Staphylococcus aureus (SA) is an extremely common bacterial infection; About 30% of people have Staph colonies living in their nose. AS is often harmless, but it is also a leading cause of hospital-acquired and community-associated infections.
In a new study they tested a new hypothesis that staph bacteria can cause the body to release non-protective antibodies when they first colonize or infect humans. When the individual is subsequently vaccinated, these non-protective antibodies are preferentially recalled, making the Vaccine ineffective.
The results of research were published in published in Cell Reports Medicine.
Staphylococcus: this is why an effective vaccine is urgently needed
A staph vaccine would represent a public health game changer, but for decades all AS vaccine candidates have failed in clinical trials despite successful preclinical studies in mice. Researchers at the University of California at San Diego School of Medicine have finally explained why.
Staph has a unique relationship with humans. Although it causes many dangerous health complications, including wound and bloodstream infections, the bacterium is also a normal part of the healthy human microbiome, where it lives peacefully in the nose and on the skin.
“Staph has been with humans for a long time, so it has learned how to be a part-time symbiont and part-time deadly pathogen,” said senior author George Liu M.D., Ph.D., professor in the Department of UC San Diego Pediatrics. School of Medicine. “If we want to develop effective staph vaccines, we need to understand and overcome the strategies used to maintain this lifestyle.”
The immune system releases protective antibodies in response to molecules it suspects are foreign, called antigens. These antibodies are then saved in the immune system's memory, so the next time the immune system encounters the same antigen, it will generally remember its previous immune response rather than launch a new attack.
“This is an effective system for conferring long-term protection against pathogens, but it only works when the initial immune response to that pathogen has actually been protective,” said co-lead author JR Caldera, Ph.D. ., who completed his doctoral research in the Liu Laboratory.
“What sets staph apart is that the bacteria themselves have ways of evading the immune system from the moment they encounter us, and these evasive strategies are only strengthened by vaccination.”
Although staph vaccines have failed unilaterally in clinical trials, they generally perform well in preclinical studies in mice. To understand why, the researchers collected blood serum from healthy volunteers, quantifying and purifying the anti-SA antibodies present in the samples. They then transferred these antibodies to mice to explore how protective they were against SA and how they affected the effectiveness of several clinically tested SA vaccine candidates.
The researchers found that the vaccines were ineffective in mice given human anti-SA antibodies, as well as in mice that had previously been exposed to SA. However, in mice that had never been exposed to either SA or human antibodies, the vaccines worked.
Unlike previous mouse studies of staph vaccines, the researchers' results were consistent with those from failed clinical trials, suggesting that their experimental model could help predict the clinical success of SA vaccines while they are still being tested in preclinical studies on mice.
Furthermore, they found that specific antibodies were responsible for the observed effect. Antibodies that attack the cell walls of staph bacteria, which are the basis for most current SA vaccines, did not protect mice from SA. In contrast, antibodies that target the toxins produced by AS were able to successfully neutralize them.
“A pathogen can have many different antigens that the immune system responds to, but there is a hierarchy as to which antigen is dominant,” said co-lead author Chih Ming Tsai, Ph.D., project scientist at the Liu Lab.
“Most vaccines rely on the dominant antigen to trigger the strongest possible immune response. But our results suggest that for SA the rules are different and it is more advantageous to target the so-called subdominant antigens, which triggered a weak immune response in the first place.”
In addition to exploring the possibility of targeting new antigens with future staph vaccines, researchers are also interested in exploring the deeper question at play here: Why is the natural human immune response to this bacterium so ineffective to begin with?
“Somehow, staph is able to trick our immune system into figuring out how it will help us improve existing SA vaccines and develop new ones,” Liu said. “More broadly, these findings suggest an entirely new way to reevaluate failed vaccines, which could have implications far beyond this bacterium.”
In most cases, the bacterium Staphylococcus aureus is common and harmless and poses no threat to the humans it coexists with. Occasionally, however, it can become an opportunistic pathogen, causing skin and blood 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 over the past 30 years. In all subsequent human trials, however, these vaccine candidates have failed.
“This is a long-standing question and one of the most puzzling in the field of staphylococci,” said George Liu, M.D., Ph.D., professor of pediatrics at the University of California at San Diego School of Medicine and chief of the Division of Infectious Diseases at Rady Children's Hospital-San Diego. “None of these human experiments worked, and scientists have struggled to find a reason why.”
The issue 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 common staph infections.
MRSA is the primary source of infections acquired in hospitals and other healthcare facilities, such as nursing homes. A study published in 2022 estimated that bacterial antimicrobial resistance resulted in tens of millions of infections and 1.2 million deaths worldwide in 2019, with MRSA as the leading factor.
“Vaccines are the most effective way to reduce healthcare burden and reduce antibiotic resistance,” Liu said, highlighting successes with childhood vaccinations and the more recent COVID-19 vaccines.
In another study, published in the journal Cell Host & Microbe, senior author Liu and colleagues say they have found the answer to the S. aureus puzzle, including the mechanism that explains why vaccine trials have so far failed and ways to get over it.
Fundamentally, the difference lies in previous exposure to the pathogen, the authors write. Laboratory mice used in research are designed (bred/raised/maintained) to be free from the specific target pathogen; have had little or no exposure to Staph. aureus before vaccination.
Humans, in contrast, are very rapidly exposed to Staphylococcus aureus after birth. By two months, half of babies develop active colonies and abundant antibodies that can fend off most infections.
With first author Chih-Ming Tsai, Ph.D., a project scientist in his lab, and others, Liu hypothesized that while laboratory mice with no prior exposure to S. aureus respond well to potential vaccines because they are human versions completely new ones do not work because S. aureus has developed defenses to repel the therapeutic attack.
“Staph vaccines seem so easy to make in laboratory mice because they rarely see S. aureus, but humans are exposed to staph starting in the first weeks of life, and to coexist, staph appears to have developed many strategies to render our vaccines ineffective.” immune response against them,” Tsai said.
If the mice had staph infections before vaccination, we think the vaccine candidates might not work.”
To test their hypothesis, Liu, Tsai, and co-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 the iron needed for operation.
In mice not exposed to normal staph, the IsdB vaccine worked, generating antibodies that targeted the entire protein and disrupted bacterial functions. But in mice previously exposed to staph, the vaccine only generated antibodies against the unprotected portion of the IsdB protein, leaving the bacteria's functioning intact.
Subsequent boosters primarily amplified the ineffective antibody response, and, exacerbating 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 produced by the vaccine, the latter stopped working. “We hypothesized that if we could vaccinate only against the protective component of IsdB, we might be able to prevent suppression due to poor memory of the immune response,” Tsai said.
And indeed 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 previously exposed to Staphylococcus aureus.
Combined with other experiments, Liu said the findings suggest that faulty memory of a pathogen and its corresponding immune response are likely explanations for failed staph vaccine trials in humans.
“It is also possible that the same principle could also explain why many other difficult-to-produce vaccines have failed,” he said. “If we are right, an effective staph vaccine may not be too far away.”
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