scholarly journals Structural Basis and Mode of Action for Two Broadly Neutralizing Antibodies Against SARS-CoV-2 Emerging Variants of Concern

Cell Reports ◽  
2021 ◽  
pp. 110210
Author(s):  
Wenwei Li ◽  
Yaozong Chen ◽  
Jérémie Prévost ◽  
Irfan Ullah ◽  
Maolin Lu ◽  
...  
Keyword(s):  
Mode Of Action ◽  
Neutralizing Antibodies ◽  
Structural Basis ◽  
Broadly Neutralizing Antibodies

scholarly journals Structural Basis and Mode of Action for Two Broadly Neutralizing Antibodies Against SARS-CoV-2 Emerging Variants of Concern

2021 ◽  
Author(s):  
Walther Mothes ◽  
Wenwei Li ◽  
Yaozong Chen ◽  
Jeremie Prevost ◽  
Irfan Ullah ◽  
...  
Keyword(s):  
Immune Responses ◽  
Mode Of Action ◽  
Neutralizing Antibodies ◽  
Structural Basis ◽  
Receptor Binding Domain ◽  
Broadly Neutralizing Antibodies ◽  
Vaccine Immunogen ◽  
Immunogen Design

Emerging variants of concern for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit more efficiently and partially evade protective immune responses, thus necessitating continued refinement of antibody therapies and immunogen design. Here we elucidate the structural basis and mode of action for two potent SARS-CoV-2 Spike (S) neutralizing monoclonal antibodies CV3-1 and CV3-25 that remained effective against emerging variants of concern in vitro and in vivo. CV3-1 bound to the (485-GFN-487) loop within the receptor-binding domain (RBD) in the RBD-up position and triggered potent shedding of the S1 subunit. In contrast, CV3-25 inhibited membrane fusion by binding to an epitope in the stem helix region of the S2 subunit that is highly conserved among beta-coronaviruses. Thus, vaccine immunogen designs that incorporate the conserved regions in RBD and stem helix region are candidates to elicit pan-coronavirus protective immune responses.

scholarly journals Structural basis for broad sarbecovirus neutralization by a human monoclonal antibody

2021 ◽  
Author(s):  
M. Alejandra Tortorici ◽  
Nadine Czudnochowski ◽  
Tyler N Starr ◽  
Roberta Marzi ◽  
Alexandra C. Walls ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Neutralizing Antibodies ◽  
Wide Spectrum ◽  
Human Monoclonal Antibody ◽  
Antigenic Site ◽  
Antigenic Drift ◽  
Structural Basis ◽  
Broadly Neutralizing Antibodies ◽  
Zoonotic Infections ◽  
Recent Emergence

The recent emergence of SARS-CoV-2 variants of concern (VOC) and the recurrent spillovers of coronaviruses in the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here, we describe a human monoclonal antibody (mAb), designated S2X259, recognizing a highly conserved cryptic receptor-binding domain (RBD) epitope and cross-reacting with spikes from all sarbecovirus clades. S2X259 broadly neutralizes spike-mediated entry of SARS-CoV-2 including the B.1.1.7, B.1.351, P.1 and B.1.427/B.1.429 VOC, as well as a wide spectrum of human and zoonotic sarbecoviruses through inhibition of ACE2 binding to the RBD. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses a remarkably high barrier to the emergence of resistance mutants. We show that prophylactic administration of S2X259 protects Syrian hamsters against challenges with the prototypic SARS-CoV-2 and the B.1.351 variant, suggesting this mAb is a promising candidate for the prevention and treatment of emergent VOC and zoonotic infections. Our data unveil a key antigenic site targeted by broadly-neutralizing antibodies and will guide the design of pan-sarbecovirus vaccines.

scholarly journals Structural basis of broad HIV neutralization by a vaccine-induced cow antibody

2020 ◽  
Vol 6 (22) ◽  
pp. eaba0468 ◽  
Author(s):  
Robyn L. Stanfield ◽  
Zachary T. Berndsen ◽  
Ruiqi Huang ◽  
Devin Sok ◽  
Gabrielle Warner ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Site Directed Mutagenesis ◽  
Structural Basis ◽  
Broadly Neutralizing Antibodies ◽  
Receptor Binding Site ◽  
X Ray Crystallography ◽  
Cryo Electron Microscopy ◽  
Small Footprint ◽  
Hiv Neutralization ◽  
Hiv Envelope

Potent broadly neutralizing antibodies (bnAbs) to HIV have been very challenging to elicit by vaccination in wild-type animals. Here, by x-ray crystallography, cryo–electron microscopy, and site-directed mutagenesis, we structurally and functionally elucidate the mode of binding of a potent bnAb (NC-Cow1) elicited in cows by immunization with the HIV envelope (Env) trimer BG505 SOSIP.664. The exceptionally long (60 residues) third complementarity-determining region of the heavy chain (CDR H3) of NC-Cow1 forms a mini domain (knob) on an extended stalk that navigates through the dense glycan shield on Env to target a small footprint on the gp120 CD4 receptor binding site with no contact of the other CDRs to the rest of the Env trimer. These findings illustrate, in molecular detail, how an unusual vaccine-induced cow bnAb to HIV Env can neutralize with high potency and breadth.

scholarly journals Structural basis for germline antibody recognition of HIV-1 immunogens

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Louise Scharf ◽  
Anthony P West ◽  
Stuart A Sievers ◽  
Courtney Chen ◽  
Siduo Jiang ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Affinity Maturation ◽  
Structural Basis ◽  
Binding Modes ◽  
Broadly Neutralizing Antibodies ◽  
Antibody Recognition ◽  
Immunogen Design ◽  
Cd4 Binding Site ◽  
Modified Forms ◽  
Hiv 1

Efforts to elicit broadly neutralizing antibodies (bNAbs) against HIV-1 require understanding germline bNAb recognition of HIV-1 envelope glycoprotein (Env). The VRC01-class bNAb family derived from the VH1-2*02 germline allele arose in multiple HIV-1–infected donors, yet targets the CD4-binding site on Env with common interactions. Modified forms of the 426c Env that activate germline-reverted B cell receptors are candidate immunogens for eliciting VRC01-class bNAbs. We present structures of germline-reverted VRC01-class bNAbs alone and complexed with 426c-based gp120 immunogens. Germline bNAb–426c gp120 complexes showed preservation of VRC01-class signature residues and gp120 contacts, but detectably different binding modes compared to mature bNAb-gp120 complexes. Unlike typical antibody-antigen interactions, VRC01–class germline antibodies exhibited preformed antigen-binding conformations for recognizing immunogens. Affinity maturation introduced substitutions increasing induced-fit recognition and electropositivity, potentially to accommodate negatively-charged complex-type N-glycans on gp120. These results provide general principles relevant to the unusual evolution of VRC01–class bNAbs and guidelines for structure-based immunogen design.

Broadly Neutralizing Antibodies (BNAbs): templates for HIV-1 vaccine design

2017 ◽  
Vol 2 (4) ◽  
Author(s):  
Lixin Yan ◽  
◽  
Lihong Liu ◽  
Yilin Wang ◽  
Xi Huang ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccine Design ◽  
Broadly Neutralizing Antibodies ◽  
Hiv 1

scholarly journals Unique structural solution from a VH3-30 antibody targeting the hemagglutinin stem of influenza A viruses

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Wayne D. Harshbarger ◽  
Derrick Deming ◽  
Gordon J. Lockbaum ◽  
Nattapol Attatippaholkun ◽  
Maliwan Kamkaew ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Influenza A ◽  
Critical Role ◽  
Binding Activity ◽  
Human Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Influenza A Viruses ◽  
Universal Vaccine ◽  
Structural Details ◽  
Structural Solution

AbstractBroadly neutralizing antibodies (bnAbs) targeting conserved influenza A virus (IAV) hemagglutinin (HA) epitopes can provide valuable information for accelerating universal vaccine designs. Here, we report structural details for heterosubtypic recognition of HA from circulating and emerging IAVs by the human antibody 3I14. Somatic hypermutations play a critical role in shaping the HCDR3, which alone and uniquely among VH3-30 derived antibodies, forms contacts with five sub-pockets within the HA-stem hydrophobic groove. 3I14 light-chain interactions are also key for binding HA and contribute a large buried surface area spanning two HA protomers. Comparison of 3I14 to bnAbs from several defined classes provide insights to the bias selection of VH3-30 antibodies and reveals that 3I14 represents a novel structural solution within the VH3-30 repertoire. The structures reported here improve our understanding of cross-group heterosubtypic binding activity, providing the basis for advancing immunogen designs aimed at eliciting a broadly protective response to IAV.

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