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      An mRNA Vaccine against SARS-CoV-2 — Preliminary Report

      research-article
      , M.D., M.P.H. , , M.D., , M.D., , Ph.D., , M.D., M.P.H., , Ph.D., , M.P.H., , M.D., Ph.D., , M.D., , M.S., , Ph.D., , Ph.D., , Ph.D., , Ph.D., , Ph.D., , Ph.D., , M.S., , B.S., , Ph.D., , B.S., , M.D., , M.D., , M.Sc., , M.D., , R.N., , Ph.D., , M.S., , M.S., , B.S.N., M.S., , B.S., , D.O., , M.D., , M.D. *
      The New England Journal of Medicine
      Massachusetts Medical Society
      Keyword part (code): 18Keyword part (keyword): Infectious DiseaseKeyword part (code): 18_1Keyword part (keyword): Infectious Disease GeneralKeyword part (code): 18_2Keyword part (keyword): VaccinesKeyword part (code): 18_6Keyword part (keyword): Viral Infections , 18, Infectious Disease, Keyword part (code): 18_1Keyword part (keyword): Infectious Disease GeneralKeyword part (code): 18_2Keyword part (keyword): VaccinesKeyword part (code): 18_6Keyword part (keyword): Viral Infections , 18_1, Infectious Disease General, 18_2, Vaccines, 18_6, Viral Infections

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          Abstract

          Background

          The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein.

          Methods

          We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group.

          Results

          After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti–S-2P antibody geometric mean titer [GMT], 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events.

          Conclusions

          The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461).

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          Most cited references20

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          Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

          Structure of the nCoV trimeric spike The World Health Organization has declared the outbreak of a novel coronavirus (2019-nCoV) to be a public health emergency of international concern. The virus binds to host cells through its trimeric spike glycoprotein, making this protein a key target for potential therapies and diagnostics. Wrapp et al. determined a 3.5-angstrom-resolution structure of the 2019-nCoV trimeric spike protein by cryo–electron microscopy. Using biophysical assays, the authors show that this protein binds at least 10 times more tightly than the corresponding spike protein of severe acute respiratory syndrome (SARS)–CoV to their common host cell receptor. They also tested three antibodies known to bind to the SARS-CoV spike protein but did not detect binding to the 2019-nCoV spike protein. These studies provide valuable information to guide the development of medical counter-measures for 2019-nCoV. Science, this issue p. 1260
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            Severe Acute Respiratory Syndrome Coronavirus 2−Specific Antibody Responses in Coronavirus Disease Patients

            A new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has recently emerged to cause a human pandemic. Although molecular diagnostic tests were rapidly developed, serologic assays are still lacking, yet urgently needed. Validated serologic assays are needed for contact tracing, identifying the viral reservoir, and epidemiologic studies. We developed serologic assays for detection of SARS-CoV-2 neutralizing, spike protein–specific, and nucleocapsid-specific antibodies. Using serum samples from patients with PCR-confirmed SARS-CoV-2 infections, other coronaviruses, or other respiratory pathogenic infections, we validated and tested various antigens in different in-house and commercial ELISAs. We demonstrated that most PCR-confirmed SARS-CoV-2–infected persons seroconverted by 2 weeks after disease onset. We found that commercial S1 IgG or IgA ELISAs were of lower specificity, and sensitivity varied between the 2 assays; the IgA ELISA showed higher sensitivity. Overall, the validated assays described can be instrumental for detection of SARS-CoV-2–specific antibodies for diagnostic, seroepidemiologic, and vaccine evaluation studies.
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              Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial

              Summary Background A vaccine to protect against COVID-19 is urgently needed. We aimed to assess the safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine expressing the spike glycoprotein of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain. Methods We did a dose-escalation, single-centre, open-label, non-randomised, phase 1 trial of an Ad5 vectored COVID-19 vaccine in Wuhan, China. Healthy adults aged between 18 and 60 years were sequentially enrolled and allocated to one of three dose groups (5 × 1010, 1 × 1011, and 1·5 × 1011 viral particles) to receive an intramuscular injection of vaccine. The primary outcome was adverse events in the 7 days post-vaccination. Safety was assessed over 28 days post-vaccination. Specific antibodies were measured with ELISA, and the neutralising antibody responses induced by vaccination were detected with SARS-CoV-2 virus neutralisation and pseudovirus neutralisation tests. T-cell responses were assessed by enzyme-linked immunospot and flow-cytometry assays. This study is registered with ClinicalTrials.gov, NCT04313127. Findings Between March 16 and March 27, 2020, we screened 195 individuals for eligibility. Of them, 108 participants (51% male, 49% female; mean age 36·3 years) were recruited and received the low dose (n=36), middle dose (n=36), or high dose (n=36) of the vaccine. All enrolled participants were included in the analysis. At least one adverse reaction within the first 7 days after the vaccination was reported in 30 (83%) participants in the low dose group, 30 (83%) participants in the middle dose group, and 27 (75%) participants in the high dose group. The most common injection site adverse reaction was pain, which was reported in 58 (54%) vaccine recipients, and the most commonly reported systematic adverse reactions were fever (50 [46%]), fatigue (47 [44%]), headache (42 [39%]), and muscle pain (18 [17%]. Most adverse reactions that were reported in all dose groups were mild or moderate in severity. No serious adverse event was noted within 28 days post-vaccination. ELISA antibodies and neutralising antibodies increased significantly at day 14, and peaked 28 days post-vaccination. Specific T-cell response peaked at day 14 post-vaccination. Interpretation The Ad5 vectored COVID-19 vaccine is tolerable and immunogenic at 28 days post-vaccination. Humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination in healthy adults, and rapid specific T-cell responses were noted from day 14 post-vaccination. Our findings suggest that the Ad5 vectored COVID-19 vaccine warrants further investigation. Funding National Key R&D Program of China, National Science and Technology Major Project, and CanSino Biologics.
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                Author and article information

                Journal
                N Engl J Med
                N. Engl. J. Med
                nejm
                The New England Journal of Medicine
                Massachusetts Medical Society
                0028-4793
                1533-4406
                14 July 2020
                : NEJMoa2022483
                Affiliations
                From Kaiser Permanente Washington Health Research Institute (L.A.J.) and the Center for Global Infectious Disease Research (CGIDR), Seattle Children’s Research Institute (R.N.C.) — both in Seattle; the Department of Medicine, Center for Childhood Infections and Vaccines (CCIV) of Children’s Healthcare of Atlanta and Emory University Department of Pediatrics, Atlanta (E.J.A., E.P.), and Hope Clinic, Department of Medicine, Emory University School of Medicine, Decatur (N.G.R., M.P.M.) — both in Georgia; the Division of Microbiology and Infectious Diseases (P.C.R., M. Makhene, W.B., R.P.-T., J.H.B.) and the Vaccine Research Center (A.M., B.F., N.A.D.-R., K.S.C., K.M.M., S.O., S.D.S., P.A.S., M.P., J.R.M., J.E.L., B.S.G.), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, the University of Maryland School of Medicine, Baltimore (K.M.N.), and the Emmes Company, Rockville (M. Makowski, J.A., K.C.) — all in Maryland; the Departments of Pediatrics (J.D.C., M.R.D., L.J.S., A.J.P.) and Pathology, Microbiology, and Immunology (M.R.D.), and the Vanderbilt Institute for Infection, Immunology, and Inflammation (J.D.C., M.R.D., A.J.P.), Vanderbilt University Medical Center, Nashville; and Moderna, Cambridge, MA (H.B., W.S.).
                Author notes
                Address reprint requests to Dr. Jackson at Kaiser Permanente Washington Health Research Institute, 1730 Minor Ave., Suite 1600, Seattle, WA 98101, or at lisa.a.jackson@ 123456kp.org .
                [*]

                The mRNA-1273 Study Group members are listed in the Supplementary Appendix, available at NEJM.org.

                Drs. Graham and Beigel contributed equally to this article.

                Author information
                http://orcid.org/0000-0002-1785-0218
                http://orcid.org/0000-0002-5731-3054
                http://orcid.org/0000-0002-4879-4941
                Article
                NJ202007143830002
                10.1056/NEJMoa2022483
                7377258
                32663912
                b24f04e4-b944-4130-87e2-79540f5487df
                Copyright © 2020 Massachusetts Medical Society. All rights reserved.

                This article is made available via the PMC Open Access Subset for unrestricted re-use, except commercial resale, and analyses in any form or by any means with acknowledgment of the original source. These permissions are granted for the duration of the Covid-19 pandemic or until revoked in writing. Upon expiration of these permissions, PMC is granted a license to make this article available via PMC and Europe PMC, subject to existing copyright protections.

                History
                Funding
                Funded by: National Institute of Allergy and Infectious Diseases, FundRef http://dx.doi.org/10.13039/100000060;
                Award ID: HHSN272201500002C
                Award ID: UM1AI148373
                Award ID: UM1AI148576
                Award ID: UM1AI148684
                Funded by: National Center for Advancing Translational Sciences, FundRef http://dx.doi.org/10.13039/100006108;
                Award ID: UL1 TR002243
                Funded by: Dolly Parton COVID-19 Research Fund (Vanderbilt University Medical Center), FundRef http://dx.doi.org/10.13039/100013017;
                Categories
                Original Article
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                2020-07-14T17:00:00-04:00
                2020
                07
                14
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