California Researchers Solve Staphylococcal Mystery

Researchers at the University of California – San Diego have discovered the mechanism by which Staphylococcus aureus has repeatedly evaded vaccines that worked well in animal models.

While the bacterium is common and normally harmless—coexisting with humans without causing harm—it occasionally can become an opportunistic pathogen, causing skin and bloodstream infections or food poisoning. For more than a century, scientists have searched for an effective vaccine, including at least 15 successful preclinical studies using animal models in the past 30 years. In all of the subsequent human trials, however, these vaccine candidates failed.

“It’s a longstanding and one of the most enigmatic issues of the staphylococcal field,” said George Liu, MD, PhD, professor of pediatrics at University of California San Diego School of Medicine and chief of the Division of Infectious Diseases at Rady Children’s Hospital-San Diego. “None of these human trials have worked and scientists have struggled to find a reason.”

The question has gained greater urgency with the spread of methicillin-resistant S. aureus (MRSA), a type of staph bacteria that has become increasingly resistant to antibiotics commonly used to treat ordinary staph infections. MRSA is the primary source of infections acquired within hospitals and other health care settings, such as nursing homes. A study published in 2022 estimated that bacterial antimicrobial resistance resulted tens of millions of infections and 1.2 million deaths worldwide in 2019, with MRSA as the primary driver.

“Vaccines are the most effective way to cut down that health burden and reduce antibiotic resistance,” adds Liu, pointing to successes with childhood inoculations and the more recent COVID-19 vaccines.

In a new paper, publishing recently in the journal Cell Host & Microbe, Liu and colleagues say they may have found the answer to S. aureus evasive abilities.  Fundamentally, the difference lies in prior exposure to the pathogen. Laboratory mice used in research are engineered (bred/raised/maintained) to be free of the specific target pathogen; they have had little or no exposure to S. aureus prior to vaccination.

Humans, by contrast, are very quickly exposed to S. aureus after birth. Within two months, half of babies host active colonies and abundant antibodies to fend off most infections.

Liu and colleagues hypothesized that while laboratory mice with no previous exposure to S. aureus respond well to potential vaccines because they are entirely new, human versions do not work because S. aureus has evolved defenses to fend off therapeutic attack.

“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,” says Chih-Ming Tsai, PhD, a project scientist in Liu’s lab. “If mice had staph infections before vaccination, we think that the vaccine candidates might not work.”

To test their hypothesis, the authors conducted a series of experiments simulating one of the largest failed staph vaccine trials in humans, which targeted the IsdB protein used by S. aureus to acquire needed iron for functioning.

In mice unexposed to normal staph, the IsdB vaccine worked, generating antibodies that targeted the whole protein and disrupted bacterial functions. But in mice previously exposed to staph, the vaccine generated only antibodies against the unprotected portion of the IsdB protein, leaving bacterial functioning unimpaired. Subsequent boosters primarily amplified the ineffective antibody response and, compounding the problem, the ineffective antibodies competed with any existing, protective antibodies.

When researchers tried mixing human IsdB antibodies with protective antibodies made from the vaccine, the latter stopped working. “We surmised that if we could vaccinate only against the protective component of IsdB, we might be able to prevent suppression by bad immune response memory,” said Tsai.

This, in fact, turned out to be the case. When they vaccinated mice solely against the protective component of the IsdB protein, the animals were effectively protected, even if previously exposed to S. aureus.

Liu said the findings suggest that faulty memory of a pathogen and its corresponding immune response are likely explanations for the failed staph vaccine trials in humans. “It is even possible that the same principle might also explain why many other hard-to-make vaccines have failed,” he said. “If we are proven correct, an effective staph vaccine may not be too far away.”