Despite many attempts, there is currently no approved vaccine to prevent Staphylococcus aureus infections. Preclinical vaccination models have failed to predict vaccine efficacy in humans as S. aureus exposure in humans imprints an immune response that is lacking in naive animals. In this issue of the JCI, Tsai and colleagues identify the cytokine IL-10 as the driver of humoral imprinting by S. aureus. Upon vaccination, S. aureus-experienced animals produced copious levels of IL-10, resulting in the hyper-α2,3 sialylation of antibodies, which interfered with the phagocytic-promoting properties of the vaccine-elicited anti-S. aureus antibodies. These findings correlate with the observation that hyperproduction of IL-10 in humans also induces hyper-α2,3 sialylation of antibodies and provide a possible mechanism for previous vaccine failures.