key: cord-1043937-tsrvt356
authors: Singh, Satarudra Prakash; Pritam, Manisha; Pandey, Brijesh; Yadav, Thakur Prasad
title: Microstructure, pathophysiology and potential therapeutics of COVID‐19: A comprehensive review
date: 2020-07-03
journal: J Med Virol
DOI: 10.1002/jmv.26254
sha: 06b33da1728bc412c4c4a8aea2e5f7023c38350c
doc_id: 1043937
cord_uid: tsrvt356

There have been over 7 million cases and almost 413,372 deaths globally due to the novel coronavirus (2019‐nCoV) associated disease COVID‐19, as of June 11, 2020. Phylogenetic analysis suggests that there is a common source for these infections. The overall sequence similarities between the spike protein of 2019‐nCoV and that of SARS‐CoV are known to be around 76‐78% and 73‐76% for whole protein and receptor‐binding domain (RBD), respectively. Thus, they have the potential to serve as drug and/ or vaccine candidate. However, the individual response against 2019‐nCoV differs due to genetic variations in the human population. Understanding the variations in Angiotensin‐converting enzyme 2 (ACE2) and human leukocyte antigen (HLA) that may affect the severity of 2019‐nCoV infection could help in identifying individuals at higher risk from the COVID‐19. A number of potential drugs/vaccines as well as antibody/cytokine‐based therapeutics are running in various developmental stages of preclinical/clinical trials against SARS‐CoV, MERS‐CoV and 2019‐nCoV with substantial cross‐reactivity, which may be used against COVID‐19. For diagnosis, reverse transcription polymerase chain reaction (RT‐PCR) is the gold standard test for initial diagnosis of COVID‐19. Kit based on serological tests are also recommended for investigating the spread of COVID‐19 but it is challenging due to antibodies cross‐reactivity. This review comprehensively summarizes the recent reports available regarding the host‐pathogen interaction, morphological and genomic structure of the virus, and the diagnostic techniques as well as available and potential therapeutics against COVID‐19. This article is protected by copyright. All rights reserved.

a.a) as well as eight accessory proteins (3a, 3b, p6, 7a, 7b, 8b, 9b, and orf14) with less functional annotation ( Figure 1 ). 19, [21] [22] [23] [24] [25] The monomer of S protein consists of two subunits (S1 and S2), which self-assemble naturally into a homo-trimer (S-Trimer), typically similar to the class I membrane fusion protein. Further, the S1 subunit contains two domains namely the N-terminal domain (NTD) and the C-terminal domain (CTD) involving the receptor binding domain (RBD) while the S2 subunit contains the basic elements required for membrane fusion, including an internal membrane fusion peptide (FP), two 7-peptide repeats (PR), a membrane proximal external region (MPER), and a trans-membrane (TM) domain. The S1 and S2 domains are conserved among the related coronaviruses with 70 and 99% sequence identity to SARS-CoV, respectively. The RBD of S1 has been reported to come into direct contact with the human receptor angiotensin converting enzyme 2 (ACE2) expressed by epithelia and lung cells.

Although, the exact origin of the novel coronavirus remains unconfirmed 1 

The S protein of 2019-nCoV has been found to be crucial in determining host-pathogen interaction through the mediation of receptor binding and membrane fusion for releasing viral RNA into the cytoplasm for replication. During interactions with humans, the S protein mainly binds to the ACE2 receptor. This receptor is expressed on the cell surface of different organs such as heart, endothelium, liver, kidney, testis, intestine lung and other tissues, out of which alveolar epithelial type II cells include 83% of ACE2presenting cells. [35] [36] [37] [38] [39] [40] The ACE2 receptor binds with higher binding affinity to S protein of 2019-nCoV compared to SARS-CoV due to association of some other receptors including TMPRSS2. 32, [41] [42] [43] [44] The TMPRSS2 is a type II cellular transmembrane serine protease, which is expressed on the surface of epithelial cells and is essential for the activation of S protein, leading to the fusion of the viral membrane into the host cell. 45, 46 Besides these, some analytical evidences also suggest that during evolution of 2019-nCoV certain mutations in the receptor-binding motif (RBM) of RBD favors the binding affinity towards ACE2 and is ultimately responsible for increased transmission rate This article is protected by copyright. All rights reserved.

( Figure 3 ). The RBM motif includes certain important amino acid residues (Gln493, Asn501) that augments the interaction between S protein and ACE2. 47 Therefore, both the S and TMPRSS2 proteins can be used as drug targets to prevent the invasion of 2019-nCoV in host cells. [48] [49] [50] [51] Apart from S protein activation, other factors like valosin-containing protein (VCP) also play role in this infection process. Role of VCP in release of virus from endosome has been shown by mutagenesis. 52 Host factors like interferon inducible transmembrane protein have also been proposed to play role in host-pathogen interaction as antiviral factor in case of RNA viruses affecting humans including human coronaviruses. 53 Post infection replication, transcription and translation of viral genome requires formation of many multi-subunit complexes. One such complex assembled by corona virus contains nsp 14, which acts as exoribonuclease (ExoN) with proof reading ability. 54 Its C-terminal domain causes viral mRNA capping through its N7-guanine methyl transferase (N7-MTase) activity while the N-terminal proof reading ExoN domain plays a role in prevention of lethal mutagenesis. The ExoN may boost the fidelity of RNA synthesis by correcting nucleotide incorporation errors made by the RNA-dependent RNA polymerase (RdRp). The RdRp activity is encoded in nsp12. 55 The aforementioned role of nsp14 has been further evident by binding of a cap-precursor guanosine-P3-adenosine-5′,5′triphosphate to S-adenosyl methionine in proximity of a highly contracted pocket between two β-sheets to accomplish methyl transfer. 56 The crystal structure of SARS-CoV nsp14 has shed light on the interplay between these two domains, and on nsp14's interactions with nsp10. The nsp10 is a cofactor that has been shown to strongly enhance ExoN activity, through in vitro assays. Further in vivo and in vitro studies targeting the factors regulating the structure-function relationships of ExoN and its interactions with other (viral and/or host) members of the CoV replication machinery will be key to reveal the enzyme's role in viral RNA synthesis and pathogenesis. 57 In addition, the phosphorylation of N protein (which also act as RNA chaperon and regulates template switching) by glycogen synthase kinase 3 58 and association of N protein by heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) also regulates viral RNA synthesis. 59 All such events are important as far as the strategies to combat the viral threat are concerned.

When 2019-nCoV enters the human body it interacts with ACE2 receptors and releases its RNA inside the epithelial cells (ECs) where it replicates and released for further infection to neighboring cells and spread from nasal passage to alveolar area of lung. 60 The gaseous exchange is mediated by alveoli but due to 2019-nCoV infection, there is vascular integrity defect (increased permeability and leakage), which causes pulmonary oedema, activation of disseminated intravascular coagulation (DIC), pulmonary ischaemia, hypoxic respiratory failure and progressive lung damage. 61 Further, it enters the blood from respiratory tract through infecting ECs and travel throughout the different parts of the body including brain, gastrointestinal tract, heart, kidney and liver that may lead to cerebral haemorrhage, neural disorder, ischemic stroke, coma, paralysis and eventually death. 62 Moreover, the vulnerability and severity of 2019-nCoV infection in individuals is highly impacted with co-morbidities including hypertension, diabetes and lung diseases and also linked with age and dysregulated innate immune response. This may be due to enhanced expression of ACE2 receptor (an integral membrane protein) on the surface of several organs, including the lung, heart, kidney, intestine as well as ECs of the host. 63 The 2019-nCoV infects ECs through binding with ACE-2 and initiates localized inflammation, endothelial activation, tissue damage, and disordered cytokine release. The severe aggravation of the "cytokine storm" through secretion of vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), IL-8 and reduced E-cadherin expression on ECs contribute to vascular permeability and leakage, which participate in the pathophysiology of hypotension and pulmonary dysfunction in acute respiratory distress syndrome (ARDS). The majority of the COVID-19 patients die due to ARDS where pulmonary ECs contribute to the start and broadcast of ARDS by changing vessel barrier integrity, supporting a pro-coagulative condition, inducing vascular inflammation and reconciling inflammatory cell infiltration. 64 Therefore, understanding the various complications that are attributed to 2019-nCoV on the vasculature is of great significance. The lung ECs are more enhanced in This article is protected by copyright. All rights reserved.

immunomodulatory signatures compared to ECs of other organs including high level expressions of genes associated with major histocompatbility complex (MHC) class IImediated antigen processing, loading and presentation. This suggests that a subtype of lung ECs are acting as semi-professional antigen-presenting cells against respiratory pathogens. It has been also hypothesized that ECs play a central role in the pathogenesis of ARDS and multi-organ failure in patients with COVID-19. In severe COVID-19 infection, there is an activation of coagulation pathways with potential development of DIC. As a result of the DIC and clogging/congestion of the small capillaries by inflammatory cells, as well as possible thrombosis in larger vessels, lung tissue ischaemia develops, which triggers angiogenesis and potential ECs hyperplasia. 65, 66 There are multiple mechanisms proposed for increased vascular permeability and vascular leakage in severe COVID-19 patients elaborately described by Teuwen et al. (2020) . 61 In brief, i) the 2019-nCoV can directly affect ECs that exhibit widespread endotheliitis characterized by EC dysfunction, lysis and death, ii) Further, in order to enter the host cells, 2019-nCoV binds to the ACE2 receptor, which reduces the activity of ACE2, which indirectly turn on the kallikrein-bradykinin pathway with increased vascular permeability, iii) activated neutrophils, recruited to pulmonary ECs, produce histotoxic mediators including reactive oxygen species, iv) immune cells, inflammatory cytokines and vasoactive molecules lead to the increased ECs contractility and the loosening/gap of inter-endothelial junctions, v) the cytokines IL-1β and TNF activate glucuronidases that degrade the glycocalyx but also upregulate hyaluronic acid synthase 2, leading to increased deposition of hyaluronic acid in the extracellular matrix and promoting fluid retention. 67, 61 Moreover, the high levels of cytokines intensify the destructive progression that lead to additional ECs dysfunction, DIC, inflammation and vasodilation of the pulmonary capillary bed. Altogether, these disorders ultimately lead to multi-organ failure and death due to alveolar dysfunction and ARDS with hypoxic respiratory failure. Moreover, it has been proposed that denudation of the pulmonary vasculature could lead to activation of the complement system, promoting the accumulation of neutrophils and proinflammatory monocytes that enhance the cytokine storm, which was also observed during influenza virus infection where pulmonary ECs induce an amplification loop, involving interferon-producing cells and virus-infected pulmonary ECs. 68 Normalization of the vascular wall through metabolic interventions could be considered as an added route of intervention and paves the way for future therapeutic opportunities along with anti-inflammatory, anti-cytokine drugs and ACE inhibitors etc.,. 67 However, some additional indirect evidence also suggests a link between ECs, pericytes and COVID-19.

Therefore, the consequences of 2019-nCoV on the entire vasculature require more concentration. 60 

The micro-structural characterization of 2019-nCoV virus has been carried out using both scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The name Corona was given based on the original SEM image which resembles a crown, as shown in Figure 4 (a, b) . However, the first microstructure of the 2019-nCoV sample was taken from an infected patient at the Vector Institute in Novosibirsk using JEM-1400 TEM with negative contrast method ( Figure 5 ). 69 The size of the 2019-nCoV spherical particle was found to be in the range of 60-140 nanometers ( Figure 6 ). In another study, the negative stained grids and ultrathin sections of the human airway epithelial cell were also observed under TEM by Chinese researchers 70 and these demonstrated some pleomorphism, as shown in Figure 7 (a). Distinctive spikes of about 9-12 nm have been also observed on the external surface of the virus. Additionally, extracellular free viral particles and inclusion bodies filled with virus particles present in membrane bound vesicles in the cytoplasm were observed as shown in Figure 7 (b). Indian scientists from the National Institute of Virology, Pune have also obtained the TEM Images of 2019-nCoV from a sample taken directly from the throat swab specimen of a female patient who returned from Wuhan. 71 A total of seven negative-stained viral particles were imaged in the fields scanned as shown in Figure 8 , clearly depicting the spherical shape of the virus with a cobbled surface structure having envelope projections 75 nm in size.

The presence of stalk-like projections with round peplomeric structures have been observed, along with patchy stain pooling on the surface and a distinct envelope projection ending in round peplomeric (glycoprotein spike on the viral surface) parts.

The immunosenescence, comorbidity, weak immune system, diminished fitness, age related diseases, chronic medical condition and increased frailty because of aging have been found as primary reason for the exacerbated rate of infection and mortality. 72 For the development of efficient active and passive immunization against 2019-nCoV, it is necessary to understand the immuno-pathogenesis of COVID-19. 30 Although, the data available currently on host immune responses against 2019-nCoV is not sufficient, the existing immuno-pathogenesis data of SARS-CoV could be utilized to hypothesize an efficient immunization therapy against COVID-19. 73, 74 According to available evidences, 2019-nCoV can induce innate, cellular as well as humoral immune responses in human. 75, 76 There are many reports suggesting the death of COVID-19 patients due to an extreme response of their immune system i.e., abnormal release of circulating cytokines, termed cytokine release syndrome (CRS). These numerous cytokines released in COVID-19 patients are termed as "cytokine storm" including IL-6, IL-1, IL-2, IL-10, TNF-α and IFN-γ. 77 which showed a positive correlation with disease severity. In addition, increased level of anti-inflammatory cytokines such as IL-4 and IL-10 were also induced by the human immune system against 2019-nCoV infections. 7, [80] [81] [82] [83] [84] The over secretion of cytokines could damage the lung, resulting in the death of the COVID-19 patient. Thus, in order to reduce the lung damage, neutralizing anti-TNF-α, -IL1 and -IL6 antibodies may be utilized to block their biological activity, as they have been previously used in the treatment of other diseases such as cancer, type 2 diabetes, leukemia, etc. [85] [86] [87] During pretreatment study of type I interferon, 2019-nCoV has shown higher sensitivity than SARS-CoV. 88 This variation may be due to several types of modifications in SARS-CoV genome, such as the lack of ORF3b and variations in ORF6 (short truncation). In addition, high level of follicular helper T cells, antibody-secreting cells, antibodies (IgM and IgG), and activated CD4+ as well as CD8+ T cells were confirmed in the infected patients. 40, 89 With respect to humoral immune responses, 403 B cell assays have been reported, which involve different antibodies (IgA, IgG, IgG1, IgG2a, IgG2b and IgM) including linear and discontinuous B-cell epitopes. A comparative study of known epitopes (432 B cell epitopes and 164 T cell epitope) of SARS-CoV with predicted epitopes of 2019-nCoV using contemporary bioinformatics tools has been conducted by Grifoni et al. 90 (Table 1 ).

The 3D structure of S protein of 2019-nCoV in closed state (PDB ID: 6VXX) and open state (PDB ID: 6VYB) is also available at RCSB PDB database 37 and the same has been utilized to predict a potential B cell epitope for designing therapeutics e.g., vaccine and neutralizing antibodies (NAbs). 91, 92 These NAbs can be used for passive immunization therapy (e.g., Convalescent plasma therapy (CPT)), which have shown significant benefits in treatment of severe COVID19 patients. 93, 94 Although, cellular immune responses (CD4+ and CD8+ T cells) against 2019-nCoV have been found activated but due to innate immune escape mechanism of 2019-nCoV, T cell immune response is delayed and it failed to provide significant protection to COVID-19 patients. [95] [96] [97] [98] Besides these, "cytokine storm" also results in functional collapse of T cell counts in COVID-19 patients. While, during recovery, decrease in level of IL-6, IL-10, and TNF-α increases the total T cell (CD4+ and CD8+) counts in COVID-19 patients. 99 The immune escape mechanism of 2019-nCoV can be overcome by blocking the overexpression of NK group 2 member A (NKG2A) receptor using monoclonal antibody such as Monalizumab. 100 

components, and life-cycle stages; and ii) the host response, including the synthesis of micro or macro metabolites. For a virus like 2019-nCoV, where the genome and nucleocapsids are considerably similar to epidemic predecessors like SARS-CoV or MERS-CoV viruses, diagnostic development with high species specificity becomes a challenge. As per WHO guidelines and suggestions, the diagnosis of 2019-nCoV may rely upon methods that take into account two or more targets simultaneously. For screening purposes, RT-PCR based methods that target of more than one region of viral RNA (one specific for 2019-nCoV and another from related β-coronaviruses) have been recommended for asymptomatic or mildly symptomatic cases. Depending upon expertise and automation, the real-time RT-PCR based diagnostics require 2-5 hours. These two requirements make the molecular testing slow and limited as it requires at least BSL-2 and/ or BSL-3 facilities for the testing and culture of deadly viruses, respectively. Beyond this method, a nucleic acid amplification test (NAAT) is not sufficient and the test for confirmation of beta-coronavirus is also required. As per advice, the NAAT needs to include dual controls (both external and internal). Therefore, final confirmation needs to be done by nucleic acid sequencing and additional alignment with known strains. The Abott Company has developed a rapid test kit which produces results within 5 minutes of testing (Abbott ID Now™ . This molecular test relies on isothermal amplification of nucleic acid and uses an instrument called ID Now to monitor RNA dependent RNA polymerase (RdRP) of 2019-nCoV. 102 Another German company Tib-MolBiol has developed a detection system that relies upon RT-PCR and focuses on RdRP as well as E gene assays. It has claimed no cross-reaction with other coronaviruses. 103 In addition, Chu et al 104 have also reported another assay based on RT-PCR of ORF1b (screening gene) and N gene (confirmatory gene).

Comparatively rapid methods (in 1 hr) SHERLOCK and DETECTR (based on CRISPR technology) have been developed for diagnosis by Sherlock biosciences and Mammoth biosciences, respectively. 105 Former method relies on Cas13, which excises reporter RNA sequence when activated by 2019-nCoV guide RNA (https://www.broadinstitute.org/files/publications/special/COVID-19%20detection%20(updated).pdf). The later one relies on identification of viral E and N specific RNAs by Cas12a using the reporter RNA. 106 Another method called amplicon based metagenomic sequencing 107 (using MiniION based sequencing) has also been proposed, which claims the process to be completed within 8 hrs. In a more diverse approach the next generation sequencing (NGS) method for sequencing whole genome of 2019-nCoV has also been reported where viral RNA has been reverse transcribed and the sequencing library was created and subjected to sequencing and analysis by Miseq150 PE and CLC workbench. 108 Alternatively, serological tests are also recommended for investigating the extent and spread of ongoing the outbreak and to verify the efficacy of any tests that will be devised in the future. Although, serological testing for the confirmation of COVID-19 is a challenge due to antibodies cross-reactivity with other related coronaviruses but they hold their own significance with regard to screening and evaluation of disease status.

Recently, an IgM and IgG (produced in response to 2019-nCoV infection) based test has been proposed by Bio Medomics, USA that can be used to assess the infectious cases merely in 10 minutes, after 10-30 days and 20 days of antibody production, respectively. 109 Moreover, such tests require only a little volume of blood (10-20 microliters). These antibody based assays not only contribute significantly towards screening the patients and health workers, but also indicate their health and immune status. 102 

Vaccinations is the most effective and economical way to prevent and control corona infections, but have so far been unsuccessful due to the extensive antigenic sequence diversity of the virus. 112 The aforementioned limitations could be avoided by selection of non exposed N protein as DNA vaccine candidate that can induce antibodies that will not be able to facilitate viral entry, while simultaneously being capable of eliminating the virus from the host through cellular immune response. 129 Another significant hindrance is the higher genetic diversity (hyper mutation) of RNA viruses compared to DNA viruses. 145, 146 Animal models (mouse and rhesus monkey) related to human ACE2 transgenic of COVID-19

have been well established for vaccine development, 147 including synthetic reconstruction of SARS-CoV-2 genome. 148

There is substantial progress in the design and development of vaccines, involving the This article is protected by copyright. All rights reserved.

Diseases (NIAID) and CEPI (https://www.modernatx.com/modernas-work-potentialvaccine-against-covid-19). 155 The mRNA based vaccines is advantageous over DNA vaccines due to non-requirement of host genome integration, the improved immune responses, and production of multimeric antigens. 156 Researchers for membrane fusion. 160 Chloroquine also hampers entry of virus by glycosylating ACE2 and S protein. 161 Hydroxychloroquine has been found to cause delay in the entry and post-entry stage 162 and therefore, seems to possess a prophylactic role. Accumulation of chloroquine or its analogs leads to the dysfunction of several enzymes of these organelles responsible, particularly those for post translational modification of viral proteins or proteolytic processing. 163 In a news release, National Institutes of Health, U.S.

azithromycin to assess their impact on COVID-19 patients as therapeutic agent (https://www.nih.gov/news-events/news-releases/nih-begins-clinical-trialhydroxychloroquine-azithromycin-treat-covid-19). The foundation has been laid down by a report where hydroxyxchloroquine supplemented with Azithromycin has been found effective in treatment of COVID-19 patients in a random trial. 164 However, in light of recent publications and uncertainties related to the safety and efficacy of chloroquine/ hydroxychloroquine, it is worth being careful to use these drugs in medical prescription until further elevated quality randomized clinical trials are available to elucidate their function in the management of COVID-19 (https://www.who.int/dg/speeches/detail/whodirector-general-s-opening-remarks-at-the-media-briefing-on-covid-19---03-june-2020). 165, 166 In addition the α-interferon (e.g., 5 million units by aerosol inhalation twice per day) is also being used. In Italy, a major investigation led by the Istituto Nazionale Tumori, Fondazione Pascale di Napoli is focused on the use of Tolicizumab. It is a humanized IgG1 mAb, directed against the IL-6 receptor that is commonly used in the treatment of rheumatoid arthritis. 167 Preclinical studies suggested that remdesivir 

TMPRSS2 activity that eventually prevents entry of 2019-nCoV to the host cell. [170] [171] [172] Several in silico studies have also lit a ray of hope in the search for potential drugs ( Figure 9 ). In an important study to find RdRP inhibitors, Elfiky 173 has reported the efficacy of sofosbuvir, IDX-184, ribavirin, and remdesivir, based on molecular docking studies. In view of many suggestions from clinical practitioners to go with symptom management during COVID-19, the role of anti-inflammatory agents cannot be underestimated. Russell et al. 174 have concluded in a review that corticosteroids may be used as anti-inflammatory but not in the acute stages of infection. It has further been reported that intravenous administration of vitamin C may also reduce mortality. 175 

As 

public health should move towards the risk of COVID-19 by promoting spatial distance together with social closeness. 182 Further, some lower-and middle-income countries like African, Asian, and Latin American ones require technical and financial support to successfully respond against COVID-19 by rapidly developing the capacity for testing.

Epidemiological reports in China advocate that up to 85% of human-to-human transmission has occurred in family clusters. 183 Based on the data available so far, and analysis conducted by Mantovani et al. (2020) , it has been revealed that COVID-19 infect men and women similarly, but men appear to have a higher risk of death than women due to higher expression of ACE2 receptor linked with higher prevalence of smoking. 184 Qazi et al. (2020) evaluated the influence of information (formal and informal) sources on situational awareness of the public for adopting health-protective behaviors such as social distancing towards COVID-19 using a questionnaire-based survey model. 185 In which, the information sources, formal (P = 0.001) and informal (P = 0.007) were found to be significantly related to perceived understanding and further, social distancing is significantly influenced by situational awareness (P = 0.000). This article is protected by copyright. All rights reserved.

• The large scale, international, multi-centric, individually randomized controlled clinical trial will facilitate the synchronized evaluation of the benefits as well as risks of each promising drug and vaccine candidate within one year.

• Before we get the successful therapy against COVID-19 that may ultimately be helpful in controlling worldwide pandemic, each person must follow the WHO recommendations and guidelines to prevent the transmission of the novel virus.

•We believe that these coordinated research and development efforts will help to reduce duplication of the work as well as increase the possibility of getting one or more safe and effective therapy to the vulnerable world population.

This study was self-financed and did not receive any grant from funding agency.

The authors declare that they have no conflicts of interest. 

This article is protected by copyright. All rights reserved.

We acknowledge the support from Global initiative on sharing all influenza data (GISAID) and others for providing images related to COVID-19. Pre-Clinical

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Characterization of novel monoclonal antibodies against MERS-coronavirus spike protein

A novel neutralizing monoclonal antibody targeting the N-terminal domain of the MERS-CoV spike protein

The recombinant N-terminal domain of spike proteins is a potential vaccine against Middle East respiratory syndrome coronavirus (MERS-CoV) infection

Efficacy of an Adjuvanted Middle East Respiratory Syndrome Coronavirus Spike Protein Vaccine in Dromedary Camels and Alpacas

T-cell immunity of SARS-CoV: Implications for vaccine development against MERS-CoV

Antibody response of patients with severe acute respiratory syndrome (SARS) targets the viral nucleocapsid

Cytotoxic T lymphocytes are critical in the control of infectious bronchitis virus in poultry

Adoptive transfer of infectious bronchitis virus primed alphabeta T cells bearing CD8 antigen protects chicks from acute infection

Generation and characterization of DNA vaccines targeting the nucleocapsid protein of severe acute respiratory syndrome coronavirus

Severe acute respiratory syndrome coronavirus envelope protein ion channel activity promotes virus fitness and pathogenesis

Epitope-Based Vaccine Target Screening against Highly Pathogenic MERS-CoV: An In Silico Approach Applied to Emerging Infectious Diseases

Design of multi epitope-based peptide vaccine against E protein of human 2019-nCoV: An immunoinformatics approach. bioRxiv 2020

Understanding of COVID-19 based on current evidence

COVID-19, an emerging coronavirus infection: advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics

Possible method for the production of a Covid-19 vaccine

Probable Pangolin Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak

Human transbodies that interfere with the functions of Ebola virus VP35 protein in genome replication and transcription and innate immune antagonism

New coronavirus threat galvanizes scientists

Composition and divergence of coronavirus spike proteins and host ACE2 receptors predict potential intermediate hosts of SARS-CoV-2

Modulation of Dengue/Zika Virus Pathogenicity by Antibody-Dependent Enhancement and Strategies to Protect Against Enhancement in Zika Virus Infection

Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry

Why are RNA virus mutation rates so damn high?

Current Status of Epidemiology, Diagnosis, Therapeutics, and Vaccines for Novel Coronavirus Disease 2019 (COVID-19)

Rapid reconstruction of SARS-CoV-2 using a synthetic genomics platform

Human challenge studies to accelerate coronavirus vaccine licensure

Developing Covid-19 Vaccines at Pandemic Speed

Recent Advances in the Vaccine Development Against Middle East Respiratory Syndrome-Coronavirus

Development of epitope-based peptide vaccine against novel coronavirus 2019 (SARS-COV-2): Immunoinformatics approach

Potential Rapid Diagnostics, Vaccine and Therapeutics for 2019 Novel Coronavirus (2019-nCoV): A Systematic Review

Progress and challenges in research and development of new coronavirus vaccines. Advance online publication

mRNA vaccines -a new era in vaccinology

Ensuring global access to COVID-19 vaccines

Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro

Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion

New insights into the antiviral effects of chloroquine

Community Transmission of Severe Acute Respiratory Syndrome Coronavirus 2

Effects of chloroquine on viral infections: an old drug against today's diseases?

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label nonrandomized clinical trial

Therapeutic use of chloroquine and hydroxychloroquine in COVID-19 and other viral infections: A narrative review

Evaluation and Treatment Coronavirus (COVID-19)

The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus

Middle East respiratory syndrome coronavirus infection mediated by the transmembrane serine protease TMPRSS2

Coronavirus puts drug repurposing on the fast track

2019-nCoV) uses the SARS coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells

Associations between immunesuppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence

A new clinical trial to test high-dose vitamin C in patients with COVID-19

Effectiveness of convalescent plasma therapy in severe COVID-19 patients

Convalescent serum lines up as first-choice treatment for coronavirus

Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review

SARS-CoV-2 and SARS-CoV Spike-RBD Structure and Receptor Binding Comparison and Potential Implications on Neutralizing Antibody and Vaccine Development

The COVID-19 pandemic calls for spatial distancing and social closeness: not for social distancing!

COVID-19: towards controlling of a pandemic

Coronavirus disease 2019 (COVID-19): we don't leave women alone

Analyzing situational awareness through public opinion to predict adoption of social distancing amid pandemic COVID

RNA Replicating Defective SARS-CoV-2 derived RNAs Centro Nacional Biotecnología (CNB-CSIC)