A Phase 2 Study Evaluating the Safety, Tolerability, and Immunogenicity of Two 3-Dose Regimens of a Clostridium difficile Vaccine in Healthy US Adults Aged 65 to 85 Years

Nicholas Kitchin, Shon A Remich, James Peterson, Yahong Peng, William C Gruber, Kathrin U Jansen, Michael W Pride, Annaliesa S Anderson, Charles Knirsch, Chris Webber, Nicholas Kitchin, Shon A Remich, James Peterson, Yahong Peng, William C Gruber, Kathrin U Jansen, Michael W Pride, Annaliesa S Anderson, Charles Knirsch, Chris Webber

Abstract

Background: Clostridium difficile causes toxin-mediated nosocomial diarrhea and community-acquired infections; no preventive vaccine is licensed. In this phase 2 study, we explored safety, tolerability, and immunogenicity in older US adults of an investigational bivalent C. difficile vaccine that contains equal dosages of genetically and chemically detoxified toxins A and B.

Methods: Conducted from July 2015 through March 2017, 855 healthy adults aged 65-85 years from 15 US centers were randomized 3:3:1 to receive vaccine (100 or 200 μg) or placebo at 0, 1, and 6 months (month regimen) or 1, 8, and 30 days (day regimen). Serum toxin A- and B-specific neutralizing antibodies were measured. Participant-reported local reactions (LRs) and systemic events (SEs), adverse events (AEs), serious AEs, newly diagnosed chronic medical conditions, and immediate AEs were recorded.

Results: The 200-μg dose level elicited higher immune responses than the 100-µg dose level across regimens. Compared with the day regimen, the month regimen induced stronger and more persistent immune responses that remained elevated 12 months after dose 3. Responses peaked at month 7 (month regimen) and day 37 (day regimen). LRs (primarily injection site pain) were more frequent in vaccine recipients than controls; SE frequency was similar across groups. More related AEs were reported in the day regimen group than the month regimen group.

Conclusions: The C. difficile vaccine was safe, well tolerated, and immunogenic in healthy US adults aged 65-85 years. Immune responses were particularly robust in the 200-μg month regimen group. These results support continued vaccine development.

Clinical trials registration: NCT02561195.

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

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.
Figure 1.
CONSORT diagram with participant dispositions in the (A) month and (B) day regimens. Reasons for withdrawals after vaccination include all withdrawals from dose 1 onward. *One participant in the 100-μg dose level group in the day regimen withdrew after randomization before receiving any study vaccination.
Figure 2.
Figure 2.
Percentages of participants who achieved prespecified levels of toxin A– and toxin B–specific neutralizing antibodies in the month and day regimens. Arrows indicate days on which doses were administered. Abbreviation: C diff, Clostridium difficile vaccine.
Figure 3.
Figure 3.
Geometric mean concentrations of toxin A– and toxin B–specific neutralizing antibodies for baseline seronegative, baseline seropositive, and all participants in the 200-µg group in the month and day regimens. Arrows indicate days on which doses were administered. Abbreviation: GMC, geometric mean concentration.
Figure 4.
Figure 4.
Local reactions and systemic events by dose in the (A) month and (B) day regimens. Abbreviations: 100 = 100 μg Clostridium difficile vaccine; 200 = 200 μg Clostridium difficile vaccine; P, placebo.

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