Vaccines targeting Staphylococcus aureus (SA), an extremely common bacterial infection, have failed miserably up to this point, and a new study sheds light on why.
Researchers from the University of California San Diego School of Medicine set out to find an explanation as to why all previous vaccines targeting staph — a bacterial infection that is often harmless but can be fatal in some cases — were effective in preclinical mice studies but later failed in clinical trials with humans.
The new study, published in Cell Reports Medicine on Tuesday, tested a hypothesis that staph bacteria can trick the body into releasing non-protective antibodies when they first colonize or infect humans, leading the non-protective antibodies to kick in upon vaccination and rendering the vaccine ineffective.
A staph infection is unique in that it can be a normal part of the healthy human microbiome — approximately 30% of people have staph colonies living in their noses. But it can become serious if it gets into the blood, with the potential to lead to sepsis or even death.
The immune system typically protects the body from foreign, potentially dangerous molecules by releasing antibodies or antigens. Like muscle memory, the immune system remembers this initial response so it can recall those same antigens the next time it’s exposed to those same molecules.
Vaccines work the same way, but this is only effective when the initial immune response is actually protective against these harmful molecules. In the case of staph, researchers suspected that the immune system’s response was ineffective to begin with, causing vaccination to be as well.
To test their hypothesis, researchers collected blood serum from healthy volunteers, extracted the anti-staph antibodies present in the samples, and transferred the antibodies to mice. The goal was to determine how effective they would be at protecting the mice from staph and how they would impact the effectiveness of a number of clinically tested staph vaccine candidates.
The results showed that the vaccine candidates did not work in the mice that had received human antibodies, nor in the mice that had been previously exposed to staph. However, the vaccines did work in the mice that had neither been exposed to staph or received human antibodies — confirming their hypothesis.
In other words, they found that the immune system’s initial response to staph is what eventually leads to the vaccines being ineffective.
The researchers also found that the antibodies that attack the cell walls of staph bacteria, which are the basis for most current staph vaccines, didn’t protect the mice, but antibodies that target the toxins produced by staph were able to neutralize 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, Ph.D., a project scientist in the Liu Lab, in a news release. "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 subdominant antigens, which triggered a weak immune response in the first place."
The findings suggest that staph is essentially able to trick the immune system, and the researchers’ next goal is to figure out why. This study is a step towards improving existing vaccines, developing new ones, and reevaluating other failed vaccines targeting other bacteria.
- Cell Reports Medicine. The characteristics of pre-existing humoral imprint determine efficacy of S. aureus vaccines and support alternative vaccine approaches.
- University of California San Diego. We Need a Staph Vaccine: Here’s Why We Don’t Have One.
- Centers for Disease Control and Prevention. Staph infections can kill.