It is proposed that there is somatic hypermutation of existing B cell clones rather than de novo generation from naive B cells in JN.1-adapted booster vaccines and this finding indicates maturation of pre-existing, class-switched MBC rather than substantial de novo recruitment of naïve B cells.
Abstract
The antigenic drift of SARS-CoV-2 toward the JN.1 lineage has prompted the development of variant-adapted COVID-19 booster vaccines. However, these boosters are thought to primarily recall pre-existing memory B cells (MBC), raising concerns about their ability to realign the immune response in highly pre-exposed populations. Here we analyze antibody and B cell responses in pre-exposed individuals (n = 42; median 4.5 prior COVID-19 vaccinations; 90% with at least one prior SARS-CoV-2 infection) following vaccination with a JN.1-adapted mRNA vaccine. Vaccination is associated with increased IgG binding and enhanced neutralization of JN.1 and related descendant variants. Longitudinal profiling of antigen-specific MBC shows that Wu01-only and Wu01/JN.1 cross-reactive cells remain dominant, while JN.1-only cells modestly increase by day 21. Single-cell RNA-sequencing of antigen-specific MBC in a representative sub-cohort (n = 7), combined with functional monoclonal antibody analyses, demonstrates that somatic hypermutation (SHM) drives intra-clonotype specialization toward improved JN.1 binding and neutralization. These findings indicate maturation of pre-existing, class-switched MBC rather than substantial de novo recruitment of naïve B cells. In conclusion, JN.1-adapted booster vaccination is associated with refinement of pre-existing MBC repertoires toward the JN.1 antigenic space and with enhanced neutralization of contemporary and antigenically proximate variants. Because of the continuous evolution of SARS-CoV-2, pre-existing immune responses may not be as effective against new viral variants. Here the authors investigate whether B cell responses to ancestral SARS-CoV-2 are stimulated by JN.1-adapted booster vaccines and propose that there is somatic hypermutation of existing B cell clones rather than de novo generation from naive B cells.
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”.
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.
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.
Collectively, multi-color inverted assays provide a suitable methodology for assessment of Bmem cross-reactivity in larger donor cohorts.
N/A
Viral Immunology (VIR)
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