SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies

Nature, Journal Year: 2020, Volume and Issue: 588(7839), P. 682 - 687

Published: Oct. 12, 2020

The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein

Language: Английский

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Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera

Cell, Journal Year: 2021, Volume and Issue: 184(9), P. 2348 - 2361.e6

Published: Feb. 23, 2021

Highlights•Reduced B.1.351 neutralization by mAbs and sera induced early SARS-CoV-2 isolates•B.1.351 titer reduced 8- to 9-fold for Pfizer AstraZeneca vaccinees•E484K, K417N, N501Y cause widespread escape from mAbs•NTD deletion in abrogates a potent neutralizing human mAbSummaryThe race produce vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began when the first sequence was published, this forms basis currently deployed globally. Independent lineages of have recently been reported: UK, B.1.1.7; South Africa, B.1.351; Brazil, P.1. These variants multiple changes immunodominant spike protein that facilitates viral cell entry via angiotensin-converting enzyme-2 (ACE2) receptor. Mutations receptor recognition site on are great concern their potential immune escape. Here, we describe structure-function analysis using large cohort convalescent vaccinee serum samples. The receptor-binding domain mutations provide tighter ACE2 binding monoclonal antibody largely driven E484K, although K417N act together some important classes. In number cases, it would appear vaccine offers limited protection variant.Graphical abstract

Language: Английский

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SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses

Cell, Journal Year: 2022, Volume and Issue: 185(3), P. 467 - 484.e15

Published: Jan. 4, 2022

On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, failed to neutralize. Titers against boosted third vaccine doses high both vaccinated individuals those Delta. Mutations knock out reduce neutralization most large panel potent monoclonal antibodies under commercial development. S has structural changes earlier viruses uses that confer tight binding ACE2 unleash evolution driven immune escape. This leads number site rebalances receptor affinity viruses.

Language: Английский

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Antibody escape of SARS-CoV-2 Omicron BA.4 and BA.5 from vaccine and BA.1 serum

Cell, Journal Year: 2022, Volume and Issue: 185(14), P. 2422 - 2433.e13

Published: June 9, 2022

The Omicron lineage of SARS-CoV-2, which was first described in November 2021, spread rapidly to become globally dominant and has split into a number sublineages. BA.1 dominated the initial wave but been replaced by BA.2 many countries. Recent sequencing from South Africa's Gauteng region uncovered two new sublineages, BA.4 BA.5, are taking over locally, driving wave. BA.5 contain identical spike sequences, although closely related BA.2, they further mutations receptor-binding domain their spikes. Here, we study neutralization BA.4/5 using range vaccine naturally immune serum panels monoclonal antibodies. shows reduced individuals vaccinated with triple doses AstraZeneca or Pfizer compared BA.2. Furthermore, breakthrough infections, there are, likewise, significant reductions BA.4/5, raising possibility repeat infections.

Language: Английский

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Antibody evasion by the P.1 strain of SARS-CoV-2

Cell, Journal Year: 2021, Volume and Issue: 184(11), P. 2939 - 2954.e9

Published: March 30, 2021

Highlights•Despite similar RBD mutations, P.1 is easier to neutralize than B.1.351•P.1, B.1.351, and B.1.1.7 partially or fully escape most VH3-53 antibodies•mAb 222 (VH3-53) retains neutralization against all three variants•Neutralization restored in chimeric antibodies with mAb LCSummaryTerminating the SARS-CoV-2 pandemic relies upon pan-global vaccination. Current vaccines elicit neutralizing antibody responses virus spike derived from early isolates. However, new strains have emerged multiple including Brazil, B.1.351 South Africa, UK (12, 10, 9 changes spike, respectively). All mutations ACE2 binding site, having a virtually identical triplet (E484K, K417N/T, N501Y), which we show confer increased affinity for ACE2. We that, surprisingly, significantly less resistant naturally acquired vaccine-induced suggesting that outside receptor-binding domain (RBD) impact neutralization. Monoclonal (mAb) neutralizes variants despite interacting two of ACE2-binding site mutations. explain this through structural analysis use light chain largely restore potency major class public antibodies.Graphical abstract

Language: Английский

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Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera

Cell, Journal Year: 2021, Volume and Issue: 184(8), P. 2201 - 2211.e7

Published: Feb. 18, 2021

SARS-CoV-2 has caused over 2 million deaths in little a year. Vaccines are being deployed at scale, aiming to generate responses against the virus spike. The scale of pandemic and error-prone replication is leading appearance mutant viruses potentially escape from antibody responses. Variant B.1.1.7, now dominant UK, with increased transmission, harbors 9 amino acid changes spike, including N501Y ACE2 interacting surface. We examine ability B.1.1.7 evade elicited by natural infection or vaccination. map impact structure/function analysis large panel well-characterized monoclonal antibodies. harder neutralize than parental virus, compromising neutralization some members major class public antibodies through light-chain contacts residue 501. However, widespread generated vaccination was not observed.

Language: Английский

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Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2

Cell, Journal Year: 2020, Volume and Issue: 183(5), P. 1367 - 1382.e17

Published: Oct. 31, 2020

A safe, effective, and scalable vaccine is needed to halt the ongoing SARS-CoV-2 pandemic. We describe structure-based design of self-assembling protein nanoparticle immunogens that elicit potent protective antibody responses against in mice. The vaccines display 60 spike receptor-binding domains (RBDs) a highly immunogenic array induce neutralizing titers 10-fold higher than prefusion-stabilized despite 5-fold lower dose. Antibodies elicited by RBD nanoparticles target multiple distinct epitopes, suggesting they may not be easily susceptible escape mutations, exhibit binding:neutralizing ratio convalescent human sera, which minimize risk vaccine-associated enhanced respiratory disease. high yield stability assembled suggest manufacture will scalable. These results highlight utility robust antigen platforms have launched cGMP manufacturing efforts advance SARS-CoV-2-RBD into clinic.

Language: Английский

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Structural biology of SARS-CoV-2 and implications for therapeutic development

Nature Reviews Microbiology, Journal Year: 2021, Volume and Issue: 19(11), P. 685 - 700

Published: Sept. 17, 2021

Language: Английский

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The antigenic anatomy of SARS-CoV-2 receptor binding domain

Cell, Journal Year: 2021, Volume and Issue: 184(8), P. 2183 - 2200.e22

Published: Feb. 18, 2021

Antibodies are crucial to immune protection against SARS-CoV-2, with some in emergency use as therapeutics. Here, we identify 377 human monoclonal antibodies (mAbs) recognizing the virus spike and focus mainly on 80 that bind receptor binding domain (RBD). We devise a competition data-driven method map RBD sites. find although antibody sites widely dispersed, neutralizing is focused, nearly all highly inhibitory mAbs (IC

Language: Английский

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COVID-19 and Cardiovascular Disease

Circulation Research, Journal Year: 2021, Volume and Issue: 128(8), P. 1214 - 1236

Published: April 15, 2021

A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health millions people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), etiologic agent COVID-19, can infect heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), host cell receptor for viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation COVID-19 with chronic consequences. This update provides review clinical manifestations involvement, direct SARS-CoV-2 indirect immune response mechanisms impacting system, implications management patients after recovery from infection.

Language: Английский

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