S aureus Vaccine for Heart Surgery Appears Harmful

Ricki Lewis, PhD

April 02, 2013

A vaccine to prevent postoperative infection with Staphylococcus aureus in patients undergoing cardiothoracic surgery is associated with an overall lack of efficacy and a higher mortality rate among patients who become infected, according to a study published in the April 3 issue of JAMA.

Case-fatality ratios approach 50% in patients with S aureus infection after bypass surgery or valve replacement. A candidate vaccine from Merck, V710, appears safe and evoked an antibody response in healthy volunteers but is neither efficacious nor safe in surgical patients who become infected.

Vance G. Fowler Jr, MD, MHS, from Duke University Medical Center, Durham, North Carolina, and colleagues conducted a multicenter, 4-year, primary modified intention-to-treat randomized phase 2b/3 clinical trial evaluating a single intramuscular injection of vaccine. The investigators randomly assigned 4015 patients to receive the vaccine within 14 to 60 days of cardiothoracic surgery and 4016 to receive a placebo. The vaccine is based on the 0657nI iron surface determinant B.

The primary endpoint was bacteremia and/or deep sternal wound infection during 90 days postoperation. The secondary endpoint was all invasive and surgical site S aureus infections through 90 days postoperation.

The vaccine elicited antibodies but was not significantly more effective in preventing infection than placebo (22/3528 for recipients included in the analysis vs 27/3517 for control patients) at any time during the trial.

Adverse events occurred in 30.8% (95% confidence interval [CI], 29.4% - 32.3%) of the experimental group in the 2-week postvaccination period compared with 21.8% (95% CI, 20.6% - 23.1%) of the control patients. However, 31 cases of multiorgan failure occurred among the vaccinated patients compared with 17 among the control patients. Among all cases of S aureus infection, the 5 deaths attributed to multiorgan failure were all in vaccine recipients.

Stratifying participants by those who became infected revealed a possible exacerbating association to the vaccine, although the researchers caution that this is not causal evidence. Fifteen (23.0%; 95% CI, 12.9% - 37.9%) of 73 vaccinated patients who had any level of S aureus infection died compared with 4 (4.2%; 95% CI, 1.2% - 10.8%) of 96 infected control patients.

In noncorrected follow-up analysis, the investigators found greater efficacy against methicillin-sensitive compared with methicillin-resistant strains, in superficial vs deep surgical site infections, and in patients who already had nasal S aureus colonization vs those who did not.

The data safety monitory board recommended closing the study after the second interim analysis. "These findings do not support the use of the V710 vaccine for patients undergoing surgical interventions," the researchers concur.

The researchers cite other vaccines that seemed to have made matters worse (influenza, respiratory syncytial virus, and dengue) and hypothesize that humoral immunity may be insufficient to prevent S aureus infection postoperatively.

In an accompanying editorial, Preeti N. Malani, MD, MSJ, from the Divisions of Infectious Diseases and Geriatric and Palliative Medicine, Department of Internal Medicine, University of Michigan Health System, Veterans Affairs, Ann Arbor Healthcare System, Geriatric Research Education and Clinical Center, Ann Arbor, Michigan, discusses the compelling need for the study. "Given the enormous adverse consequences of infectious complications on surgical outcomes, prevention efforts grounded in the best evidence remain essential," she writes.

Dr. Malani emphasizes that the negative effects on infected patients are more important than the overall lack of efficacy. "This evidence of probable harm coupled with poor efficacy data prompted early termination of the study," she writes.

Dr. Fowler previously presented the results of the study at ID Week 2012.

The study was sponsored and funded by Merck Sharp & Dohme Corp, which employs 9 of the 18 authors. Dr. Fowler and several coauthors have consulted for many pharmaceutical companies. Dr. Malani has disclosed no relevant financial relationships.

JAMA. 2013;309:1368-1378, 1408-1409.

processing....