A Phase 2 Extension Study Evaluating the Immunogenicity, Safety, and Tolerability of 3 or 4 Doses of a Clostridioides difficile Vaccine in Healthy US Adults Aged 65 to 85 Years

Abstract

Background: This phase 2 extension explored the long-term antibody persistence of an investigational Clostridioides difficile vaccine and the safety, tolerability, and immunogenicity of dose 4 approximately 12 months post-dose 3.

Methods: One year post-dose 3, healthy US 65- to 85-year-olds (N = 300) were randomized to dose 4 of vaccine at previously received antigen levels (100 or 200 μg) or placebo. Assessments included safety and percentages of participants achieving neutralizing antibody titers above prespecified thresholds (≥219 and ≥2586 neutralization units/mL for toxins A and B, respectively).

Results: In participants previously given three 200-µg doses and placebo in the extension, toxin A and B neutralizing antibodies were above prevaccination levels 48 months post-dose 3 (36 months after placebo); 24.0% and 26.0% had toxin A and B antibodies at or above prespecified thresholds, respectively. Neutralizing antibodies increased post-dose 4 (12 months post-dose 3) and persisted to 36 months post-dose 4. Thirty days post-dose 4, all participants had toxin A and 86.5% to 100% had toxin B titers at or above prespecified thresholds. Local reactions were more frequent in vaccine recipients. Systemic and adverse event frequencies were similar across groups.

Conclusions: C difficile vaccine immune responses persisted 48 months post-dose 3. Dose 4 was immunogenic and well tolerated, supporting continued development. Clinical Trials Registration. ClinicalTrials.gov NCT02561195.

Keywords: Clostridioides difficile infection; United States; adults; nosocomial diarrhea; toxoid vaccine.

Figure 1.

CONSORT diagram with participant dispositions in the (A) month and (B) day regimens during the extension phase. C difficile, Clostridioides difficile.

Figure 2.

GMCs of toxin A– and toxin B–specific neutralizing antibodies in the initial and extension phases for the 200- and 100-μg dose levels. A, Month regimen. B, Day regimen. Arrows indicate days on which doses were administered. Error bars indicate 95% CIs. Blood samples were drawn on day 1 of the extension phase immediately before administration of dose 4. C difficile, Clostridioides difficile; GMC, geometric mean concentration (neutralizing units per milliliter).

Figure 3.

Percentages of participants achieving prespecified levels of toxin A– and toxin B–specific neutralizing antibodies in the (A) month and (B) day regimens during the extension phase. Blood samples were drawn on day 1 of the extension phase immediately before administration of dose 4. Toxin A– and toxin B–specific thresholds were ≥219 and ≥2586 neutralization units/mL, respectively. Error bars indicate 95% CIs. C difficile, Clostridioides difficile.

Figure 4.

Local reactions and systemic events by dose in the (A) month and (B) day regimens during the extension phase. 100P, 100 μg/placebo; 100, 100-μg Clostridioides difficile vaccine; 200P, 200 μg/placebo; 200, 200-μg Clostridioides difficile vaccine.