Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift

Cameroni, Elisabetta; Saliba, Christian; Bowen, John E.; Rosen, Laura E.; Culap, Katja; Pinto, Dora; VanBlargan, Laura A.; Zepeda, Samantha K; Iulio, Julia di; Kaiser, Hannah; Noack, Julia; Czudnochowski, Nadine; Havenar-Daughton, Colin; Sprouse, Kaitlin R.; Chen, Alex; Maher, M. Cyrus; Gustafsson, Claes; Bassi, Jessica; Silacci-Fregni, Chiara; Iqbal, Najeeha Talat; Franko, Nicholas; Geffner, Jorge; Mazzitelli, Ignacio; Gori, Andrea; Grifantini, Renata; Giannini, Olivier; Ferrari, Paolo; Garzoni, Christian; Cippà, Pietro E; Piccoli, Luca; Walls, Alexandra C.; Telenti, Amalio; Virgin, Herbert W.; Lanzavecchia, Antonio; Pizzuto, Matteo Samuele; Diamond, Michael S.; Veesler, David; Snell, Gyorgy; Corti, Davide

doi:10.1101/2021.12.12.472269

Cited by 84 publications

(124 citation statements)

References 71 publications

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“…For therapeutic strategies to overcome virus mutation, some antibodies are used in the form of a cocktail and others are designed to target a conserved region, in order to prevent mutational escape. However, Omicron exhibits the ability to pass through combinations of antibodies (3,4) and acquired mutations even in highly conserved vulnerable sites (S371L, S373P, S375F). These observations provide a sobering outlook for the development of monoclonal antibodies against viruses in the context of escape mutation.…”

Section: Discussionmentioning

confidence: 99%

“…According to routine surveillance data from South Africa, Omicron has higher transmission and risk of reinfection due to immune evasion (1). In addition, multiple mutations in the RBD can impact escape from therapeutic monoclonal antibodies, even in cocktail regimen (3,4).…”

Section: Introductionmentioning

confidence: 99%

“…We previously developed an engineered ACE2 containing mutations to enhance the affinity toward SARS-CoV-2 spike that showed virus-neutralizing capacity comparable to therapeutic monoclonal antibodies (3). The advantage of the ACE2-based decoy is its resistance to virus escape mutations.…”

Section: Introductionmentioning

confidence: 99%

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Engineered ACE2 counteracts vaccine-evading SARS-CoV-2 Omicron variant

Ikemura

Taminishi

Inaba

et al. 2021

Preprint

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The novel SARS-CoV-2 variant, Omicron (B.1.1.529) contains an unusually high number of mutations (>30) in the spike protein, raising concerns of escape from vaccines, convalescent sera and therapeutic drugs. Here we analyze the alteration of neutralizing titer with Omicron pseudovirus. Sera of 3 months after double BNT162b2 vaccination exhibit approximately 18-fold lower neutralization titers against Omicron. Convalescent sera from Alpha and Delta patients allow similar levels of breakthrough by Omicron. However, some Delta patients have relatively preserved neutralization efficacy, comparable to 3-month double BNT162b2 vaccination. Domain-wise analysis using chimeric spike revealed that this efficient evasion was, at least in part, caused by multiple mutations in the N-terminal domain. Omicron escapes the therapeutic cocktail of imdevimab and casirivimab, whereas sotrovimab, which targets a conserved region to avoid viral mutation, remains effective against Omicron. The ACE2 decoy is another virus-neutralizing drug modality that is free, at least in theory, from mutational escape. Deep mutational analysis demonstrated that, indeed, the engineered ACE2 overcomes every single-residue mutation in the receptor-binding domain, similar to immunized sera. Like previous SARS-CoV-2 variants, Omicron and some other sarbecoviruses showed high sensitivity against engineered ACE2, confirming the therapeutic value against diverse variants, including those that are yet to emerge.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Engineered ACE2 counteracts vaccine-evading SARS-CoV-2 Omicron variant

Ikemura

Taminishi

Inaba

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…In addition to the impact on ACE2 binding, the mutations in the RBD enable the Omicron variant to escape from antibody recognition and neutralization. Several recent studies have evaluated the neutralizing activities of antibodies against the Omicron variant [1,2,17,18] . Their results showed that most of the studied antibodies, especially Class I and Class II antibodies, lost their neutralizing activities due to mutations in the epitopes such as K417N and E484A, which is consistent with previous studies [19–21] .…”

mentioning

confidence: 99%

Structural and computational insights into the SARS-CoV-2 Omicron RBD-ACE2 interaction

wang

Wang

et al. 2022

Preprint

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Since SARS-CoV-2 Omicron variant (B.1.1.529) was reported in November 2021, it has quickly spread to many countries and outcompeted the globally dominant Delta variant in several countries. The Omicron variant contains the largest number of mutations to date, with 32 mutations located at spike (S) glycoprotein, which raised great concern for its enhanced viral fitness and immune escape[1-4]. In this study, we reported the crystal structure of the receptor binding domain (RBD) of Omicron variant S glycoprotein bound to human ACE2 at a resolution of 2.6 angstrom. Structural comparison, molecular dynamics simulation and binding free energy calculation collectively identified four key mutations (S477N, G496S, Q498R and N501Y) for the enhanced binding of ACE2 by the Omicron RBD compared to the WT RBD. Representative states of the WT and Omicron RBD-ACE2 systems were identified by Markov State Model, which provides a dynamic explanation for the enhanced binding of Omicron RBD. The effects of the mutations in the RBD for antibody recognition were analyzed, especially for the S371L/S373P/S375F substitutions significantly changing the local conformation of the residing loop to deactivate several class IV neutralizing antibodies.

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“…The unceasing accumulation of mutations in the SARS-CoV-2 Spike causes the loss of efficacy for some established neutralizing antibodies 26 . Iterative discovery and identification of neutralizing antibodies against emerging variants will provide a solid stockpile for global pandemic solutions.…”

Section: Selection and Design Of Neutralizing Nbs With Potent Activity And Affinitymentioning

confidence: 99%

An ultrapotent RBD-targeted biparatopic nanobody neutralizes broad SARS-CoV-2 variants

Chi

Zhang

Pan

et al. 2021

Preprint

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The wide transmission and host adaptation of SARS-CoV-2 have led to the rapid accumulation of mutations, posing significant challenges to the effectiveness of vaccines and therapeutic antibodies. Although several neutralizing antibodies were authorized for emergency clinical use, natural antibodies isolated from convalescent patients are vulnerable to SARS-CoV-2 Spike mutations. Here, we describe the screen of a panel of SARS-CoV-2 receptor-binding domain (RBD) targeted nanobodies (Nbs) from a synthetic library and the design of a biparatopic Nb dimer, named Nb1-Nb2, with tight affinity and super wide neutralization breadth against multiple SARS-CoV-2 variants of concern or interest. Deep-mutational scanning experiments identify the potential binding epitopes of the monomeric Nb1 and Nb2 on the RBD and demonstrate that bivalent Nb1-Nb2 has a strong escape resistant feature against more than 60 tested RBD amino acid substitutions. Using pseudovirion-based and trans-complementation SARS-CoV-2 tools, we determine that Nb1-Nb2 broadly neutralizes SARS-CoV-2, including variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Kappa (B.1.617.1) and Mu (B.1.621). Furthermore, a heavy chain antibody is constructed by fusing the human IgG1 Fc to the biparatopic Nb (designated as Nb1-Nb2-Fc) to improve its neutralization potency, yield, stability and potential half-life extension. For the new Omicron variant (B.1.1.529) that harbors unprecedented multiple RBD mutations, Nb1-Nb2-Fc keeps a firm affinity (KD < 1.0*10E-12 M) and neutralizing activity (IC50 = 0.0017 nM). Together, we developed a biparatopic human heavy chain antibody with ultrapotent and broad-spectrum SARS-CoV-2 neutralization activity which highlights the potential clinical applications.

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Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift

Cited by 84 publications

References 71 publications

Engineered ACE2 counteracts vaccine-evading SARS-CoV-2 Omicron variant

Engineered ACE2 counteracts vaccine-evading SARS-CoV-2 Omicron variant

Structural and computational insights into the SARS-CoV-2 Omicron RBD-ACE2 interaction

An ultrapotent RBD-targeted biparatopic nanobody neutralizes broad SARS-CoV-2 variants

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