Grade 3 injection site redness led to the predefined stopping rules for 10 patients in the clinical trials.
While resulting in an immune response, safety concerns has led to the premature stop of a pair of vaccine trials for Clostridioides difficile infection (CDI).
A team, led by Jody Lawrence, MD, Pfizer Vaccine Clinical Research & Development, tested the safety and efficacy of 2 differently formulated investigational bivalent C difficile vaccine candidates comprised of QS-21 adjuvanted toxoid and toxoid-alone for adult patients between 50-85 years.
In the first randomized study, there was a 3:1 ratio of patients receiving the QS-21 adjuvanted toxoid vaccine to 100 μg QS-21–containing C difficile vaccine or placebo. Each vaccine was administered in a shortened-month (month 0, 1, 3) or day (day 1, 8, 30) regimen.
The second study involved patients randomized in a 3:3:1 ratio to receive either 100 or 200 μg unadjuvanted C difficile vaccine formulation or placebo in Stages 1 and 2 (sentinel cohorts of different age groups), and 3:1 to receive the selected dose of unadjuvanted C difficile vaccine formulation or placebo in Stage 3 (days 1, 8, 30).
The investigators sought primary outcomes of safety for both study.
They also determined immunogenicity by measuring serum toxin A—and B—specific neutralizing antibodies.
For the day regimen, grade 3 injection site redness following the second dose triggered the predefined stopping rules for 10 patients. The local reactions more common in both studies in the vaccine recipients than they were for patients who received the placebo and injection site pain predominated and was generally only mild in severity.
In the QS-21 study, adverse events were reported by 50-75% of the patients. This was significantly higher than the toxoid-alone study, where adverse events were reported in 16.7-50.0% of patients.
In addition, the investigators found immune responses generally peaked around day 37 in the shortened-month regimen or between day 15 and month 2 in the day regimen. The immune response remained above baseline throughout the follow-up period.
“Both formulations demonstrated robust immunogenicity,” the authors wrote. “Both studies stopped early due to grade 3 injection site redness postdose 2 of the day regimen; neither formulation progressed to later stage development.”
However, there is a C difficile vaccine candidate that did make it to later phase clinical trials.
“Instead, an aluminum hydroxide-containing formulation of the vaccine candidate administered at 0, 1, and 6 months, which was safe and immunogenic in phase 1 and 2 studies, advanced to phase 3 studies,” the authors wrote.
There currently is not a C difficile available in the US approved by the US Food and Drug Administration (FDA).
Last year, a team, led by Guy de Bruyn, MD, Sanofi Pasteur, evaluated the efficacy, immunogenicity, and safety of a toxoid vaccine candidate in a study that was ultimately terminated following the first planned interim analysis due to futility.
In the C. diff vaccine group, there were 34 infections reported over 11,697.2 person years at risk (0.29 infections per 100 person-years; 95% CI, 0.20–0.41) compared with 16 infections over 5789.4 person-years at risk in the placebo group (0.28 infections per 100 person-years; 95% CI, 0.16–0.45).
This indicates the vaccine’s efficacy is -5.2% (95% CI, -104.1-43.5).
The study, “Safety and immunogenicity of different Clostridioides (Clostridium) difficile vaccine formulations in two early phase randomized studies of healthy adults aged 50–85 years,” was published online in Vaccine.