By delivering Staphylococcus aureus antigens in a shell made of the yeast cell wall component beta-glucan, investigators at Cedars-Sinai Medical Center have managed to evoke an effective immune response against the bacterium in mouse models of infection.

The findings could enable the development of a staph aureus vaccine -- something, David Underhill told BioWorld Science, that is "desperately" sought by the medical field, as staph infections are becoming increasingly common, and S. aureus itself is becoming more drug-resistant.

There are several reasons why staph infections are common. One is that it is a commensal bacterium, "most of us are probably colonized with staph," Underhill, who is professor and chair of the Department of Biomedical Sciences at Cedars-Sinai Medical Center, told BioWorld Science.

But another problem is that even after an infection, the immune system does not retain the sort of immune memory that leads to lasting immunity.

How staph manages to evade long-term immunity is "far from established doctrine," he said. But it does not appear to do so by mutating, or shifting its expression of the surface proteins that could serve as antigens.

Instead, "Staph seems to trick the immune system into not caring," Underhill said. "I think it actively induces a suppressive immune response to its antigens." But the molecular details of how it does so are unknown.

Underhill's background is in antifungal immunity, where the situation is largely the opposite of that of staph.

The rise of Candida auris notwithstanding, in general, "our immunity to fungi is really very good," Underhill said. "Healthy people don't stay home from work because they got a fungal infection."

Immunocompromised individuals, however, can become susceptible to fungal infections. And when they do, they also become more susceptible to staph.

Looking at the literature, Underhill said, he realized that in reports of coinfections, "it was always fungal infections and staph infections ... Not flu, not pneumonia."

That link "suggests that the kind of immunity that the body mounts against fungi must be quite similar to the kind of immunity that the body wants against staph."

Trojan yeast

Underhill and his colleagues went on to test the idea that by combining staph antigens with an adjuvant that would stimulate antifungal immunity, they would be able to elicit more durable immunity than staph antigens could on their own.

In order to test their hypothesis, the team developed a vaccine made of a shell of fungal beta-glucan particles loaded with four S. aureus antigens, which they called 4X-SA-GP. Mice were vaccinated once a week for 3 weeks with 4X-SA-GP.

The mice developed both an antibody and a T-cell response to vaccination. Underhill pointed out that although vaccine development tends to focus mainly on evoking a neutralizing antibody response, "in our mice, that T-cell-mediated immunity was really critical for the protection. If we'd optimized the vaccine for antibodies ... It wouldn't have worked as well."

The vaccine was effective for up to 8 weeks after vaccination, a time point where vaccination with only the beta-glucan shell had ceased to be of any benefit.

They reported their findings in the August 20, 2020, online issue of PLoS Pathogens.

Underhill and his colleagues plan to investigate the molecular details of the response in more detail, in particular to understand why the vaccine evokes a strong T-cell response.

Beyond the specifics of the work now reported in PLoS Pathogens, Underhill said that the work is an illustration that not just antigens, but also adjuvants can be tailored to specific pathogens in vaccines.

"Vaccines should be designed to elicit the kind of immune response that's right for that kind of agent," he said.

Adjuvants are sometimes considered as a way to rile up the immune system whose details don't matter, he said, but "the kind of angry that you evoke from the immune system is important." (Paterson, M.J. et al. PLoS Pathog 2020, 16(8): e1008733).

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