Ashwini M. Patila Joachim R. Götherta Vishal Khairnarb
aDepartment of Hematology, West German Cancer Center (WTZ), University Hospital of Essen, University of Duisburg-Essen, Essen, Germany, bInstitute of Immunology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Key Words
COVID-19 • SARS-CoV-2 • Transmission • Therapeutic options • Antiviral therapies
Abstract
The pandemic of the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 at the end of 2019 marked the third outbreak of a highly pathogenic coronavirus affecting the human population in the past twenty years. Cross-species zoonotic transmission of SARS-CoV-2 has caused severe pathogenicity and led to more than 655,000 fatalities worldwide until July 28, 2020. Outbursts of this virus underlined the importance of controlling infectious pathogens across international frontiers. Unfortunately, there is currently no clinically approved antiviral drug or vaccine against SARS-CoV-2, although several broad-spectrum antiviral drugs targeting multiple RNA viruses have shown a positive response and improved recovery in patients. In this review, we compile our current knowledge of the emergence, transmission, and pathogenesis of SARS-CoV-2 and explore several features of SARS-CoV-2. We emphasize the current therapeutic approaches used to treat infected patients. We also highlight the results of in vitro and in vivo data from several studies, which have broadened our knowledge of potential drug candidates for the successful treatment of patients infected with and discuss possible virus and host-based treatment options against SARS-CoV-2.
Introduction
Beginning in December 2019, a cluster of pneumonia-like cases of unidentified etiology emerged at the Wuhan livestock market in Wuhan, China [1, 2],initially referred to as novel coronavirus 2019 (2019-nCoV) [3, 4].On 30 January 2020, the World Health Organization (WHO) declared this an outbreak, which was recognized as a pandemic on 11 March 2020 [5]. Genome sequencing of 2019-nCoV showed the virus shared 79.5 % similarity in genetic sequence with SARS-CoV, the previously known coronavirus responsible for the 2002-2003 SARS epidemic [6]. Therefore, the International Committee for the Taxonomy of Viruses has renamed the coronavirus 2019-nCoV to SARS-CoV-2, causing Coronavirus Disease 2019 (COVID-19). The coronaviruses are named after their crown-like spines on the surface [7]. SARS-CoV-2 was spread to other Asian countries through people who became infected and then traveled outside of China [8]. On 13 January 2020, the first known infection outside Mainland China was reported in Thailand [9], and then soon after, in Japan on 15 January 2020 [10]. Since then, the infection has spread to more than 188 countries and territories, resulting in community transmission in those countries, which caused a widespread outbreak resulting in a significant death toll worldwide.
The SARS-CoV-2 is the most recent in a whole family of seven coronaviruses known to infect humans. Although SARS-CoV and MERS-CoV are the deadliest coronaviruses of the group, the other four human coronaviruses such as HCoV-OC43 [11], HCoV-229E [12], HCoV-NL63 [13], and HCoV-HKU1 [14] are known to cause the majority of all common cold cases [15, 16]. In several instances, these coronaviruses can lead to severe illnesses such as pneumonia and bronchiolitis [13, 14]. These coronaviruses are also known to be associated with the development of neurological diseases [17, 18]. Of the entire family of the virus, SARS-CoV-2 has proven to be the deadliest coronavirus to date, infecting more than 16 million people globally, with an approximate mortality rate of 4.0 % at the time of writing this review [19]. Respiratory droplets primarily spread the virus by coughing and sneezing [20]. In addition, it is known that the virus can live on various surfaces for hours, and on some, up to several days [21]. Individuals can become infected by coming into contact with a contaminated surface and then touching their face soon after without a proper washing in between [20]. Once on the body, the coronavirus can pass through the eyes, nose, or mouth, and may enter the upper airways of the respiratory system [20]. Like SARS, SARS-CoV-2 can penetrate the respiratory system and the lung epithelial cells where the primary viral replication occurs. It can then further spread to the epithelial membranes of the upper gastrointestinal tract (GI), secondary lymphatic organs, and small systemic vessels [6, 22-26]. The virus can then infiltrate the cells, which can lead to frequent symptoms such as fever, cough, and fatigue, although it can also cause symptoms such as shortness of breath, sore throat, and diarrhea [27, 28]. Most cases lead to mild symptoms, while others can develop into an acute respiratory distress syndrome (ARDS), multiple organ failure, septic shock, and blood clots [2, 29-31]. Additionally, patients affected by SARS-CoV-2 have shown neurological symptoms such as seizures, stroke, encephalitis, and Guillain-Barre syndrome [32]. A significant percentage of COVID-19-infected patients have shown elevated levels of liver enzymes, including alanine transaminase (ALT) and aspartate aminotransferase (AST), indicating severe immunopathology causing liver damage [33].
The exponential spread of SARS-CoV-2 infection has presented a severe threat to public health even with universal prevention, social distancing, and quarantine measures employed throughout most countries. The lack of specific antiviral treatments/drugs, along with a high load of infected patients, has resulted in several thousands of direct and indirect deaths worldwide. This review addresses the pandemic and possible treatment options for emerging SARS-CoV-2. In general, we focus on the current state of knowledge regarding SARS-CoV-2, including its transmission, pathogenesis, the possible antiviral and immunotherapeutic approaches and alternatives available to treat infected patients.
The pathogenesis of coronaviruses
In humans, coronaviruses (CoVs) cause various diseases, including central nervous system diseases, gastroenteritis, and respiratory illness. CoVs are associated with a high mutation rate, which makes the Coronaviridae family dynamic and diverse in terms of pathogenicity [34]. Seven coronaviruses are known to infect humans (HCoVs) circulating worldwide, with a higher infection rate being observed mainly in infants. The first human coronaviruses identified in the mid-1960s, HCoV-OC43 [11], and HCoV-229E [12], were associated with a range of respiratory symptoms. At the beginning of the 21st century in November 2002, the first known case of the SARS-CoV was reported in Foshan, southern China [35]. This virus soon became a global outbreak spreading to neighboring regions and countries with 8437 cases reported along with a mortality rate of 10.0 % [36]. Subsequently, in 2004 and 2005, two new strains of human coronaviruses were discovered, HCoV-NL63 [13] and HCoV-HKU1 [14], respectively. The next coronavirus outbreak occurred nearly a decade after SARS-CoV, in 2012, when a second highly pathogenic CoV, known as the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), emerged in Saudi Arabia with 2494 confirmed cases and with a 35.0 % mortality rate [37-39]. The identification of diverse coronaviruses in bats, including many SARS-related coronaviruses, provides strong evidence that zoonotic transmission events may continue in the future, resulting in periodic outbreaks of coronaviruses in humans over time [6, 40, 41].
The SARS and MERS outbreaks were zoonotic transmissions resulting from hospital-acquired human-to-human transmissions associated with high mortality rates [38]. The hypothesis has been put forward that CoVs entered the human population through one or more intermediate animal hosts. In SARS and MERS, the intermediate host animal is believed to be civet cats, and dromedary camels, respectively [42-44]. The virus probably jumped from bats to such hosts [40, 45]. The virus then underwent several rounds of replication and acquired mutations in the hosts that facilitated its transmission to the human population [46-48]. Unlike SARS, the MERS infections are still periodic, and probably not circulating in the human population. Although this virus does not transmit very well from humans to humans, the new cases are thought to occur from occasional recurrent spillovers from dromedary camels into the human population. It is of enormous concern that the third deadliest coronavirus in recent times, SARS-CoV-2 has caused zoonotic leaps into the human population in less than twenty years. It has posed another challenge to virologists and pathologists to understand the mechanism of viral transmission.
At the overall genome level, Pangolin-CoV showed 91.02 % similarity to SARS-CoV-2, and 90.55 % to Bat-CoV-RaTG13. The genome of Pangolin-CoV is most closely related to SARS-CoV-2, suggesting that pangolin could serve as a reservoir and intermediate host for the zoonotic transmission of the new SARS-CoV-2 (Fig. 1) [49, 50].
Structure and Genomics of SARS-CoV-2
Coronaviruses contain the largest genomes ranging from 26 to 32 kilobases (kb) of all RNA virus types. The RNA genome of SARS-CoV-2 is composed of single-stranded RNA with a size of 29.9 kb [51]. Human CoVs, including the novel 2019 SARS-CoV-2, are positive-stranded RNA viruses [52, 53]. CoVs are enveloped viruses (envelope is a lipid bilayer derived from the host cell membrane) with the viral structure formed primarily of structural proteins such as envelope (E), membrane (M), nucleocapsid (N) proteins, hemagglutinin-esterase (HE) protein, and spike (S) protein (Fig. 2A left panel) [34, 54, 55]. According to the International Committee for the Taxonomy of Viruses, the human coronaviruses HCoV-OC43 and HCoV-HKU1 are members of the betacoronavirus genus [56, 57] and bind to the 9-O-acetylated sialic acid (9-O-Sia) receptor located on the host cell [58, 59], which causes illnesses such as cold and upper and lower respiratory diseases. However, HCoV-229E and HCoV-NL63 belong to the genus of alphacoronaviruses [60, 61], which trigger the common cold in humans by binding to the aminopeptidase N (APN [62] and angiotensin-converting enzyme 2 (ACE-2) [63] receptors respectively. While SARS-CoV, MERS-CoV, and SARS-CoV-2 are members of the genus of betacoronaviruses [53], MERS-CoV attaches to human dipeptidyl peptidase 4 (hDPP4) [64] while SARS-CoV and SARS-CoV-2 bind to the human ACE-2 (hACE-2) receptor [65, 66] located on the host cell via spike (S) protein to enter the target cells [67, 68].
The receptor-binding domain (RBD) in the spike (S) protein recognizes the ACE-2 receptor expressed on the epithelial layer of lungs, heart, kidneys, and intestine and is responsible for the attachment of the virus to the host cell membrane [69]. During infection, the monomer of the homomeric S protein of the viral particle is cleaved into two subunits (S1 and S2) by proteases [70, 71]. The cleavage and subsequent activation of the S protein prior to membrane fusion is necessary to release the fusion peptide into the host cell membrane. Within the structure, the N- and C-terminal sections of S1 fold up in two independent domains, the N-terminal domain (NTD) and the C-terminal domain (CTD). Either the NTD or the CTD can serve as RBD, depending on the virus. However, the majority of other CoVs, such as SARS-CoV and MERS-CoV, utilize the CTD to bind their receptors [72, 73]. The S2 subunit is further cleaved and activated by the host transmembrane protease serine 2 (TMPRSS2), which is crucial for the invasion of SARS-CoV-2 (Fig. 2A, right panel)[74, 75]. Following the attachment of a SARS-CoV-2 viral particle to a target cell, the cellular protease TMPRSS2 cleaves the spike protein of the virus, thereby releasing a fusion peptide. The virion subsequently releases RNA intracellularly via mechanisms described below, which causes the cell to generate and disseminate replicas of the viral particle that can infect other cells.
The SARS-CoV-2 genome consists of 5’ and 3’ terminal sequences (265 nt in the 5’-terminal and 229 nt in the 3’-terminal region) [51]. The genome of CoVs contains a variable number of open reading frames (ORFs) [76]. The viral RNA of the first ORF (ORF1a/b) codes for two polyproteins, pp1a and pp1ab, and encodes 16 non-structural proteins (NSP). The rest of the ORFs encode accessory and structural proteins, which are processed by virally encoded chymotrypsin-like protease (3CLpro) or main protease (Mpro), and further by two viral papain-like proteases PL1pro and PL2pro to produce 16 non-structural proteins (nsp1 to nsp16) (Fig. 2B). It also produces various proteins, including RNA-dependent RNA polymerase (RdRp), RNA helicase, and exoribonuclease (ExoN) [52, 77]. This leads to the formation of a replication complex, including RdRp, which directly facilitates the synthesis of negative-sense genomic RNA from positive-sense. After replication and subgenomic RNA synthesis, the viral structural proteins S, E, and M are translated and packed into the endoplasmic reticulum (ER). As a result, the proteins migrate along the secretory pathway into the endoplasmic reticulum-Golgi (ERGIC) inter compartment [52, 78]. The N protein, capsid, and viral genomes in ERGIC membranes are assembled with viral structural proteins and form mature virions [79]. These newly synthesized virions are transported in vesicles to the cell surface and released by exocytosis (Fig. 3).
According to Zhou P. et al., a short region of RdRp isolated from bat coronavirus (Bat-CoV-RaTG13) has shown high sequence similarity with SARS-CoV-2 [6]. Additionally, the spike (S) protein of SARS-CoV-2 shares about 76.0 % and 97.0 % of the amino acid (AA) sequence with SARS-CoV and Bat-CoV-RaTG13, respectively. The AA sequence of the RBD of SARS-CoV-2 is approximately 74.0 % and 90.1 % homologous to SARS-CoV and Bat-CoV-RaTG13, respectively [80].
Current and potential treatment options for SARS-CoV-2
The interaction between the RBD in the S protein of SARS-CoV-2 and the ACE-2 receptor on the cell surface of the host triggers the infection. Current therapeutic approaches to eradicate the infection are based mainly on either use of antiviral drugs or therapeutic molecules that target any phase of the viral life cycle in the host cell or targeting the cell surface receptor, which can block the interaction of the virus with the receptor ACE-2, and its entry in the host cell (Fig. 3 and Table 1).
Antibody treatment against SARS-CoV-2
As the global spread of SARS-CoV-2 continues to harm large populations, development of an antiviral antibody-based treatment could effectively produce a passive immunity against viral infection. Neutralizing antibodies secreted by B cells are potent in the antiviral immune defense system as they last longer compared to T cell memory [81]. Previously, we along with others, have shown that neutralizing antibodies are more efficient in priming CD8+ T cells and viral control with minimal immunopathology [82, 83]. Several studies carried out using various animal models indicate that neutralizing antibodies targeting the spike (S) protein of SARS-CoV is efficient in protecting against disease by directly reducing viral titers in the lungs [84-86]. SARS-CoV can elicit both humoral and cellular immune response as high levels of neutralizing antibodies, and virus-specific T cell responses have been detected in patients who have successfully recovered from this infection [86-88]. Neutralizing antibodies, which are capable of targeting RBD in spike protein or antibodies that bind to the ACE-2 can effectively block the entry of the virus and improve the outcome of the infection. In addition, antibodies that recognize epitopes within the RBD could prevent the virus from attaching to its receptor. In line with this, an antibody that had previously shown binding to epitopes upstream of the RBD prevented the SARS-CoV entry by inhibiting post-binding events [89]. Although recent studies report the development of few SARS-CoV-2 specific neutralizing antibodies, the previous research and data generated for SARS-CoV and MERS-CoV can be used to identify effective monoclonal antibodies against SARS-CoV-2 [90]. To this end, CR3022, a SARS-CoV-specific human monoclonal antibody, showed potent binding only to the RBD of SARS-CoV-2, which leaves the ACE-2 receptor to target for combinational antibody therapy [91]. One of the most recent studies identified 47D11 H2L2 as a potent monoclonal antibody (mAb) showing an effective inhibition of the pseudotyped Vesicular Stomatitis Virus (VSV) SARS-CoV-2 infection by an unknown mechanism [92]. However, literature on RBD-targeting antibodies suggests that the most likely mechanism could be antibody-mediated inactivation of the spike (S) protein [92]. In addition, the combination of the mAbs identified from memory B cells of SARS-CoV infected individual showed an effective cross-neutralization of SARS-CoV-2 [93]. Similarly, two SARS-CoV-2 specific mAbs CA1 and CB6 isolated from a convalescent COVID-19 patient demonstrated potent neutralization activity in vitro [94]. Therefore, antigen cross-reactivity and complete cross-neutralization of the live virus must be analyzed for immunogen design and vaccine development, and the use of a combination of neutralizing antibodies could be a better strategy to nullify escape mutants.
Considering the severity and urgency of the current situation, critically ill or high-risk patients infected with SARS-CoV-2 require immediate treatment options. A potentially useful approach could be the use of intravenous immunoglobulin (IVIg) pull of IgG from fully recovered donors from the same city or area to neutralize the virus in patients effectively [95]. According to present knowledge on the treatment of the viral infections, administration of convalescent plasma or hyper-immune immunoglobulin from the patients who have successfully recovered from SARS-CoV-2 infection and are without detectable levels of viral titers in sera is likely able to reduce the viral load and mortality in infected patients [85, 96]. In this scenario, the administration of convalescent plasma containing neutralizing antibodies in patients infected with SARS-CoV-2 improved their health status within 2 to 5 weeks, with reduction in body temperature (within three days) and negative viral loads (within 12 days) after transfusion [97]. However, a vital challenge of this method is the availability of enough samples, donors, and viral kinetics data. Developing highly specific antiviral monoclonal antibodies is an effective and safe way to prevent the spread of infectious diseases. However, an anti-SARS-CoV antibody response may be short-lived compared to SARS-CoV-specific memory CD8+ T cells, which can be detected up to 6 years post-infection [98, 99]. Although anti-SARS-CoV neutralizing antibodies are effective in controlling viral infection [100], pre-existing SARS-CoV-specific CD8+ T cell response in mice protected the host against a fatal second SARS-CoV infection due to an efficient effector/memory CD8+ T cell response that resulted in faster elimination of viral load in the host [101]. However, this approach requires an effective CD4+ T cell help and antibody response too [98, 101, 102]. Therefore, the therapeutic outcome of the treatment with antibody or convalescent plasma depends on other effector functions and T cell help. Thus, immunotherapeutic approaches can be a breakthrough in the current pandemic situation by providing additional support through the administration of antibodies that bind to multiple epitopes in RBD as well as other regions that either can block the binding of the virus and its cellular receptor or neutralize the virus to minimize the mutant escape.
Inhibitors for target receptors
Inclusion of SARS-CoV in the host cell is associated with the binding of the spike (S) protein to its cellular receptor ACE-2 in the type II pneumocytes in the lungs. TMPRSS2, a type II transmembrane protease mediates cleavage of ACE-2, which facilitates the internalization and activation of the viral particle in the cell [74, 103]. Recently, it was discovered that SARS-CoV-2 binds to the receptor ACE-2 [68]. Therefore, targeting ACE-2 and/or TMPRSS2 are effective strategies for reducing viral invasion and replication of the virus in the host cells. Chloroquine, which is generally used in malaria treatment, showed a significant antiviral response against SARS-CoV-2 both prior and post viral infection [104]. Mechanistically it interferes with the terminal glycosylation of cellular receptor ACE-2, which blocks the virus-cell fusion [105]. Although there is sufficient preclinical evidence for the efficacy of chloroquine treatment, the clinical value of this drug in patients with SARS-CoV-2 infection and the drug dosage should be further evaluated in ongoing clinical trials [106-108]. Losartan and Telmisartan are angiotensin II type 1 receptor (AT1R) antagonists that are widely used in the clinic to treat hypertension and kidney disorders may limit the entry of SARS-CoV-2 into the cell and could help to reduce ARDS and aggressive inflammation [109, 110]. Patients with previous health conditions such as hypertension, heart disease, diabetes mellitus, chronic kidney diseases, as well as elderly patients receiving renin-angiotensin treatment or angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) are not required to discontinue current treatment due to the increased expression of ACE-2 receptor in the bloodstream [111, 112]. ACEIs and ARBs do not lead to any complications associated with COVID-19 [113, 114]. Similarly, a TMPRSS2-targeting serine protease inhibitor Camostat mesylate efficiently blocked the entry of replication-deficient VSV carrying SARS-CoV-S protein, which is a licensed drug for oesophagitis and pancreatitis in Japan [75, 115]. Nafamostat mesylate, another clinically approved TMPRSS2 inhibitor, is also found to be effective in inhibiting the cell entry of SARS-CoV-2 [104, 116]. Collectively, preventing the binding of the viral particles by targeting the cell surface receptors can affect virus-cell fusion and viral invasion and may significantly improve the health status of COVID-19 patients.
Endocytosis blockers
Viral entry and subsequent replication in cells depend on the interaction between the viral envelope and the host cell membrane receptors. Following the binding of SARS-CoV-2 to the cell surface receptors, the virus requires exposure to host cytosol by the fusion of viral and cellular membranes by endocytosis, which is the formation of the endosome, internalizing viral particles surrounded by the cell membrane. Subsequently, the viral genome is released by endosomal acidification and exocytosis into the cytoplasm of the host cells [52]. A recent study has shown that cathepsin L mediated endocytosis transmits SARS-CoV-2 into the cell [80]. Therefore, agents that block the virus-cell or cell-cell endocytic fusion are potentially interesting candidates to suppress viral replication in patients infected by SARS-CoV-2. Teicoplanin, a glycopeptide antibiotic, was shown to be effective in blocking the entry of Ebola by inhibiting cell invasion, as well as both SARS-CoV and MERS-CoV by specifically inhibiting the activity of cathepsin L [117]. Teicoplanin was also shown to effectively inhibit the entry of SARS-CoV-2 spike pseudoviruses into the cytoplasm of A549, HEK293T, and Huh7 cells [118]. Coleman CM et al. showed Imatinib, an Abelson (Abl) kinase inhibitor, effectively blocked the entry of pseudotyped virions which expressed the S protein of SARS-CoV, and MERS-CoV [119]. Using the infectious bronchitis virus model, Sisk JM et al., have shown that Imatinib and two other Abl kinase inhibitors, GNF2 and GNF5, significantly reduced infectious bronchitis viral (IBV) levels by inhibiting virus-cell and cell-cell fusion events [120]. Baricitinib (a Janus Kinase inhibitor) a known regulator of endocytosis, which also inhibits AP2-associated protein kinase 1 (AAK1), and binds to cyclin G-associated kinase, could be trialed to reduce the viral entry into the cell and inflammation in patients infected with SARS-CoV-2 [121]. Together, blocking the host-based cellular process of pathogen internalization could be an effective method to impede the transmission of viral RNA into the host cytoplasm.
Antiviral agents/drugs
In the context of the rapid increase in the number of positive cases for SARS-CoV-2, assessing the benefits of current antiviral agents and drugs against this infection has become a great interest. Such drugs have an advantage over newly developed drugs due to their known pharmacokinetic and pharmacodynamics properties such as safety, toxicity, dosage, and treatment period. These already acquired data can save a significant amount of time in establishing the clinical potential of antiviral agents in COVID-19 patients. According to in vitro cytotoxicity assay, both Remdesivir and Nitazoxanide inhibited SARS-CoV-2 viral infection even at relatively modest levels [104]. Remdesivir, a nucleotide analog that inhibits viral RNA-dependent RNA polymerase (RdRp), effectively impeded viral replication upon entry into the cell [104, 122]. A recent study involving 1063 patients showed that compared to placebo, treatment with Remdesivir shortened the recovery period in patients infected with COVID-19 [123]. Besides, the ribonucleoside analog β-D-N4-hydroxycytidine (NHC, EIDD-1931) and its orally bioavailable prodrug (EIDD-2801) has produced efficacy against MERS-CoV, SARS-CoV, and SARS-CoV-2 with minimal cytotoxicity in human airway epithelial cell cultures [124, 125]. NHC also has an increased sensitivity to mutant strains of mouse hepatitis coronavirus (MHV) as well as genetically distinct Bat-CoV compared to Remdesivir due to its ability to induce high genetic mutation rates in the viral genome [124, 125]. Previously, a combination treatment of Lopinavir/Ritonavir and Ribavirin had shown better outcomes in SARS-CoV patients, which resulted in a steady decrease in viral loads on day 5, as well as increased lymphocyte counts after the treatment [126]. Following this approach, three out of four patients infected with SARS-CoV-2 received Lopinavir/Ritonavir, Arbidol, and traditional Chinese medicine (Shufeng Jiedu Capsule, SFJDC) showed improved pneumonia symptoms [127]. Lopinavir/Ritonavir (Kaletra, AbbVie) treatment for SARS-CoV-2 patients also showed a significant reduction of the viral load on the first day after treatment [128]. However, in a randomized, controlled, open-label trial with Lopinavir/Ritonavir in hospitalized patients with COVID-19 no benefit was observed [129].
Furthermore, anti-hepatitis C virus drugs targeting RdRp that showed potent antiviral activity against SARS-CoV-2 includes IDX-184, Sofosbuvir, and Ribavirin [130]. Niclosamide, an anthelminthic drug reported to have a strong anti-SARS-CoV activity at a moderate concentration. Considering its extensive antiviral properties, Niclosamide would be a promising candidate to study its effectiveness against SARS-CoV-2 [131-133]. Also, Ciclesonide, a corticosteroid approved by the FDA for the treatment of asthma and allergic rhinitis, is effective in suppressing viral replication by targeting NSP15 of SARS-CoV-2 at significantly lower concentrations than Camostat and Lopinavir [134, 135]. Tilorone, a broad-spectrum antiviral drug tested against respiratory tract infections in humans in Russia and neighboring countries, possesses high efficacy and a better IC50 value compared to chloroquine, which could be further analyzed against SARS-CoV-2 infection [136, 137]. Favipiravir is also known to effectively inhibit RNA polymerase activity and has already been shown to be effective against several RNA viruses that could have an advantage in inhibiting the replication of the SARS-CoV-2 virus in the host cell [138-140]. Patient data suggested that Favipiravir together with interferon-α showed faster SARS-CoV2 viral clearance and a better improvement rate in chest imaging with fewer adverse reactions than patients treated with Lopinavir/Ritonavir plus interferon-α [141]. A retrospective trial in China involving 69 patients infected with SARS-CoV-2 showed that treatment with Arbidol, which has been used to treat influenza A/B virus infections, showed a tendency of improving the condition of the patients and reduced the fatality rate. In contrast, the use of corticosteroids deteriorated the outcome [142].
Type I interferons (IFN-α/β) are potent antiviral agents; they represent the first antiviral cytokines secreted within hours after the viral infection and essential for activating an effective antiviral CD8+ T cell response leading to rapid control of viral spread [143, 144]. Previous studies showed that human interferons have a high antiviral potential against SARS-CoV and MERS-CoV [145, 146]. Interferon-α2b, along with Ribavirin as well as interferon-β acting alone or with the combination of mycophenolic acid, showed a significant reduction of the viral titers of SARS-CoV and MERS-CoV, respectively [145-147]. In line with a recent study that showed that the pre-treatment of Vero cells with IFN-α and IFN-β at a concentration of 50 international units (IU) resulted in an approximate four-fold reduction in viral titers of SARS-CoV-2 [148]. RNA viruses are potent in triggering the type I interferon signaling pathway, which encodes hundreds of interferon-stimulated genes (ISGs) that can target several steps of the viral life cycle, including entry, uncoating, transcription, translation, assembly, or exocytosis [149, 150]. One of the advantages of such antiviral drugs and reagents is that they can be easily accessible with known pharmacological properties. Another anti-inflammatory and anti-oxidative molecule, Melatonin, with a high efficacy profile and well-known antiviral properties, could also be useful for patients infected with SARS-CoV-2 [151, 152]. In summary, targeting distinct steps of viral replication could be useful in limiting viral load and subsequent spread of the virus, leading to an effective antiviral T-cell response and could improve the outcome of the disease.
Proteolytic agents
Following successful penetration of SARS-CoV-2 into the cytoplasm of the cell by attachment to the cell surface and subsequent ingestion, the virus releases its genomic material into the cytoplasm of the host to translate the viral polyproteins pp1a and pp1ab. A pair of proteases, 3CLpro and PLpro, mediate this process and translate the product from viral RNA into the protein components necessary for the generation of fully functional virus that is ready to emerge and replicate (Fig. 3) [153]. Disulfiram, an alcohol-aversive drug was shown to inhibit PLpro protease of MERS-CoV and SARS-CoV [154]. Furthermore, it is also known that Lopinavir/Ritonavir inhibits the activity of the 3CLpro protease and is currently studied to treat SARS-CoV-2 patients [129, 155]. Another study using the three-dimensional model of the SARS-CoV-2 3C-like protease (3CLpro), proposed 16 potent purchasable drugs, including Ledipasvir or Velpatasvir, for treatment [156]. Additionally, it is also well known that lipid rafts serve as a platform in trafficking the virus into the cell [157-159]. In the case of the coronavirus IBV model, depletion of cholesterol activity by the treatment with methyl-β-cyclodextrin (MβCD) or Mevastatin significantly suppressed IBV infection by impairing the attachment of the virus to the cell surface [160].
In order to discover drug leads that target the main protease for therapeutic use, a group at Shanghai Tech University, Shanghai, China, initiated an integrated structure-assisted drug design, virtual drug screening, and high-throughput screening program to transform existing drugs into therapies against the SARS-CoV-2 Mpro [161]. Mpro, a crucial enzyme of the coronavirus, acts as a mediator of viral replication and transcription, making it an interesting target for treatment [162]. After analyzing over 10,000 different compounds, Ebselen, and N3 showed potent anti-SARS-CoV-2 activity in cell-based assays [161]. This new approach could employ an efficient screening strategy and establish a new paradigm for the rapid discovery of drug targets with the potential to develop a clinical response to viral infectious diseases [161]. Similarly, utilizing homology models based on the SARS Mpro structure and docking score suggested that Nelfinavir may be a potential inhibitor against SARS-CoV-2 Mpro [163]. Another approach that utilizes deep learning Molecular Transformer Drug-Target Interaction (MT-DTI) model to target viral proteins of SARS-CoV-2 showed that Atazanavir, an antiretroviral drug which is in use to treat human immunodeficiency virus (HIV), has high inhibitory potency against the 3C-like proteinase of SARS-CoV-2 compared to Remdesivir, Efavirenz, Ritonavir, and Dolutegravir [164]. In summary, patients infected with SARS-CoV-2 might benefit from treatment with drugs that inhibit the action of the proteases 3CLpro and PLpro by lowering the viral load.
Blocking the cytokine responses
A tight balance between innate immune activation and resulting adaptive immune responses is crucial for regulating viral control. Dysregulation of this tightly controlled axis can result in an overwhelming immune reaction resulting in severe immunopathology [165]. A deregulated immune response can lead to hyperinflammatory conditions, which patients with pre-existing health problems may be potentially at higher risk for. The average fatality rate of elderly patients, cancer patients, patients with other health conditions, and males compared to females infected with SARS-CoV-2 is significantly higher than that of infected young patients [166-169]. Recently, many studies have shown that some patients infected with SARS-CoV-2 can develop ARDS. In many cases, this leads to multi-organ failure due to cytokine storm. Several studies have reported that patients with severe symptoms more often had dyspnea, lymphopenia, and hypoalbuminemia with severe immunopathology than patients with mild symptoms due to elevated levels of ALT, AST, and cytokines such as interleukin (IL)-2R, IL-6, IL-10, and TNF-α with a reduction in T cell numbers [170-172].
A separate study conducted by the Chinese Academy of Science, involving 33 patients, showed that infection with SARS-CoV-2 induced rapid activation of CD4+ T cells, which proliferated and differentiated into T helper 1 (Th1) cells secreting cytokines including IL-6, IFN-γ, and GM-CSF [173, 174]. Therefore, the use of Tocilizumab (an IL-6 receptor antagonist) approved for the treatment of rheumatoid arthritis (RA), and glycyrrhetinic acid (an IL-6 blocker) were reported to improve the health condition of critically ill patients with elevated levels of IL-6 [173, 175]. Sarilumab, a monoclonal antibody against the IL-6 receptor approved for treating moderate to severe active RA may be another candidate for the treatment of COVID-19 patients with ARDS [176]. Other cytokines and chemokines showed a dramatic increase in infected patients include IL-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17, IFN-γ, TNF-α, monocyte chemoattractant protein (MCP), IFN-gamma-inducible protein-10 (IP-10). This induction of cytokines together with significant alterations in the number of leukocytes presumably lead to the development of ARDS [2, 173, 177-180]. While IL-37 and IL-38 are potent suppressors of IL-1β, other proinflammatory IL-family members may improve viral load and inflammation with the potential to function as an additional therapeutic strategy to treat SARS-CoV-2 patients [181]. A Chinese traditional medicine Lianhuaqingwen has also been shown to lead to a significant reduction in SARS-CoV-2 viral replication and pro-inflammatory cytokines (IL-6, TNF-α, CCL2/MCP-1, and CXCL-10/IP-10) levels by in vitro assays [182]. Therefore, combinations of antibodies capable of blocking these inflammatory cytokines could prevent the development of an ARDS. This may improve the fatality rate in elderly patients and in those with secondary health conditions.
Vaccine development against SARS-CoV-2
Although several studies are demonstrating the success of vaccination as a treatment for SARS-CoV, it is enigmatic that there are currently no approved vaccines or therapeutics to treat coronavirus infections that can induce protective neutralizing antibodies. A study has shown that intranasal administration of the inactivated vaccine candidate, the RBD region of the Fc domain of human IgG1 (RBD-Fc) fused with the SARS-CoV S protein and recombinant adeno-associated virus (RBD-rAAV), induced both potent anti-SARS-CoV neutralizing antibodies and a healthy cytotoxic T-cell (CTL) response [183]. Similarly, the administration of a vaccine based on parainfluenza virus 5 (PIV5), expressing the MERS-CoV envelope spike protein induced a potent neutralizing antibody and T cell response, and protected mice from a lethal MERS-CoV challenge [184]. Taken together, these data indicate that it is possible to use existing knowledge and test the previous vaccine candidates from SARS-CoV research to validate their potency to prevent SARS-CoV-2 infection. The SARS-CoV-2 RBD region binds explicitly to the ACE-2 receptor with high affinity on the host cell surface. The CoV spike (S) protein is essential for viral invasion of the host, and therefore the SARS-CoV-2 spike protein can be useful in neutralizing SARS-CoV-2 infection [68, 185]. Accordingly, it has been shown that the SARS-CoV-2 RBD protein efficiently blocked the entry of the SARS-CoV-2 pseudovirus into human ACE-2 expressing 293T cells [185]. As a result of the phylogenetic similarity between SARS-CoV and SARS-CoV-2, anti-SARS-CoV-specific antibodies were also potent in neutralizing SARS-CoV-2 pseudovirus infection [185]. Intracutaneous delivery of the SARS-CoV-2 S1-subunit vaccine into mice by microneedle array (MNA) generated significant anti-SARS-CoV-2 specific neutralizing antibody response within two weeks post-immunization [186]. A recent study showing the development of purified inactivated SARS-CoV-2 virus vaccine candidate (PiCoVacc) generated neutralizing antibodies against ten representative SARS-CoV-2 strains, demonstrating its broader neutralizing capacity [187]. In addition, a DNA-based vaccine candidate INO-4800, targeting the SARS-CoV-2 S protein, led to the generation of anti-SARS-CoV-2 neutralizing antibodies that block the interaction of the spike (S) protein with the ACE-2 receptor and induced a potent cytotoxic T cell response [188].
At the moment, several research institutes and biopharma industries worldwide are in the race to develop a SARS-CoV-2 vaccine, while many vaccine candidates are currently in clinical trials (phase II and III) [189]. Early human trials confirm that the vaccine developed by the University of Oxford (Oxford COVID Vaccine Trail Group, UK) and Moderna Therapeutics (mRNA-1273 Study Group, USA) triggered strong anti-SARS-CoV-2 antibody responses and cellular immune responses without serious adverse events [190, 191]. Various vaccine development strategies are being tested, including live attenuated vaccines, vaccines based on viral vectors, recombinant vaccines based on proteins and DNA, and mRNA vaccines [192-194]. Vaccines can potentially trigger immune hyperactivation, which can cause severe immunopathology due to exhilarating T cell activation. Therefore, due to the novelty of the strain, all vaccine candidates must undergo rigorous testing, including toxicology, immunogenicity, safety, and efficacy, and need to follow ongoing good manufacturing practices (cGMP) to meet the FDA rules and regulations. Given the urgency of the current situation, even with a probable acceleration of some approval and licensing steps, it may take 12-18 months before the vaccine is available.
Herd immunity
Herd immunity or the herd effect is the indirect protection of non-immune individuals from an infectious disease or outbreak. This is due to the presence of a large part of the population that is immune to infection through vaccination or the presence of an immunological memory because of the previous infection [195]. In a population where many individuals are immune, herd immunity protects the transmission of disease by interrupting the chain of virus spread [196]. A person can become immune through vaccination or due to recovery from a previous infection or immunosuppression. This leads to a steady decline in the infection rate due to a decrease in the basic reproduction number (R0). The R0 of COVID-19 is estimated to be between 2.39 and 4.13 [197]. Considering that other coronaviruses do not provide lifelong immunity, developing a vaccine against COVID-19 can be considered essential. Vaccinating or immunizing several members of the population against SARS-CoV-2 can be a reliable and potentially quicker way to re-open the economy and bring back the normalcy that has been lost due to the spread of this virus.
Outlook and future prospective
The COVID-19 pandemic highlights that existing treatment options for potentially life-threatening zoonotic coronavirus infections remain limited. Although the previous outbreaks of SARS in 2003 and MERS in 2012 have triggered significant research efforts, there are currently no direct treatments or vaccines available against any zoonotic coronavirus that may resurface in the future and pose a threat to global public health and the world economy. The discovery of broad-spectrum therapeutic options that can reduce the consequences of human coronavirus infection remains a significant challenge ahead. As our understanding of the pathogenesis of newly emerging coronaviruses continues to grow, the possibilities for the rational development of therapeutics targeting viral replication or immunosuppression continues to increase.
In this review, we have summarized the current state of knowledge on the origin, zoonotic transmission, pathophysiology, and genome of the novel SARS-CoV-2. In detail, we have also discussed the virus- and host-based treatment options reported in various studies targeting different stages of the viral life cycle. Most strategies are based on the use of therapies aimed to treat different types of diseases, viral infections, and the suppression of specific signaling pathways in the infected cell. The so far collected preclinical and COVID-19 patient data show that the use of antiviral drugs in combination with anti-inflammatory agents has the potential to emerge as a successful strategy for the treatment of young and elderly individuals as well as patients with ARDS. Although progress has undoubtedly been made in the identification of several vaccine candidates by leading pharmaceutical companies and research institutes to develop potential vaccines and antiviral therapies against SARS-CoV-2, more research and rigorous testing options are needed to advance the development of these candidates [189].
Clinical trials were quickly initiated when the status of the virus had elevated to a pandemic, and some of the leading candidates developed for alternative applications were approved in a fast-track procedure for the treatment of SARS-CoV-2. Though some of these therapies are already showing promising results in the early stages of trials, the results must be closely monitored over a specified period. The drugs currently in use specifically target the replication cycle of the virus, and those based on immunotherapeutic approaches aim either to enhance the innate antiviral immune response or to reduce inflammatory damage caused by dysregulated immune reactions. The effects of vaccines and therapeutic antibodies specifically directed against SARS-CoV-2 also need to be studied, as this is the long-term solution providing immunity against SARS-CoV-2 infection. In addition to current approaches and strategies, research must be encouraged, and facilities should be made available to study and prevent the zoonotic transmission of viruses from animals to humans and the re-emergence of current strains. Efforts must be made to collect and study wild viruses and their potential for zoonotic transmissions or transmission to the host, and they should be screened for pathogenicity in advance, as this could be a way to avoid future pandemics.
Abbreviations
2019-nCov (Novel coronavirus 2019); 3CLpro (Chymotrypsin-like protease); Abl (Abelson kinase inhibitor); ALT (Alanine aminotransferase); ARDS (Acute respiratory distress syndrome); AST (Aspartate aminotransferase); CCL2 (C-C Motif Chemokine Ligand 2); COVID-19 (Coronavirus Disease 2019); CoVs (Coronaviruses); CXCL10 (C-X-C motif chemokine 10); E (Envelope); ER (Endoplasmic reticulum); ERGIC (Endoplasmic reticulum Golgi intermediate compartment); hACE-2 (Human angiotensin-converting enzyme 2); hDPP4 (Human dipeptidyl peptidase 4); HE (Hemagglutinin-esterase protein); IBV (Infectious Bronchitis virus); IFN-α (Interferons α); IFN-β (Interferons β); IL6 (Interleukin 6); IL-8 (Interleukin 8); M (Membrane); mAb (Monoclonal antibody); MHV (Mouse hepatitis coronavirus); MNA (Microneedle array); Mpro (Main Protease); MβCD (Methyl-β-cyclodextrin); N (Nucleocapsid proteins); NTD (N-terminal domain); ORF (Open reading frame); PIV5 (Parainfluenza virus 5); PL1, 2pro (Papain-like proteases); RBD (Receptor-binding domain); RdRp (RNA-dependent RNA polymerase); S (Spike protein); ssRNA (Single stranded RNA); TMPRSS2 (Transmembrane protease serine 2); TNF (Tumor necrosis factor).
Acknowledgements
The author would like to thank Prof. Dr. Karl S. Lang (Institute of Immunology, University Hospital Essen, Essen, Germany) for an excellent and extensive discussion of the literature and valuable input in drafting the review. We would also like to acknowledge Mr. Paresh Vishwasrao (City of Hope National Medical Center, Beckman Cancer Research Institute. Duarte, CA, USA), and Mr. Anthony Abarientos (University of California, San Francisco, CA, USA) for their input in drafting the review.
Author contributions
AMP initiated and designed the review. AMP and VK collected literature, prepared figures, wrote the article, and finalized the draft. JRG was involved in discussing the literature and reviewed final draft.
The authors have no ethical conflicts to disclose.
Disclosure Statement
The authors declare no competing financial interest.
References
|
1
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W, Lu R,
Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W: A Novel Coronavirus
from Patients with Pneumonia in China, 2019. N Engl J Med 2020;382:727-733. |
|
|
|
|
|
2 Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y,
Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W,
Li H, Liu M, et al.: Clinical features of patients infected with 2019 novel
coronavirus in Wuhan, China. Lancet 2020;395:497-506. |
|
|
|
|
|
3 World Health Organization: Surveillance case definitions for human infection with novel coronavirus (nCoV): interim guidance v1, January 2020. URL: https://apps.who.int/iris/handle/10665/330376. |
|
|
|
|
|
4 World Health Organization: Novel Coronavirus (2019-nCoV): situation report, 10. 2020; URL: https://apps.who.int/iris/handle/10665/330775. |
|
|
|
|
|
5 Organization WH: WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020. 2020; URL: https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-march-2020. |
|
|
|
|
|
6 Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang
W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu
MQ, Chen Y, Shen XR, et al.: A pneumonia outbreak associated with a new
coronavirus of probable bat origin. Nature 2020;579:270-273. |
|
|
|
|
|
7 Coronaviridae Study Group of the International
Committee on Taxonomy of Viruses: The species Severe acute respiratory
syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2.
Nat Microbiol 2020;5:536-544. |
|
|
|
|
|
8 World Health Organization: WHO Timeline - COVID-19. 2020; URL: https://www.who.int/news-room/detail/08-04-2020-who-timeline---covid-19. |
|
|
|
|
|
9 Organization WH: Novel Coronavirus - Thailand (ex-China). 2020; URL: https://www.who.int/csr/don/14-january-2020-novel-coronavirus-thailand-ex-china/en/. |
|
|
|
|
|
10 Organization WH: Novel Coronavirus - Japan (ex-China). 2020; URL: https://www.who.int/csr/don/17-january-2020-novel-coronavirus-japan-ex-china/en/. |
|
|
|
|
|
11 Tyrrell DA, Bynoe ML: Cultivation of a Novel
Type of Common-Cold Virus in Organ Cultures. Br Med J 1965;1:1467-1470. |
|
|
|
|
|
12 Hamre D, Procknow JJ: A new virus isolated
from the human respiratory tract. Proc Soc Exp Biol Med 1966;121:190-193. |
|
|
|
|
|
13 Van der Hoek L, Pyrc K, Jebbink MF,
Vermeulen-Oost W, Berkhout RJ, Wolthers KC, Wertheim-van Dillen PM, Kaandorp
J, Spaargaren J, Berkhout B: Identification of a new human coronavirus. Nat
Med 2004;10:368-373. |
|
|
|
|
|
14 Woo PC, Lau SK, Chu CM, Chan KH, Tsoi HW,
Huang Y, Wong BH, Poon RW, Cai JJ, Luk WK, Poon LL, Wong SS, Guan Y, Peiris
JS, Yuen KY: Characterization and complete genome sequence of a novel
coronavirus, coronavirus HKU1, from patients with pneumonia. J Virol
2005;79:884-895. |
|
|
|
|
|
15 Greenberg SB: Update on rhinovirus and
coronavirus infections. Semin Respir Crit Care Med 2011;32:433-446. |
|
|
|
|
|
16 Cecere TE, Todd SM, Richmond OB: Boca Raton:
Human Coronavirus Respiratory Infections; in Singh SK (ed): Human Respiratory
Viral Infections. Boca Raton, CRC Press, 2014, pp 547-558. |
|
|
|
|
|
17 Arbour N, Ekande S, Cote G, Lachance C,
Chagnon F, Tardieu M, Cashman NR, Talbot PJ: Persistent infection of human
oligodendrocytic and neuroglial cell lines by human coronavirus 229E. J Virol
1999;73:3326-3337. |
|
|
|
|
|
18 Jacomy H, Fragoso G, Almazan G, Mushynski WE,
Talbot PJ: Human coronavirus OC43 infection induces chronic encephalitis
leading to disabilities in BALB/C mice. Virology 2006;349:335-346. |
|
|
|
|
|
19 COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE), Johns Hopkins University and Medicine. 2020; URL: https://coronavirus.jhu.edu/map.html. |
|
|
|
|
|
20 Centers for Disease Control and Prevention: How COVID-19 Spreads. 2020; URL: https://web.archive.org/web/20200402212420/https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/how-covid-spreads.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fprepare%2Ftransmission.html. |
|
|
|
|
|
21 Van Doremalen N, Bushmaker T, Morris DH,
Holbrook MG, Gamble A, Williamson BN, Tamin A, Harcourt JL, Thornburg NJ,
Gerber SI, Lloyd-Smith JO, de Wit E, Munster VJ: Aerosol and Surface
Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med
2020;382:1564-1567. |
|
|
|
|
|
22 Ding Y, Wang H, Shen H, Li Z, Geng J, Han H,
Cai J, Li X, Kang W, Weng D, Lu Y, Wu D, He L, Yao K: The clinical pathology
of severe acute respiratory syndrome (SARS): a report from China. J Pathol
2003;200:282-289. |
|
|
|
|
|
23 Hamming I, Timens W, Bulthuis ML, Lely AT,
Navis G, van Goor H: Tissue distribution of ACE2 protein, the functional
receptor for SARS coronavirus. A first step in understanding SARS
pathogenesis. J Pathol 2004;203:631-637. |
|
|
|
|
|
24 Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM,
Miao VN, Tzouanas CN, Cao Y, Yousif AS, Bals J, Hauser BM, Feldman J, Muus C,
Wadsworth MH 2nd, Kazer SW, Hughes TK, Doran B, Gatter GJ, Vukovic M,
Taliaferro F, Mead BE, et al.: SARS-CoV-2 Receptor ACE2 Is an
Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected
in Specific Cell Subsets across Tissues. Cell 2020;181:1016-1035.e19. |
|
|
|
|
|
25 Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX,
Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang
CL, Wang T, Chen PY, Xiang J, Li SY, et al.: Clinical Characteristics of
Coronavirus Disease 2019 in China. N Engl J Med 2020;382:1708-1720. |
|
|
|
|
|
26 Parasa S, Desai M, Thoguluva Chandrasekar V,
Patel HK, Kennedy KF, Roesch T, Spadaccini M, Colombo M, Gabbiadini R,
Artifon ELA, Repici A, Sharma P: Prevalence of Gastrointestinal Symptoms and
Fecal Viral Shedding in Patients With Coronavirus Disease 2019: A Systematic
Review and Meta-analysis. JAMA Netw Open 2020;3:e2011335. |
|
|
|
|
|
27 Lai CC, Ko WC, Lee PI, Jean SS, Hsueh PR:
Extra-respiratory manifestations of COVID-19. Int J Antimicrob Agents
2020:106024. |
|
|
|
|
|
28 Organization WH: Coronavirus symptoms. 2020; URL: https://www.who.int/health-topics/coronavirus#tab=tab_3. |
|
|
|
|
|
29 Murthy S, Gomersall CD, Fowler RA: Care for
Critically Ill Patients With COVID-19. JAMA 2020;323:1499-1500. |
|
|
|
|
|
30 Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R: Features, Evaluation and Treatment Coronavirus (COVID-19), in: StatPearls [Internet]. Treasure Island (FL), StatPearls Publishing; 2020. |
|
|
|
|
|
31 Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J,
Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z: Clinical
Characteristics of 138 Hospitalized Patients With 2019 Novel
Coronavirus-Infected Pneumonia in Wuhan, China. JAMA 2020;323:1061-1069. |
|
|
|
|
|
32 Carod-Artal FJ: Neurological complications of
coronavirus and COVID-19. Rev Neurol 2020;70:311-322. |
|
|
|
|
|
33 Xu L, Liu J, Lu M, Yang D, Zheng X: Liver
injury during highly pathogenic human coronavirus infections. Liver Int
2020;40:998-1004. |
|
|
|
|
|
34 Cui J, Li F, Shi ZL: Origin and evolution of
pathogenic coronaviruses. Nat Rev Microbiol 2019;17:181-192. |
|
|
|
|
|
35 Zhong NS, Zheng BJ, Li YM, Poon, Xie ZH, Chan
KH, Li PH, Tan SY, Chang Q, Xie JP, Liu XQ, Xu J, Li DX, Yuen KY, Peiris,
Guan Y: Epidemiology and cause of severe acute respiratory syndrome (SARS) in
Guangdong, People's Republic of China, in February, 2003. Lancet
2003;362:1353-1358. |
|
|
|
|
|
36 Ksiazek TG, Erdman D, Goldsmith CS, Zaki SR,
Peret T, Emery S, Tong S, Urbani C, Comer JA, Lim W, Rollin PE, Dowell SF,
Ling AE, Humphrey CD, Shieh WJ, Guarner J, Paddock CD, Rota P, Fields B, et
al.: A novel coronavirus associated with severe acute respiratory syndrome. N
Engl J Med 2003;348:1953-1966. |
|
|
|
|
|
37 Zaki AM, van Boheemen S, Bestebroer TM,
Osterhaus AD, Fouchier RA: Isolation of a novel coronavirus from a man with
pneumonia in Saudi Arabia. N Engl J Med 2012;367:1814-1820. |
|
|
|
|
|
38 Yin Y, Wunderink RG: MERS, SARS and other
coronaviruses as causes of pneumonia. Respirology 2018;23:130-137. |
|
|
|
|
|
39 World Health Organization: Middle East respiratory syndrome coronavirus (MERS-CoV). 2020; URL: https://www.who.int/en/news-room/fact-sheets/detail/middle-east-respiratory-syndrome-coronavirus-(mers-cov). |
|
|
|
|
|
40 Li W, Shi Z, Yu M, Ren W, Smith C, Epstein
JH, Wang H, Crameri G, Hu Z, Zhang H, Zhang J, McEachern J, Field H, Daszak
P, Eaton BT, Zhang S, Wang LF: Bats are natural reservoirs of SARS-like
coronaviruses. Science 2005;310:676-679. |
|
|
|
|
|
41 Menachery VD, Yount BL, Jr., Debbink K,
Agnihothram S, Gralinski LE, Plante JA, Graham RL, Scobey T, Ge XY, Donaldson
EF, Randell SH, Lanzavecchia A, Marasco WA, Shi ZL, Baric RS: A SARS-like
cluster of circulating bat coronaviruses shows potential for human emergence.
Nat Med 2015;21:1508-1513. |
|
|
|
|
|
42 Guan Y, Zheng BJ, He YQ, Liu XL, Zhuang ZX,
Cheung CL, Luo SW, Li PH, Zhang LJ, Guan YJ, Butt KM, Wong KL, Chan KW, Lim
W, Shortridge KF, Yuen KY, Peiris JS, Poon LL: Isolation and characterization
of viruses related to the SARS coronavirus from animals in southern China.
Science 2003;302:276-278. |
|
|
|
|
|
43 Wang LF, Eaton BT: Bats, civets and the
emergence of SARS. Curr Top Microbiol Immunol 2007;315:325-344. |
|
|
|
|
|
44 Azhar EI, El-Kafrawy SA, Farraj SA, Hassan
AM, Al-Saeed MS, Hashem AM, Madani TA: Evidence for camel-to-human
transmission of MERS coronavirus. N Engl J Med 2014;370:2499-2505. |
|
|
|
|
|
45 Ithete NL, Stoffberg S, Corman VM, Cottontail
VM, Richards LR, Schoeman MC, Drosten C, Drexler JF, Preiser W: Close
relative of human Middle East respiratory syndrome coronavirus in bat, South
Africa. Emerg Infect Dis 2013;19:1697-1699. |
|
|
|
|
|
46 Kan B, Wang M, Jing H, Xu H, Jiang X, Yan M,
Liang W, Zheng H, Wan K, Liu Q, Cui B, Xu Y, Zhang E, Wang H, Ye J, Li G, Li
M, Cui Z, Qi X, Chen K, et al.: Molecular evolution analysis and geographic
investigation of severe acute respiratory syndrome coronavirus-like virus in
palm civets at an animal market and on farms. J Virol 2005;79:11892-11900. |
|
|
|
|
|
47 Wang M, Yan M, Xu H, Liang W, Kan B, Zheng B,
Chen H, Zheng H, Xu Y, Zhang E, Wang H, Ye J, Li G, Li M, Cui Z, Liu YF, Guo
RT, Liu XN, Zhan LH, Zhou DH, et al.: SARS-CoV infection in a restaurant from
palm civet. Emerg Infect Dis 2005;11:1860-1865. |
|
|
|
|
|
48 Lau SK, Woo PC, Li KS, Huang Y, Tsoi HW, Wong
BH, Wong SS, Leung SY, Chan KH, Yuen KY: Severe acute respiratory syndrome
coronavirus-like virus in Chinese horseshoe bats. Proc Natl Acad Sci U S A
2005;102:14040-14045. |
|
|
|
|
|
49 Lam TT, Shum MH, Zhu HC, Tong YG, Ni XB, Liao
YS, Wei W, Cheung WY, Li WJ, Li LF, Leung GM, Holmes EC, Hu YL, Guan Y:
Identifying SARS-CoV-2 related coronaviruses in Malayan pangolins. Nature
2020;583:282-285. |
|
|
|
|
|
50 Zhang T, Wu Q, Zhang Z: Probable Pangolin
Origin of SARS-CoV-2 Associated with the COVID-19 Outbreak. Curr Biol
2020;30:1346-1351.e2. |
|
|
|
|
|
51 Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG,
Hu Y, Tao ZW, Tian JH, Pei YY, Yuan ML, Zhang YL, Dai FH, Liu Y, Wang QM,
Zheng JJ, Xu L, Holmes EC, Zhang YZ: A new coronavirus associated with human
respiratory disease in China. Nature 2020;579:265-269. |
|
|
|
|
|
52 Fehr AR, Perlman S: Coronaviruses: an
overview of their replication and pathogenesis. Methods Mol Biol
2015;1282:1-23. |
|
|
|
|
|
53 Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Wang
W, Song H, Huang B, Zhu N, Bi Y, Ma X, Zhan F, Wang L, Hu T, Zhou H, Hu Z,
Zhou W, Zhao L, Chen J, et al.: Genomic characterisation and epidemiology of
2019 novel coronavirus: implications for virus origins and receptor binding.
Lancet 2020;395:565-574. |
|
|
|
|
|
54 Lai MM: Coronavirus: organization,
replication and expression of genome. Annu Rev Microbiol 1990;44:303-333. |
|
|
|
|
|
55 Lai MM, Cavanagh D: The molecular biology of
coronaviruses. Adv Virus Res 1997;48:1-100. |
|
|
|
|
|
56 ICTV: Coronaviridae, Virus Taxonomy: 2019 Release. 2019; URL: https://talk.ictvonline.org/ictv-reports/ictv_9th_report/positive-sense-rna-viruses-2011/w/posrna_viruses/222/coronaviridae. |
|
|
|
|
|
57 Liu DX, Liang JQ, Fung TS: Human
Coronavirus-229E, -OC43, -NL63, and -HKU1. Reference Module in Life Sciences
2020; DOI:10.1016/B978-0-12-809633-8.21501-X. |
|
|
|
|
|
58 Vlasak R, Luytjes W, Spaan W, Palese P: Human
and bovine coronaviruses recognize sialic acid-containing receptors similar
to those of influenza C viruses. Proc Natl Acad Sci U S A 1988;85:4526-4529. |
|
|
|
|
|
59 Huang X, Dong W, Milewska A, Golda A, Qi Y,
Zhu QK, Marasco WA, Baric RS, Sims AC, Pyrc K, Li W, Sui J: Human Coronavirus
HKU1 Spike Protein Uses O-Acetylated Sialic Acid as an Attachment Receptor
Determinant and Employs Hemagglutinin-Esterase Protein as a Receptor-Destroying
Enzyme. J Virol 2015;89:7202-7213. |
|
|
|
|
|
60 Woo PC, Huang Y, Lau SK, Yuen KY: Coronavirus
genomics and bioinformatics analysis. Viruses 2010;2:1804-1820. |
|
|
|
|
|
61 Walker PJ, Siddell SG, Lefkowitz EJ,
Mushegian AR, Dempsey DM, Dutilh BE, Harrach B, Harrison RL, Hendrickson RC,
Junglen S, Knowles NJ, Kropinski AM, Krupovic M, Kuhn JH, Nibert M, Rubino L,
Sabanadzovic S, Simmonds P, Varsani A, Zerbini FM, Davison AJ: Changes to
virus taxonomy and the International Code of Virus Classification and
Nomenclature ratified by the International Committee on Taxonomy of Viruses
(2019). Arch Virol 2019;164:2417-2429. |
|
|
|
|
|
62 Yeager CL, Ashmun RA, Williams RK,
Cardellichio CB, Shapiro LH, Look AT, Holmes KV: Human aminopeptidase N is a
receptor for human coronavirus 229E. Nature 1992;357:420-422. |
|
|
|
|
|
63 Hofmann H, Pyrc K, van der Hoek L, Geier M,
Berkhout B, Pohlmann S: Human coronavirus NL63 employs the severe acute
respiratory syndrome coronavirus receptor for cellular entry. Proc Natl Acad
Sci U S A 2005;102:7988-7993. |
|
|
|
|
|
64 Raj VS, Mou H, Smits SL, Dekkers DH, Muller
MA, Dijkman R, Muth D, Demmers JA, Zaki A, Fouchier RA, Thiel V, Drosten C,
Rottier PJ, Osterhaus AD, Bosch BJ, Haagmans BL: Dipeptidyl peptidase 4 is a
functional receptor for the emerging human coronavirus-EMC. Nature
2013;495:251-254. |
|
|
|
|
|
65 Li W, Moore MJ, Vasilieva N, Sui J, Wong SK,
Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H,
Farzan M: Angiotensin-converting enzyme 2 is a functional receptor for the
SARS coronavirus. Nature 2003;426:450-454. |
|
|
|
|
|
66 Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S,
Zhang Q, Shi X, Wang Q, Zhang L, Wang X: Structure of the SARS-CoV-2 spike
receptor-binding domain bound to the ACE2 receptor. Nature 2020;581:215-220. |
|
|
|
|
|
67 Song W, Gui M, Wang X, Xiang Y: Cryo-EM
structure of the SARS coronavirus spike glycoprotein in complex with its host
cell receptor ACE2. PLoS Pathog 2018;14:e1007236. |
|
|
|
|
|
68 Wrapp D, Wang N, Corbett KS, Goldsmith JA,
Hsieh CL, Abiona O, Graham BS, McLellan JS: Cryo-EM structure of the
2019-nCoV spike in the prefusion conformation. Science 2020;367:1260-1263. |
|
|
|
|
|
69 Harmer D, Gilbert M, Borman R, Clark KL:
Quantitative mRNA expression profiling of ACE 2, a novel homologue of
angiotensin converting enzyme. FEBS Lett 2002;532:107-110. |
|
|
|
|
|
70 Bosch BJ, van der Zee R, de Haan CA, Rottier
PJ: The coronavirus spike protein is a class I virus fusion protein:
structural and functional characterization of the fusion core complex. J
Virol 2003;77:8801-8811. |
|
|
|
|
|
71 Izaguirre G: The Proteolytic Regulation of
Virus Cell Entry by Furin and Other Proprotein Convertases. Viruses
2019;11:837. |
|
|
|
|
|
72 Li F, Li W, Farzan M, Harrison SC: Structure
of SARS coronavirus spike receptor-binding domain complexed with receptor.
Science 2005;309:1864-1868. |
|
|
|
|
|
73 Lu G, Hu Y, Wang Q, Qi J, Gao F, Li Y, Zhang
Y, Zhang W, Yuan Y, Bao J, Zhang B, Shi Y, Yan J, Gao GF: Molecular basis of
binding between novel human coronavirus MERS-CoV and its receptor CD26.
Nature 2013;500:227-231. |
|
|
|
|
|
74 Glowacka I, Bertram S, Muller MA, Allen P,
Soilleux E, Pfefferle S, Steffen I, Tsegaye TS, He Y, Gnirss K, Niemeyer D,
Schneider H, Drosten C, Pohlmann S: Evidence that TMPRSS2 activates the
severe acute respiratory syndrome coronavirus spike protein for membrane
fusion and reduces viral control by the humoral immune response. J Virol
2011;85:4122-4134. |
|
|
|
|
|
75 Hoffmann M, Kleine-Weber H, Schroeder S,
Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A,
Muller MA, Drosten C, Pohlmann S: SARS-CoV-2 Cell Entry Depends on ACE2 and
TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell
2020;181:271-280.e8. |
|
|
|
|
|
76 Perlman S, Netland J: Coronaviruses
post-SARS: update on replication and pathogenesis. Nat Rev Microbiol
2009;7:439-450. |
|
|
|
|
|
77 Masters PS: The molecular biology of
coronaviruses. Adv Virus Res 2006;66:193-292. |
|
|
|
|
|
78 Krijnse-Locker J, Ericsson M, Rottier PJ,
Griffiths G: Characterization of the budding compartment of mouse hepatitis
virus: evidence that transport from the RER to the Golgi complex requires
only one vesicular transport step. J Cell Biol 1994;124:55-70. |
|
|
|
|
|
79 de Haan CA, Rottier PJ: Molecular
interactions in the assembly of coronaviruses. Adv Virus Res 2005;64:165-230. |
|
|
|
|
|
80 Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, Guo L,
Guo R, Chen T, Hu J, Xiang Z, Mu Z, Chen X, Chen J, Hu K, Jin Q, Wang J, Qian
Z: Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and
its immune cross-reactivity with SARS-CoV. Nat Commun 2020;11:1620. |
|
|
|
|
|
81 Slifka MK: Immunological memory to viral
infection. Curr Opin Immunol 2004;16:443-450. |
|
|
|
|
|
82 Robbins JB, Schneerson R, Szu SC:
Perspective: hypothesis: serum IgG antibody is sufficient to confer
protection against infectious diseases by inactivating the inoculum. J Infect
Dis 1995;171:1387-1398. |
|
|
|
|
|
83 Duhan V, Khairnar V, Friedrich SK, Zhou F,
Gassa A, Honke N, Shaabani N, Gailus N, Botezatu L, Khandanpour C, Dittmer U,
Haussinger D, Recher M, Hardt C, Lang PA, Lang KS: Virus-specific antibodies
allow viral replication in the marginal zone, thereby promoting CD8(+) T-cell
priming and viral control. Sci Rep 2016;6:19191. |
|
|
|
|
|
84 Zhao G, Ni B, Jiang H, Luo D, Pacal M, Zhou
L, Zhang L, Xing L, Zhang L, Jia Z, Lin Z, Wang L, Li J, Liang Y, Shi X, Zhao
T, Zhou L, Wu Y, Wang X: Inhibition of severe acute respiratory
syndrome-associated coronavirus infection by equine neutralizing antibody in
golden Syrian hamsters. Viral Immunol 2007;20:197-205. |
|
|
|
|
|
85 Ishii K, Hasegawa H, Nagata N, Ami Y, Fukushi
S, Taguchi F, Tsunetsugu-Yokota Y: Neutralizing antibody against severe acute
respiratory syndrome (SARS)-coronavirus spike is highly effective for the
protection of mice in the murine SARS model. Microbiol Immunol 2009;53:75-82. |
|
|
|
|
|
86 Du L, He Y, Zhou Y, Liu S, Zheng BJ, Jiang S:
The spike protein of SARS-CoV--a target for vaccine and therapeutic
development. Nat Rev Microbiol 2009;7:226-236. |
|
|
|
|
|
87 Xu X, Gao X: Immunological responses against SARS-coronavirus infection in humans. Cell Mol Immunol 2004;1:119-122. |
|
|
|
|
|
88 Zhong X, Yang H, Guo ZF, Sin WY, Chen W, Xu
J, Fu L, Wu J, Mak CK, Cheng CS, Yang Y, Cao S, Wong TY, Lai ST, Xie Y, Guo
Z: B-cell responses in patients who have recovered from severe acute
respiratory syndrome target a dominant site in the S2 domain of the surface
spike glycoprotein. J Virol 2005;79:3401-3408. |
|
|
|
|
|
89 Coughlin MM, Babcook J, Prabhakar BS: Human
monoclonal antibodies to SARS-coronavirus inhibit infection by different mechanisms.
Virology 2009;394:39-46. |
|
|
|
|
|
90 Shanmugaraj B, Siriwattananon K, Wangkanont K, Phoolcharoen W: Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19). Asian Pac J Allergy Immunol 2020;38:10-18. |
|
|
|
|
|
91 Tian X, Li C, Huang A, Xia S, Lu S, Shi Z, Lu
L, Jiang S, Yang Z, Wu Y, Ying T: Potent binding of 2019 novel coronavirus
spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerg
Microbes Infect 2020;9:382-385. |
|
|
|
|
|
92 Wang C, Li W, Drabek D, Okba NMA, van Haperen
R, Osterhaus A, van Kuppeveld FJM, Haagmans BL, Grosveld F, Bosch BJ: A human
monoclonal antibody blocking SARS-CoV-2 infection. Nat Commun 2020;11:2251. |
|
|
|
|
|
93 Pinto D, Park YJ, Beltramello M, Walls AC,
Tortorici MA, Bianchi S, Jaconi S, Culap K, Zatta F, De Marco A, Peter A,
Guarino B, Spreafico R, Cameroni E, Case JB, Chen RE, Havenar-Daughton C,
Snell G, Telenti A, Virgin HW, et al.: Cross-neutralization of SARS-CoV-2 by
a human monoclonal SARS-CoV antibody. Nature 2020;583:290-295. |
|
|
|
|
|
94 Shi R, Shan C, Duan X, Chen Z, Liu P, Song J,
Song T, Bi X, Han C, Wu L, Gao G, Hu X, Zhang Y, Tong Z, Huang W, Liu WJ, Wu
G, Zhang B, Wang L, et al.: A human neutralizing antibody targets the
receptor-binding site of SARS-CoV-2. Natur 2020;584:120-124. |
|
|
|
|
|
95 Jawhara S: Could Intravenous Immunoglobulin
Collected from Recovered Coronavirus Patients Protect against COVID-19 and
Strengthen the Immune System of New Patients? Int J Mol Sci 2020;21:2272. |
|
|
|
|
|
96 Mair-Jenkins J, Saavedra-Campos M, Baillie
JK, Cleary P, Khaw FM, Lim WS, Makki S, Rooney KD, Nguyen-Van-Tam JS, Beck
CR, Convalescent Plasma Study G: The effectiveness of convalescent plasma and
hyperimmune immunoglobulin for the treatment of severe acute respiratory
infections of viral etiology: a systematic review and exploratory
meta-analysis. J Infect Dis 2015;211:80-90. |
|
|
|
|
|
97 Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J,
Wang F, Li D, Yang M, Xing L, Wei J, Xiao H, Yang Y, Qu J, Qing L, Chen L, Xu
Z, Peng L, Li Y, Zheng H, et al.: Treatment of 5 Critically Ill Patients With
COVID-19 With Convalescent Plasma. JAMA 2020;323:1582-1589. |
|
|
|
|
|
98 Yang LT, Peng H, Zhu ZL, Li G, Huang ZT, Zhao
ZX, Koup RA, Bailer RT, Wu CY: Long-lived effector/central memory T-cell
responses to severe acute respiratory syndrome coronavirus (SARS-CoV) S
antigen in recovered SARS patients. Clin Immunol 2006;120:171-178. |
|
|
|
|
|
99 Peng H, Yang LT, Wang LY, Li J, Huang J, Lu
ZQ, Koup RA, Bailer RT, Wu CY: Long-lived memory T lymphocyte responses
against SARS coronavirus nucleocapsid protein in SARS-recovered patients.
Virology 2006;351:466-475. |
|
|
|
|
|
100 Jiang S, Hillyer C, Du L: Neutralizing
Antibodies against SARS-CoV-2 and Other Human Coronaviruses. Trends Immunol
2020;41:355-359. |
|
|
|
|
|
101 Channappanavar R, Fett C, Zhao J, Meyerholz
DK, Perlman S: Virus-specific memory CD8 T cells provide substantial
protection from lethal severe acute respiratory syndrome coronavirus
infection. J Virol 2014;88:11034-11044. |
|
|
|
|
|
102 Yang L, Peng H, Zhu Z, Li G, Huang Z, Zhao
Z, Koup RA, Bailer RT, Wu C: Persistent memory CD4+ and CD8+ T-cell responses
in recovered severe acute respiratory syndrome (SARS) patients to SARS
coronavirus M antigen. J Gen Virol 2007;88:2740-2748. |
|
|
|
|
|
103 Heurich A, Hofmann-Winkler H, Gierer S,
Liepold T, Jahn O, Pohlmann S: TMPRSS2 and ADAM17 cleave ACE2 differentially
and only proteolysis by TMPRSS2 augments entry driven by the severe acute
respiratory syndrome coronavirus spike protein. J Virol 2014;88:1293-1307. |
|
|
|
|
|
104 Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M,
Shi Z, Hu Z, Zhong W, Xiao G: Remdesivir and chloroquine effectively inhibit
the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res
2020;30:269-271. |
|
|
|
|
|
105 Vincent MJ, Bergeron E, Benjannet S,
Erickson BR, Rollin PE, Ksiazek TG, Seidah NG, Nichol ST: Chloroquine is a
potent inhibitor of SARS coronavirus infection and spread. Virol J 2005;2:69. |
|
|
|
|
|
106 Cortegiani A, Ingoglia G, Ippolito M,
Giarratano A, Einav S: A systematic review on the efficacy and safety of
chloroquine for the treatment of COVID-19. J Crit Care 2020;57:279-283. |
|
|
|
|
|
107 Gupta N, Agrawal S, Ish P: Chloroquine in
COVID-19: the evidence. Monaldi Arch Chest Dis 2020;90. |
|
|
|
|
|
108 Boulware DR, Pullen MF, Bangdiwala AS,
Pastick KA, Lofgren SM, Okafor EC, Skipper CP, Nascene AA, Nicol MR, Abassi
M, Engen NW, Cheng MP, LaBar D, Lother SA, MacKenzie LJ, Drobot G, Marten N,
Zarychanski R, Kelly LE, Schwartz IS, et al.: A Randomized Trial of
Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med
2020;383:517-525. |
|
|
|
|
|
109 Zhang P, Zhu L, Cai J, Lei F, Qin JJ, Xie J,
Liu YM, Zhao YC, Huang X, Lin L, Xia M, Chen MM, Cheng X, Zhang X, Guo D,
Peng Y, Ji YX, Chen J, She ZG, Wang Y, et al.: Association of Inpatient Use
of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor
Blockers With Mortality Among Patients With Hypertension Hospitalized With
COVID-19. Circ Res 2020;126:1671-1681. |
|
|
|
|
|
110 Offringa A, Montijn R, Singh S, Paul M,
Pinto YM, Pinto-Sietsma SJ: The mechanistic overview of SARS-CoV-2 using
angiotensin-converting enzyme 2 to enter the cell for replication: possible
treatment options related to the renin-angiotensin system. Eur Heart J
Cardiovasc Pharmacother 2020; DOI:10.1093/ehjcvp/pvaa053. |
|
|
|
|
|
111 Danser AHJ, Epstein M, Batlle D:
Renin-Angiotensin System Blockers and the COVID-19 Pandemic: At Present There
Is No Evidence to Abandon Renin-Angiotensin System Blockers. Hypertension
2020;75:1382-1385. |
|
|
|
|
|
112 Guo J, Huang Z, Lin L, Lv J: Coronavirus
Disease 2019 (COVID-19) and Cardiovascular Disease: A Viewpoint on the
Potential Influence of Angiotensin-Converting Enzyme Inhibitors/Angiotensin
Receptor Blockers on Onset and Severity of Severe Acute Respiratory Syndrome
Coronavirus 2 Infection. J Am Heart Assoc 2020;9:e016219. |
|
|
|
|
|
113 Rico-Mesa JS, White A, Anderson AS: Outcomes
in Patients with COVID-19 Infection Taking ACEI/ARB. Curr Cardiol Rep
2020;22:31. |
|
|
|
|
|
114 Sriram K, Insel PA: Risks of ACE inhibitor
and ARB usage in COVID-19: evaluating the evidence. Clin Pharmacol Ther
2020;108:236-241. |
|
|
|
|
|
115 Zhou Y, Vedantham P, Lu K, Agudelo J,
Carrion R, Jr., Nunneley JW, Barnard D, Pohlmann S, McKerrow JH, Renslo AR,
Simmons G: Protease inhibitors targeting coronavirus and filovirus entry.
Antiviral Res 2015;116:76-84. |
|
|
|
|
|
116 McKee DL, Sternberg A, Stange U, Laufer S,
Naujokat C: Candidate drugs against SARS-CoV-2 and COVID-19. Pharmacol Res
2020;157:104859. |
|
|
|
|
|
117 Zhou N, Pan T, Zhang J, Li Q, Zhang X, Bai
C, Huang F, Peng T, Zhang J, Liu C, Tao L, Zhang H: Glycopeptide Antibiotics
Potently Inhibit Cathepsin L in the Late Endosome/Lysosome and Block the
Entry of Ebola Virus, Middle East Respiratory Syndrome Coronavirus
(MERS-CoV), and Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV). J
Biol Chem 2016;291:9218-9232. |
|
|
|
|
|
118 Zhang J, Ma X, Yu F, Liu J, Zou F, Pan T,
Zhang H: Teicoplanin potently blocks the cell entry of 2019-nCoV [preprint].
bioRxiv 2020; DOI:10.1101/2020.02.05.935387. |
|
|
|
|
|
119 Coleman CM, Sisk JM, Mingo RM, Nelson EA,
White JM, Frieman MB: Abelson Kinase Inhibitors Are Potent Inhibitors of
Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory
Syndrome Coronavirus Fusion. J Virol 2016;90:8924-8933. |
|
|
|
|
|
120 Sisk JM, Frieman MB, Machamer CE:
Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl
kinase inhibitors. J Gen Virol 2018;99:619-630. |
|
|
|
|
|
121 Richardson P, Griffin I, Tucker C, Smith D,
Oechsle O, Phelan A, Stebbing J: Baricitinib as potential treatment for
2019-nCoV acute respiratory disease. Lancet 2020;395:e30-e31. |
|
|
|
|
|
122 Sheahan TP, Sims AC, Graham RL, Menachery
VD, Gralinski LE, Case JB, Leist SR, Pyrc K, Feng JY, Trantcheva I, Bannister
R, Park Y, Babusis D, Clarke MO, Mackman RL, Spahn JE, Palmiotti CA, Siegel
D, Ray AS, Cihlar T, Jordan R, Denison MR, Baric RS: Broad-spectrum antiviral
GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med
2017;9:eaal3653. |
|
|
|
|
|
123 Beigel JH, Tomashek KM, Dodd LE, Mehta AK,
Zingman BS, Kalil AC, Hohmann E, Chu HY, Luetkemeyer A, Kline S, Lopez de
Castilla D, Finberg RW, Dierberg K, Tapson V, Hsieh L, Patterson TF, Paredes
R, Sweeney DA, Short WR, Touloumi G, et al.: Remdesivir for the Treatment of
Covid-19 - Preliminary Report. N Engl J Med 2020; DOI:10.1056/NEJMoa2007764. |
|
|
|
|
|
124 Agostini ML, Pruijssers AJ, Chappell JD,
Gribble J, Lu X, Andres EL, Bluemling GR, Lockwood MA, Sheahan TP, Sims AC,
Natchus MG, Saindane M, Kolykhalov AA, Painter GR, Baric RS, Denison MR:
Small-Molecule Antiviral beta-d-N (4)-Hydroxycytidine Inhibits a
Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance. J
Virol 2019; DOI:10.1128/JVI.01348-19. |
|
|
|
|
|
125 Sheahan TP, Sims AC, Zhou S, Graham RL,
Pruijssers AJ, Agostini ML, Leist SR, Schafer A, Dinnon KH, 3rd, Stevens LJ,
Chappell JD, Lu X, Hughes TM, George AS, Hill CS, Montgomery SA, Brown AJ,
Bluemling GR, Natchus MG, Saindane M, et al.: An orally bioavailable
broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell
cultures and multiple coronaviruses in mice. Sci Transl Med 2020;12:eabb5883. |
|
|
|
|
|
126 Chu CM, Cheng VC, Hung IF, Wong MM, Chan KH,
Chan KS, Kao RY, Poon LL, Wong CL, Guan Y, Peiris JS, Yuen KY, Group HUSS:
Role of lopinavir/ritonavir in the treatment of SARS: initial virological and
clinical findings. Thorax 2004;59:252-256. |
|
|
|
|
|
127 Wang Z, Chen X, Lu Y, Chen F, Zhang W:
Clinical characteristics and therapeutic procedure for four cases with 2019
novel coronavirus pneumonia receiving combined Chinese and Western medicine
treatment. Biosci Trends 2020;14:64-68. |
|
|
|
|
|
128 Lim J, Jeon S, Shin HY, Kim MJ, Seong YM,
Lee WJ, Choe KW, Kang YM, Lee B, Park SJ: Case of the Index Patient Who
Caused Tertiary Transmission of COVID-19 Infection in Korea: the Application
of Lopinavir/Ritonavir for the Treatment of COVID-19 Infected Pneumonia
Monitored by Quantitative RT-PCR. J Korean Med Sci 2020;35:e79. |
|
|
|
|
|
129 Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G,
Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie
X, Zhang L, Li C, Yuan Y, et al.: A Trial of Lopinavir-Ritonavir in Adults
Hospitalized with Severe Covid-19. N Engl J Med 2020;382:1787-1799. |
|
|
|
|
|
130 Elfiky AA: Anti-HCV, nucleotide inhibitors,
repurposing against COVID-19. Life Sci 2020;248:117477. |
|
|
|
|
|
131 Wu CJ, Jan JT, Chen CM, Hsieh HP, Hwang DR,
Liu HW, Liu CY, Huang HW, Chen SC, Hong CF, Lin RK, Chao YS, Hsu JT: Inhibition
of severe acute respiratory syndrome coronavirus replication by niclosamide.
Antimicrob Agents Chemother 2004;48:2693-2696. |
|
|
|
|
|
132 Wen CC, Kuo YH, Jan JT, Liang PH, Wang SY,
Liu HG, Lee CK, Chang ST, Kuo CJ, Lee SS, Hou CC, Hsiao PW, Chien SC, Shyur
LF, Yang NS: Specific plant terpenoids and lignoids possess potent antiviral
activities against severe acute respiratory syndrome coronavirus. J Med Chem
2007;50:4087-4095. |
|
|
|
|
|
133 Xu J, Shi PY, Li H, Zhou J: Broad Spectrum
Antiviral Agent Niclosamide and Its Therapeutic Potential. ACS Infect Dis
2020; DOI:10.1021/acsinfecdis.0c00052. |
|
|
|
|
|
134 Jeon S, Ko M, Lee J, Choi I, Byun SY, Park
S, Shum D, Kim S: Identification of antiviral drug candidates against
SARS-CoV-2 from FDA-approved drugs. Antimicrob Agents Chemother 2020;
DOI:10.1128/AAC.00819-20. |
|
|
|
|
|
135 Matsuyama S, Kawase M, Nao N, Shirato K,
Ujike M, Kamitani W, Shimojima M, Fukushi S: The inhaled corticosteroid
ciclesonide blocks coronavirus RNA replication by targeting viral NSP15
[preprint]. bioRxiv 2020; DOI:10.1101/2020.03.11.987016. |
|
|
|
|
|
136 Sel'kova EP, Semenenko TA, Nosik NN, Iudina TI, Amarian MP, Lavrukhina LA, Pantiukhova TN, Tarasova G: [Effect of amyxin--a domestic analog of tilorone--on characteristics of interferon and immune status of man]. Zh Mikrobiol Epidemiol Immunobiol 2001:31-35. |
|
|
|
|
|
137 Ekins S, Lane TR, Madrid PB: Tilorone: a
Broad-Spectrum Antiviral Invented in the USA and Commercialized in Russia and
beyond. Pharm Res 2020;37:71. |
|
|
|
|
|
138 Furuta Y, Komeno T, Nakamura T: Favipiravir
(T-705), a broad spectrum inhibitor of viral RNA polymerase. Proc Jpn Acad
Ser B Phys Biol Sci 2017;93:449-463. |
|
|
|
|
|
139 De Clercq E: New Nucleoside Analogues for
the Treatment of Hemorrhagic Fever Virus Infections. Chem Asian J
2019;14:3962-3968. |
|
|
|
|
|
140 Du YX, Chen XP: Favipiravir:
Pharmacokinetics and Concerns About Clinical Trials for 2019-nCoV Infection.
Clin Pharmacol Ther 2020; DOI:10.1002/cpt.1844. |
|
|
|
|
|
141 Cai Q, Yang M, Liu D, Chen J, Shu D, Xia J,
Liao X, Gu Y, Cai Q, Yang Y, Shen C, Li X, Peng L, Huang D, Zhang J, Zhang S,
Wang F, Liu J, Chen L, Chen S, et al.: Experimental Treatment with
Favipiravir for COVID-19: An Open-Label Control Study. Engineering (Beijing)
2020; DOI:10.1016/j.eng.2020.03.007. |
|
|
|
|
|
142 Wang Z, Yang B, Li Q, Wen L, Zhang R:
Clinical Features of 69 Cases with Coronavirus Disease 2019 in Wuhan, China.
Clin Infect Dis 2020; DOI:10.1093/cid/ciaa272. |
|
|
|
|
|
143 Perry AK, Chen G, Zheng D, Tang H, Cheng G:
The host type I interferon response to viral and bacterial infections. Cell
Res 2005;15:407-422. |
|
|
|
|
|
144 Kolumam GA, Thomas S, Thompson LJ, Sprent J,
Murali-Krishna K: Type I interferons act directly on CD8 T cells to allow
clonal expansion and memory formation in response to viral infection. J Exp
Med 2005;202:637-650. |
|
|
|
|
|
145 Cinatl J, Morgenstern B, Bauer G, Chandra P,
Rabenau H, Doerr HW: Treatment of SARS with human interferons. Lancet
2003;362:293-294. |
|
|
|
|
|
146 Chan JF, Chan KH, Kao RY, To KK, Zheng BJ,
Li CP, Li PT, Dai J, Mok FK, Chen H, Hayden FG, Yuen KY: Broad-spectrum
antivirals for the emerging Middle East respiratory syndrome coronavirus. J
Infect 2013;67:606-616. |
|
|
|
|
|
147 Falzarano D, de Wit E, Martellaro C,
Callison J, Munster VJ, Feldmann H: Inhibition of novel beta coronavirus
replication by a combination of interferon-alpha2b and ribavirin. Sci Rep
2013;3:1686. |
|
|
|
|
|
148 Mantlo E, Bukreyeva N, Maruyama J, Paessler
S, Huang C: Antiviral activities of type I interferons to SARS-CoV-2
infection. Antiviral Res 2020;179:104811. |
|
|
|
|
|
149 Samuel CE: Antiviral actions of interferons.
Clin Microbiol Rev 2001;14:778-809. |
|
|
|
|
|
150 Schoggins JW, Rice CM: Interferon-stimulated
genes and their antiviral effector functions. Curr Opin Virol 2011;1:519-525. |
|
|
|
|
|
151 Tan DX, Korkmaz A, Reiter RJ, Manchester LC:
Ebola virus disease: potential use of melatonin as a treatment. J Pineal Res
2014;57:381-384. |
|
|
|
|
|
152 Zhang R, Wang X, Ni L, Di X, Ma B, Niu S,
Liu C, Reiter RJ: COVID-19: Melatonin as a potential adjuvant treatment. Life
Sci 2020;250:117583. |
|
|
|
|
|
153 Morse JS, Lalonde T, Xu S, Liu WR: Learning
from the Past: Possible Urgent Prevention and Treatment Options for Severe
Acute Respiratory Infections Caused by 2019-nCoV. Chembiochem
2020;21:730-738. |
|
|
|
|
|
154 Lin MH, Moses DC, Hsieh CH, Cheng SC, Chen
YH, Sun CY, Chou CY: Disulfiram can inhibit MERS and SARS coronavirus
papain-like proteases via different modes. Antiviral Res 2018;150:155-163. |
|
|
|
|
|
155 Dong L, Hu S, Gao J: Discovering drugs to
treat coronavirus disease 2019 (COVID-19). Drug Discov Ther 2020;14:58-60. |
|
|
|
|
|
156 Chen YW, Yiu CB, Wong KY: Prediction of the
SARS-CoV-2 (2019-nCoV) 3C-like protease (3CL (pro)) structure: virtual
screening reveals velpatasvir, ledipasvir, and other drug repurposing
candidates. F1000Res 2020;9:129. |
|
|
|
|
|
157 Chazal N, Gerlier D: Virus entry, assembly,
budding, and membrane rafts. Microbiol Mol Biol Rev 2003;67:226-237. |
|
|
|
|
|
158 Choi KS, Aizaki H, Lai MM: Murine
coronavirus requires lipid rafts for virus entry and cell-cell fusion but not
for virus release. J Virol 2005;79:9862-9871. |
|
|
|
|
|
159 Pietiainen VM, Marjomaki V, Heino J, Hyypia
T: Viral entry, lipid rafts and caveosomes. Ann Med 2005;37:394-403. |
|
|
|
|
|
160 Guo H, Huang M, Yuan Q, Wei Y, Gao Y, Mao L,
Gu L, Tan YW, Zhong Y, Liu D, Sun S: The Important Role of Lipid
Raft-Mediated Attachment in the Infection of Cultured Cells by Coronavirus
Infectious Bronchitis Virus Beaudette Strain. PLoS One 2017;12:e0170123. |
|
|
|
|
|
161 Jin Z, Du X, Xu Y, Deng Y, Liu M, Zhao Y,
Zhang B, Li X, Zhang L, Peng C, Duan Y, Yu J, Wang L, Yang K, Liu F, Jiang R,
Yang X, You T, Liu X, et al.: Structure of M(pro) from COVID-19 virus and
discovery of its inhibitors. Nature 2020; DOI:10.1038/s41586-020-2223-y. |
|
|
|
|
|
162 Pillaiyar T, Manickam M, Namasivayam V,
Hayashi Y, Jung SH: An Overview of Severe Acute Respiratory
Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and
Small Molecule Chemotherapy. J Med Chem 2016;59:6595-6628. |
|
|
|
|
|
163 Xu Z, Peng C, Shi Y, Zhu Z, Mu K, Wang X,
Zhu W: Nelfinavir was predicted to be a potential inhibitor of 2019-nCov main
protease by an integrative approach combining homology modelling, molecular
docking and binding free energy calculation [preprint]. bioRxiv 2020;
DOI:10.1101/2020.01.27.921627. |
|
|
|
|
|
164 Beck BR, Shin B, Choi Y, Park S, Kang K:
Predicting commercially available antiviral drugs that may act on the novel
coronavirus (SARS-CoV-2) through a drug-target interaction deep learning
model. Comput Struct Biotechnol J 2020;18:784-790. |
|
|
|
|
|
165 Shaabani N, Khairnar V, Duhan V, Zhou F, Tur
RF, Haussinger D, Recher M, Tumanov AV, Hardt C, Pinschewer D, Christen U,
Lang PA, Honke N, Lang KS: Two separate mechanisms of enforced viral
replication balance innate and adaptive immune activation. J Autoimmun
2016;67:82-89. |
|
|
|
|
|
166 Chen Y, Li T, Ye Y, Chen Y, Pan J: Impact of
fundamental diseases on patients with COVID-19. Disaster Med Public Health
Prep 2020:1-15. |
|
|
|
|
|
167 Dai M, Liu D, Liu M, Zhou F, Li G, Chen Z,
Zhang Z, You H, Wu M, Zheng Q, Xiong Y, Xiong H, Wang C, Chen C, Xiong F,
Zhang Y, Peng Y, Ge S, Zhen B, Yu T, et al.: Patients with cancer appear more
vulnerable to SARS-COV-2: a multi-center study during the COVID-19 outbreak.
Cancer Discov 2020; DOI:10.1158/2159-8290.CD-20-0422. |
|
|
|
|
|
168 Borghesi A, Zigliani A, Masciullo R, Golemi
S, Maculotti P, Farina D, Maroldi R: Radiographic severity index in COVID-19
pneumonia: relationship to age and sex in 783 Italian patients. Radiol Med
2020;125:461-464. |
|
|
|
|
|
169 Zheng Z, Peng F, Xu B, Zhao J, Liu H, Peng
J, Li Q, Jiang C, Zhou Y, Liu S, Ye C, Zhang P, Xing Y, Guo H, Tang W: Risk
factors of critical & mortal COVID-19 cases: A systematic literature
review and meta-analysis. J Infect 2020;81:316-e25. |
|
|
|
|
|
170 Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H,
Wang T, Zhang X, Chen H, Yu H, Zhang X, Zhang M, Wu S, Song J, Chen T, Han M,
Li S, Luo X, Zhao J, Ning Q: Clinical and immunologic features in severe and
moderate Coronavirus Disease 2019. J Clin Invest 2020;130:2620-2629. |
|
|
|
|
|
171 Wang F, Nie J, Wang H, Zhao Q, Xiong Y, Deng
L, Song S, Ma Z, Mo P, Zhang Y: Characteristics of Peripheral Lymphocyte
Subset Alteration in COVID-19 Pneumonia. J Infect Dis 2020;221:1762-1769. |
|
|
|
|
|
172 Wan S, Yi Q, Fan S, Lv J, Zhang X, Guo L,
Lang C, Xiao Q, Xiao K, Yi Z, Qiang M, Xiang J, Zhang B, Chen Y:
Characteristics of lymphocyte subsets and cytokines in peripheral blood of
123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP).
medRxiv 2020; DOI:10.1101/2020.02.10.20021832. |
|
|
|
|
|
173 Chen C, Zhang XR, Ju ZY, He WF: [Advances in the research of cytokine storm mechanism induced by Corona Virus Disease 2019 and the corresponding immunotherapies]. Zhonghua Shao Shang Za Zhi 2020;36:E005. |
|
|
|
|
|
174 Zhou Y, Fu B, Zheng X, Wang D, Zhao C, qi Y,
Sun R, Tian Z, Xu X, Wei H: Aberrant pathogenic GM-CSF+ T cells and
inflammatory CD14+CD16+ monocytes in severe pulmonary syndrome patients of a
new coronavirus [preprint]. bioRxiv 2020; DOI:10.1101/2020.02.12.945576. |
|
|
|
|
|
175 Zhang C, Wu Z, Li JW, Zhao H, Wang GQ: The
cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor
(IL-6R) antagonist Tocilizumab may be the key to reduce the mortality. Int J
Antimicrob Agents 2020:105954. |
|
|
|
|
|
176 Lamb YN, Deeks ED: Sarilumab: A Review in
Moderate to Severe Rheumatoid Arthritis. Drugs 2018;78:929-940. |
|
|
|
|
|
177 Chen L, Liu HG, Liu W, Liu J, Liu K, Shang J, Deng Y, Wei S: [Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi 2020;43:203-208. |
|
|
|
|
|
178 Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, Chan
IH, Lit LC, Hui DS, Chan MH, Chung SS, Sung JJ: Plasma inflammatory cytokines
and chemokines in severe acute respiratory syndrome. Clin Exp Immunol
2004;136:95-103. |
|
|
|
|
|
179 Guo YR, Cao QD, Hong ZS, Tan YY, Chen SD,
Jin HJ, Tan KS, Wang DY, Yan Y: The origin, transmission and clinical
therapies on coronavirus disease 2019 (COVID-19) outbreak - an update on the
status. Mil Med Res 2020;7:11. |
|
|
|
|
|
180 Wang J, Jiang M, Chen X, Montaner LJ:
Cytokine storm and leukocyte changes in mild versus severe SARS-CoV-2 infection:
Review of 3939 COVID-19 patients in China and emerging pathogenesis and
therapy concepts. J Leukoc Biol 2020;108:17-41. |
|
|
|
|
|
181 Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, Kritas SK: Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents 2020;34:327-331. |
|
|
|
|
|
182 Runfeng L, Yunlong H, Jicheng H, Weiqi P,
Qinhai M, Yongxia S, Chufang L, Jin Z, Zhenhua J, Haiming J, Kui Z, Shuxiang
H, Jun D, Xiaobo L, Xiaotao H, Lin W, Nanshan Z, Zifeng Y: Lianhuaqingwen
exerts anti-viral and anti-inflammatory activity against novel coronavirus
(SARS-CoV-2). Pharmacol Res 2020:104761. |
|
|
|
|
|
183 Zheng BJ, Du LY, Zhao GY, Lin YP, Sui HY, Chan C, Ma S, Guan Y, Yuen KY: Studies of SARS virus vaccines. Hong Kong Med J 2008;14:39-43. |
|
|
|
|
|
184 Li K, Li Z, Wohlford-Lenane C, Meyerholz DK,
Channappanavar R, An D, Perlman S, McCray PB, Jr., He B: Single-Dose,
Intranasal Immunization with Recombinant Parainfluenza Virus 5 Expressing
Middle East Respiratory Syndrome Coronavirus (MERS-CoV) Spike Protein
Protects Mice from Fatal MERS-CoV Infection. mBio 2020;
DOI:10.1128/mBio.00554-20. |
|
|
|
|
|
185 Tai W, He L, Zhang X, Pu J, Voronin D, Jiang
S, Zhou Y, Du L: Characterization of the receptor-binding domain (RBD) of
2019 novel coronavirus: implication for development of RBD protein as a viral
attachment inhibitor and vaccine. Cell Mol Immunol 2020; 17:613-620 |
|
|
|
|
|
186 Kim E, Erdos G, Huang S, Kenniston TW,
Balmert SC, Carey CD, Raj VS, Epperly MW, Klimstra WB, Haagmans BL, Korkmaz
E, Falo LD, Jr., Gambotto A: Microneedle array delivered recombinant
coronavirus vaccines: Immunogenicity and rapid translational development.
EBioMedicine 2020:102743. |
|
|
|
|
|
187 Gao Q, Bao L, Mao H, Wang L, Xu K, Yang M,
Li Y, Zhu L, Wang N, Lv Z, Gao H, Ge X, Kan B, Hu Y, Liu J, Cai F, Jiang D,
Yin Y, Qin C, Li J, et al.: Development of an inactivated vaccine candidate
for SARS-CoV-2. Science 2020;369:77-81. |
|
|
|
|
|
188 Smith TRF, Patel A, Ramos S, Elwood D, Zhu
X, Yan J, Gary EN, Walker SN, Schultheis K, Purwar M, Xu Z, Walters J,
Bhojnagarwala P, Yang M, Chokkalingam N, Pezzoli P, Parzych E, Reuschel EL,
Doan A, Tursi N, et al.: Immunogenicity of a DNA vaccine candidate for
COVID-19. Nat Commun 2020;11:2601. |
|
|
|
|
|
189 ClinicalTrials.gov: COVID-19 clinical trials. 2020; URL: https://clinicaltrials.gov/ct2/results?cond=COVID-19. |
|
|
|
|
|
190 Folegatti PM, Ewer KJ, Aley PK, Angus B,
Becker S, Belij-Rammerstorfer S, Bellamy D, Bibi S, Bittaye M, Clutterbuck
EA, Dold C, Faust SN, Finn A, Flaxman AL, Hallis B, Heath P, Jenkin D,
Lazarus R, Makinson R, Minassian AM, et al.: Safety and immunogenicity of the
ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase
1/2, single-blind, randomised controlled trial. Lancet 2020;396:467-478. |
|
|
|
|
|
191 Jackson LA, Anderson EJ, Rouphael NG,
Roberts PC, Makhene M, Coler RN, McCullough MP, Chappell JD, Denison MR,
Stevens LJ, Pruijssers AJ, McDermott A, Flach B, Doria-Rose NA, Corbett KS,
Morabito KM, O'Dell S, Schmidt SD, Swanson PA, 2nd, Padilla M, et al.: An
mRNA Vaccine against SARS-CoV-2 - Preliminary Report. N Engl J Med 2020;
DOI:10.1056/NEJMoa2022483. |
|
|
|
|
|
192 Amanat F, Krammer F: SARS-CoV-2 Vaccines:
Status Report. Immunity 2020;52:583-589. |
|
|
|
|
|
193 Chen WH, Strych U, Hotez PJ, Bottazzi ME:
The SARS-CoV-2 Vaccine Pipeline: an Overview. Curr Trop Med Rep 2020:1-4. |
|
|
|
|
|
194 Calina D, Docea AO, Petrakis D, Egorov AM,
Ishmukhametov AA, Gabibov AG, Shtilman MI, Kostoff R, Carvalho F, Vinceti M,
Spandidos DA, Tsatsakis A: Towards effective COVID19 vaccines: Updates,
perspectives and challenges (Review). Int J Mol Med 2020;46:3-16. |
|
|
|
|
|
195 Fine P, Eames K, Heymann DL: "Herd
immunity": a rough guide. Clin Infect Dis 2011;52:911-916. |
|
|
|
|
|
196 Merrill RM: Introduction to Epidemiology. Burlington, MA, Jones & Bartlett, 2013, ed 6, pp 68-71. |
|
|
|
|
|
197 Read JM, Bridgen JR, Cummings DA, Ho A,
Jewell CP: Novel coronavirus 2019-nCoV: early estimation of epidemiological
parameters and epidemic predictions. medRxiv 2020; DOI:10.1101/2020.01.23.20018549 |
|
|
|
|
|
198 Lythgoe MP, Middleton P: Ongoing Clinical
Trials for the Management of the COVID-19 Pandemic. Trends Pharmacol Sci
2020;41:363-382. |
|