Isolation of potent SARS-CoV-2 neutralizing antibodies and protection from disease in a small animal model.

Countermeasures to prevent and treat coronavirus disease 2019 (COVID-19) are a global health priority. We enrolled a cohort of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-recovered participants, developed neutralization assays to investigate antibody responses, adapted our high-throughput antibody generation pipeline to rapidly screen more than 1800 antibodies, and established an animal model to test protection. We isolated potent neutralizing antibodies (nAbs) to two epitopes on the receptor binding domain (RBD) and to distinct non-RBD epitopes on the spike (S) protein. As indicated by maintained weight and low lung viral titers in treated animals, the passive transfer of a nAb provides protection against disease in high-dose SARS-CoV-2 challenge in Syrian hamsters. The study suggests a role for nAbs in prophylaxis, and potentially therapy, of COVID-19. The nAbs also define protective epitopes to guide vaccine design.

Rogers TF ，Zhao F ，Huang D ，Beutler N ，Burns A ，He WT ，Limbo O ，Smith C ，Song G ，Woehl J ，Yang L ，Abbott RK ，Callaghan S ，Garcia E ，Hurtado J ，Parren M ，Peng L ，Ramirez S ，Ricketts J ，Ricciardi MJ ，Rawlings SA ，Wu NC ，Yuan M ，Smith DM ，Nemazee D ，Teijaro JR ，Voss JE ，Wilson IA ，Andrabi R ，Briney B ，Landais E ，Sok D ，Jardine JG ，Burton DR ... -  《-》

Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability.

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a large impact on global health, travel, and economy. Therefore, preventative and therapeutic measures are urgently needed. Here, we isolated monoclonal antibodies from three convalescent coronavirus disease 2019 (COVID-19) patients using a SARS-CoV-2 stabilized prefusion spike protein. These antibodies had low levels of somatic hypermutation and showed a strong enrichment in VH1-69, VH3-30-3, and VH1-24 gene usage. A subset of the antibodies was able to potently inhibit authentic SARS-CoV-2 infection at a concentration as low as 0.007 micrograms per milliliter. Competition and electron microscopy studies illustrate that the SARS-CoV-2 spike protein contains multiple distinct antigenic sites, including several receptor-binding domain (RBD) epitopes as well as non-RBD epitopes. In addition to providing guidance for vaccine design, the antibodies described here are promising candidates for COVID-19 treatment and prevention.

Brouwer PJM ，Caniels TG ，van der Straten K ，Snitselaar JL ，Aldon Y ，Bangaru S ，Torres JL ，Okba NMA ，Claireaux M ，Kerster G ，Bentlage AEH ，van Haaren MM ，Guerra D ，Burger JA ，Schermer EE ，Verheul KD ，van der Velde N ，van der Kooi A ，van Schooten J ，van Breemen MJ ，Bijl TPL ，Sliepen K ，Aartse A ，Derking R ，Bontjer I ，Kootstra NA ，Wiersinga WJ ，Vidarsson G ，Haagmans BL ，Ward AB ，de Bree GJ ，Sanders RW ，van Gils MJ ... -  《-》

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 ... -  《-》

Ultrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms.

Efficient therapeutic options are needed to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has caused more than 922,000 fatalities as of 13 September 2020. We report the isolation and characterization of two ultrapotent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that protect hamsters against SARS-CoV-2 challenge. Cryo-electron microscopy structures show that S2E12 and S2M11 competitively block angiotensin-converting enzyme 2 (ACE2) attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains. Antibody cocktails that include S2M11, S2E12, or the previously identified S309 antibody broadly neutralize a panel of circulating SARS-CoV-2 isolates and activate effector functions. Our results pave the way to implement antibody cocktails for prophylaxis or therapy, circumventing or limiting the emergence of viral escape mutants.

Tortorici MA ，Beltramello M ，Lempp FA ，Pinto D ，Dang HV ，Rosen LE ，McCallum M ，Bowen J ，Minola A ，Jaconi S ，Zatta F ，De Marco A ，Guarino B ，Bianchi S ，Lauron EJ ，Tucker H ，Zhou J ，Peter A ，Havenar-Daughton C ，Wojcechowskyj JA ，Case JB ，Chen RE ，Kaiser H ，Montiel-Ruiz M ，Meury M ，Czudnochowski N ，Spreafico R ，Dillen J ，Ng C ，Sprugasci N ，Culap K ，Benigni F ，Abdelnabi R ，Foo SC ，Schmid MA ，Cameroni E ，Riva A ，Gabrieli A ，Galli M ，Pizzuto MS ，Neyts J ，Diamond MS ，Virgin HW ，Snell G ，Corti D ，Fink K ，Veesler D ... -  《-》

Isolation and characterization of cross-neutralizing coronavirus antibodies from COVID-19+ subjects.

SARS-CoV-2 is one of three coronaviruses that have crossed the animal-to-human barrier and caused widespread disease in the past two decades. The development of a universal human coronavirus vaccine could prevent future pandemics. We characterize 198 antibodies isolated from four COVID-19+ subjects and identify 14 SARS-CoV-2 neutralizing antibodies. One targets the N-terminal domain (NTD), one recognizes an epitope in S2, and 11 bind the receptor-binding domain (RBD). Three anti-RBD neutralizing antibodies cross-neutralize SARS-CoV-1 by effectively blocking binding of both the SARS-CoV-1 and SARS-CoV-2 RBDs to the ACE2 receptor. Using the K18-hACE transgenic mouse model, we demonstrate that the neutralization potency and antibody epitope specificity regulates the in vivo protective potential of anti-SARS-CoV-2 antibodies. All four cross-neutralizing antibodies neutralize the B.1.351 mutant strain. Thus, our study reveals that epitopes in S2 can serve as blueprints for the design of immunogens capable of eliciting cross-neutralizing coronavirus antibodies.

Jennewein MF ，MacCamy AJ ，Akins NR ，Feng J ，Homad LJ ，Hurlburt NK ，Seydoux E ，Wan YH ，Stuart AB ，Edara VV ，Floyd K ，Vanderheiden A ，Mascola JR ，Doria-Rose N ，Wang L ，Yang ES ，Chu HY ，Torres JL ，Ozorowski G ，Ward AB ，Whaley RE ，Cohen KW ，Pancera M ，McElrath MJ ，Englund JA ，Finzi A ，Suthar MS ，McGuire AT ，Stamatatos L ... -  《Cell Reports》