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      Long‐term immune response to Omicron‐specific mRNA vaccination in mice, hamsters, and nonhuman primates

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          Abstract

          Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) Omicron and its subvariants (such as BQ.1, XBB and the latest variants, including XBB.1.16, EG.5, and BA.2.86), as the dominant variants, currently account for almost all new infections in the world due to their high transmissibility and immune escape ability. Omicron‐specific mRNA vaccines showed great potential to protect against Omicron infections. However, whether the vaccine could provide long‐term protection is unknown. Toward this goal, we evaluated the immunogenicity of a preclinical Omicron (BA.1)‐specific mRNA vaccine (S Omicron‐6P) in different animal models. S Omicron‐6P induced the highest levels of antibody titers at 1–2 weeks in different animals after the second dose. Even 9 months after the immunization, we observed modest neutralizing activity against Omicron subvariants in macaques. In addition, immunological memory cells can be rapidly reactivated upon stimulation. S Omicron‐6P at concentrations higher than 10 μg effectively protected hamsters from BA.1 challenge 253 days after the first immunization, which could be attributed to the reactivation of immune systems. In addition, the toxicity tests conducted in rats revealed a highly favorable biosafety profile for S Omicron‐6P, even at high dosages. Our data suggest that the Omicron‐specific mRNA vaccine is highly effective and safe in animal models and provides long‐term immunologic protection against SARS‐CoV‐2 Omicron infections.

          Abstract

          Long‐term immune responses to S Omicron‐6P were assessed in three animal models. Mice and macaques showed significant decay in antibody titers against BA.1 but remained at high levels around 9 months post‐vaccination. Modest neutralizing antibodies against Omicron subvariants were observed in macaques after 9 months. Immunological memory cells can be rapidly reactivated. S Omicron‐6P provides durable protection against Omicron challenge in hamsters.

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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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            Rapid epidemic expansion of the SARS-CoV-2 Omicron variant in southern Africa

            The SARS-CoV-2 epidemic in southern Africa has been characterized by three distinct waves. The first was associated with a mix of SARS-CoV-2 lineages, while the second and third waves were driven by the Beta (B.1.351) and Delta (B.1.617.2) variants, respectively 1–3 . In November 2021, genomic surveillance teams in South Africa and Botswana detected a new SARS-CoV-2 variant associated with a rapid resurgence of infections in Gauteng province, South Africa. Within three days of the first genome being uploaded, it was designated a variant of concern (Omicron, B.1.1.529) by the World Health Organization and, within three weeks, had been identified in 87 countries. The Omicron variant is exceptional for carrying over 30 mutations in the spike glycoprotein, which are predicted to influence antibody neutralization and spike function 4 . Here we describe the genomic profile and early transmission dynamics of Omicron, highlighting the rapid spread in regions with high levels of population immunity.
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              Considerable escape of SARS-CoV-2 Omicron to antibody neutralization

              The SARS-CoV-2 Omicron variant was first identified in November 2021 in Botswana and South Africa1-3. It has since spread to many countries and is expected to rapidly become dominant worldwide. The lineage is characterized by the presence of around 32 mutations in spike-located mostly in the N-terminal domain and the receptor-binding domain-that may enhance viral fitness and enable antibody evasion. Here we isolated an infectious Omicron virus in Belgium from a traveller returning from Egypt. We examined its sensitivity to nine monoclonal antibodies that have been clinically approved or are in development4, and to antibodies present in 115 serum samples from COVID-19 vaccine recipients or individuals who have recovered from COVID-19. Omicron was completely or partially resistant to neutralization by all monoclonal antibodies tested. Sera from recipients of the Pfizer or AstraZeneca vaccine, sampled five months after complete vaccination, barely inhibited Omicron. Sera from COVID-19-convalescent patients collected 6 or 12 months after symptoms displayed low or no neutralizing activity against Omicron. Administration of a booster Pfizer dose as well as vaccination of previously infected individuals generated an anti-Omicron neutralizing response, with titres 6-fold to 23-fold lower against Omicron compared with those against Delta. Thus, Omicron escapes most therapeutic monoclonal antibodies and, to a large extent, vaccine-elicited antibodies. However, Omicron is neutralized by antibodies generated by a booster vaccine dose.
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                Author and article information

                Contributors
                wangwei@wh.iov.cn
                yucaiwang@ustc.edu.cn
                qiux@ustc.edu.cn
                Journal
                MedComm (2020)
                MedComm (2020)
                10.1002/(ISSN)2688-2663
                MCO2
                MedComm
                John Wiley and Sons Inc. (Hoboken )
                2688-2663
                15 December 2023
                December 2023
                : 4
                : 6 ( doiID: 10.1002/mco2.v4.6 )
                : e460
                Affiliations
                [ 1 ] Department of Laboratory Medicine The First Affiliated Hospital of USTC Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui P. R. China
                [ 2 ] Division of Life Sciences and Medicine University of Science and Technology of China Hefei Anhui P. R. China
                [ 3 ] State Key Laboratory of Virology Wuhan Institute of Virology Center for Biosafety Mega‐Science Chinese Academy of Sciences Wuhan P. R. China
                [ 4 ] University of Chinese Academy of Sciences Beijing P. R. China
                [ 5 ] RNAlfa Biotech Hefei Anhui P. R. China
                [ 6 ] Department Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases Hefei Anhui P. R. China
                [ 7 ] Core Unit of National Clinical Research Center for Laboratory Medicine Hefei Anhui P. R. China
                Author notes
                [*] [* ] Correspondence

                Wei Wang, State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega‐Science, Chinese Academy of Sciences, Wuhan 430062, P. R. China.

                Email: wangwei@ 123456wh.iov.cn

                Yucai Wang, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230027, P. R. China.

                Email: yucaiwang@ 123456ustc.edu.cn

                Sandra Chiu, Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230031, P. R. China.

                Email: qiux@ 123456ustc.edu.cn

                Author information
                https://orcid.org/0000-0002-8696-9773
                Article
                MCO2460
                10.1002/mco2.460
                10724501
                38107058
                1d36d23f-011f-492d-af16-54d877420ef6
                © 2023 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 28 November 2023
                : 17 August 2023
                : 04 December 2023
                Page count
                Figures: 8, Tables: 0, Pages: 15, Words: 7478
                Funding
                Funded by: National Key R&D Program of China , doi 10.13039/501100012166;
                Award ID: 2020YFA0710700
                Funded by: Strategic Priority Research Program of the Chinese Academy of Sciences
                Award ID: XDB0490000
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 52025036
                Award ID: 51961145109
                Funded by: Fundamental Research Fund for the Central Universities , doi 10.13039/501100012226;
                Award ID: WK9100000014
                Award ID: WK2480000006
                Funded by: Project of Collaborative Innovation for Colleges of Anhui Province
                Award ID: GXXT‐2021‐070
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                December 2023
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.3.6 mode:remove_FC converted:16.12.2023

                antibody response,immunological memory,long‐term immune response,omicron subvariants,protective efficacy,sars‐cov‐2

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