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A toxoid vaccine candidate against Clostridioides difficile failed to reduce the incidence of infection in at-risk adults ages 50 and older, according to results of the phase III CLOVER trial.

Of trial participants who received three shots of the vaccine (PF-06425090) included in the analysis, the vaccine efficacy (VE) for reducing the incidence of C. difficile infection was 31%, but it fell well short of statistical significance (96.4% CI -38.7 to 66.6), reported Erik Lamberth, MD, of Vaccine and Research Development at Pfizer in Collegeville, Pennsylvania, and colleagues.

Of the 7,724 participants in this group, 17 developed a first C. difficile infection episode 14 or more days after the third shot, versus 25 of 7,818 participants in the placebo group, the study authors detailed in .

The vaccine is a genetically detoxified C. difficile toxin vaccine formulated with modified toxins A and B. Phase I/II studies found that the vaccine elicited strong toxin neutralizing antibody activity in older adults.

Results were similar among trial participants who received only two vaccine doses, with a nonsignificant VE of about 29% (96.4% CI -28.4 to 61.0).

VE was also nonsignificant for incidence of one or more recurrent C. difficile infection episodes 14 or more days after the third shot (estimated VE of -69.3%, 98.2% CI -1,533.1 to 75.6).

However, duration of C. difficile infection appeared shorter among those who received three doses of the vaccine versus placebo (1 vs 4 days, nominal P=0.02). Also, in a post-hoc assessment, zero participants who developed a first primary C. difficile infection episode at least 14 days after the third dose sought medical attention for infection, versus 11 in the placebo group. Moreover, no participants in this population required antibiotic treatment, compared with 10 in the placebo group.

"Although the primary endpoint was not met, secondary and post hoc analysis results indicated [three] PF-06425090 doses reduced median time to CDI [C. difficile infection] resolution by 75%," the study authors commented. In addition, the post-hoc analyses "suggest clinically meaningful results, including potential prevention of community-onset cases requiring medical intervention."

"Limiting need for medical attention not only alleviates healthcare resource strains but reduces potential for antibiotic exposure, which may help mitigate increasing global threats of antimicrobial resistance," they wrote.

However, in an , Ed Kuijper, MD, PhD, of Leiden University Medical Center in the Netherlands, and Dale Gerding, MD, of the Edward Hines, Jr. Veterans Affairs Hospital in Hines, Illinois, commented that "these results add to a recent disappointing report of another phase III multicenter randomized, controlled trial with toxoid A and B vaccine."

They were referring to the , which found another bivalent toxoid vaccine did not prevent C. difficile infection. Clinical development of that vaccine candidate was subsequently stopped.

"Vaccine antigens to protect against CDI can target toxins or surface proteins, and immunization can be performed by parenteral or mucosal routes," the editorialists wrote. "The disappointing results of parenterally administered toxoid vaccines open the way for new approaches with both toxin and non-toxin C. difficile antigens administered by the oral route."

They pointed to the oral cholera vaccine (Vaxchora) and oral vaccine candidates against enterotoxigenic Escherichia coli that appear to induce protective immunity at the intestinal mucosal surface, rather than by the production of serum antibodies alone.

The global, multicenter CLOVER trial enrolled 17,535 participants randomized to receive either the PF-06425090 vaccine or placebo. To be included in the trial, participants had to be 50 years or older and at increased risk for C. difficile infection. Criteria for increased risk included living in a nursing home or skilled nursing facility, having one or more inpatient hospitalizations for more than 2 nights over the previous year or scheduled at least 37 days after randomization, two or more emergency department visits or at least 10 outpatient visits in the previous year, and recent systemic antibiotic receipt.

Among both the vaccine and placebo groups, about 90% received the full three-dose series. Approximately 63% completed the study and the mean follow-up duration after the first dose was about 38 months in both groups. The majority of participants were white, 65% were from North America, and just over half were female. At randomization, the mean age was 68 years. Cases of C. difficile infection were confirmed by laboratory testing from self-collected stool samples.

The vaccine was found to be safe and well-tolerated. Injection-site pain and fatigue were the most common reactions for both the vaccine and placebo groups. About 5% or fewer participants reported severe reactogenicity and 0.2% or fewer reported grade 4 events. Serious adverse events leading to death were similar between the two groups, at 2.4% in the vaccine group and 2.2% in the placebo group. No deaths were associated with the vaccine.

The authors acknowledged several limitations of the study. The trial did not distinguish between community- and healthcare-acquired C. difficile infection. Because participants collected their own stool samples, they may not have accurately assessed stool characteristics and they may not have sent in samples if infections were mild and self-limiting. Part of the trial was conducted during the COVID-19 pandemic, which may have affected trial activities.

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