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      Detection of R.1 lineage severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with spike protein W152L/E484K/G769V mutations in Japan

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      PLoS Pathogens

      Public Library of Science

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          Abstract

          We aimed to investigate novel emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages in Japan that harbor variants in the spike protein receptor-binding domain (RBD). The total nucleic acid contents of samples from 159 patients with coronavirus disease 2019 (COVID-19) were subjected to whole genome sequencing. The SARS-CoV-2 genome sequences from these patients were examined for variants in spike protein RBD. In January 2021, three family members (one aged in their 40s and two aged under 10 years old) were found to be infected with SARS-CoV-2 harboring W152L/E484K/G769V mutations. These three patients were living in Japan and had no history of traveling abroad. After identifying these cases, we developed a TaqMan assay to screen for the above hallmark mutations and identified an additional 14 patients with the same mutations. The associated virus strain was classified into the GR clade (Global Initiative on Sharing Avian Influenza Data [GISAID]), 20B clade (Nextstrain), and R.1 lineage (Phylogenetic Assignment of Named Global Outbreak [PANGO] Lineages). As of April 22, 2021, R.1 lineage SARS-CoV-2 has been identified in 2,388 SARS-CoV-2 entries in the GISAID database, many of which were from Japan (38.2%; 913/2,388) and the United States (47.1%; 1,125/2,388). Compared with that in the United States, the percentage of SARS-CoV-2 isolates belonging to the R.1 lineage in Japan increased more rapidly over the period from October 24, 2020 to April 18, 2021. R.1 lineage SARS-CoV-2 has potential escape mutations in the spike protein RBD (E484K) and N-terminal domain (W152L); therefore, it will be necessary to continue to monitor the R.1 lineage as it spreads around the world.

          Author summary

          A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in December 2019 in Wuhan, China. SARS-CoV-2 had evolved and spread around the world, threatening human life. Several mutations, which alter the viral fitness, virulence, and transmissibility, were identified in SARS-CoV-2. Here, we detected R.1 lineage SARS-CoV-2 harboring mutations in spike protein. The R.1 lineage have spread at the beginning of 2021 in Japan. This lineage has potential escape mutations in the spike protein receptor-binding domain (E484K) and N-terminal domain (W152L). We also developed a novel TaqMan assay targeting the hallmark mutations occurring in the spike proteins of R.1 lineage for screening. Our data indicate that emergent variants are dominated by the natural selection and need to be monitored by genomic epidemiological research.

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          Most cited references 42

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          Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

          Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)
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            Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

            Abstract Background Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. Methods This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. Results The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. Conclusions The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)
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              Nextstrain: real-time tracking of pathogen evolution

              Abstract Summary Understanding the spread and evolution of pathogens is important for effective public health measures and surveillance. Nextstrain consists of a database of viral genomes, a bioinformatics pipeline for phylodynamics analysis, and an interactive visualization platform. Together these present a real-time view into the evolution and spread of a range of viral pathogens of high public health importance. The visualization integrates sequence data with other data types such as geographic information, serology, or host species. Nextstrain compiles our current understanding into a single accessible location, open to health professionals, epidemiologists, virologists and the public alike. Availability and implementation All code (predominantly JavaScript and Python) is freely available from github.com/nextstrain and the web-application is available at nextstrain.org.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                7 June 2021
                June 2021
                : 17
                : 6
                Affiliations
                [1 ] Genome Analysis Center, Yamanashi Central Hospital, Fujimi, Kofu, Yamanashi, Japan
                [2 ] Department of Gastroenterology, Yamanashi Central Hospital, Fujimi, Kofu, Yamanashi, Japan
                [3 ] The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, Japan
                Icahn School of Medicine at Mount Sinai, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Article
                PPATHOGENS-D-21-00692
                10.1371/journal.ppat.1009619
                8238201
                34097716
                © 2021 Hirotsu, Omata

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 3, Tables: 2, Pages: 13
                Product
                Funding
                Funded by: Yamanashi Prefecture
                Award ID: Grant-in-Aid for the Genome Research Project
                Award Recipient :
                Funded by: Yamanashi Prefecture
                Award ID: Grant-in-Aid for the Genome Research Project
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: KAKENHI Early-Career Scientists JP18K16292
                Award Recipient :
                Funded by: Japan Society for the Promotion of Science
                Award ID: Grant-in-Aid for Scientific Research (B) 20H03668
                Award Recipient :
                Funded by: Japan Society for the Promotion of Science
                Award ID: Research Grant for Young Scholars
                Award Recipient :
                Funded by: YASUDA Medical Foundation
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100008732, Uehara Memorial Foundation;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100007449, Takeda Science Foundation;
                Award ID: Medical Research Grants
                Award Recipient :
                This study was supported by a Grant-in-Aid for the Genome Research Project from Yamanashi Prefecture (to Y.H. and M.O.), Grant-in-Aid for Early-Career Scientists 18K16292 (to Y.H.) and Grant-in-Aid for Scientific Research (B) 20H03668 (to Y.H.) from the Japan Society for the Promotion of Science (JSPS) KAKENHI, a Research Grant for Young Scholars (to Y.H.) from Satoshi Omura Foundation, the YASUDA Medical Foundation (to Y.H.), the Uehara Memorial Foundation (to Y.H.), and Medical Research Grants from the Takeda Science Foundation (to Y.H.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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