A study in JCI Insight in July 2024 presents work from researchers at Trinity College Dublin who sought to improve vaccine responses to Staphylococcus aureus. The “potentially deadly bacterium” induces IL-10, which “impedes effector T cell responses” to allow persistence during colonisation and infection. In the study, IL-10 expression was elevated in the nares of persistent carriers of S. aureus, which was associated with reduced systemic S. aureus-specific Th1 responses. From this, the authors infer that systemic responses are remodelled through commensal exposure to S. aureus, negatively affecting vaccine function. They found that blocking IL-10 during vaccination enhanced T cell responses and improved bacterial clearance in subsequent systemic and subcutaneous infection, possibly indicating a novel strategy for improved efficacy.
An urgent need for effective interventions
S. aureus is a leading cause of both community-acquired and hospital-acquired bacterial infections and is associated with more than 1 million deaths each year. Although it is a major source of fatal bloodstream infections, the most common manifestations of infections are chronic and recurrent skin and soft tissues infections (SSTIs). Treatment of staphylococcal infections is “increasingly challenging” in the face of antimicrobial resistance (AMR), and S. aureus is the leading cause of AMR deaths in high-income countries.
“The health risk posed by S. aureus infection urgently necessitates the development of novel effective therapies that improve clinical outcomes by providing broad-spectrum protection, regardless of antimicrobial resistance patterns. The development of an efficacious, prophylactic anti-S. aureus vaccine is now more urgent than ever, as treatment options narrow further.”
Despite “significant” efforts over recent decades, there is no effective vaccine against S. aureus infection. Antibody-based vaccination strategies are “not working” and effective vaccines will need to induce protective cellular as well as humoral immunity.
The role of the microbiota in vaccine-induced immune responses is becoming more appreciated as the association between the composition of the infant microbiota and immune responses to vaccination is reported in more studies. The microbiota can negatively influence vaccine efficacy and has been reported to inhibit BCG-induced protection against Mycobacterium tuberculosis infection by “skewing” vaccine-induced immunity in favour of suppressive Tregs (regulatory T cells). Data suggest that exposure to organisms with capacity to drive immunosuppression can “interfere” with vaccine-induced effector responses.
In the context of S. aureus, research suggests that exposure could “imprint” the immune system in a suppressive manner. Therefore, past exposure could affect the ability of vaccines to drive protective T cells responses during subsequent infection. In nasal colonisation and skin infection, S. aureus drives local production of the immunosuppressive cytokine IL-10 to dampen effector T cell responses and facilitate bacterial persistence. The researchers believe that, if there is an immunosuppressive imprint that interferes with vaccine-induced T cell function, inhibition of anti-inflammatory immune responses during vaccination could be a way of enhancing vaccine efficacy.
The study
“This study reveals a potential bottleneck that may need to be circumvented to realise an effective vaccine.”
The researchers demonstrate that S. aureus colonisation drives the production of IL-10 in the nasal cavity of healthy adults, likely to facilitate bacterial persistence. This is associated with “altered circulating memory T cell responses” when exposed to S. aureus antigens. In preclinical models, they demonstrate that the transient inhibition of IL-10 during immunisation improved vaccine-induced T cell responses to lead to a more effective clearance of infection. This approach was more effective when the vaccine was administered with adjuvants to drive antigen-specific Th1/Th17 responses.
“This study supports the premise that colonisation status has a direct impact upon system S. aureus-specific memory T cell responses, which could be hindering vaccine function due to the promotion of an immunosuppressive state.”
After offering insight into the “critical role” that IL-10 plays in “impeding” anti-S. aureus vaccine efficacy by “dampening” vaccine-induced protective T cells responses, the authors propose a method of improving vaccine efficacy by inhibiting IL-10 production during vaccination. This leads to enhanced antigen-specific T cell responses and improved bacterial clearance.
Professor Rachel McLoughlin at Trinity College Dublin’s School of Biochemistry and Immunology led the research team and believes that their results “offer significant promise for what would be a novel strategy for improving the efficacy of vaccines developed with the aim of suppressive S. aureus infection”.
“Our work also strongly suggests that prior exposures to this bacterium may create a situation whereby our immune system no longer sees it as a threat and thus does not respond appropriately to a vaccine due to the creation of this immune-suppressed state. Again, this underlines why immunisation delivered with something that helps neutralise IL-10 offers renewed hope for effective vaccines against S. aureus.”
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