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      Levels of SARS-CoV-2 antibodies among fully vaccinated individuals with Delta or Omicron variant breakthrough infections

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      Nature Communications
      Nature Publishing Group UK
      Preventive medicine, Viral infection, Epidemiology, SARS-CoV-2

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          Abstract

          SARS-CoV-2 variants of concern have continuously evolved and may erode vaccine induced immunity. In this observational cohort study, we determine the risk of breakthrough infection in a fully vaccinated cohort. SARS-CoV-2 anti-spike IgG levels were measured before first SARS-CoV-2 vaccination and at day 21–28, 90 and 180, as well as after booster vaccination. Breakthrough infections were captured through the Danish National Microbiology database. incidence rate ratio (IRR) for breakthrough infection at time-updated anti-spike IgG levels was determined using Poisson regression. Among 6076 participants, 127 and 364 breakthrough infections due to Delta and Omicron variants were observed. IRR was 0.29 (95% CI 0.15–0.56) for breakthrough infection with the Delta variant, comparing the highest and lowest quintiles of anti-spike IgG. For Omicron, no significant differences in IRR were observed. These results suggest that quantitative level of anti-spike IgG have limited impact on the risk of breakthrough infection with Omicron.

          Abstract

          The SARS-CoV-2 Omicron variant is associated with high rates of vaccine breakthrough infections, but the immunological basis for this is not well characterised. Here, the authors show that increased anti-Spike IgG antibody levels are associated with a reduced risk of infection with the Delta variant, but not with Omicron.

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

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

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

              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
                ninase@rm.dk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                1 August 2022
                1 August 2022
                2022
                : 13
                : 4466
                Affiliations
                [1 ]GRID grid.154185.c, ISNI 0000 0004 0512 597X, Department of Infectious Diseases, , Aarhus University Hospital, ; Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark
                [2 ]GRID grid.7048.b, ISNI 0000 0001 1956 2722, Department of Clinical Medicine, , Aarhus University, ; Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark
                [3 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Center of Excellence for Health, Immunity and Infections, Rigshospitalet, , University of Copenhagen, ; Blegdamsvej 9, 2100 Copenhagen, Denmark
                [4 ]GRID grid.27530.33, ISNI 0000 0004 0646 7349, Department of Infectious Diseases, , Aalborg University Hospital, ; Hobrovej 18, 9000 Aalborg, Denmark
                [5 ]GRID grid.5117.2, ISNI 0000 0001 0742 471X, Department of Clinical Medicine, , Aalborg University, ; Sdr. Skovvej 15, 9000 Aalborg, Denmark
                [6 ]GRID grid.4973.9, ISNI 0000 0004 0646 7373, Department of Infectious Diseases, , Copenhagen University Hospital—Amager and Hvidovre, ; Kettegård allé 30, 2650 Hvidovre, Denmark
                [7 ]GRID grid.5254.6, ISNI 0000 0001 0674 042X, Departments of Clinical Medicine and Public Health, , University of Copenhagen, ; Blegdamsvej 3B, 2200 Copenhagen, Denmark
                [8 ]GRID grid.476266.7, Department of Medicine, , Zealand University Hospital, ; Sygehusvej 10, 4000 Roskilde, Denmark
                [9 ]GRID grid.411646.0, ISNI 0000 0004 0646 7402, Department of Cardiology and Department of Emergency Medicine, , Herlev-Gentofte Hospital, ; Borgmester Ib Juuls Vej 1, 2730 Herlev, Denmark
                [10 ]GRID grid.7143.1, ISNI 0000 0004 0512 5013, Department of Infectious Diseases, , Odense University Hospital, ; J. B. Winsløws Vej 4, 5000 Odense, Denmark
                [11 ]GRID grid.10825.3e, ISNI 0000 0001 0728 0170, Department of Clinical Research, , University of Southern Denmark, ; J. B. Winsløws Vej 19.3, 5000 Odense C, Denmark
                [12 ]GRID grid.475435.4, Department of Clinical Immunology, , Rigshospitalet, ; Tagensvej 20 2200, Copenhagen, Denmark
                [13 ]GRID grid.154185.c, ISNI 0000 0004 0512 597X, Department of Clinical Immunology, , Aarhus University Hospital, ; Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Denmark
                [14 ]GRID grid.4973.9, ISNI 0000 0004 0646 7373, Department of Clinical Research, , Nordsjællands University Hospital, ; Dyrehavevej 29, 3400 Hillerød, Denmark
                Author information
                http://orcid.org/0000-0002-5834-2033
                http://orcid.org/0000-0001-8529-3559
                http://orcid.org/0000-0003-0698-9385
                http://orcid.org/0000-0001-5288-3851
                http://orcid.org/0000-0001-6551-6647
                http://orcid.org/0000-0003-4812-980X
                http://orcid.org/0000-0001-8901-7850
                http://orcid.org/0000-0001-9107-2023
                Article
                32254
                10.1038/s41467-022-32254-8
                9342834
                35915081
                365c7931-fb86-4b71-9dd0-81a1a3451250
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 4 April 2022
                : 21 July 2022
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                © The Author(s) 2022

                Uncategorized
                preventive medicine,viral infection,epidemiology,sars-cov-2
                Uncategorized
                preventive medicine, viral infection, epidemiology, sars-cov-2

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