Defining the risk of SARS-CoV-2 variants on immune protection

doi:10.1038/s41586-022-04690-5

Review

. 2022 May;605(7911):640-652.

doi: 10.1038/s41586-022-04690-5. Epub 2022 Mar 31.

Defining the risk of SARS-CoV-2 variants on immune protection

Marciela M DeGrace^#^{1

2}, Elodie Ghedin^#^{1

3}, Matthew B Frieman^#⁴, Florian Krammer^#^{5

6}, Alba Grifoni^#⁷, Arghavan Alisoltani⁸, Galit Alter⁹, Rama R Amara¹⁰, Ralph S Baric^{11

12}, Dan H Barouch¹³, Jesse D Bloom¹⁴, Louis-Marie Bloyet¹⁵, Gaston Bonenfant¹⁶, Adrianus C M Boon¹⁷, Eli A Boritz^{1

2

18}, Debbie L Bratt^{1

2

19}, Traci L Bricker¹⁷, Liliana Brown^{1

2}, William J Buchser²⁰, Juan Manuel Carreño²¹, Liel Cohen-Lavi²², Tamarand L Darling¹⁷, Meredith E Davis-Gardner²³, Bethany L Dearlove²⁴, Han Di¹⁶, Meike Dittmann²⁵, Nicole A Doria-Rose^{1

18}, Daniel C Douek^{1

18}, Christian Drosten²⁶, Venkata-Viswanadh Edara²³, Ali Ellebedy²⁷, Thomas P Fabrizio²⁸, Guido Ferrari²⁹, Will M Fischer³⁰, William C Florence^{1

2}, Ron A M Fouchier³¹, John Franks²⁸, Adolfo García-Sastre^{21

32

33

34

35}, Adam Godzik⁸, Ana Silvia Gonzalez-Reiche³⁶, Aubree Gordon³⁷, Bart L Haagmans³¹, Peter J Halfmann³⁸, David D Ho³⁹, Michael R Holbrook⁴⁰, Yaoxing Huang³⁹, Sarah L James⁴¹, Lukasz Jaroszewski⁸, Trushar Jeevan²⁸, Robert M Johnson⁴, Terry C Jones^{26

41}, Astha Joshi¹⁷, Yoshihiro Kawaoka^{38

42

43}, Lisa Kercher²⁸, Marion P G Koopmans³¹, Bette Korber³⁰, Eilay Koren^{22

44}, Richard A Koup^{1

18}, Eric B LeGresley⁴¹, Jacob E Lemieux⁴⁵, Mariel J Liebeskind²⁰, Zhuoming Liu¹⁵, Brandi Livingston²⁸, James P Logue⁴, Yang Luo³⁹, Adrian B McDermott^{1

18}, Margaret J McElrath⁴⁶, Victoria A Meliopoulos²⁸, Vineet D Menachery⁴⁷, David C Montefiori⁴⁸, Barbara Mühlemann^{26

41}, Vincent J Munster⁴⁹, Jenny E Munt¹¹, Manoj S Nair³⁹, Antonia Netzl⁴¹, Anna M Niewiadomska⁵⁰, Sijy O'Dell^{1

18}, Andrew Pekosz⁵¹, Stanley Perlman⁵², Marjorie C Pontelli¹⁵, Barry Rockx³¹, Morgane Rolland²⁴, Paul W Rothlauf¹⁵, Sinai Sacharen^{22

44}, Richard H Scheuermann⁵⁰, Stephen D Schmidt^{1

18}, Michael Schotsaert^{21

35}, Stacey Schultz-Cherry²⁸, Robert A Seder^{1

18}, Mayya Sedova⁸, Alessandro Sette^{7

53}, Reed S Shabman^{1

2}, Xiaoying Shen²⁹, Pei-Yong Shi⁵⁴, Maulik Shukla^{55

56}, Viviana Simon^{21

32

33

35}, Spencer Stumpf¹⁵, Nancy J Sullivan^{1

18}, Larissa B Thackray¹⁷, James Theiler³⁰, Paul G Thomas⁵⁷, Sanja Trifkovic²⁸, Sina Türeli⁴¹, Samuel A Turner⁴¹, Maria A Vakaki²⁰, Harm van Bakel³⁶, Laura A VanBlargan¹⁷, Leah R Vincent^{1

2}, Zachary S Wallace^{50

58}, Li Wang¹⁶, Maple Wang³⁹, Pengfei Wang³⁹, Wei Wang⁵⁹, Scott C Weaver⁴⁷, Richard J Webby²⁸, Carol D Weiss⁵⁹, David E Wentworth¹⁶, Stuart M Weston⁴, Sean P J Whelan¹⁵, Bradley M Whitener¹⁷, Samuel H Wilks⁴¹, Xuping Xie⁵⁴, Baoling Ying¹⁷, Hyejin Yoon³⁰, Bin Zhou¹⁶, Tomer Hertz⁶⁰, Derek J Smith⁶¹, Michael S Diamond^{62

63

64

65}, Diane J Post^{66

67}, Mehul S Suthar⁶⁸

Affiliations

¹ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
² Division of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
³ Systems Genomics Section, Laboratory of Parasitic Diseases, National Institutes of Health, Rockville, MD, USA.
⁴ Center for Pathogen Research, Department of Microbiology and Immunology, The University of Maryland School of Medicine, Baltimore, MD, USA.
⁵ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. florian.krammer@mssm.edu.
⁶ Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. florian.krammer@mssm.edu.
⁷ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA, USA.
⁸ University of California Riverside School of Medicine, Riverside, CA, USA.
⁹ Ragon Institute of MGH, MIT, and Harvard, Boston, MA, USA.
¹⁰ Department of Microbiology and Immunology, Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, GA, USA.
¹¹ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹² Department of Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹⁴ Fred Hutch Cancer Center, Howard Hughes Medical Institute, Seattle, WA, USA.
¹⁵ Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA.
¹⁶ CDC COVID-19 Emergency Response, Centers for Disease Control and Prevention, Atlanta, GA, USA.
¹⁷ Department of Medicine, Washington University in St Louis, St Louis, MO, USA.
¹⁸ Vaccine Research Center, Bethesda, MD, USA.
¹⁹ CAMRIS, Contractor for NIAID, Bethesda, MD, USA.
²⁰ High Throughput Screening Center, Washington University School of Medicine, St Louis, MO, USA.
²¹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²² National Institute for Biotechnology in the Negev, Department of Industrial Engineering and Management, Ben-Gurion University of the Negev, Be'er-Sheva, Israel.
²³ Center for Childhood Infections and Vaccines of Children's Healthcare of Atlanta, Department of Pediatrics, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.
²⁴ US Military HIV Research Program, Henry M. Jackson Foundation for the Advancement of Military Medicine, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
²⁵ Microbiology Department, New York University Grossman School of Medicine, New York, NY, USA.
²⁶ Institute of Virology, Charité-Universitätsmedizin and German Center for Infection Research (DZIF), Berlin, Germany.
²⁷ Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
²⁸ Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA.
²⁹ Department of Surgery, Duke University Medical Center, Durham, NC, USA.
³⁰ Los Alamos National Laboratory, New Mexico Consortium, Los Alamos, NM, USA.
³¹ Department Viroscience, Erasmus MC, Rotterdam, The Netherlands.
³² Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³³ Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁴ The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁵ Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁶ Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁷ Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
³⁸ Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, USA.
³⁹ Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
⁴⁰ National Institute of Allergy and Infectious Diseases Integrated Research Facility, Frederick, MD, USA.
⁴¹ Center for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, UK.
⁴² Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁴³ Disease Control and Prevention Center, National Center for Global Health and Medicine Hospital, Tokyo, Japan.
⁴⁴ The Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
⁴⁵ Broad Institute of MIT and Harvard, Boston, MA, USA.
⁴⁶ Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴⁷ Department of Microbiology and Immunology, Institute for Human Infection and Immunity, World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA.
⁴⁸ Duke University Medical Center, Durham, NC, USA.
⁴⁹ Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.
⁵⁰ Department of Informatics, J. Craig Venter Institute, La Jolla, CA, USA.
⁵¹ Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁵² Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA.
⁵³ Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA, USA.
⁵⁴ Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA.
⁵⁵ University of Chicago Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, USA.
⁵⁶ Data Science and Learning Division, Argonne National Laboratory, Argonne, IL, USA.
⁵⁷ Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
⁵⁸ Department of Computer Science and Engineering, University of California, San Diego, CA, USA.
⁵⁹ Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
⁶⁰ Department of Microbiology, Immunology and Genetics Faculty of Health Sciences Ben-Gurion University of the Negev, Be'er Sheva, Israel. thertz@bgu.ac.il.
⁶¹ Center for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, UK. djs200@cam.ac.uk.
⁶² Department of Medicine, Washington University in St Louis, St Louis, MO, USA. mdiamond@wustl.edu.
⁶³ Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO, USA. mdiamond@wustl.edu.
⁶⁴ Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA. mdiamond@wustl.edu.
⁶⁵ The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, USA. mdiamond@wustl.edu.
⁶⁶ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA. postd@niaid.nih.gov.
⁶⁷ Division of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, USA. postd@niaid.nih.gov.
⁶⁸ Center for Childhood Infections and Vaccines of Children's Healthcare of Atlanta, Department of Pediatrics, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. mehul.s.suthar@emory.edu.

^# Contributed equally.

PMID: 35361968
PMCID: PMC9345323
DOI: 10.1038/s41586-022-04690-5

Review

Defining the risk of SARS-CoV-2 variants on immune protection

Marciela M DeGrace et al. Nature. 2022 May.

. 2022 May;605(7911):640-652.

doi: 10.1038/s41586-022-04690-5. Epub 2022 Mar 31.

Authors

Affiliations

¹ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
² Division of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
³ Systems Genomics Section, Laboratory of Parasitic Diseases, National Institutes of Health, Rockville, MD, USA.
⁴ Center for Pathogen Research, Department of Microbiology and Immunology, The University of Maryland School of Medicine, Baltimore, MD, USA.
⁵ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. florian.krammer@mssm.edu.
⁶ Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. florian.krammer@mssm.edu.
⁷ Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA, USA.
⁸ University of California Riverside School of Medicine, Riverside, CA, USA.
⁹ Ragon Institute of MGH, MIT, and Harvard, Boston, MA, USA.
¹⁰ Department of Microbiology and Immunology, Emory Vaccine Center, Division of Microbiology and Immunology, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, GA, USA.
¹¹ Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹² Department of Microbiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹⁴ Fred Hutch Cancer Center, Howard Hughes Medical Institute, Seattle, WA, USA.
¹⁵ Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA.
¹⁶ CDC COVID-19 Emergency Response, Centers for Disease Control and Prevention, Atlanta, GA, USA.
¹⁷ Department of Medicine, Washington University in St Louis, St Louis, MO, USA.
¹⁸ Vaccine Research Center, Bethesda, MD, USA.
¹⁹ CAMRIS, Contractor for NIAID, Bethesda, MD, USA.
²⁰ High Throughput Screening Center, Washington University School of Medicine, St Louis, MO, USA.
²¹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²² National Institute for Biotechnology in the Negev, Department of Industrial Engineering and Management, Ben-Gurion University of the Negev, Be'er-Sheva, Israel.
²³ Center for Childhood Infections and Vaccines of Children's Healthcare of Atlanta, Department of Pediatrics, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA.
²⁴ US Military HIV Research Program, Henry M. Jackson Foundation for the Advancement of Military Medicine, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
²⁵ Microbiology Department, New York University Grossman School of Medicine, New York, NY, USA.
²⁶ Institute of Virology, Charité-Universitätsmedizin and German Center for Infection Research (DZIF), Berlin, Germany.
²⁷ Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
²⁸ Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA.
²⁹ Department of Surgery, Duke University Medical Center, Durham, NC, USA.
³⁰ Los Alamos National Laboratory, New Mexico Consortium, Los Alamos, NM, USA.
³¹ Department Viroscience, Erasmus MC, Rotterdam, The Netherlands.
³² Department of Pathology, Molecular and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³³ Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁴ The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁵ Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁶ Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³⁷ Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
³⁸ Influenza Research Institute, Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI, USA.
³⁹ Aaron Diamond AIDS Research Center, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA.
⁴⁰ National Institute of Allergy and Infectious Diseases Integrated Research Facility, Frederick, MD, USA.
⁴¹ Center for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, UK.
⁴² Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁴³ Disease Control and Prevention Center, National Center for Global Health and Medicine Hospital, Tokyo, Japan.
⁴⁴ The Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
⁴⁵ Broad Institute of MIT and Harvard, Boston, MA, USA.
⁴⁶ Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁴⁷ Department of Microbiology and Immunology, Institute for Human Infection and Immunity, World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA.
⁴⁸ Duke University Medical Center, Durham, NC, USA.
⁴⁹ Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA.
⁵⁰ Department of Informatics, J. Craig Venter Institute, La Jolla, CA, USA.
⁵¹ Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁵² Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA.
⁵³ Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego (UCSD), La Jolla, CA, USA.
⁵⁴ Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX, USA.
⁵⁵ University of Chicago Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, USA.
⁵⁶ Data Science and Learning Division, Argonne National Laboratory, Argonne, IL, USA.
⁵⁷ Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA.
⁵⁸ Department of Computer Science and Engineering, University of California, San Diego, CA, USA.
⁵⁹ Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
⁶⁰ Department of Microbiology, Immunology and Genetics Faculty of Health Sciences Ben-Gurion University of the Negev, Be'er Sheva, Israel. thertz@bgu.ac.il.
⁶¹ Center for Pathogen Evolution, Department of Zoology, University of Cambridge, Cambridge, UK. djs200@cam.ac.uk.
⁶² Department of Medicine, Washington University in St Louis, St Louis, MO, USA. mdiamond@wustl.edu.
⁶³ Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO, USA. mdiamond@wustl.edu.
⁶⁴ Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA. mdiamond@wustl.edu.
⁶⁵ The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, USA. mdiamond@wustl.edu.
⁶⁶ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA. postd@niaid.nih.gov.
⁶⁷ Division of Microbiology and Infectious Diseases, National Institutes of Health, Rockville, MD, USA. postd@niaid.nih.gov.
⁶⁸ Center for Childhood Infections and Vaccines of Children's Healthcare of Atlanta, Department of Pediatrics, Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. mehul.s.suthar@emory.edu.

^# Contributed equally.

PMID: 35361968
PMCID: PMC9345323
DOI: 10.1038/s41586-022-04690-5

Abstract

The global emergence of many severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants jeopardizes the protective antiviral immunity induced after infection or vaccination. To address the public health threat caused by the increasing SARS-CoV-2 genomic diversity, the National Institute of Allergy and Infectious Diseases within the National Institutes of Health established the SARS-CoV-2 Assessment of Viral Evolution (SAVE) programme. This effort was designed to provide a real-time risk assessment of SARS-CoV-2 variants that could potentially affect the transmission, virulence, and resistance to infection- and vaccine-induced immunity. The SAVE programme is a critical data-generating component of the US Government SARS-CoV-2 Interagency Group to assess implications of SARS-CoV-2 variants on diagnostics, vaccines and therapeutics, and for communicating public health risk. Here we describe the coordinated approach used to identify and curate data about emerging variants, their impact on immunity and effects on vaccine protection using animal models. We report the development of reagents, methodologies, models and notable findings facilitated by this collaborative approach and identify future challenges. This programme is a template for the response to rapidly evolving pathogens with pandemic potential by monitoring viral evolution in the human population to identify variants that could reduce the effectiveness of countermeasures.

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Conflict of interest statement

Conflicts of Interest:

DHB is a co-inventor on provisional vaccine patents (63/121,482; 63/133,969; 63/135,182), JDB consults for Moderna and Flagship Labs 77 on topics related to viral evolution, and is an inventor on Fred Hutch licensed patents related to viral deep mutational scanning, The Boon laboratory has received unrelated funding support in sponsored research agreements from AI Therapeutics, GreenLight Biosciences Inc., and Nano targeting & Therapy Biopharma Inc. The Boon laboratory has received funding support from AbbVie Inc., for the commercial development of SARS-CoV-2 mAb. A.C.M.B. was a recipient of a licensing agreement with Abbvie Inc., for commercial development of SARS-CoV-2 mAb, M.S.D. is a consultant for Inbios, Vir Biotechnology, Senda Biosciences, and Carnival Corporation, and on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has received unrelated funding support in sponsored research agreements from Vir Biotechnology, Moderna, and Emergent BioSolutions, The Ellebedy laboratory received funding under sponsored research agreements that are unrelated to the data presented in the current study from Emergent BioSolutions and from AbbVie. A.H.E. has received consulting fees from InBios International, Inc, Fimbrion Therapeutics, Mubadala Investment Company and Goldman Sachs and is the founder of ImmuneBio Consulting, MBF has funding from Novavax which is outside the scope of this research. They had no role in the funded research from the SAVES consortium, the Garcia-Sastre laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines and Merck, outside of the reported work. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar and Pfizer, outside of the reported work. A.G.-S. is inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work, Aubree Gordon serves on a scientific advisory board for Janssen, Erasmus MC has a Proprietary IP on MERS, BK is part of provisional patent applications for strategies for next generation SARS-CoV-2 vaccines that address diversity, The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays which lists Viviana Simon as a co-inventor and NDV-based SARS-CoV-2 vaccines which list Florian Krammer as co-inventor, Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2. Florian Krammer has consulted for Merck and Pfizer (before 2020), and is currently consulting for Pfizer, Seqirus, 3rd Rock Ventures and Avimex. The Krammer laboratory is also collaborating with Pfizer on animal models of SARS-CoV-2, VDM have filed a patent on the reverse genetic system and reporter SARS-CoV-2, DCM receives funding from Moderna to perform blinded assessments of vaccine-elicited neutralizing antibody responses in clinical studies of their COVID-19 vaccines, A.S. is a consultant for Gritstone Bio, Flow Pharma, Arcturus Therapeutics, ImmunoScape, CellCarta, Avalia, Moderna, Fortress and Repertoire., PYS laboratory has received funding support in sponsored research agreements from GSK, Pfizer, Gilead, Novartis, Merck, IGM Biosciences, and Atea Pharmaceuticals. P.Y.S. is a member of the Scientific Advisory Boards of AbImmune and is Founder of FlaviTech, M.S.S serves on the advisory board for Moderna and Ocugen, PGT serves on the scientific advisory board for Immunoscape and Cytoagents and has consulted for Johnson and Johnson. PGT has received travel support and honoraria from Illumina and 10X Genomics. PGT has patents related to viral infection treatment and T cell receptor biology. S.P.J.W. and Z.L. have filed a patent with Washington University for VSV- SARS-CoV-2 mutants to characterize antibody panels. S.P.J.W has received unrelated funding support in sponsored research agreements with Vir Biotechnology, AbbVie, and sAB therapeutics. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention. Use of trade names is for identification only and does not imply endorsement by the US Centers for Disease Control and Prevention or the US Department of Health and Human Services.

Figures

**Figure 1.. Overview of the SAVE program.**
The SAVE program is divided into three working groups to provide real-time risk assessment of SARS-CoV-2 variants on infection and vaccine-induced immunity. The Early Detection and Analysis group curates and prioritizes emerging SARS-CoV-2 variants. The *In Vitro* group evaluates the impact of SARS-CoV-2 variants on humoral and cell-mediated immune responses. The *In Vivo* group uses animal models to test vaccine efficacy, transmission, and define immune mechanisms/correlates of protection. These data are fed into the SARS-CoV-2 Interagency Group (SIG), which coordinates between different U.S. government agencies to assess the impact of variants on critical SARS-CoV-2 countermeasures, including vaccines, therapeutics, and diagnostics. This iterative approach allows for information flow between the SAVE program and the SIG to continue prioritizing and testing SARS-CoV-2 variants. Created in part with BioRender.com

**Figure 2.. Prioritization of variants by the Early Detection and Analysis group.**
**(a)** The trajectory of SARS-CoV-2 variant sequence prevalence over a one-year period, Jan. 01, 2021 to Dec 31, 2021, tracking frequencies of weekly counts based on PANGO lineage designations. The data in the graphs was based on the 4.8 million SARS-CoV-2 sequences sampled in 2021 and made available through the GISAID Initiative. Updated graphs can be found at cov.lanl.gov (the tracking tool is called Embers). **Top.** A global summary and status on five continents is provided. Europe and North America remain the most highly sampled regions of the world, biasing the global sampling. **(b)** Tangle plots for comparative prioritization of circulating variants across subgroups. The list of variants to prioritize is collectively built by the whole group and prioritized by individual teams to arrive at a consensus list. Each column graph refers to the prioritization order made by each sub-team for circulating variants in December 2021 (top-highest, bottom- lowest priority): A. Cambridge University, B. LANL; C. ISMMS; D. JCVI/BV-BRC; E. UCR SOM; F. Broad Institute; G. WRAIR. The final consensus ranking of the 43 variants is produced by ordering the lineages by their mean rank across the different teams, who also have the option to defer from ranking a lineage, or to assign multiple lineages a tied ranking, and after discussion with the group to determine priority categories. The dashed arrow indicates the order of priority, top being highest priority variants for analysis, bottom means lowest priority. Colors refer to each PANGO lineage tracked but multiple blocks of the same color can also refer to different variants within a PANGO lineage. For example, besides the colored Delta AY.* sublineages indicated, Delta has 26 subvariants (purple) with different combinations of mutations that are being prioritized for analysis.

**Figure 3-. *In Vitro* group.**
**(a)** Live virus- nasal swabs in viral transport media or seed stocks are obtained followed by plaque purification and deep-sequencing. Pseudotyped virus- plasmids encoding the variant spike sequence are synthesized to generate pseudotyped lentivirus stocks. Vesicular Stomatitis virus (VSV) chimeric virus- the glycoprotein gene (G) is replaced with the spike protein of SARS-CoV-2 (VSV-eGFP-SARS-CoV-2) and a GFP reporter gene. **(b)** The *In Vitro* group conducted performance testing between 12 neutralization assays involving live authentic virus consisting of focus-reduction neutralization test (FRNT-1), recombinant SARS-CoV-2 reporter virus FRNT (FRNT-2), plaque reduction neutralization test (PRNT), recombinant SARS-CoV-2 expressing nano-luc (Nano-luc), cytopathic effect assay (CPE), microneutralization assay (MNA), and focus-reduction neutralization assay (FRNA) and lentivirus and VSV pseudotyped neutralization assays, and VSV chimeric assays. Example dataset between wild-type (WT) and Beta virus is presented. **(c)** Antigenic cartography. ID50 neutralization titers in a lentivirus-based pseudovirus assay were determined against a panel of SARS-CoV-2 variants and serum from Moderna vaccinated or infected individuals. Distance between serum to an antigen corresponds to the titer of that serum for the antigen. Grid lines represent 2-fold dilution of antiserum. Vertical and horizontal axes represent antigenic distance. Antigens- circle; Sera-squares. **(d)** SARS-CoV-2 variant T cell responses. Sequence data are curated for coding mutations (pink boxes). Curated mutations are tested on convalescent T cell responses using functional assays (Activation Induced Marker- AIM assays; green boxes). Immune Epitope Database (IEDB) and the Immunocode Multiplex Identification of T cell Receptor Antigen Specificity dataset (MIRA) are analyzed to generate curated peptide sets of immunodominant epitopes (blue boxes). Data are integrated to produce a ranked score list of variant epitope changes weighted by their likelihood to disrupt epitope binding and the relative size of the affected population (gray boxes). Created in part with BioRender.com.

**Figure 4-. *In Vivo* group.**
**(a)** Animal model development. After selection of variants to analysis by the Early Detection and *In Vitro* Analysis Group, isolates are grown, validated by next-generation sequencing, and analyzed in each animal model at different doses to determine pathogenicity, viral kinetics and transmission (in hamsters). Weight loss, lung titer and lung pathology as assessed to have benchmarks for vaccine studies. **(b)** Vaccine Challenge. Each animal model is immunized with selected vaccines. Animal serum is examined after vaccination for neutralizing antibody levels and across a systems serology analysis before viral challenge with the chosen variants. Protection against infection and disease in each model is analyzed to determine the protective capability of each vaccine and variant. Data on protection of each animal model with each vaccine platform and challenged with variant viruses is shared with the SAVE consortium and SIG. Created with BioRender.com

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References

1. Krammer F SARS-CoV-2 vaccines in development. Nature 586, 516–527, doi:10.1038/s41586-020-2798-3 (2020). - DOI - PubMed
1. Plante JA et al. The variant gambit: COVID-19’s next move. Cell Host Microbe 29, 508–515, doi:10.1016/j.chom.2021.02.020 (2021). - DOI - PMC - PubMed
1. Walensky RP, Walke HT & Fauci AS SARS-CoV-2 Variants of Concern in the United States-Challenges and Opportunities. JAMA 325, 1037–1038, doi:10.1001/jama.2021.2294 (2021). - DOI - PMC - PubMed
1. Fischer W et al. HIV-1 and SARS-CoV-2: Patterns in the evolution of two pandemic pathogens. Cell Host Microbe 29, 1093–1110, doi:10.1016/j.chom.2021.05.012 (2021). - DOI - PMC - PubMed
1. Korber B et al. Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell 182, 812–827 e819, doi:10.1016/j.cell.2020.06.043 (2020).
  *This was the first study showing that a newly emerging mutation in the Spike protein could come to rapidly dominate across the globe, indicating a fitness advantage.

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[1] Krammer F SARS-CoV-2 vaccines in development. Nature 586, 516–527, doi:10.1038/s41586-020-2798-3 (2020). - DOI - PubMed

[2] Krammer F SARS-CoV-2 vaccines in development. Nature 586, 516–527, doi:10.1038/s41586-020-2798-3 (2020). - DOI - PubMed

[3] Plante JA et al. The variant gambit: COVID-19’s next move. Cell Host Microbe 29, 508–515, doi:10.1016/j.chom.2021.02.020 (2021). - DOI - PMC - PubMed

[4] Plante JA et al. The variant gambit: COVID-19’s next move. Cell Host Microbe 29, 508–515, doi:10.1016/j.chom.2021.02.020 (2021). - DOI - PMC - PubMed

[5] Walensky RP, Walke HT & Fauci AS SARS-CoV-2 Variants of Concern in the United States-Challenges and Opportunities. JAMA 325, 1037–1038, doi:10.1001/jama.2021.2294 (2021). - DOI - PMC - PubMed

[6] Walensky RP, Walke HT & Fauci AS SARS-CoV-2 Variants of Concern in the United States-Challenges and Opportunities. JAMA 325, 1037–1038, doi:10.1001/jama.2021.2294 (2021). - DOI - PMC - PubMed

[7] Fischer W et al. HIV-1 and SARS-CoV-2: Patterns in the evolution of two pandemic pathogens. Cell Host Microbe 29, 1093–1110, doi:10.1016/j.chom.2021.05.012 (2021). - DOI - PMC - PubMed

[8] Fischer W et al. HIV-1 and SARS-CoV-2: Patterns in the evolution of two pandemic pathogens. Cell Host Microbe 29, 1093–1110, doi:10.1016/j.chom.2021.05.012 (2021). - DOI - PMC - PubMed

[9] Korber B et al. Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell 182, 812–827 e819, doi:10.1016/j.cell.2020.06.043 (2020).
*This was the first study showing that a newly emerging mutation in the Spike protein could come to rapidly dominate across the globe, indicating a fitness advantage.

[10] Korber B et al. Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell 182, 812–827 e819, doi:10.1016/j.cell.2020.06.043 (2020).
*This was the first study showing that a newly emerging mutation in the Spike protein could come to rapidly dominate across the globe, indicating a fitness advantage.

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Defining the risk of SARS-CoV-2 variants on immune protection

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