Abstract
Clostridioides difficile causes antibiotic-associated diarrhea and pseudomembranous colitis. The pathogenesis of C difficile infection is driven by 2 exotoxins, TcdA and TcdB, making them priority targets for therapeutic intervention. Several vaccine formulations targeting these toxins have reached phase 3 clinical trials, but none have successfully prevented colonization or disease. Recent advances in understanding C difficile pathogenesis and vaccinology have revitalized efforts to develop an effective vaccine. Here, we discuss basic and clinical research insights to provide a framework for developing next-generation C difficile vaccines.