal Nature a novel vaccine approach that protected against C. diff disease and recurrence.
Lacy and Eric Skaar, PhD, MPH, the Ernest W. Goodpasture Professor of Pathology and director of the Vanderbilt Institute for Infection, Immunology and Inflammation, are the program’s principal investigators.
The grant includes support for a clinical data and biospecimen repository core led by Nicholson and Buddy Creech, MD, MPH, director of the Vanderbilt Vaccine Research Program; a protein expression core led by Ben Spiller, PhD, associate professor of Pharmacology; a single-cell technologies core led by Ivelin Georgiev, PhD, director of the Vanderbilt Program in Computational Microbiology and Immunology; and a small animal core led by Skaar.
An important new addition to the Lacy lab’s tool kit is the nanobody, an engineered antibody fragment with impressive diagnostic and therapeutic potential. Nanobodies are derived from unique “heavy chain” antibodies produced by some sharks and by a family of hooved mammals that includes camels, llamas and alpacas.
Nanobodies are small, easy to produce, and bind very tightly to their specific targets. When coupled to a therapeutic antibody, the resulting complex recognizes two or three binding sequences (called “epitopes”) on the surface of the toxin, rather than just one.
“The nanobody on its own binds really tightly,” Lacy said, “but once you pair it (with a second nanobody) and make it bispecific, it’s just not coming off.”
Zinplava, the only approved monoclonal antibody for C. diff infections that was recently taken off the market, “was working,” Lacy said. “It reduced the risk of recurrence by about 50%. But it was expensive.”
The hope is that a bispecific nanobody that binds more tightly to its target and requires a smaller dose of antibody — when given with antibiotic — will achieve the same or better results at a lower cost. “I’m really excited about the potential, what can be done with this,” she said.
“It would be wonderful if patients were able to have better treatment options,” agreed Caleb’s mother. “Six months of constant pain and diarrhea in a 4-year-old is brutal. And fixing it fast would avoid long-term effects.”
In the meantime, Caleb offered some advice for others who are experiencing what he did. “Stay strong. Don’t give up,” he said. “It’s going to be hard … but push through.”
