Study Finds Low Natural Antibody Response to Clostridioides difficile

Clostridioides difficile infection (CDI) is typically treated with oral antibiotics, which pose a risk for recurrence. A recent exploratory study aimed to investigate the natural antibody response to CDI to provide insight on the clinical course of the disease and possible novel treatments.

The main pathogenic factor for CDI development is toxin production, with disease-causing C diff strains harboring C diff toxins A (TcdA) and B (TcdB). Some strains, such as ribotype 027 (RT027), are considered hypervirulent and express binary toxin. These hypervirulent strains have higher toxin production and cause more severe disease; however, learning more about the natural immune response is key. “The immunological response against C diff is crucial for an improved understanding of disease mechanisms and the development of novel therapeutic strategies,” the authors wrote.

Potential therapies beyond antibiotics include toxin-absorbing substances, which have been effective in animal models but not humans, and antibody-based treatments. Monoclonal antibodies and vaccines are currently in development; bezlotoxumab, which neutralizes TcdB, was approved to prevent recurrences in 2017.

The current study analyzed the clinical course and treatment response to strains RT027, RT014, and strain RT010, with RT010 serving as a nontoxigenic control group. The study also examined the prevalence of the toxin-unrelated antiglutamate dehydrogenase (GDH) antibodies and anti–cell-wall protein 84 (CWP84) antibodies.

On days 1, 3, and 6 post diagnosis, plasma samples were taken and analyzed for the presence of anti-GDH, anti-TcdA, anti-TcdB, and anti-CWP84 antibodies in 46 patients. The toxin-unrelated antibodies were more abundant, with 85% of patients positive for anti-GDH and 61% harboring anti-CWP84. In contrast, 11% of patients had anti-TcdA and 28% had anti-TcdB antibodies.

Twenty-six percent of patients had antibodies against RT027, and 5 of those patients (11% of all patients) were also able to neutralize RT014. None of the samples could neutralize RT014 without also being able to neutralize RT027.

The presence of antibodies against C diff was not related to typical risk factors for CDI. In a group of voluntary healthy controls, 30% had anti-TcdB antibodies, 30% had anti-GDH antibodies, and 50% had anti-CWP84 antibodies. Those with anti-TcdB antibodies also tended to have neutralizing antibodies to RT027 toxins and RT014 toxins, but there was no link between anti-TcdA, anti-GDH, or anti-CWP84 antibodies and the presence of neutralizing antibodies.

“Surprisingly, the presence of antigen-specific and neutralizing antibodies was not associated with symptoms, severity of disease, therapy, treatment response, and recurrences,” the authors wrote. At 1, 3, and 6 days after diagnosis, they added, there was no increase in antigen-specific or neutralizing antibodies. This finding applied to both primary and recurrent infections.

These findings suggest that natural C diff antibody response is low, and the samples in this cohort did not experience booster effects with exposure to toxic strains. Antibody production also was not evident throughout the testing period, which covered the first week of infection. Further, the presence of antibodies was not associated with disease severity, risk factors, or symptoms.

“The correlation between the anti-TcdB with toxin neutralization confirms the importance of TcdB for virulence of CDI,” the authors concluded. “Alternative sensitization strategies (eg, through vaccine development) are required to overcome the regular low-titer antibody production following natural intestinal C diff exposure.”

Reference

Roth S, Jung P, Boone J, et al. Antigen-specific vs. neutralizing antibodies against conditioned media of patients with Clostridioides difficile infection: a prospective exploratory study. Front Microbiol. Published online February 24, 2022. doi:10.3389/fmicb.2022.859037