Staphylococcal vaccine ineffective in previously exposed individuals

Antibiotic resistance is a growing problem as dangerous pathogens learn to mutate to evade effective treatments. Staphylococcus aureus (S. aureus; SA) is one of these resistant microbes, and researchers have attempted to develop a vaccine for some time.

Animal studies have yielded potential AS vaccine candidates, but not all of these have successfully translated to humans. One to studyPosted in Cell host and microbenoted that a key difference between animals and humans is that humans are naturally exposed to S. aureus. Indeed, previously infected mice could not mount an adequate immune response to SA vaccination, unlike infection naïve mice.

“Staphylococcal vaccines seem so easy to make in lab mice because they rarely see S. aureus“, said Chih-Ming Tsai, PhD, the first author of the study. our immune response against them.”

Tsai and his fellow researchers made the discovery after recreating one of the largest failed human AS vaccine trials, a Phase 3 study of an iron-regulated surface-determining protein B (IsdB) vaccine candidate.

The team intraperitoneally infected 6 mice with SA 1-3 times per week, seeking a stable serum IsdB antibody titer. Next, they vaccinated the mice with the recombinant IsdB candidate and assessed the bacterial load and mortality of the mice.

The researchers found that the IsdB vaccine was very effective against AS in naïve mice, but mice with 2-3 previous AS infections did not have an adequate antibody response to the vaccine candidate.

To determine why this was so, the researchers compared IsdB-specific antibodies generated by SA infection, antibodies generated by infection followed by vaccination, and antibodies generated by vaccination alone. They noted that opsonophagocytic (OPK) destruction of SA by neutrophils was more efficient in SA vaccinated and infection naïve mice.

This observation led researchers to explore antibody glycosylation, which has been shown to reduce opsonophagocytosis by attenuating the binding of FcgRIII and FcgRIIb. After finding no difference in FcgRIIb binding between antibodies from naïve and infected mice, the researchers concluded that α2,3 sialylation of anti-IsdB antibodies likely attenuated opsonophagocytosis through interaction with another receptor on myeloid cells.

When the researchers vaccinated mice only against the protective component of the IsdB protein, SA-infected and SA-naïve mice were protected. The investigators concluded that “previous vaccines have failed due to defective memory of the pathogen and corresponding immune response.”

An effective staphylococcal vaccine would likely be the most effective way to reduce the burden of infections and the progression of antimicrobial resistance. “Based on a new understanding of staphylococcal vaccine failure, we could search for new ways to overcome the root cause of vaccine failure in our study – the non-protective memory left behind by previous exposure to the staphylococcus,” said study author George Liu, MD, PhD. .

Unlike mice and other laboratory animals, more than 50% of human infants are exposed to SA during their first 2 months of life. This mechanistic framework explaining the failure of the IsdB vaccine trial could soon lead to success S. aureus vaccine.