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 ... -  《-》

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 ... -  《-》

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 ... -  《-》

COVID-19 Vaccines: "Warp Speed" Needs Mind Melds, Not Warped Minds.

In this review, we address issues that relate to the rapid "Warp Speed" development of vaccines to counter the COVID-19 pandemic. We review the antibody response that is triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of humans and how it may inform vaccine research. The isolation and properties of neutralizing monoclonal antibodies from COVID-19 patients provide additional information on what vaccines should try to elicit. The nature and longevity of the antibody response to coronaviruses are relevant to the potency and duration of vaccine-induced immunity. We summarize the immunogenicity of leading vaccine candidates tested to date in animals and humans and discuss the outcome and interpretation of virus challenge experiments in animals. By far the most immunogenic vaccine candidates for antibody responses are recombinant proteins, which were not included in the initial wave of Warp Speed immunogens. A substantial concern for SARS-CoV-2 vaccines is adverse events, which we review by considering what was seen in studies of SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) vaccines. We conclude by outlining the possible outcomes of the Warp Speed vaccine program, which range from the hoped-for rapid success to a catastrophic adverse influence on vaccine uptake generally.

Moore JP ，Klasse 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 ... -  《-》