American Journal of Infectious Diseases and Microbiology
ISSN (Print): 2328-4056 ISSN (Online): 2328-4064 Website: http://www.sciepub.com/journal/ajidm Editor-in-chief: Maysaa El Sayed Zaki
Open Access
Journal Browser
Go
American Journal of Infectious Diseases and Microbiology. 2020, 8(2), 64-74
DOI: 10.12691/ajidm-8-2-4
Open AccessReview Article

Understanding COVID-19 - A Molecular Perspective

Michael O. Okpara1, and Miebaka Jamabo2

1Department of Biochemistry, Federal University of Technology, Akure, P.M.B. 704, Akure, Ondo State, Nigeria

2Department of Biochemistry, Rivers State University, Nkpolu-Oroworukwo, P.M.B 5080, Port Harcourt, Rivers State, Nigeria

Pub. Date: June 08, 2020

Cite this paper:
Michael O. Okpara and Miebaka Jamabo. Understanding COVID-19 - A Molecular Perspective. American Journal of Infectious Diseases and Microbiology. 2020; 8(2):64-74. doi: 10.12691/ajidm-8-2-4

Abstract

Coronavirus disease (COVID-19) is an infectious disease caused by a novel coronavirus now identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the Coronavirus Study Group (CSG) of the International Committee on Taxonomy of Viruses (ICTV). COVID-19 was first identified in Wuhan, China in December 2019 but has spread globally. As of May 11, 2020, over 4 million people have been infected with over 280,000 deaths reported globally. This pandemic has severely affected the global economy as most countries had to take pro-active measures to curb the spread of the disease by shutting their borders, making this one of the most devastating health crises in the past century. Coronavirus epidemics are not new to the human populace. The severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) caused epidemics in 2002 and 2012, respectively. These three coronaviruses belong to the beta-coronavirus genus. Despite the past experience from the previous coronavirus epidemics, the world was unprepared for this new outbreak. Therefore, it is important to understand the biology of the virus and the possibility of targeting its components for developing therapeutic drugs and vaccines. This review gives an overview of the biology, transmissibility, and genome organization of SARS-CoV-2. Furthermore, we described the available diagnostic, therapeutic and vaccine strategies for COVID-19.

Keywords:
COVID-19 coronavirus SARS-CoV-2 diagnostics therapeutics vaccines

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

References:

[1]  WHO, “Novel Coronavirus - China,” 2020. [Online]. Available: https://www.who.int/csr/don/12-january-2020-novel-coronavirus-china/en/. [Accessed: 23-Apr-2020].
 
[2]  J. F. W. Chan et al., “A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster,” Lancet, vol. 395, no. 10223, pp. 514-523, 2020.
 
[3]  WHO, “Modes of transmission of virus causing COVID-19: implications for IPC precaution recommendations,” 2020. [Online]. Available: https://www.who.int/news-room/commentaries/detail/modes-of-transmission-of-virus- causing-covid-19-implications-for-ipc-precaution- recommendations. [Accessed: 23-Apr-2020].
 
[4]  Y. Bai et al., “Presumed asymptomatic carrier transmission of COVID-19,” JAMA, vol. 323, no. 14, pp. 1406-1407, 2020.
 
[5]  Worldometer, “COVID-19 Coronavirus Pandemic,” 2020. [Online]. Available: https://www.worldometers.info/coronavirus/. [Accessed: 11-May-2020].
 
[6]  R. Lu et al., “Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding,” Lancet, vol. 395, no. 10224, pp. 565-574, 2020.
 
[7]  N. Zhu et al., “A novel coronavirus from patients with pneumonia in China, 2019,” N. Engl. J. Med., vol. 382, no. 8, pp. 727-733, 2020.
 
[8]  A. E. Gorbalenyaet al., “Severe acute respiratory syndrome-related coronavirus: the species and its viruses - a statement of the Coronavirus Study Group,” Biorxiv (Cold Spring Harb. Lab., p. 2020.02.07.937862, 2020.
 
[9]  WHO, “WHO announces COVID-19 outbreak a pandemic,” 2020. [Online]. Available: http://www.euro.who.int/en/health-topics/health-emergencies/coronavirus-covid- 19/news/news/2020/3/who-announces-covid-19-outbreak-a- pandemic. [Accessed: 23-Apr-2020].
 
[10]  D. L. Heymann and N. Shindo, “COVID-19: what is next for public health?,” Lancet, vol. 395, no. 10224, pp. 542-545, 2020.
 
[11]  C. Huang et al., “Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China,” Lancet, vol. 395, no. 10223, pp. 497-506, 2020.
 
[12]  O. Abodunrin, G. Oloye, and B. Adesola, “Coronavirus pandemic and its implication on global economy,” Int. J. Arts, Lang. Bus. Stud., vol. 4, pp. 13-23, 2020.
 
[13]  A. R. Fehr and S. Perlman, “Coronaviruses: an overview of their replication and pathogenesis,” in Coronaviruses: Methods and Protocols, H. J. Maier, E. Bickerton, and P. Britton, Eds. New York: Springer US, 2015, pp. 1-23.
 
[14]  F. Li, “Structure, function, and evolution of coronavirus spike proteins,” Annu. Rev. Virol., vol. 3, no. 1, pp. 237-261, 2016.
 
[15]  ICTV, “ICTV Virus Taxonomy,” 2017. [Online]. Available: https://talk.ictvonline.org/ictv-reports/ictv_online_report/introduction/w/introduction-to-the-ictv- online-report/418/virus-properties.
 
[16]  E. J. Lefkowitz, D. M. Dempsey, R. C. Hendrickson, R. J. Orton, S. G. Siddell, and D. B. Smith, “Virus taxonomy: The database of the International Committee on Taxonomy of Viruses (ICTV),” Nucleic Acids Res., vol. 46, pp. D708-D717, 2018.
 
[17]  W. Li et al., “Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus,” Nature, vol. 426, pp. 450-454, 2003.
 
[18]  V. S. Raj et al., “Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC,” Nature, vol. 495, no. 7440, pp. 251-254, 2013.
 
[19]  Y. Yang et al., “Receptor usage and cell entry of bat coronavirus HKU4 provide insight into bat-to-human transmission of MERS coronavirus,” Proc. Natl. Acad. Sci. U. S. A., vol. 111, no. 34, pp. 12516-12521, 2014.
 
[20]  X. Ouet al., “Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV,” Nat. Commun., vol. 11, no. 1, pp. 1-12, 2020.
 
[21]  M. Letko, A. Marzi, and V. Munster, “Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses,” Nat. Microbiol., vol. 5, no. 4, pp. 562-569, 2020.
 
[22]  Y. Wan, J. Shang, R. Graham, R. S. Baric, and F. Li, “Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus,” J. Virol., vol. 94, no. 7, pp. 1-9, 2020.
 
[23]  M. Kawase, K. Shirato, L. van der Hoek, F. Taguchi, and S. Matsuyama, “Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry,” J. Virol., vol. 86, no. 12, pp. 6537-6545, 2012.
 
[24]  M. Hoffmann et al., “SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor,” Cell, vol. 181, no. 2, pp. 271-280, 2020.
 
[25]  Y. Zhou et al., “Protease inhibitors targeting coronavirus and filovirus entry,” Antiviral Res., vol. 116, pp. 76-84, 2015.
 
[26]  F. Qi, S. Qian, S. Zhang, and Z. Zhang, “Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses,” Biochem. Biophys. Res. Commun., vol. 526, no. 1, pp. 135-140, 2020.
 
[27]  X. Zou, K. Chen, J. Zou, P. Han, J. Hao, and Z. Han, “Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection,” Front. Med., 2020.
 
[28]  D. Wrappet al., “Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation,” Science (80-. )., vol. 367, no. 6483, pp. 1260-1263, 2020.
 
[29]  J. Ziebuhr, E. J. Snijder, and A. E. Gorbalenya, “Virus-encoded proteinases and proteolytic processing in the Nidovirales,” J. Gen. Virol., vol. 81, no. 4, pp. 853-879, 2000.
 
[30]  Y. M. Báez-Santos, S. E. St. John, and A. D. Mesecar, “The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds,” Antiviral Res., vol. 115, pp. 21-38, 2015.
 
[31]  I. Sola, F. Almazán, S. Zúñiga, and L. Enjuanes, “Continuous and discontinuous RNA synthesis in coronaviruses,” Annu. Rev. Virol., vol. 2, no. 1, pp. 265-288, 2015.
 
[32]  A. O. Pasternak, W. J. M. Spaan, and E. J. Snijder, “Nidovirus transcription: how to make sense...?,” J. Gen. Virol., vol. 87, no. 6, pp. 1403-1421, 2006.
 
[33]  N. Zhang, S. Jiang, and L. Du, “Current advancements and potential strategies in the development of MERS-CoV vaccines,” Expert Rev. Vaccines, vol. 13, no. 6, pp. 761-774, 2014.
 
[34]  J. Pan et al., “Genome-wide analysis of protein-protein interactions and involvement of viral proteins in SARS-CoV replication,” PLoS One, vol. 3, no. 10, 2008.
 
[35]  K. Narayanan, C. Huang, and S. Makino, “SARS coronavirus accessory proteins,” Virus Res., vol. 133, no. 1, pp. 113-121, 2008.
 
[36]  Y. W. Chen, C. P. B. Yiu, and K. Y. Wong, “Prediction of the SARS-CoV-2 (2019-nCoV) 3C-like protease (3CLpro) structure: Virtual screening reveals velpatasvir, ledipasvir, and other drug repurposing candidates,” F1000Research, vol. 9, pp. 1-17, 2020.
 
[37]  F. Wu et al., “A new coronavirus associated with human respiratory disease in China,” Nature, vol. 579, no. 7798, pp. 265-269, 2020.
 
[38]  A. Wu et al., “Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China,” Cell Host Microbe, vol. 27, no. 3, pp. 325-328, 2020.
 
[39]  S. G. Sawicki, D. L. Sawicki, and S. G. Siddell, “A contemporary view of coronavirus transcription,” J. Virol., vol. 81, no. 1, pp. 20-29, 2007.
 
[40]  R. J. de Groot et al., “Order Nidovirales,” in Virus Taxonomy, Ninth Report of the International Committee on Taxonomy of Viruses, A. M. Q. King, M. J. Adams, E. B. Carstens, and E. J. Lefkowitz, Eds. London: Elsevier Inc., 2012, pp. 785-795.
 
[41]  A. von Brunnet al., “Analysis of intraviral protein-protein interactions of the SARS coronavirus ORFeome,” PLoS One, vol. 2, no. 5, 2007.
 
[42]  L. Enjuanes, S. Zuñiga, C. Castaño-Rodriguez, J. Gutierrez-Alvarez, J. Canton, and I. Sola, “Molecular basis of coronavirus virulence and vaccine development,” Adv. Virus Res., vol. 96, pp. 245-286, 2016.
 
[43]  Q. Li et al., “Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia,” N. Engl. J. Med., vol. 382, no. 13, pp. 1199-1207, 2020.
 
[44]  Y. Liu, A. A. Gayle, A. Wilder-Smith, and J. Rocklöv, “The reproductive number of COVID-19 is higher compared to SARS coronavirus,” J. Travel Med., vol. 27, no. 2, pp. 1-4, 2020.
 
[45]  J. T. Wu, K. Leung, and G. M. Leung, “Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: a modelling study,” Lancet, vol. 395, no. 10225, pp. 689-697, 2020.
 
[46]  E. Prompetchara, C. Ketloy, and T. Palaga, “Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic,” Asian Pacific J. allergy Immunol., vol. 38, no. 1, pp. 1-9, 2020.
 
[47]  R. Breban, J. Riou, and A. Fontanet, “Interhuman transmissibility of Middle East respiratory syndrome coronavirus: Estimation of pandemic risk,” Lancet, vol. 382, no. 9893, pp. 694-699, 2013.
 
[48]  WHO, “Middle East respiratory syndrome coronavirus (MERS-CoV),” 2019. [Online]. Available: https://www.who.int/emergencies/mers-cov/en/. [Accessed: 23-Apr-2020].
 
[49]  V. M. Corman et al., “Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR,” Eurosurveillance, vol. 25, no. 3, pp. 1-8, 2020.
 
[50]  BGI, “BGI develops real-time fluorescent RT-PCR kit for detecting the 2019 novel coronavirus,” 2020. [Online]. Available: https://www.bgi.com/global/company/news/bgi-develops-real- time-dna-based-kit-for-detecting-the-2019-novel-coronavirus/. [Accessed: 23-Apr-2020].
 
[51]  MGI, “BGI responds to novel coronavirus with real-time detection kits, deploys emergency team to Wuhan,” 2020. [Online]. Available: https://en.mgitech.cn/news/129/. [Accessed: 23-Apr-2020].
 
[52]  Cepheid, “Xpert® Xpress SARS-CoV-2 has received FDA Emergency Use Authorization,” 2020. [Online]. Available: https://www.cepheid.com/coronavirus. [Accessed: 23-Apr-2020].
 
[53]  N. M. A. Okbaet al., “Severe acute respiratory syndrome coronavirus 2−specific antibody responses in coronavirus disease 2019 patients,” Emerg. Infect. Dis., vol. 26, no. 7, 2020.
 
[54]  DiaSorin, “Diasorin announces the launch of a fully automated serology test to detect antibodies against SARS-CoV-2 in COVID-19 patients within the end of April 2020, allowing identification of immune response development to the virus,” Saluggia, 2020.
 
[55]  Abbott, “Abbott launches COVID-19 antibody test,” 2020. [Online]. Available: https://www.abbott.com/corpnewsroom/product-and- innovation/abbott-launches-covid-19-antibody-test.html. [Accessed: 28-Apr-2020].
 
[56]  Roche, “Roche’s COVID-19 antibody test receives FDA Emergency Use Authorization and is available in markets accepting the CE mark,” Basel, 2020.
 
[57]  M. J. Kellner, J. G. Koob, J. S. Gootenberg, O. O. Abudayyeh, and F. Zhang, “SHERLOCK: nucleic acid detection with CRISPR nucleases,” Nat. Protoc., vol. 14, no. 10, pp. 2986-3012, 2019.
 
[58]  Y. Zhang et al., “Rapid molecular detection of SARS-CoV-2 (COVID-19) virus RNA using colorimetric LAMP,” medRxiv, vol. 2, p. 2020.02.26.20028373, 2020.
 
[59]  C. Yan et al., “Rapid and visual detection of 2019 novel coronavirus (SARS-CoV-2) by a reverse transcription loop-mediated isothermal amplification assay,” Clin. Microbiol. Infect., pp. 1-7, 2020.
 
[60]  Jeffrey P. Kanne, “Chest CT findings in 2019 novel coronavirus (2019-nCoV) infections from Wuhan, China: key points for the radiologist,” Radiology, vol. 295, pp. 16-17, 2020.
 
[61]  S. Wang et al., “A deep learning algorithm using CT images to screen for Corona Virus Disease (COVID-19),” medRxiv, p. 2020.02.14.20023028, 2020.
 
[62]  H.-P. Hsieh and J. T.-A. Hsu, “Strategies of development of antiviral agents directed against influenza virus replication,” Curr. Pharm. Des., vol. 13, no. 34, pp. 3531-3542, 2007.
 
[63]  Ono Pharmaceutical, “FOIPAN® Tablets 100mg,” 2009. [Online]. Available: http://www.shijiebiaopin.net/upload/product/201272318373223.PDF. [Accessed: 23-Apr-2020].
 
[64]  J. Giboet al., “Camostatmesilate attenuates pancreatic fibrosis via inhibition of monocytes and pancreatic stellate cells activity,” Lab. Investig., vol. 85, no. 1, pp. 75-89, 2005.
 
[65]  R. U. Kadam and I. A. Wilson, “Structural basis of influenza virus fusion inhibition by the antiviral drug Arbidol,” Proc. Natl. Acad. Sci. U. S. A., vol. 114, no. 2, pp. 206-214, 2017.
 
[66]  R. Khamitov, Si. Loginova, V. Shchukina, S. Borisevich, V. Maksimov, and A. Shuster, “Antiviral activity of arbidol and its derivatives against the pathogen of severe acute respiratory syndrome in the cell cultures,” Vopr. Virusol., vol. 53, no. 4, pp. 9-13, 2008.
 
[67]  L. Deng et al., “Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: a retrospective cohort study,” J. Infect., pp. 1-5, 2020.
 
[68]  Guangzhou 8th People’s Hospital, “The efficacy of lopinavir plus ritonavir and arbidol against novel coronavirus infection (ELACOI),” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04252885. [Accessed: 24-Apr-2020].
 
[69]  Z. Lv, Y. Chu, and Y. Wang, “HIV protease inhibitors: a review of molecular selectivity and toxicity,” HIV/AIDS - Res. Palliat. Care, vol. 7, pp. 95-104, 2015.
 
[70]  C. M. Chu et al., “Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings,” Thorax, vol. 59, no. 3, pp. 252-256, 2004.
 
[71]  G. Li and E. De Clercq, “Therapeutic options for the 2019 novel coronavirus (2019-nCoV),” Nat. Rev. Drug Discov., vol. 19, no. 3, pp. 149-150, 2020.
 
[72]  R. Han, Y. Wang, M. Dabbous, S. Liang, T. Qiu, and M. Toumi, “Chinese clinical studies for pharmacological treatments of coronavirus disease,” Preprints, p. 202004.0279.v1, 2020.
 
[73]  T. K. Warren et al., “Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys,” Nature, vol. 531, no. 7594, pp. 381-385, 2016.
 
[74]  M. L. Agostini et al., “Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease,” MBio, vol. 9, no. 2, pp. 1-15, 2018.
 
[75]  T. P. Sheahan et al., “Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV,” Nat. Commun., vol. 11, no. 1, 2020.
 
[76]  T. P. Sheahan et al., “Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses,” Sci. Transl. Med., vol. 9, no. 396, 2017.
 
[77]  U.S. Food & Drug Administration, “Coronavirus (COVID-19) update: FDA issues emergency use authorization for potential COVID-19 treatment.,” 2020. [Online]. Available: https://www.fda.gov/news-events/press- announcements/coronavirus-covid-19-update-fda-issues- emergency-use-authorization-potential-covid-19-treatment. [Accessed: 02-May-2020].
 
[78]  Gilead Sciences, “Study to evaluate the safety and antiviral activity of Remdesivir (GS-5734TM) in participants with severe coronavirus disease (COVID-19),” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/study/NCT04292899?term=rem desivir&cond=COVID19&cntry=US&draw=2&rank=1. [Accessed: 24-Apr-2020].
 
[79]  T. Pillaiyar, S. Meenakshisundaram, and M. Manickam, “Recent discovery and development of inhibitors targeting coronaviruses,” Drug Discov. Today, vol. 25, no. 4, pp. 668-688, 2020.
 
[80]  M. Hay, D. W. Thomas, J. L. Craighead, C. Economides, and J. Rosenthal, “Clinical development success rates for investigational drugs,” Nat. Biotechnol., vol. 32, no. 1, pp. 40-51, 2014.
 
[81]  C. H. Wong, K. W. Siah, and A. W. Lo, “Estimation of clinical trial success rates and related parameters,” Biostatistics, vol. 20, no. 2, pp. 273-286, 2019.
 
[82]  David W. Thomas, Justin Burns, John Audette, Adam Carroll, Corey Dow-Hygelund, and Michael Hay, “Clinical Development Success Rates,” BioMedTracker, 2016.
 
[83]  R. Veugelers and G. Zachmann, “Racing against COVID-19: a vaccines strategy for Europe,” Brussels, 2020.
 
[84]  R. H. See et al., “Comparative evaluation of two severe acute respiratory syndrome (SARS) vaccine candidates in mice challenged with SARS coronavirus,” J. Gen. Virol., vol. 87, no. 3, pp. 641-650, 2006.
 
[85]  C. Te Tseng et al., “Immunization with SARS coronavirus vaccines leads to pulmonary immunopathology on challenge with the SARS virus,” PLoS One, vol. 7, no. 4, pp. 1-13, 2012.
 
[86]  Z. Zhou et al., “A recombinant baculovirus-expressed S glycoprotein vaccine elicits high titers of SARS-associated coronavirus (SARS-CoV) neutralizing antibodies in mice,” Vaccine, vol. 24, no. 17, pp. 3624-3631, 2006.
 
[87]  Z. Y. Yang et al., “A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice,” Nature, vol. 428, no. 6982, pp. 561-564, 2004.
 
[88]  J. E. Martin et al., “A SARS DNA vaccine induces neutralizing antibody and cellular immune responses in healthy adults in a Phase I clinical trial,” Vaccine, vol. 26, no. 50, pp. 6338-6343, 2008.
 
[89]  National Institute of Allergy and Infectious Diseases (NIAID), “Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis of SARS-CoV-2 Infection (COVID-19),” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04283461. [Accessed: 05-May-2020].
 
[90]  CanSino Biologics Inc., “Phase I Clinical Trial of a COVID-19 Vaccine in 18-60 Healthy Adults (CTCOVID-19),” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04313127. [Accessed: 05-May-2020].
 
[91]  Institute of Biotechnology, Academy of Military Medical Sciences, PLA of China, “A Phase II Clinical Trial to Evaluate the Recombinant Vaccine for COVID-19 (Adenovirus Vector) (CTII-nCoV),” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04341389. [Accessed: 05-May-2020].
 
[92]  University of Oxford, “A Study of a Candidate COVID-19 Vaccine (COV001),” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04324606. [Accessed: 05-May-2020].
 
[93]  Shenzhen Geno-Immune Medical Institute, “Safety and Immunity of Covid-19 aAPC Vaccine,” 2020. [Online]. Available: https://www.clinicaltrials.gov/ct2/show/NCT04299724. [Accessed: 05-May-2020].
 
[94]  Shenzhen Geno-Immune Medical Institute, “Immunity and Safety of Covid-19 Synthetic Minigene Vaccine,” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04276896. [Accessed: 05-May-2020].
 
[95]  Biontech SE, “Study to Describe the Safety, Tolerability, Immunogenicity, and Potential Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults,” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04368728. [Accessed: 05-May-2020].
 
[96]  Symvivo Corporation, “Evaluating the Safety, Tolerability and Immunogenicity of bacTRL-Spike Vaccine for Prevention of COVID-19,” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04334980. [Accessed: 05-May-2020].
 
[97]  Sinovac Research and Development Co. Ltd., “Safety and Immunogenicity Study of Inactivated Vaccine for Prophylaxis of SARS CoV-2 Infection (COVID-19),” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04352608. [Accessed: 05-May-2020].
 
[98]  Novavax, “Evaluation of the Safety and Immunogenicity of a SARS-CoV-2 rS (COVID-19) Nanoparticle Vaccine With/Without Matrix-M Adjuvant,” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04368988. [Accessed: 05-May-2020].
 
[99]  Inovio Pharmaceuticals, “Safety, Tolerability and Immunogenicity of INO-4800 for COVID-19 in Healthy Volunteers,” 2020. [Online]. Available: https://www.clinicaltrials.gov/ct2/show/NCT04336410. [Accessed: 05-May-2020].
 
[100]  University of Campinas Brazil, “COVID-19: BCG As Therapeutic Vaccine, Transmission Limitation, and Immunoglobulin Enhancement (BATTLE),” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04369794. [Accessed: 05-May-2020].
 
[101]  Ain Shams University, “Application of BCG Vaccine for Immune-prophylaxis Among Egyptian Healthcare Workers During the Pandemic of COVID-19,” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04350931. [Accessed: 05-May-2020].
 
[102]  Texas A&M University, “BCG Vaccine for Health Care Workers as Defense Against COVID 19 (BADAS),” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04348370. [Accessed: 05-May-2020].
 
[103]  Murdoch Childrens Research Institute, “BCG Vaccination to Protect Healthcare Workers Against COVID-19 (BRACE),” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04327206. [Accessed: 05-May-2020].
 
[104]  Universidad de Antioquia, “Performance Evaluation of BCG Vaccination in Healthcare Personnel to Reduce the Severity of SARS-COV-2 Infection,” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04362124. [Accessed: 05-May-2020].
 
[105]  Kasr El Aini Hospital, “Measles Vaccine in HCW (MV-COVID19),” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04357028. [Accessed: 05-May-2020].
 
[106]  ConsorciSanitari de Terrassa, “Influenza Vaccination, ACEI and ARB in the Evolution of SARS-Covid19 Infection,” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04367883. [Accessed: 05-May-2020].
 
[107]  Hilton Pharma, “Experimental Use of Convalescent Plasma for Passive Immunization in Current COVID-19 Pandemic in Pakistan in 2020,” 2020. [Online]. Available: https://clinicaltrials.gov/ct2/show/NCT04352751. [Accessed: 05-May-2020].