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The Spike Proteins of SARS-CoV-2 B.1.617 and B.1.618 Variants Identified in India Provide Partial Resistance to Vaccine-elicited and Therapeutic Monoclonal Antibodies

Takuya Tada, Hao Zhou, Belinda M Dcosta, Marie I. Samanovic, Mark J. Mulligan, Nathaniel R. Landau 
16 May 2021-bioRxiv (Cold Spring Harbor Laboratory)-
TL;DR: In this article, the authors showed that B.1.617 and B.618 have mutations within the spike protein that may contribute to their increased transmissibility and that could potentially result in re-infection or resistance to vaccine-elicited antibody.
Abstract: Highly transmissible SARS-CoV-2 variants recently identified in India designated B.1.617 and B.1.618 have mutations within the spike protein that may contribute to their increased transmissibility and that could potentially result in re-infection or resistance to vaccine-elicited antibody. B.1.617 encodes a spike protein with mutations L452R, E484Q, D614G and P681R while the B.1.618 spike has mutations {Delta}145-146, E484K and D614G. We generated lentiviruses pseudotyped by the variant proteins and determined their resistance to neutralization by convalescent sera, vaccine-elicited antibodies and therapeutic monoclonal antibodies. Viruses with B.1.617 and B.1.618 spike were neutralized with a 2-5-fold decrease in titer by convalescent sera and vaccine-elicited antibodies. The E484Q and E484K versions were neutralized with a 2-4-fold decrease in titer. Virus with the B.1.617 spike protein was neutralized with a 4.7-fold decrease in titer by the Regeneron monoclonal antibody cocktail as a result of the L452R mutation. The modest neutralization resistance of the variant spike proteins to vaccine elicited antibody suggests that current vaccines will remain protective against the B.1.617 and B.1.618 variants.

Summary (2 min read)

Jump to: [Introduction] – [Generation] – [Variant pseudotype neutralization by Regeneron REGN10933 and REGN10987] – [B.1.617, B.1.618 have increased affinity for ACE2.] – [Human Sera and monoclonal antibodies] – [SARS-CoV-2 spike lentiviral pseudotypes] – [Soluble ACE2 Neutralization assay] and [Quantification and Statistical Analysis]

Introduction

  • Generating novel variants with mutations selected for immunoevasion and increased transmissibility.
  • The authors addressed the questions of antibody resistance and variant spike protein affinity for ACE2 using lentiviruses pseudotyped by the B.1.617 and B.1.618 spike proteins.
  • In addition, the variants were partially resistant to REGN10933, one of the two mAbs constituting the Regeneron COV2 therapy.

Generation

  • The authors constructed expression vectors for the B.1.617 and B.1.618 spike proteins and for spike proteins with the individual point mutations and used these to produce lentiviral pseudotypes that with a genome encoding GFP and luciferase reporters.
  • To determine the sensitivity of the Indian variants to antibody neutralization, the authors tested the serum specimens from convalescent patients who had been infected prior to the emergence of the variants for neutralization of the panel of pseudotyped viruses.

Variant pseudotype neutralization by Regeneron REGN10933 and REGN10987

  • MAbs. Monoclonal antibody therapy for COVID-19 has been shown to reduce disease symptoms and to reduce the number of patients requiring hospitalization [19] .
  • The treatment is subject to becoming less effective in patients infected with a variant in which the antibody epitope on the spike protein is altered by mutation.
  • To address this question, the authors tested the ability of the mAbs to neutralize the panel of variant spike protein pseudotyped viruses.

B.1.617, B.1.618 have increased affinity for ACE2.

  • The apparent increased transmissibility of the variants could be caused by increased affinity for ACE2 as has been found for other variants.
  • To determine the relative ACE2 affinities of the variant spikes, the authors used an ACE2 binding assay in which the pseudotyped viruses were incubated with soluble ACE2 (sACE2) and then tested for infectivity on ACE2.293T cells relative to that of virus with the D614G mutation, an assay that they have used previously to analyze variant spike protein affinity [11] .
  • The assay shows a 6-fold increase in ACE2 affinity for the N501Y mutation, a result consistent with that reported previously (Fig. 4 ).
  • The authors results lend confidence that current vaccines will provide protection against variants identified to date.
  • The results do not preclude the possibility that variants that are more resistant to current vaccines will emerge.

Human Sera and monoclonal antibodies

  • Convalescent sera and sera from BNT162b2 or Moderna-vaccinated individuals were collected on day 28 following the second immunization at the NYU Vaccine Center with written consent under IRB approved protocols (IRB 18-02035 and IRB 18-02037).
  • Regeneron monoclonal antibodies (REGN10933 and REGN10987) were prepared as previously described [21] .

SARS-CoV-2 spike lentiviral pseudotypes

  • Lentiviral pseudotypes with variant SARS-CoV-2 spikes were produced as previously reported [21] .
  • Viruses were concentrated by ultracentrifugation and normalized for reverse transcriptase (RT) activity.
  • To determine neutralizing antibody titers, sera or mAbs were serially diluted 2-fold and then incubated with pseudotyped virus (approximately 2.5 X 10 7 cps) for 30 minutes at room temperature and then added to ACE2.293T cells.
  • Luciferase activity was measured as previously described [22] .

Soluble ACE2 Neutralization assay

  • Serially diluted recombinant soluble ACE2 protein [22] was incubated with pseudotyped virus for 30 minutes at room temperature and added to 1 X 10 4 ACE2.293T cells.
  • After 2 days, luciferase activity was measured using Nano-Glo luciferase substrate in an Envision 2103 microplate luminometer .

Quantification and Statistical Analysis

  • All experiments were in technical duplicates or triplicates and the data were analyzed using GraphPad Prism 8.
  • Statistical significance was determined by the two-tailed, unpaired t-test.
  • Significance was based on two-sided testing and attributed to p< 0.05.

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1
The Spike Proteins of SARS-CoV-2 B.1.617 and B.1.618 Variants Identified in India
1
Provide Partial Resistance to Vaccine-elicited and Therapeutic Monoclonal
2
Antibodies.
3
4
Takuya Tada
a*
, Hao Zhou
a*
, Belinda M. Dcosta
a
, Marie I. Samanovic
b
, Mark J. Mulligan
b
,
5
and Nathaniel R. Landau
a
#
6
7
a
Department of Microbiology, NYU Grossman School of Medicine, New York, NY, USA
8
b
NYU Langone Vaccine Center and Department of Medicine, NYU Grossman School of
9
Medicine, New York, NY, USA.
10
11
*authors contributed equally
12
13
Running Head: Neutralization of B.1.617 and B.1.618 SARS-CoV-2 Variant Spikes.
14
15
# Address correspondence to Nathaniel R. Landau, nathaniel.landau@med.nyu.edu
16
17
Nathaniel R. Landau, Ph.D.
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NYU Grossman School of Medicine
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430 East 29th Street, Alexandria West Building, Rm 509, New York, NY 10016
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Phone: (212) 263-9197
21
Email: nathaniel.landau@med.nyu.edu
22
23
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted May 16, 2021. ; https://doi.org/10.1101/2021.05.14.444076doi: bioRxiv preprint
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted May 16, 2021. ; https://doi.org/10.1101/2021.05.14.444076doi: bioRxiv preprint
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted May 16, 2021. ; https://doi.org/10.1101/2021.05.14.444076doi: bioRxiv preprint
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted May 16, 2021. ; https://doi.org/10.1101/2021.05.14.444076doi: bioRxiv preprint
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted May 16, 2021. ; https://doi.org/10.1101/2021.05.14.444076doi: bioRxiv preprint
2
Key words: SARS-CoV-2, Neutralization, B.1.617, B.1.618, spike protein, Pfizer
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BNT162b2, Moderna mRNA-1273, REGN10933, REGN10987.
25
26
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted May 16, 2021. ; https://doi.org/10.1101/2021.05.14.444076doi: bioRxiv preprint
3
Abstract
27
Highly transmissible SARS-CoV-2 variants recently identified in India designated B.1.617
28
and B.1.618 have mutations within the spike protein that may contribute to their increased
29
transmissibility and that could potentially result in re-infection or resistance to vaccine-
30
elicited antibody. B.1.617 encodes a spike protein with mutations L452R, E484Q, D614G
31
and P681R while the B.1.618 spike has mutations D145-146, E484K and D614G. We
32
generated lentiviruses pseudotyped by the variant proteins and determined their
33
resistance to neutralization by convalescent sera, vaccine-elicited antibodies and
34
therapeutic monoclonal antibodies. Viruses with B.1.617 and B.1.618 spike were
35
neutralized with a 2-5-fold decrease in titer by convalescent sera and vaccine-elicited
36
antibodies. The E484Q and E484K versions were neutralized with a 2-4-fold decrease in
37
titer. Virus with the B.1.617 spike protein was neutralized with a 4.7-fold decrease in titer
38
by the Regeneron monoclonal antibody cocktail as a result of the L452R mutation. The
39
modest neutralization resistance of the variant spike proteins to vaccine elicited antibody
40
suggests that current vaccines will remain protective against the B.1.617 and B.1.618
41
variants.
42
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted May 16, 2021. ; https://doi.org/10.1101/2021.05.14.444076doi: bioRxiv preprint
4
Introduction
43
Despite efforts to contain severe acute respiratory syndrome coronavirus-2 (SARS-CoV-
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2) the virus has continued to spread throughout the world’s population, generating novel
45
variants with mutations selected for immunoevasion and increased transmissibility. The
46
variants contain point mutations and short deletions in the spike protein driven by
47
selective pressure for increased affinity for its receptor, ACE2, and escape from
48
neutralizing antibody. Major variants identified to date include B.1.1.7 [1, 2], B.1.351 [3],
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B.1.526 [4], P.1 [5], P.3 (EpiCoVTM database of the Global Initiative for Sharing All
50
Influenza Data (GISAID) : accession numbers EPI_ISL_1122426 to EPI_ISL_ 1122458)
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and mink cluster 5 [6]. The variants have increased transmissibility, a feature that is, at
52
least in part, the result of mutations in the spike protein that allow for increased ACE2
53
affinity and/or resistance to antibody. Several of the point mutations have been found to
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lead to increased viral fitness. The N501Y mutation in B.1.1.7 results in increased affinity
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for ACE2 [7-10] while the E484K mutation in the B.1.351, B.1.526, P.1 and P.3 spike
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proteins provides partial resistance to neutralizing antibodies in recovered individuals and
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antibodies elicited by vaccination [11-16].
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Recent months have seen a dramatic increase in India in the rate of spread of SARS-
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CoV-2 infection accompanied by an increase in mortality. The increased spread is
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associated with newly identified novel SARS-CoV-2 variants B.1.617 [17] and B.1.618
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(http://cov-lineages.org) with mutated spike proteins. The B.1.617 spike protein has
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L452R, E484Q, D614G and P681R mutations [17]; and the B.1.618 spike has mutations
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D145-146, E484K and D614G. Residues 452 and 484 are in the receptor binding domain
65
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted May 16, 2021. ; https://doi.org/10.1101/2021.05.14.444076doi: bioRxiv preprint
5
(RBD) and thus could play a role in immunoevasion and/or resistance to antibody
66
neutralization. D145-146 lies in the N-terminal domain that is a known antibody binding
67
site [18] and P681R lies within S1/S2 where it could affect proteolytic processing (Fig. 1A
68
and B). Which of the mutations contributes to increased ACE2 affinity and resistance to
69
antibody neutralization that might account for the increased transmissibility of the variants
70
is not well understood.
71
72
In this study, we addressed the questions of antibody resistance and variant spike protein
73
affinity for ACE2 using lentiviruses pseudotyped by the B.1.617 and B.1.618 spike
74
proteins. We found that the viruses with the Indian spike proteins were partially resistant
75
to neutralization by convalescent serum antibody and vaccine-elicited antibodies. The
76
resistance was caused by the L452R, E484Q and E484K mutations. In addition, the
77
variants were partially resistant to REGN10933, one of the two mAbs constituting the
78
Regeneron COV2 therapy.
79
80
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted May 16, 2021. ; https://doi.org/10.1101/2021.05.14.444076doi: bioRxiv preprint
Citations
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Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization.

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Delphine Planas1, David Veyer2, Artem Baidaliuk1, Isabelle Staropoli1, Florence Guivel-Benhassine1, Maaran Michael Rajah2, Maaran Michael Rajah1, Cyril Planchais1, Françoise Porrot1, Nicolas Robillard2, Julien Puech2, Matthieu Prot1, Floriane Gallais3, Pierre Gantner3, Aurélie Velay3, Julien Le Guen, Najiby Kassis-Chikhani, Dhiaeddine Edriss2, Laurent Bélec2, Aymeric Sève, Laura Courtellemont, Hélène Péré2, Laurent Hocqueloux, Samira Fafi-Kremer3, Thierry Prazuck, Hugo Mouquet1, Timothée Bruel1, Etienne Simon-Loriere1, Félix A. Rey1, Olivier Schwartz1 •
Pasteur Institute1, University of Paris2, University of Strasbourg3
08 Jul 2021-Nature
TL;DR: In this paper, an infectious strain of the SARS-CoV-2 Delta variant was isolated from an individual with COVID-19 who had returned to France from India.
Abstract: The SARS-CoV-2 B.1.617 lineage was identified in October 2020 in India1–5. Since then, it has become dominant in some regions of India and in the UK, and has spread to many other countries6. The lineage includes three main subtypes (B1.617.1, B.1.617.2 and B.1.617.3), which contain diverse mutations in the N-terminal domain (NTD) and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein that may increase the immune evasion potential of these variants. B.1.617.2—also termed the Delta variant—is believed to spread faster than other variants. Here we isolated an infectious strain of the Delta variant from an individual with COVID-19 who had returned to France from India. We examined the sensitivity of this strain to monoclonal antibodies and to antibodies present in sera from individuals who had recovered from COVID-19 (hereafter referred to as convalescent individuals) or who had received a COVID-19 vaccine, and then compared this strain with other strains of SARS-CoV-2. The Delta variant was resistant to neutralization by some anti-NTD and anti-RBD monoclonal antibodies, including bamlanivimab, and these antibodies showed impaired binding to the spike protein. Sera collected from convalescent individuals up to 12 months after the onset of symptoms were fourfold less potent against the Delta variant relative to the Alpha variant (B.1.1.7). Sera from individuals who had received one dose of the Pfizer or the AstraZeneca vaccine had a barely discernible inhibitory effect on the Delta variant. Administration of two doses of the vaccine generated a neutralizing response in 95% of individuals, with titres three- to fivefold lower against the Delta variant than against the Alpha variant. Thus, the spread of the Delta variant is associated with an escape from antibodies that target non-RBD and RBD epitopes of the spike protein. The SARS-CoV-2 Delta variant partially evades neutralization by several monoclonal antibodies and by sera from individuals who have had COVID-19, but two doses of anti-COVID-19 vaccines still generate a strong neutralizing response.

1,462 citations

Journal Article•DOI•
SARS-CoV-2 Spike Mutations, L452R, T478K, E484Q and P681R, in the Second Wave of COVID-19 in Maharashtra, India.

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Sarah S. Cherian1, Varsha Potdar1, Santosh Jadhav1, Pragya D Yadav1, Nivedita Gupta2, Mousumi Das1, Partha Rakshit3, Sujeet Kumar Singh3, Priya Abraham1, Samiran Panda2, Nic team •
National Institute of Virology1, Indian Council of Medical Research2, National Centre for Disease Control3
20 Jul 2021
TL;DR: In this paper, the signature mutations possessed by these strains were L452R, T478K, E484Q, D614G and P681R in the spike protein, including within the receptor-binding domain.
Abstract: As the global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic expands, genomic epidemiology and whole genome sequencing are being used to investigate its transmission and evolution. Against the backdrop of the global emergence of “variants of concern” (VOCs) during December 2020 and an upsurge in a state in the western part of India since January 2021, whole genome sequencing and analysis of spike protein mutations using sequence and structural approaches were undertaken to identify possible new variants and gauge the fitness of the current circulating strains. Phylogenetic analysis revealed that newly identified lineages B.1.617.1 and B.1.617.2 were predominantly circulating. The signature mutations possessed by these strains were L452R, T478K, E484Q, D614G and P681R in the spike protein, including within the receptor-binding domain (RBD). Of these, the mutations at residue positions 452, 484 and 681 have been reported in other globally circulating lineages. The structural analysis of RBD mutations L452R, T478K and E484Q revealed that these may possibly result in increased ACE2 binding while P681R in the furin cleavage site could increase the rate of S1-S2 cleavage, resulting in better transmissibility. The two RBD mutations, L452R and E484Q, indicated decreased binding to select monoclonal antibodies (mAbs) and may affect their neutralization potential. Further in vitro/in vivo studies would help confirm the phenotypic changes of the mutant strains. Overall, the study revealed that the newly emerged variants were responsible for the second wave of COVID-19 in Maharashtra. Lineage B.1.617.2 has been designated as a VOC delta and B.1.617.1 as a variant of interest kappa, and they are being widely reported in the rest of the country as well as globally. Continuous monitoring of these and emerging variants in India is essential.

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BNT162b2-elicited neutralization of B.1.617 and other SARS-CoV-2 variants.

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Jianying Liu1, Yang Liu1, Hongjie Xia1, Jing Zou1, Scott C. Weaver, Kena A. Swanson2, Hui Cai2, Mark Cutler2, David A. Cooper2, Alexander Muik, Kathrin U. Jansen2, Ugur Sahin, Xuping Xie1, Philip R. Dormitzer2, Pei Yong Shi •
University of Texas Medical Branch1, Pfizer2
10 Jun 2021-Nature
TL;DR: The authors showed that serum samples taken from twenty human volunteers, two or four weeks after their second dose of the BNT162b2 vaccine, neutralize engineered SARS-CoV-2 with a USA-WA1/2020 genetic background (a virus strain isolated in January 2020) and spike glycoproteins from the recently identified B.1.617.
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuing to evolve around the world, generating new variants that are of concern on the basis of their potential for altered transmissibility, pathogenicity, and coverage by vaccines and therapeutic agents1–5. Here we show that serum samples taken from twenty human volunteers, two or four weeks after their second dose of the BNT162b2 vaccine, neutralize engineered SARS-CoV-2 with a USA-WA1/2020 genetic background (a virus strain isolated in January 2020) and spike glycoproteins from the recently identified B.1.617.1, B.1.617.2, B.1.618 (all of which were first identified in India) or B.1.525 (first identified in Nigeria) lineages. Geometric mean plaque reduction neutralization titres against the variant viruses—particularly the B.1.617.1 variant—seemed to be lower than the titre against the USA-WA1/2020 virus, but all sera tested neutralized the variant viruses at titres of at least 1:40. The susceptibility of the variant strains to neutralization elicited by the BNT162b2 vaccine supports mass immunization as a central strategy to end the coronavirus disease 2019 (COVID-19) pandemic globally. Samples of serum from individuals immunized with the BNT162b2 vaccine show neutralization activity against engineered SARS-CoV-2s bearing the spike mutations from B.1.617 and other variants.

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Posted Content•DOI•
Reduced sensitivity of infectious SARS-CoV-2 variant B.1.617.2 to monoclonal antibodies and sera from convalescent and vaccinated individuals

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Delphine Planas1, David Veyer2, Artem Baidaliuk1, Isabelle Staropoli1, Florence Guivel-Benhassine1, Maaran Michael Rajah2, Maaran Michael Rajah1, Cyril Planchais1, Françoise Porrot1, Nicolas Robillard, Julien Puech, Matthieu Prot1, Floriane Gallais3, Pierre Gantner3, Aurélie Velay3, Julien Le Guen, Najibi Kassis-Chikhani, Dhiaeddine Edriss, Laurent Bélec, Aymeric Sève, Hélène Péré2, Laura Courtellemenont, Laurent Hocqueloux, Samira Fafi-Kremer3, Thierry Prazuck, Hugo Mouquet1, Timothée Bruel1, Etienne Simon-Loriere1, Félix A. Rey1, Olivier Schwartz1 •
Pasteur Institute1, University of Paris2, University of Strasbourg3
27 May 2021-bioRxiv
TL;DR: The SARS-CoV-2 B.1.617 lineage emerged in October 2020 in India1-6.7.1 and has since then become dominant in some indian regions and further spread to many countries.
Abstract: The SARS-CoV-2 B.1.617 lineage emerged in October 2020 in India1-6. It has since then become dominant in some indian regions and further spread to many countries. The lineage includes three main subtypes (B1.617.1, B.1617.2 and B.1.617.3), which harbour diverse Spike mutations in the N-terminal domain (NTD) and the receptor binding domain (RBD) which may increase their immune evasion potential. B.1.617.2 is believed to spread faster than the other versions. Here, we isolated infectious B.1.617.2 from a traveller returning from India. We examined its sensitivity to monoclonal antibodies (mAbs) and to antibodies present in sera from COVID-19 convalescent individuals or vaccine recipients, in comparison to other viral lineages. B.1.617.2 was resistant to neutralization by some anti-NTD and anti-RBD mAbs, including Bamlanivimab, which were impaired in binding to the B.1.617.2 Spike. Sera from convalescent patients collected up to 12 months post symptoms and from Pfizer Comirnaty vaccine recipients were 3 to 6 fold less potent against B.1.617.2, relative to B.1.1.7. Sera from individuals having received one dose of AstraZeneca Vaxzevria barely inhibited B.1.617.2. Thus, B.1.617.2 spread is associated with an escape to antibodies targeting non-RBD and RBD Spike epitopes.

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Transmission event of SARS-CoV-2 delta variant reveals multiple vaccine breakthrough infections.

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Timothy Farinholt1, Harsha Doddapaneni1, Xiang Qin1, Vipin Kumar Menon1, Qingchang Meng1, Ginger A. Metcalf1, Hsu Chao1, Marie-Claude Gingras1, Vasanthi Avadhanula1, Paige Farinholt1, Charu Agrawal1, Donna M. Muzny1, Pedro A. Piedra1, Richard A. Gibbs1, Joseph F. Petrosino1 •
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01 Oct 2021-BMC Medicine
TL;DR: In this paper, the causative strain of SARS-CoV-2 in a cluster of vaccine breakthroughs was identified by using Swift Normalase Amplicon Panels to determine the causal variant.
Abstract: This study aims to identify the causative strain of SARS-CoV-2 in a cluster of vaccine breakthroughs. Vaccine breakthrough by a highly transmissible SARS-CoV-2 strain is a risk to global public health. Nasopharyngeal swabs from suspected vaccine breakthrough cases were tested for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) by qPCR (quantitative polymerase chain reaction) for Wuhan-Hu1 and alpha variant. Positive samples were then sequenced by Swift Normalase Amplicon Panels to determine the causal variant. GATK (genome analysis toolkit) variants were filtered with allele fraction ≥80 and min read depth 30x. Viral sequencing revealed an infection cluster of 6 vaccinated patients infected with the delta (B.1.617.2) SARS-CoV-2 variant. With no history of vaccine breakthrough, this suggests the delta variant may possess immune evasion in patients that received the Pfizer BNT162b2, Moderna mRNA-1273, and Covaxin BBV152. Delta variant may pose the highest risk out of any currently circulating SARS-CoV-2 variants, with previously described increased transmissibility over alpha variant and now, possible vaccine breakthrough. Parts of this work was supported by the National Institute of Allergy and Infectious Diseases (1U19AI144297) and Baylor College of Medicine internal funding.

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References
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Journal Article•DOI•
Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7.

[...]

Pengfei Wang1, Manoj S. Nair1, Lihong Liu1, Sho Iketani2, Sho Iketani1, Yang Luo1, Yicheng Guo1, Maple Wang1, Jian Yu1, Baoshan Zhang3, Peter D. Kwong2, Peter D. Kwong3, Barney S. Graham3, John R. Mascola3, Jennifer Y Chang1, Jennifer Y Chang2, Michael T. Yin2, Michael T. Yin1, Magdalena E. Sobieszczyk2, Magdalena E. Sobieszczyk1, Christos A. Kyratsous4, Lawrence Shapiro1, Lawrence Shapiro2, Zizhang Sheng1, Yaoxing Huang1, David D. Ho1, David D. Ho2 •
Aaron Diamond AIDS Research Center1, Columbia University2, National Institutes of Health3, Regeneron4
08 Mar 2021-Nature
TL;DR: In this paper, the authors show that B.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclanal antibody against the receptor-binding domain.
Abstract: The COVID-19 pandemic has had widespread effects across the globe, and its causative agent, SARS-CoV-2, continues to spread. Effective interventions need to be developed to end this pandemic. Single and combination therapies with monoclonal antibodies have received emergency use authorization1-3, and more treatments are under development4-7. Furthermore, multiple vaccine constructs have shown promise8, including two that have an approximately 95% protective efficacy against COVID-199,10. However, these interventions were directed against the initial SARS-CoV-2 virus that emerged in 2019. The recent detection of SARS-CoV-2 variants B.1.1.7 in the UK11 and B.1.351 in South Africa12 is of concern because of their purported ease of transmission and extensive mutations in the spike protein. Here we show that B.1.1.7 is refractory to neutralization by most monoclonal antibodies against the N-terminal domain of the spike protein and is relatively resistant to a few monoclonal antibodies against the receptor-binding domain. It is not more resistant to plasma from individuals who have recovered from COVID-19 or sera from individuals who have been vaccinated against SARS-CoV-2. The B.1.351 variant is not only refractory to neutralization by most monoclonal antibodies against the N-terminal domain but also by multiple individual monoclonal antibodies against the receptor-binding motif of the receptor-binding domain, which is mostly due to a mutation causing an E484K substitution. Moreover, compared to wild-type SARS-CoV-2, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4-fold) and sera from individuals who have been vaccinated (10.3-12.4-fold). B.1.351 and emergent variants13,14 with similar mutations in the spike protein present new challenges for monoclonal antibody therapies and threaten the protective efficacy of current vaccines.

1,641 citations

Journal Article•DOI•
Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding.

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Tyler N. Starr1, Allison J. Greaney1, Allison J. Greaney2, Sarah K Hilton2, Sarah K Hilton1, Daniel Ellis2, Katharine H.D. Crawford1, Katharine H.D. Crawford2, Adam S. Dingens1, Mary Jane Navarro2, John E. Bowen2, M. Alejandra Tortorici2, Alexandra C. Walls2, Neil P. King2, David Veesler2, Jesse D. Bloom2, Jesse D. Bloom1, Jesse D. Bloom3 •
Fred Hutchinson Cancer Research Center1, University of Washington2, Howard Hughes Medical Institute3
03 Sep 2020-Cell
TL;DR: It is found that a substantial number of mutations to the RBD are well tolerated or even enhance ACE2 binding, including at ACE2 interface residues that vary across SARS-related coronaviruses.

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REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19.

[...]

David M. Weinreich1, Sumathi Sivapalasingam1, Thomas Norton1, Shazia Ali2, Haitao Gao1, Rafia Bhore1, Bret J Musser1, Yuhwen Soo1, Diana Rofail1, Joseph Im1, Christina Perry1, Cynthia Pan1, Romana Hosain1, Adnan Mahmood1, John D. Davis1, Kenneth C. Turner1, Andrea T. Hooper1, Jennifer D. Hamilton1, Alina Baum1, Christos A. Kyratsous1, Yunji Kim1, Amanda Cook1, Wendy Kampman1, Anita Kohli1, Yessica Sachdeva1, Ximena Graber, Bari Kowal1, Thomas DiCioccio1, Neil Stahl1, Leah Lipsich1, Ned Braunstein1, Gary Herman1, George D. Yancopoulos1 •
Regeneron1, Abertawe Bro Morgannwg University Health Board2
21 Jan 2021-The New England Journal of Medicine
TL;DR: In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline.
Abstract: Background Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads. Methods In this ongoing, double-blind, phase 1–3 tr...

1,375 citations

Journal Article•DOI•
A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2.

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Chi Xiangyang1, Renhong Yan2, Jun Zhang1, Zhang Guanying1, Yuanyuan Zhang2, Hao Meng1, Zhe Zhang1, Pengfei Fan1, Dong Yunzhu1, Yilong Yang1, Chen Zhengshan1, Yingying Guo2, Jinlong Zhang1, Yaning Li3, Xiaohong Song1, Chen Yi1, Lu Xia2, Ling Fu1, Lihua Hou1, Junjie Xu1, Changming Yu1, Jianmin Li1, Qiang Zhou2, Wei Chen1 •
Academy of Military Medical Sciences1, Westlake University2, Tsinghua University3
22 Jun 2020-Science
TL;DR: The epitope of 4A8 is defined as the N-terminal domain (NTD) of the S protein by determining with cryo–eletron microscopy its structure in complex with the Sprotein, which points to the NTD as a promising target for therapeutic mAbs against COVID-19.
Abstract: Developing therapeutics against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could be guided by the distribution of epitopes, not only on the receptor binding domain (RBD) of the Spike (S) protein but also across the full Spike (S) protein We isolated and characterized monoclonal antibodies (mAbs) from 10 convalescent COVID-19 patients Three mAbs showed neutralizing activities against authentic SARS-CoV-2 One mAb, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2 but does not bind the RBD We defined the epitope of 4A8 as the N-terminal domain (NTD) of the S protein by determining with cryo-eletron microscopy its structure in complex with the S protein to an overall resolution of 31 angstroms and local resolution of 33 angstroms for the 4A8-NTD interface This points to the NTD as a promising target for therapeutic mAbs against COVID-19

1,189 citations

Journal Article•DOI•
Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity.

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Wilfredo F. Garcia-Beltran1, Wilfredo F. Garcia-Beltran2, Evan C. Lam3, Kerri St. Denis3, Adam Nitido3, Zeidy H. Garcia3, Blake M. Hauser3, Jared Feldman3, Maia N. Pavlovic2, David Gregory2, Mark C. Poznansky2, Alex Sigal4, Alex Sigal5, Aaron G. Schmidt3, A. John Iafrate2, Vivek Naranbhai6, Vivek Naranbhai2, Alejandro B. Balazs3 •
Brigham and Women's Hospital1, Harvard University2, Ragon Institute of MGH, MIT and Harvard3, Max Planck Society4, University of KwaZulu-Natal5, Centre for the AIDS Programme of Research in South Africa6
29 Apr 2021-Cell
TL;DR: In this article, the authors evaluated the neutralization potency of 99 individuals that received one or two doses of either BNT162b2 or mRNA-1273 vaccines against pseudoviruses representing 10 globally circulating strains of SARS-CoV-2.

1,109 citations

Related Papers (5)
Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein.

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16 Apr 2020-Cell
Alexandra C. Walls, Young-Jun Park, M. Alejandra Tortorici, M. Alejandra Tortorici, Abigail Wall, Andrew T. McGuire, Andrew T. McGuire, David Veesler 
A pneumonia outbreak associated with a new coronavirus of probable bat origin

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03 Feb 2020-Nature
Peng Zhou, Xing-Lou Yang, Xian Guang Wang, Ben Hu, Lei Zhang, Wei Zhang, Hao Rui Si, Yan Zhu, Bei Li, Chao Lin Huang, Hui-Dong Chen, Jing Chen, Yun Luo, Hua Guo, Ren Di Jiang, Meiqin Liu, Ying Chen, Xu Rui Shen, Xi Wang, Xiao Shuang Zheng, Kai Zhao, Quanjiao Chen, Fei Deng, Lin Lin Liu, Bing Yan, Fa Xian Zhan, Yan-Yi Wang, Gengfu Xiao, Zhengli Shi 
A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology.

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15 Jul 2020-Nature microbiology
Andrew Rambaut, Edward C. Holmes, Áine O'Toole, Verity Hill, John T. McCrone, Christopher Ruis, Louis du Plessis, Oliver G. Pybus 
Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7.

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08 Mar 2021-Nature
Pengfei Wang, Manoj S. Nair, Lihong Liu, Sho Iketani, Sho Iketani, Yang Luo, Yicheng Guo, Maple Wang, Jian Yu, Baoshan Zhang, Peter D. Kwong, Peter D. Kwong, Barney S. Graham, John R. Mascola, Jennifer Y Chang, Jennifer Y Chang, Michael T. Yin, Michael T. Yin, Magdalena E. Sobieszczyk, Magdalena E. Sobieszczyk, Christos A. Kyratsous, Lawrence Shapiro, Lawrence Shapiro, Zizhang Sheng, Yaoxing Huang, David D. Ho, David D. Ho 
Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants.

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08 Jul 2021-The New England Journal of Medicine
Laith J. Abu-Raddad, Hiam Chemaitelly, Adeel A. Butt
Frequently Asked Questions (8)
Q1. What is the titer of the B.1.617 variant?

The 39 modest neutralization resistance of the variant spike proteins to vaccine elicited antibody 40 suggests that current vaccines will remain protective against the B.1.617 and B.1.618 41 variants. 

166 167 The L452R mutation, which is present in the California B.1.427/B.1.429 was found to have 168 a significant effect on resistance to vaccine-elicited and monoclonal antibodies. 

The authors found that the viruses with the Indian spike proteins were partially resistant 75 to neutralization by convalescent serum antibody and vaccine-elicited antibodies. 

Mutation of the same position, E484Q, in B.1.617 caused a 2-4-fold 175 decrease of neutralization by serum, demonstrating the importance of this residue as an 176 epitope for antibody recognition. 

D145-146 lies in the N-terminal domain that is a known antibody binding 67site [18] and P681R lies within S1/S2 where it could affect proteolytic processing (Fig. 1A 68 and B). 

The apparent increased 140 transmissibility of the variants could be caused by increased affinity for ACE2 as has been 141 found for other variants. 

Even with the 3-4-fold decrease in neutralization titer of 162 vaccine elicited antibodies, average titers were around 1:500, a titer well above that found 163 in the sera of individuals who have recovered from infection with earlier unmutated viruses. 

The 179 increase was not associated with an increase in infectivity on ACE2.293T cells but might 180 have an effect on the infection in primary cells in vivo.