Nicholas J. Matheson, Paul J. Lehner
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Thiruselvam Viswanathan, Shailee Arya, Siu-Hong Chan, Shan Qi, Nan Dai, Anurag Misra, Jun-Gyu Park, Fatai Oladunni, Dmytro Kovalskyy, Robert A. Hromas, Luis Martinez-Sobrido, Yogesh K. Gupta
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19 illness, has caused millions of infections worldwide. In SARS coronaviruses, the non-structural protein 16 (nsp16), in conjunction with nsp10, methylates the 5′-end of virally encoded mRNAs to mimic cellular mRNAs, thus protecting the virus from host innate immune restriction. We report here the high-resolution structure of a ternary complex of SARS-CoV-2 nsp16 and nsp10 in the presence of cognate RNA substrate analogue and methyl donor, S-adenosyl methionine (SAM). The nsp16/nsp10 heterodimer is captured in the act of 2′-O methylation of the ribose sugar of the first nucleotide of SARS-CoV-2 mRNA. We observe large conformational changes associated with substrate binding as the enzyme transitions from a binary to a ternary state. This induced fit model provides mechanistic insights into the 2′-O methylation of the viral mRNA cap. We also discover a distant (25 Å) ligand-binding site unique to SARS-CoV-2, which can alternatively be targeted, in addition to RNA cap and SAM pockets, for antiviral development.
Caspar I. van der Made, Annet Simons, Janneke Schuurs-Hoeijmakers, Guus van den Heuvel, Tuomo Mantere, Simone Kersten, Rosanne C. van Deuren, Marloes Steehouwer, Simon V. van Reijmersdal, Martin Jaeger Tom Hofste, Galuh Astuti, Jordi Corominas Galbany, Vyne van der Schoot, Hans van der Hoeven, Wanda Hagmolen, Eva Klijn, Catrien van den Meer, Jeroen Fiddelaers, Quirijn de Mast, Chantal P. Bleeker-Rovers, Leo A. B. Joosten, Helger G. Yntema, Christian Gilissen, Marcel Nelen, Jos W. M. van der Meer, Han G. Brunner, Mihai G. Netea, Frank L. van de Veerdonk, Alexander Hoischen
Importance Severe coronavirus disease 2019 (COVID-19) can occur in younger, predominantly male, patients without preexisting medical conditions. Some individuals may have primary immunodeficiencies that predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Objective To explore the presence of genetic variants associated with primary immunodeficiencies among young patients with COVID-19.
Design, Setting, and Participants Case series of pairs of brothers without medical history meeting the selection criteria of young (age <35 years) brother pairs admitted to the intensive care unit (ICU) due to severe COVID-19. Four men from 2 unrelated families were admitted to the ICUs of 4 hospitals in the Netherlands between March 23 and April 12, 2020. The final date of follow-up was May 16, 2020. Available family members were included for genetic variant segregation analysis and as controls for functional experiments.
Exposure Severe COVID-19.
Main Outcome and Measures Results of rapid clinical whole-exome sequencing, performed to identify a potential monogenic cause. Subsequently, basic genetic and immunological tests were performed in primary immune cells isolated from the patients and family members to characterize any immune defects.
Results The 4 male patients had a mean age of 26 years (range, 21-32), with no history of major chronic disease. They were previously well before developing respiratory insufficiency due to severe COVID-19, requiring mechanical ventilation in the ICU. The mean duration of ventilatory support was 10 days (range, 9-11); the mean duration of ICU stay was 13 days (range, 10-16). One patient died. Rapid clinical whole-exome sequencing of the patients and segregation in available family members identified loss-of-function variants of the X-chromosomal TLR7. In members of family 1, a maternally inherited 4-nucleotide deletion was identified (c.2129_2132del; p.[Gln710Argfs*18]); the affected members of family 2 carried a missense variant (c.2383G>T; p.[Val795Phe]). In primary peripheral blood mononuclear cells from the patients, downstream type I interferon (IFN) signaling was transcriptionally downregulated, as measured by significantly decreased mRNA expression of IRF7, IFNB1, and ISG15 on stimulation with the TLR7 agonist imiquimod as compared with family members and controls. The production of IFN-γ, a type II IFN, was decreased in patients in response to stimulation with imiquimod.
Conclusions and Relevance In this case series of 4 young male patients with severe COVID-19, rare putative loss-of-function variants of X-chromosomal TLR7 were identified that were associated with impaired type I and II IFN responses. These preliminary findings provide insights into the pathogenesis of COVID-19.
Kevin P Fennelly
Pierpaolo Correale, Luciano Mutti, Francesca Pentimalli, Giovanni Baglio, Rita Emilena Saladino,Pierpaolo Sileri, Antonio Giordano
The spread of COVID-19 is showing huge, unexplained, differences between northern and southern Italy. We hypothesized that the regional prevalence of specific class I human leukocyte antigen (HLA) alleles, which shape the anti-viral immune response, might partly underlie these differences. Through an ecological approach, we analyzed whether a set of HLA alleles (A, B, C), known to be involved in the immune response against infections, correlates with COVID-19 incidence. COVID-19 data were provided by the National Civil Protection Department, whereas HLA allele prevalence was retrieved through the Italian Bone-Marrow Donors Registry. Among all the alleles, HLA-A*25, B*08, B*44, B*15:01, B*51, C*01, and C*03 showed a positive log-linear correlation with COVID-19 incidence rate fixed on 9 April 2020 in proximity of the national outbreak peak (Pearson’s coefficients between 0.50 and 0.70, p-value < 0.0001), whereas HLA-B*14, B*18, and B*49 showed an inverse log-linear correlation (Pearson’s coefficients between −0.47 and −0.59, p-value < 0.0001). When alleles were examined simultaneously using a multiple regression model to control for confounding factors, HLA-B*44 and C*01 were still positively and independently associated with COVID-19: a growth rate of 16% (95%CI: 0.1–35%) per 1% point increase in B*44 prevalence; and of 19% (95%CI: 1–41%) per 1% point increase in C*01 prevalence. Our epidemiologic analysis, despite the limits of the ecological approach, is strongly suggestive of a permissive role of HLA-C*01 and B*44 towards SARS-CoV-2 infection, which warrants further investigation in case-control studies. This study opens a new potential avenue for the identification of sub-populations at risk, which could provide Health Services with a tool to define more targeted clinical management strategies and priorities in vaccination campaigns.
Ching-Lin Hsieh, Jory A. Goldsmith, Jeffrey M. Schaub, Andrea M. DiVenere, Hung-Che Kuo, Kamyab Javanmardi, Kevin C. Le, Daniel Wrapp, Alison G. Lee, Yutong Liu, Chia-Wei Chou, Patrick O. Byrne, Christy K. Hjorth, Nicole V. Johnson, John Ludes-Meyers, Annalee W. Nguyen, Juyeon Park, Nianshuang Wang, Dzifa Amengor, Jason J. Lavinder, Gregory C. Ippolito, Jennifer A. Maynard2, Ilya J. Finkelstein, Jason S. McLellan
The COVID-19 pandemic has led to accelerated efforts to develop therapeutics and vaccines. A key target of these efforts is the spike (S) protein, which is metastable and difficult to produce recombinantly. Here, we characterized 100 structure-guided spike designs and identified 26 individual substitutions that increased protein yields and stability. Testing combinations of beneficial substitutions resulted in the identification of HexaPro, a variant with six beneficial proline substitutions exhibiting ~10-fold higher expression than its parental construct and the ability to withstand heat stress, storage at room temperature, and three freeze-thaw cycles. A 3.2 Å-resolution cryo-EM structure of HexaPro confirmed that it retains the prefusion spike conformation. High-yield production of a stabilized prefusion spike protein will accelerate the development of vaccines and serological diagnostics for SARS-CoV-2.
Lihong Liu, Pengfei Wang, Manoj S. Nair, Jian Yu, Micah Rapp, Qian Wang, Yang Luo, Jasper F-W. Chan, Vincent Sahi, Amir Figueroa, Xinzheng V. Guo, Gabriele Cerutti, Jude Bimela, Jason Gorman, Tongqing Zhou, Zhiwei Chen, Kwok-Yung Yuen, Peter D. Kwong, Joseph G. Sodroski, Michael T. Yin, Zizhang Sheng, Yaoxing Huang, Lawrence Shapiro, David D. Ho
The SARS-CoV-2 pandemic rages on with devasting consequences on human lives and the global economy1,2. The discovery and development of virus-neutralizing monoclonal antibodies could be one approach to treat or prevent infection by this novel coronavirus. Here we report the isolation of 61 SARS-CoV-2-neutralizing monoclonal antibodies from 5 infected patients hospitalized with severe disease. Among these are 19 antibodies that potently neutralized the authentic SARS-CoV-2 in vitro, 9 of which exhibited exquisite potency, with 50% virus-inhibitory concentrations of 0.7 to 9 ng/mL. Epitope mapping showed this collection of 19 antibodies to be about equally divided between those directed to the receptor-binding domain (RBD) and those to the N-terminal domain (NTD), indicating that both of these regions at the top of the viral spike are immunogenic. In addition, two other powerful neutralizing antibodies recognized quaternary epitopes that overlap with the domains at the top of the spike. Cryo-electron microscopy reconstructions of one antibody targeting RBD, a second targeting NTD, and a third bridging two separate RBDs revealed recognition of the closed, “all RBD-down” conformation of the spike. Several of these monoclonal antibodies are promising candidates for clinical development as potential therapeutic and/or prophylactic agents against SARS-CoV-2.
Yvonne C. F. Su, Danielle E. Anderson, Barnaby E. Young, Martin Linster, Feng Zhu, Jayanthi Jayakumar, Yan Zhuang, Shirin Kalimuddin, Jenny G. H. Low, Chee Wah Tan, Wan Ni Chia, Tze Minn Mak, Sophie Octavia, Jean-Marc Chavatte, Raphael T. C. Lee, Surinder Pada, Seow Yen Tan, Louisa Sun, Gabriel Z. Yan, Sebastian Maurer-Stroh, Ian H. Mendenhall, Yee-Sin Leo, David Chien Lye, Lin-Fa Wang, Gavin J. D. Smith
To date, limited genetic changes in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome have been described. Here, we report a 382-nucleotide (nt) deletion in SARS-CoV-2 that truncates open reading frame 7b (ORF7b) and ORF8, removing the ORF8 transcription regulatory sequence (TRS) and eliminating ORF8 transcription. The earliest 382-nt deletion variant was detected in Singapore on 29 January 2020, with the deletion viruses circulating in the country and accounting for 23.6% (45/191) of SARS-CoV-2 samples screened in this study. SARS-CoV-2 with the same deletion has since been detected in Taiwan, and other ORF7b/8 deletions of various lengths, ranging from 62 nt to 345 nt, have been observed in other geographic locations, including Australia, Bangladesh, and Spain. Mutations or deletions in ORF8 of SARS-CoV have been associated with reduced replicative fitness and virus attenuation. In contrast, the SARS-CoV-2 382-nt deletion viruses showed significantly higher replicative fitness in vitro than the wild type, while no difference was observed in patient viral load, indicating that the deletion variant viruses retained their replicative fitness. A robust antibody response to ORF8 has been observed in SARS-CoV-2 infection, suggesting that the emergence of ORF8 deletions may be due to immune-driven selection and that further deletion variants may emerge during the sustained transmission of SARS-CoV-2 in humans.
Elisa Benetti, Rossella Tita, Ottavia Spiga, Andrea Ciolfi, Giovanni Birolo, Alessandro Bruselles, Gabriella Doddato, Annarita Giliberti, Caterina Marconi, Francesco Musacchia, Tommaso Pippucci, Annalaura Torella, Alfonso Trezza, Floriana Valentino, Margherita Baldassarri, Alfredo Brusco, Rosanna Asselta, Mirella Bruttini, Simone Furini, Marco Seri, Vincenzo Nigro, Giuseppe Matullo, Marco Tartaglia, Francesca Mari, GEN-COVID Multicenter Study, Alessandra Renieri & Anna Maria Pinto
In December 2019, an initial cluster of interstitial bilateral pneumonia emerged in Wuhan, China. A human-to-human transmission was assumed and a previously unrecognized entity, termed coronavirus disease-19 (COVID-19) due to a novel coronavirus (SARS-CoV-2) was described. The infection has rapidly spread out all over the world and Italy has been the first European country experiencing the endemic wave with unexpected clinical severity in comparison with Asian countries. It has been shown that SARS-CoV-2 utilizes angiotensin converting enzyme 2 (ACE2) as host receptor and host proteases for cell surface binding and internalization. Thus, a predisposing genetic background can give reason for interindividual disease susceptibility and/or severity. Taking advantage of the Network of Italian Genomes (NIG), here we mined whole-exome sequencing data of 6930 Italian control individuals from five different centers looking for ACE2 variants. A number of variants with a potential impact on protein stability were identified. Among these, three more common missense changes, p.(Asn720Asp), p.(Lys26Arg), and p.(Gly211Arg) were predicted to interfere with protein structure and stabilization. Rare variants likely interfering with the internalization process, namely p.(Leu351Val) and p.(Pro389His), predicted to interfere with SARS-CoV-2 spike protein binding, were also observed. Comparison of ACE2 WES data between a cohort of 131 patients and 258 controls allowed identifying a statistically significant (P value < 0.029) higher allelic variability in controls compared with patients. These findings suggest that a predisposing genetic background may contribute to the observed interindividual clinical variability associated with COVID-19, allowing an evidence-based risk assessment leading to personalized preventive measures and therapeutic options.
W. Joost Wiersinga, Andrew Rhodes, Allen C. Cheng, Sharon J. Peacock, Hallie C. Prescott
Importance The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease. This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19.
Observations SARS-CoV-2 is spread primarily via respiratory droplets during close face-to-face contact. Infection can be spread by asymptomatic, presymptomatic, and symptomatic carriers. The average time from exposure to symptom onset is 5 days, and 97.5% of people who develop symptoms do so within 11.5 days. The most common symptoms are fever, dry cough, and shortness of breath. Radiographic and laboratory abnormalities, such as lymphopenia and elevated lactate dehydrogenase, are common, but nonspecific. Diagnosis is made by detection of SARS-CoV-2 via reverse transcription polymerase chain reaction testing, although false-negative test results may occur in up to 20% to 67% of patients; however, this is dependent on the quality and timing of testing. Manifestations of COVID-19 include asymptomatic carriers and fulminant disease characterized by sepsis and acute respiratory failure. Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. More than 75% of patients hospitalized with COVID-19 require supplemental oxygen. Treatment for individuals with COVID-19 includes best practices for supportive management of acute hypoxic respiratory failure. Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care (21.6% vs 24.6%; age-adjusted rate ratio, 0.83 [95% CI, 0.74-0.92]) and that remdesivir improves time to recovery (hospital discharge or no supplemental oxygen requirement) from 15 to 11 days. In a randomized trial of 103 patients with COVID-19, convalescent plasma did not shorten time to recovery. Ongoing trials are testing antiviral therapies, immune modulators, and anticoagulants. The case-fatality rate for COVID-19 varies markedly by age, ranging from 0.3 deaths per 1000 cases among patients aged 5 to 17 years to 304.9 deaths per 1000 cases among patients aged 85 years or older in the US. Among patients hospitalized in the intensive care unit, the case fatality is up to 40%. At least 120 SARS-CoV-2 vaccines are under development. Until an effective vaccine is available, the primary methods to reduce spread are face masks, social distancing, and contact tracing. Monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies.
Conclusions and Relevance As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions.
Antoni G. Wrobel, Donald J. Benton, Pengqi Xu, Chloë Roustan, Stephen R. Martin, Peter B. Rosenthal, John J. Skehel, Steven J. Gamblin
SARS-CoV-2 is thought to have emerged from bats, possibly via a secondary host. Here, we investigate the relationship of spike (S) glycoprotein from SARS-CoV-2 with the S protein of a closely related bat virus, RaTG13. We determined cryo-EM structures for RaTG13 S and for both furin-cleaved and uncleaved SARS-CoV-2 S; we compared these with recently reported structures for uncleaved SARS-CoV-2 S. We also biochemically characterized their relative stabilities and affinities for the SARS-CoV-2 receptor ACE2. Although the overall structures of human and bat virus S proteins are similar, there are key differences in their properties, including a more stable precleavage form of human S and about 1,000-fold tighter binding of SARS-CoV-2 to human receptor. These observations suggest that cleavage at the furin-cleavage site decreases the overall stability of SARS-CoV-2 S and facilitates the adoption of the open conformation that is required for S to bind to the ACE2 receptor.
Kore Schlottau, Melanie Rissmann, Annika Graaf, Jacob Schön, Julia Sehl, Claudia Wylezich, Dirk Höper, Thomas C Mettenleiter, Anne Balkema-Buschmann, Timm Harder, Christian Grund, Donata Hoffmann, Angele Breithaupt, Martin Beer
Jing Sun, Zhen Zhuang, Jian Zheng, Paul B. McCray, Jr., Stanley Perlman, Jincun Zhao
Nathan D. Grubaugh, William P. Hanage, Angela L. Rasmussen
Korber et al. (2020) found that a SARS-CoV-2 variant in the spike protein, D614G, rapidly became dominant around the world. While clinical and in vitro data suggest that D614G changes the virus phenotype, the impact of the mutation on transmission, disease, and vaccine and therapeutic development are largely unknown.
WILEY ONLINE LIBRARY
John P. Abraham, Brian D. Plourde, Lijing Cheng
ANESTHESIA & ANALGESIA
Ludwig, Stephan, Zarbock, Alexander
In late December 2019, several cases of pneumonia of unknown origin were reported from China, which in early January 2020 were announced to be caused by a novel coronavirus. The virus was later denominated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and defined as the causal agent of coronavirus disease 2019 (COVID-19). Despite massive attempts to contain the disease in China, the virus has spread globally, and COVID-19 was declared a pandemic by the World Health Organization (WHO) in March 2020. Here we provide a short background on coronaviruses, and describe in more detail the novel SARS-CoV-2 and attempts to identify effective therapies against COVID-19.
Nicola Clementi, Roberto Ferrarese, Marco Tonelli, Virginia Amato, Sara Racca, Massimo Locatelli, Giuseppe Lippi, Guido Silvestri, Massimo Clementi, Nicasio Mancini
A milder clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been anecdotally reported over the latest phase of COVID-19 pandemic in Italy. Several factors may contribute to this observation, including the effect of lockdown, social distancing, lower humidity, lower air pollution, and potential changes in the intrinsic pathogenicity of the virus. In this regard, the clinical severity of COVID-19 could be attenuated by mutations in SARS-CoV-2 genome that decrease its virulence, as well as by lower virus inocula.
In this pilot study, we compared the reverse transcription polymerase chain reaction (RT-PCR) amplification profile of 100 nasopharyngeal swabs consecutively collected in April, during the peak of SARS-CoV-2 epidemic, to that of 100 swabs collected using the same procedure in May.
The mean Ct value of positive samples collected in May was significantly higher than that of samples collected in the previous period (ORF 1a/b gene: 31.85 ± 0.32 vs. 28.37 ± 0.5, p<0.001; E gene: 33.76 ± 0.38 vs. 29.79 ± 0.63, p<0.001), suggesting a lower viral load at the time of sampling. No significant differences were observed between male and females in the two periods, whilst higher viral loads were found in (i) patients over 60-years old, and (ii) patients that experienced severe COVID-19 during the early stages of the pandemic.
This pilot study prompts further investigation on the correlation between SARS-CoV-2 load and different clinical manifestation of COVID-19 during different phases of the pandemic. Laboratories should consider reporting quantitative viral load data in the molecular diagnosis of SARS-CoV-2 infection.
EUROPEAN MEDICAL OF RESEARCH
Christiane Matuschek, Friedrich Moll, Heiner Fangerau, Johannes C. Fischer, Kurt Zänker, Martijn van Griensven, Marion Schneider, Detlef Kindgen-Milles, Wolfram Trudo Knoefel, Artur Lichtenberg, Bálint Tamaskovics, Freddy Joel Djiepmo-Njanang, Wilfried Budach, Stefanie Corradini, Dieter Häussinger, Torsten Feldt, Björn Jensen, Rainer Pelka, Klaus Orth, Matthias Peiper, Olaf Grebe, Kitti Maas, Edwin Bölke, Jan Haussmann
In the human population, social contacts are a key for transmission of bacteria and viruses. The use of face masks
seems to be critical to prevent the transmission of SARS-CoV-2 for the period, in which therapeutic interventions are
lacking. In this review, we describe the history of masks from the middle age to modern times.
Gary R. Whittaker, Susan Daniel
Lakshmanane Premkumar, Bruno Segovia-Chumbez , Ramesh Jadi, David R. Martinez, Rajendra Raut, Alena Markmann, Caleb Cornaby, Luther Bartelt, Susan Weiss, Yara Park, Caitlin E. Edwards, Eric Weimer, Erin M. Scherer, Nadine Rouphael, Srilatha Edupuganti, Daniela Weiskopf, Longping V. Ts, Yixuan J. Hou, David Margolis, Alessandro Sette, Matthew H. Collins, John Schmitz, Ralph S. Baric, Aravinda M. de Silva
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that first emerged in late 2019 is responsible for a pandemic of severe respiratory illness. People infected with this highly contagious virus can present with clinically inapparent, mild, or severe disease. Currently, the virus infection in individuals and at the population level is being monitored by PCR testing of symptomatic patients for the presence of viral RNA. There is an urgent need for SARS-CoV-2 serologic tests to identify all infected individuals, irrespective of clinical symptoms, to conduct surveillance and implement strategies to contain spread. As the receptor binding domain (RBD) of the spike protein is poorly conserved between SARS-CoVs and other pathogenic human coronaviruses, the RBD represents a promising antigen for detecting CoV-specific antibodies in people. Here we use a large panel of human sera (63 SARS-CoV-2 patients and 71 control subjects) and hyperimmune sera from animals exposed to zoonotic CoVs to evaluate RBD's performance as an antigen for reliable detection of SARS-CoV-2-specific antibodies. By day 9 after the onset of symptoms, the recombinant SARS-CoV-2 RBD antigen was highly sensitive (98%) and specific (100%) for antibodies induced by SARS-CoVs. We observed a strong correlation between levels of RBD binding antibodies and SARS-CoV-2 neutralizing antibodies in patients. Our results, which reveal the early kinetics of SARS-CoV-2 antibody responses, support using the RBD antigen in serological diagnostic assays and RBD-specific antibody levels as a correlate of SARS-CoV-2 neutralizing antibodies in people.
Jianjun Chen , Chaolin Huang , Yanan Zhang , Sai Zhang , Meilin Jin
Salvatore DiGiorgio, Filippo Martignano, Maria Gabriella Torcia, Giorgio Mattiuz, Silvestro G. Conticello
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 combat the disease. RNA editing by host deaminases is an innate restriction process to counter virus infection, but it is not yet known whether this process operates against coronaviruses. Here, we analyze RNA sequences from bronchoalveolar lavage fluids obtained from coronavirus-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 deaminases. Mutational analysis of genomes from different strains of Coronaviridae from human hosts reveals mutational patterns consistent with those observed in the transcriptomic data. However, the reduced ADAR signature in these data raises the possibility that ADARs might be more effective than APOBECs in restricting viral propagation. 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.
THE NEW ENGLAND JOURNAL OF MEDICINE
The Severe Covid-19 GWAS Group
There is considerable variation in disease behavior among patients infected with
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that
causes coronavirus disease 2019 (Covid-19). Genomewide association analysis may
allow for the identification of potential genetic factors involved in the development
We conducted a genomewide association study involving 1980 patients with Covid-19
and severe disease (defined as respiratory failure) at seven hospitals in the Italian
and Spanish epicenters of the SARS-CoV-2 pandemic in Europe. After quality con-
trol and the exclusion of population outliers, 835 patients and 1255 control par-
ticipants from Italy and 775 patients and 950 control participants from Spain were
included in the final analysis. In total, we analyzed 8,582,968 single-nucleotide
polymorphisms and conducted a meta-analysis of the two case–control panels.
We detected cross-replicating associations with rs11385942 at locus 3p21.31 and
with rs657152 at locus 9q34.2, which were significant at the genomewide level
(P<5×10−8) in the meta-analysis of the two case–control panels (odds ratio, 1.77;
95% confidence interval [CI], 1.48 to 2.11; P=1.15×10−10; and odds ratio, 1.32; 95%
CI, 1.20 to 1.47; P=4.95×10−8, respectively). At locus 3p21.31, the association signal
spanned the genes SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6 and XCR1. The association
signal at locus 9q34.2 coincided with the ABO blood group locus; in this cohort, a
blood-group–specific analysis showed a higher risk in blood group A than in other
blood groups (odds ratio, 1.45; 95% CI, 1.20 to 1.75; P=1.48×10−4) and a protective
effect in blood group O as compared with other blood groups (odds ratio, 0.65;
95% CI, 0.53 to 0.79; P=1.06×10−5).
We identified a 3p21.31 gene cluster as a genetic susceptibility locus in patients
with Covid-19 with respiratory failure and confirmed a potential involvement of the
ABO blood-group system. (Funded by Stein Erik Hagen and others.)
Cristiano Conte, Francesco Sogni , Paola Affanni , Licia Veronesi , Alberto Argentiero, Susanna Esposito
The emerging epidemic caused by the new coronavirus SARS-CoV-2 represents the most
important socio-health threat of the 21st century. The high contagiousness of the virus, the strong
impact on the health system of the various countries and the absence to date of treatments able to
improve the prognosis of the disease make the introduction of a vaccine indispensable, even though
there are currently no approved human coronavirus vaccines. The aim of the study is to carry out a
review of the medical literature concerning vaccine candidates for the main coronaviruses responsible for human epidemics, including recent advances in the development of a vaccine against COVID-19.
This extensive review carried out on the vaccine candidates of the main epidemic coronaviruses of
the past has shown that the studies in animal models suggest a high efficacy of potential vaccines
in providing protection against viral challenges. Similar human studies have not yet been carried
out, as the main trials are aimed at assessing mainly vaccine safety and immunogenicity. Whereas
the severe acute respiratory syndrome (SARS-CoV) epidemic ended almost two decades ago and
the Middle East respiratory syndrome (MERS-CoV) epidemic is now better controlled, as it is less
contagious due to the high lethality of the virus, the current SARS-CoV-2 pandemic represents a
problem that is certainly more compelling, which pushes us to accelerate the studies not only for the production of vaccines but also for innovative pharmacological treatments. SARS-CoV-2 vaccines
might come too late to affect the first wave of this pandemic, but they might be useful if additional subsequent waves occur or in a post-pandemic perspective in which the virus continues to circulate
as a seasonal virus.
Kanta Subbarao, Siddhartha Mahanty
Jonathan M. Metzl, Aletha Maybank; Fernando De Maio
JOURNAL OF MEDICAL VIROLOGY
Domenico Benvenuto Ayse Banu Demir Marta Giovanetti Martina Bianchi Silvia Angeletti Stefano Pascarella Roberto Cauda Massimo Ciccozzi Antonio Cassone
Italy is the first western country suffering heavy SARS‐CoV‐2 transmission and disease impact after Covid‐19 pandemia started in China. Even though the presence of mutations on spike glycoprotein and nucleocapsid in Italian isolates has been reported, the potential impact of these mutations on viral transmission has not been evaluated. We have compared SARS‐CoV‐2 genome sequences from Italian patients with virus sequences from Chinese patients. We focussed upon three non‐synonimous mutations of genes coding for S(one) and N (two) viral proteins present in Italian isolates and absent in Chinese ones, using various bio‐informatic tools. Amino acid analysis and changes in three‐dimensional protein structure suggests the mutations reduce protein stability and, particularly for S1 mutation, the enhanced torsional ability of the molecule could favour virus binding to cell receptor(s). This theoretical interpretation awaits experimental and clinical confirmation.
G Aernout Somsen, Cees van Rijn, Stefan Kooij, Reinout A Bem, Daniel Bonn
Jerry M. Parks, Jeremy C. Smith
Muhammad AdnanShereen, Suliman Khana, AbeerKazmic, NadiaBashira, Rabeea Siddique
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.
Salvatore Di Giorgio, Filippo Martignano, Maria Gabriella Torcia, Giorgio Mattiuz, Silvestro G. Conticello
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.
THE PARIS REVIEW
Oscar A. MacLean, Richard J. Orton, Joshua B. Singer, David L. Robertson
A recent study by Tang et al. claimed that two major types of severe acute respiratory syndrome-coronavirus-2 (CoV-2) had evolved in the ongoing CoV disease-2019 pandemic and that one of these types was more ‘aggressive’ than the other. Given the repercussions of these claims and the intense media coverage of these types of articles, we have examined in detail the data presented by Tang et al., and show that the major conclusions of that paper cannot be substantiated. Using examples from other viral outbreaks, we discuss the difficulty in demonstrating the existence or nature of a functional effect of a viral mutation, and we advise against overinterpretation of genomic data during the pandemic.
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
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 , 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.
Meng Yuan, Nicholas C. Wu, Xueyong Zhu, Chang-Chun D. Lee, Ray T. Y. So, Huibin Lv, Chris K. P. Mok, Ian A. Wilson
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.
ISTITUTO SUPERIORE DI SANITA'
ISTITUTO SUPERIORE DI SANITA'
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
ABSTRACTThe 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
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
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.
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
Tarek Mohamed Abd El-Aziza, James D. Stockanda
ANNALS OF INTERNAL MEDICINE
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,
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
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.
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
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
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.
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
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.
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
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.
Ayal B. Gussow, Noam Auslander, Yuri I. Wolf, Eugene V. Koonin
SARS-CoV-2 poses an immediate, urgent and major threat to public health across the globe. Here we report an in-depth molecular analysis to reconstruct the evolutionary origins of the enhanced pathogenicity of SARS-CoV-2 and other coronaviruses that are severe human pathogens. Using integrated comparative genomics and machine learning techniques, we identify key genomic features that differentiate SARS-CoV-2 and the viruses behind the two previous coronavirus outbreaks, SARS-CoV and MERS-CoV, from less pathogenic coronaviruses. The identified features could be crucial elements of coronavirus pathogenicity and possible targets for diagnostics, prognostication and interventions.
Peter Forstera, Lucy Forsterd, Colin Renfrewb, Michael Forsterc
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.
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
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.
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
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.
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
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.
Imperial College London
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
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
The New Egland Journal of Medicine
Anthony S. Fauci, Clifford Lane, Robert R. Redfield
Mehrdad Mohammadi, Maryam Meskini, Anderia Lucia do Nascimento Pinto
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.
Graziano Onder, Giovanni Rezza, Silvio Brusaferro
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
Kristian G. Andersen, Andrew Rambaut, W. Ian Lipkin, Edward C. Holmes, Robert F. Garry
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
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.
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.
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.
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
Shibo Jiang, Zhengli Shi, Yuelong Shu, Jingdong Song, George F Gao, Wenjie Tan, Deyin Guo
Wiley Online Library
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
Michael Letko, Andrea Marzi, Vincent Munster
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.
The NEW ENGLAND JOURNAL of MEDICINE
Marc Lipsitch, D.Phil., David L. Swerdlow, and Lyn Finelli
Lirong Zou, et all
Lisa F P Ng, Julian A Hiscox
Zhangkai J. Cheng, Jing Shan
There is a current worldwide outbreak of a new type of coronavirus (2019-nCoV), which originated from Wuhan in China and has now spread to 17 other countries. Governments are under increased pressure to stop the outbreak spiraling into a global health emergency. At this stage, preparedness, transparency, and sharing of information are crucial to risk assessments and beginning outbreak control activities. This information should include reports from outbreak sites and from laboratories supporting the investigation. This paper aggregates and consolidates the virology, epidemiology, clinical management strategies from both English and Chinese literature, official news channels, and other official government documents. In addition, by fitting the number of infections with a single-term exponential model, we report that the infection is spreading at an exponential rate, with a doubling period of 1.8 days.
Taylor and Francis Group
Shan-Lu Liu, Linda J. Saif, Susan R. Weiss & Lishan Su
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.
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
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.
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.
The 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.
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.
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.
Jie Cui, Fang Li, Zheng-Li Shi
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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