Staph infections pose one of the most serious microbial threats to people. Yet efforts to prevent them with vaccines have consistently failed, even as the bacterium responsible becomes increasingly resistant to antibiotics. Now, an experimental vaccine with novel ingredients has proven highly protective in rabbits against staph pneumonia, one of the most dangerous outcomes of the bacterial infection. The inventor hopes to take it into human studies soon.
Staphylococcus aureus is thought to colonize the noses of about one-third of humans at any given time, but it also causes about half a million hospitalizations and 20,000 deaths each year in the United States. Strains of the bacterium that are resistant to most antibiotics, particularly varieties dubbed MRSA (methicillin-resistant S. aureus), have become a major danger, highlighting the need for a vaccine against the microbe.
However, a series of vaccines has suffered dramatic failures in the past few years. A candidate from NABI Biopharmaceuticals of Rockville, Maryland, flopped in two trials among dialysis patients in the United States, and a Merck vaccine was abandoned in 2012 after millions of dollars were spent testing it.
Microbiologist Patrick Schlievert of the University of Iowa in Iowa City believes that pharmaceutical companies have been going about a vaccine the wrong way. Previous staph vaccines attempted to offer protection by including proteins or carbohydrates contained in the natural capsule that surrounds the staph bacterium's cell wall and enables it to elude the immune system. This approach succeeded for vaccines against other bacteria like Haemophilus influenzae type B and Streptococcus pneumoniae, but did not work with S. aureus. Other vaccines that failed included single proteins from the cell wall of the S. aureus bacterium.
In an article published online this month in The Journal of Infectious Diseases, Schlievert and colleagues took a new approach. The strategy involves an entirely different class of substances taken from the S. aureus bacterium. These included so-called superantigens and cytolysins—proteins that are produced by S. aureus's internal structures and play major roles in the illnesses caused by the bacterium. The researchers vaccinated 88 rabbits, split into several groups, with different combinations of the substances. All but two of the animals survived when S. aureus organisms were sprayed into their lungs. Of 88 unvaccinated rabbits exposed to the same bacteria, only one survived.
In another experiment, the researchers found evidence that typical vaccines may actually make those immunized more vulnerable to a staph infection. They vaccinated five rabbits with neutralized proteins from the cell surface of S. aureus—the type of substances used in most previous and current vaccine candidates. All five of those animals died within 6 hours of exposure to a common MRSA strain; in contrast, five nonvaccinated animals survived at least 4 days postexposure.
The studies' counterintuitive findings are in agreement with prior research by Schlievert indicating that cell-surface antigens, which are frequently used to create bacterial vaccines, are a poor choice for preventives aimed at S. aureus because of the organism's particular way of causing disease, he says.
“One of the ways staph works is by creating aggregations of bacteria that block blood vessels and airways,” Schlievert says. Consequently, vaccines that stimulate the creation of antibodies to cell-surface antigens may be more dangerous than no vaccine at all, he says, because in binding with those antigens, they create molecular complexes that intensify the clumping phenomenon.
Schlievert also believes that his results are more relevant to humans than other animal studies with staph vaccines. While other researchers have tested S. aureus vaccines in mice and nonhuman primates, he contends that the immune system of the rabbit is more similar to that of humans, at least when it comes to how it responds to this bacterium. Staph researchers say that Schlievert’s new study is provocative but not entirely convincing. “He shows that superantigens are more protective than surface antigens—in rabbits undergoing experimental infection,” says Robert Daum, pediatrician and microbiologist at the University of Chicago in Illinois. It remains to be seen whether the same holds true in humans, he says. “Lots of people have been using surface antigens [in vaccines] for a long time. It hasn't been a great success story, but there are few data that suggest the vaccines make it worse.”
Daum considers the suggestion that rabbits were better than mice as experimental animals to be intriguing. It is true that mice are not especially good models in S. aureus, he says, but on the other hand the rodents are inexpensive and well-studied. “If he's right that rabbits are a better model, it will roil the field, because they are much more expensive and difficult to work with. To my mind, rabbits haven't been studied enough yet to conclude that they are better.” Most of the data to this effect comes from Schlievert's group.
Daum argues that failures in previous vaccines have shown that defeating S. aureus requires more basic science before new vaccine antigens are trotted out. Too little is understood about the human immune response to S. aureus, which can cause deadly infections, yet often lives in and on us without causing disease at all. “We don't want to eliminate all staph. We want to eliminate the nasty ones that cause disease. So we need to understand the immunology, and we're not there yet,” Daum says.
Schlievert says that unpublished data from his group show that his superantigen-based vaccines also prevent skin infections in rabbits. He next plans to ask the Food and Drug Administration to allow him to conduct basic human safety studies of the vaccine.