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Clinical Trial
. 2024 Dec 17;79(6):1503-1511.
doi: 10.1093/cid/ciae410.

CLOVER (CLOstridium difficile Vaccine Efficacy tRial) Study: A Phase 3, Randomized Trial Investigating the Efficacy and Safety of a Detoxified Toxin A/B Vaccine in Adults 50 Years and Older at Increased Risk of Clostridioides difficile Infection

Curtis J Donskey  1 , Erik R Dubberke  2 , Nicola P Klein  3 , Elizabeth G Liles  4 , Katarzyna Szymkowiak  5 , Mark H Wilcox  6 , Jody Lawrence  7 , Salim Bouguermouh  8 , Haiying Zhang  7 , Kenneth Koury  8 , Ruth Bailey  9 , Helen M Smith  9 , Stephen Lockhart  9 , Erik Lamberth  7 , Warren V Kalina  8 , Michael W Pride  8 , Chris Webber  9 , Annaliesa S Anderson  8 , Kathrin U Jansen  8 , William C Gruber  8 , Nicholas Kitchin  9
Affiliations
Clinical Trial

CLOVER (CLOstridium difficile Vaccine Efficacy tRial) Study: A Phase 3, Randomized Trial Investigating the Efficacy and Safety of a Detoxified Toxin A/B Vaccine in Adults 50 Years and Older at Increased Risk of Clostridioides difficile Infection

Curtis J Donskey et al. Clin Infect Dis. .

Abstract

Background: Clostridioides difficile infection (CDI) causes substantial mortality and healthcare burden. We assessed the detoxified toxin-A/B PF-06425090 vaccine for primary CDI prevention.

Methods: This phase 3 observer-blinded study randomized (1:1) ≥50-year-olds at increased CDI risk (N = 17 535) to receive 3 PF-06425090 or placebo doses (0, 1, and 6 months). Primary end points were first CDI episode (≥3 unformed stools within 24 hours; central laboratory-confirmed toxin A/B positive) ≥14 days post-dose 3 (PD3; first primary) and post-dose 2 (PD2; second primary). CDI duration, need for CDI-related medical attention (secondary end points), and antibiotic use (post hoc analysis) PD3 were evaluated. Tolerability and safety were assessed.

Results: The primary end point was not met (17 PF-06425090 and 25 placebo recipients had first CDI episode ≥14 days PD3 [vaccine efficacy (VE) = 31.0% (96.4% confidence interval [CI], -38.7% to 66.6%)]; 24 PF-06425090 and 34 placebo recipients had first CDI episode ≥14 days PD2 [VE = 28.6% (96.4% CI, -28.4% to 61.0%)]. Median CDI duration was lower with PF-06425090 (1 day) versus placebo (4 days; 2-sided nominal P = .02). Of participants with first CDI episode, 0 PF-06425090 and 11 placebo recipients sought CDI-related medical attention (post hoc analysis estimated VE = 100%; 95% CI, 59.6% to 100.0%) and 0 PF-06425090 and 10 placebo recipients required antibiotic treatment (VE = 100%; 95% CI, 54.8% to 100.0%). Local reactions were more frequent in PF-06425090 recipients, and systemic events were generally similar between groups; most were mild to moderate. Adverse event rates were similar between groups.

Conclusions: Three PF-06425090 doses were safe and well tolerated. Although the primary end point was not met, PF-06425090 reduced symptom duration, CDI that required medical attention, and CDI-directed antibiotic treatment, highlighting its potential to reduce CDI-associated healthcare burden.

Clinical trials registration: NCT03090191.

Keywords: Clostridioides difficile; Clostridioides difficile infection; adults; infectious disease; vaccine.

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Conflict of interest statement

Potential conflicts of interest. C. J. D. receives research support from Pfizer, Clorox, and Ecolab. E. R. D. receives research support from Theriva Biologics, Ferring, and Pfizer and is a consultant for Merck, Pfizer, Seres, Ferring, AstraZeneca, Abbott, Summit, and GSK. N. P. K. receives research support from Pfizer, Merck, Sanofi Pasteur, and GSK. E. G. L. receives research support from Pfizer. K. S. reports no conflicts of interest. M. H. W. has received consulting fees from Ferring, GSK, Nestlé, Paion, Pfizer, Phico Therapeutics, Qpex Biopharma, Seres, Summit, Tillotts, and Vedanta; lecture fees from GSK, Pfizer, Seres, and Tillotts; and grant support from GSK, Pfizer, Seres, Summit, the European Tissue Symposium, and Tillotts. J. L., S. B., H. Z., K. K., R. B., H. M. S., S. L., E. L., W. V. K., M. W. P. C. W., A. S. A., K. U. J., W. C. G., and N. K. are current or former employees of Pfizer and may hold stock or stock options. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Participant disposition. Abbreviation: PP, per-protocol.
Figure 2.
Figure 2.
Cumulative incidence for the first primary episode of CDI ≥14 days after dose 3 (per-protocol [PP]-3 population). The PP-3 population included all randomized participants who received doses 1, 2, and 3 for the vaccine group to which they were randomized and had no major protocol violations up to and including 14 days after dose 3. The PP-2 population included all randomized participants who received doses 1 and 2 for the vaccine group to which they were randomized and had no major protocol violations up to and including 14 days after dose 2. Vaccine efficacy by cumulative time period is provided in Supplementary Table 2. Abbreviations: CDI, Clostridioides difficile infection; CI, confidence interval.
Figure 3.
Figure 3.
Local reactions (A) and systemic events (B) reported within 7 days after any vaccine dose. Results are from the safety population (PF-06425090, N = 8643; placebo, N = 8615). The severity scale is provided in Supplementary Table 1. The numbers above the bar are the percentage of participants with that local reaction or systemic event. Error bars are the 95% confidence intervals based on the Clopper–Pearson method. Severe local reactions after any dose were reported by 2.8% (244 of 8643) and 0.5% (42 of 8615) of participants in the PF-06425090 and placebo groups, respectively. One participant in the placebo group experienced a grade 4 local reaction (injection site pain). Severe systemic events after any dose were reported by 4.9% (423 of 8643) and 5.1% (437 of 8615) of participants in the PF-06425090 and placebo group, respectively. Grade 4 systemic events or fever >40.0°C were reported by 0.2% (17 of 8643) and 0.2% (18 of 8615) of participants in the PF-06425090 and placebo groups, respectively, and included fever >40.0°C (PF-06425090, 0.2% [15 of 8643]; placebo, 0.2% [18 of 8615]), fatigue (PF-06425090, <0.1% [1 of 8643]), muscle pain (PF-06425090, <0.1% [1 of 8643]), and joint pain (PF-06425090, <0.1% [1 of 8643]).
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