Graduate Student Vanderbilt Univ. Med. Ctr. Nashville, Tennessee, United States
Introduction/Rationale: Clostridioides difficile infection (CDI) is a leading cause of healthcare-associated infections in the United States. Recent vaccine strategies targeting the toxins responsible for CDI symptoms were unsuccessful in reducing C. difficile colonization in Phase III clinical trials. Colonization prevention or bacterial clearance would eliminate transmission of C. difficile spores and forestall recurrent CDI. Therefore, new vaccination strategies aim to identify novel surface antigens that promote mucosal immunity and bacterial clearance.
Methods: To start, we immunized mice with four candidate surface antigens by both parenteral and mucosal routes of administration and challenged with C. difficile. Three of these antigens reduced colonization burden in vivo, but only when administered by mucosal vaccination. We then immunized mice with a formula containing the three effective surface antigens and inactivated C. difficile toxins, again using both routes of administration.
Results: Both immunization routes protected against epithelial tissue damage, weight loss, and mortality. The mice that received mucosal immunization cleared both spores and vegetative bacteria, which was confirmed via tissue and fecal qPCR. However, those that received parenteral immunization were unable to do so, despite a robust systemic humoral response. We did not detect anti-surface-antigen systemic IgG nor fecal IgA in mice that received mucosal vaccination. Correlates of decolonization included fecal IgG responses to vegetative surface antigens, which reduce bacterial mobility, and a colonic, Th17-skewed tissue-resident memory T cell response against spore antigen.
Conclusion: We have demonstrated, for the first time, the clearance of C. difficile from the host after mucosal immunization. Our results demarcate notable differences in correlates of protection and pathogen clearance between administration routes and highlight mucosal immunization as the paramount strategy to elicit sterilizing immunity against CDI.
