The sometimes-pathogenic bacteria has a long and intimate relationship with humans, which aids in its resistance to our immune response.

Exemption breeds familiarity
Although Staphylococcus aureus bacteria are generally harmless, they can occasionally become an opportunistic pathogen. Attempts to develop a vaccine in the past have been futile. Credit: of the National Institute of Allergy and Infectious Diseases.

Researchers believe they have discovered why multiple human clinical trials of staphylococcus vaccines have failed: the bacteria knows too much about us.

The bacterium Staphylococcus aureus is, for the most part, common and harmless, posing no threat to humans with whom it coexists. However, it can occasionally become an opportunistic pathogen, causing skin and bloodstream infections or food poisoning.

Scientists have been looking for an effective vaccine for over a century, with at least 15 successful preclinical studies using animal models in the last 30 years. However, in all subsequent human trials, these vaccine candidates failed.

“It’s a longstanding and enigma in the staphylococcal field,” said George Liu, MD, PhD, professor of pediatrics at the 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 succeeded, and scientists have struggled to understand why.”

The question has become more pressing as methicillin-resistant S. aureus (MRSA) has spread, a type of staph bacteria that has become increasingly resistant to antibiotics commonly used to treat common staph infections. MRSA is the most common cause of infections in hospitals and other health-care settings, such as nursing homes. According to a 2022 study, bacterial antimicrobial resistance caused tens of millions of infections and 1.2 million deaths worldwide in 2019, with MRSA being the primary cause.

“Vaccines are the most effective way to reduce that health burden and antibiotic resistance,” Liu said, citing successes with childhood immunizations and the more recent COVID-19 vaccines as examples.

In a new paper, published on July 7, 2022 in the journal Cell Host & Microbe, senior author Liu and colleagues claim to have discovered the answer to the S. aureus conundrum, including the mechanism that explains why vaccine trials have so far failed and ways to overcome it.

The authors write that the fundamental difference is prior exposure to the pathogen. Laboratory mice are engineered (bred/raised/maintained) to be free of the specific target pathogen; they have had little or no prior exposure to S. aureus.

Humans, on the other hand, are exposed to S. aureus almost immediately after birth. Within two months, half of all babies have active colonies and enough antibodies to fight off most infections.

Liu hypothesized, along with first author Chih-Ming Tsai, PhD, a project scientist in his lab, and others, that while laboratory mice with no previous exposure to S. aureus respond well to potential vaccines because they are completely novel, human versions do not because S. aureus has evolved defenses to fend off the therapeutic attack.

“Staph vaccines appear to be so simple 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 staph appears to have developed many strategies to render our immune response against them ineffective,” Tsai explained.

“If the mice had staph infections prior to vaccination, we believe the vaccine candidates may not work.”

To test their hypothesis, Liu, Tsai, and co-authors replicated one of the largest failed staph vaccine trials in humans by targeting the IsdB protein, which S. aureus uses to acquire needed iron for functioning.

The IsdB vaccine worked in mice that had never been exposed to normal staph, generating antibodies that targeted the entire protein and disrupted bacterial functions. However, in mice that had previously been exposed to staph, the vaccine only produced antibodies against the unprotected portion of the IsdB protein, leaving bacterial function unaffected. Subsequent boosters primarily amplified the ineffective antibody response, exacerbating the problem by competing with any existing, protective antibodies.

When researchers mixed human IsdB antibodies with vaccine-derived protective antibodies, the latter stopped working. “We reasoned that if we could only vaccinate against the protective component of IsdB, we might be able to avoid immune response memory suppression,” Tsai said.

That is exactly what the researchers discovered: when they vaccinated mice solely against the protective component of the IsdB protein, the animals were effectively protected, even if they had previously been exposed to S. aureus.

The findings, when combined with other experiments, suggest that faulty pathogen memory and the corresponding immune response are likely explanations for the failed staph vaccine trials in humans, according to Liu.

“It’s even possible that the same principle explains why many other difficult-to-make vaccines have failed,” he says. “If our hypothesis is correct, an effective staph vaccine may not be far away.”

Source: Materials provided by University of California – San Diego

Reference:DOI: 10.1016/j.chom.2022.06.006

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