key: cord-1034967-4zmqplz0
authors: Zhang, Jiancheng; Xie, Bing; Hashimoto, Kenji
title: Current status of potential therapeutic candidates for the COVID-19 crisis
date: 2020-04-22
journal: Brain Behav Immun
DOI: 10.1016/j.bbi.2020.04.046
sha: c2e74aedfcc7484bbfff6c1916d713ee4f0f0c8b
doc_id: 1034967
cord_uid: 4zmqplz0

Abstract As of April 15, 2020, the ongoing coronavirus disease 2019 (COVID-2019) pandemic has swept through 213 countries and infected more than 1,870,000 individuals, posing an unprecedented threat to international health and the economy. There is currently no specific treatment available for patients with COVID-19 infection. The lessons learned from past management of respiratory viral infections have provided insights into treating COVID-19. Numerous potential therapies, including supportive intervention, immunomodulatory agents, antiviral therapy, and convalescent plasma transfusion, have been tentatively applied in clinical settings. A number of these therapies have provided substantially curative benefits in treating patients with COVID-19 infection. Furthermore, intensive research and clinical trials are underway to assess the efficacy of existing drugs and identify potential therapeutic targets to develop new drugs for treating COVID-19. Herein, we summarize the current potential therapeutic approaches for diseases related to COVID-19 infection and introduce their mechanisms of action, safety, and effectiveness.

Coronavirus disease 2019 (COVID-2019), which causes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China in December 2019 and spread rapidly across the world due to its high transmissibility and pathogenicity (Munster et al., 2020; Zhu et al., 2020) . SARS-CoV-2 is a distinct clade of beta coronaviruses encompassing severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) . Although most cases of the disease caused by most pathogenic coronaviruses are mild (Su et al., 2016) , the SARS-CoV and MERS-CoV outbreak in 2002 and 2012, respectively, demonstrated their high lethality (Schoeman and Fielding, 2019) . SARS-CoV-2 bears an 82% resemblance to the genomic sequence of SARS-CoV (Chan et al., 2020) ; however, COVID-19 presents a lower case fatality rate and higher infectiousness than SARS, with mortality rates of approximately 3.7%

for COVID-19 and 10% for SARS (WHO, 2003; WHO, 2020a) . COVID-19 patients often exhibit mild symptoms, such as fever, cough, myalgia, and fatigue and generally have a good prognosis. However, a large proportion of COVID-19 cases have rapidly progressed to severe types, especially among older men with underlying diseases (Chen et al., 2020c; Liu et al., 2020c; Wang et al., 2020a) . Severe cases can include dyspnea , shock , organ dysfunction [acute respiratory distress syndrome (ARDS)] (Guan et al., 2020; Wang et al., 2020a; Xu et al., 2020; Yang et al., 2020; Yao et al., 2020) , acute cardiac injury (Han et al., 2020a; Strabelli and Uip, 2020; Wang et al., 2020a; Yao et al., 2020; Zhou et al., 2020a) , acute kidney injury (Guan et al., 2020; Li et al., 2020a; Pan et al., 2020; Wang et al., 2020a; Yao et al., 2020) , acute liver injury Xu et al., 2020; Yao et al., 2020; Zhang et al., 2020c) , neurological injury (Mao et al., 2020; Wu et al., 2020) , gastrointestinal injury (Yao et al., 2020) , immune injury Guan et al., 2020; Liu et al., 2020b; Qin et al., 2020; Wang et al., 2020b; Yao et al., 2020; Zhang et al., 2020a; Zheng et al., 2020) , coagulation impairment Tang et al., 2020a) , and even death Wang et al., 2020a) (Fig. 1) . In addition, COVID-19 pandemic has great impact in psychological stress and mental health worldwide (Bao et al., 2020; Kang et al., 2020; Pfefferbaum and North, 2020; Shi et al., 2020a) .

At present, the pathogenesis and etiology of COVID-19 remains unclear, and there are no targeted therapies for COVID-19 patients, who are empirically administered symptomatic treatments, with organ support for those who are seriously ill . Given the pandemic spread of COVID-19 and the resulting global economic loss, developing alternative agents to contain SARS-CoV-2 is imperative. In this review, we summarize the potential therapeutic candidates under development for COVID-19 based on clinical trials and describe their potential mechanisms of action ( Fig. 2 and Fig. 3 ).

Remdesivir, a nucleotide prodrug, originally developed to control the Ebola virus (Siegel et al., 2017) and subsequently demonstrated its efficacy in inhibiting coronaviruses such as SARS-CoV and MERS-CoV in vitro (Sheahan et al., 2017) , presents antiviral activity by interfering with RNA-dependent RNA polymerase, thereby attacking the virus's ability to replicate in the body (Fig. 2) (Agostini et al., 2018) . A recent study indicated that remdesivir efficiently protected a human cell line against SARS-CoV-2 infection . Treatment with intravenous remdesivir successfully improved the clinical state of the first U.S. COVID-19 patient (Holshue et al., 2020) . Remdesivir is now being tested in several clinical trials designed to evaluate its efficacy and safety for the treatment of COVID-19. Notably, Gilead Sciences announced the result of a very recent clinical study on the efficacy of remdesivir on COVID-19 (Grein et al., 2020) . In this report, 53 patients infected with severe COVID-19 were tracked, and 34 patients of whom were critically ill, with 30 patients requiring mechanical ventilation and 4 patients relying on extracorporeal membrane oxygenation (ECMO). Over a median follow-up of 18 days, 36 patients (68%) presented with improved oxygen-support class. 20 patients of 34 severely ill patients showed improvement in clinical conditions, with 17 of 30 patients stopped receiving invasive mechanical ventilation and 3 of 4 patients stopped receiving ECMO treatment respectively. The treatment of remdesivir limited the mortality rate of seriously ill patients needing invasive ventilation to 18%, and 5% for those who did not needed. Generally, the efficacy of remdesivir reflected in this study is hopeful.

However, the sample size of this study was quite small, and definite effectiveness of remdesivir in the treatment of COVID-19 needs to be further verified ( Table 1) .

Lopinavir/ritonavir (LPV-r) is a co-formulated human immunodeficiency virus (HIV)-specific protease inhibitor that serves as first-line therapy for HIV (Barragan and Podzamczer, 2008) . Concomitant use of ritonavir could increase the plasma half-life of lopinavir through cytochrome P450 inhibition in the liver. During the 2003 SARS outbreak, LPV-r was reported to have in vitro inhibitory activity against SARS-CoV (Chu et al., 2004a) , and combination therapy of LPV-r and ribavirin provided favorable results in treating patients with SARS ( Fig. 2) (Chu et al., 2004b) .

Triple combination therapy with LPV-r, ribavirin, and IFN-α has shown clinical effectiveness for MERS (Kim et al., 2016) . Notwithstanding, a recent open-label randomized study with 199 patients in Wuhan showed that LPV-r monotherapy did not produce any therapeutic benefits for COVID-19 patients compared with standard supportive care, which might be caused by the higher throat viral loads in the LPV-r group, concurrent pharmacologic interventions, and late treatment initiation (Table 1 ) . The enrolled COVID-19 patients were critically ill, and LPV-r treatment might have been started relatively late. However, in another retrospective cohort study, combination therapy of LPV-r and arbidol was associated with improved pulmonary computed tomography images (Deng et al., 2020) . Collectively, the combination therapy of LPV-r and other antiviral agents in early stages of COVID-19 infection might hold promise for treating COVID-19.

Favipiravir, also known as Avigan ® and originally developed and approved for the influenza virus infection epidemic in Japan, has a broad spectrum of antiviral activity (Furuta et al., 2013) . Once it enters cells, favipiravir undergoes phosphorylation to convert into its active phosphorylated form (favipinavir-RTP), which potently inhibits viral RNA polymerase, thereby interfering with viral genome replication (Fig. 2 ) (Furuta et al., 2005) . Favipiravir demonstrated efficacy in inhibiting a wide range of viruses, including resistant influenza viruses and other RNA viruses, such as arenaviruses, bunyaviruses, and filoviruses (Delang et al., 2018) . Previous studies have showed that favipiravir is efficacious against Ebola virus in rodent models (Oestereich et al., 2014; Smither et al., 2014) , while its effectiveness in humans is unproven (Sissoko et al., 2016) . Favipiravir appears to be effective in COVID-19.

Two clinical trials involving a total of 340 patients were conducted in Wuhan and Shenzhen. At a press conference in March 17, 2020, Xinmin Zhang, an official of China's Science and Technology Ministry, stated that favipiravir appeared to be effective in COVID-19 (Hackett, 2020) . Preliminary clinical data from 80 patients in the Third People's Hospital of Shenzhen suggested that favipiravir exerted antiviral effects more potently than LPV-r, with no overt adverse reactions (Third People's Hospital of Shenzhen, 2020). The other clinical trial in Wuhan showed that, based on conventional therapy, favipiravir demonstrated higher efficacy than arbidol in terms of the 7-day recovery rate and duration of symptom attenuation in patients with moderate COVID-19 infection . Taken together, the clinical results of favipiravir are favorable (Table 1) ; however, further study of favipiravir monotherapy using a large sample size is needed.

Researchers from Emory University, the University of North Carolina, and Vanderbilt University Medical Center tested a new drug, EIDD-2801, for its in vitro efficacy against SARS-CoV-2, and its laboratory results are encouraging (Sheahan et al., 2020) . Based on EIDD-1931, an orally bioavailable ribonucleotide analog, EIDD-2801 is designed to optimize oral bioavailability and improve drug uptake in humans and non-human primates (Fig. 2) . EIDD-1931 has a variety of antiviral activities against numerous causal agents of deleterious viral infectious diseases, including influenza, chikungunya, Ebola, Venezuelan equine encephalitis, and coronavirus-associated diseases (Agostini et al., 2019; Painter et al., 2019; Reynard et al., 2015; Toots et al., 2019) . As a ribonucleotide analog, EIDD-1931 shares similar mechanisms of action with remdesivir and exerts antiviral effects by mimicking a ribonucleotide, thereby mistakenly being incorporated into viral RNA, leading to lethal mutagenesis during virion RNA synthesis and inhibiting the RNA-dependent RNA polymerase encoded by the virus during viral replication (Fig. 2) Sheahan et al., 2020) . The study suggested that EIDD-1931 robustly blocked the replication of SARS-CoV, MERS-CoV, and the newly emerging SARS-CoV-2 in cell assays. EIDD-2801 demonstrated its prophylactic and therapeutic effects in murine models of SARS and MERS, showing diminished viral lung titers, attenuated weight loss, ameliorated lung damage, and improved pulmonary function, which are dependent on the administered dosage and the treatment initiation time. Compared with remdesivir, EIDD-2801 appears to be favorable. EIDD-2801 has a more convenient oral administration, while remdesivir must rely on intravenous administration by a trained specialist. More importantly, EIDD-2801 showed active antiviral activity against remdesivir-resistant viruses, according to the data presented by the study. Of significant importance, EIDD-1931 appeared to be effective not just for SARS-CoV, MERS-CoV, and SARS-CoV-2 but also other coronavirus species, indicating its potential efficacy for emerging coronaviruses in the future. The U.S. Food and Drug Administration (FDA) has approved an Investigational New Drug application for EIDD-2801, and clinical studies with humans are expected to start as soon as possible (Table 1 ) (BioSpace, 2020).

Convalescent plasma collected from donors who have survived an infectious disease by producing protective antibodies is considered to provide a great degree of protection for recipients affected by the emerging virus (Dodd, 2012) . Convalescent plasma has been successfully employed to treat numerous infectious diseases, including the 2003 SARS- CoV-1 epidemic, 2009 -2010 H1N1 influenza virus pandemic, and 2012 MERS-CoV epidemic (Dodd, 2012 Hung et al., 2011; Mair-Jenkins et al., 2015) , for which modern medicine has no specifically effective treatment. In the absence of specific antiviral agents and vaccines for COVID-19, clinical trials have been conducted aimed at investigating the efficacy of convalescent plasma in treating COVID-19. A very recently published study by Chinese researchers confirmed the efficacy of convalescent plasma in controlling SARS-CoV-2 (Table 1) (Roback and Guarner, 2020) . The report suggested that COVID-19 patients showed signs of improvement approximately 1 week after convalescent plasma transfusion. Another clinical study involved 10 critically ill patients infected with COVID-19 from 3 different hospitals in Wuhan suggested high-titer convalescent plasma transfusion can effectively neutralize SARS-CoV-2, leading to impeded inflammatory responses and improved symptom conditions without severe adverse events. All 10 patients receiving convalescent plasma transfusion showed improvement of clinical outcomes or were cured and discharged from hospital (Duan et al., 2020) . Given the clinical effectiveness of convalescent plasma, the FDA has granted clinical permission for applying convalescent plasma to the treatment of critically ill COVID-19 patients (FDA, 2020).

4.1. Angiotensin-converting enzyme 2 (ACE2) serves as a negative regulator of the renin angiotensin system (RAS) and is widely distributed among lung tissue and many extrapulmonary tissues, including brain, heart, liver, kidney, endothelium, and intestine ( Fig. 2) (Crackower et al., 2002; Ding et al., 2004; Hamming et al., 2004) .

Of these, alveolar epithelial type Ⅱ cells possess an abundance of ACE2 receptors . Unfortunately, ACE2 is also a functional receptor of SARS-CoV (Li et al., 2003) and SARS-CoV-2 . The spike (S) protein of SARS-CoV and SARS-CoV-2 binds to the host ACE2 receptor and then enters target cells (Fig. 2) . Critically, SARS-CoV-2 shows higher affinity for ACE2 than SARS-CoV (Wrapp et al., 2020) . Moreover, the S protein of SARS-CoV-2 contains a site that can be recognized and activated by a host enzyme called furin, which is highly expressed in the lungs (Coutard et al., 2020) . These findings might provide strong evidence for the high pathogenicity of SARS-CoV-2. Due to the pivotal role of widely distributed ACE2 in the entry and replication of viruses, blocking S protein binding to ACE2 might offer some protection against SARS-CoV-2 infection (Fig. 1) .

A study using a murine model of SARS showed that SARS-CoV S protein binding to ACE2 led to RAS downregulation and consequently contributed to severe lung injury . Therefore, recombinant human ACE2 (rhACE2) might protect host lungs against infection through an enhanced ACE2 level to neutralize the S protein on the SARS-CoV-2 surface. Clinical evidence has demonstrated the safety of rhACE2 application (Haschke et al., 2013; Khan et al., 2017) . A recent in vitro study demonstrated that the fusion protein of rhACE2 with an Fc fragment shows high affinity binding to the receptor-binding domain of SARS-CoV-2 and potently neutralizes SARS-CoV-2 . Additionally, the findings from a newly online published report in Cell were strongly supportive of potential efficacy of rhACE2 for SARS-CoV-2 infection (Monteil et al., 2020) . The study showed that clinical-grade human recombinant soluble ACE2 (hrsACE2) displayed potently inhibitory activity against SARS-CoV-2 in cell cultures and in engineered replicas of human blood vessels and kidneys in a dose-dependent manner. The researchers found that before infecting cells, SARS-CoV-2 co-incubated with hrsACE2, rather than mouse recombinant soluble ACE2, demonstrated dropped activity to infect cells. In the organoid level, administration of hrsACE2 significantly blocked SARS-CoV-2 infection in both engineered human blood vessels and kidneys without observed toxicity. However, note that this study focused on the early stages of SARS-CoV-2 infection, it is still unclear whether hrsACE2 can play a role in the later infection process. Taken together, it is likely that rhACE2 has potentially curative effectiveness in COVID-19. A clinical trial is underway to investigate the efficacy of rhACE2 in the treatment of COVID-19 (NCT04287686) ( Table 1) .

ACE inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) are widely used for treating cardiovascular diseases. Studies have shown that ACEIs/ARBs can upregulate ACE2 expression (Ferrario et al., 2005; Ishiyama et al., 2004; Karram et al., 2005) , which might correlate with the susceptibility to SARS-CoV-2. However, evidence has shown that RAS activation and decreased ACE2 expression contribute to the pathological process of lung injury after SARS-CoV infection . Serum angiotensin II levels are markedly elevated and exhibit a linear positive correlation to viral load and lung injury in COVID-19 .

Consequently, the effects of ACEIs/ARBs on lung-specific ACE2 expression in COVID-19 remain unknown. ACEIs/ARBs might have a dual role in COVID-19. On the one hand, the elevated ACE2 level might increase susceptibility to SARS-CoV-2, while on the other, ACE2 activation and RAS deregulation might ameliorate the acute lung injury, heart injury, and renal damage induced by SARS-CoV-2 . However, there has been no definite evidence on whether taking ACEIs/ARBs is beneficial or harmful for COVID-19 patients.

Chloroquine (CQ), a drug widely used in treating malarial and autoimmune diseases, also confers considerable broad-spectrum antiviral effects even against SARS-CoV (Table 1 ) (Keyaerts et al., 2004b; Savarino et al., 2006; Yan et al., 2013) . A recent study demonstrated that CQ has anti-SARS-CoV-2 activity in vitro (Fig. 3) . A subsequent letter in Bioscience confirmed that CQ is efficacious in treating COVID-19 pneumonia in numerous related clinical trials .

CQ therapy resulted in improved pulmonary lesions, shortened disease course, and good outcomes ( Table 1 ) . Given the efficiency displayed by CQ in clinical practice, CQ has been included in the Guidelines for the Diagnosis and Treatment of COVID-19 (7th edition) issued by the National Commission of the People's Republic of China (NHPFC, 2020).

Hydroxychloroquine sulfate (HCQ) shares a similar chemical structure and mechanisms of action with CQ but with lower ocular toxicity (Lim et al., 2009 ) and has proven efficacious in containing SARS-CoV-2 in vitro . CQ and HCQ exert antiviral function through various mechanisms. CQ has been shown to interfere with the glycosylation process of ACE2 in host cells, thereby inhibiting the efficiency of the binding of S protein with ACE2, in turn disrupting the virus/cell fusion process (Fig. 3 ) (Savarino et al., 2006) . CQ can increase the pH of acidic cellular organelles required for virus entry into host cells (Savarino et al., 2003) . In addition to its direct antiviral activity, CQ and HCQ can attenuate major "cytokine storms" (an overreaction of the immune system causing inflammatory "storms") by decreasing cytokine production (interleukin [IL]-1, IL-6, and tumor necrosis factor

[TNF], etc.) ( Fig. 3 ) (van den Borne et al., 1997) . Notably, high cytokine concentrations have been observed in seriously ill COVID-19 patients , indicating that over-reactive immune responses exacerbate COVID-19. Therefore, the immune-modulating activity of HCQ might partially account for its efficient control of SARS-CoV-2 infection. CQ and HCQ are therefore promising drugs of choice for large-scale use due to their low cost, wide availability and potential efficacy for treating COVID-19. CQ and HCQ need to be administered with caution when treating COVID-19 infection to prevent toxicity.

A recent open-label study in France showed that HCQ treatment was significantly associated with viral load reduction/disappearance in COVID-19 patients and that its effect was reinforced by azithromycin (Gautret et al., 2020) . Although this study is an open-label study using small sample size, the combination of HCQ and azithromycin could be promising candidate for COVID-19 patients. In contrast, a multinational, network cohort and self-controlled case series study demonstrated that short-term HCQ treatment is safe (Lane et al., 2020) . However, combination of HCQ and azithromycin may induce an increased risk of 30 day cardiovascular mortality, chest pain/angina, and heart failure (Lane et al., 2020) . Therefore, we must pay the attention for the combination therapy in the management of COVID-19 patients.

Tocilizumab (TCZ) and sarilumab are monoclonal antibodies against IL-6 receptors and have been employed to treat rheumatoid arthritis (Nishimoto et al., 2000; Raimondo et al., 2017) . TCZ and sarilumab efficiently inhibit IL-6 through both membrane-bound and soluble IL-6R ( Fig. 3 ) (Raimondo et al., 2017; Sakkas, 2016) . TCZ has been approved by the FDA for treating cytokine release syndrome marked by excessive cytokine production and consequently rapid multiorgan damage (lungs, kidney, and heart) (Shimabukuro-Vornhagen et al., 2018). COVID-19 disease severity depends on the increase in pro-inflammatory factors [IL-6, IL-1, IL-2, IL-7, IL-10, granulocyte-colony stimulating factor, interferon-γ-inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein-1 alpha, and TNF-α] Ruan et al., 2020; Zhou et al., 2020a) , suggesting that cytokine storms are involved in the development of COVID-19. One of the key cytokines involved in the immune system perturbation is IL-6 (Mehta et al., 2020). As IL-6 receptor antagonists, TCZ and sarilumab have therefore been hypothesized to exert suppressive effects on exuberant and dysfunctional systematic inflammation in patients infected with SARS-CoV-2 and further improve patients' condition. Three clinical trials (ChiCTR2000030196, ChiCTR2000030442, and ChiCTR2000029765) for TCZ have been approved for COVID-19, and the National Health and Family Planning Commission of China has approved the treatment with TCZ in patients with elevated IL-6 level. (Table 1 ) (NHPFC, 2020) . Encouraging results have been seen in Italy where three seriously ill patients administered TCZ showed the signs of improvement (Italian ANSA News Agency, 2020). According to the announcement from Regeneron Pharmaceuticals and Sanofi on March 16, 2020, a phase Ⅱ/Ⅲ clinical trial in the U.S. for sarilumab has been conducted to assess its therapeutic effects in patients with severe COVID-19 infection (Table 1) (Regeneron, 2020) .

Bevacizumab is a monoclonal anti-vascular endothelial growth factor (VEGF) antibody that competes with VEGF receptors on the surface of endothelial cells for VEGF binding, thereby inhibiting the effects cause by binding VEGF to its receptors, such as endothelial cell proliferation and neovascularization ( Fig. 3 ) (Ferrara et al., 2004) . VEGF produced by various inflammatory and epithelial cells is a potent vascular permeability inducer (Dvorak et al., 1995) . Previous reports have shown that plasma VEGF levels markedly increase in patients with ARDS (Thickett et al., 2001) .

Given the causal link between ARDS and increased vascular permeability and pulmonary edema (Fanelli and Ranieri, 2015) . Bevacizumab might be a potential anti-VEGF therapeutic approach. ARDS is a common complication in severe cases of COVID-19 ( Fig. 1) . Bevacizumab is therefore likely to be a promising therapy against COVID-19 (Table 1) .

Baricitinib, a highly selective janus kinase (JAK) inhibitor, has been approved for treating rheumatoid arthritis (Al-Salama and Scott, 2018). JAK-dependent pathways are responsible for producing a variety of cytokines involved in the pathogenesis of the progression process of COVID-19 characterized by elevated levels of inflammatory factors (e.g., IL-6, IL-7, and IL-2) (O'Shea and Plenge, 2012; . Baricitinib also serves as an inhibitor of adaptor-associated kinase 1 (AAK1, a member of the numb-associated kinase family), which plays a central role in regulating endocytosis through which the virus invades host cells (Fig. 3 ) (Richardson et al., 2020) . Therefore, baricitinib might exert beneficial effects on COVID-19 pneumonia, not only by impeding overexuberant immune responses by hijacking cytokine signaling pathways but also preventing SARS-CoV-2 from entering host cells. However, blockage of JAK-dependent pathways by baricitinib can also inhibit production of interferons (IFNs) (O'Shea and Plenge, 2012), which might have antiviral activity against SARS-CoV-2 ( Fig. 3) (Ströher et al., 2004) . Baricitinib treatment is therefore a double-edged sword (Table 1) , and choosing the appropriate time to administer baricitinib is vitally important. For severely ill patients with abnormal biomarkers, cautious baricitinib treatment might yield clinically beneficial effects.

Mesenchymal stem cells (MSCs) are multipotent cells isolated from diverse mesenchymal tissues (e.g., bone marrow, umbilical cord, adipose tissue) (Lv et al., 2014) . By virtue of their low immunogenicity (Chamberlain et al., 2007) , proven safety (Zheng et al., 2014) , and reparative and immunomodulatory properties (Galipeau and Sensébé, 2018; Mei et al., 2010) , MSCs are attractive therapeutic candidates for treating a wide range of diseases [e.g., graft-versus-host disease (Le Blanc et al., 2008) , sepsis, and ARDS] (Fig. 3) (Asmussen et al., 2014; Krasnodembskaya et al., 2012) . A large body of preclinical data has demonstrated the efficacy of MSCs in treating ARDS, manifested in reduced pulmonary edema, decreased plasma concentrations of pro-inflammatory cytokines, and reduced mortality rates (Chimenti et al., 2012; Devaney et al., 2015; Xu et al., 2007) .

Although not fully understood, the mechanisms by which MSCs exert protective effects include their direct regenerative ability and secretion of multiple paracrine factors including antibacterial peptides and anti-inflammatory cytokines such as IL-10 (Gupta et al., 2012; Gupta et al., 2007) . Another attractive property of MSCs is immune response modulation (Aggarwal and Pittenger, 2005) . MSCs have been shown to enlarge the proportion of regulatory T cells and decrease pro-inflammatory factors such as IL-6 and TNF-α (Fig. 3) (Gupta et al., 2012; Li et al., 2012; Prevosto et al., 2007) . MSCs showed positive efficacy in a recent study of COVID-19 patients.

Treatment with allogenic MSC transplantation at Beijing YouAn Hospital showed significantly improved functional outcomes without obvious adverse effects in 7 COVID-19 patients ( Table 1 ) (Zikuan Leng, 2020) . Adoptive MSC transfer might therefore be a valuable treatment option for COVID-19.

Nitric oxide (NO) is a key endogenous molecule implicated in a variety of physiological and pathological processes including smooth muscle relaxation, immune responses and antimicrobial activities (Saura et al., 1999; Schmidt and Walter, 1994) . Due to its potent and selective pulmonary vasodilation, iNO has been extensively applied to treat pulmonary hypertension, ARDS and other respiratory diseases with a relative good safety profile (Fig. 3 ) (Griffiths and Evans, 2005; Pepke-Zaba et al., 1991) . Of note, previously published in-vitro studies indicated NO possessed inhibitory effects on SARS-CoV replication ( Fig. 2) (Akerström et al., 2005; Keyaerts et al., 2004a) . Moreover, a small-sample clinical study testing the efficacy of iNO in the treatment of SARS showed, 6 severely infected patients receiving iNO therapy presented with improved arterial oxygenation and reduction in a need for ventilator support (Chen et al., 2004) . In view of the high incidence of pulmonary complications in COVID-19 infected patients, iNO therapy may serve as a promising candidate for treating severe cases of COVID-19 via alleviating lung damage. Currently, a related phase Ⅱ clinical trial testing iNO is underway in COVID-19 infected patients complicated with ARDS (NCT04306393 and NCT04305457).

Traditional Chinese medicine (TCM) is a unique and well-established system of medicine widely employed for thousands of years to prevent and treat numerous diseases in China. In the battle to stop the epidemic situation of COVID-19, the integration of traditional Chinese and western medicine is a unique scheme in China. (Ren et al., 2020) . Lianhua Qingwen (LHQW) has a broad-spectrum antiviral effect on a host of influenza viruses, such as influenza A (H1N1), and HPAI A (H7N9) viruses, by inhibiting viral propagation and regulating immune function (Fig. 3) (Ding et al., 2017; Dong et al., 2014) . LHQW has been commonly used for treating viral influenza clinically and played a key role in controlling SARS-CoV during the 2003 outbreak. Recently, LHQW was reported to have inhibitory activity against SARS-CoV-2 and anti-inflammatory effects in vitro ( Table 1 ) (Runfeng et al., 2020) .

Xuebijing (whose chemical composition includes safflower yellow A, paginin, ferulic acid, and salvianolic acid B) functions as an endotoxin antagonist, anti-inflammatory agent, and anticoagulant (He et al., 2013; Sun et al., 2010; Xu et al., 2009; Zhang et al., 2006) and has been widely used in China as therapy for sepsis ( Fig.   3 ) (Chen et al., 2018) . A clinical trial showed that injecting Xuebijing improved the symptoms of severe pneumonia . Given the cytokine storms in severe COVID-19 infection, administering Xuebijing could turn critically ill cases into mild ones by attenuating the overactivated immune responses and preventing progressive pathological deterioration. Two clinical trials aimed at testing the efficacy and safety of Xuebijing injection for COVID-19 have been registered in the Chinese Clinical Trial Registry (ChiCTR2000030388 and ChiCTR2000029381) ( Table 1 ).

In addition to LHQW and Xuebijing, the Chinese clinical guidelines for COVID-19 pneumonia treatment include Jinhua Qinggan granules, Shufeng Jiedu capsules, and Lung Cleansing and Detoxifying Decoction, given their potential efficacy and few adverse effects in clinically treating COVID-19 infection (NHPFC, 2020).

IFNs are large families of numerous type Ⅰ species (IFN-α, IFN-β, IFN-ε, IFN-κ, and IFN-ω) and one type Ⅱ species (IFN-γ) (Liu, 2005; Parkin and Cohen, 2001) . Type Ⅰ IFNs have demonstrated inhibitory effects on a wide range of viruses including SARS-CoV (Fig. 3) (Minagawa et al., 1987; Sperber and Hayden, 1989; Ströher et al., 2004; Tan et al., 2004) . When they encounter viruses, host cells form and release IFNs, which protect the original and adjacent cells against attack. The antiviral state produces its effects by several means, such as inhibiting viral RNA transcription, protein translation, and post-translational modification ( Fig. 2 and Fig. 3 ) (De Andrea et al., 2002) . To date, the clinical effect of IFN intervention in COVID-19 infection is ambiguous. Previous evidence confirmed IFN efficacy in inhibiting SARS-CoV (Cinatl et al., 2003; Sainz et al., 2004) . IFN-α showed in vitro inhibitory effects on SARS-CoV at concentrations of 1000 IU/ml (Ströher et al., 2004) . Interestingly, recombinant human IFN-β1a within a safe dose range exhibited more potent activity on SARS-CoV (Hensley et al., 2004) . As a registered agent for chronic hepatitis C, IFN-α2b was reported to protect type 1 pneumocytes against SARS coronavirus infection in macaques (Haagmans et al., 2004) . Combined treatment of IFN-α-2a and ribavirin was shown to have antiviral effects on MERS-CoV (Falzarano et al., 2013) .

In addition to their antiviral activity, IFNs show an immunomodulatory capability; type Ⅰ interferons can enhance natural killer (NK)-cell cytotoxicity, enhance the expression of major histocompatibility complex Ⅰ proteins, and promote IFN production and the proliferation of NK cells and macrophages (De Andrea et al., 2002; Goodbourn et al., 2000; Sen, 2001) . IFN-α in conjunction with corticosteroids were shown to improve oxygen saturation and facilitate more rapid resolution of radiographic lung abnormalities in SARS infection (Loutfy et al., 2003) . Given the inconclusive effects of IFNs in treating viral infectious diseases, IFNs and combined therapy should be prudently employed with COVID-19 infection ( Table 1) .

Intravenous gamma globulin (IVIG) as purified IgG products prepared from pooled human plasma have been widely used for treated numerous inflammation-related diseases including heart failure, adult respiratory distress syndrome, and vasculitis (Jolles et al., 2005) . IVIG demonstrates its passive immunity and anti-inflammatory effects by supplying idiotypic antibodies (Kaveri et al., 1991) , binding to Fc receptors (Fehr et al., 1982) , suppressing pathogenic cytokines (Andersson and Andersson, 1990; Andersson et al., 1993) , preventing formation of membranolytic attack complexes (Lutz et al., 1996) , and modulating T-cell function (Fig. 3) (Marchalonis et al., 1992) . Transchromosomic bovine-produced human polyclonal immunoglobulin G antibodies inhibited MERS-CoV in murine models and in vitro assays (Luke et al., 2016) . Due to the scarcity of human-derived IgG products (or convalescent plasma), therapeutic immunoglobulin might provide insights for COVID-19 treatment ( Table   1 ). However, IVIG should be carefully administered given its numerous adverse effects (e.g., myalgia, fever, renal failure (Achiron, 1997; Bertorini et al., 1996; Wajanaponsan and Cheng, 2004) , and venous thromboembolism (Hoffmann and Enk, 2019) . Thromboembolism was found in a third of patients with SARS who underwent IVIG treatment during the SARS outbreak in Singapore (Lew et al., 2003) .

NK cells, a small subset of peripheral white blood cells, serve as an essential part of innate immune response. NK cells can elicit rapid and robust protective effects in defense against viral infections through direct cytotoxicity and immunomodulatory capability (Fig. 3) (Vivier et al., 2008) . Once recognizing infected host cells, NK cells trigger targeted cell apoptosis by perforin-and granzyme B-mediated pathways and secrete multiple cytokines involved in regulation of innate and adaptive immune responses, which facilitate viral clearance (Iannello et al., 2008) . NK cell-based immunotherapies have long been investigated for treating malignancies, albeit with limited clinical practice due to the difficulty to obtain sufficient cell numbers for adoptive transfer (Lee, 2019) . Recently, CYNK-001, an investigational allogeneic NK cell therapy derived from placental hematopoietic stem cells, has passed through an investigational new drug application approved by FDA (Celularity, 2020). As a NK cell product, CYNK-001 harbors the potential for inhibiting viral infection through direct killing SARS-CoV-2 infected host cells and indirect inducing immune responses. However, there exists controversy about whether the elicited strong inflammatory responses are favorable or detrimental for patients infected with severe COVID-19. The efficacy and safety of NK cell therapy for COVID-19 require to be tested by ongoing related clinical trials.

Due to their excellent anti-inflammatory, antifibrotic properties and ability to suppress collagen deposition, corticosteroids are frequently used to treat ARDS and sepsis ( Fig.   3 ) (Heming et al., 2018; Rhen and Cidlowski, 2005; Thompson, 2003) . Despite the long history of administering corticosteroids, their therapeutic effectiveness and safety remains controversial. Several clinical trials and meta-analyses have indicated that corticosteroids are associated with increased mortality, a tendency for requiring mechanical ventilation therapy, and relatively longer hospitalizations for SARS, MERS, and H1N1 infections (Arabi et al., 2018; Han et al., 2011; Stockman et al., 2006) . These adverse events are partly due to the suppression of normal host immune responses and impeded viral clearance. Numerous studies have, however, demonstrated corticosteroids' beneficial effects on physiologic outcomes in virus-associated respiratory diseases, supporting the proper application of corticosteroids in these cases, especially critical cases (Li et al., 2017; Siemieniuk et al., 2015) . A retrospective study of 401 patients with SARS showed that corticosteroids reduced case fatality rates and shorten hospital stays (Chen et al., 2006 ). An accurate conclusion regarding the therapeutic effect of corticosteroids in treating COVID-19 cannot therefore be drawn ( Table 1) . High corticosteroid doses are closely associated with adverse events such as secondary infections, delayed viral clearance, and emergence of viral resistance. According to the Guidelines for the Diagnosis and Treatment of COVID19 (7th edition) in China (NHPFC, 2020), however, prudent low-to-moderate doses of corticosteroids could yield potential therapeutic benefits for a subset of seriously ill patients with COVID-19 pneumonia, recommendations in line with the interim clinical management guidance for COVID-19 released by the World Health Organization, which advised against routinely administering corticosteroids except for clinical indications such as exacerbated chronic obstructive pulmonary disease and septic shock (WHO, 2020b).

severe COVID-19. The D-dimer, prothrombin time and age were positively, and platelet count was negatively correlated with 28-day mortality. There was no difference on 28-day mortality between heparin users and nonusers. However, the 28-day mortality of heparin users was lower than nonusers. This study suggests that anticoagulant therapy with heparin appears to be associated with better prognosis in severe COVID-19 patients (Tang et al., 2020b) . Interestingly, patients with severe pneumonia by COVID-19 had higher platelet count than those induced non-COVID-19, and only the former with markedly elevated D-dimer may benefit from anticoagulant therapy . Future study using a large sample size is needed to confirm the effects of heparin in the management of COVID-19 patients.

A recent study demonstrated the interaction between the SARS-CoV-2 spike S1 protein receptor binding domain (SARS-CoV-2 S1 RBD) and heparin, suggesting the development of heparin-based therapeutics (Mycroft-West et al., 2020) . It is of great interest to develop the novel heparin-based compounds for COVID-19.

Vitamin C has pleiotropic roles in modulating the immune system (Carr and Maggini, 2017) and is known for its antioxidant properties, and antioxidants are generally accepted as an adjuvant therapy for critically ill patients, whose vitamin C levels are markedly decreased (Carr et al., 2017; Nakano and Suzuki, 1984) . Vitamin C exerts positive effects on the immune system by stimulating INF production, supporting lymphocyte proliferation, and boosting neutrophil phagocytic capability (Fig. 3) (May and Harrison, 2013; Oudemans-van Straaten et al., 2014; Wilson, 2013) . In acute lung injury and ARDS, excessive neutrophil accumulation in inflammatory loci results in lung tissue damage through the release of necrotic cell contents (known as neutrophil extracellular traps) (Papayannopoulos, 2018; Weiss, 1989) , and vitamin C is reported to prevent this process (Mohammed et al., 2013) . In animal models of sepsis, vitamin C was shown to protect lung barrier function and reduce lung vascular injury through diminishing inflammatory responses and coagulant changes (Fisher et al., 2012; Fisher et al., 2011) . A phase Ⅰ trial with patients with critically severe sepsis reported that high doses of vitamin C reduced the extent of multiple organ failure and mitigated circulating injury biomarker levels (Fowler et al., 2014) . Placebo-controlled trials have shown that vitamin C could reduce the duration of colds (Hemilä and Chalker, 2013) . Given that COVID-19 patients frequently present lung damage, vitamin C could be a promising candidate (Table 1) .

Vitamin D is known to modulate the innate and adaptive immune system, and its deficiency is associated with increased autoimmunity as well as in an increased susceptibility to infection (Aranow, 2011). Grant et al. (2020) 

The non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen have been widely used to treat fever or pain. In March 11, 2020 reported the hypothesis that ibuprofen can increase the risk of developing severe and fatal COVID-19 since ibuprofen is known to upregulate ACE2 receptors. However, there is no evidence indicating that ibuprofen worsens the clinical symptoms of COVID-19 infected patients (FitzGerald, 2020; Kakodkar et al., 2020) . In March 23, 2020, US FDA announced that it is not aware of any evidence that NSAIDs such as ibuprofen could worsen COVID-19.

There is no specific vaccine currently available for containing COVID-19 infection.

To meet the urgent need for an effective vaccine in the context of active SARS-CoV-2 transmission, companies and institutions worldwide have been working on a SARS-CoV-2 vaccine through various approaches, resulting in a series of vaccine candidates (Routley, 2020) . One of the most promising of which is mRNA-1273, developed by National Institute of Allergy and Infectious Disease scientists together with biotechnology company Moderna (Fig. 3) (Moderna, 2020a) . As an mRNA vaccine, mRNA-1273 embedded in lipid nanoparticles encodes viral S proteins of SARS-CoV-2 and then delivers the antigen into human cells to elicit SARS-CoV-2-specific neutralizing antibodies and potent immune responses, thereby protecting healthy individuals against COVID-19 infection (Fig. 3) . mRNA vaccine is superior to other conventional vaccines, given its high potency, short production cycles and safety as lack of actual viral genome (Ahn et al., 2020 mRNA-1273 was the first vaccine to be tested in a clinical trial, followed closely by another promising candidate called Ad5-nCoV, which was jointly developed by Tianjin-based biotechnology company Cansino and the Institute of

Cansino's adenovirus-based viral vector vaccine technology platform, Ad5-nCoV uses replication-defective adenovirus type 5 as a vector to load SARS-CoV-2 gene fragments onto it to express the SARS-CoV-2 S protein (Fig. 3) .

According to Cansino, preclinical data in animal models demonstrated that Ad5-nCoV can elicit robust immune responses and a favorable safety profile (Mak, 2020) . Currently, the phase Ⅰ clinical trial evaluating the safety and efficacy of Ad5-nCoV has been initiated in Wuhan (Table 1 ) .

A recently published study in the Lancet introduced a newly developed potentially effective SARS-CoV-2 vaccine named PittCoVacc, short for Pittsburgh Coronavirus Vaccine, developed by University of Pittsburgh School of Medicine scientists (Kim et al., 2020) . PittCoVacc uses S-protein fragments of SARS-CoV-2 to stimulate the generation of specific antibodies (Fig. 3) . PittCoVacc is delivered with a novel technique known as microneedle array, a fingertip-sized patch of 400 tiny needles. This strategy can elicit more potent immune responses than conventional subcutaneous needle injection and has been demonstrated to be sufficiently safe.

PittCoVacc has been tested immunogenicity in mice with the emergence of substantial SARS-CoV-2 antibodies within 2 weeks after prime immunization. The research team hoped to test PittCoVacc in humans in clinical trials in the next few months (Table 1) (ScienceDaily, 2020).

The US-based company Novavax has identified a vaccine candidate NVX-CoV2373, a stable, prefusion protein developed through the advanced nanoparticle technology (Table 1 and Fig. 3) . The Matrix-M adjuvant will be incorporated with NVX-CoV2373 to enhance immune responses and stimulate increased levels of neutralizing antibodies (Novavax, 2020) . A first-in-human trial will be started in May, 2020. Other types of vaccines (e.g., DNA, RNA, vector, whole-cell killed and live-attenuated vaccines) are in the rapid development process (Routley, 2020) . A phase 1 study of the novel DNA vaccine INO-4800 (NCT04336410) is underway (Inovio, 2020) . Despite the seriousness of the pandemic ravaging the world, researchers should take the time to assess the safety and efficacy of vaccines in animal models and then conduct related human clinical trials to prevent more harm than good from occurring with hastily produced vaccines.

Zinc, a trace mineral, is necessary for the immune system since zinc-deficient patients had severe immune dysfunctions (Prasad, 2008) . Interestingly, there are numerous reports showing the loss of sense of smell and taste in the early stages of COVIOD-19 infected peoples (Keyhan et al., 2020; Lechien et al., 2020) . It is well known that zinc deficiency is associated with loss of taste, and that zinc supplementation has beneficial effects in subjects with loss of taste (Doty, 2019; Heyneman, 1996; Yagi et al., 2013) . Collectively, it is likely that zinc deficiency in patients with infection may be associated with the loss of smell and taste in these patients. 

The findings of a recent in vitro study by Australian researchers are notable. They found that ivermectin (an anti-parasitic drug) could effectively block SARS-CoV-2 growth in cell cultures within 48 hours, even at a single dose (Fig. 2) . However, the mechanism though which ivernectin exerts its antiviral action is unknown. This study only demonstrated the effectiveness of ivernectin for the control of SARS-CoV-2 in vitro (Caly et al., 2020) . Further study of its efficacy and safety for inhibiting SARS-CoV-2 in humans or animals needs to be investigated.

The COVID-19 pandemic is an unprecedented crisis for public health and world economy and has had a huge impact not only on China but other countries. In the fight against COVID-19, we should unite and understand that benefiting one benefits all, whereas harming one harms all. Scientists worldwide struggle to seek efficacious COVID-19 treatments. Learning from previous experience in coping with SARS and MERS, a series of existing drugs have been used in clinical practice to treat COVID-19 infection and clinical trials evaluating their efficacy and safety for COVID-19 are ongoing. Given the unique viral structure and distinct pathogenesis, there is an urgent need for novel COVID-19-specific therapies, including vaccines and antivirals. As discussed above, there are many different candidates for COVID-19 infected patients. Part of patients with COVID-19 infection has been medicated with other drugs for their illness. Therefore, potential drug-drug interactions should be considered for the combination .

Research teams from China, Singapore and the United States published (Anderson et al., 2020) . Through systematic and comprehensive screening of more than 20,000 genes in bat cells, the teams identified MTHFV1, a gene indispensable for viral replication in bat and human cells and found that carolacton, a host protein MTHFV1 inhibitor, could effectively inhibit replication of several RNA viruses including SARS-CoV-2, suggesting that carolacton (a natural bacteria-derived product) could be a novel therapeutic drug for COVID-19.

Finally, further understanding of SARS-CoV-2 mechanisms in humans could help in developing novel therapeutic drugs for COVID-19. We must protect against COVID-19 infection ourselves until the aforementioned candidates for COVID-19 are approved.

JZ and BX performed the study design, data collection, data analysis, data interpretation, and writing. KH performed the study design, data interpretation, and writing. All authors approved the final manuscript.

The author declares no competing interest.

Achiron 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., Chen, H., Li, H., Huang, H., Tu, S., Gong, F., Liu, Y., Wei, Y., Dong, C., Zhou, F., Gu, X., Xu, J., Liu, Z., Zhang, Y., Li, H., Shang, L., Wang, K., Li, K., Zhou, X., Dong, X., Qu, Z., Lu, S., Hu, X., Ruan, S., Luo, S., Wu, J., Peng, L., Cheng, F., Pan, L., Zou, J., Jia, C., Wang, J., Liu, X., Wang, S., Wu, X., Ge, Q., He, J., Zhan, H., Qiu, F., Guo, L., Huang, C., Jaki, T., Hayden, F.G., Horby, P.W., Zhang, D., Wang, C., 2020 Ding, Y., He, L., Zhang, Q., Huang, Z., Che, X., Hou, J., Wang, H., Shen, H., Qiu, L., Li, Z., Geng, J., Cai, J., Han, H., Li, X., Kang, W., Weng, D., Liang, P., Jiang, S., 2004 . Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways. J. Pathol. 203, 622-630. Ding, Y., Zeng, L., Li, R., Chen, Q., Zhou, B., Chen, Q., Cheng, P.L., Yutao, W., Zheng, J., Yang, Z., Zhang, F., 2017 Duan, K., Liu, B., Li, C., Zhang, H., Yu, T., Qu, J., Zhou, M., Chen, L., Meng, S., Hu, Y., Peng, C., Yuan, M., Huang, J., Wang, Z., Yu, J., Gao, X., Wang, D., Yu, X., Li, L., Zhang, J., Wu, X., Li, B., Xu, Y., Chen, W., Peng, Y., Hu, Y., Lin, L., Liu, X., Huang, S., Zhou, Z., Zhang, L., Wang, Y., Zhang, Z., Deng, K., Xia, Z., Gong, Q., Zhang, W., Zheng, X., Liu, Y., Yang, H., Zhou, D., Yu, D., Hou, J., Shi, Z., Chen, S., Chen, Z., Zhang, X., Yang, X., 2020 Vitamin C might inhibit SARS-CoV-2 and alleviate the illness by decreasing inflammatory cytokines, stimulating IFN production, supporting lymphocyte proliferation, boosting the phagocytic capability of neutrophils, monocytes, and macrophages, protecting lung barrier function and reducing lung vascular injury, increasing IFN secretion from alveolar Mφ, Mo-Mφ, DCs, NK cells, and CD8 + T cells.

IFNs could enhance NK cell cytotoxicity, enhance expression of major histocompatibility complex Ⅰ proteins, and promote the production of IFNs and the proliferation of NK cells and Mφ. Bevacizumab could reduce vascular permeability.

Vaccines (mRNA1273, Ad5-nCoV, PittCoVacc, and NVX-CoV2373) could induce protective antiviral immune memory, while MSCs could decrease pro-inflammatory cytokines, promote regeneration, secrete multiple paracrine factors and anti-inflammatory cytokines, and enlarge the proportion of Treg cells. iNO could alleviate pulmonary hypertension through its selective pulmonary vasodilation.

Corticosteroids, LHQW, Xuebijing, IVIG, tocilizumab, sarilumab, baricitinib, vitamin D, CQ, and HCQ could also reduce inflammation. Heparin blocks the thrombus formation. Abbreviations: AT I, type I alveolar epithelial cell; AT Ⅱ, type Ⅱ alveolar epithelial cell; CQ, chloroquine; DC, dendritic cell; G-CSF, granulocyte-colony stimulating factor; HCQ, hydroxychloroquine sulfate; IFN-γ, interferon gamma; IL, interleukin; iNO, inhaled nitric oxide; IP-10, interferon-inducible protein-10; IVIG, intravenous gamma globulin; LHQW, Lianhua Qingwen; MCP-1, monocyte chemotactic protein 1; MIP-1A, macrophage inflammatory protein-1a; Mo-Mφ, monocyte-macrophage; MSCs, mesenchymal stem cells; NK, natural killer cell; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Th, helper T cell;

TNF-α, tumor necrosis factor alpha; Treg, regulatory T cell. 

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IFNs, interferons; iNO, inhaled nitric oxide

SARS-CoV-2, severe acute respiratory syndrome coronavirus 2

Ad5-nCoV Vaccine Ad5-nCoV uses replication-defective adenovirus type 5 as vector to load some gene fragments of SARS-CoV-2 on it to express SARS-CoV-2 S protein S-protein of SARS-CoV-2 into body Prepared for phase Ⅰ clinical trials NVX-CoV2373 Vaccine NVX-CoV2373 is a stable

Abbreviation: ARDS, acute respiratory distress syndrome

HIV, human immunodeficiency virus; IFNs, interferons; IL-6, interleukin 6; iNO, inhaled nitric oxide; IVIG

mesenchymal stem cells; NK, natural killer cell; NSAIDs, non-steroidal anti-inflammatory drugs; rhACE2, recombinant human angiotensin-converting enzyme 2

SARS, severe acute respiratory syndrome; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TCM, traditional Chinese medicine

This work was partly supported by the grants of Japan Society for the Promotion of Science (to K.H., 17H04243 and 19H05203) and Japan Agency for Medical Research and Development, AMED (to K.H., JP20dm0107119).