‘Most vaccines are based on the dominant antigen to trigger the strongest possible immune response. But our findings suggest that for SA, the rules are different.’
Researchers from the University of California San Diego School of Medicine have published a study in Cell Reports Medicine today, which they say explains why vaccines designed to tackle Staphylococcus aureus (SA) have failed in clinical trials, despite successful preclinical studies in mice.
An extremely common bacterial infection, SA is often harmless, but it is also a leading cause of hospital-acquired infections and the research team hypothesise that SA bacteria can trick the body into releasing non-protective antibodies when they first colonise or infect humans. If a previously infected person is later vaccinated, these non-protective antibodies are preferentially recalled, making the vaccine ineffective.
This illustration shows SA (golden spheres) and various antigens and antibodies. Dominant antigens (purple) cause SA to produce non-protective antibodies (red with purple tips). These non-protective antibodies outcompete antibodies derived from vaccination (green with purple tips). Vaccines targeting subdominant antigens (blue) could help yield more protective antibodies (green with blue tips), making the vaccine more effective.Credit: JR Caldera/UC San Diego Health Sciences
SA vaccines have performed well in pre-clinical studies on mice but failed in clinical trials. To understand why these vaccines failed, 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 on their own, as well as how they influenced the efficacy of several clinically tested SA vaccine candidates.
The researchers found that the vaccines were ineffective in mice that had been given human anti-SA antibodies, as well as mice that had been previously exposed to SA. However, in mice that had never been exposed to SA or human antibodies the vaccines worked.
They also discovered that antibodies that attack the cell walls of SA bacteria – which are the basis for most SA vaccines – didn’t protect the mice against SA. By contrast, antibodies that target the toxins produced by SA were able to successfully neutralise them.
‘One pathogen can have many different antigens that the immune system responds to, but there is a hierarchy as far as which antigen is dominant,’ said co-lead author, Chih Ming Tsai, PhD.
‘Most vaccines are based on the dominant antigen to trigger the strongest possible immune response. But our findings suggest that for SA, the rules are different, and it is more beneficial to target so-called sub-dominant antigens, which triggered a weak immune response in the first place.’
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