Structural basis for potent antibody neutralization of SARS-CoV-2 variants including B.1.1.529

Zhou, Tongqing; Wang, Lingshu; Misasi, John; Pegu, Amarendra; Zhang, Yi; Harris, Darcy R.; Olia, Adam S.; Talana, Chloe Adrienna; Yang, Eun Sung; Chen, Man; Choe, Misook; Shi, Wei; Teng, I-Ting; Creanga, Adrian; Jenkins, Claudia; Leung, Kwanyee; Liu, Tracy; Stancofski, Erik-Stephane D.; Stephens, Tyler; Zhang, Baoshan; Tsybovsky, Yaroslav; Graham, Barney S.; Mascola, John R.; Sullivan, Nancy J.; Kwong, Peter D.

doi:10.1126/science.abn8897

Cited by 142 publications

(161 citation statements)

References 63 publications

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“…In vitro studies have shown that AZD7442 and its parental antibodies (CoV-2130 plus CoV-2196) retain some neutralizing activity against the BA.1 subvariant of the B.1.1.259 (omicron) variant, with neutralizing activity reduced by a factor of 12 to 30 in live-virus assays 30-32 and by a factor of 132 to 183 in pseudovirus 30 , 33 assays. The potency of AZD7442 (half-maximal inhibitory concentration geometric mean titer of 51 to 277 ng per milliliter 33 , 34 ) is higher than that of convalescent serum; therefore, AZD7442 is likely to be clinically active against the BA.1 subvariant. Emerging evidence suggests that the neutralizing activity of AZD7442 against the BA.2 subvariant is only minimally lower than that against the wild-type virus (lower by a factor of five in live-virus assays and by a factor of three in pseudovirus assays).…”

Section: Discussionmentioning

confidence: 99%

Intramuscular AZD7442 (Tixagevimab–Cilgavimab) for Prevention of Covid-19

Levin

Ustianowski

Wit³

et al. 2022

N Engl J Med

569

547

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Background The monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to have prophylactic and therapeutic effects in animal models. Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days. Methods In an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase–polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183. Results A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19–related deaths occurred, all in the placebo group. Conclusions A single dose of AZD7442 had efficacy for the prevention of Covid-19, without evident safety concerns. (Funded by AstraZeneca and the U.S. government; PROVENT ClinicalTrials.gov number, NCT04625725 .)

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Section: Discussionmentioning

confidence: 99%

Intramuscular AZD7442 (Tixagevimab–Cilgavimab) for Prevention of Covid-19

Levin

Ustianowski

Wit³

et al. 2022

N Engl J Med

569

547

View full text Add to dashboard Cite

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“…The Omicron variant, which carries 37 mutations in the spike protein and 15 amino acid substitutions in the receptor-binding domain, appears to preferentially infect and replicate in the upper respiratory tract. This is in comparison to Delta and other variants that favor the lower respiratory tract, and Omicron has a decreased ability to infect lung tissue [ 80 ].…”

Section: Discussionmentioning

confidence: 99%

The Multifaceted Manifestations of Multisystem Inflammatory Syndrome during the SARS-CoV-2 Pandemic

et al. 2022

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The novel coronavirus SARS-CoV-2, which has similarities to the 2002–2003 severe acute respiratory syndrome coronavirus known as SARS-CoV-1, causes the infectious disease designated COVID-19 by the World Health Organization (Coronavirus Disease 2019). Although the first reports indicated that activity of the virus is centered in the lungs, it was soon acknowledged that SARS-CoV-2 causes a multisystem disease. Indeed, this new pathogen causes a variety of syndromes, including asymptomatic disease; mild disease; moderate disease; a severe form that requires hospitalization, intensive care, and mechanical ventilation; multisystem inflammatory disease; and a condition called long COVID or postacute sequelae of SARS-CoV-2 infection. Some of these syndromes resemble previously described disorders, including those with no confirmed etiology, such as Kawasaki disease. After recognition of a distinct multisystem inflammatory syndrome in children, followed by a similar syndrome in adults, various multisystem syndromes occurring during the pandemic associated or related to SARS-CoV-2 began to be identified. A typical pattern of cytokine and chemokine dysregulation occurs in these complex syndromes; however, the disorders have distinct immunological determinants that may help to differentiate them. This review discusses the origins of the different trajectories of the inflammatory syndromes related to SARS-CoV-2 infection.

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“…A19-46.1 could not bind probes with L452R/Q mutation, as seen with S2P probes (Figs 3D , 6D and 7D ). Residue 452 is located in the center of the A19-46.1 epitope ( S1C Fig ) and plays an important role in binding interactions [ 40 ]. On the other hand, the Class III RBD antibody A19-61.1 substantially reduced binding to the B.1.1.529 RBD probe, which has mutations at residues 446 and 493 on the periphery of A19-61.1 epitope ( S1C Fig ), but retained binding to most other RBD or RBD-SD1 variant probes (Figs 6D and 7D ).…”

Section: Resultsmentioning

confidence: 99%

Molecular probes of spike ectodomain and its subdomains for SARS-CoV-2 variants, Alpha through Omicron

et al. 2022

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Since the outbreak of the COVID-19 pandemic, widespread infections have allowed SARS-CoV-2 to evolve in human, leading to the emergence of multiple circulating variants. Some of these variants show increased resistance to vaccine-elicited immunity, convalescent plasma, or monoclonal antibodies. In particular, mutations in the SARS-CoV-2 spike have drawn attention. To facilitate the isolation of neutralizing antibodies and the monitoring of vaccine effectiveness against these variants, we designed and produced biotin-labeled molecular probes of variant SARS-CoV-2 spikes and their subdomains, using a structure-based construct design that incorporated an N-terminal purification tag, a specific amino acid sequence for protease cleavage, the variant spike-based region of interest, and a C-terminal sequence targeted by biotin ligase. These probes could be produced by a single step using in-process biotinylation and purification. We characterized the physical properties and antigenicity of these probes, comprising the N-terminal domain (NTD), the receptor-binding domain (RBD), the RBD and subdomain 1 (RBD-SD1), and the prefusion-stabilized spike ectodomain (S2P) with sequences from SARS-CoV-2 variants of concern or of interest, including variants Alpha, Beta, Gamma, Epsilon, Iota, Kappa, Delta, Lambda, Mu, and Omicron. We functionally validated probes by using yeast expressing a panel of nine SARS-CoV-2 spike-binding antibodies and confirmed sorting capabilities of variant probes using yeast displaying libraries of plasma antibodies from COVID-19 convalescent donors. We deposited these constructs to Addgene to enable their dissemination. Overall, this study describes a matrix of SARS-CoV-2 variant molecular probes that allow for assessment of immune responses, identification of serum antibody specificity, and isolation and characterization of neutralizing antibodies.

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Structural basis for potent antibody neutralization of SARS-CoV-2 variants including B.1.1.529

Cited by 142 publications

References 63 publications

Intramuscular AZD7442 (Tixagevimab–Cilgavimab) for Prevention of Covid-19

Intramuscular AZD7442 (Tixagevimab–Cilgavimab) for Prevention of Covid-19

The Multifaceted Manifestations of Multisystem Inflammatory Syndrome during the SARS-CoV-2 Pandemic

Molecular probes of spike ectodomain and its subdomains for SARS-CoV-2 variants, Alpha through Omicron

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