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Virus name: hCoV-19/USA/MN-MDH-142/2020 Accession ID: EPI_ISL_427281 Type: betacoronavirus Passage details/history: Original Sample information Collection date: 2020-03-18 Location: North America / USA / Minnesota Host: Human

Virus name: hCoV-19/USA/MN-MDH-143/2020 Accession ID: EPI_ISL_427282 Type: betacoronavirus Passage details/history: Original Sample information Collection date: 2020-03-22 Location: North America / USA / Minnesota Host: Human

Virus name: hCoV-19/USA/MN-MDH-144/2020 Accession ID: EPI_ISL_427283 Type: betacoronavirus Passage details/history: Original Sample information Collection date: 2020-03-22 Location: North America / USA / Minnesota Host: Human

Virus name: hCoV-19/USA/MN-MDH-145/2020 Accession ID: EPI_ISL_427284 Type: betacoronavirus Passage details/history: Original Sample information Collection date: 2020-03-22 Location: North America / USA / Minnesota Host: Human

Virus name: hCoV-19/USA/MN-MDH-146/2020 Accession ID: EPI_ISL_427285 Type: betacoronavirus Passage details/history: Original Sample information Collection date: 2020-03-22 Location: North America / USA / Minnesota Host: Human

Virus name: hCoV-19/USA/MN-MDH-147/2020 Accession ID: EPI_ISL_427286 Type: betacoronavirus Passage details/history: Original Sample information Collection date: 2020-03-23 Location: North America / USA / Minnesota Host: Human

Virus name: hCoV-19/USA/MN-MDH-149/2020 Accession ID: EPI_ISL_427287 Type: betacoronavirus Passage details/history: Original Sample information Collection date: 2020-03-23 Location: North America / USA / Minnesota Host: Human

The Minnesota DHPH Lab released (at GISAID) 15 sequences from Minnesota patients. 14 were the Italian lineage.

Apr 16 http://mediaarchives.gsradio.net/rense/special/rense_041620_hr3.mp3

Coronavirus Disease 2019 (COVID-19) in Illinois Test Results Positive 27,575 Deaths 1,134 Total Tests Performed* 130,163 *Total tests performed and reported electronically for testing of COVID-19 at IDPH, commercial or hospital laboratories. Deaths are included in the number of positive cases All numbers displayed are provisional and subject to change. http://www.dph.illinois.gov/topics-services/diseases-and-conditions/diseases-a-z-list/coronavirus Information last updated on 4/17/2020. Information to be updated daily.

As of April 17, 2020 Confirmed Cases Reported =34402 CATEGORY NUMBER OF CONFIRMED CASES County Barnstable 573 Berkshire 383 Bristol 1659 Dukes 12 Essex 4584 Franklin 173 Hampden 2134 Hampshire 258 Middlesex 7744 Nantucket 9 Norfolk 3499 Plymouth 2577 Suffolk 7272 Worcester 2765 Unknown 760 Sex Female 17823 Male 14991 Unknown 1588 Age Group ≤19 years of age 803 20-29 years of age 4095 30-39 years of age 5040 40-49 years of age 5071 50-59 years of age 6158 60-69 years of age 4850 70-79 years of age 3342 ≥ 80 years of age 4777 Unknown 266 Deaths Attributed to COVID-19 1404 There were 7,971 new tests conducted for a total of 148,744. • There are 2,221 new cases for a total of 34,402. • 159 new deaths were reported for a total of 1,404. • Details are below. • There is day-to-day variability in cases reported by testing laboratories and no single day change is indicative of overall cases trends. COVID-19 Cases in Long-Term Care Facilities* Residents/Healthcare workers of LongTerm Care Facilities 5142 Long-Term Care Facilities Reporting At Least One Case of COVID-19 240 Deaths Reported in Long-Term Care Facilities 702 Total Cases and Deaths by Race/Ethnicity Confirmed Cases N (%) Deaths N (%) Hispanic 3185 (9%) 58 (4%) Non-Hispanic White 6537 (19%) 414 (30%) Non-Hispanic Black/African American 2144 (6%) 59 (4%) Non-Hispanic Asian 485 (1%) 21 (1%) Non-Hispanic Other4 1082 (3%) 34 (2%) Unknown 14676 (43%) 549 (40%) Missing 6293 (18%) 269 (19%) Total 34402 1404 Reported Deaths – April 17, 2020 (Dates of Death: 4/2/2020 – 4/17/2020) Sex Age County Preexisting Conditions Hospitalized Male 40s Suffolk Yes Yes Male 50s Hampden Yes Yes Male 50s Plymouth Unknown Yes Male 50s Middlesex Yes Yes Male 50s Bristol Yes Yes Female 50s Suffolk Unknown Unknown Male 50s Hampshire Yes Yes Male 60s Bristol No Yes Male 60s Essex Yes Yes Male 60s Norfolk No Yes Male 60s Bristol Unknown Unknown Female 60s Plymouth Unknown Yes Male 60s Norfolk Unknown Unknown Male 60s Essex Yes Yes Male 60s Bristol Unknown Unknown Male 60s Plymouth Yes Yes Male 60s Middlesex Unknown Yes Male 60s Essex Unknown No Female 60s Middlesex Unknown Unknown Male 60s Bristol Unknown Unknown Female 70s Worcester Unknown No Male 70s Worcester Unknown Yes Female 70s Unknown Yes Yes Male 70s Essex Yes Yes Male 70s Essex Unknown Yes Female 70s Worcester Yes Yes Male 70s Hampden Yes Yes Male 70s Norfolk Yes Yes Male 70s Essex Unknown Unknown Female 70s Suffolk Unknown Unknown Male 70s Suffolk Unknown Yes Female 70s Norfolk Unknown Unknown Female 70s Hampden Unknown Unknown Female 70s Norfolk Unknown Yes Female 70s Essex Unknown Yes Male 70s Norfolk Unknown Yes Male 70s Hampden Unknown Unknown Male 70s Worcester Yes Unknown Male 70s Middlesex Yes Unknown Male 70s Middlesex Unknown Yes Male 70s Plymouth Yes Yes Female 70s Middlesex Unknown Yes Male 70s Essex No Yes Male 70s Plymouth Unknown Yes MASSACHUSETTS DEPARTMENT OF PUBLIC HEALTH Male 70s Hampden Yes Yes Male 70s Hampden Yes Yes Female 70s Hampden Unknown Yes Male 70s Middlesex Unknown Yes Male 70s Middlesex Yes Yes Male 70s Plymouth Yes Yes Male 70s Middlesex Yes Yes Male 70s Norfolk Yes Yes Male 80s Suffolk Unknown No Male 80s Plymouth Unknown Yes Female 80s Middlesex Yes Yes Male 80s Middlesex Unknown Unknown Female 80s Suffolk Yes Yes Male 80s Norfolk Unknown Unknown Male 80s Suffolk Yes Unknown Male 80s Middlesex Unknown Unknown Male 80s Essex Unknown Yes Male 80s Hampden Unknown Yes Male 80s Norfolk Yes Yes Female 80s Hampden Unknown Unknown Female 80s Bristol Unknown Yes Male 80s Middlesex Unknown Yes Male 80s Suffolk Unknown Yes Female 80s Bristol Yes Yes Female 80s Essex Unknown Yes Male 80s Suffolk Unknown No Male 80s Suffolk Unknown Yes Male 80s Norfolk Unknown Unknown Male 80s Middlesex Unknown Yes Female 80s Bristol Unknown Yes Male 80s Norfolk Unknown No Female 80s Plymouth Unknown Yes Male 80s Suffolk Yes Unknown Male 80s Norfolk Unknown Unknown Female 80s Unknown Unknown Unknown Female 80s Suffolk Unknown Unknown Male 80s Norfolk Unknown No Male 80s Norfolk Yes Unknown Female 80s Suffolk Unknown Yes Male 80s Bristol Yes Yes Male 80s Hampden No Yes Male 80s Norfolk Unknown Yes Male 80s Essex Unknown Yes Female 80s Middlesex Unknown Unknown Female 80s Middlesex Unknown Unknown Female 80s Suffolk Unknown Unknown Male 80s Middlesex Unknown Yes Male 80s Norfolk Unknown Yes Female 80s Middlesex Unknown Unknown Female 80s Worcester Unknown No MASSACHUSETTS DEPARTMENT OF PUBLIC HEALTH Male 80s Plymouth Unknown Yes Female 80s Middlesex Unknown Unknown Female 80s Middlesex Yes Yes Male 80s Middlesex Yes Yes Male 80s Bristol Unknown Unknown Male 80s Essex Unknown Unknown Female 80s Essex Unknown Unknown Female 80s Essex Unknown Unknown Male 80s Hampden Yes No Male 80s Middlesex Yes Yes Male 80s Suffolk Unknown Yes Female 80s Unknown Unknown Unknown Female 80s Plymouth Unknown No Male 80s Suffolk Unknown Yes Female 80s Essex Yes Yes Male 90s Suffolk Unknown Unknown Female 90s Middlesex Yes Unknown Female 90s Essex Unknown Yes Female 90s Hampden Yes No Male 90s Suffolk Unknown Yes Female 90s Plymouth Unknown Unknown Female 90s Worcester Unknown No Female 90s Barnstable Yes Unknown Female 90s Middlesex Unknown Yes Female 90s Bristol Unknown Yes Male 90s Hampden Yes Unknown Female 90s Middlesex Unknown Unknown Male 90s Hampden Unknown Unknown Male 90s Barnstable Unknown Yes Female 90s Suffolk Unknown Unknown Female 90s Middlesex Unknown Yes Male 90s Norfolk Unknown No Female 90s Hampden Yes Unknown Female 90s Middlesex Unknown Yes Female 90s Middlesex Unknown Unknown Female 90s Worcester Unknown Unknown Female 90s Essex Yes No Female 90s Middlesex Unknown Unknown Female 90s Norfolk Unknown Unknown Male 90s Suffolk Yes Yes Female 90s Essex Unknown Unknown Female 90s Middlesex Unknown Unknown Female 90s Middlesex Unknown Yes Female 90s Hampden Unknown No Female 90s Norfolk Unknown Unknown Female 90s Middlesex Unknown Unknown Female 90s Suffolk Unknown Yes Female 90s Middlesex Unknown Unknown Male 90s Middlesex Unknown Unknown Male 90s Middlesex Unknown Unknown MASSACHUSETTS DEPARTMENT OF PUBLIC HEALTH Female 90s Hampden Unknown Unknown Female 90s Suffolk Unknown Unknown Male 90s Hampden Yes Yes Male 90s Suffolk Yes Yes Female 90s Hampden Unknown Unknown Female 90s Suffolk Unknown Unknown Male 90s Bristol Unknown Yes Female 90s Norfolk Yes Yes Female 90s Plymouth Unknown Unknown Male 90s Essex Unknown Yes Female 90s Norfolk Unknown Yes Female 100s Worcester Unknown No Male 100s Middlesex Yes Yes Female 100s Hampden Unknown Unknown Female 100s Norfolk Unknown Unknown Laboratory Total Patients Positive Total Patients Tested MA State Public Health Laboratory 1793 9678 AFC Urgent Care 71 214 ARUP Laboratories 19 194 Baystate Medical Center 449 1809 Bedford Research Foundation 25 139 Berkshire Medical Center 6 50 Beth Israel Deaconess Medical Center 2444 10164 BioReference Laboratories 25 141 Boston Medical Center 1297 2874 BROAD Institute CRSP 4941 17302 Centers for Disease Control and Prevention 1 10 Children’s Hospital Boston 36 556 CVS 1091 5878 Cambridge Health Alliance 26 26 East Side Clinical Laboratory 50 295 Emerson Hospital 8 115 Excelsior 6 11 Genesys Diagnostics 684 1743 Harrington Memorial Hospital 20 50 LabCorp 2505 9440 Lemuel Shattuck Hospital 12 39 Mayo Clinic Labs 459 2407 Orig3n 16 40 Other Public Health Laboratories 14 21 Partners Healthcare 2634 9594 Quest Laboratories 12117 61384 South Shore Hospital 73 318 Steward Health Care 385 1039 Tufts Medical Center 1805 6387 UMASS Memorial Medical Center 824 3838 VA Healthcare Sites 108 512 Vikor Scientific 174 447 Viracor 83 1363 Point of Care Testing 100 406 Other 101 260 Total Patients Tested* 34402 148744 https://www.mass.gov/doc/covid-19-cases-in-massachusetts-as-of-april-17-2020/download

Coronavirus Disease 2019 (COVID-19) Cases in MA As of April 16, 2020 Confirmed Cases Reported =32,181 CATEGORY NUMBER OF CONFIRMED CASES County Barnstable 550 Berkshire 382 Bristol 1605 Dukes 12 Essex 4245 Franklin 170 Hampden 1985 Hampshire 248 Middlesex 7206 Nantucket 9 Norfolk 3342 Plymouth 2466 Suffolk 6820 Worcester 2503 Unknown 638 Sex Female 16794 Male 14176 Unknown 1211 Age Group ≤19 years of age 737 20-29 years of age 3826 30-39 years of age 4706 40-49 years of age 4754 50-59 years of age 5784 60-69 years of age 4562 70-79 years of age 3142 ≥ 80 years of age 4423 Unknown 247 Deaths Attributed to COVID-19 1245 COVID-19 Cases in Long-Term Care Facilities* Residents/Healthcare workers of LongTerm Care Facilities 4798 Long-Term Care Facilities Reporting At Least One Case of COVID-19 232 Deaths Reported in Long-Term Care Facilities 610 Total Cases and Deaths by Race/Ethnicity Confirmed Cases N (%) Deaths N (%) Hispanic 2865 (9%) 56 (5%) Non-Hispanic White 6014 (19%) 356 (29%) Non-Hispanic Black/African American 1942 (6%) 47 (4%) Non-Hispanic Asian 451 (1%) 19 (1%) Non-Hispanic Other4 994 (3%) 25 (2%) Unknown 14206 (44%) 506 (41%) Missing 5709 (18%) 236 (19%) Total 32181 1245 Reported Deaths – April 16, 2020 (Dates of Death: 4/2/2020 – 4/16/2020) Sex Age County Preexisting Conditions Hospitalized Male 40s Middlesex Yes Yes Male 40s Norfolk Yes Yes Female 50s Essex Unknown Yes Male 50s Suffolk Unknown Yes Female 50s Hampden Yes Yes Male 50s Middlesex Yes Yes Male 60s Suffolk Yes Unknown Male 60s Middlesex Yes Yes Male 60s Essex Yes Unknown Male 60s Suffolk Unknown Yes Male 60s Norfolk Yes Yes Male 60s Worcester Unknown Yes Female 60s Norfolk Yes Unknown Male 60s Suffolk Unknown Unknown Male 60s Worcester Yes No Male 60s Essex Unknown Unknown Female 60s Berkshire Yes Yes Female 60s Norfolk Yes Yes Male 60s Norfolk Unknown Unknown Male 60s Norfolk Unknown Unknown Female 60s Middlesex Yes Yes Female 60s Unknown Unknown Yes Male 60s Essex Unknown Unknown Male 70s Middlesex Unknown Yes Female 70s Suffolk Unknown Yes Male 70s Essex Unknown Yes Female 70s Suffolk Unknown Yes Female 70s Suffolk Unknown Yes Male 70s Hampden Yes Yes Female 70s Suffolk Yes Yes Male 70s Suffolk Unknown Unknown Female 70s Bristol Unknown Yes Female 70s Plymouth Unknown Unknown Female 70s Middlesex Yes Yes Male 70s Essex Unknown Unknown Female 70s Hampden Unknown Yes Female 70s Middlesex Unknown Yes Female 70s Suffolk Unknown Unknown Male 70s Middlesex Unknown Unknown Female 70s Norfolk Unknown Unknown Female 70s Middlesex Unknown Yes Female 70s Middlesex Unknown Unknown Male 70s Middlesex Yes Yes Female 70s Suffolk Unknown Yes Male 70s Essex Yes Yes Male 70s Middlesex Unknown Unknown MASSACHUSETTS DEPARTMENT OF PUBLIC HEALTH Male 70s Suffolk Unknown Unknown Male 70s Middlesex Unknown Yes Male 70s Middlesex Yes Yes Female 70s Hampden Unknown No Female 70s Norfolk Unknown Unknown Male 70s Middlesex Unknown Unknown Male 70s Essex Unknown Yes Male 70s Essex Unknown Yes Female 70s Hampden Unknown Unknown Female 70s Middlesex Unknown Yes Male 70s Suffolk Unknown Yes Male 80s Norfolk Yes Yes Female 80s Plymouth Unknown Unknown Male 80s Suffolk Unknown Yes Female 80s Berkshire Unknown Yes Male 80s Middlesex Yes Unknown Male 80s Worcester Unknown Unknown Female 80s Suffolk Unknown Yes Female 80s Norfolk Unknown Yes Male 80s Hampden Unknown Yes Female 80s Bristol Unknown Yes Female 80s Middlesex Yes Yes Male 80s Essex Yes Yes Female 80s Middlesex Yes Yes Female 80s Bristol Yes Yes Female 80s Bristol Unknown Unknown Male 80s Essex Unknown Unknown Male 80s Middlesex Yes No Male 80s Hampden Unknown Yes Female 80s Middlesex Unknown Yes Female 80s Suffolk Unknown No Female 80s Norfolk Unknown Yes Female 80s Norfolk Unknown Yes Female 80s Norfolk Unknown Yes Female 80s Worcester Yes Unknown Female 80s Essex Yes Yes Female 80s Middlesex Unknown Yes Female 80s Essex Unknown Unknown Female 80s Worcester Yes No Female 80s Essex Unknown Unknown Male 80s Middlesex Yes Unknown Female 80s Essex Unknown Unknown Female 80s Middlesex Unknown Unknown Female 80s Worcester Unknown No Male 80s Worcester Yes Unknown Male 80s Norfolk Unknown Unknown Male 80s Middlesex Unknown Unknown Female 80s Worcester Unknown Yes Female 80s Bristol Unknown Yes Female 80s Norfolk Unknown Unknown MASSACHUSETTS DEPARTMENT OF PUBLIC HEALTH Male 80s Norfolk Yes Yes Male 80s Suffolk Unknown No Female 80s Norfolk Unknown Yes Female 80s Worcester Yes Yes Male 80s Middlesex Unknown Unknown Male 80s Suffolk Unknown Yes Male 80s Worcester Unknown Yes Male 80s Hampden Unknown Unknown Male 80s Norfolk Yes Yes Female 90s Berkshire Yes Unknown Female 90s Plymouth Unknown Yes Male 90s Bristol Unknown Yes Female 90s Bristol Unknown Yes Male 90s Norfolk Unknown Unknown Female 90s Norfolk Yes Unknown Female 90s Norfolk Unknown Unknown Male 90s Middlesex Yes Yes Female 90s Suffolk Unknown Unknown Female 90s Norfolk Yes Yes Male 90s Middlesex Unknown Yes Female 90s Middlesex Unknown Unknown Female 90s Middlesex Unknown Unknown Male 90s Plymouth Unknown Yes Female 90s Middlesex Unknown Unknown Female 90s Middlesex Unknown Unknown Female 90s Essex Unknown Unknown Female 90s Essex Unknown Unknown Male 90s Middlesex Yes Yes Female 90s Essex Unknown Yes Male 90s Norfolk Unknown Yes Female 90s Norfolk Unknown Unknown Female 90s Middlesex Yes Yes Male 90s Norfolk Yes Yes Male 90s Middlesex Unknown Yes Female 90s Essex Unknown Unknown Female 90s Hampden Yes Unknown Male 90s Middlesex Unknown Unknown Female 90s Hampden Unknown Yes Female 90s Middlesex Unknown Unknown Female 90s Norfolk Unknown Yes Female 100s Unknown Unknown Unknown Laboratory Total Patients Positive Total Patients Tested MA State Public Health Laboratory 1760 9568 ARUP Laboratories 19 193 Baystate Medical Center 407 1584 Bedford Research Foundation 116 597 Berkshire Medical Center 6 38 Beth Israel Deaconess Medical Center 2270 9537 BioReference Laboratories 24 140 Boston Medical Center 1232 2731 BROAD Institute CRSP 4445 15469 Centers for Disease Control and Prevention 1 10 Children’s Hospital Boston 32 517 CVS 775 4684 Cambridge Health Alliance 19 19 East Side Clinical Laboratory 45 285 Excelsior 6 11 Genesys Diagnostics 606 1570 Harrington Memorial Hospital 19 49 LabCorp 2302 8999 Mayo Clinic Labs 458 2407 Orig3n 16 40 Other Public Health Laboratories 12 19 Partners Healthcare 2433 9043 Quest Laboratories 11750 59709 South Shore Hospital 67 300 Steward Health Care 358 947 Tufts Medical Center 1706 6049 UMASS Memorial Medical Center 726 3477 VA Healthcare Sites 104 510 Vikor Scientific 160 195 Viracor 82 1341 Point of Care Testing 100 406 Other 125 329 Total Patients Tested* 32181 140773 https://www.mass.gov/doc/covid-19-cases-in-massachusetts-as-of-april-16-2020/download

23,118 Cases Reported* 1,213 Deaths Reported Reported COVID-19 Patients in Hospitals 1,868 363 of those on ventilators Tests Completed 6,102 by State Lab Commercial Tests Completed 125,885 and Reported to State** 64 of 64 Parishes with Reported Cases http://ldh.la.gov/coronavirus/

References 1. Lo MK, Jordan R, Arvey A, et al. GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses. Sci Rep 2017;7:43395. 2. Sheahan TP, Sims AC, Graham RL, et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med 2017;9. 3. Remdesivir. 2020. (Accessed 04/09/2020, at https://clinicaltrials.gov/ct2/results?cond=&term=remdesivir&cntry=&state=&city=&dist=.) 4. de Wit E, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A 2020. 5. Sheahan TP, Sims AC, Leist SR, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 2020;11:222. 6. Choy KT, Yin-Lam Wong A, Kaewpreedee P, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res 2020:104786. 7. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30:269-71. 8. Agostini ML, Andres EL, Sims AC, et al. Coronavirus Susceptibility to the Antiviral Remdesivir (GS5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio 2018;9. 9. Munster VJ, Feldmann F, Williamson BN, et al. Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2. BioRxiv2020. 10. Brining DL, Mattoon JS, Kercher L, et al. Thoracic radiography as a refinement methodology for the study of H1N1 influenza in cynomologus macaques (Macaca fascicularis). Comparative medicine 2010;60:389-95. 11. Harcourt J, Tamin A, Lu X, et al. Severe Acute Respiratory Syndrome Coronavirus 2 from Patient with 2019 Novel Coronavirus Disease, United States. Emerg Infect Dis 2020;26. 12. Corman VM, Landt O, Kaiser M, et al. Detection of 2019 novel coronavirus (2019-nCoV) by realtime RT-PCR. Euro Surveill 2020;25. 13. Briese T, Kapoor A, Mishra N, et al. Virome Capture Sequencing Enables Sensitive Viral Diagnosis and Comprehensive Virome Analysis. mBio 2015;6:e01491-15. 14. Martin M. Cutadapt Removes Adapter Sequences From High-Throughput Sequencing Reads. EMBnetjournal 2011;17. 15. Langmead B, Salzberg SL. Fast gapped-read alignment with Bowtie 2. Nat Methods 2012;9:357- 9. 16. McKenna A, Hanna M, Banks E, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 2010;20:1297-303. 17. Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 2016;531:381-5. 18. Sheahan TP, Sims AC, Zhou S, et al. An orally bioavailable broad-spectrum antiviral inhibits SARSCoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med 2020.

Discussion Remdesivir is the first antiviral treatment with proven efficacy against SARS-CoV-2 in an animal model of COVID-19. Remdesivir treatment in rhesus macaques infected with SARS-CoV-2 was highly effective in reducing clinical disease and damage to the lungs. The remdesivir dosing used in rhesus macaques is equivalent to that used in humans; however, due to the acute nature of the disease in rhesus macaques, it is hard to directly translate the timing of treatment used to corresponding disease stages in humans. In our study, treatment was administered close to the peak of virus replication in the lungs as indicated by viral loads in bronchoalveolar lavages and the first effects of treatment on clinical signs and virus replication were observed within 12 hours. The efficacy of direct-acting antivirals against acute viral respiratory tract infections typically decreases with delays in treatment initation18. Thus, remdesivir treatment in COVID-19 patients should be initiated as early as possible to achieve the maximum treatment effect. a CC0 license. author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under bioRxiv preprint doi: https://doi.org/10.1101/2020.04.15.043166. The copyright holder for this preprint (which was not peer-reviewed) is the 13 Despite the lack of obvious respiratory signs and reduced virus replication in the lungs of remdesivirtreated animals, there was no reduction in virus shedding. This finding is of great significance for patient management, where a clinical improvement should not be interpreted as a lack of infectiousness. While our study demonstrates the presence of remdesivir metabolites in the lower respiratory tract, the drug levels in upper respiratory tract have not been characterized and novel formulations with alternative route of drug delivery should be considered to improve the distribution to the upper respiratory tract, thereby reducing shedding and the potential transmission risk. However, since severe COVID-19 disease is a result of virus infection of the lungs, this organ is the main target of remdesivir treatment. The bioavailability and protective effect of remdesivir in the lungs of infected rhesus macaques supports treatment of COVID-19 patients with remdesivir. Data from clinical trials in humans are pending, but our data in rhesus macaques indicate that remdesivir treatment should be considered as early as clinically possible to prevent progression to severe pneumonia in COVID-19 patients. Conflict of interest The authors affiliated with Gilead Sciences are employees of the company and own company stock. The authors affiliated with NIH have no conflict of interest to report. Acknowledgements The authors would like to thank Elaine Bunyan (Gilead Sciences) for preparing remdesivir; Darius Babusis (Gilead Sciences) for providing synthetic standards for molecular analysis; Anita Mora (NIAID) for preparing figures; Tina Thomas, Rebecca Rosenke and Dan Long (all NIAID) for assistance with histology; Myndi Holbrook (NIAID) for technical assistance and RMVB staff (NIAID) for animal care. This study was supported by the Intramural Research Program of NIAID, NIH.

Results Remdesivir is distributed to the main target tissue of SARS-CoV-2, the lungs Two groups of six rhesus macaques were inoculated with SARS-CoV-2 strain nCoV-WA1-2020. Twelve hours post inoculation, one group was administered 10mg/kg intravenous remdesivir and the other group was treated with an equal volume of vehicle solution (2ml/kg). Treatment was continued 12hrs after the first treatment, and every 24 hrs thereafter with a dose of 5 mg/kg remdesivir or an equal volume of vehicle solution (1ml/kg). The serum concentration of remdesivir was determined in serum collected 12 hrs after the initial treatment and 24 hrs after subsequent treatments were administered and immediately before the next dose of treatment was administered. Detectable levels of remdesivir (prodrug GS-5734) as well as the downstream alanine metabolite (GS-704277) and parent nucleoside (GS-441524) were observed in all remdesivir-treated animals (Fig. S1A). Serum levels of the prodrug and the downstream metabolites were consistent with previously published plasma levels of these compounds in healthy rhesus macaques, which showed a short systemic half-life for GS-5734 (0.39 hrs) resulting in transient conversion to the intermediate GS-704277 and persistence of the downstream GS441524 product at higher plasma levels17. a CC0 license. author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under bioRxiv preprint doi: https://doi.org/10.1101/2020.04.15.043166. The copyright holder for this preprint (which was not peer-reviewed) is the 10 Concentrations of metabolite GS-441524 were determined in lung tissue collected from each lung lobe on 7 dpi, 24 hrs after the last remdesivir treatment was administered and was readily detectable in all remdesivir-treated animals. GS-441524 was generally distributed amongst all six lobes of the lung (Fig S1B). GS-704277 was not detected in the lung tissue. While the pharmacologically active metabolite of remdesivir is the triphosphate of GS-441524, lung homogenate samples spiked with the triphosphate metabolite demonstrated rapid decay of the metabolite in this matrix (data not shown). GS-441524 levels were taken as a surrogate for tissue loading and suggest that the current dosing strategy delivered drug metabolites to the sites of SARS-CoV-2 replication in infected animals. Lack of respiratory disease in rhesus macaques infected with SARS-CoV-2 and treated with remdesivir After inoculation with SARS-CoV-2, the animals were assigned a daily clinical score based on a preestablished scoring sheet in a blinded fashion. Twelve hours after the first remdesivir treatment, clinical scores in remdesivir-treated animals were significantly lower than in control animals receiving vehicle solution. This difference in clinical score was maintained throughout the study (Fig. 1A). Only one of the six remdesivir-treated animals showed mild dyspnea, whereas tachypnea and dyspnea were observed in all vehicle-treated controls (Table S1). Radiographic pulmonary infiltrates are one of the hallmarks of COVID-19 in humans. Radiographs taken on 0, 1, 3, 5, and 7 dpi showed significantly less lung lobe involvement and less severe of pulmonary infiltration in animals treated with remdesivir as compared to those receiving vehicle (Fig. 1B and C). Reduced virus replication in the lower, but not upper respiratory tract after remdesivir treatment On 1, 3 and 7 dpi BAL were performed as an indicator of virus replication in the lower respiratory tract. Although viral loads in BAL were reduced in remdesivir-treated animals this difference was not statistically significant (Fig. 2A). However, 12 hours after the first remdesivir treatment was administered, the infectious virus titer in BAL was ~100-fold lower in remdesivir-treated animals than controls. By 3 dpi, infectious virus could no longer be detected in BAL from remdesivir-treated animals, a CC0 license. author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under bioRxiv preprint doi: https://doi.org/10.1101/2020.04.15.043166. The copyright holder for this preprint (which was not peer-reviewed) is the 11 whereas virus was still detected in BAL from four out of six control animals (Fig. 2B). Despite this reduction in virus replication in the lower respiratory tract, neither viral loads nor infectious virus titers were reduced in nose, throat or rectal swabs collected from remdesivir-treated animals, except a significant difference in virus titer in throat swabs collected on 1 dpi and in viral loads in throat swabs collected on 4 dpi (Fig. 3). Decreased viral loads in lungs after remdesivir treatment All animals were euthanized on 7 dpi. Tissue samples were collected from each lung lobe to compare virus replication in remdesivir-treated and vehicle-treated control animals. In 10 out of 36 lung lobe samples collected from remdesivir-treated animals, viral RNA could not be detected, whereas this was the case in only 3 out of 36 lung lobes collected from control animals. In general, comparison across individual lung lobes in the two groups showed lower geometric mean of viral RNA in remdesivir-treated group (Fig. 4A). Taken together, the viral load was significantly lower in lungs from remdesivir-treated animals than in vehicle-treated controls (Fig. 4B). Virus could be isolated from lung lobes of five out of six vehicle-treated control animals, but none of the lung tissue collected from remdesivir-treated animals was positive in virus isolation. Although fewer tissues from other positions in the respiratory tract were positive by qRT-PCR in remdesivir-treated animals, these differences were not statistically significant (Fig. 4C). Reduced pneumonia after remdesivir treatment At necropsy on 7 dpi, lungs were assessed grossly for presence of lesions. Gross lung lesions were observed in one out of six remdesivir-treated animals. In contrast, all six vehicle controls had visible lesions, resulting in statistically significantly difference in the area of the lungs affected by lesions (Fig. 5A, B and Fig. 6A, B). This difference was also evident when calculating the lung weight to bodyweight ratio as an indicator of pneumonia, with a statistically significantly lower ratio observed in remdesivirtreated compared to vehicle-treated animals (Fig. 5C). Histologically, there was a clear effect of a CC0 license. author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under bioRxiv preprint doi: https://doi.org/10.1101/2020.04.15.043166. The copyright holder for this preprint (which was not peer-reviewed) is the 12 remdesivir treatment on lung lesions, with fewer and less severe lesions in the remdesivir animals than in vehicle-treated controls. Histologic lung lesions were absent in three of six remdesivir-treated animals; the three remaining animals developed minimal pulmonary pathology. Lesions in these animals were characterized as widely separated, minimal, interstitial pneumonia frequently located in subpleural spaces (Fig. 6C, E). Five out six vehicle-treated animals developed multifocal, mild to moderate, interstitial pneumonia (Fig. 6D, F). Viral antigen was detected in all animals regardless of treatment (Fig. 6G, H). Absence of resistance mutations Deep sequencing was successful on samples from all remdesivir-treated animals and vehicle controls. Known mutations in the RNA dependent RNA polymerase that confer resistance to remdesivir in coronaviruses8 were not detected in any of the samples tested (Table S2).

Methods Ethics and biosafety statement All animal experiments were approved by the Institutional Animal Care and Use Committee of Rocky Mountain Laboratories, NIH and carried out by certified staff in an Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International accredited facility, according to the institution’s guidelines for animal use, following the guidelines and basic principles in the NIH Guide for the Care and Use of Laboratory Animals, the Animal Welfare Act, United States Department of a CC0 license. author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under bioRxiv preprint doi: https://doi.org/10.1101/2020.04.15.043166. The copyright holder for this preprint (which was not peer-reviewed) is the 4 Agriculture and the United States Public Health Service Policy on Humane Care and Use of Laboratory Animals. Rhesus macaques were housed in adjacent individual primate cages allowing social interactions, in a climate-controlled room with a fixed light-dark cycle (12-hr light/12-hr dark). Animals were monitored at least twice daily throughout the experiment. Commercial monkey chow, treats, and fruit were provided twice daily by trained personnel. Water was available ad libitum. Environmental enrichment consisted of a variety of human interaction, manipulanda, commercial toys, videos, and music. The Institutional Biosafety Committee (IBC) approved work with infectious SARS-CoV-2 strains under BSL3 conditions. Sample inactivation was performed according to IBC-approved standard operating procedures for removal of specimens from high containment. Study design To evaluate the effect of remdesivir treatment on SARS-CoV-2 disease outcome, we used the recently established rhesus macaque model of SARS-CoV-2 infection that results in transient lower respiratory tract disease9 . Twelve animals were randomly assigned to two groups and inoculated as described previously with a total dose of 2.6x106 TCID50 of SARS-CoV-2 strain nCoV-WA1-2020 via intranasal, oral, ocular and intratracheal routes. The efficacy of therapeutic remdesivir treatment was tested in two groups of six adult rhesus macaques (3 males and 3 females each; 3.6-5.7kg). Due to the acute nature of the SARS-CoV-2 model in rhesus macaques, therapeutic treatment was initiated at 12 hours after inoculation with SARS-CoV-2 and continued once daily through 6 days post inoculation (dpi). One group of rhesus macaques was treated with a loading dose of 10mg/kg remdesivir, followed by a daily maintenance dose of 5 mg/kg. The other group of six animals served as infected controls and were administered an equal dose volume (i.e. 2 ml/kg loading dose and 1 ml/kg thereafter) of vehicle solution (12% sulfobutylether-β-cyclodextrin in water and hydrochloric acid, pH3.5) according to the same treatment schedule. This dosing scheme in rhesus macaques mimics the daily dosing tested in clinicals studies with COVID-19 patients and results in a similar systemic drug exposure. Treatment was delivered a CC0 license. author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under bioRxiv preprint doi: https://doi.org/10.1101/2020.04.15.043166. The copyright holder for this preprint (which was not peer-reviewed) is the 5 as an intravenous bolus injection (total dose delivered over approximately 5 minutes) administered alternatingly in the left or right cephalic or saphenous veins. The animals were observed twice daily for clinical signs of disease using a standardized scoring sheet as described previously10; the same person, who was blinded to the group assignment of the animals, assessed the animals throughout the study. The predetermined endpoint for this experiment was 7 dpi. Nose, throat and rectal swabs were collected daily during treatment administration. Clinical exams were performed on 0, 1, 3, 5, and 7 dpi on anaesthetized animals. On exam days, clinical parameters such as bodyweight, temperature, pulse oximetry, blood pressure and respiration rate were collected, as well as dorsal-ventral and lateral chest radiographs. Radiographs were analyzed by a clinical veterinarian blinded to the group assignment of the animals. On 1, 3 and 7 dpi a bronchoalveolar lavage (BAL) was performed using 10ml of sterile saline. After euthanasia on 7 dpi, necropsies were performed. The percentage of gross lung lesions were scored by a board-certified veterinary pathologist blinded to the group assignment of the animals and samples of the following tissues were collected: cervical lymph node, conjunctiva, nasal mucosa, oropharynx, tonsil, trachea, all lung lobes, mediastinal lymph node, right and left bronchus, heart, liver, spleen, kidney, stomach, duodenum, jejunum, ileum, cecum, colon, and urinary bladder. Histopathological analysis of tissue slides was performed by a board-certified veterinary pathologist blinded to the group assignment of the animals. Virus and cells SARS-CoV-2 isolate nCoV-WA1-2020 (MN985325.1)11 (Vero passage 3) was kindly provided by CDC and propagated once in Vero E6 cells in DMEM (Sigma) supplemented with 2% fetal bovine serum (Gibco), 1 mM L-glutamine (Gibco), 50 U/ml penicillin and 50 μg/ml streptomycin (Gibco) (virus isolation medium). The virus stock used was 100% identical to the initial deposited Genbank sequence (MN985325.1) and no contaminants were detected. VeroE6 cells were maintained in DMEM supplemented with 10% fetal calf serum, 1 mM L-glutamine, 50 U/ml penicillin and 50 μg/ml streptomycin. a CC0 license. author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under bioRxiv preprint doi: https://doi.org/10.1101/2020.04.15.043166. The copyright holder for this preprint (which was not peer-reviewed) is the 6 Remdesivir (GS-5734) Remdesivir (RDV; GS-5734) was manufactured at Gilead Sciences by the Department of Process Chemistry (Alberta, Canada) under Good Manufacturing Practice (GMP) conditions. Batch number 5734- BC-1P was solubilized in 12% sulfobutylether-β-cyclodextrin in water and matching vehicle solution was provided to NIH. Liquid chromatography mass spectrometry Tributylamine was purchased from Millipore Sigma. LCMS grade water, acetone, methanol, isopropanol and acetic acid were purchased through Fisher Scientific. All synthetic standards for molecular analysis were provided by Gilead Sciences Inc. Serum and cleared lung homogenates were gamma-irradiated (2 MRad) to inactivate infectious virus potentially present in these samples prior to analysis. Samples were prepared for small molecule analysis by diluting a 50 µL aliquot of either serum or clarified lung homogenate with 950 µL of 50% acetone, 35% methanol, 15% water (v/v) on ice. Samples were incubated at room temperature for 15 min and then centrifuged at 16k xg for 5 minutes. The clarified supernatants (850 µL) were recovered and taken to dryness in a Savant™ DNA120 SpeedVac™ concentrator (Thermo Fisher). Samples were resuspended in 100 µL of 50% methanol, 50% water (v/v) and centrifuged as before. The supernatant was taken to a sample vial for LCMS analysis. Samples were separated using an ion-pairing liquid chromatography strategy on a Sciex ExionLC™ AC system. Samples were injected onto a Waters Atlantis T3 column (100 Å, 3 µm, 3 mm X 100 mm) and eluted using a binary gradient from 5 mM tributylamine, 5 mM acetic acid in 2% isopropanol, 5% methanol, 93% water (v/v) to 100% isopropanol over 5.5 minutes. Analytes were measured using a Sciex 5500 QTRAP® mass spectrometer in negative mode. Multiple reaction monitoring was performed using two signal pairs for each analyte and signal fidelity was confirmed by collecting triggered product ion spectra and comparing back to spectra of synthetically pure standards. a CC0 license. author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under bioRxiv preprint doi: https://doi.org/10.1101/2020.04.15.043166. The copyright holder for this preprint (which was not peer-reviewed) is the 7 All analytes were quantified against an 8-point calibration curve of the respective synthetic standard prepared in the target matrix (i.e. serum or cleared lung homogenate) and processed in the same manner as experimental samples. Limit of quantification (LOQ) was approximated at a signal to noise of 10. The LOQs for the measured molecules in each matrix were 5 nM for GS-441524 in both lung homogenate and serum, 1 nM for GS-704277 in both lung homogenate and serum and 0.08 nM for GS5734 in serum. Instability of GS-5734 and the tri-phosphorylated nucleotide metabolite in the lung homogenate during tissue lysis prevented detection of these metabolites in the lung tissue. Quantitative PCR RNA was extracted from swabs and BAL using the QiaAmp Viral RNA kit (Qiagen) according to the manufacturer’s instructions. Tissues (30 mg) were homogenized in RLT buffer and RNA was extracted using the RNeasy kit (Qiagen) according to the manufacturer’s instructions. For detection of viral RNA, 5 µl RNA was used in a one-step real-time RT-PCR E assay12 using the Rotor-Gene probe kit (Qiagen) according to instructions of the manufacturer. In each run, standard dilutions of RNA standards counted by droplet digital PCR were run in parallel, to calculate copy numbers in the samples. Virus titration Virus titrations were performed by end-point titration in Vero E6 cells. Tissue was homogenized in 1ml DMEM using a TissueLyser (Qiagen). Cells were inoculated with 10-fold serial dilutions of swab and BAL samples. Virus isolation was performed on lung tissues by homogenizing the tissue in 1ml DMEM and inoculating Vero E6 cells in a 24 well plate with 250 µl of cleared homogenate and a 1:10 dilution thereof. One hour after inoculation of cells, the inoculum was removed and replaced with 100 µl (virus titration) or 500 µl virus isolation medium. Six days after inoculation, CPE was scored and the TCID50 was calculated. Histopathology and immunohistochemistry a CC0 license. author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under bioRxiv preprint doi: https://doi.org/10.1101/2020.04.15.043166. The copyright holder for this preprint (which was not peer-reviewed) is the 8 Histopathology and immunohistochemistry were performed on rhesus macaque tissues. After fixation for a minimum of 7 days in 10% neutral-buffered formalin and embedding in paraffin, tissue sections were stained with hematoxylin and eosin (HE). To detect SARS-CoV-2 antigen, immunohistochemistry was performed using a custom-made rabbit antiserum against SARS-CoV-2 N at a 1:1000 dilution. Stained slides were analyzed by a board-certified veterinary pathologist. Next generation sequencing of viral RNA Viral RNA was extracted as described above. cDNAs were prepared according to Briese et al., with minor modifications13. Briefly, 3 to 12 µl of extracted RNA was depleted of rRNA using Ribo-Zero Gold H/M/R (Illumina) and then reverse-transcribed using random hexamers and SuperScript IV (ThermoFisher Scientific). Following RNaseH treatment, second strand synthesis was performed using Klenow fragment (New England Biolabs) and resulting double-stranded cDNAs were treated with a combined mixture of RiboShredder RNase Blend (Lucigen) and RNase, DNase-free, high conc (Roche Diagnostics, Indianapolis, IN) and then purified using Ampure XP bead purification (Beckman Coulter). Kapa’s HyperPlus library preparation kit (Roche Sequencing Solutions) was used to prepare sequencing libraries from the doublestranded cDNAs. To facilitate multiplexing, adapter ligation was performed with KAPA Unique DualIndexed Adapters and samples were enriched for adapter-ligated product using KAPA HiFi HotStart Ready mix and 7 PCR amplification cycles, according to the manufacturer’s manual. Pools consisting of eight sample libraries were used for hybrid-capture virus enrichment using myBaits® Expert Virus SARSCoV-2 panel and following the manufacturer’s manual, version 4.01, with 14 cycles of post-capture PCR amplification (Arbor Biosciences). Purified, enriched libraries were quantified using Kapa Library Quantification kit (Roche Sequencing Solutions) and sequenced as 2 X 150 base pair reads on the Illumina NextSeq 550 instrument (Illumina). Raw fastq reads were trimmed of Illumina adapter sequences using cutadapt version 1.1214 and then trimmed and filtered for quality using the FASTX-Toolkit (Hannon Lab). Remaining reads were mapped a CC0 license. author/funder. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under bioRxiv preprint doi: https://doi.org/10.1101/2020.04.15.043166. The copyright holder for this preprint (which was not peer-reviewed) is the 9 to the SARS-CoV-2 2019-nCoV/USA-WA1/2020 genome (MN985325.1) using Bowtie2 version 2.2.915 with parameters --local --no-mixed -X 1500. PCR duplicates were removed using picard MarkDuplicates (Broad Institute) and variants were called using GATK HaplotypeCaller version 4.1.2.016 with parameter - ploidy 2. Variants were filtered for QUAL > 1000 and DP > 20 using bcftools. Statistical analysis Statistical analyses were performed using GraphPad Prism software version 8.2.1. Data sharing All data included in this manuscript have been deposited in Figshare (https://doi.org/10.35092/yhjc.12111570). Results Remdesivir is distributed to the main target ti

Introduction Effective treatments for COVID-19 are urgently needed. While a large number of investigational as well as approved and repurposed drugs have been suggested to have utility for treatment of COVID-19, preclinical data from animal models can guide a more focused search for effective treatments in humans by ruling out treatments without proven efficacy in vivo. Remdesivir (GS-5734) is a nucleotide analog prodrug with broad antiviral activity1 , including against coronaviruses2 , that is currently investigated in COVID-19 clinical trials worldwide, including in China, the US and Europe (summarized in3 ). In animal models, remdesivir treatment was effective against MERS-CoV and SARS-CoV infection. 2,4,5 In vitro, remdesivir inhibited replication of SARS-CoV-2.6,7 Moreover, in vitro experiments have shown that mutations conferring resistance to remdesivir do not easily emerge in coronaviruses8 . Here, we investigated the efficacy of remdesivir treatment in our recently established rhesus macaque model of SARS-CoV-2 infection. In this model, infected rhesus macaques develop mild to moderate, transient respiratory disease with pulmonary infiltrates visible on radiographs, and a shedding pattern similar to that observed in COVID-19 patients9 . Therapeutic treatment of rhesus macaques with remdesivir shortly before the peak of virus replication resulted in a significant clinical improvement, reduction in pulmonary infiltrates, and a reduction in pulmonary pathology. https://www.biorxiv.org/content/10.1101/2020.04.15.043166v1.full.pdf

Abstract Background: Effective therapeutics to treat COVID-19 are urgently needed. Remdesivir is a nucleotide prodrug with in vitro and in vivo efficacy against coronaviruses. Here, we tested the efficacy of remdesivir treatment in a rhesus macaque model of SARS-CoV-2 infection. Methods: To evaluate the effect of remdesivir treatment on SARS-CoV-2 disease outcome, we used the recently established rhesus macaque model of SARS-CoV-2 infection that results in transient lower respiratory tract disease. Two groups of six rhesus macaques were infected with SARS-CoV-2 and treated with intravenous remdesivir or an equal volume of vehicle solution once daily. Clinical, virological and histological parameters were assessed regularly during the study and at necropsy to determine treatment efficacy. Results: In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs. Virus titers in bronchoalveolar lavages were significantly reduced as early as 12hrs after the first treatment was administered. At necropsy on day 7 after inoculation, lung viral loads of remdesivir-treated animals were significantly lower and there was a clear reduction in damage to the lung tissue. Conclusions: Therapeutic remdesivir treatment initiated early during infection has a clear clinical benefit in SARS-CoV-2-infected rhesus macaques. These data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to severe pneumonia.

Brandi Williamson, Friederike Feldmann, Benjamin Schwarz, Kimberly Meade-White, Danielle Porter, Jonathan Schulz, Neeltje van Doremalen, Ian Leighton, Claude Kwe Yinda, Lizzette Perez-Perez, Atsushi Okumura, Jamie Lovaglio, Patrick Hanley, Greg Saturday, Catharine Bosio, Sarah Anzick, Kent Barbian, Tomas Chilar, Craig Martens, Dana Scott, View ORCID ProfileVincent Munster, Emmie de Wit doi: https://doi.org/10.1101/2020.04.15.043166 Brandi N. Williamson1 , MPH; Friederike Feldmann2 , AS; Benjamin Schwarz3 , PhD; Kimberly MeadeWhite1 , MSc; Danielle P. Porter5 , PhD; Jonathan Schulz1 , BSc; Neeltje van Doremalen1 , PhD; Ian Leighton, BA3 ; Claude Kwe Yinda1 , PhD; Lizzette Pérez-Pérez1 , MSc; Atsushi Okumura1 , DVM; Jamie Lovaglio2 , DVM; Patrick W. Hanley2 , DVM; Greg Saturday2 , DVM; Catharine M. Bosio3 , PhD; Sarah Anzick4 , PhD; Kent Barbian4 , MSc; Tomas Cihlar5 , PhD; Craig Martens4 , PhD; Dana P. Scott2 , DVM; Vincent J. Munster1 , PhD; Emmie de Wit1*, PhD 1 Laboratory of Virology, 2 Rocky Mountain Veterinary Branch, 3 Laboratory of Bacteriology and 4 Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, United States of America; 5 Gilead Sciences, Foster City, CA, United States of America Corresponding author: [email protected]

In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs. Virus titers in bronchoalveolar lavages were significantly reduced as early as 12hrs after the first treatment was administered. https://www.biorxiv.org/content/10.1101/2020.04.15.043166v1?ct=ct

This information is updated daily at 3 p.m., with COVID-19 results included as of 10 a.m. Confirmed COVID-19 Cases by Jurisdiction updated 4/17/2020 County Confirmed Cases Reported Deaths Alcona 1 Allegan 29 Alpena 2 1 Antrim 8 Arenac 7 Barry 21 1 Bay 69 2 Berrien 144 8 Branch 35 2 Calhoun 130 5 Cass 22 1 Charlevoix 11 1 Cheboygan 12 1 Clare 7 1 Clinton 103 6 Crawford 22 2 Delta 10 1 Detroit City 7414 582 Dickinson 3 2 Eaton 87 5 Emmet 21 2 Genesee 1197 106 Gladwin 8 Gogebic 4 1 Grand Traverse 17 4 Gratiot 7 Hillsdale 85 10 Houghton 2 Huron 8 Ingham 298 6 Ionia 20 2 Iosco 8 1 Isabella 46 6 Jackson 227 9 Kalamazoo 130 9 Kalkaska 17 2 Kent 430 20 Lake 2 Lapeer 140 13 Leelanau 7 Lenawee 59 Livingston 269 9 Luce 1 Mackinac 5 Macomb 4145 373 Manistee 11 Marquette 29 5 Mason 4 Mecosta 12 1 Menominee 1 Midland 42 1 Missaukee 3 1 Monroe 223 10 Montcalm 24 1 Montmorency 3 Muskegon 128 5 Newaygo 7 Oakland 5901 442 Oceana 4 1 Ogemaw 5 Osceola 6 Oscoda 4 Otsego 45 3 Ottawa 88 5 Presque Isle 2 Roscommon 9 Saginaw 369 24 Sanilac 27 3 Schoolcraft 3 Shiawassee 86 2 St Clair 236 8 St Joseph 23 1 Tuscola 54 10 Van Buren 28 2 Washtenaw 855 25 Wayne 5819 462 Wexford 7 1 MDOC* 514 15 FCI** 44 Unknown 46 4 Out of State 71 1 Totals 30023 2227 City of Detroit and Wayne County are reported separately. *Michigan Department of Corrections **Federal Correctional Institute Note on cumulative counts: This report is provisional and subject to change. As public health investigations of individual cases continue, there will be corrections to the status and details of referred cases that result in changes to this report. Note on the deaths: Deaths must be reported by health care providers, medical examiners/coroners, and recorded by local health departments in order to be counted. Note on jurisdictional classification: In order to provide more accurate data, the “Other” jurisdiction category will no longer be used. Michigan Department of Corrections cases will be listed under “MDOC”. Federal Correctional Institution cases will be listed under “FCI”. Note on Case Fatality Rate: The case fatality rate is the number of people who have died from causes associated with COVID-19 out of the total number of people with confirmed COVID-19 infections. It is used as one measure of illness severity. Several factors can affect this number. Until recently, COVID-19 lab testing has prioritized for hospitalized individuals due to limited testing availability. As a result, COVID-19 infections were identified more often in people who were more severely ill. This would lead to a higher case fatality rate. As more people with mild illness are tested, it is likely the case fatality rate will go down. Links DAILY COUNTS LAB TESTING DATA ABOUT PLACES CORONAVIRUS SYMPTOMS Age Data of Overall Deceased Average Age 73.7 years Median Age 75 years Age Range 20-107 years Overall Case Fatality Rate Statewide Confimed Cases 7% Cases by Sex Sex Percentage of Overall Cases by Sex Percentage of Deceased Cases by Sex Male 45% 56% Female 54% 44% Unknown 1% <1% Totals may not add to 100% due to rounding Cases by Age Age Percentage of Overall Cases by Age Percentage of Deceased Cases by Age 0 to 19 1% 0% 20 to 29 9% <1% 30 to 39 13% 1% 40 to 49 16% 4% 50 to 59 19% 10% 60 to 69 18% 19% 70 to 79 13% 27% 80+ 11% 38% Unknown <1% 0% Totals may not add to 100% due to rounding Cases by Race Race Percentage of Overall Cases by Race Percentage of Deceased Cases by Race American Indian or Alaska Native <1% <1% Asian/Pacific Islander 2% 1% Black or African American 33% 40% Caucasian 29% 41% Multiple Races 6% 2% Other 3% 2% Unknown 27% 13% Totals may not add to 100% due to rounding Cases by Hispanic/Latino Ethnicity Hispanic/Latino Ethnicity Percentage of Overall Cases by Ethnicity Percentage of Deceased Cases by Ethnicity Hispanic/Latino 2% 1% Non-Hispanic Latino 55% 70% Unknown 43% 29% Totals may not add to 100% due to rounding Cases by Arab Ethnicity Arab Ethnicity Percentage of Overall Cases by Ethnicity Percentage of Deceased Cases by Ethnicity Arab 1% 1% Non-Arab 22% 21% Unknown 77% 78% Totals may not add to 100% due to rounding Cumulative Total of Recovered COVID-19 Cases (as of 4/10/2020): 433 Note on recovery: During this response, MDHHS is reviewing vital records statistics to identify any laboratory confirmed COVID-19 cases who are 30 days out from their onset of illness to represent recovery status. As the pandemic continues to impact Michigan, this pool will expand to include more cases. Recovered is defined as the number of persons with a confirmed COVID-19 diagnosis who are alive 30 days post-onset (or referral date if onset is not available). The number of persons recovered on April 10, 2020 represents COVID-19 confirmed individuals with an onset date on or prior to March 11, 2020. These numbers will be updated every Saturday. Source: Michigan Disease Surveillance System and Vital Records https://www.michigan.gov/coronavirus/0,9753,7-406-98163_98173---,00.html

https://www.azdhs.gov/preparedness/epidemiology-disease-control/infectious-disease-epidemiology/index.php#novel-coronavirus-home

Arkansas Totals Cumulative Cases 1,620 Last update: a few seconds ago Recoveries 548 Last update: a few seconds ago Deaths 37 https://adem.maps.arcgis.com/apps/opsdashboard/index.html#/f533ac8a8b6040e5896b05b47b17a647

CONFIRMED CASES 4,456 TOTAL TESTED 37,848 REPORTED DEATHS 142 https://alpublichealth.maps.arcgis.com/apps/opsdashboard/index.html#/6d2771faa9da4a2786a509d82c8cf0f7