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PreprintCited by 11SARS-CoV-2 and COVID-19 Researchvaccines and immunoinformatics approachesAnimal Virus Infections Studies

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Molecular basis of SARS-CoV-2 Omicron variant evasion from shared neutralizing antibody response

Open access
Patel, Anamika, Kumar, Sanjeev, Lai, Lilin, Chakravarthy, Chennareddy, Valanparambil, Rajesh, Reddy, Elluri Seetharami, Gottimukkala, Kamalvishnu, Bajpai, Prashant, Raju, Dinesh Ravindra, Edara, Venkata Viswanadh, Davis-Gardner, Meredith E., Linderman, Susanne, Dixit, Kritika, Sharma, Pragati, Mantus, Grace, Cheedarla, Narayanaiah, Verkerke, Hans P., Frank, Filipp, Neish, Andrew S., Roback, John D., Davis, Carl W., Wrammert, Jens, Ahmed, Rafi, Suthar, Mehul S., Sharma, Amit, Murali-Krishna, Kaja, Chandele, Anmol, Ortlund, Eric A.·2022·Structure
DOI 10.1101/2022.10.24.513517PMC PMC10171968

Preprint — published as 10.1016/j.str.2023.04.010

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Abstract

A detailed understanding of the molecular features of the neutralizing epitopes developed by viral escape mutants is important for predicting and developing vaccines or therapeutic antibodies against continuously emerging SARS-CoV-2 variants. Here, we report three human monoclonal antibodies (mAbs) generated from COVID-19 recovered individuals during first wave of pandemic in India. These mAbs had publicly shared near germline gene usage and potently neutralized Alpha and Delta, but poorly neutralized Beta and completely failed to neutralize Omicron BA.1 SARS-CoV-2 variants. Structural analysis of these three mAbs in complex with trimeric spike protein showed that all three mAbs are involved in bivalent spike binding with two mAbs targeting class-1 and one targeting class-4 Receptor Binding Domain (RBD) epitope. Comparison of immunogenetic makeup, structure, and function of these three mAbs with our recently reported class-3 RBD binding mAb that potently neutralized all SARS-CoV-2 variants revealed precise antibody footprint, specific molecular interactions associated with the most potent multi-variant binding / neutralization efficacy. This knowledge has timely significance for understanding how a combination of certain mutations affect the binding or neutralization of an antibody and thus have implications for predicting structural features of emerging SARS-CoV-2 escape variants and to develop vaccines or therapeutic antibodies against these.

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Metadata

Authors
Patel, A., Kumar, S., Lai, L., Chakravarthy, C., Valanparambil, R., Reddy, E. S., Gottimukkala, K., Bajpai, P., Raju, D. R., Edara, V. V., Davis-Gardner, M. E., Linderman, S., Dixit, K., Sharma, P., Mantus, G., Cheedarla, N., Verkerke, H. P., Frank, F., Neish, A. S., Roback, J. D., Davis, C. W., Wrammert, J., Ahmed, R., Suthar, M. S., Sharma, A., Murali-Krishna, K., Chandele, A., & Ortlund, E. A.
Affiliations
  • Emory University (US)
  • International Centre for Genetic Engineering and Biotechnology (ZA)
  • Georgia Institute of Technology (US)
  • Brigham and Women's Hospital (US)
  • International Centre for Genetic Engineering and Biotechnology (IN)
Corresponding author
  • Sharma, Amit
  • Chandele, Anmol
  • Ortlund, Eric A.
ORCID
Venue
Structure
Publisher
openRxiv
Published
2022-10-24
Volume
31
Issue
7
Pages
801-811.e5
ISSN
0969-2126 (ISSN-L)
DOI
10.1101/2022.10.24.513517
PMC
PMC10171968
OpenAlex
W4376140686
Cited by
11
References
1
Citations by year
2026: 2 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 1
FWCI
2.06
Type
journal article
Language
en
Open access
Locations
  • Structure (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • SSRN Electronic Journal (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • U.S. Department of Health and Human Services (P51OD011132, U54EB015408, HHSN272201400004C, 75N93021C00017, U19 AI142790)
  • Emory University (COVID-Catalyst-I3 Funds)
  • Wellcome Trust
  • Children's Healthcare of Atlanta
  • Department of Biotechnology, Ministry of Science and Technology, India (BT/NBM099/02/18, BT/PR30260/MED/15/194/2018)
  • Indian Council of Medical Research (COVID-19, VIR/COVID-19/02/2020/ECD-1)
  • The Wellcome Trust DBT India Alliance (IA/E/18/1/504307)
  • National Institutes of Health (75N93021C00017, 75N92019P00328, COVID-19, HHSN272201400004C, P51OD011132)
  • National Institute of General Medical Sciences (T32GM008169, U24GM129539, T32GM139776, T32GM142617)
  • National Institute of Allergy and Infectious Diseases (COVID-19, 75N93021C00017, U19AI142790, HHSN272201400004C)
  • National Institute of Biomedical Imaging and Bioengineering (U54EB015408, 75N92019P00328, U54EB027690)
  • Common Fund (U24 GM129539)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
Keywords
Omicron variant, neutralizing antibodies, monoclonal antibodies, antibody escape, spike protein, receptor binding domain, SARS-CoV-2 variants, Alpha variant, Delta variant, Beta variant, Omicron BA.1, antibody-antigen complex structure, germline gene usage

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