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Immune imprinting is a phenomenon in which prior antigen exposure limits variant-specific de novo immune responses to subsequent related antigens. The serum response to Omicron boosters in mice and human are strongly imprinted by prior vaccines encoding SARS-CoV-2 Wuhan-1 spike (e.g., mRNA-1273). Strategies including changes of dosage and interval have had limited success in enhancing variant-specific immunity. Intranasal (i.n.) vaccination is a promising approach that elicits mucosal and systemic immunity. Here we analysed the response of variant boosters delivered i.m. or i.n. after mRNA-1273 priming at the serum, cellular, and B cell repertoire levels to understand how boosting routes modulate the imprinting effect. C57BL/6 mice were primed i.m. with mRNA-1273 and heterologously boosted i.m. or i.n. with a chimpanzee adenoviral-vectored vaccine (ChAd-SARS-CoV-2-S) against XBB.1.5 spike. Serum and bronchoalveolar lavage fluid (BALF) were analysed for cross-reactive and strain-specific spike-binding IgG/IgA. Neutralizing activity was assessed using pseudovirus neutralization assays. Cross-reactive and strain-specific spike-binding memory B cells (MBCs) in draining lymph nodes (dLNs) were quantified. Ongoing studies are using single-cell BCR sequencing to analyse plasmablast clonotypes, with selected ones expressed as mAbs for functional and epitope analyses. Intranasal boosting with ChAd-SARS-CoV-2-S against XBB.1.5 spike induced higher fractions of XBB.1.5-specific serum IgG and BALF IgA with greater neutralizing activity. Intranasal vaccination increased XBB.1.5-specific MBCs in dLNs, indicating a route-dependent shift in B cell specificity. Intranasal boosting promotes greater variant-specific response at both the serum and cellular levels than i.m. boosting. Ongoing B cell repertoire and mAb analyses will provide mechanistic insight into how vaccination route reshapes clonal selection and maturation, informing rational vaccination design. Moderna and NIH R01AI157155 Vaccines and Immunotherapy (VAC)
