Staphylococcus aureus is the leading global cause of bacterial infection-associated mortality, as vaccine development has been elusive. S. aureus alpha-toxin (Hla) is an essential virulence factor in disease. In children, the anti-Hla neutralizing antibody response is the only known correlate of human protective immunity. We demonstrate that the anti-Hla response is limited in the first 2 years of life, illuminating a vaccine-targetable population. We assessed whether Hla antigenic variants would enhance vaccine-mediated immunity in neonatal mice. We identified a variant (HlaH35L/R66C/E70C, HlaHRE) that elicits a nearly 100-fold increase in the neutralizing anti-Hla antibody response compared to other candidate Hla antigens. HlaHRE immunization durably protects against skin and soft tissue infection, enhancing the T follicular helper response and germinal center B cell response. Protective immunity was also conferred to offspring following maternal immunization with HlaHRE. These findings thereby define a novel path for universal S. aureus vaccine development at the maternal-infant interface.