Heterologous infection and vaccination shapes immunity against SARS-CoV-2 variants

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Immune imprinting

For severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), immune responses to heterologous variants are influenced by a person’s infection history. Healthcare workers (HCWs) may be exposed to several doses and types of antigens, either by natural infection or by vaccination. Reynolds et al. studied a cohort of UK HCWs followed since March 2020. The immunological profiles of these people depended on how often the subject had encountered antigen and which variant was involved. Vaccine responses after infection were found to be less effective if the infection involved heterologous spike from a variant virus. Unfortunately, the N501Y spike mutation, found in many variants, seems to induce the regulatory T cell transcription factor FOXP3, indicating that the virus could subvert effective T cell function. Changes to antibody binding between variants also means that serology data using the Wuhan Hu-1 S1 receptor-binding domain sequence may not be a reliable measure of protection. —CA

Abstract

SARS-CoV-2 B.1.1.7 infection differentially shapes heterologous immunity against subsequent variants in two-dose vaccinees.

Abstract

The impact of the initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infecting strain on downstream immunity to heterologous variants of concern (VOCs) is unknown. Studying a longitudinal healthcare worker cohort, we found that after three antigen exposures (infection plus two vaccine doses), S1 antibody, memory B cells, and heterologous neutralization of B.1.351, P.1, and B.1.617.2 plateaued, whereas B.1.1.7 neutralization and spike T cell responses increased. Serology using the Wuhan Hu-1 spike receptor binding domain poorly predicted neutralizing immunity against VOCs. Neutralization potency against VOCs changed with heterologous virus encounter and number of antigen exposures. Neutralization potency fell differentially depending on targeted VOCs over the 5 months from the second vaccine dose. Heterologous combinations of spike encountered during infection and vaccination shape subsequent cross-protection against VOC, with implications for future-proof next-generation vaccines.

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Most cited references 40

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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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Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization

Delphine Planas, David Veyer, Artem Baidaliuk … (2021)

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.

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Author and article information

Contributors

Catherine J. Reynolds:

ORCID: https://orcid.org/0000-0002-1371-653X

Role: Data curationRole: Formal analysisRole: InvestigationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Joseph M. Gibbons:

ORCID: https://orcid.org/0000-0002-7238-2381

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - review & editing

Corinna Pade:

ORCID: https://orcid.org/0000-0003-0626-2346

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - review & editing

Kai-Min Lin:

ORCID: https://orcid.org/0000-0003-2109-1530

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

Diana Muñoz Sandoval:

ORCID: https://orcid.org/0000-0001-8350-3989

Role: Investigation

Franziska Pieper:

ORCID: https://orcid.org/0000-0002-4857-0518

Role: Investigation

David K. Butler:

ORCID: https://orcid.org/0000-0003-1882-8159

Role: Formal analysisRole: InvestigationRole: Visualization

Siyi Liu:

ORCID: https://orcid.org/0000-0003-0206-9661

Role: Investigation

Ashley D. Otter:

ORCID: https://orcid.org/0000-0002-8317-9194

Role: InvestigationRole: Resources

George Joy:

ORCID: https://orcid.org/0000-0003-1467-5490

Role: Investigation

Katia Menacho:

ORCID: https://orcid.org/0000-0001-5183-5655

Role: Investigation

Marianna Fontana:

ORCID: https://orcid.org/0000-0002-9233-9831

Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: Writing - review & editing

Angelique Smit:

ORCID: https://orcid.org/0000-0002-2144-1249

Role: Data curationRole: InvestigationRole: Project administrationRole: Supervision

Beatrix Kele:

ORCID: https://orcid.org/0000-0003-1273-7299

Role: InvestigationRole: ResourcesRole: Validation

Teresa Cutino-Moguel:

ORCID: https://orcid.org/0000-0002-1726-4278

Role: InvestigationRole: ResourcesRole: Validation

Mala K. Maini:

ORCID: https://orcid.org/0000-0001-6384-1462

Role: ConceptualizationRole: Writing - review & editing

Mahdad Noursadeghi:

ORCID: https://orcid.org/0000-0002-4774-0853

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

Tim Brooks:

ORCID: https://orcid.org/0000-0002-3783-1284

Role: ConceptualizationRole: InvestigationRole: Project administrationRole: ResourcesRole: Supervision

Amanda Semper:

ORCID: https://orcid.org/0000-0003-3656-1363

Role: Project administrationRole: SupervisionRole: Writing - review & editing

Charlotte Manisty:

ORCID: https://orcid.org/0000-0003-0245-7090

Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: Writing - review & editing

Thomas A. Treibel:

ORCID: https://orcid.org/0000-0003-1560-7414

Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: ResourcesRole: ValidationRole: Writing - review & editing

James C. Moon:

ORCID: https://orcid.org/0000-0001-8071-1491

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

Áine McKnight:

ORCID: https://orcid.org/0000-0002-8113-817X

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

Daniel M. Altmann:

ORCID: https://orcid.org/0000-0002-2436-6192

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Rosemary J. Boyton:

ORCID: https://orcid.org/0000-0002-5608-0797

Journal

Journal ID (nlm-ta): Science

Journal ID (iso-abbrev): Science

Journal ID (publisher-id): science

Title: Science (New York, N.y.)

Publisher: American Association for the Advancement of Science

ISSN (Print): 0036-8075

ISSN (Electronic): 1095-9203

Publication date (Print, pub): 14 January 2022

Publication date (Electronic): 02 December 2021

Publication date PMC-release: 02 December 2021

Volume: 375

Issue: 6577

Pages: 183-192

Affiliations

[1 ]Department of Infectious Disease, Imperial College London, London, UK.

[2 ]Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

[3 ]UK Health Security Agency, Porton Down, UK.

[4 ]St. Bartholomew’s Hospital, Barts Health NHS Trust, London, UK.

[5 ]Royal Free London NHS Foundation Trust, London, UK.

[6 ]Division of Infection and Immunity, University College London, London, UK.

[7 ]Institute of Cardiovascular Science, University College London, London, UK.

[8 ]Department of Immunology and Inflammation, Imperial College London, London, UK.

[9 ]Lung Division, Royal Brompton and Harefield Hospitals, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK.

Author notes

[* ]Corresponding author. Email: r.boyton@ 123456imperial.ac.uk

[†]

These authors contributed equally to this work and are co-first authors.

[‡]

The members of the COVIDsortium Immune Correlates Network and COVIDsortium Investigators are listed in the supplementary materials.

[§]

These authors contributed equally to this work and are co-senior authors.

Author information

Catherine J. Reynolds https://orcid.org/0000-0002-1371-653X

Joseph M. Gibbons https://orcid.org/0000-0002-7238-2381

Corinna Pade https://orcid.org/0000-0003-0626-2346

Kai-Min Lin https://orcid.org/0000-0003-2109-1530

Diana Muñoz Sandoval https://orcid.org/0000-0001-8350-3989

Franziska Pieper https://orcid.org/0000-0002-4857-0518

David K. Butler https://orcid.org/0000-0003-1882-8159

Siyi Liu https://orcid.org/0000-0003-0206-9661

Ashley D. Otter https://orcid.org/0000-0002-8317-9194

George Joy https://orcid.org/0000-0003-1467-5490

Katia Menacho https://orcid.org/0000-0001-5183-5655

Marianna Fontana https://orcid.org/0000-0002-9233-9831

Angelique Smit https://orcid.org/0000-0002-2144-1249

Beatrix Kele https://orcid.org/0000-0003-1273-7299

Teresa Cutino-Moguel https://orcid.org/0000-0002-1726-4278

Mala K. Maini https://orcid.org/0000-0001-6384-1462

Mahdad Noursadeghi https://orcid.org/0000-0002-4774-0853

Tim Brooks https://orcid.org/0000-0002-3783-1284

Amanda Semper https://orcid.org/0000-0003-3656-1363

Charlotte Manisty https://orcid.org/0000-0003-0245-7090

Thomas A. Treibel https://orcid.org/0000-0003-1560-7414

James C. Moon https://orcid.org/0000-0001-8071-1491

Áine McKnight https://orcid.org/0000-0002-8113-817X

Daniel M. Altmann https://orcid.org/0000-0002-2436-6192

Rosemary J. Boyton https://orcid.org/0000-0002-5608-0797

Article

Publisher ID: abm0811

DOI: 10.1126/science.abm0811

PMC ID: 10186585

PubMed ID: 34855510

SO-VID: 06931d49-9338-4006-8534-0ca1f059771d

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 : 25 August 2021

Date accepted : 25 November 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000265, Medical Research Council;

Award ID: MR/W020610/1

Funded by: FundRef http://dx.doi.org/10.13039/501100006041, Innovate UK;

Award ID: SBRI 10008614

Funded by: FundRef http://dx.doi.org/10.13039/501100008721, University College London Hospitals NHS Foundation Trust;

Funded by: FundRef http://dx.doi.org/10.13039/501100012317, UCLH Biomedical Research Centre;

Award ID: MR/S019553/1

Funded by: MRC;

Award ID: MR/R02622X/1

Funded by: MRC;

Award ID: MR/V036939/1

Funded by: MRC;

Award ID: MR/W020610/1

Funded by: NIHR EME Fast Track;

Award ID: NIHR134607

Funded by: Wellcome Trust UK;

Award ID: 207511/Z/17/Z

Funded by: Wellcome Trust Senior Investigator Award;

Award ID: 214191/Z/18/Z

Funded by: CRUK;

Award ID: 26603

Funded by: British Heart Foundation Intermediate Research Fellowship;

Award ID: FS/19/35/34374

Funded by: NIHR;

Award ID: COV-LT2-0027

Funded by: Cystic Fibrosis Trust UK;

Award ID: 2019SRC015

Funded by: NIHR EME Fast Track;

Award ID: NIHR134607

Funded by: NIHR;

Award ID: COV-LT2-0027

Funded by: UKRI;

Award ID: MR/W020610/1

Funded by: NIHR;

Award ID: COV-LT2-0027

Funded by: FundRef http://dx.doi.org/10.13039/501100013342, NIHR Imperial Biomedical Research Centre;

Award ID: NIHR Imperial Biomedical Research Centre (BRC):ITMAT,

Funded by: UKRI;

Award ID: MR/S019553/1

Funded by: Horizon 2020 Maria Sklodowska-Curie Innovative Training Network (ITN) European Training Network;

Heterologous infection and vaccination shapes immunity against SARS-CoV-2 variants

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Immune imprinting

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UCL: Covid-19 Research

Most cited references 40

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

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

Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization

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