How a Sepsis-Causing Bacterium Thwarts Vaccines
The pathogen that causes sepsis has thwarted vaccines, but researchers now know why.
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Staphylococcus aureus (S. aureus) is a major cause of skin and soft tissue infections that can sometimes lead to sepsis and toxic shock syndrome. The microbe poses a significant threat to public health, made worse by the spread of methicillin-resistant Staphylococcus aureus bacteria (MRSA) in recent years. According to The Lancet, S. aureus was associated with more than one million deaths around the globe in 2019.
“It is a pathogen in dire need of control because it causes significant morbidity and mortality not just in the United States, but worldwide,” said George Liu, M.D., Ph.D., professor of and chief of pediatric infectious diseases at University of California San Diego School of Medicine and Rady Children’s Hospital-San Diego.
Yet, despite working well in mouse models, approximately 30 clinical trials to date have failed to result in an effective human vaccine for S. aureus. Now, UC San Diego researchers have identified a key reason for these failures, indicating that it may be possible to modify the vaccines to work in humans. In a study published on December 16, 2024 in the Journal of Clinical Investigation (JCI), they report that S. aureus induces an overabundance of a protein called interleukin-10 (IL-10) in B cells, leading to the inactivation of antibodies, rendering them unable to kill S. aureus.
“The IL-10 is helping make tons of this sugar type and by doing so, it's turning off our immune system,” said Tsai. However, the researchers also found that blocking IL-10 at the time of immunization restores vaccine efficacy. “The same vaccine that didn't work before now works perfectly in mice,” he added.
T cells
While the JCI study focused on the role of IL-10 in B cells, the Nature Communications paper, led by first author Irshad A. Hajam, Ph.D., an assistant project scientist in Liu’s lab, examined how S. aureus interacts with CD4+ T lymphocytes, also known as helper T cells. These are white blood cells that detect infections and activate other immune cells to attack and kill pathogens.
The researchers found that like B cells, helper T cells also secrete an overabundance of IL-10 in response to S. aureus in mice previously exposed to and later vaccinated for S. aureus.
IL-10 shuts down the ability of the helper T cells to produce interleukin-17 (IL-17A), a cytokine that is particularly effective at fighting S. aureus infections. 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.
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Subscribe for FREEThe findings from both studies could be good news for human S. aureus vaccine development. Liu says it may be possible to make already-developed but failed S. aureus vaccines effective by blocking IL-10 or boosting IL-17A during vaccination. He adds that IL-10 production by a number of other microbes including (Clostridioides difficile and malaria) could be a reason why promising vaccines for these conditions have failed in human clinical trials, suggesting that blocking the cytokine could restore their efficacy as well.
Reference: Tsai CM, Hajam IA, Caldera JR, et al. Pathobiont-driven antibody sialylation through IL-10 undermines vaccination. J Clin Invest. 2024;134(24). doi: 10.1172/JCI179563
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