By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Synopsis: A Phase III randomized clinical trial on adults 50 years of age and older found that a detoxified toxin A/B vaccine failed to reach its primary endpoint of preventing Clostridioides difficile infection. The vaccine was safe and well tolerated.
Source: Donskey CJ, Dubberke ER, Klein NP, et al. 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. Clin Infect Dis 2024;79:1503-1511.
Clostridioides difficile infection (CDI) is associated with significant morbidity, mortality, and cost to the healthcare system, making its prevention an important public health goal. The Centers for Disease Control and Prevention (CDC) has classified CDI as an urgent threat and recommended multiple strategies to mitigate CDI-associated healthcare burden, including vaccine development. PF-06425090 is a genetically detoxified C. difficile toxin vaccine formulated with toxin A and B. Phase I and II studies indicated that the vaccine was well tolerated and generated robust toxin A and B neutralizing antibodies in participants 50 to 85 years of age. In 2014, the U.S. Food and Drug Administration (FDA) fast tracked development of the vaccine based on Phase II data. Donskey and colleagues sought to determine whether the vaccine would prevent CDI in older patients at increased risk for primary CDI.
The study was a global Phase III randomized, placebo-controlled trial conducted at 382 sites in 23 countries between March 2017 and December 2021. Subjects were randomized 1:1 to receive either 0.5 mL of vaccine or 0.5 mL of saline placebo in the deltoid at 0, one, and six months. The staff who administered the vaccine were not blinded, but other personnel and the subjects were blinded. Subjects received stool sample collection kits and were instructed to collect a stool sample whenever they developed three or more unformed stools in a 24-hour period, regardless of whether they sought medical attention.
Subjects were included who were at least 50 years of age and considered to be at high risk of acquiring CDI. High risk was defined as nursing home or skilled nursing facility residency, having one or more inpatient hospitalizations in the preceding 12 months, two or more emergency department visits or 10 or more outpatient visits in the preceding 12 months, and systemic antibiotic receipt in the preceding 12 weeks. Subjects were excluded who had one or more confirmed prior episodes of CDI, prior C. difficile vaccination or monoclonal antibody therapy, known human immunodeficiency virus (HIV) infection, frequent noninfectious diarrhea, or inability to respond to vaccination, such as those taking chronic immunosuppression.
The primary objective of the study was to show that the vaccine prevented the first occurrence of CDI. The primary endpoints were first CDI episode incidence 14 days or more after dose 3 and 14 days or more after dose 2. The secondary endpoints were time to diarrhea resolution and proportion of subjects with primary CDI who required medical attention after dose 3. The safety objectives were to measure reactogenicity and adverse event rates.
There were 17,535 subjects in the study, of whom 8,766 were randomized to receive vaccine and 8,769 were randomized to receive placebo, with 5,533 and 5,574 subjects completing the study, respectively. The mean age was 68 years, 79% of the participants were white, 51% were female, and 65% were from North America. Most of the stool samples were collected at home.
Among the subjects who received all three doses, 17 vaccine recipients and 25 placebo recipients developed a first episode of CDI 14 days or more after the third dose, leading to a vaccine efficacy of 31% (96.4% confidence interval [CI], -38.7% to 66.6%). Thus, the primary efficacy endpoint was not met. In the population that only received two doses of vaccine, the vaccine efficacy was 28.6% (96.4% CI, -28.4% to 61%). The median duration of CDI symptoms was lower in vaccine group (one day) compared to the placebo group (four days; P = 0.02). Furthermore, in the subjects with CDI, none in the vaccine group compared to 11 in the placebo group sought medical attention, and zero in the vaccine group compared to 10 placebo recipients required antibiotic treatment.
Adverse events were similar between the groups (52.1% for vaccine vs. 51.0% for placebo). Most of the adverse events were classified as mild to moderate. The most common local reaction was injection-site pain, and the most common systemic reaction was fatigue. Significant adverse events occurred in 14.9% of vaccine recipients and in 14.5% of placebo recipients. Death occurred in 2.4% of those who received the vaccine and in 2.2% in the placebo group.
Commentary
This was a global clinical trial that included a large number of subjects. The primary endpoint was not met because the vaccine efficacy of 31% did not meet the predetermined success criterion of a two-sided lower bound 96.4% CI of < 20%. While this is disappointing, the vaccine did reduce median time to CDI resolution by 75% and the need for both CDI-related medical attention and anti-C. difficile antibiotic treatment.
An interesting question arises from these results: Why does bezlotoxumab, a systemically administered anti-toxin B monoclonal antibody, prevent CDI recurrence but the anti-toxin A and B vaccine did not prevent primary CDI? A possible explanation is that bezlotoxumab is coadministered with antibiotic therapy while the toxin inflammatory response still is active, thereby allowing the antibody to enter the intestinal lumen. This pathophysiology would not be present in healthy, uninfected individuals.
Parenteral C. difficile toxin vaccines do not prevent colonization and shedding of the bacteria into the environment. Now that there is evidence they do not prevent primary CDI infection either, the research paradigm likely will shift toward oral mucosa vaccines that prevent colonization and symptomatic CDI. It is hoped that the results of the current study will help facilitate the development of new approaches for preventing C. difficile colonization and CDI.
Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC, is Professor of Medicine, Division of Infectious Diseases, Northeast Ohio Medical University, Rootstown, OH.
A Phase III randomized clinical trial on adults 50 years of age and older found that a detoxified toxin A/B vaccine failed to reach its primary endpoint of preventing Clostridioides difficile infection. The vaccine was safe and well tolerated.
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