A Serologic Correlate of Protective Immunity Against Community-Onset Staphylococcus aureus Infection

Background. Staphylococcus aureus is among the leading causes of human infection. Widespread drug resistance, emergence of highly virulent strains, and the ability of S. aureus to colonize >30% of the human population contribute to this organism's pathogenic success. Human serologic responses to S. aureus and their relationship to protective immunity remain incompletely defined, challenging the strategic development of efficacious vaccines. Methods. We measured humoral responses to 2 staphylococcal exotoxins, alpha-hemolysin (Hla) and Panton-Valentine leukocidin (PVL; LukF-PV/LukS-PV subunits), both premier targets of current vaccine and immunotherapy development. We correlated acute and convalescent serum antibody levels with incidence of recurrent infection over 12 months follow-up in 235 children with S. aureus colonization, primary or recurrent skin and soft tissue infection, or invasive disease. Results. Cutaneous infection elicited transient increases in anti-Hla and anti-PVL antibodies; however, subsequent infection risk was similar between primary and recurrent cutaneous infection cohorts. Patients with invasive infections had the lowest preexisting titers against Hla and LukF but displayed the highest convalescent titers. Across cohorts, convalescent anti-Hla titers correlated with protection against subsequent S. aureus infection. Conclusions. Cutaneous S. aureus infection does not reliably provoke durable, protective immune responses. This study provides the first link between protection from disease recurrence and the humoral response to Hla, a virulence factor already implicated in disease pathogenesis. These observations can be utilized to refine ongoing vaccine and immunotherapy efforts and inform the design of clinical trials.