TCD research finds key to S aureus vaccine

Efforts to develop a vaccine for Staphylococcus aureus (S aureus) have moved one step closer. Researchers at Trinity College Dublin (TCD) have discovered that incorporating interleukin blockade into a future vaccine could improve efficacy.

The treatment of staphylococcal infections has become increasingly challenging because of the rapid emergence of antimicrobial resistance (AMR). S aureus is currently the leading cause of AMR deaths in high-income countries. The development of an effective vaccine against S aureus has never been more urgent.

Unfortunately, despite more than two decades of research and development, a vaccine remains elusive. It is now widely accepted that antibody-based vaccination strategies are not working and that effective S aureus vaccines will need to induce both cellular and humoral immunity.

There has been increasing focus on bacterially induced immunosuppression. S aureus induces interleukin (IL)-10, which impedes effector T cell responses, facilitating persistence during both colonisation and infection. Hence, it has been hypothesised that targeting IL-10 might improve vaccine efficacy.

Post-hoc analysis of data from the phase 2b/3 study of the failed Merck vaccine candidate supports the benefit of vaccine-induced T cell responses. The study demonstrated 100 per cent mortality in vaccinated patients with undetectable IL-2 levels who subsequently developed S aureus infection, suggesting that even in the presence of an antibody response, a protective immune response requires the generation of certain T cell subsets.

To provide proof of concept that targeting immunosuppressive responses during vaccination could be a useful approach to improve vaccine efficacy, the TCD researchers immunised mice with T cell activating vaccines in combination with IL-10–neutralising antibodies.

The mice received a subcutaneous injection of 100µL of the vaccine (CpG 50µg from Hycult Biotech or LP1569 50µg, + cGMP 10µg from InvivoGen, adjuvant + ClfA 5µg), vaccine plus blocking antibody (anti–IL-10 150µg, 2BScientific), or vaccine plus isotype (IgG1 150µg, 2BScientific) on day 0, 14, and 28. On day 42, mice were challenged with an S aureus systemic or subcutaneous infection.

At 24 hours and 72 hours after infection, significant increases in the frequency of both IL-17-producing Th17 and IFN-γ–producing Th1 cells were observed in the mice that received the vaccine plus anti-IL-10, compared with those who received the vaccine plus isotope (controls).

The vaccine plus anti-IL-10 also led to significant increases in populations of IL-17-producing and IFN-γ–producing γδ+ T cells and CD8+ cells.

These enhanced local T cell responses led to improved clearance of the infection.

The research also demonstrated the importance of adjuvant choice in vaccine design when targeting different anatomical sites. The use of a novel TLR2/STING agonist adjuvant was shown to be particularly effective for targeting S aureus skin infection.

There is also growing evidence suggesting that exposure to S aureus may remodel the immune system. An individual’s past exposure to S aureus could affect the ability of vaccines to drive T cell responses during subsequent infection.

The current study found that healthy adults who are persistently colonised with S aureus show an enhanced local IL-10 response compared to non-colonised individuals, and this is associated with dysregulated systemic S aureus antigen-specific effector T cell responses, supporting the conjecture that prior exposure to S aureus through nasal colonisation could influence vaccine function.

Commenting on the research, senior author, Prof Rachel McLoughlin, Professor in Immunology at TCD’s School of Biochemistry and Immunology, said: “Taken in combination, our results offer significant promise for what would be a novel strategy for improving the efficacy of vaccines developed with the aim of suppressing 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.”