C difficile Vaccine: CLOVER Trial Shows Mixed Results

There's mixed news from Pfizer on results from their CLOVER trial (CLOstridium difficile Vaccine Efficacy TRial), a phase 3 study involving 17,500 adults aged 50 and older that evaluated their candidate vaccine (PF-06425090) against Clostridioides difficile (C diff) for the prevention of C diff infection (CDI).

The bad news is that the trial didn't meet its efficacy endpoint — the prevention of primary CDI. According to a Pfizer press release, "Vaccine efficacy under the primary endpoint was 31% (96.4% CI -38.7, 66.6) following the third dose and 28.6% (96.4% CI -28.4, 61.0) following the second dose. For all CDI cases recorded at 14 days post dose 3, vaccine efficacy was 49%, 47% and 31% up to 12 months, 24 months and at final analysis, respectively."

(Medscape Medical News requested an interview with a Pfizer spokesperson, but the company declined to comment further.)

The good news is that the vaccine did meet its secondary endpoint. There were no cases of CDI requiring medical attention among vaccine recipients; by comparison, there were 11 cases among those who received placebo.

The Centers for Disease Control and Prevention classifies C diff with other antimicrobial resistance "threat" organisms, as the two often go hand in hand. Their 2019 report noted that in 2017, 223,900 people in the US required hospitalization for CDI, and at least 12,800 died. C diff is the most common cause of healthcare-associated infection and increasingly occurs outside of acute care hospitals. Age older than 65 is a risk factor for disease. And at least 20% of patients experience recurrence.

The trial enrolled people older than 50 who were at higher risk of CDI because of having received antibiotics within the previous 12 weeks or because they were likely to have contact with healthcare systems. They received three doses of an investigational vaccine containing detoxified toxins A and B. These are the principal virulence factors produced by C diff. Doses were given at 0, 1, and 6 months.

Dr David Aronoff

Medscape Medical News asked C diff specialist David Aronoff, MD, chair of the Department of Medicine at Indiana University, for comment. Aronoff was not involved in the Pfizer clinical trials. He told Medscape Medical News via email,"Given the very low number of cases, I am impressed, from the limited data that have been made available, that the vaccine appears to have efficacy of around 50% for reducing CDI and, importantly, might reduce the severity of disease significantly, possibly preventing hospitalizations or worse clinical outcomes. It is unclear if the vaccine reduces the risk of recurrent CDI, but that would be a strong finding if true. I think we need to see these data after being subject to peer review, to better define its potential role in preventing CDI on a larger scale."

Asked about the numbers needed to treat and cost-effectiveness of treatment, Aronoff added, "It is not clear how many people would need to receive the vaccine to prevent one hospitalization from CDI, or one death, or one case. Because the study groups had fewer episodes of CDI than anticipated, it watered down the power of this investigation to provide definitive answers regarding its true efficacy."

Aronoff concluded, "All things considered, I am a cup half-full type of person on these topline results, since there are indications of reducing disease incidence and severity. We can build on these results."

Aronoff had a basic science C diff research grant from Pfizer in 2018–2019 that was not related to vaccines or therapeutics.

Judy Stone, MD, is an infectious disease specialist and author of Resilience: One Family's Story of Hope and Triumph Over Evil and of Conducting Clinical Research, the essential guide to the topic. You can find her at drjudystone.com or on Twitter @drjudystone.

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