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      Pre-existing immunity to SARS-CoV-2: the knowns and unknowns

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      Author(s): 1 , 2 , , 1 , 2 ,
      Publication date (Electronic):
      Journal: Nature Reviews. Immunology
      Publisher: Nature Publishing Group UK
      Keywords: Viral infection, Vaccines

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          Abstract

          T cell reactivity against SARS-CoV-2 was observed in unexposed people; however, the source and clinical relevance of the reactivity remains unknown. It is speculated that this reflects T cell memory to circulating ‘common cold’ coronaviruses. It will be important to define specificities of these T cells and assess their association with COVID-19 disease severity and vaccine responses.

          Abstract

          Recent studies have shown T cell reactivity to SARS-CoV-2 in 20–50% of unexposed individuals; it is speculated that this is due to T cell memory to common cold coronaviruses. Here, Crotty and Sette discuss the potential implications of these findings for disease severity, herd immunity and vaccine development.

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          Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals

          Alba Grifoni, Daniela Weiskopf, Sydney Ramirez … (2020)
          Summary Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide ‘megapools’, circulating SARS-CoV-2−specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike and N proteins each accounted for 11-27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2−reactive CD4+ T cells in ∼40-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating ‘common cold’ coronaviruses and SARS-CoV-2.
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            Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus.

            Kathy Hancock, Vic Veguilla, Xiuhua Lu … (2009)
            A new pandemic influenza A (H1N1) virus has emerged, causing illness globally, primarily in younger age groups. To assess the level of preexisting immunity in humans and to evaluate seasonal vaccine strategies, we measured the antibody response to the pandemic virus resulting from previous influenza infection or vaccination in different age groups. Using a microneutralization assay, we measured cross-reactive antibodies to pandemic H1N1 virus (2009 H1N1) in stored serum samples from persons who either donated blood or were vaccinated with recent seasonal or 1976 swine influenza vaccines. A total of 4 of 107 persons (4%) who were born after 1980 had preexisting cross-reactive antibody titers of 40 or more against 2009 H1N1, whereas 39 of 115 persons (34%) born before 1950 had titers of 80 or more. Vaccination with seasonal trivalent inactivated influenza vaccines resulted in an increase in the level of cross-reactive antibody to 2009 H1N1 by a factor of four or more in none of 55 children between the ages of 6 months and 9 years, in 12 to 22% of 231 adults between the ages of 18 and 64 years, and in 5% or less of 113 adults 60 years of age or older. Seasonal vaccines that were formulated with adjuvant did not further enhance cross-reactive antibody responses. Vaccination with the A/New Jersey/1976 swine influenza vaccine substantially boosted cross-reactive antibodies to 2009 H1N1 in adults. Vaccination with recent seasonal nonadjuvanted or adjuvanted influenza vaccines induced little or no cross-reactive antibody response to 2009 H1N1 in any age group. Persons under the age of 30 years had little evidence of cross-reactive antibodies to the pandemic virus. However, a proportion of older adults had preexisting cross-reactive antibodies. 2009 Massachusetts Medical Society
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              Presence of SARS-CoV-2 reactive T cells in COVID-19 patients and healthy donors

              Julian Braun, Lucie Loyal, Marco Frentsch … (2020)
              The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a rapidly unfolding pandemic, overwhelming health care systems worldwide1. Clinical manifestations of Corona-virus-disease 2019 (COVID-19) vary broadly, ranging from asymptomatic infection to acute respiratory failure and death2, yet the underlying physiological conditions and mechanisms for this high variability are still unknown. Also, the role of host immune responses in viral clearance and its involvement in pathogenesis remains unresolved. For SARS-CoV (2002/03), however, CD4+ T cell responses are generally associated with positive outcomes3,4, while cellular immune responses to SARS-CoV-2 have not yet been investigated. Here we describe an assay that allows direct detection and characterization of SARS-CoV-2 spike glycoprotein (S)-reactive CD4+ T cells in peripheral blood. We demonstrate the presence of S-reactive CD4+ T cells in 83% of COVID-19 patients, as well as in 34% of SARS-CoV-2 seronegative healthy donors, albeit at lower frequencies. Strikingly, in COVID-19 patients S-reactive CD4+ T cells equally targeted both N-terminal and C-terminal parts of S whereas in healthy donors S-reactive CD4+ T cells reacted almost exclusively to the Cterminal part that is a) characterized by higher homology to spike glycoprotein of human endemic "common cold" coronaviruses, and b) contains the S2 subunit of S with the cytoplasmic peptide (CP), the fusion peptide (FP), and the transmembrane domain (TM) but not the receptor-binding domain (RBD). S-reactive CD4+ T cells from COVID-19 patients were further distinct to those from healthy donors as they co-expressed higher levels of CD38 and HLA-DR, indicating their recent in vivo activation. Our study is the first to directly measure SARS-CoV-2-reactive T cell responses providing critical tools for large scale testing, in depth epitope mapping and characterization of potential cross-reactive cellular immunity to SARS-CoV-2. The presence of pre-existing SARS-CoV-2-reactive T cells in healthy donors is of high interest but larger scale prospective cohort studies are needed to assess whether their presence is a correlate of protection or pathology. Results of such studies will be key for a mechanistic understanding of the SARS-CoV-2 pandemic, adaptation of containment methods and to support vaccine development.
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                Author and article information

                Contributors
                Alessandro Sette: alex@lji.org
                Shane Crotty:
                ORCID: http://orcid.org/0000-0002-6484-6262
                shane@lji.org
                Journal
                Journal ID (nlm-ta): Nat Rev Immunol
                Journal ID (iso-abbrev): Nat. Rev. Immunol
                Title: Nature Reviews. Immunology
                Publisher: Nature Publishing Group UK (London )
                ISSN (Print): 1474-1733
                ISSN (Electronic): 1474-1741
                Publication date (Electronic): 7 July 2020
                Pages: 1-2
                Affiliations
                [1 ]ISNI 0000 0004 0461 3162, GRID grid.185006.a, Center for Infectious Disease and Vaccine Research, , La Jolla Institute for Immunology (LJI), ; La Jolla, CA USA
                [2 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Department of Medicine, Division of Infectious Diseases and Global Public Health, , University of California, San Diego (UCSD), ; La Jolla, CA USA
                Author information
                http://orcid.org/0000-0002-6484-6262
                Article
                Publisher ID: 389
                DOI: 10.1038/s41577-020-0389-z
                PMC ID: 7339790
                PubMed ID: 32636479
                SO-VID: 89b9f6f4-4856-4e49-9eee-8b69600a32cc
                Copyright © © Springer Nature Limited 2020
                License:

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

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                Subject: Comment

                Keywords: viral infection,vaccines
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                Keywords: viral infection, vaccines

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