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Id Subject Object Predicate Lexical cue
T1 0-135 Sentence denotes Measures for diagnosing and treating infections by a novel coronavirus responsible for a pneumonia outbreak originating in Wuhan, China
T2 137-145 Sentence denotes Abstract
T3 146-308 Sentence denotes On 10 January 2020, a new coronavirus causing a pneumonia outbreak in Wuhan City in central China was denoted as 2019-nCoV by the World Health Organization (WHO).
T4 309-446 Sentence denotes As of 24 January 2020, there were 887 confirmed cases of 2019-nCoV infection, including 26 deaths, reported in China and other countries.
T5 447-532 Sentence denotes Therefore, combating this new virus and stopping the epidemic is a matter of urgency.
T6 533-707 Sentence denotes Here, we focus on advances in research and development of fast diagnosis methods, as well as potential prophylactics and therapeutics to prevent or treat 2019-nCoV infection.
T7 709-951 Sentence denotes Coronaviruses (CoVs), which are enveloped, positive-sense, single-stranded RNA viruses of zoonotic origin and belong to the family Coronaviridae in the order Nidovirales, are divided into four genera: alpha, beta, delta and gamma coronavirus.
T8 952-1219 Sentence denotes The emerging CoVs, including severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), both belonging to beta coronavirus, have caused recent pandemics of respiratory infectious diseases with high mortality.
T9 1220-1378 Sentence denotes At the end of December 2019, the Wuhan Municipal Health Commission reported the outbreak of viral pneumonia caused by an unknown pathogen in Wuhan, China [1].
T10 1379-1535 Sentence denotes Subsequently, the unknown pathogen was identified as a novel coronavirus denoted as 2019-nCoV by the World Health Organization (WHO) on 10 January 2020 [1].
T11 1536-1645 Sentence denotes On 12 and 13 January 2020, the full genomic sequence of 2019-nCoV, denoted WIV04 strain (GISAID accession no.
T12 1646-1748 Sentence denotes EPI_ISL_402124), was released, with about 82% homology to that of SARS-CoV Tor2 (GenBank accession no.
T13 1749-1833 Sentence denotes AY274119) and bat SARS-like coronavirus WIV1 (bat SL-CoV-WIV1, GenBank accession no.
T14 1834-1846 Sentence denotes KF367457.1).
T15 1847-2028 Sentence denotes By 24 January, this new emerging virus had caused 887 confirmed cases, including 26 deaths, in the original epidemic area, Wuhan, and other cities in China and in foreign countries.
T16 2029-2195 Sentence denotes More seriously, 15 healthcare workers were infected with 2019-nCoV after close contact with one infected patient, suggesting human-to-human transmission of 2019-nCoV.
T17 2196-2288 Sentence denotes Improved molecular technologies made it possible to rapidly identify this novel coronavirus.
T18 2289-2605 Sentence denotes In this review, we summarize advances made in technologies for rapid diagnosis and identification of respiratory infections caused by coronavirus, as well as strategies for research and development of vaccines, prophylactics and therapeutics to combat 2019-nCoV and other emerging coronaviruses now or in the future.
T19 2607-2657 Sentence denotes 1 Rapid identification of an emerging coronavirus
T20 2658-2751 Sentence denotes Identification of pathogens mainly includes virus isolation and viral nucleic acid detection.
T21 2752-2877 Sentence denotes According to the traditional Koch’s postulates, virus isolation is the “gold standard” for virus diagnosis in the laboratory.
T22 2878-2949 Sentence denotes First, viral culture is a prerequisite for diagnosing viral infections.
T23 2950-3211 Sentence denotes A variety of specimens (such as swabs, nasal swabs, nasopharynx or trachea extracts, sputum or lung tissue, blood and feces) should be retained for testing in a timely manner, which gives a higher rate of positive detection of lower respiratory tract specimens.
T24 3212-3649 Sentence denotes Then, immunological methods – including immunofluorescence assay, protein microarray, direct fluorescent antibody assay, MAb-based rapid NP (nucleocapsid protein) detection, semiconductor quantum dots, and the microneutralization test – which measure binding between the antigen from the whole virus or protein of the coronavirus and corresponding antibody, are easy to operate rapidly but have a lower sensitivity and specificity [3,4].
T25 3650-3865 Sentence denotes In addition, other immunological methods, including microneutralization ppNT assay (pseudo-particle neutralization) are highly sensitive and specific by using the gene coding for the coronavirus spike protein [5,6].
T26 3866-4075 Sentence denotes In the case of 2019-nCoV, viral research institutions can conduct preliminary identification of the virus through the classical Koch’s Postulates or observing its morphology through an electron microscopy [7].
T27 4076-4231 Sentence denotes Serology could also be used to identify the virus when 2019-nCoV-associated antigens and monoclonal antibodies are developed in the future [[7], [8], [9]].
T28 4232-4295 Sentence denotes All the examples above are traditional virus detection methods.
T29 4296-4353 Sentence denotes Viral nucleic acids can also be used for early diagnosis.
T30 4354-4418 Sentence denotes The following are some of the new coronavirus detection methods.
T31 4419-4537 Sentence denotes Polymerase chain reaction (PCR) is a molecular biological diagnosis technology based on the sequence of nucleic acids.
T32 4538-4739 Sentence denotes The full gene sequence of 2019-nCoV has now been obtained [10], so patients who are suspected of being infected with 2019-nCoV [8] can be diagnosed by pan-coronavirus PCR for virus identification [11].
T33 4740-4904 Sentence denotes Reverse transcription polymerase chain reaction (RT-PCR) is a technology combining RNA reverse transcription (RT) with polymerase chain amplification (PCR) of cDNA.
T34 4905-5039 Sentence denotes A duplex RT-PCR assay can be used to detect SARS-CoV and MERS-CoV using pUC57SARS-pS2 and pGEM-MERSS2 as templates, respectively [12].
T35 5040-5295 Sentence denotes Also, samples collected from the upper respiratory tract (oropharyngeal and nasopharyngeal) and lower respiratory tract (endotracheal aspirate, expectorated sputum, or bronchoalveolar lavage) of suspected 2019-nCoV patients can be diagnosed by RT-PCR [8].
T36 5296-5562 Sentence denotes Reverse transcription-insulated isothermal polymerase chain reaction (RT-iiPCR), quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), Real-time RT-PCR (rtRT-PCR), and one-step rtRT-PCR were all further optimized [[13], [14], [15], [16]].
T37 5563-5735 Sentence denotes These optimized RT-PCR methods were used to detect the MERS-CoV envelope gene (upE) and the open reading frame 1a (ORF1a) or open reading frame 1b (ORF1b) genes separately.
T38 5736-5903 Sentence denotes However, rtRT-PCR was used to identify 2019-nCoV through preliminary and validation detection of its E gene, RNA-dependent RNA polymerase (RdRp) gene, and N gene [17].
T39 5904-6022 Sentence denotes There are other molecular-based detection techniques in addition to RT-PCR and similar optimized detection techniques.
T40 6023-6201 Sentence denotes For example, reverse transcription loop-mediated isothermal amplification (RT-LAMP) is an RNA amplification technique that detects the N gene of MERS-CoV and the ORF1a gene [18].
T41 6202-6501 Sentence denotes One-pot reverse transcription loop-mediated isothermal amplification (one-pot RT-LAMP) is the optimized RT-LAMP [19], while RT-LAMP-VF is the deformation of RT-LAMP [20], which is the combination of reverse transcription loop-mediated isothermal amplification and vertical flow visualization strips.
T42 6502-6618 Sentence denotes Both are used to detect the N gene of MERS-CoV, making detection easier, faster, more efficient and highly specific.
T43 6619-6761 Sentence denotes Besides these three methods, reverse transcription recombinase polymerase amplification assay (RT-PRA) is also used to identify MERS-CoV [21].
T44 6762-6849 Sentence denotes Finally, the following multiplex tests can detect both coronaviruses and other viruses.
T45 6850-7133 Sentence denotes MCoV-MS (multiplexed CoV mass spectrometry) uses an array matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) system to accurately identify known human coronaviruses (hCoVs) and to provide phylogenetic evidence for emerging unknown hCoVs [22].
T46 7134-7288 Sentence denotes Another new test method, arch-shaped multiple-target sensor, is used to amplify the target for rapid identification of pathogens in clinical samples [23].
T47 7289-7345 Sentence denotes The method can detect hCoVs, and Zika and Ebola viruses.
T48 7346-7513 Sentence denotes The last one, the paper-based colorimetric assay, uses Pyrrolidinyl Peptide Nucleic Acid-induced silver nanoparticles (AgNPs) aggregation of pathogen DNA testing [24].
T49 7514-7639 Sentence denotes The color change of AgNPs can distinguish between MERS-CoV, Mycobacterium tuberculosis (MTB), and human papillomavirus (HPV).
T50 7641-7680 Sentence denotes 2 Research and development of vaccines
T51 7681-7820 Sentence denotes The cellular receptors of SARS-CoV and MERS-CoV have been identified [25,26], and the virion spike (S) glycoprotein, was also well studied.
T52 7821-7935 Sentence denotes S glycoprotein includes two subunits [27], S1 and S2, resulting from cleavage of the one precursor into two parts.
T53 7936-8183 Sentence denotes S1 determines the virus host range and cellular tropism with the key functional domain - receptor binding domain (RBD), while S2 contains two tandem domains, heptad repeats 1 (HR1) and heptad repeats 2 (HR2), to mediate virus-cell membrane fusion.
T54 8184-8638 Sentence denotes It is believed that the fusion process is similar to that of HIV-1 [28]; for example, when S1 binds to the receptor on the cell membrane, the fusion peptide at the N terminus of S2 inserts into the cell membrane, then three HR1s attach to each other in parallel as a trimer, followed by binding of three HR2s separately onto the outside of the trimer to form a 6-helix bundle, thus bringing virus and cell membranes close to each other to trigger fusion.
T55 8639-8763 Sentence denotes As the major vaccine target, the S protein has been evaluated in different types of vaccines against infection by CoVs [29].
T56 8764-8926 Sentence denotes Apart from the inactive whole virus particle [30], live attenuated virus with gene deletion [31] , four more vaccines which mainly contain S protein were studied.
T57 8927-9294 Sentence denotes These include a virus-like particle which incorporated S protein into hepatitis virus or influenza virus protein [32,33]; virus vectors, such as modified vaccinia virus Ankara (MVA) or Adenovirus carrying S protein [34,35]; S protein subunit vaccine, like RBD-based protein [29,36]; and DNA vaccine which encodes the full length or part of the S protein gene [37,38].
T58 9295-9398 Sentence denotes Most of them have been tested in mouse models and showed the ability to elicit neutralizing antibodies.
T59 9399-9608 Sentence denotes The first SARS-CoV DNA vaccine was tested in humans only 19 months after the virus sequence was published [38], while the DNA vaccine GLS-5300, the first MERS-CoV vaccine, went to clinical trials in 2016 [39].
T60 9609-9879 Sentence denotes In addition to these conventional vaccines, Liu et al. analyzed the T cell epitopes of SARS-CoV and MERS-CoV, revealed the potential cross-reactivity of the coronaviruses, and assessed the possibility of developing universal vaccines against coronavirus infections [40].
T61 9880-10086 Sentence denotes Most CoVs share a similar viral structure, similar infection pathway, and a similar structure of the S proteins [41], suggesting that similar research strategies should also be applicable for the 2019-nCoV.
T62 10087-10215 Sentence denotes For example, the study of MERS-CoV vaccines was accelerated by virtue of strategies that had been established for SARS-CoV [42].
T63 10216-10302 Sentence denotes It has been reported that the 2019-nCoV is also genetically close to SARS-CoV [43,44].
T64 10303-10567 Sentence denotes Therefore, to predict whether vaccines developed for SARS-CoV will also be effective against 2019-nCoV infection, the full length S protein sequences from the 2019-nCoV, a SARS-CoV, and two genetically similar bat CoV strains were selected for alignment (Fig. 1 ).
T65 10568-10628 Sentence denotes The results indicated more than 50% homology of the viruses.
T66 10629-10982 Sentence denotes However, the most variable residues are located in S1, a critical vaccine target, implying that neutralizing antibodies that were so effective against SARS-CoV infection may fail to recognize the 2019-nCoV, and that multiple amino acid differences at the receptor binding motif may modify virus tropism, a possible reason for cross-species transmission.
T67 10983-11041 Sentence denotes Fig. 1 Comparison of S protein sequences of coronaviruses.
T68 11042-11139 Sentence denotes Multiple alignment of full amino acid sequences of S protein from 2019-nCoV (GISAID accession no.
T69 11140-11188 Sentence denotes EPI_ISL_402124), SARS-CoV (GenBank accession no.
T70 11189-11237 Sentence denotes AY278489), bat-SL-CoVZC45 (GenBank accession no.
T71 11238-11293 Sentence denotes MG772933.1), and bat-SL-CoVZXC21 (GenBank accession no.
T72 11294-11478 Sentence denotes MG772934.1) was performed and displayed with clustalx1.83 and MEGA4 respectively. ‘‘-” represents the unconfirmed amino acid residues, “.” represents the identical amino acid residues.
T73 11479-11706 Sentence denotes The functional domains were labeled based on the research on SARS-CoV [41]; light blue box was for RBD region; dark blue box for receptor binding motif (RBM); light purple box for HR1; and dark purple box for HR2, respectively.
T74 11707-11873 Sentence denotes Double underlined regions in HR1 and HR2 are fusion cores, which are critical regions responsible for the formation of stable six-helical bundles between HR1 and HR2.
T75 11874-11970 Sentence denotes However, several bottlenecks typically delay the approval of vaccines to prevent CoVs infection.
T76 11971-12041 Sentence denotes First, a lack of proper animal models for evaluating vaccine efficacy.
T77 12042-12321 Sentence denotes Second, there are limitations from the S protein itself, such as mutations in the neutralization antibody epitopes in S protein that can cause virus escape [45], or non-neutralization antibody epitopes in vaccines that may elicit antibody-mediated disease enhancement (ADE) [46].
T78 12322-12375 Sentence denotes Third, DNA vaccines may recombine with other viruses.
T79 12376-12481 Sentence denotes Fourth, pre-existing immunity may eliminate the vaccine by removing the general human virus vectors [47].
T80 12482-12619 Sentence denotes Finally, there is the problem of return on investment which may be slow and, hence, inhibit investments and slow down the clinical study.
T81 12620-12877 Sentence denotes Jiang and colleagues have demonstrated that RBD in the SARS-CoV S protein is the major target of neutralizing antibodies in SARS patients and is able to induce highly potent neutralizing antibody responses and long-term protective immunity in animal models.
T82 12878-13048 Sentence denotes It contains 6 different conformational neutralizing epitopes, to which a series of mouse monoclonal antibodies (mAbs) with different neutralizing activity were generated.
T83 13049-13287 Sentence denotes Interestingly, these mAbs exhibited cross-neutralizing activities against divergent SARS-CoV strains isolated from SARS patients at different stages of SARS epidemics in 2002–2004 and those from palm civets [[48], [49], [50], [51], [52]].
T84 13288-13498 Sentence denotes This group has also shown that these SARS-CoV-RBD-specific neutralizing mAbs can cross-neutralize bat SL-CoVs, such as bat SL-CoV-W1V1 [53], indicating that these antibodies may also cross-neutralize 2019-nCoV.
T85 13499-13808 Sentence denotes Most importantly, RBD-based vaccine could induce neutralizing antibody responses and protection against SARS-CoV infection in the immunized animals, while it did not elicit ADE or other harmful immune responses, unlike the virus-inactivated vaccines or full-length S protein-based vaccines as discussed above.
T86 13809-13944 Sentence denotes Therefore, this RBD-based SARS vaccine is expected to be safer and more effective than the vaccines targeting other sites in S protein.
T87 13945-14222 Sentence denotes Jiang and Du’s groups have collaborated with Hotez’s group at Baylor College of Medicine in Houston and Tseng’s group at the University of Texas Medical Branch at Galveston, Texas, USA in development of an effective and safe vaccine at the late stage of preclinical study [54].
T88 14223-14325 Sentence denotes The antibodies induced by this vaccine candidate are expected to cross-neutralize 2019-nCoV infection.
T89 14326-14581 Sentence denotes If it is confirmed, this vaccine candidate has the great potential to be further developed promptly in clinical trials in both China and the United State through the continuous collaborations among the four groups of Drs. Hotez, Tseng, Du, and Jiang [55].
T90 14583-14644 Sentence denotes 3 Research and development of therapeutics and prophylactics
T91 14645-14750 Sentence denotes At the present, no specific antiviral therapy has been approved for treatment of infection by human CoVs.
T92 14751-14959 Sentence denotes As development of vaccines and compounds for prevention and treatment of infection have been brought to priority status by WHO and governments [56], numerous drug studies have been done or are moving forward.
T93 14960-15177 Sentence denotes Some of them focus on the CoV fusion/entry process either by inhibition of S1 mediated virus attachment or by blocking of S2 mediated virus-cell membrane fusion, and some of them interfere with viral replication [57].
T94 15179-15211 Sentence denotes 3.1 CoV fusion/entry inhibitors
T95 15212-15416 Sentence denotes Based on the previous experience in developing the HIV-1 fusion inhibitor SJ-2176 [58], Jiang et al. discovered the first anti-SARS-CoV peptide (SC-1) from the HR2 domain of SARS-CoV S protein S2 subunit.
T96 15417-15573 Sentence denotes SC-1 could bind onto the HR1 domain to form a six-helical bundle (6-HB), blocking S protein-mediated membrane fusion and inhibiting SARS-CoV infection [59].
T97 15574-15841 Sentence denotes When MERS-CoV was circulating in human populations in 2012, following similar mechanistic design, Jiang’s research group developed another peptide, designated HR2P, which was derived from the virus HR2 region as well and effectively inhibited MERS-CoV infection [60].
T98 15842-15964 Sentence denotes The further modified version of HR2P, HR2P-M2, presented even better anti-MERS-CoV activity and pharmaceutical properties.
T99 15965-16104 Sentence denotes Development of broad-spectrum pan-CoV fusion inhibitors would be an ideal way to cope with epidemics or pandemics caused by emerging HCoVs.
T100 16105-16254 Sentence denotes The conservative amino acid sequence of the HR1 region across different CoVs has the potential to be a target domain for development of an inhibitor.
T101 16255-16440 Sentence denotes Continuing to work on the HR1 and HR2 domains, Jiang’s group discovered that the peptide OC43-HR2P, derived from the HR2 domain of HCoV-OC43, broadly inhibited fusion by multiple HCoVs.
T102 16441-16521 Sentence denotes By optimization of this peptide, a pan-CoV fusion inhibitor, EK1, was generated.
T103 16522-16685 Sentence denotes It could form a stable six-helix bundle (6-HB) structure with HR1s and showed significantly improved fusion-inhibitory activity and pharmaceutical properties [61].
T104 16686-16907 Sentence denotes The alignment of S protein in Fig. 1 exhibited 100% identity at the HR2 domains between the 2019-nCoV and SARS-CoV; however, they found 7 amino acid changes in the fusion core of the HR1, located in the EK1 binding motif.
T105 16908-17146 Sentence denotes Fortunately, the substitutions were conservative replacements which would not dramatically disrupt the interactions between EK1 and HR1, meaning that EK1 would still have the potential to be an effective inhibitor for 2019-nCoV infection.
T106 17148-17195 Sentence denotes 3.2 CoV S-RBD-specific neutralizing antibodies
T107 17196-17279 Sentence denotes So far, most neutralizing antibodies recognize the RBD in the S protein S2 of CoVs.
T108 17280-17508 Sentence denotes Compared with the high mutation rate in the S1 protein, S2 is much more conservative, thereby decreasing the off-target risk caused by amino acid replacement [62], and also bypassing the special epitopes that may cause ADE [63].
T109 17509-17654 Sentence denotes This means that the cocktail of monoclonal antibodies binding to different epitopes of RBD would be more desirable for therapeutic purposes [64].
T110 17655-17795 Sentence denotes For treatment, the monoclonal antibodies are from a human source or are humanized antibodies, isolated or generated with various approaches.
T111 17796-17893 Sentence denotes For example, wild-type mice were immunized with soluble recombinant RBD containing the S protein.
T112 17894-18044 Sentence denotes Then mouse antibodies were humanized and isolated, or transgenic mice were directly immunized, to express human versions of the antibodies [50,65,66].
T113 18045-18211 Sentence denotes However, direct cloning of single B cells from human survivors, used in combination with the phage-display antibody library, could provide authentic human antibodies.
T114 18212-18375 Sentence denotes Until now, it should be noted that many neutralizing antibodies have been successfully discovered for treatment of SARS-CoV [67] and MERS-CoV infection [45,68,69].
T115 18376-18456 Sentence denotes These antibodies have all been described favorably in the literature [29,70,71].
T116 18457-18672 Sentence denotes A similar approach is known as single chain fragment variable (scFv) library screening, whereby the use of RBD as a bait protein allows some neutralizing antibodies to be screened out from non-immune humans [72,73].
T117 18673-18856 Sentence denotes Antibodies effective at inhibiting SARS-CoV infection should also have the potential for treatment of 2019-nCoV as well, as long as the binding motif in RBD shares the same sequences.
T118 18857-18974 Sentence denotes The new neutralizing monoclonal antibodies would also be isolated from the patients using the established techniques.
T119 18976-19007 Sentence denotes 3.3 CoV replication inhibitors
T120 19008-19112 Sentence denotes Similar to developing vaccines, drugs effective against other RNA viruses were also repurposed for CoVs.
T121 19113-19186 Sentence denotes Two major types of drugs being nucleoside analogues and immunomodulators.
T122 19187-19317 Sentence denotes So far, the most common therapies tried in patients with CoVs are ribavirin, lopinavir/ritonavir, IFN, or their combinations [74].
T123 19318-19664 Sentence denotes Despite the antiviral activity observed with in vitro studies, the clinical effect was not consistent [75], in that ribavirin does not prolong the survival of SARS-CoV patients [74,76], while lopinavir/ritonavir plus ribavirin seemed to improve clinical outcomes for SARS patients [77], but the improvement was not confirmed in MERS-CoV patients.
T124 19665-19831 Sentence denotes IFNs showed effective at inducing antiviral activity against both SARS-CoV and MRES-CoV, but without significant improvement in the outcomes for the patients [78,79].
T125 19832-19998 Sentence denotes In addition to the drug regimens used in patients, numerous drugs developed for the treatment of infection with CoVs were thoroughly discussed in the literature [57].
T126 19999-20099 Sentence denotes However, replication of an RNA virus usually generates progeny viruses with a highly diverse genome.
T127 20100-20272 Sentence denotes Recombination also easily takes place between viral genomes [80], and these gene level changes may result in drug resistance if the mutations affect the drug target domain.
T128 20273-20490 Sentence denotes Development of drugs is also hampered by various evaluation methods and animal models used for testing drug activity among different labs worldwide, which could postpone selection of the best drug for clinical trials.
T129 20492-20519 Sentence denotes 4 Conclusion and prospects
T130 20520-20630 Sentence denotes Taken together, 2019-nCoV is a new coronavirus, and like SARS-CoV and MERS-CoV, it belongs to Betacoronavirus.
T131 20631-20782 Sentence denotes Both SARS-CoV and MERS-CoV were able to spread around the globe and posed a major challenge to clinical management and a great threat to public health.
T132 20783-20924 Sentence denotes Similarly to SARS-CoV and MERS-CoV, based on the monitoring and scientific forecast, 2019-nCoV may cause a worldwide threat to public health.
T133 20925-21051 Sentence denotes Over the years, research on CoVs has resulted in multiple strategies for diagnosis, prevention and treatment of CoV infection.
T134 21052-21196 Sentence denotes This brief review has demonstrated that such an achievement could very well apply to 2019-nCoV, or indeed, any newly emergent CoV in the future.
T135 21197-21438 Sentence denotes At present, many companies engaged in the development of biologicals have marketed nucleic acid detection kits for 2019-nCoV, such as the new coronavirus nucleic acid detection kit (double fluorescence PCR method) from Shuoshi Biotechnology.
T136 21439-21540 Sentence denotes Currently, however, no diagnostic test kit is available for the detection of antibodies to 2019-nCoV.
T137 21542-21575 Sentence denotes Declaration of Competing Interest
T138 21576-21636 Sentence denotes The authors declare that they have no conflicts of interest.
T139 21638-21654 Sentence denotes Acknowledgements
T140 21655-21784 Sentence denotes We thank Dr. Zengli Shi for providing us permission for analysis of the spike protein sequence of 2019-nCoV (GISAID accession no.
T141 21785-21815 Sentence denotes EPI_ISL_402124) in this study.