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Positive Mid-Stage Data Reported for Investigational Clostridium difficile Vaccine

Candidate vaccine generates immune response against C. difficile toxins A and B

Promising phase II results have been reported for an investigational vaccine for the prevention of Clostridium difficile infection (CDI) at the 114th general meeting of the American Society for Microbiology (ASM), being held May 17–20 in Boston. The vaccine was developed by Sanofi Pasteur.

The study met its primary objectives; reactions were generally mild and of short duration; and the candidate vaccine generated an immune response against C. difficile toxins A and B. These toxins are largely responsible for CDI, which can cause potentially life-threatening gut inflammation and diarrhea.

Based on these mid-stage results, a high-dose plus adjuvant vaccine formulation administered on days 0 (baseline), 7, and 30 was selected for further evaluation in a global efficacy program, Cdiffense. This ongoing phase III trial began in August 2013 with plans to include up to 200 sites in 17 countries.

The phase II vaccine study was a randomized trial divided into two stages. The first stage, conducted in 455 volunteers, was placebo-controlled, double-blind, and designed for dose and formulation selection. The second stage, which included 206 additional volunteers, was designed to compare the dose and formulation chosen in the first stage with two alternate dosing schedules. Participants in the study were adults (40 to 75 years of age) who were at risk of CDI because of impending hospitalization or residence in a long-term health care facility.

In stage 1 of this trial, the volunteers were randomly assigned to one of five study groups: high-dose or low-dose vaccine either with or without adjuvant, or placebo. Each formulation was administered on days 0, 7, and 30. Immune responses were measured using both the Enzyme-Linked Immunosorbent Assay (ELISA), which assesses anti-toxin A and B immunoglobulin G (IgG) concentrations, and Toxin Neutralization Activity (TNA), which measures anti-toxin A and B neutralizing activity. A composite ELISA ranking analysis determined that the group given the high-dose plus adjuvant vaccine formulation generated the greatest immune response over a 60-day period. ELISA results also showed four-fold increases in the development of detectable antibodies for both toxins A and B.

The high-dose plus adjuvant vaccine formulation was then selected for further study in stage 2 of the trial, which compared use of the vaccine across three schedules: days 0, 7 and 30 (group 3, n = 101); days 0, 7, and 180 (group 6, n = 103); and days 0, 30, and 180 (group 7, n = 102). Analyses were conducted on days 0, 7, 14, 30, 60, 180, and 210.

Increased immune responses were observed in all vaccine groups and with each dose, according to ELISA and TNA assessments. Overall, group 3 demonstrated the most favorable immune profile over the 30-, 60- and 180-day assessment periods, particularly in volunteers aged 65 to 75 years.

The safety profile of all of the vaccine doses was deemed acceptable throughout the phase II study. Reactions were monitored until day 210 and were found to be generally mild in severity and of short duration. Moreover, vaccine reactions did not lead to study discontinuations and were not considered clinically significant.

C. difficile is a potentially life-threatening, spore-forming bacterium that causes intestinal disease. Despite improvements in reducing some health care-associated infections, C. difficile remains at historically high levels. The risk of contracting CDI increases with age, antibiotic treatment, and the time spent in hospitals or nursing homes, where multiple cases can lead to outbreaks. A main source of C. difficile bacteria is infected patients, who release spores into the environment that can infect other patients.

When antibiotics disrupt the gut’s normal flora and a patient has ingested C. difficile spores, the C. difficile bacteria multiply and release potent toxins that can damage a patient’s intestinal lining and cause CDI. Symptoms of CDI range from fever to diarrhea and often include dehydration, nausea, and abdominal pain. Complications include perforation of the colon, sepsis, life-threatening pseudomembranous colitis, and toxic megacolon, a lethal condition.

Data indicate that CDI may have resulted in up to $4.8 billion in excess costs in acute-care facilities in the U.S. in 2008. In 2009, U.S. hospital stays in which CDI was a principal diagnosis averaged 6.9 days and $10,100 in costs. When CDI was a complicating factor in already-complex principal diagnoses (such as septicemia, pneumonia, congestive heart failure, and renal failure), hospital stays more than doubled and costs more than tripled (16 days and $31,500, respectively).

Source: PR Newswire; May 19, 2014.

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