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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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          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: (View ORCID Profile)
                Bonny Gaby Lui: (View ORCID Profile)
                Ann-Kathrin Wallisch: (View ORCID Profile)
                Aras Toker: (View ORCID Profile)
                Carla Iris Cadima Couto: (View ORCID Profile)
                Alptekin Güler: (View ORCID Profile)
                Thomas Ziegenhals: (View ORCID Profile)
                Jonas Reinholz: (View ORCID Profile)
                Hossam Hefesha: (View ORCID Profile)
                Hui Cai: (View ORCID Profile)
                Qi Yang: (View ORCID Profile)
                Andrew Finlayson: (View ORCID Profile)
                Orkun Ozhelvaci: (View ORCID Profile)
                Katharina Grikscheit: (View ORCID Profile)
                Niko Kohmer: (View ORCID Profile)
                Sandra Ciesek: (View ORCID Profile)
                Kena A. Swanson: (View ORCID Profile)
                Annette B. Vogel: (View ORCID Profile)
                Ugur Sahin: (View ORCID Profile)
                Journal
                Title: Science Immunology
                Abbreviated Title: Sci. Immunol.
                Publisher: American Association for the Advancement of Science (AAAS)
                ISSN (Electronic): 2470-9468
                Publication date (Electronic): November 15 2022
                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.
                Article
                DOI: 10.1126/sciimmunol.ade9888
                SO-VID: 436074e9-0a13-4bb3-a040-c6fed6d1d9dc
                Copyright © © 2022
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