Experimental Staph Vaccine Linked to Multiorgan Failure and Death / Medscape
Posted Oct 24 2012 7:30pm
Merck's new vaccine candidate, V710, was designed to prevent post-op staph infections, a frequent and potentially devastating complication that occurs after many types of surgery. However, in a large clinical trial that studied over 3500 patients, not only did the vaccine fail to provide this protection, but there were many initial adverse reactions, and recipients who got staph infections were 5 times as likely to get multi-organ failure and die of the infection as those who did not get vaccinated. From Medscape , which reported on the October 20 conference presentation at the IDWeek 2012 conference:
SAN DIEGO, California — A trial of an experimental vaccine against Staphylococcus aureus to prevent bacteremia and wound infections after surgery has produced disappointing results, despite eliciting a robust immunologic response.
Vance Fowler Jr., MD, MHS, professor of medicine in the division of infectious diseases at the Duke University Medical Center in Durham, North Carolina, presented results from the trial of V710 vaccine (Merck) in a late-breaker session here at the ID Week 2012.
The vaccine induced opsonophagocytic antibodies when administered ahead of cardiothoracic surgery, but it did not reduce the incidence of S aureus bloodstream or deep sternal wound infections after surgery. Even worse, postoperative multiorgan failure and mortality were more common in the patients who received the V710 vaccine than in those who received placebo.
V710, which has been shown to be protective in animal models and was well tolerated and immunogenic in phase 1 studies, is directed against the S aureus iron surface determinant B antigen. This antigen is expressed and highly conserved in all S aureus strains tested, and is immunogenic during acute infections. A phase 2 study of patients with end-stage renal disease on hemodialysis showed V710 to be immunogenic, safe, and well tolerated.
In their randomized, multicenter, double-blind, group-sequential efficacy study, known as V710-003, Dr. Fowler and colleagues compared a single dose of V710 60 μg in adults scheduled for cardiothoracic surgery with placebo. Participants were randomized and vaccinated on day 1 and underwent surgery 14 to 60 days later. The prespecified criterion for success was an efficacy rate of greater than 20%.
The vaccine and placebo groups were well matched for demographic characteristics such as age (median, 65 to 66 years), sex (67% male), nasal colonization with S aureus (18%), and positivity for methicillin-resistant S aureus (MRSA) (2%). Surgery occurred a median of 24 days after vaccination in each group.
Of the 4005 patients randomized to each group, approximately 3520 were included in the primary efficacy analysis and approximately 2575 completed the postoperative day 360 safety follow-up period. Most exclusions from the original randomized population were because the study was terminated early by the sponsor.
V710 Failed to Protect Against Bacteremia or Wound Infections
During the study period, 49 patients developed S aureus bacteremia or deep sternal wound infection (the primary end points): 22 (0.6%) in the V710 group and 27 (0.8%) in the placebo group, Dr. Fowler reported.
The efficacy rate of 18.5% means that the vaccine "failed to meet prespecified criteria for success" (95% confidence interval [CI], –48.6 to 55.8; P = .584). Forty percent of the infections were caused by MRSA. The vaccine appeared to be more effective against infections caused by methicillin-sensitiveS aureus, but even there it failed to meet the criterion for success.
These findings occurred despite robust immune responses to the vaccine. Antibody responses were similar in V710 recipients who developed S aureus infection and in those who did not. "These results suggest that lack of efficacy of V710 was not due to a failure to mount antibody titers," Dr. Fowler said.
Higher Rate of Multiorgan Failure With V710
In the 2-week period after vaccination, V710 recipients experienced significantly more injection-site and systemic adverse events than placebo recipients, but there were no differences in serious adverse events (SAEs) or mortality. By day 360, rates of SAEs, SAEs involving a diagnosis ofS aureus, and death were similar in the 2 groups. However, multiorgan failure was significantly more common in the V710 group than in the placebo group (0.9 vs 0.5/100 person-years; P = .042).
The Data Safety and Monitoring Board recommended terminating the study because of the incidence of multiorgan failure, the numerically higher mortality rate in V710 recipients, and the low efficacy rate of the vaccine. Among patients who developed S aureus infection, those in the V710 group were approximately 5 times more likely to die, and die of multiorgan system failure, than those in the placebo group, Dr. Fowler reported. He explained that the biologic basis for this association has not been established...