This article is more than 5 years old. Information may no longer be current.
S. aureus vaccine increased infection-related mortality in surgical patients
Click Here to Manage Email Alerts
An investigational vaccine to prevent Staphylococcus aureus did not reduce the incidence of postoperative S. aureus infections after cardiothoracic surgery and was associated with increased mortality among those who developed infections, according to recent study results.
“To say these results were surprising is an understatement — these results blindsided us,” Vance Fowler, MD, professor at Duke University, told Infectious Disease News. “These data speak most directly to investigators that continue the critical work of developing a much-needed S. aureus vaccine. On the preclinical end, consider efficacy studies in at least one non-murine model system. Once things advance to clinical trials, keep a close eye on possible safety signals.”
Vance Fowler
Participants in the trial were randomly assigned to V710 vaccine (Merck) or placebo, given as a single 0.5-mL intramuscular injection. The study took place from December 2007 to August 2011 and included 8,031 patients who were scheduled for a full median sternotomy within 14 to 60 days after vaccination.
After the second interim analysis on April 8, 2011, the data monitoring committee recommended enrollment suspension due to concerns of higher mortality rates associated with the vaccine. On June 22, 2011, the committee recommended the study be permanently closed.
In the modified intention-to-treat analysis, the vaccine was not more efficacious at preventing S. aureus bacteremia or deep sternal wound infections compared with placebo. The rate of infection was 2.6 per 100 person-years for the vaccine vs. 3.2 per 100 person-years for placebo (RR=0.81; 95% CI, 0.44-1.48). This was despite an increase in immunogenicity immediately after vaccination.
There were more adverse events within 14 days of vaccination among those who received the vaccine: 30.8% of vaccine recipients experienced reactions, vs. 21.8% of those who received placebo. The most common reaction was an injection-site reaction. Patients who received the vaccine also had a higher rate of multi-organ failure during the study, with a rate of 0.9 events per 100 person-years compared with 0.5 events per 100 person-years for placebo.
Among those who developed S. aureus infections, the mortality rate was higher among those who had received the vaccine: 23 per 100 person-years vs. 4.2 per 100 person-years for placebo.
“This study raised huge questions, the biggest of which is why vaccinated patients who were infected with S. aureus were more likely to die than placebo recipients who developed S. aureus infections,” Fowler said. “If this finding is accurate, and the degree of difference between the two groups suggests to me that it is, then it implies that we still have huge gaps in our understanding of how we recognize and respond to S. aureus.”
In an accompanying editorial, Preeti N. Malani, MD, of the University of Michigan Health System, wrote that the prevention of S. aureus infections should remain a priority, but novel approaches must go beyond vaccines and beyond S. aureus.
“Even if a viable staphylococcal vaccine were to be developed, this would not address non-S. aureus infections,” Malani wrote. “Burgeoning antimicrobial resistance results in an urgent, worldwide public health mandate. Progress in this arena will require expansion of preventive efforts and interventions that cover all organisms.”
For more information:
Fowler V. JAMA. 2013;309:1368-1378.
Malani P. JAMA. 2013;309:1408-1409.
Disclosure: Fowler reports financial relationships with Achaogen, Advanced Liquid Logics, Affinium, Cerexa, Cubist, Durata, Galderma, Medicines Co., MedImmune, Merck, NCGR, Novadigm, Novartis, Pfizer, Theravance and UpToDate. Malani reports no relevant financial disclosures.
Perspective
Back to Top
Trish M. Perl, MD, Msc
This is the second Staphylococcus aureus vaccine for which the clinical trial data were not as promising as the preliminary data had suggested. It’s discouraging because an S. aureus vaccine would be a very exciting thing to add to our armamentarium to prevent infections. What’s interesting about this trial and the previous trial is that they included patient populations that are at high-risk for complications, and thus are at a higher risk for mortality and morbidity related to infections. A lot of potential harm could be prevented if we had a vaccine for S. aureus, since it is the most common cause of post-operative infections. Not only would a vaccine decrease the number of infections and the associated morbidity and mortality, but it would also decrease antibiotic use, which could help alleviate the increasing antimicrobial resistance issues.
We don’t want to stop testing these compounds because if we find the right one, it could be very successful. In HIV, for example, we tested many drugs before we came across the ones that really changed lives. The fact that JAMA published this negative study is significant because it opens the door for more innovation. This was a very well-done clinical trial: It wasn’t successful, but the data are out there so that people can start having the scientific discussions we need to have to find the right components and the right population for a successful S. aureus vaccine.
Click Here to Manage Email Alerts