Omicron BA.1 breakthrough infection drives long-term remodeling of the memory B cell repertoire in vaccinated individuals

Abstract

How infection by a viral variant showing antigenic drift impacts a preformed mature human memory B cell (MBC) repertoire remains an open question. Here, we studied the MBC response up to 6 months after Omicron BA.1 breakthrough infection in individuals previously vaccinated with three doses of mRNA vaccine. Longitudinal analysis, using single-cell multi-omics and functional analysis of monoclonal antibodies from RBD-specific MBCs, revealed that a BA.1 breakthrough infection mostly recruited pre-existing cross-reactive MBCs with limited de novo response against BA.1-restricted epitopes. Reorganization of clonal hierarchy and new rounds of germinal center reaction, however, combined to maintain diversity and induce progressive maturation of the MBC repertoire against common Hu-1 and BA.1, but not BA.5-restricted, SARS-CoV-2 Spike RBD epitopes. Such remodeling was further associated with marked improvement in overall neutralizing breadth and potency. These findings have fundamental implications for the design of future vaccination booster strategies.

Enhanced neutralization of SARS-CoV-2 XBB sub-lineages and BA.2.86 by a tetravalent COVID-19 vaccine booster

“…This heightened MBC response may be instrumental in generating robust levels of neutralizing antibodies capable of thwarting reinfections by newly emergent variants. These results lend credence to the idea that repeated exposure to viral antigens, whether through natural infection or booster immunization with a novel vaccine, can fortify our B-cell immune response against evolving strains [28][29][30] . Moreover, a robust SARS-CoV-2-specific T-cell response, whether induced by vaccination or natural infection, can effectively eradicate infected cells, curb further viral spread, and guard against severe disease 31 .…”

Durable reprogramming of neutralizing antibody responses following Omicron breakthrough infection

“…Kaku et al (12) reported that BA.1 breakthrough infection drove affinity maturation of cross-reactive B cells and antibodies toward Omicron BA.1 over time, although our data suggest that, mechanistically, this occurs through selective reexpansion of B cell memory. Supporting this, studies of the clonal repertoire of expanded crossreactive memory responses after breakthrough infection show a strong conservation of vaccine-established clones and clonal families (12,13). In addition, there was little evidence of additional gains in Vgene somatic mutation in responding memory B cells (13), again suggesting that affinity maturation of the polyclonal antibody response toward Omicron spike is via selective expansion of higher affinity B cells instead of secondary germinal center activity.…”

“…Supporting this, studies of the clonal repertoire of expanded crossreactive memory responses after breakthrough infection show a strong conservation of vaccine-established clones and clonal families (12,13). In addition, there was little evidence of additional gains in Vgene somatic mutation in responding memory B cells (13), again suggesting that affinity maturation of the polyclonal antibody response toward Omicron spike is via selective expansion of higher affinity B cells instead of secondary germinal center activity. While the isolation of receptor binding domain (RBD)-specific monoclonal antibodies (mAbs) specific for the BA.1 RBD that do not crossreact with ancestral RBD has been reported, these comprised only a small fraction (median, 4%) of the response to RBD (12), confirming that neo-epitopes are poorly recognized during breakthrough infection.…”

Germinal centers are permissive to subdominant antibody responses

“…In this study, we focus on investigating the immune response in primary GC responses and therefore neglect the presence of memory B cells, pre-existing serum antibodies and the contribution of an altered immune properties such as age (Linterman et al, 2023) or the degree of chronic inflammation. Although it is clear that memory cells participate in secondary GC reactions (Sokal et al, 2023), the extent of participation is unclear (Mesin et al, 2020). In our previous study (Robert et al, 2021), considering 5% of founder B cells as memory B cells substantially increased the affinity of output cells.…”

“…Apart from the antigen structure, the availability of BCRs (Abbott et al, 2018) that bind different domains of the antigen and their competition in the GC are also critical for the establishment of immunodominance. The availability of memory cells from previous immunizations (Sokal et al, 2023) can mitigate the relative response to different antigens. It has also been proposed that the memory response to a previous antigen variant might decrease the strength of recognition to newer strains by skewed recognition to those antigens, termed the "Original Antigenic Sin" (Francis, 1960) while computer simulations suggested that memory responses would promote a shift to antibody responses to less immunogenic epitopes (Meyer-Hermann, 2019).…”