Omicron BA.1 breakthrough infection drives cross-variant neutralization and memory B cell formation against conserved epitopes

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Abstract

Omicron is the evolutionarily most distinct SARS-CoV-2 variant of concern (VOC) to date. We report that Omicron BA.1 breakthrough infection in BNT162b2-vaccinated individuals resulted in strong neutralizing activity against Omicron BA.1, BA.2 and previous SARS-CoV-2 VOCs, but not against the Omicron sublineages BA.4 and BA.5. BA.1 breakthrough infection induced a robust recall response, primarily expanding B _MEM cells against epitopes shared broadly amongst variants, rather than inducing BA.1-specific B cells. The vaccination-imprinted B _MEM cell pool had sufficient plasticity to be remodeled by heterologous SARS-CoV-2 spike glycoprotein exposure. While selective amplification of B _MEM cells recognizing shared epitopes allows for effective neutralization of most variants that evade previously established immunity, susceptibility to escape by variants that acquire alterations at hitherto conserved sites may be heightened.

Abstract

BA.1 infection after BNT162b2 vaccination drives cross-variant neutralization and memory B cell formation against conserved epitopes.

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Most cited references 43

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Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection

David Khoury, Deborah Cromer, Arnold Reynaldi … (2021)

Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4-28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7-13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.

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SARS-CoV-2 variants, spike mutations and immune escape

William T. Harvey, Alessandro M. Carabelli, Ben Jackson … (2021)

Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively neutral, a small proportion will affect functional properties and may alter infectivity, disease severity or interactions with host immunity. The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Since late 2020, however, SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations, in the context of ‘variants of concern’, that impact virus characteristics, including transmissibility and antigenicity, probably in response to the changing immune profile of the human population. There is emerging evidence of reduced neutralization of some SARS-CoV-2 variants by postvaccination serum; however, a greater understanding of correlates of protection is required to evaluate how this may impact vaccine effectiveness. Nonetheless, manufacturers are preparing platforms for a possible update of vaccine sequences, and it is crucial that surveillance of genetic and antigenic changes in the global virus population is done alongside experiments to elucidate the phenotypic impacts of mutations. In this Review, we summarize the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets. The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been characterized by the emergence of mutations and so-called variants of concern that impact virus characteristics, including transmissibility and antigenicity. In this Review, members of the COVID-19 Genomics UK (COG-UK) Consortium and colleagues summarize mutations of the SARS-CoV-2 spike protein, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets.

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Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody

Dora Pinto, Young-Jun Park, Martina Beltramello … (2020)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerged coronavirus that is responsible for the current pandemic of coronavirus disease 2019 (COVID-19), which has resulted in more than 3.7 million infections and 260,000 deaths as of 6 May 20201,2. Vaccine and therapeutic discovery efforts are paramount to curb the pandemic spread of this zoonotic virus. The SARS-CoV-2 spike (S) glycoprotein promotes entry into host cells and is the main target of neutralizing antibodies. Here we describe several monoclonal antibodies that target the S glycoprotein of SARS-CoV-2, which we identified from memory B cells of an individual who was infected with severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003. One antibody (named S309) potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2, by engaging the receptor-binding domain of the S glycoprotein. Using cryo-electron microscopy and binding assays, we show that S309 recognizes an epitope containing a glycan that is conserved within the Sarbecovirus subgenus, without competing with receptor attachment. Antibody cocktails that include S309 in combination with other antibodies that we identified further enhanced SARS-CoV-2 neutralization, and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309 and antibody cocktails containing S309 for prophylaxis in individuals at a high risk of exposure or as a post-exposure therapy to limit or treat severe disease.

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Author and article information

Contributors

Jasmin Quandt:

ORCID: https://orcid.org/0000-0001-9589-9941

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

Alexander Muik:

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

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

Nadine Salisch: Role: Writing - original draftRole: Writing - review & editing

Bonny Gaby Lui:

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

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: Validation

Sebastian Lutz:

ORCID: https://orcid.org/0000-0002-8415-6437

Role: Formal analysisRole: InvestigationRole: ValidationRole: Writing - review & editing

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

Ann-Kathrin Wallisch:

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

Role: Investigation

Petra Adams-Quack:

ORCID: https://orcid.org/0000-0003-0056-0844

Role: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: Validation

Maren Bacher: Role: Investigation

Andrew Finlayson:

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

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

Orkun Ozhelvaci:

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

Role: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Isabel Vogler:

ORCID: https://orcid.org/0000-0001-9757-9618

Role: ConceptualizationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing - review & editing

Katharina Grikscheit: Role: Project administrationRole: Resources

Sebastian Hoehl:

ORCID: https://orcid.org/0000-0002-5100-9385

Role: ConceptualizationRole: Data curationRole: InvestigationRole: Resources

Udo Goetsch: Role: Resources

Sandra Ciesek: Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - review & editing

Özlem Türeci:

ORCID: https://orcid.org/0000-0002-0623-1497

Role: ConceptualizationRole: Data curationRole: Project administrationRole: SupervisionRole: ValidationRole: Writing - review & editing

Ugur Sahin:

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

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: Writing - review & editing

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): 02 June 2022

Publication date PMC-release: 02 June 2022

Electronic Location Identifier: eabq2427

Affiliations

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

[ ² ]Institute for Medical Virology, University Hospital, Goethe University Frankfurt, 60596 Frankfurt am Main, Germany.

[ ³ ]Health Protection Authority, City of Frankfurt, 60313 Frankfurt, Germany.

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

[ # ]

Contributed equally

[* ]Correspondence to: Ugur.Sahin@ 123456biontech.de

Author information

Jasmin Quandt https://orcid.org/0000-0001-9589-9941

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

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

Sebastian Lutz https://orcid.org/0000-0002-8415-6437

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

Petra Adams-Quack https://orcid.org/0000-0003-0056-0844

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

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

Isabel Vogler https://orcid.org/0000-0001-9757-9618

Sebastian Hoehl https://orcid.org/0000-0002-5100-9385

Özlem Türeci https://orcid.org/0000-0002-0623-1497

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

Article

Publisher ID: abq2427

DOI: 10.1126/sciimmunol.abq2427

PMC ID: 9162083

PubMed ID: 35653438

SO-VID: 45a1a61d-4fc4-4143-9968-545afe7391e1

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 : 27 March 2022

Date accepted : 28 May 2022

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Omicron BA.1 breakthrough infection drives cross-variant neutralization and memory B cell formation against conserved epitopes

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Novel Coronavirus Disease COVID-19

Most cited references 43

Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection

SARS-CoV-2 variants, spike mutations and immune escape

Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody

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