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      Recall of pre-existing cross-reactive B cell memory following Omicron BA.1 breakthrough infection

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          Abstract

          Understanding immune responses following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) breakthrough infection will facilitate the development of next-generation vaccines. Here, we profiled spike (S)-specific B cell responses following Omicron/BA.1 infection in mRNA-vaccinated donors. The acute antibody response was characterized by high levels of somatic hypermutation (SHM) and a bias toward recognition of ancestral SARS-CoV-2 strains, suggesting the early activation of vaccine-induced memory B cells (MBCs). BA.1 breakthrough infection induced a shift in B cell immunodominance hierarchy from the S2 subunit, which is highly conserved across SARS-CoV-2 variants of concern (VOCs), and toward the antigenically variable receptor binding domain (RBD). A large proportion of RBD-directed neutralizing antibodies isolated from BA.1 breakthrough infection donors displayed convergent sequence features and broadly recognized SARS-CoV-2 VOCs. Together, these findings provide insights into the role of pre-existing immunity in shaping the B cell response to heterologous SARS-CoV-2 variant exposure.

          Abstract

          BA.1 breakthrough infection activates pre-existing memory B cells with broad activity against SARS-CoV-2 variants.

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          Covid-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant

          Nick Andrews, Julia Stowe, Freja Kirsebom … (2022)
          Background A rapid increase in coronavirus disease 2019 (Covid-19) cases due to the omicron (B.1.1.529) variant of severe acute respiratory syndrome coronavirus 2 in highly vaccinated populations has aroused concerns about the effectiveness of current vaccines. Methods We used a test-negative case–control design to estimate vaccine effectiveness against symptomatic disease caused by the omicron and delta (B.1.617.2) variants in England. Vaccine effectiveness was calculated after primary immunization with two doses of BNT162b2 (Pfizer–BioNTech), ChAdOx1 nCoV-19 (AstraZeneca), or mRNA-1273 (Moderna) vaccine and after a booster dose of BNT162b2, ChAdOx1 nCoV-19, or mRNA-1273. Results Between November 27, 2021, and January 12, 2022, a total of 886,774 eligible persons infected with the omicron variant, 204,154 eligible persons infected with the delta variant, and 1,572,621 eligible test-negative controls were identified. At all time points investigated and for all combinations of primary course and booster vaccines, vaccine effectiveness against symptomatic disease was higher for the delta variant than for the omicron variant. No effect against the omicron variant was noted from 20 weeks after two ChAdOx1 nCoV-19 doses, whereas vaccine effectiveness after two BNT162b2 doses was 65.5% (95% confidence interval [CI], 63.9 to 67.0) at 2 to 4 weeks, dropping to 8.8% (95% CI, 7.0 to 10.5) at 25 or more weeks. Among ChAdOx1 nCoV-19 primary course recipients, vaccine effectiveness increased to 62.4% (95% CI, 61.8 to 63.0) at 2 to 4 weeks after a BNT162b2 booster before decreasing to 39.6% (95% CI, 38.0 to 41.1) at 10 or more weeks. Among BNT162b2 primary course recipients, vaccine effectiveness increased to 67.2% (95% CI, 66.5 to 67.8) at 2 to 4 weeks after a BNT162b2 booster before declining to 45.7% (95% CI, 44.7 to 46.7) at 10 or more weeks. Vaccine effectiveness after a ChAdOx1 nCoV-19 primary course increased to 70.1% (95% CI, 69.5 to 70.7) at 2 to 4 weeks after an mRNA-1273 booster and decreased to 60.9% (95% CI, 59.7 to 62.1) at 5 to 9 weeks. After a BNT162b2 primary course, the mRNA-1273 booster increased vaccine effectiveness to 73.9% (95% CI, 73.1 to 74.6) at 2 to 4 weeks; vaccine effectiveness fell to 64.4% (95% CI, 62.6 to 66.1) at 5 to 9 weeks. Conclusions Primary immunization with two doses of ChAdOx1 nCoV-19 or BNT162b2 vaccine provided limited protection against symptomatic disease caused by the omicron variant. A BNT162b2 or mRNA-1273 booster after either the ChAdOx1 nCoV-19 or BNT162b2 primary course substantially increased protection, but that protection waned over time. (Funded by the U.K. Health Security Agency.)
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            Convergent Antibody Responses to SARS-CoV-2 in Convalescent Individuals

            Davide Robbiani, Christian Gaebler, Frauke Muecksch … (2020)
            During the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-2 1–5 . Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal pseudovirus neutralizing titers: less than 1:50 in 33% and below 1:1000 in 79%, while only 1% showed titers >1:5000. Antibody sequencing revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titers, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC50s) as low as single digit ng/mL. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.
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              SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies

              Christopher Barnes, Claudia A. Jette, Morgan E. Abernathy … (2020)
              The coronavirus disease 2019 (COVID-19) pandemic presents an urgent health crisis. Human neutralizing antibodies that target the host ACE2 receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein1-5 show promise therapeutically and are being evaluated clinically6-8. Here, to identify the structural correlates of SARS-CoV-2 neutralization, we solved eight new structures of distinct COVID-19 human neutralizing antibodies5 in complex with the SARS-CoV-2 spike trimer or RBD. Structural comparisons allowed us to classify the antibodies into categories: (1) neutralizing antibodies encoded by the VH3-53 gene segment with short CDRH3 loops that block ACE2 and bind only to 'up' RBDs; (2) ACE2-blocking neutralizing antibodies that bind both up and 'down' RBDs and can contact adjacent RBDs; (3) neutralizing antibodies that bind outside the ACE2 site and recognize both up and down RBDs; and (4) previously described antibodies that do not block ACE2 and bind only to up RBDs9. Class 2 contained four neutralizing antibodies with epitopes that bridged RBDs, including a VH3-53 antibody that used a long CDRH3 with a hydrophobic tip to bridge between adjacent down RBDs, thereby locking the spike into a closed conformation. Epitope and paratope mapping revealed few interactions with host-derived N-glycans and minor contributions of antibody somatic hypermutations to epitope contacts. Affinity measurements and mapping of naturally occurring and in vitro-selected spike mutants in 3D provided insight into the potential for SARS-CoV-2 to escape from antibodies elicited during infection or delivered therapeutically. These classifications and structural analyses provide rules for assigning current and future human RBD-targeting antibodies into classes, evaluating avidity effects and suggesting combinations for clinical use, and provide insight into immune responses against SARS-CoV-2.
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                Author and article information

                Contributors
                Chengzi I. Kaku:
                ORCID: https://orcid.org/0000-0002-9854-8351
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing - original draft
                Alan J. Bergeron: Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Clas Ahlm:
                ORCID: https://orcid.org/0000-0003-2018-8592
                Role: InvestigationRole: Resources
                Johan Normark:
                ORCID: https://orcid.org/0000-0001-5831-4369
                Role: InvestigationRole: Project administrationRole: Resources
                Mrunal Sakharkar:
                ORCID: https://orcid.org/0000-0002-2717-5201
                Role: InvestigationRole: Resources
                Mattias N. E. Forsell:
                ORCID: https://orcid.org/0000-0001-6904-742X
                Role: Funding acquisitionRole: InvestigationRole: Resources
                Laura M. Walker:
                ORCID: https://orcid.org/0000-0001-7704-3197
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: 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): 12 May 2022
                Publication date PMC-release: 12 May 2022
                Electronic Location Identifier: eabq3511
                Affiliations
                [ 1 ]Adimab, LLC, Lebanon, NH 03766, USA
                [ 2 ]Norris Cotton Cancer Center, Dartmouth Hitchcock Medical Center, Lebanon, NH 03766, USA.
                [ 3 ]Department of Microbiology and Immunology, Dartmouth College, Hanover, NH 03755, USA.
                [ 4 ]Division of Immunology, Department of Clinical Microbiology, Umea University, Umea,
                [5]Sweden.
                [ 5 ]Adagio Therapeutics, Inc., Waltham, MA 02451, USA.
                Author notes
                [* ]Corresponding author. E-mail: lwalker@ 123456adagiotx.com (L.M.W.)
                Author information
                https://orcid.org/0000-0002-9854-8351
                https://orcid.org/0000-0003-2018-8592
                https://orcid.org/0000-0001-5831-4369
                https://orcid.org/0000-0002-2717-5201
                https://orcid.org/0000-0001-6904-742X
                https://orcid.org/0000-0001-7704-3197
                Article
                Publisher ID: abq3511
                DOI: 10.1126/sciimmunol.abq3511
                PMC ID: 9097882
                PubMed ID: 35549299
                SO-VID: ef83541d-a0f6-4961-94a0-7452c514f1ac
                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
                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 : 02 April 2022
                Date accepted : 06 May 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100018776, Cancer Center, University of Florida Health;
                Award ID: 5P30 CA023108-41
                Funded by: FundRef http://dx.doi.org/10.13039/501100004359, Vetenskapsrådet;
                Award ID: 2020-06235
                Funded by: FundRef http://dx.doi.org/10.13039/501100004359, Vetenskapsrådet;
                Award ID: 2021-04665
                Funded by: FundRef http://dx.doi.org/10.13039/501100009252, Science for Life Laboratory;
                Award ID: COVID-19 R
                Funded by: FundRef http://dx.doi.org/10.13039/501100009252, Science for Life Laboratory;
                Award ID: VC-2020-0015
                Categories
                Subject: Reports
                Subject: Reports
                Subject: Reports
                Subject: Coronavirus
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