Cross-Neutralization of a SARS-CoV-2 Antibody to a Functionally Conserved Site Is Mediated by Avidity.

Most antibodies isolated from individuals with coronavirus disease 2019 (COVID-19) are specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here, we determined a crystal structure of the COVA1-16 antibody fragment (Fab) with the SARS-CoV-2 receptor-binding domain (RBD) and negative-stain electron microscopy reconstructions with the spike glycoprotein trimer to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long complementarity-determining region (CDR) H3, and competes with the angiotensin-converting enzyme 2 (ACE2) receptor because of steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with the structural and functional rationale for epitope conservation, provide insights for development of more universal SARS-like coronavirus vaccines and therapies.

Liu H ，Wu NC ，Yuan M ，Bangaru S ，Torres JL ，Caniels TG ，van Schooten J ，Zhu X ，Lee CD ，Brouwer PJM ，van Gils MJ ，Sanders RW ，Ward AB ，Wilson IA ... -  《-》

Cross-neutralization of a SARS-CoV-2 antibody to a functionally conserved site is mediated by avidity.

Liu H ，Wu NC ，Yuan M ，Bangaru S ，Torres JL ，Caniels TG ，van Schooten J ，Zhu X ，Lee CD ，Brouwer PJM ，van Gils MJ ，Sanders RW ，Ward AB ，Wilson IA ... -  《-》

SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape.

An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape1-3, have activity against diverse sarbecoviruses4-7, and be highly protective through viral neutralization8-11 and effector functions12,13. Understanding how these properties relate to each other and vary across epitopes would aid the development of therapeutic antibodies and guide vaccine design. Here we comprehensively characterize escape, breadth and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a trade-off between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies that target the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we also characterize a potent RBM antibody (S2E128) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth and potency among antibodies that target the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.

Starr TN ，Czudnochowski N ，Liu Z ，Zatta F ，Park YJ ，Addetia A ，Pinto D ，Beltramello M ，Hernandez P ，Greaney AJ ，Marzi R ，Glass WG ，Zhang I ，Dingens AS ，Bowen JE ，Tortorici MA ，Walls AC ，Wojcechowskyj JA ，De Marco A ，Rosen LE ，Zhou J ，Montiel-Ruiz M ，Kaiser H ，Dillen JR ，Tucker H ，Bassi J ，Silacci-Fregni C ，Housley MP ，di Iulio J ，Lombardo G ，Agostini M ，Sprugasci N ，Culap K ，Jaconi S ，Meury M ，Dellota E Jr ，Abdelnabi R ，Foo SC ，Cameroni E ，Stumpf S ，Croll TI ，Nix JC ，Havenar-Daughton C ，Piccoli L ，Benigni F ，Neyts J ，Telenti A ，Lempp FA ，Pizzuto MS ，Chodera JD ，Hebner CM ，Virgin HW ，Whelan SPJ ，Veesler D ，Corti D ，Bloom JD ，Snell G ... -  《-》

SARS-CoV-2 BA.4/5 infection triggers more cross-reactive FcγRIIIa signaling and neutralization than BA.1, in the context of hybrid immunity.

Richardson SI ，Mzindle N ，Motlou T ，Manamela NP ，van der Mescht MA ，Lambson BE ，Everatt J ，Amoako DG ，Balla S ，von Gottberg A ，Wolter N ，de Beer Z ，de Villiers TR ，Bodenstein A ，van den Berg G ，Abdullah F ，Rossouw TM ，Boswell MT ，Ueckermann V ，Bhiman JN ，Moore PL ... -  《-》

Structures of Human Antibodies Bound to SARS-CoV-2 Spike Reveal Common Epitopes and Recurrent Features of Antibodies.

Neutralizing antibody responses to coronaviruses mainly target the receptor-binding domain (RBD) of the trimeric spike. Here, we characterized polyclonal immunoglobulin Gs (IgGs) and Fabs from COVID-19 convalescent individuals for recognition of coronavirus spikes. Plasma IgGs differed in their focus on RBD epitopes, recognition of alpha- and beta-coronaviruses, and contributions of avidity to increased binding/neutralization of IgGs over Fabs. Using electron microscopy, we examined specificities of polyclonal plasma Fabs, revealing recognition of both S1A and RBD epitopes on SARS-CoV-2 spike. Moreover, a 3.4 Å cryo-electron microscopy (cryo-EM) structure of a neutralizing monoclonal Fab-spike complex revealed an epitope that blocks ACE2 receptor binding. Modeling based on these structures suggested different potentials for inter-spike crosslinking by IgGs on viruses, and characterized IgGs would not be affected by identified SARS-CoV-2 spike mutations. Overall, our studies structurally define a recurrent anti-SARS-CoV-2 antibody class derived from VH3-53/VH3-66 and similarity to a SARS-CoV VH3-30 antibody, providing criteria for evaluating vaccine-elicited antibodies.

Barnes CO ，West AP Jr ，Huey-Tubman KE ，Hoffmann MAG ，Sharaf NG ，Hoffman PR ，Koranda N ，Gristick HB ，Gaebler C ，Muecksch F ，Lorenzi JCC ，Finkin S ，Hägglöf T ，Hurley A ，Millard KG ，Weisblum Y ，Schmidt F ，Hatziioannou T ，Bieniasz PD ，Caskey M ，Robbiani DF ，Nussenzweig MC ，Bjorkman PJ ... -  《-》