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      SARS-CoV-2 mRNA Vaccine Design Enabled by Prototype Pathogen Preparedness

      1 , 2 , 3 , 1 , 1 , 1 , 2 , 3 , 1 , 1 , 3 , 2 , 2 , 2 , 4 , 3 , 5 , 5 , 5 , 1 , 2 , 2 , 2 , 2 , 2 , 2 , 1 , 1 , 1 , 1 , 1 , 6 , 1 , 1 , 2 , 2 , 2 , 2 , 1 , 1 , 1 , 1 , 1 , 3 , 3 , 7 , 8 , 8 , 1 , 2 , 2 , 1 , 9 , 1 , 8 , 7 , 7 , 5 , 1 , 1 , 3 , 4 , 2 , * , 1 , *

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          A severe acute respiratory syndrome coronavirus (SARS-CoV-2) vaccine is needed to control the global coronavirus infectious disease (COVID-19) public health crisis. Atomic-level structures directed the application of prefusion-stabilizing mutations that improved expression and immunogenicity of betacoronavirus spike proteins 1 . Using this established immunogen design, the release of SARS-CoV-2 sequences triggered immediate rapid manufacturing of an mRNA vaccine expressing the prefusion-stabilized SARS-CoV-2 spike trimer (mRNA-1273). Here, we show that mRNA-1273 induces both potent neutralizing antibody responses to wild-type (D614) and D614G mutant 2 SARS-CoV-2 and CD8 T cell responses and protects against SARS-CoV-2 infection in lungs and noses of mice without evidence of immunopathology. mRNA-1273 is currently in Phase 3 efficacy evaluation.

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          Most cited references40

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          An interactive web-based dashboard to track COVID-19 in real time

          In December, 2019, a local outbreak of pneumonia of initially unknown cause was detected in Wuhan (Hubei, China), and was quickly determined to be caused by a novel coronavirus, 1 namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The outbreak has since spread to every province of mainland China as well as 27 other countries and regions, with more than 70 000 confirmed cases as of Feb 17, 2020. 2 In response to this ongoing public health emergency, we developed an online interactive dashboard, hosted by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University, Baltimore, MD, USA, to visualise and track reported cases of coronavirus disease 2019 (COVID-19) in real time. The dashboard, first shared publicly on Jan 22, illustrates the location and number of confirmed COVID-19 cases, deaths, and recoveries for all affected countries. It was developed to provide researchers, public health authorities, and the general public with a user-friendly tool to track the outbreak as it unfolds. All data collected and displayed are made freely available, initially through Google Sheets and now through a GitHub repository, along with the feature layers of the dashboard, which are now included in the Esri Living Atlas. The dashboard reports cases at the province level in China; at the city level in the USA, Australia, and Canada; and at the country level otherwise. During Jan 22–31, all data collection and processing were done manually, and updates were typically done twice a day, morning and night (US Eastern Time). As the outbreak evolved, the manual reporting process became unsustainable; therefore, on Feb 1, we adopted a semi-automated living data stream strategy. Our primary data source is DXY, an online platform run by members of the Chinese medical community, which aggregates local media and government reports to provide cumulative totals of COVID-19 cases in near real time at the province level in China and at the country level otherwise. Every 15 min, the cumulative case counts are updated from DXY for all provinces in China and for other affected countries and regions. For countries and regions outside mainland China (including Hong Kong, Macau, and Taiwan), we found DXY cumulative case counts to frequently lag behind other sources; we therefore manually update these case numbers throughout the day when new cases are identified. To identify new cases, we monitor various Twitter feeds, online news services, and direct communication sent through the dashboard. Before manually updating the dashboard, we confirm the case numbers with regional and local health departments, including the respective centres for disease control and prevention (CDC) of China, Taiwan, and Europe, the Hong Kong Department of Health, the Macau Government, and WHO, as well as city-level and state-level health authorities. For city-level case reports in the USA, Australia, and Canada, which we began reporting on Feb 1, we rely on the US CDC, the government of Canada, the Australian Government Department of Health, and various state or territory health authorities. All manual updates (for countries and regions outside mainland China) are coordinated by a team at Johns Hopkins University. The case data reported on the dashboard aligns with the daily Chinese CDC 3 and WHO situation reports 2 for within and outside of mainland China, respectively (figure ). Furthermore, the dashboard is particularly effective at capturing the timing of the first reported case of COVID-19 in new countries or regions (appendix). With the exception of Australia, Hong Kong, and Italy, the CSSE at Johns Hopkins University has reported newly infected countries ahead of WHO, with Hong Kong and Italy reported within hours of the corresponding WHO situation report. Figure Comparison of COVID-19 case reporting from different sources Daily cumulative case numbers (starting Jan 22, 2020) reported by the Johns Hopkins University Center for Systems Science and Engineering (CSSE), WHO situation reports, and the Chinese Center for Disease Control and Prevention (Chinese CDC) for within (A) and outside (B) mainland China. Given the popularity and impact of the dashboard to date, we plan to continue hosting and managing the tool throughout the entirety of the COVID-19 outbreak and to build out its capabilities to establish a standing tool to monitor and report on future outbreaks. We believe our efforts are crucial to help inform modelling efforts and control measures during the earliest stages of the outbreak.
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            Is Open Access

            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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              Tracking changes in SARS-CoV-2 Spike: evidence that D614G increases infectivity of the COVID-19 virus

              Summary A SARS-CoV-2 variant carrying the Spike protein amino acid change D614G has become the most prevalent form in the global pandemic. Dynamic tracking of variant frequencies revealed a recurrent pattern of G614 increase at multiple geographic levels: national, regional and municipal. The shift occurred even in local epidemics where the original D614 form was well established prior to the introduction of the G614 variant. The consistency of this pattern was highly statistically significant, suggesting that the G614 variant may have a fitness advantage. We found that the G614 variant grows to higher titer as pseudotyped virions. In infected individuals G614 is associated with lower RT-PCR cycle thresholds, suggestive of higher upper respiratory tract viral loads, although not with increased disease severity. These findings illuminate changes important for a mechanistic understanding of the virus, and support continuing surveillance of Spike mutations to aid in the development of immunological interventions.

                Author and article information

                1 August 2020
                05 August 2020
                October 2020
                05 February 2021
                : 586
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                [1 ]Vaccine Research Center; National Institute of Allergy and Infectious Diseases; National Institutes of Health; Bethesda, Maryland, 20892; United States of America
                [2 ]Moderna Inc., Cambridge, MA, 02139; United States of America
                [3 ]Department of Epidemiology; University of North Carolina at Chapel Hill; Chapel Hill, North Carolina, 27599; United States of America
                [4 ]Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill; Chapel Hill, North Carolina, 27599; United States of America
                [5 ]National Institute of Allergy and Infectious Diseases; National Institutes of Health; Bethesda, Maryland, 20892; United States of America
                [6 ]Institute for Biomedical Sciences, George Washington University, Washington, DC 20052, United States of America
                [7 ]Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, 37212; United States of America
                [8 ]Department of Molecular Biosciences; University of Texas at Austin; Austin, Texas, 78712; United States of America
                [9 ]Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, Maryland, 20892; United States of America
                Author notes
                [* ]Correspondence and requests for materials should be addressed to Barney S. Graham at bgraham@ 123456nih.gov and Andrea Carfi at andrea.carfi@ 123456modernatx.com .

                Authors have equal contribution to this study

                Author Contributions

                K.S.C., D.K.E., S.R.L., O.M.A, S.B.B., R.A.G., S.H., A.S., C.Z., A.T.D., K.H.D., S.E., C.A.S., A.W., E.J.F., D.R.M, K.W.B., M.M., B.M.N., G.B.H., K.W., C.H., K.B., D.G.D., L.M., I.R., W.P.K, S.S., L.W., Y.Z., J.C., L.S., L.A.C., E.P., R.J.L., N.E.A., E.N., M.M., V.P., C.L., M.K.L., W.S., K.G., K.L., E.S.Y., A.W., G.A., N.A.D.R., G.S.J., H.B., G.S.A., M.N., T.J.R., M.R.D., I.N.M., K.M.M., J.R.M., R.S.B., A.C., and B.S.G. designed, completed, and/or analyzed experiments. K.S.C., O.M.A., G.B.H., N.W., D.W., J.S.M., and B.S.G. contributed new reagents/analytic tools. K.S.C., K.M.M, and B.S.G. wrote the manuscript. All authors contributed to discussions in regard to and editing of the manuscript.


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