Non-protective immune imprint underlies failure of S. aureus IsdB vaccine

The failure to date of all S. aureus vaccine trials has been a conundrum and underlines fundamental flaws in current translational models. A major difference between humans and laboratory animals is the early and frequent exposure of humans to S. aureus compared to animals, which is not accounted for in vaccine studies. In recapitulating the failed IsdB human vaccine trial, we showed that mice previously infected with S. aureus do not mount a protective vaccine antibody response, unlike naïve mice. S. aureus infection induces robust but non-neutralizing anti-IsdB antibodies that target different but overlapping IsdB epitopes compared to IsdB vaccine. In the setting of prior S. aureus infection, however, IsdB vaccine recalls the non-protective humoral response which further competes and reduces efficacy of protective vaccine-generated specific antibodies. Vaccination against the heme-binding domain of IsdB or select IsdB epitope can overcome interference by S. aureus infection. Using an adoptive transfer model, we showed that human serum antibodies against IsdB and another vaccine target, ClfA, are also non-protective and blocked anti-staphylococcal immunity conferred by passive immunizations. Overall, our study demonstrates proof of concept that failure of anti-S. aureus active and passive immunizations could be explained by non-protective imprint of prior host-pathogen interaction. Overall design: Single-cell immune profiling of the S. aureus IsdB vaccine. In this study, we conducted BCR sequencing for three different samples: LAC (LAC-infected mice given adjuvant alone), LAC/IsdB (LAC-infected mice vaccinated with IsdB) and N/IsdB (Naïve mice vaccinated with IsdB).