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Maturation of SARS-CoV-2 Spike-specific memory B cells drives resilience to viral escape.

ABSTRACT: Memory B cells (MBCs) generate rapid antibody responses upon secondary encounter with a pathogen. Here, we investigated the kinetics, avidity, and cross-reactivity of serum antibodies and MBCs in 155 SARS-CoV-2 infected and vaccinated individuals over a 16-month time frame. SARS-CoV-2-specific MBCs and serum antibodies reached steady-state titers with comparable kinetics in infected and vaccinated individuals. Whereas MBCs of infected individuals targeted both prefusion and postfusion Spike (S), most vaccine-elicited MBCs were specific for prefusion S, consistent with the use of prefusion-stabilized S in mRNA vaccines. Furthermore, a large fraction of MBCs recognizing postfusion S cross-reacted with human betacoronaviruses. The avidity of MBC-derived and serum antibodies increased over time resulting in enhanced resilience to viral escape by SARS-CoV-2 variants, including Omicron BA.1 and BA.2 sublineages, albeit only partially for BA.4 and BA.5 sublineages. Overall, the maturation of high-affinity and broadly reactive MBCs provides the basis for effective recall responses to future SARS-CoV-2 variants.

SUBMITTER: Marzi R

PROVIDER: S-EPMC9721160 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Maturation of SARS-CoV-2 Spike-specific memory B cells drives resilience to viral escape.

Marzi Roberta R Bassi Jessica J Silacci-Fregni Chiara C Bartha Istvan I Muoio Francesco F Culap Katja K Sprugasci Nicole N Lombardo Gloria G Saliba Christian C Cameroni Elisabetta E Cassotta Antonino A Low Jun Siong JS Walls Alexandra C AC McCallum Matthew M Tortorici M Alejandra MA Bowen John E JE Dellota Exequiel A EA Dillen Josh R JR Czudnochowski Nadine N Pertusini Laura L Terrot Tatiana T Lepori Valentino V Tarkowski Maciej M Riva Agostino A Biggiogero Maira M Franzetti-Pellanda Alessandra A Garzoni Christian C Ferrari Paolo P Ceschi Alessandro A Giannini Olivier O Havenar-Daughton Colin C Telenti Amalio A Arvin Ann A Virgin Herbert W HW Sallusto Federica F Veesler David D Lanzavecchia Antonio A Corti Davide D Piccoli Luca L

iScience 20221205 1

Memory B cells (MBCs) generate rapid antibody responses upon secondary encounter with a pathogen. Here, we investigated the kinetics, avidity, and cross-reactivity of serum antibodies and MBCs in 155 SARS-CoV-2 infected and vaccinated individuals over a 16-month time frame. SARS-CoV-2-specific MBCs and serum antibodies reached steady-state titers with comparable kinetics in infected and vaccinated individuals. Whereas MBCs of infected individuals targeted both prefusion and postfusion Spike (S), ...[more]

PMID: 36507220

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Project description:The SARS-CoV-2 Omicron BA.1 variant emerged in late 2021 and is characterised by multiple spike mutations across all spike domains. Here we show that Omicron BA.1 has higher affinity for ACE2 compared to Delta, and confers very significant evasion of therapeutic monoclonal and vaccine-elicited polyclonal neutralising antibodies after two doses. mRNA vaccination as a third vaccine dose rescues and broadens neutralisation. Importantly, antiviral drugs remdesevir and molnupiravir retain efficacy against Omicron BA.1. We found that in human nasal epithelial 3D cultures replication was similar for both Omicron and Delta. However, in lower airway organoids, Calu-3 lung cells and gut adenocarcinoma cell lines live Omicron virus demonstrated significantly lower replication in comparison to Delta. We noted that despite presence of mutations predicted to favour spike S1/S2 cleavage, the spike protein is less efficiently cleaved in live Omicron virions compared to Delta virions. We mapped the replication differences between the variants to entry efficiency using spike pseudotyped virus (PV) entry assays. The defect for Omicron PV in specific cell types correlated with higher cellular RNA expression of TMPRSS2, and accordingly knock down of TMPRSS2 impacted Delta entry to a greater extent as compared to Omicron. Furthermore, drug inhibitors targeting specific entry pathways demonstrated that the Omicron spike inefficiently utilises the cellular protease TMPRSS2 that mediates cell entry via plasma membrane fusion. Instead, we demonstrate that Omicron spike has greater dependency on cell entry via the endocytic pathway requiring the activity of endosomal cathepsins to cleave spike. Consistent with suboptimal S1/S2 cleavage and inability to utilise TMPRSS2, syncytium formation by the Omicron spike was dramatically impaired compared to the Delta spike. Overall, Omicron appears to have gained significant evasion from neutralising antibodies whilst maintaining sensitivity to antiviral drugs targeting the polymerase. Omicron has shifted cellular tropism away from TMPRSS2 expressing cells that are enriched in cells found in the lower respiratory and GI tracts, with implications for altered pathogenesis.

Dataset Information

Maturation of SARS-CoV-2 Spike-specific memory B cells drives resilience to viral escape.

Publications

Maturation of SARS-CoV-2 Spike-specific memory B cells drives resilience to viral escape.

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