Staphylococcus aureus (SA) is a widespread bacterial infection, with approximately 30% of people harboring S. aureus colonies in their nasal cavities. Although usually harmless, Staphylococcus aureus is a major cause of hospital-acquired and community-acquired infections. Vaccine development against SA has great potential to transform public health. However, despite promising results from preclinical studies using mice, all vaccine candidates against SA have historically been unsuccessful in clinical trials.

Researchers at the University of California, San Diego School of Medicine recently provided an explanation for this discrepancy.

In a new study recently published in Cell Reports Medicine, they tested a new hypothesis: SA bacteria trick the body into releasing non-protective antibodies when they first colonize or infect humans. When the body is subsequently vaccinated, these non-protective antibodies are preferentially recalled, rendering the vaccine ineffective.

The figure shows SA (golden sphere) and various antigens and antibodies. The dominant antigen (purple) causes the SA to produce non-protective antibodies (red, with a purple tip). These non-protective antibodies compete with antibodies produced by vaccination (green, with purple tips). Vaccines targeting subdominant antigens (blue) can help produce more protective antibodies (green with blue tips), making the vaccine more effective. Source: JRCaldera/UC San Diego Health Sciences

SA has a unique relationship with humans. While it can cause many dangerous health complications, including wound and bloodstream infections, this bacterium is also a normal part of a healthy human microbiome, living comfortably in the nasal cavity and skin.

"SA has been with humans for so long that it has learned how to serve as both a commensal and a deadly pathogen," said senior author George Liu, MD, professor in the Department of Pediatrics at the UC San Diego School of Medicine. "If we are to develop an effective vaccine against SA, we must understand and overcome the strategies it uses to maintain this lifestyle."

Research findings and implications

The immune system releases protective antibodies in response to molecules (called antigens) that it considers foreign. These antibodies are stored in the immune system's memory, so the next time the immune system encounters the same antigen, it will generally recall the previous immune response rather than launch a new attack.

"This is an effective system that can confer long-term protection against pathogens, but it only works if the initial immune response to the pathogen is actually protective," said co-first author J.R. Caldera, Ph.D., who completed his doctoral research in Liu's lab. "What makes SA unique is that the bacteria themselves have ways to evade the immune system from the moment they encounter us, and vaccination only reinforces these evasion strategies."

Although SA vaccines have unilaterally failed in clinical trials, they generally perform well in preclinical studies in mice. To find out why, the researchers collected serum from healthy volunteers, quantified and purified the anti-SA antibodies in the samples. They then transferred these antibodies into mice to explore their own protective effects against SA and how they affected the efficacy of several clinically tested SA vaccine candidates.

This graphic abstract shows the experimental approach used by researchers to study the immune response following vaccination with the SA vaccine. Vaccines targeting subdominant antigens, such as toxins produced by bacteria, may provide more protection than vaccines targeting dominant antigens. Source: UC San Diego Health Sciences Division

The researchers found that the vaccines were ineffective against mice injected with human anti-SA antibodies and mice previously exposed to SA. However, in mice that had never been exposed to SA or human antibodies, the vaccine worked. Unlike previous SA vaccine mouse studies, the researchers' results are consistent with clinical trial failures, suggesting that their experimental model can help predict the success of SA vaccines in preclinical mouse studies.

Challenges and future directions for vaccine development

Furthermore, they found that specific antibodies were responsible for the effects they observed. Antibodies that attack the cell wall of SA bacteria, on which most current SA vaccines are based, did not protect mice from SA infection. In contrast, antibodies directed against toxins produced by SA successfully neutralized them.

"A pathogen may have many different antigens to which the immune system responds, but there is a hierarchy of which antigens are dominant," said co-first author Dr. Chih Ming Tsai, a project scientist in Liu's lab. "Most vaccines are based on dominant antigens to elicit the strongest immune response. But our results show that for SA, the rules are different and it would be more beneficial to target so-called subdominant antigens, which elicit weak immune responses at first."

In addition to exploring the possibility of future SA vaccines targeting neoantigens, the researchers are also interested in exploring a deeper question: Why are humans' natural immune responses to this bacterium so ineffective in the first place?

"Somehow, SA is able to trick our immune system, and figuring out how it tricks our immune system will help us improve existing SA vaccines and develop new ones," Liu said. "More broadly, these findings suggest an entirely new way to re-evaluate failed vaccines, with implications that may extend far beyond this one bacterium."

Compiled source: ScitechDaily