Evaluating memory B cell cross-reactivity between ancestral and future SARS-CoV-2 variants — evidence for original antigenic sin 2219641

Abstract Introduction A hallmark of adaptive immunity is the generation of immunological memory and ability to mount a robust recall response following encounter with the same antigen. In the context of mutable pathogens, the specificity of memory B cells (Bmem) generated following the initial exposure can constrain the response elicited by an antigenic drift variant — a phenomenon referred to as “original antigenic sin”. Methods To investigate whether human donors with verified SARS-CoV-2 infection in early 2022, likely with Omicron (BA.1), generated variant-specific Bmem responses or whether WH1-reactive Bmem were preferentially boosted, we established a novel ImmunoSpot assay to assess cross-reactivity at single-cell resolution. Results Bmem capable of recognizing BA.1 RBD were already present in convalescent donors collected early in the COVID-19 pandemic, and such secretory footprints were equally labelled with WH1 and BA.1 RBD probes. In contrast, assessment of Bmem following BA.1 infection revealed an increased frequency of WH1/BA.1 dual-reactivity and few, if any, BA.1 strain-specific footprints providing evidence for preferential boosting of Bmem recognizing shared epitopes. Moreover, we observed increased heterogeneity in the size of the secretory footprints revealed by the RBD probes, indicating cross-reactive Bmem maintained an increased affinity for the WH1 strain. Conclusion Collectively, multi-color inverted assays provide a suitable methodology for assessment of Bmem cross-reactivity in larger donor cohorts. Funding Source N/A Topic Categories Viral Immunology (VIR)