Irshad Hajam examines Staphylococcus aureus cultures. Credit: Kyle Dykes/UC San Diego Health Sciences

Despite working well in mouse models, approximately 30 clinical trials to date have failed to result in an effective human vaccine for Staphylococcus aureus, the bacteria that causes MRSA. Now, two new studies from George Liu's lab at UC San Diego point to a key reason for these failures -- history and a protein known as interleukin-10 (IL-10).

Starting in infancy, the majority of humans are colonized with S. aureus, which hitches a ride in our nasal passages. For the most part, it doesn't harm us but previous research has shown that this early exposure fools our immune cells into producing modified antibodies that fail to mount an effective defense against S. aureus. What's more, the bacteria retain a "memory" of those non-protective antibodies that can be brought back during later infections. This is why vaccine candidates that have worked well in mice -- who all had no previous exposure to the pathogen -- have failed.

In this breakthrough work, researchers also identified a protein that -- when produced in excess -- shuts down the ability of antibodies and cells to kill S. aureus. This finding suggests it may be possible to modify already-developed vaccines to now effectively target S. aureus in humans.

In a study published in the Journal of Clinical Investigation, Liu, M.D., Ph.D., professor and chief of pediatric infectious diseases at UC San Diego School of Medicine and Rady Children's Hospital, and team exposed mice to S. aureus and later inoculated them with Iron Surface Determinant B (IsdB) vaccine.

The researchers found that B cells -- white blood cells that make antibodies -- secrete an abundance of a protein called interleukin-10 (IL-10) when presented with S. aureus for a second time. Within the B cells, IL-10 directs the enzymes to add a sugar called sialic acid to the Fc region of the antibodies -- the region responsible for generating an appropriate immune response. With the sugar present, the anti-staphylococcal activity of antibodies produced by the B cells is neutralized, making them incapable of killing the pathogen. However, when the researchers blocked IL-10 at time of immunization, they were able to restore vaccine efficacy.

"The IL-10 is helping make tons of this sugar type and by doing so, it's turning off our immune system," said Chih-Ming Tsai, an assistant project scientist in Liu's lab. "The same vaccine that didn't work before now works perfectly in mice."

Researchers implicated an overabundance of IL-10 as the problem in another study recently published by a team from Liu's laboratory. Led by Irshad Hajam, an assistant project scientist, the researchers found that helper T cells -- white blood cells that detect infections and activate immune cells to attack -- act similarly to B cells in mice previously exposed to and later vaccinated for S. aureus.

The study, published in Nature Communications, showed that IL-10 shuts down the ability of the helper T cells to produce interleukin-17 (IL-17A), a cytokine that is very effective at fighting S. aureus. But by blocking IL-10 or adding a substance called CAF01 -- known to enhance vaccine efficacy by increasing the response of T cells to microbial infections -- the researchers were able to restore IL-17A levels.

"Adding CAF01 during vaccination helped turn the ineffective IsdB vaccine into one that worked in S. aureus-exposed mice," said Hajam. "Surprisingly, it also worked with several other failed vaccines against S. aureus."

Beside S. aureus, IL-10 production is common to several other pathogens, including Clostridioides difficile and malaria. As seems to be the case with S. aureus, Liu says the overproduction of IL-10 could be why seemingly promising vaccines failed in clinical trials for these conditions as well, suggesting that blocking the cytokine could restore vaccine efficacy.