Reasons Behind Failed Staph Vaccine Trials Proposed

U.S. researchers have discovered why potential vaccines against Staphylococcus aureus have failed in clinical trials despite showing promise in laboratory studies.

The team reports in Cell Host and Microbe that prior exposure to the bacterium appeared to be key in determining whether vaccine candidates could work.

Specifically, prior staph exposure seemed to pre-program the host immune system to respond poorly to vaccines, with antibody competition further reducing their efficacy.

The early positive vaccine studies used laboratory mice with little or no contact with S. aureus, hence their success. In contrast, humans are exposed to the bacterium early on, with half of all babies hosting colonies within their first two months of life.

“Staph vaccines appear so easy to make in laboratory mice because they rarely see S. aureus, but humans are exposed to staph beginning in the first weeks of life and, in order to coexist, staph appears to have developed many strategies to render ineffective our immune response against them,” explained researcher Chih-Ming Tsai, a project scientist at the University of California at San Diego.

“If mice had staph infections before vaccination, we think that the vaccine candidates might not work.”

The findings might explain why trials of vaccines against other pathogens have failed and could also pave the way to an effective S. aureus vaccine.

In a series of experiments in mice, the researchers simulated one of the most notable failed staph vaccine trials that targeted the iron-regulated surface determinant protein B (IsdB), which is used by the bacterium to acquire iron from its host.

They found that the IsdB vaccine worked in mice that had not been exposed to normal S. aureus and generated antibodies that targeted the whole protein and disrupted the function of the bacterium.

But in staph-exposed mice, the vaccine generated solely antibodies against the unprotected portion of the IsdB protein and did not impact on bacterial function.

Prior exposure to S. aureus exposure made the otherwise protective IsdB vaccine non-protective, the study showed.

And any boosters that followed mostly amplified the ineffective antibody response, with further issues caused by ineffective antibodies competed with pre-existing, protective ones.

When the researchers tried mixing human IsdB antibodies with protective antibodies made from the vaccine, they found that latter stopped working.

However, when they vaccinated mice only against the protective component of the IsdB protein, even previously exposed animals were protected against S. aureus.

Senior researcher George Liu, a professor of pediatrics who runs his own UCSD lab, said failed staph human vaccine trials were likely due faulty memory of a pathogen and the corresponding immune response.

“It is even possible that the same principle might also explain why many other hard-to-make vaccines have failed,” he conjectured. “If we are proven correct, an effective staph vaccine may not be too far away.”