Date Published: November 5, 2015
Publisher: Public Library of Science
Author(s): Aisling F. Brown, Alison G. Murphy, Stephen J. Lalor, John M. Leech, Kate M. O’Keeffe, Micheál Mac Aogáin, Dara P. O’Halloran, Keenan A. Lacey, Mehri Tavakol, Claire H. Hearnden, Deirdre Fitzgerald-Hughes, Hilary Humphreys, Jérôme P. Fennell, Willem J. van Wamel, Timothy J. Foster, Joan A. Geoghegan, Ed C. Lavelle, Thomas R. Rogers, Rachel M. McLoughlin, Lloyd S Miller.
Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans.
Staphylococcus aureus is a leading cause of community- and hospital-acquired bacterial infections. It is one of the most common causes of bloodstream infection (BSI), and carries a higher mortality than any other bacteraemia (20–40% within 30 days) despite appropriate treatment . It is also the leading cause of other serious infections including osteomyelitis, septic arthritis, endocarditis and device-related infections, and leads to significant healthcare costs . The burden of S. aureus disease is amplified by the fact that resistance has been demonstrated to every licensed anti-staphylococcal agent to date . Consequently, there is an urgent unmet clinical need to develop a vaccine against S. aureus.
This study demonstrates, for the first time, a correlate of protective immunity in S. aureus infection in mice that is also evident in human infection. S. aureus antigen-specific IFNγ-producing CD4+ (Th1) cells are expanded in both humans and mice following infection, and these cells are definitively protective in mice. This protection is manifested as a significantly accelerated clearance of bacteria and mediated–at least in part–by enhanced macrophage responses. We have utilised this information in rational vaccine design, and generated a novel S. aureus vaccine to specifically target memory Th1 cells. Critically important in that process was establishing that our chosen antigen can induce a human Th1 response, and then combining this antigen with a proven Th1-driving adjuvant to enhance anti-S. aureus Th1 protective immunity.