Intranasal boosting induces variant-specific responses in SARS-CoV-2 vaccine-imprinted mice

The continued evolution of SARS-CoV-2 variants that evade immunity highlights a need to develop vaccines that elicit variant-specific antibodies and neutralize emerging strains. However, immune imprinting from antecedent SARS-CoV-2 exposure can limit the generation of such antibodies. Here, we evaluate strategies to enhance variant-specific antibody responses in female mice primed with Wuhan-1 spike-based mRNA or chimpanzee adenoviral-vectored (ChAd) vaccines and boosted with Omicron variant-matched vaccines. Altering the intramuscular injection site did not substantially affect variant-specific serum antibody responses. However, increasing booster antigen doses, performing repeated boosters, and administering booster vaccines intranasally enhanced variant-specific responses against the vaccine-matched Omicron strain. Boosting intranasally with a ChAd vaccine encoding the spike protein of Omicron XBB.1.5 elicited stronger XBB.1.5-specific responses in serum, bronchoalveolar lavage fluid, and draining lymph nodes than intramuscular boosting with the same vaccine. Regardless of booster regimen, neutralizing activity against XBB.1.5 was predominantly mediated by antibodies that were non-reactive to Wuhan-1 spike. These findings establish that in mice, intranasal or repeated variant-matched boosting can overcome the effects of imprinting and enhance immunity against SARS-CoV-2 strains.