Intranasal SARS-CoV-2 vaccine boosting alters immune imprinting and B cell repertoire 2331448

Abstract

Abstract Introduction 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. Methods 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. Results 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. Conclusion 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. Funding Source Moderna and NIH R01AI157155 Topic Categories Vaccines and Immunotherapy (VAC)