Effect of an Investigational Vaccine for Preventing Staphylococcus aureus Infections After Cardiothoracic Surgery: A Randomized Trial
What is the efficacy and safety of preoperative vaccination in preventing serious postoperative Staphylococcus aureus infection in patients undergoing cardiothoracic surgery?
This was a double-blind, randomized, event-driven trial conducted between December 2007 and August 2011, among 8,031 patients ages 18 years or older, who were scheduled for full median sternotomy within 14-60 days of vaccination at 165 sites in 26 countries. Participants were randomly assigned to receive a single 0.5-ml intramuscular injection of either V710 vaccine, 60 μg (n = 4,015), or placebo (n = 4,016). The primary efficacy endpoint was prevention of S aureus bacteremia and/or deep sternal wound infection (including mediastinitis) through postoperative day 90. Secondary endpoints included all S aureus surgical site and invasive infections through postoperative day 90. Three interim analyses with futility assessments were planned.
The independent data monitoring committee recommended termination of the study after the second interim analysis because of safety concerns and low efficacy. At the end of the study, the V710 vaccine was not significantly more efficacious than placebo in preventing either the primary endpoints (22/3,528 V710 vaccine recipients [2.6 per 100 person-years] vs. 27/3,517 placebo recipients [3.2 per 100 person-years]; relative risk, 0.81; 95% confidence interval [CI], 0.44-1.48; p = 0.58) or secondary endpoints despite eliciting robust antibody responses. Compared with placebo, the V710 vaccine was associated with more adverse experiences during the first 14 days after vaccination (1,219/3,958 vaccine recipients [30.8%; 95% CI, 29.4%-32.3%] and 866/3,967 placebo recipients [21.8%; 95% CI, 20.6%-23.1%], including 797 [20.1%; 95% CI, 18.9%-21.4%] and 378 [9.5%; 95% CI, 8.6%-10.5%] with injection site reactions and 66 [1.7%; 95% CI, 1.3%-2.1%] and 51 [1.3%; 95% CI, 1.0%-1.7%] with serious adverse events, respectively) and a significantly higher rate of multiorgan failure during the entire study (31 vs. 17 events; 0.9 [95% CI, 0.6-1.2] vs. 0.5 [95% CI, 0.3-0.8] events per 100 person-years; p = 0.04). Although the overall incidence of vaccine-related serious adverse events (one in each group) and the all-cause mortality rate (201/3,958 vs. 177/3,967; 5.7 [95% CI, 4.9-6.5] vs. 5.0 [95% CI, 4.3-5.7] deaths per 100 person-years; p = 0.20) were not statistically different between groups, the mortality rate in patients with staphylococcal infections was significantly higher among V710 vaccine than placebo recipients (15/73 vs. 4/96; 23.0 [95% CI, 12.9-37.9] vs. 4.2 [95% CI, 1.2-10.8] per 100 person-years; difference, 18.8 [95% CI, 8.0-34.1] per 100 person-years).
The authors concluded that among patients undergoing cardiothoracic surgery with median sternotomy, the use of a vaccine against S aureus compared with placebo did not reduce the rate of serious postoperative S aureus infections.
In this study of adult patients undergoing cardiothoracic surgery, preoperative vaccination with V710 did not significantly reduce the composite incidence of S aureus bacteremia and deep sternal wound infection. Furthermore, S aureus–infected V710 vaccine recipients were significantly more likely to die postoperatively than S aureus–infected placebo recipients. The study findings do not support the use of the V710 vaccine for patients undergoing surgical interventions, and may be potentially harmful.
Keywords: Risk, Sternotomy, Bacteremia, Mediastinitis, Clinical Trials Data Monitoring Committees, Wound Infection, Staphylococcal Vaccines, Staphylococcus aureus, Mupirocin, Postoperative Period, Sternum, Staphylococcal Infections, Perioperative Care, Injections, Intramuscular, Cardiovascular Diseases, Medical Futility, Confidence Intervals, Vaccination
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