Mostly bacteria Staphylococcus aureus are common and harmless, do not pose a danger to the people with whom they coexist. However, it can sometimes become an opportunistic microorganism, causing skin and bloodstream infections or food poisoning.
Scientists have been searching for an effective vaccine for more than a century, including at least 15 successful preclinical studies using animal models over the past 30 years. However, these vaccine candidates have failed in all subsequent human trials.
“This is a long-standing and one of the most puzzling problems of staph infection,” said George Liu, MD, 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 worked, and scientists have been scrambling to find a reason.”
The issue has become more urgent with the spread of methicillin-resistant S. aureus (MRSA), a type of staph bacteria that is becoming increasingly resistant to antibiotics commonly used to treat common staph infections. MRSA is a major source of infection acquired in hospitals and other health care settings such as nursing homes. A study published in 2022 estimated that bacterial resistance to antimicrobial drugs led to tens of millions of infections and 1.2 million deaths worldwide in 2019, with MRSA being a major factor.
“Vaccines are the most effective way to reduce this health burden and reduce antibiotic resistance,” Liu said, pointing to successes with childhood vaccinations and later vaccines against COVID-19.
In a new article published in the journal July 7, 2022 Cellular host and microbes, senior author Liu and his colleagues say they may have found the answer to the mystery S. aureusincluding the mechanism that explains why vaccine trials have so far failed and ways to overcome this.
In principle, the difference lies in the previous exposure to the pathogen, the authors write. Laboratory mice used in research have been engineered (bred/raised/maintained) to be free of a specific target pathogen; they were virtually unaffected S. aureus before vaccination.
People, on the other hand, are very quickly affected S. aureus after birth. By two months, half of the babies have active colonies and plenty of antibodies to fight off most infections.
Along with first author Chi-Ming Tsai, Ph.D., a project scientist in his lab, and others, Liu hypothesized that while lab mice not previously exposed to S. aureus respond well to potential vaccines because they are brand new, human versions don’t work because S. aureus has advanced defenses to fend off therapeutic attack.
“Staphylococcus vaccines seem so easy to make in lab mice because they rarely see S. aureusbut humans are exposed to staph starting in the first weeks of life, and in order to coexist, staph seems to have developed many strategies to make our immune response against them ineffective,” Tsai said.
“If the mice had a staph infection before vaccination, we believe that the vaccine candidates may not work.”
To test their hypothesis, Liu, Tsai and co-authors conducted a series of experiments simulating one of the largest failed human trials of a staph vaccine, which targeted the IsdB protein used S. aureus to get the iron you need to function.
In mice that had not been infected with normal staph, the IsdB vaccine worked by producing antibodies that targeted the entire protein and disrupted the bacteria’s function. But in mice previously exposed to staph, the vaccine only produced antibodies against the unprotected part of the IsdB protein, leaving the bacteria unaffected. Subsequent boosters primarily enhanced the ineffective antibody response, and to compound the problem, the ineffective antibodies competed with any existing protective antibodies.
When the researchers tried to mix the human IsdB antibodies with the protective antibodies derived from the vaccine, the latter stopped working. “We hypothesized that if we could vaccinate against only the protective component of IsdB, we would be able to prevent suppression due to poor memory of the immune response,” Tsai said.
And in fact, this is what the scientists found: when they vaccinated mice exclusively against the protective component of the IsdB protein, the animals were effectively protected, even if they had been previously exposed S. aureus.
Combined with other experiments, Liu said the findings suggest that faulty memory about the pathogen and its corresponding immune response likely explain the failed staph vaccine trials in humans.
“It’s even possible that the same principle could also explain why many other difficult-to-make vaccines have failed,” he said. “If we’re proven right, an effective staph vaccine may not be that far off.”
Co-authors include: JR Caldera, UC San Diego and Cedars-Sinai Medical Center; Irshad A. Hajjam, Austin W. T. Chang, Haining Lee, Maria Lazaro Diez, Cecia Gonzalez, Desmond Trier, and Nathan E. Lewis, all of UC San Diego; Chih-Hsiung Tsai, National Cheng Kung University, Taiwan; Ghislaine A. Martins, David M. Underhill, and Moshe Arditi, all at Cedars-Sinai Medical Center.