Exposure to BA.4/5 S protein drives neutralization of Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5 in vaccine-experienced humans and mice

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Abstract

The SARS-CoV-2 Omicron variant and its sublineages show pronounced viral escape from neutralizing antibodies elicited by vaccination or prior SARS-CoV-2 variant infection owing to over 30 amino acid alterations within the spike (S) glycoprotein. Breakthrough infection of vaccinated individuals with Omicron sublineages BA.1 and BA.2 is associated with distinct patterns of cross-neutralizing activity against SARS-CoV-2 variants of concern (VOCs). In continuation of our previous work, we characterized the effect of Omicron BA.4/BA.5 S glycoprotein exposure on the neutralizing antibody response upon breakthrough infection in vaccinated individuals and upon variant-adapted booster vaccination in mice. We found that immune sera from triple mRNA-vaccinated individuals with subsequent breakthrough infection during the Omicron BA.4/BA.5 wave showed cross-neutralizing activity against previous Omicron variants BA.1, BA.2, BA.2.12.1, and BA.4/BA.5 itself. Administration of a prototypic BA.4/BA.5-adapted mRNA booster vaccine to mice following SARS-CoV-2 wild-type strain-based primary immunization is associated with broader cross-neutralizing activity than a BA.1-adapted booster. While the Omicron BA-1-adapted mRNA vaccine in a bivalent format (wild-type + BA.1) broadens cross-neutralizing activity relative to the BA.1 monovalent booster, cross-neutralization of BA.2 and descendants is more effective in mice boosted with a bivalent wild-type + BA.4/BA.5 vaccine. In naïve mice primary immunization with the bivalent wild-type + Omicron BA.4/BA.5 vaccine induces strong cross-neutralizing activity against Omicron VOCs and previous variants. These findings suggest that when administered as boosters, mono- and bivalent Omicron BA.4/BA.5-adapted vaccines enhance neutralization breadth, and that the bivalent version also has the potential to confer protection to individuals with no pre-existing immunity against SARS-CoV-2.

Abstract

Immune sera from BA.4/BA.5 breakthrough infected individuals and BA.4/5 booster-vaccinated mice broadly neutralize Omicron sublineages.

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Nextstrain: real-time tracking of pathogen evolution

James Hadfield, Colin Megill, Sidney Bell … (2018)

Abstract Summary Understanding the spread and evolution of pathogens is important for effective public health measures and surveillance. Nextstrain consists of a database of viral genomes, a bioinformatics pipeline for phylodynamics analysis, and an interactive visualization platform. Together these present a real-time view into the evolution and spread of a range of viral pathogens of high public health importance. The visualization integrates sequence data with other data types such as geographic information, serology, or host species. Nextstrain compiles our current understanding into a single accessible location, open to health professionals, epidemiologists, virologists and the public alike. Availability and implementation All code (predominantly JavaScript and Python) is freely available from github.com/nextstrain and the web-application is available at nextstrain.org.

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Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7

Pengfei Wang, Manoj S. Nair, Lihong Liu … (2021)

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.

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Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies

Yunlong Cao, Jing WANG, Fanchong Jian … (2021)

The SARS-CoV-2 B.1.1.529 (Omicron) variant contains 15 mutations of the receptor-binding domain (RBD). How Omicron evades RBD-targeted neutralizing antibodies requires immediate investigation. Here we use high-throughput yeast display screening 1,2 to determine the profiles of RBD escaping mutations for 247 human anti-RBD neutralizing antibodies and show that the neutralizing antibodies can be classified by unsupervised clustering into six epitope groups (A–F)—a grouping that is highly concordant with knowledge-based structural classifications 3–5 . Various single mutations of Omicron can impair neutralizing antibodies of different epitope groups. Specifically, neutralizing antibodies in groups A–D, the epitopes of which overlap with the ACE2-binding motif, are largely escaped by K417N, G446S, E484A and Q493R. Antibodies in group E (for example, S309) 6 and group F (for example, CR3022) 7 , which often exhibit broad sarbecovirus neutralizing activity, are less affected by Omicron, but a subset of neutralizing antibodies are still escaped by G339D, N440K and S371L. Furthermore, Omicron pseudovirus neutralization showed that neutralizing antibodies that sustained single mutations could also be escaped, owing to multiple synergetic mutations on their epitopes. In total, over 85% of the tested neutralizing antibodies were escaped by Omicron. With regard to neutralizing-antibody-based drugs, the neutralization potency of LY-CoV016, LY-CoV555, REGN10933, REGN10987, AZD1061, AZD8895 and BRII-196 was greatly undermined by Omicron, whereas VIR-7831 and DXP-604 still functioned at a reduced efficacy. Together, our data suggest that infection with Omicron would result in considerable humoral immune evasion, and that neutralizing antibodies targeting the sarbecovirus conserved region will remain most effective. Our results inform the development of antibody-based drugs and vaccines against Omicron and future variants.

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Author and article information

Contributors

Alexander Muik:

ORCID: https://orcid.org/0000-0003-4561-2273

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Bonny Gaby Lui:

ORCID: https://orcid.org/0000-0002-8260-5075

Role: InvestigationRole: MethodologyRole: Project administrationRole: Supervision

Maren Bacher: Role: Investigation

Ann-Kathrin Wallisch:

ORCID: https://orcid.org/0000-0001-5450-3218

Role: Investigation

Aras Toker:

ORCID: https://orcid.org/0000-0001-6601-0939

Role: Formal analysisRole: VisualizationRole: Writing - original draft

Carla Iris Cadima Couto:

ORCID: https://orcid.org/0000-0001-7398-5857

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Alptekin Güler:

ORCID: https://orcid.org/0000-0001-7073-2125

Role: InvestigationRole: MethodologyRole: VisualizationRole: Writing - review & editing

Veena Mampilli: Role: Investigation

Geneva J. Schmitt: Role: InvestigationRole: ResourcesRole: Visualization

Jonathan Mottl: Role: Formal analysisRole: Investigation

Thomas Ziegenhals:

ORCID: https://orcid.org/0000-0003-3242-6914

Role: Project administrationRole: ResourcesRole: Validation

Stephanie Fesser: Role: Resources

Jonas Reinholz:

ORCID: https://orcid.org/0000-0003-2384-8541

Role: Project administrationRole: Validation

Florian Wernig: Role: InvestigationRole: Validation

Karla-Gerlinde Schraut: Role: Project administrationRole: ResourcesRole: Validation

Hossam Hefesha:

ORCID: https://orcid.org/0000-0003-3457-9949

Role: Project administration

Hui Cai:

ORCID: https://orcid.org/0000-0003-3627-7346

Role: ConceptualizationRole: MethodologyRole: ResourcesRole: Validation

Qi Yang:

ORCID: https://orcid.org/0000-0001-8838-6910

Role: Data curationRole: Formal analysisRole: InvestigationRole: Project administrationRole: ResourcesRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - review & editing

Kerstin C. Walzer: Role: Data curationRole: InvestigationRole: Project administrationRole: ResourcesRole: Writing - review & editing

Jessica Grosser: Role: Resources

Stefan Strauss: Role: InvestigationRole: Resources

Andrew Finlayson:

ORCID: https://orcid.org/0000-0003-0793-7878

Role: VisualizationRole: Writing - original draftRole: Writing - review & editing

Kimberly Krüger: Role: ResourcesRole: Writing - review & editing

Orkun Ozhelvaci:

ORCID: https://orcid.org/0000-0002-9841-3369

Role: Data curationRole: InvestigationRole: Project administrationRole: ResourcesRole: ValidationRole: Visualization

Katharina Grikscheit:

ORCID: https://orcid.org/0000-0003-1102-078X

Role: Resources

Niko Kohmer:

ORCID: https://orcid.org/0000-0002-5458-1467

Role: ResourcesRole: Writing - review & editing

Sandra Ciesek:

ORCID: https://orcid.org/0000-0002-1802-7565

Role: ConceptualizationRole: Data curationRole: MethodologyRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - review & editing

Kena A. Swanson:

ORCID: https://orcid.org/0000-0002-3389-8414

Role: ConceptualizationRole: Writing - review & editing

Annette B. Vogel:

ORCID: https://orcid.org/0000-0002-9940-5379

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Özlem Türeci: Role: ConceptualizationRole: SupervisionRole: Writing - review & editing

Ugur Sahin:

ORCID: https://orcid.org/0000-0003-0363-1564

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: Supervision

Journal

Journal ID (nlm-ta): Sci Immunol

Journal ID (iso-abbrev): Sci Immunol

Journal ID (publisher-id): sciimmunol

Journal ID (hwp): immunology

Title: Science Immunology

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2470-9468

Publication date (Electronic, pub): 15 November 2022

Publication date PMC-release: 15 November 2022

Electronic Location Identifier: eade9888

Affiliations

[ ¹ ]BioNTech, An der Goldgrube 12, 55131 Mainz, Germany.

[ ² ]Pfizer, 401 N. Middletown Rd., Pearl River, NY 10960, USA.

[ ³ ]Institute for Medical Virology, University Hospital, Goethe University Frankfurt, 60596 Frankfurt am Main, Germany.

[ ⁴ ]DZIF – German Centre for Infection Research, External Partner Site, 60596 Frankfurt am Main, Germany.

[ ⁵ ]HI-TRON – Helmholtz Institute for Translational Oncology Mainz by DKFZ, Obere Zahlbacherstr. 63, 55131 Mainz, Germany.

[ ⁶ ]TRON gGmbH – Translational Oncology at the University Medical Center of the Johannes Gutenberg University, Freiligrathstraße 12, 55131 Mainz, Germany.

Author notes

[* ]Corresponding author. Email: ugur.sahin@ 123456biontech.de

Author information

Alexander Muik https://orcid.org/0000-0003-4561-2273

Bonny Gaby Lui https://orcid.org/0000-0002-8260-5075

Ann-Kathrin Wallisch https://orcid.org/0000-0001-5450-3218

Aras Toker https://orcid.org/0000-0001-6601-0939

Carla Iris Cadima Couto https://orcid.org/0000-0001-7398-5857

Alptekin Güler https://orcid.org/0000-0001-7073-2125

Thomas Ziegenhals https://orcid.org/0000-0003-3242-6914

Jonas Reinholz https://orcid.org/0000-0003-2384-8541

Hossam Hefesha https://orcid.org/0000-0003-3457-9949

Hui Cai https://orcid.org/0000-0003-3627-7346

Qi Yang https://orcid.org/0000-0001-8838-6910

Andrew Finlayson https://orcid.org/0000-0003-0793-7878

Orkun Ozhelvaci https://orcid.org/0000-0002-9841-3369

Katharina Grikscheit https://orcid.org/0000-0003-1102-078X

Niko Kohmer https://orcid.org/0000-0002-5458-1467

Sandra Ciesek https://orcid.org/0000-0002-1802-7565

Kena A. Swanson https://orcid.org/0000-0002-3389-8414

Annette B. Vogel https://orcid.org/0000-0002-9940-5379

Ugur Sahin https://orcid.org/0000-0003-0363-1564

Article

Publisher ID: ade9888

DOI: 10.1126/sciimmunol.ade9888

PMC ID: 9765452

PubMed ID: 36378074

SO-VID: 436074e9-0a13-4bb3-a040-c6fed6d1d9dc

Copyright © Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 21 September 2022

Date accepted : 10 November 2022

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Exposure to BA.4/5 S protein drives neutralization of Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5 in vaccine-experienced humans and mice

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Most cited references 25

Nextstrain: real-time tracking of pathogen evolution

Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7

Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies

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