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The Virus

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20 /05/2020 Article
How to Discover Antiviral Drugs Quickly

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors:
Jerry M. Parks, Jeremy C. Smith

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19/05/2020 Advanced Research
COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses

Science Direct

Authors:
Muhammad AdnanShereen, Suliman Khana, AbeerKazmic, NadiaBashira, Rabeea Siddique

ABSTRACT

The coronavirus disease 19 (COVID-19) is a highly transmittable and pathogenic viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China and spread around the world. Genomic analysis revealed that SARS-CoV-2 is phylogenetically related to severe acute respiratory syndrome-like (SARS-like) bat viruses, therefore bats could be the possible primary reservoir. The intermediate source of origin and transfer to humans is not known, however, the rapid human to human transfer has been confirmed widely. There is no clinically approved antiviral drug or vaccine available to be used against COVID-19. However, few broad-spectrum antiviral drugs have been evaluated against COVID-19 in clinical trials, resulted in clinical recovery. In the current review, we summarize and comparatively analyze the emergence and pathogenicity of COVID-19 infection and previous human coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV). We also discuss the approaches for developing effective vaccines and therapeutic combinations to cope with this viral outbreak.

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18/05/2020 Research Article
Evidence for host-dependent RNA editing in the transcriptome of SARS-CoV-2 in humans

SCIENCE

Authors:
Salvatore Di Giorgio, Filippo Martignano, Maria Gabriella Torcia, Giorgio Mattiuz, Silvestro G. Conticello

ABSTRACT

The COVID-19 outbreak has become a global health risk and understanding the response of the host to the SARS-CoV-2 virus will help to contrast the disease. Editing by host deaminases is an innate restriction process to counter viruses, and it is not yet known whether it operates against Coronaviruses. Here we analyze RNA sequences from bronchoalveolar lavage fluids derived from infected patients. We identify nucleotide changes that may be signatures of RNA editing: Adenosine-to-Inosine changes from ADAR deaminases and Cytosine-to-Uracil changes from APOBEC ones. A mutational analysis of genomes from different strains of human-hosted Coronaviridae reveals mutational patterns compatible to those observed in the transcriptomic data. Our results thus suggest that both APOBECs and ADARs are involved in Coronavirus genome editing, a process that may shape the fate of both virus and patient.

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11/05/2020 Report
A Novel Bat Coronavirus Closely Related to SARS-CoV-2 Contains Natural Insertions...

A Novel Bat Coronavirus Closely Related to SARS-CoV-2 Contains Natural Insertions at the S1/S2 Cleavage Site of the Spike Protein

SCIENCE DIRECT

Authors:
Hong Zhou, Xing Chen, Tao Hu, Juan Li, Hao Song, Yanran Liu, Peihan Wang, Di Liu, Jing Yang, Edward C. Holmes, Alice C. Hughes, Yuhai Bi, Weifeng Shi

ABSTRACT The unprecedented pandemic of pneumonia caused by a novel coronavirus, SARS-CoV-2, in China and beyond has had major public health impacts on a global scale [1, 2]. Although bats are regarded as the most likely natural hosts for SARS-CoV-2 [3], the origins of the virus remain unclear. Here, we report a novel bat-derived coronavirus, denoted RmYN02, identified from a metagenomic analysis of samples from 227 bats collected from Yunnan Province in China between May and October 2019. Notably, RmYN02 shares 93.3% nucleotide identity with SARS-CoV-2 at the scale of the complete virus genome and 97.2% identity in the 1ab gene, in which it is the closest relative of SARS-CoV-2 reported to date. In contrast, RmYN02 showed low sequence identity (61.3%) to SARS-CoV-2 in the receptor-binding domain (RBD) and might not bind to angiotensin-converting enzyme 2 (ACE2). Critically, and in a similar manner to SARS-CoV-2, RmYN02 was characterized by the insertion of multiple amino acids at the junction site of the S1 and S2 subunits of the spike (S) protein. This provides strong evidence that such insertion events can occur naturally in animal betacoronaviruses.

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08/05/2020 Report
A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2...

A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV

SCIENCE

Authors:
Meng Yuan, Nicholas C. Wu, Xueyong Zhu, Chang-Chun D. Lee, Ray T. Y. So, Huibin Lv, Chris K. P. Mok, Ian A. Wilson



ABSTRACT

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) has now become a pandemic, but there is currently very little understanding of the antigenicity of the virus. We therefore determined the crystal structure of CR3022, a neutralizing antibody previously isolated from a convalescent SARS patient, in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein at 3.1-angstrom resolution. CR3022 targets a highly conserved epitope, distal from the receptor binding site, that enables cross-reactive binding between SARS-CoV-2 and SARS-CoV. Structural modeling further demonstrates that the binding epitope can only be accessed by CR3022 when at least two RBDs on the trimeric S protein are in the “up” conformation and slightly rotated. These results provide molecular insights into antibody recognition of SARS-CoV-2.

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07/05/2020 Link
Genomic epidemiology of novel coronavirus - Global subsampling

NEXSTRAIN

Authors:
NEXSTRAIN

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04/05/2020 News
Profile of a killer the complex biology powering the coronavirus pandemic

Nature

Authors:
David Cyranoski

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01/05/2020 Articles
SARS-CoV-2 productively infects human gut enterocytes

Science

Authors:
Mart M. Lamers, Joep Beumer, Jelte van der Vaart,, Kèvin Knoops, Jens Puschhof, Tim I. Breugem1, Raimond B. G. Ravelli, J. Paul van Schayck, Anna Z. Mykytyn, Hans Q. Duimel, Elly van Donselaar, Samra Riesebosch, Helma J. H. Kuijpers, Debby Schippers, Willine J. van de Wetering, Miranda de Graaf, Marion Koopmans, Edwin Cuppen, Peter J. Peters, Bart L. Haagmans, Hans Clevers
ABSTRACT
The virus severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) can cause coronavirus disease 2019 (COVID-19), an influenza-like disease that is primarily thought to infect the lungs with transmission via the respiratory route. However, clinical evidence suggests that the intestine may present another viral target organ. Indeed, the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2) is highly expressed on differentiated enterocytes. In human small intestinal organoids (hSIOs), enterocytes were readily infected by SARS-CoV and SARS-CoV-2 as demonstrated by confocal- and electron-microscopy. Consequently, significant titers of infectious viral particles were detected. mRNA expression analysis revealed strong induction of a generic viral response program. Hence, intestinal epithelium supports SARS-CoV-2 replication, and hSIOs serve as an experimental model for coronavirus infection and biology

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29/04/2020 New Result
Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2

bioRxiv

Authors:
Werner Abfalterer, Brian Foley, Elena E Giorgi, Tanmoy Bhattacharya, Matthew D Parker, David G Partridge, Cariad M Evans,Thushan de Silva, Celia C LaBranche, David C Montefiori

Abstract

We have developed an analysis pipeline to facilitate real-time mutation tracking in SARS-CoV-2, focusing initially on the Spike (S) protein because it mediates infection of human cells and is the target of most vaccine strategies and antibody-based therapeutics. To date we have identified fourteen mutations in Spike that are accumulating. Mutations are considered in a broader phylogenetic context, geographically, and over time, to provide an early warning system to reveal mutations that may confer selective advantages in transmission or resistance to interventions. Each one is evaluated for evidence of positive selection, and the implications of the mutation are explored through structural modeling. The mutation Spike D614G is of urgent concern; after beginning to spread in Europe in early February, when introduced to new regions it repeatedly and rapidly becomes the dominant form. Also, we present evidence of recombination between locally circulating strains, indicative of multiple strain infections. These finding have important implications for SARS-CoV-2 transmission, pathogenesis and immune interventions.

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21/04/2020 Articles
Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV...

Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study

The Lancet

Authors:
Hin Chu, Jasper Fuk-Woo Chan, Terrence Tsz-Tai Yuen, Huiping Shuai, Shuofeng Yuan, Yixin Wang, Bingjie Hu, Cyril Chik-Yan Yip, Jessica Oi-Ling Tsang, Xiner Huang, Yue Chai, Dong Yang, Yuxin Hou, Kenn Ka-Heng Chik, Xi Zhang, Agnes Yim-Fong Fung, Hoi-Wah Tsoi, Jian-Piao Cai, Wan-Mui Chan, Jonathan Daniel Ip, Allen Wing-Ho Chu, Jie Zhou, David Christopher Lung, Kin-Hang Kok, Kelvin Kai-Wang To, Owen Tak-Yin Tsang, Kwok-Hung Chan, Kwok-Yung Yuen

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21/04/2020 Comment
SARS-CoV-2 cellular tropism

The Lancet

Authors:
VALERIA CAGNO

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19/04/2020 Abstract
Recent progress and challenges in drug development against COVID-19...

Recent progress and challenges in drug development against COVID-19 coronavirus (SARS-CoV-2) - an update on the status

NCBI

Authors:
Tarek Mohamed Abd El-Aziza, James D. Stockanda

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18/04/2020 World Report
Flooded by the torrent: the COVID-19 drug pipeline

The Lancet

Authors:
Asher Mullard

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17/04/2020 Letter
SARS-CoV-2 Isolation From Ocular Secretions of a Patient With COVID-19 in Italy...

SARS-CoV-2 Isolation From Ocular Secretions of a Patient With COVID-19 in Italy With Prolonged Viral RNA Detection

ANNALS OF INTERNAL MEDICINE

Authors:
Francesca Colavita, Daniele Lapa, Fabrizio Carletti, Eleonora Lalle, Licia Bordi, Patrizia Marsella, Emanuele Nicastri, Nazario Bevilacqua, Maria Letizia Giancola, Angela Corpolongo, Giuseppe Ippolito, Maria Rosaria Capobianchi, Concetta Castilletti,

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16/04/2020 Correspondence
Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors:
Neeltje van Doremalen, Trenton Bushmaker, Dylan H. Morris, Myndi G. Holbrook, Amandine Gamble, Brandi N. Williamson, Azaibi Tamin, Jennifer L. Harcourt, Natalie J. Thornburg, Susan I. Gerber, James O. Lloyd-Smith, Emmie de Wit, Vincent J. Munster

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16/04/2020 Articles
SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

SCIENCE DIRECT

Authors:
Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder, Nadine Kruger, Tanja Herrler, Sandra Erichsen, Tobias S. Schiergens, Georg Herrler, Nai-Huei Wu, Andreas Nitsche, Marcel A. Muller, Christian Drosten and Stefan Pohlmann
Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.

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16/04/2020 News
Covid-19: First coronavirus was described in The BMJ in 1965

THE BMJ

Authors:
Elisabeth Mahase

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15/04/2020 Correspondence
Droplets and Aerosols in the Transmission of SARS-CoV-2

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors:
Matthew Meselson

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15/04/2020 Communication
Temporal dynamics in viral shedding and transmissibility of COVID-19

NATURE MEDICINE

Authors:
Xi He, Eric H. Y. Lau, Peng Wu, Xilong Deng, Jian Wang, Xinxin Hao, Yiu Chung Lau ,Jessica Y. Wong, Yujuan Guan, Xinghua Tan, Xiaoneng Mo, Yanqing Chen, Baolin Liao, Weilie Chen, Fengyu Hu, Qing Zhang, Mingqiu Zhong, Yanrong Wu, Lingzhai Zhao, Fuchun Zhang, Benjamin J. Cowling, Fang Li and Gabriel M. Leung

ABSTRACT

We report temporal patterns of viral shedding in 94 patients with laboratory-confirmed COVID-19 and modeled COVID-19 infectiousness profiles from a separate sample of 77 infector–infectee transmission pairs. We observed the highest viral load in throat swabs at the time of symptom onset, and inferred that infectiousness peaked on or before symptom onset. We estimated that 44% (95% confidence interval, 25–69%) of secondary cases were infected during the index cases’ presymptomatic stage, in settings with substantial household clustering, active case finding and quarantine outside the home. Disease control measures should be adjusted to account for probable substantial presymptomatic transmission.

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10 /04/2020 Report
Structure of the RNA-dependent RNA polymerase from COVID-19 virus

SCIENCE

Authors:
Yan Gao, Liming Yan,Yucen Huang, Fengjiang Liu, Yao Zhao, Lin Cao, Tao Wang, Qianqian Sun,Zhenhua Ming, Lianqi Zhang, Ji Ge, Litao Zheng, Ying Zhan, Haofeng Wang, Yan Zhu,Chen Zhu,Tianyu Hu, Tian Hua, Bing Zhang, Xiuna Yang, Jun Li, Haitao Yang, Zhijie Liu, Wenqing Xu, Luke W.Guddat, Quan Wang, Zhiyong Lou, Zihe Rao 

ABSTRACT 

A novel coronavirus (COVID-19 virus) outbreak has caused a global pandemic resulting in tens of thousands of infections and thousands of deaths worldwide. The RNA-dependent RNA polymerase (RdRp, also named nsp12) is the central component of coronaviral replication/transcription machinery and appears to be a primary target for the antiviral drug, remdesivir. We report the cryo-EM structure of COVID-19 virus full-length nsp12 in complex with cofactors nsp7 and nsp8 at 2.9-Å resolution. In addition to the conserved architecture of the polymerase core of the viral polymerase family, nsp12 possesses a newly identified β-hairpin domain at its N terminus. A comparative analysis model shows how remdesivir binds to this polymerase. The structure provides a basis for the design of new antiviral therapeutics targeting viral RdRp.

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09/04/2020 Articles
Structure of Mpro from COVID-19 virus and discovery of its inhibitors

CSH LABORATORY

Authors:
Zhenming Jin, Xiaoyu Du, Yechun Xu, Yongqiang Deng, Meiqin Liu, Yao Zhao, Bing Zhang, Xiaofeng Li, Leike Zhang, Chao Peng, Yinkai Duan, Jing Yu, Lin Wang, Kailin Yang, Fengjiang Liu, Rendi Jiang, Xinglou Yang, Tian You, Xiaoce Liu, Xiuna Yang, Fang Bai, Hong Liu, Xiang Liu, Luke W. Guddat, Wenqing Xu, Gengfu Xiao, Chengfeng Qin, Zhengli Shi, Hualiang Jiang, Zihe Rao & Haitao Yang 

Abstract
A new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan1-4. Currently there is no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 virus main protease (Mpro). Mpro is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus5,6. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 virus Mpro in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro. Six of these inhibit Mpro with IC50 values ranging from 0.67 to 21.4 μM. Ebselen also exhibited strong antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases where no specific drugs or vaccines are available.

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08/04/2020 Articles
Phylogenetic network analysis of SARS-CoV-2 genomes

PNAS

Authors:
Peter Forstera, Lucy Forsterd, Colin Renfrewb, Michael Forsterc
Summary
ABSTRACT In a phylogenetic network analysis of 160 complete human severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) genomes, we find three central variants distinguished by amino acid changes, which we have named A, B, and C, with A being the ancestral type according to the bat outgroup coronavirus. The A and C types are found in significant proportions outside East Asia, that is, in Europeans and Americans. In contrast, the B type is the most common type in East Asia, and its ancestral genome appears not to have spread outside East Asia without first mutating into derived B types, pointing to founder effects or immunological or environmental resistance against this type outside Asia. The network faithfully traces routes of infections for documented coronavirus disease 2019 (COVID-19) cases, indicating that phylogenetic networks can likewise be successfully used to help trace undocumented COVID-19 infection sources, which can then be quarantined to prevent recurrent spread of the disease worldwide.

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02/04/2020 Communication
Whole genome and phylogenetic analysis of two SARS-CoV-2 strains isolated in Italy...

Whole genome and phylogenetic analysis of two SARS-CoV-2 strains isolated in Italy in January and February 2020: additional clues on multiple introductions and further circulation in Europe

Eurosurveillance

Authors:
Paola Stefanelli , Giovanni Faggioni , Alessandra Lo Presti , Stefano Fiore , Antonella MarchI , Eleonora BenedettI , Concetta FabianI , Anna Anselmo, Andrea Ciammaruconi , Antonella Fortunato , Riccardo De Santis, Silvia Fillo , MariaRosaria Capobianchi , Maria Rita Gismondo , Alessandra Ciervo , Giovanni Rezza , Maria Rita Castrucci , Florigio Lista , on behalf of ISS COVID-19 study group6

 Abstract
Whole genome sequences of SARS-CoV-2 obtained from two patients, a Chinese tourist visiting Rome and an Italian, were compared with sequences from Europe and elsewhere. In a phylogenetic tree, the Italian patient’s sequence clustered with sequences from Germany while the tourist’s sequence clustered with other European sequences. Some additional European sequences in the tree segregated outside the two clusters containing the patients’ sequences. This suggests multiple SARS-CoV-2 introductions in Europe or virus evolution during circulation.

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30 /03/2020 Articles
Estimating the number of infections and the impact of non-pharmaceutical interventions....

Imperial College London

Estimating the number of infections and the impact of non-pharmaceutical interventions on COVID-19 in 11 European countries Authors:
Seth Flaxman, , Swapnil Mishra, Axel Gandy, H Juliette T Unwin, Helen Coupland, Thomas A Mellan, Harrison Zhu, Tresnia Berah, Jeffrey W Eaton, Pablo N P Guzman, Nora Schmit, Lucia Cilloni, Kylie E C Ainslie, Marc Baguelin, Isobel Blake, Adhiratha Boonyasiri, Olivia Boyd, Lorenzo Cattarino, Constanze Ciavarella, Laura Cooper, Zulma Cucunubá, Gina Cuomo-Dannenburg, Amy Dighe, Bimandra Djaafara, Ilaria Dorigatti, Sabine van Elsland, Rich FitzJohn, Han Fu, Katy Gaythorpe, Lily Geidelberg, Nicholas Grassly, Will Green, Timothy Hallett, Arran Hamlet, Wes Hinsley, Ben Jeffrey, David Jorgensen, Edward Knock, Daniel Laydon, Gemma Nedjati-Gilani, Pierre Nouvellet, Kris Parag, Igor Siveroni, Hayley Thompson, Robert Verity, Erik Volz, Caroline Walters, Haowei Wang, Yuanrong Wang, Oliver Watson, Peter Winskill, Xiaoyue Xi, Charles Whittaker, Patrick GT Walker, Azra Ghani, Christl A. Donnelly, Steven Riley, Lucy C Okell, Michaela A C Vollmer, Neil M. Ferguson1 and Samir Bhatt

ABSTRACT

Following the emergence of a novel coronavirus (SARS-CoV-2) and its spread outside of China, Europe is now experiencing large epidemics. In response, many European countries have implemented unprecedented non-pharmaceutical interventions including case isolation, the closure of schools and universities, banning of mass gatherings and/or public events, and most recently, widescale social distancing including local and national lockdowns. In this report, we use a semi-mechanistic Bayesian hierarchical model to attempt to infer the impact of these interventions across 11 European countries. Our methods assume that changes in the reproductive number – a measure of transmission - are an immediate response to these interventions being implemented rather than broader gradual changes in behaviour. Our model estimates these changes by calculating backwards from the deaths observed over time to estimate transmission that occurred several weeks prior, allowing for the time lag between infection and death. One of the key assumptions of the model is that each intervention has the same effect on the reproduction number across countries and over time. This allows us to leverage a greater amount of data across Europe to estimate these effects. It also means that our results are driven strongly by the data from countries with more advanced epidemics, and earlier interventions, such as Italy and Spain. We find that the slowing growth in daily reported deaths in Italy is consistent with a significant impact of interventions implemented several weeks earlier. In Italy, we estimate that the effective reproduction number, Rt, dropped to close to 1 around the time of lockdown (11th March), although with a high level of uncertainty. Overall, we estimate that countries have managed to reduce their reproduction number. Our estimates have wide credible intervals and contain 1 for countries that have implemented all interventions considered in our analysis. This means that the reproduction number may be above or below this value. With current interventions remaining in place to at least the end of March, we estimate that interventions across all 11 countries will have averted 59,000 deaths up to 31 March [95% credible interval 21,000-120,000]. Many more deaths will be averted through ensuring that interventions remain in place until transmission drops to low levels. We estimate that, across all 11 countries between 7 and 43 million individuals have been infected with SARS-CoV-2 up to 28th March, representing between 1.88% and 11.43% of the population. The proportion of the population infected to date – the attack rate - is estimated to be highest in Spain followed by Italy and lowest in Germany and Norway, reflecting the relative stages of the epidemics. Given the lag of 2-3 weeks between when transmission changes occur and when their impact can be observed in trends in mortality, for most of the countries considered here it remains too early to be certain that recent interventions have been effective. If interventions in countries at earlier stages of their epidemic, such as Germany or the UK, are more or less effective than they were in the countries with advanced epidemics, on which our estimates are largely based, or if interventions have improved or worsened over time, then our estimates of the reproduction number and deaths averted would change accordingly. It is therefore critical that the current interventions remain in place and trends in cases and deaths are closely monitored in the coming days and weeks to provide reassurance that transmission of SARS-Cov-2 is slowing

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30 /03/2020 Articles
Estimates of the severity of coronavirus disease 2019: a model-based analysis

The Lancet

Authors:
Robert Verity, Lucy C Okell, Ilaria Dorigatti*, Peter Winskill, Charles Whittaker, Natsuko Imai, Gina Cuomo-Dannenburg, Hayley Thompson, Patrick G T Walker, Han Fu, Amy Dighe, Jamie T Griffin, Marc Baguelin, Sangeeta Bhatia, Adhiratha Boonyasiri, Anne Cori, Zulma Cucunubá, Rich FitzJohn, Katy Gaythorpe, Will Green, Arran Hamlet, Wes Hinsley, Daniel Laydon, Gemma Nedjati-Gilani, Steven Riley, Sabine van Elsland, Erik Volz, Haowei Wang, Yuanrong Wang, Xiaoyue Xi, Christl A Donnelly, Azra C Ghani, Neil M Ferguson

ABSTRACT

Background

In the face of rapidly changing data, a range of case fatality ratio estimates for coronavirus disease 2019 (COVID-19) have been produced that differ substantially in magnitude. We aimed to provide robust estimates, accounting for censoring and ascertainment biases.

Findings

Using data on 24 deaths that occurred in mainland China and 165 recoveries outside of China, we estimated the mean duration from onset of symptoms to death to be 17·8 days (95% credible interval [CrI] 16·9–19·2) and to hospital discharge to be 24·7 days (22·9–28·1). In all laboratory confirmed and clinically diagnosed cases from mainland China (n=70117), we estimated a crude case fatality ratio (adjusted for censoring) of 3·67% (95% CrI 3·56–3·80). However, after further adjusting for demography and under-ascertainment, we obtained a best estimate of the case fatality ratio in China of 1·38% (1·23–1·53), with substantially higher ratios in older age groups (0·32% [0·27–0·38] in those aged <60 years vs 6·4% [5·7–7·2] in those aged ≥60 years), up to 13·4% (11·2–15·9) in those aged 80 years or older. Estimates of case fatality ratio from international cases stratified by age were consistent with those from China (parametric estimate 1·4% [0·4–3·5] in those aged <60 years [n=360] and 4·5% [1·8–11·1] in those aged ≥60 years [n=151]). Our estimated overall infection fatality ratio for China was 0·66% (0·39–1·33), with an increasing profile with age. Similarly, estimates of the proportion of infected individuals likely to be hospitalised increased with age up to a maximum of 18·4% (11·0–7·6) in those aged 80 years or older.We collected individual-case data for patients who died from COVID-19 in Hubei, mainland China (reported by national and provincial health commissions to Feb 8, 2020), and for cases outside of mainland China (from government or ministry of health websites and media reports for 37 countries, as well as Hong Kong and Macau, until Feb 25, 2020). These individual-case data were used to estimate the time between onset of symptoms and outcome (death or discharge from hospital). We next obtained age-stratified estimates of the case fatality ratio by relating the aggregate distribution of cases to the observed cumulative deaths in China, assuming a constant attack rate by age and adjusting for demography and age-based and location-based under-ascertainment. We also estimated the case fatality ratio from individual line-list data on 1334 cases identified outside of mainland China. Using data on the prevalence of PCR-confirmed cases in international residents repatriated from China, we obtained age-stratified estimates of the infection fatality ratio. Furthermore, data on age-stratified severity in a subset of 3665 cases from China were used to estimate the proportion of infected individuals who are likely to require hospitalisation.

Interpretation

These early estimates give an indication of the fatality ratio across the spectrum of COVID-19 disease and show a strong age gradient in risk of death.

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30 /03/2020 Comment
Likelihood of survival of coronavirus disease 2019

The Lancet

Authors:
Shigui Ruan

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28/03/2020 Editorial
Covid-19 — Navigating the Uncharted

The New Egland Journal of Medicine

Authors:
Anthony S. Fauci, Clifford Lane, Robert R. Redfield

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25/03/2020 Correspondence
Coordination of RECOVERY, RECOVERY-RS and PRINCIPLE trials

REMAP-CAP

Authors:
REMAP-CAP

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25/03/2020 Overview
2019 Novel coronavirus (COVID-19) overview

SPRINGER LINK

Authors:
Mehrdad Mohammadi, Maryam Meskini, Anderia Lucia do Nascimento Pinto

Abstract
Novel coronaviruses (CoVs) are zoonotic pathogens, but the first human-to-human transmission has been reported. CoVs have the best known genome of all RNA viruses, and mutations in the genome have now been found. A pneumonia of unknown cause detected in Wuhan, China, was first reported to the WHO Country Office in China on 31 December 2019. This study aims to report early findings related to COVID-19 and provide methods to prevent and treat it.

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23/03/2020 Viewpoint
Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy

JAMA

Authors:
Graziano Onder, Giovanni Rezza, Silvio Brusaferro

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19/03/2020 Articles
Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for...

Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: implication for development of RBD protein as a viral attachment inhibitor and vaccine

Springer Nature

Authors:
Wanbo Tai, Lei He, Xiujuan Zhang, Jing Pu, Denis Voronin, Shibo Jiang, Yusen Zhou, Lanying Du

The outbreak of Coronavirus Disease 2019 (COVID-19) has posed a serious threat to global public health, calling for the development of safe and effective prophylactics and therapeutics against infection of its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as 2019 novel coronavirus (2019-nCoV). The CoV spike (S) protein plays the most important roles in viral attachment, fusion and entry, and serves as a target for development of antibodies, entry inhibitors and vaccines. Here, we identified the receptor-binding domain (RBD) in SARS-CoV-2 S protein and found that the RBD protein bound strongly to human and bat angiotensin-converting enzyme 2 (ACE2) receptors. SARS-CoV-2 RBD exhibited significantly higher binding affinity to ACE2 receptor than SARS-CoV RBD and could block the binding and, hence, attachment of SARS-CoV-2 RBD and SARS-CoV RBD to ACE2-expressing cells, thus inhibiting their infection to host cells. SARS-CoV RBD-specific antibodies could cross- react with SARS-CoV-2 RBD protein, and SARS-CoV RBD-induced antisera could cross-neutralize SARS-CoV-2, suggesting the potential to develop SARS-CoV RBD-based vaccines for prevention of SARS-CoV-2 and SARS-CoV infection.

2019 novel coronavirus, SARS-CoV-2, spike protein, receptor-binding domain, viral inhibitor, cross-neutralization

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19/02/2020 Letter
SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients

THE NEW ENGLAND JOURNAL OF MEDICINE

Authors:
Lirong Zou, et all

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17/03/2020 Correspondence
The proximal origin of SARS-CoV-2

The proximal origin of SARS-CoV-2

Springer Nature

Authors:
Kristian G. Andersen, Andrew Rambaut, W. Ian Lipkin, Edward C. Holmes, Robert F. Garry

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09/03/2020 Articles
Genomic diversity of SARS-CoV-2 in Coronavirus Disease 2019 patients

Oxford Academy

Authors:
Zijie Shen, Yan Xiao, Lu Kang, Wentai Ma, Leisheng Shi, Li Zhang, Zhuo Zhou, Jing Yang, Jiaxin Zhong, Donghong Yang, Li Guo, Guoliang Zhang, Hongru Li, Yu Xu, Mingwei Chen, Zhancheng Gao, Jianwei Wang , Lili Ren, Mingkun Li

Background
A novel coronavirus (SARS-CoV-2) has infected more than 75,000 individuals and spread to over 20 countries. It is still unclear how fast the virus evolved and how the virus interacts with other microorganisms in the lung.

Methods
We have conducted metatranscriptome sequencing for the bronchoalveolar lavage fluid of eight SARS-CoV-2 patients, 25 community-acquired pneumonia (CAP) patients, and 20 healthy controls.

Results
The median number of intra-host variants was 1-4 in SARS-CoV-2 infected patients, which ranged between 0 and 51 in different samples. The distribution of variants on genes was similar to those observed in the population data (110 sequences). However, very few intra-host variants were observed in the population as polymorphism, implying either a bottleneck or purifying selection involved in the transmission of the virus, or a consequence of the limited diversity represented in the current polymorphism data. Although current evidence did not support the transmission of intra-host variants in a person-to-person spread, the risk should not be overlooked. The microbiota in SARS-CoV-2 infected patients was similar to those in CAP, either dominated by the pathogens or with elevated levels of oral and upper respiratory commensal bacteria.

Conclusion
SARS-CoV-2 evolves in vivo after infection, which may affect its virulence, infectivity, and transmissibility. Although how the intra-host variant spreads in the population is still elusive, it is necessary to strengthen the surveillance of the viral evolution in the population and associated clinical changes.

SARS-CoV-2, COVID-19, intra-host variant, microbiota, transmission

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05/03/2020 Correspondence
A distinct name is needed for the new coronavirus

The Lancet

Authors:
Shibo Jiang, Zhengli Shi, Yuelong Shu, Jingdong Song, George F Gao, Wenjie Tan, Deyin Guo

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03/2020 Correspondence
Coordination of recovery and remap cap

REMAP-CAP

Authors:
REMAP-CAP

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25/02/2020 Short Communication
Early phylogenetic estimate of the effective reproduction number of SARS‐CoV‐2

Wiley Online Library

Authors:
Alessia Lai, Annalisa Bergna, Carla Acciarri, Massimo Galli, Gianguglielmo Zehender

To reconstruct the evolutionary dynamics of the 2019 novel‐coronavirus recently causing an outbreak in Wuhan, China, 52 SARS‐CoV‐2 genomes available on 4 February 2020 at Global Initiative on Sharing All Influenza Data were analyzed. The two models used to estimate the reproduction number (coalescent‐based exponential growth and a birth‐death skyline method) indicated an estimated mean evolutionary rate of 7.8 × 10−4 subs/site/year (range, 1.1 × 10−4‐15 × 10−4) and a mean tMRCA of the tree root of 73 days. The estimated R value was 2.6 (range, 2.1‐5.1), and increased from 0.8 to 2.4 in December 2019. The estimated mean doubling time of the epidemic was between 3.6 and 4.1 days. This study proves the usefulness of phylogeny in supporting the surveillance of emerging new infections even as the epidemic is growing.

evolutionary dynamics, reproductive number, SARS‐CoV‐2

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24/02/2020 Articles
Functional assessment of cell entry and receptor usage for SARS-CoV-2....

Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses

Nature Research

Authors:
Michael Letko, Andrea Marzi, Vincent Munster

Abstract

Over the past 20 years, several coronaviruses have crossed the species barrier into humans, causing outbreaks of severe, and often fatal, respiratory illness. Since SARS-CoV was first identified in animal markets, global viromics projects have discovered thousands of coronavirus sequences in diverse animals and geographic regions. Unfortunately, there are few tools available to functionally test these viruses for their ability to infect humans, which has severely hampered efforts to predict the next zoo- notic viral outbreak. Here, we developed an approach to rapidly screen lineage B betacoronaviruses, such as SARS-CoV and the recent SARS-CoV-2, for receptor usage and their ability to infect cell types from different species. We show that host protease processing during viral entry is a significant barrier for several lineage B viruses and that bypassing this barrier allows several lineage B viruses to enter human cells through an unknown receptor. We also demonstrate how different lineage B viruses can recombine to gain entry into human cells, and confirm that human ACE2 is the receptor for the recently emerging SARS-CoV-2.

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19/02/2020 Editorial
Coronaviruses in animals and humans

The bmj

Authors:
Lisa F P Ng, Julian A Hiscox

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19/02/2020 Viewpoint
Defining the Epidemiology of Covid-19 — Studies Needed

The NEW ENGLAND JOURNAL of MEDICINE

Authors:
Marc Lipsitch, D.Phil., David L. Swerdlow, and Lyn Finelli

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13/02/2020 Articles
No credible evidence supporting claims of the

Taylor and Francis Group

Authors:
Shan-Lu Liu, Linda J. Saif, Susan R. Weiss & Lishan Su

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03/02/2020 Articles
A pneumonia outbreak associated with a new coronavirus of probable bat origin

Nature

Authors:
Peng Zhou, Xing-Lou Yang, Xian-Guang Wang, Ben Hu, Lei Zhang, Wei Zhang, Hao-Rui Si, Yan Zhu, Bei Li, Chao-Lin Huang, Hui-Dong Chen, Jing Chen, Yun Luo, Hua Guo, Ren-Di Jiang, Mei-Qin Liu, Ying Chen, Xu-Rui Shen, Xi Wang, Xiao-Shuang Zheng, Kai Zhao, Quan-Jiao Chen, Fei Deng, Lin-Lin Liu, Bing Yan, Fa-Xian Zhan, Yan-Yi Wang, Geng-Fu Xiao, Zheng-Li Shi

Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1–4
Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5–7
Here we report the identifcation and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confrmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from fve patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fuid of a critically ill patient could be neutralized by sera from several patients. Notably, we confrmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.

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30 /01/2020 Articles
Genomic characterisation and epidemiology of 2019 novel coronavirus...

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding

The Lancet

Authors:
Prof Roujian Lu, Xiang Zhao, Juan Li, Peihua Niu, Bo Yang, Honglong Wu, Wenling Wang, Hao Song, Baoying Huang, Na Zhu, Yuhai Bi, Xuejun Ma, Prof Faxian Zhan, Liang Wang, Tao Hu, Hong Zhou, Prof Zhenhong Hu, Prof Weimin Zhou, Li Zhao, Jing Chen, Yao Meng, Ji Wang, Yang Lin, Jianying Yuan, Zhihao Xie, Jinmin Ma, William J Liu, Dayan Wang,Prof Wenbo Xu, Edward C Holmes, George F Gao, Guizhen Wu

 Summary
Background
In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed. Methods We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus. 

Findings T
he ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues. 

Interpretation
2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation. Funding National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.

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10/12/2018 Reviews
Origin and evolution of pathogenic coronaviruses

Nature Reviews

Authors:
Jie Cui, Fang Li, Zheng-Li Shi

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are two highly transmissible and pathogenic viruses that emerged in humans at the beginning of the 21st century. Both viruses likely originated in bats, and genetically diverse coronaviruses that are related to SARS-CoV and MERS-CoV were discovered in bats worldwide. In this Review, we summarize the current knowledge on the origin and evolution of these two pathogenic coronaviruses and discuss their receptor usage; we also highlight the diversity and potential of spillover of bat-borne coronaviruses, as evidenced by the recent spillover of swine acute diarrhoea syndrome coronavirus (SADS-CoV) to pigs.

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