key: cord-302382-eifh95zm
authors: Owji, Hajar; Negahdaripour, Manica; Hajighahramani, Nasim
title: Immunotherapeutic approaches to curtail COVID-19
date: 2020-08-21
journal: Int Immunopharmacol
DOI: 10.1016/j.intimp.2020.106924
sha: 
doc_id: 302382
cord_uid: eifh95zm

COVID-19, the disease induced by the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has imposed an unpredictable burden on the world. Drug repurposing has been employed to rapidly find a cure; but despite great efforts, no drug or vaccine is presently available for treating or prevention of COVID-19. Apart from antivirals, immunotherapeutic strategies are suggested considering the role of the immune response as the host defense again the virus, and the fact that SARS-CoV-2 suppresses interferon induction as an immune evasion strategy. Active immunization through vaccines, interferon administration, passive immunotherapy by convalescent plasma or synthesized monoclonal and polyclonal antibodies, as well as immunomodulatory drugs, are different immunotherapeutic approaches that will be mentioned in this review. The focus would be on passive immunotherapeutic interventions. Interferons might be helpful in some stages. Vaccine development has been followed with unprecedented speed. Some of these vaccines have been advanced to human clinical trials. Convalescent plasma therapy is already practiced in many countries to help save the lives of severely ill patients. Different antibodies that target various steps of SARS-CoV-2 pathogenesis or the associated immune responses are also proposed. For treating the cytokine storm induced at a late stage of the disease in some patients, immune modulation through JAK inhibitors, corticosteroids, and some other cognate classes are evaluated. Given the changing pattern of cytokine induction and immune responses throughout the COVID-19 disease course, different adapted approaches are needed to help patients. Gaining more knowledge about the detailed pathogenesis of SARS-CoV-2, its interplay with the immune system, and viral-mediated responses are crucial to identify efficient preventive and therapeutic approaches. A systemic approach seems essential in this regard.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a newly emerged betacoronavirus, is responsible for coronavirus disease 2019 (COVID- 19) , which was first reported in Wuhan, China in December 2019. SARS-CoV-2, the third fatal virus of its group, is an enveloped positive-sense, singlestranded RNA virus [1] . While the other viruses of this family induce only mild cold symptoms, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), the two other virulent betacoronaviruses, have been presented with higher fatality rates than SARS-CoV-2. On the other hand, SARS-CoV-2 has shown a higher transmission rate and therefore a wider spread around the globe [2] .

The burden of coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been very huge on health, economy, and many other aspects of life. It has already claimed more than 550750,000 lives (as of 12 15 JulyAugust 2020 according to WHO COVID-19 dashboard at https://covid19.who.int/). The urgency of this threat has prompted scientists in many countries to seek solutions through drug repurposing and repositioning of the previously approved drugs, while the fast-tracking of vaccine and drug development are seriously followed. However, some of the repurposed candidate drugs have already failed in some clinical trials [3] .

Some antiviral drugs, developed for other similar viruses, are suggested, which may inhibit the cell entry or replication of the virus [2] . On the other hand, supporting the immune system's potential to function properly and fight with the virus is another viable strategy. Normalization of the dysregulated immune responses or even their suppression at the final stages of the disease may also be required [4] .

Generally, following the entry of an invading pathogen into the body and its recognition by the first-line immune cells, the innate immune system would be stimulated, which may be later supported by adaptive immune responses as well. The interaction of each pathogen with the immune cells could define the defense the body against it, thus understanding such interplays is fundamental. Although the role of the the immune system function in the control or overcoming COVID-19 is indisputable, and many therapeutic and preventive approaches implicate modulation of the immune system activity, there are still many questions to be answered in this regard. For instance, the pattern of cytokine secretion during the disease course has been the subject of vast investigations. The complexity of the immune system responses as well as the variations in the level of cytokines that happens during the disease period and may lead to cytokine storm, highlights the need for gaining a deep overview on such events as well as the interventional possibilities to be able to cure or prevent the disease. In this review, the pathogenesis of SARS-CoV-2 and its interplay with the immune system , which are discussed in detail in other publications [5] [6] [7] , are briefly stated. A classification of possible immune-based approaches to combat COVID-19 is presented with a focus on convalescent plasma therapy, manufactured antibodies (monoclonal and polyclonal antibodies), and immunomodulators that could potentially modify the immune system activity. Vaccines, as a potential immune-based approach to curtail COVID-19, were discussed previously [8] [9] [10], so will not be discussed in detail here.

Despite the large volume of ongoing studies on SARS-CoV-2, parts of our current knowledge on its pathogenesis is based on the studies of SARS-CoV and MERS-CoV, since the clinical manifestations of SARS-CoV-2 highly resemble the ones observed in the two latter viral infections [11] .

SARS-CoV-2 may enters the lungs from through the nasopharyngeal mucosal membrane and infect.

Alveolar alveolar macrophages and type I and II epithelial cells in the lungs are shown to be infected by SARS-CoV-2 [5] . The most prominent way of the viral entry was shown to be through the attachment of S protein and angiotensin-converting enzyme 2 (ACE2) receptors, which. Some studies clarified that viral entry may be enhanced through some proteases such as a serine protease called TMPRSS2 (transmembrane protease, serine 2) or Cathepsin L/B (CTSL/B) [6] . TMPRSS2 may, in fact, proteolytically activates SARS-CoV-2 by cleaving the S protein and promote replication and syncytium formation in the virus. Hence, TMPRSS2-expressing cells were shown to be highly susceptible to SARS-CoV-2 infection [13] . Cathepsin, which is expressed in endosomes, was shown to facilitate the fusion of the virus and endosome membrane [14] . Recent studies revealed that a combinational effect between TMPRSS2 and cathepsin is needed for an effective viral entry [15] . Another serine exopeptidase receptor, a serine exopeptidase, called dipeptidyl peptidase 4 (DPP4) or cluster of differentiation 26 (CD26), also was also shown to provide additional interactions with SARS-CoV-2 spike beside the ACE2 receptor [7] . Despite the noteworthy pieces of evidence supporting the role of ACE2 and the associated proteases in the viral entry, iIt was shown revealed that the virus can also enter the cell through clathrin-dependent and -independent endocytosis pathways.

For instance, SARS-CoV-2 may attack lymphocytes through the JAK-STAT pathway [8] .

COVID-19 patients manifest mild to severe symptoms, including fever, non-productive cough, dyspnea, malaise, fatigue, lymphopenia, and pneumonia 2-14 days after the viral attack. Moreover, laboratory results including leucopenia, elevated C-reactive protein (CRP), and higher erythrocyte sedimentation rate (ESR) are detected. A wide range of other clinical manifestations has been observed in COVID-19 involving different organs, namely heart, eyes, nose, brain, pancreas, kidney, and bladder. As reported, 7-14 days upon the manifestation of the initial symptoms of the disease, the virus may cause a second attack and an aggravation of the disease symptoms in which severe pneumonia, ground-glass opacity, acute cardiac injury, and RNAaemia are observed [9] . In this phase of the disease, the level of lymphocytes drops dramatically, and cytokine storm occurs. Cytokine storm is an uncontrolled release of inflammatory cytokines, including IFN-α, IFN-γ, GM-CSF, G-CSF, IL-1ß, IL-6, IL-12, IL-18, IL-33, TNF-α, TGF-ß and chemokines, including CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL10. The cytokines level reduces as the patient recovers. Cytokine storm has been recognized as the main cause of acute respiratory distress syndrome (ARDS), which causes lung injury, and multiple organ failure. Moreover, patients who succumbed to COVID-19 represented a higher level of neutrophils, D-dimer, blood urea nitrogen (BUN), and creatinine than the survivors [10, 11] .

As the virus enters the cell, the viral RNA is released and proceeds to the translation step. The viral proteins and RNAs, produced by the host cell, are inserted into the endoplasmic reticulum and Golgi, where the viral nucleocapsid is formed, and the viral particles are prepared to be released out of the cell membrane. The virus may enter the peripheral blood from the lungs and attack other organs that express the ACE2 receptor, including heart, kidneys, and gastrointestinal tract. The viral antigen is presented to T cells and B cells via major histocompatibility complex (MHC) on antigen-presenting cells (APCs), thus innate and humoral adaptive immunities are activated. Innate immunity is initiated by interferon secretion from the infected cells in viral infections for signaling to other cells and making them ready for the battle [4] . SARS-CoV-2 is found to antagonize the induction of type I interferons (interferon-alpha and -beta) [21, 22] thereby evading from the innate immune system defense [23] . Macrophage and dendritic cells were shown to play important roles in viral destruction and mucosal immunity. The level of CD4+ and CD8+ cells also increases, which leads to long-term immunity. It was shown that CD4+ and CD8+ cells are responsible for promoting neutralizing antibody proliferation and destruction of viral-infected cells, respectively [24] . Different immunoglobulins against viral S (spike), M (membrane), N (nucleoprotein) proteins, nsp (nonstructural proteins), and ORF (open reading frame) are produced. However, the prevalent types of immunoglobulins are against S protein and among them IgM and IgG induce short-term and long-term immunities, respectively. Moreover, it was shown that the immune system decision between Th1 response (cellular response) or Th2 response (humoral response), which is affected by the cytokine pattern, determines the viral infection control. In fact, it was reported that some infections are well controlled by Th1 response and this response was observed in 20 recovered COVID-19 patients [25] . SARS-CoV-2 was found to suppress antigen presentation through downregulation of MHC class I and II molecules, which may lead to the impediment of T cell-mediated immune defense [26] .

What mentioned above are known as the most prevalent process of SARS-CoV-2 pathogenesis and clinical manifestations; however, a closer scrutiny recently revealed a wider range of clinical manifestation for COVID-19. In fact, a direct association has been observed between the expression of viral receptors, including ACE2 and TMPRSS2 and the affected organ. Herein, organs including heart, eyes, nose, brain, pancreas, kidney, and bladderFor instance, the abundance of ACE2 receptors on endothelial cells explain why cardiovascular complications are considered as the second threat caused by SARS-CoV-2 after respiratory symptoms [27] . Moreover, SARS-CoV-2 may target the central nervous system and infect neurons in the nasal passage, which can be the cause of smell and taste disruption in some COVID -19 patients. However, the loss of taste and smell is of the most initial inflammatory responses to SARS-CoV-2 and can be reversible as the body defeats the virus [28] . were also shown to be affected by SARS-CoV-2 [12] . In addition to the role of nasal cells in SARS-CoV-2 infection, the nasal secretory cells may be exploited by the virus for transmission to the other persons.

Viral antigens are presented to T cells and B cells via major histocompatibility complex (MHC) on antigenpresenting cells (APCs), thus innate and adaptive immunities are activated. Innate immunity response is initiated by interferon secretion from the infected cells in viral infections for signaling to other cells and making them ready for the battle [4] . SARS-CoV-2 is found to antagonize the induction of type I interferons (interferon-alpha and -beta) [12, 13] thereby evading the innate immune system defense [14] . Moreover, it was shown that the immune system decision between Th1 response (cellular response) or Th2 response (humoral response), which is affected by the cytokine pattern, determines the viral infection control. In fact, it was reported that some infections were well controlled by a Th1 response, and this response was observed in 20 recovered COVID-19 patients [15] . SARS-CoV-2 was found to suppress antigen presentation through the downregulation of MHC class I and II molecules, which may lead to the impediment of T cell-mediated immune defense [16] .

In the second attack phase of the disease (usually one or two weeks after the presentation of the first symptoms), the level of lymphocytes drops dramatically, and the cytokine storm occurs. Cytokine storm is an uncontrolled release of inflammatory cytokines, including IFN-α, IFN-γ, GM-CSF, G-CSF, IL-1ß, IL-6, IL-12, IL-18, IL-33, TNF-α, TGF-ß, and chemokines, particularly CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL10. The cytokine level reduces as the patient recovers. Cytokine storm has been recognized as the main cause of acute respiratory distress syndrome (ARDS), which causes lung injury, and multiple organ failure.

Taken together, the immune system is highly impaired in critically ill COVID-19 patients.

Given the role of the immune system in host defense, immunomodulation could be regarded as an important strategy to curtail COVID-19 considering the patient's immune system condition at various phases of the disease. Such immunomodulatory interventions can be achieved using vaccines, interferons, convalescent plasma, anti-inflammatory agents, antibodies, and other classes of immunomodulators, which are described in the following.

Innate immunity, as the first immediate and general defense response, plays a key role in the protection against invading pathogens, which is initiated by interferon secretion from the infected cells in viral infections for signaling to other cells and making them ready for the battle [4] . SARS-CoV-2 is found to antagonize the induction of type I interferons (interferon-alpha and -beta) [21, 22] thereby evading from the innate immune system defense, as a mechanism of its pathogenesis [23] . Besides the yet questions in the initial responses to SARS-CoV-2 (e.g. types of receptors that are recruited for viral entry or cells that are affected), secondary responses (e.g. immune system responses) have been also under debate. For example, data concerning the beneficial or detrimental role of inflammatory mediators are controversial [4] . Cytokine storm, which is the result of increase in the levels of some cytokines as explained before, may also happen as a pathological situation of the innate immune system as well. Another disruptive activity of the virus involves the functional exhaustion of lymphocytes, which would affect the adaptive immunity.

The immunopathological conditions aroused in COVID-19, are mentioned in brief here, as they were discussed in detail elsewhere .

There are still unknowns regarding the exact interactions of the immune and adaptive immunities with the virus as well as the methods of virus for confounding the host immune system. The in-depth understanding of viral-mediated responses and interplay of the virus and the host immune system might not be feasible without a systemic approach . Nevertheless, the similarity of severe respiratory failure induced by SARS-CoV-2 to acute respiratory distress syndrome (ARDS) and the deterioration of patients' conditions in around a week following the first symptoms implicate the role of immunity dysregulation in COVID-19 profile [6] .

Therefore, immunotherapy and modulation of the immune system, which could modify these disorders, are potentially effective strategies to fight with SARS-CoV-2. Such interventions may be done through vaccines, which actively stimulates the immune responses, or administration of interferons I, which are discussed in previous publications. Passive immunotherapy and the modulation of the immune system through anti-inflammatory or immunostimulatory agents are other alternatives, which will be examined in detail in the following. Of note, these immunotherapeutic approaches should be carefully selected based on the stage of the disease and the state of the patient's immune system.

The suppression of interferon I-mediated immune responses by SARS-CoV-2 is already confirmed [12, 13] thereby evading from the innate immune system defense, as a mechanism of its pathogenesis [23] . Although interferon has beenwas shown to fight against the virus and are is suggested for to treatment of the disease [17] , some contradictory data demonstrated that interferon may enhance ACE2 expression and thus viral entry [18] . On the other hand, positive results were found by using interferons type I, including interferon-beta-1a in several clinical trials [19] . The difference in the route of administration, either subcutaneous (s.c.) and intravenous (i.v.), was proposed as a reason for the diverse effects reported about interferon beta-1a in some studies [20] . Interferon-beta is already being examined in a combination protocol in the international clinical trial launched by WHO in the partner countries, called as "Solidarity" [3] . The outcomes of the investigations on interferon therapy in COVID-19 were presented in some other publications [17, [19] [20] and as a systematic review [21] . Interferon-beta is already being examined in a combination protocol in the international clinical trial launched by WHO, called the "Solidarity" trial, in the partner countries [3] .

Vaccines are believed as the ultimate protection for saving the public from the novel virus. The lack of previous exposure of the human immune system to SARS-CoV-2 [22] is regarded as the major contributor to its high risk. Hence, active immunization through vaccines could prepare the body to resist against this infection. Very soon after finding the virus genetic sequence, vaccine development was started and followed with unprecedented speed by several research groups and pharmaceutical companies. Huge investments are dedicated by several public and private bodies to advance the this project [2] . Various platforms are employed in these investigational vaccines, including inactivated, killed or weakened pathogen, non-replicating viral vector, RNA, and DNA, VLP (virus-like particle), and protein subunit structures virus. There also some inactivated as well as replicating viral vector-based vaccines under development at preclinical stage. Each of these platforms has its own advantage and limitations.

While DNA and RNA vaccines are intensively studied mainly because of their rapid development, easy production, and safety, there are novel types not commercially available previously. Thus, their largescale production might take need more time to be set up, due to novelty and lack of previous experience in their commercial production. Additionally, more than one dose of these vaccine types is required for the immunization because of their short half-life [23] . As tThis topic is reviewed in details elsewhere [23] [24] [25] .

All in all, vaccine development is a time-consuming process. Moreover, the induction of memory in the immune system is still under question. Therefore, despite preliminary promising results, the efficiency of the investigational vaccines should be confirmed in large clinical trials.

Considering the lack of an approved drug or vaccine against SARS-CoV-2, taking advantage of a helpful alternative intervention is an urgent need [26] [27] [28] . Passive immunotherapy via antibodies has been considered as a possible strategy for defeating COVID-19 apart from anti-viral therapeutics and vaccines ( Fig. 1 ). Antibodies can be either isolated from a convalescent patient or produced in a lab [29] . These two approaches would be discussed in more detail in the following. Active immunization is provided through vaccines, which are still under development for COVID-19. Passive immunization can be performed via natural antibodies using convalescent plasma therapy (CPT) or antibodies that are manufactured. In CPT, natural neutralizing antibodies derived from a hyperimmune patient would be administered to a COVID-19 patient through plasma transfusion. This approach is already being used and investigated in many countries with acceptable levels of success. On the other hands, different polyclonal or monoclonal antibodies could be produced via using hybridoma cell-lines, animals, or cell-free protein synthesis.

Neutralizing antibodies derived from a hyperimmune patient through plasma transfusion is the most prevalent and accessible empirical approach used to treat several viral infections previously. This method, so-called convalescent plasma therapy (CPT), is also considered as a viable therapy for COVID-19 [30] [31] [32] .

It has been used to reduce the hospital stay and the mortality rate of critically ill patients with severe acute respiratory syndromes [32, 33] and shown was found beneficial in some previous epidemics of infectious diseases [34] . The use of this approach had been suggested for the first time during the outbreak of Spanish influenza (pandemic of 1918-1920) [33] . Subsequently, plasma transfusion was recommended as a safe and effective way for the prevention or treatment of the Ebola virus in 2014 and also several other severe viral infections, including MERS, SARS-CoV, and avian influenza A [35, 36] . In fact, neutralizing antibodies in the convalescent plasma (CP) could suppress the viremia through binding to the external antigens of the viruses and blocking their entry into the host cells [34, 37] . The effectiveness of CPT could vary according to the type of microorganism, it's pathogenesis, and treatment protocols, such as timing, dosing, and volume of administration [33] .

According to the previous evidence for plasma therapy of other coronaviruses, such as SARS-CoV and MERS, the early transfusion of CP can probably be more effective and improves the survival rate of critical COVD-19 patients at the early disease stage. It could be explained by the fact that in most viral infections, viremia rises in the first week of the disease [37, 38] . It should be noted that CPT may not be useful for mild or end-stage patients. Indeed, CPT is not able to significantly reduce the mortality rate well among end-stage patients because of their disease severity. On the other hand, mild patients can be self-recovered and CPT would not be required [39] .

The titer of SARS-CoV-2 neutralizing antibodies in the CP could be another important factor to increase treatment efficacy. Although, the antibodies level in the donor plasma before transfusion is not determined, some studies indicated that the specific IgG increases about three weeks after symptom onset and peaks at week 12. Therefore, the CP from donors who are at week 12 after the initiation of the symptoms is predicted to be more efficient [27, 40] .

Generally, patients with primary and secondary antibody deficiencies, need intravenous immunoglobulin (IVIG) treatment as the standard replacement therapy [41] ; and historically, administration of IVIG has been one of the important treatments in immunodeficient patients [42] . These patients are considered as a high-risk group, which can encounter several severe complications if infected with SARS-CoV-2 virus [43] .

Therefore, an effective treatment is required to help such patients survive. CP extracted from the SARS-COV-2 survivors may be a promising approach for the protection of COVID-19 patients with antibody deficiency before the development of an effective vaccine [44] .

However, the data about the potency of CPT in COVID-19 patients with primary and secondary humoral immunodeficiency is limited and has not been fully established, there are some case studies that have reported its proper effectiveness. For example, Clark et al. reported a 76-year-old COVID-19 case with lymphoma who was treated with a combination of bendamustine and rituximab that could lead to the impairment of humoral and cellular responses. After the failure of different treatment protocols against SARS-COV-2, the administration of hyperimmune plasma resulted in a rapid recovery in this patient [45] .

In another report, an immunosuppressed COVID-19 patient with myeloid malignancy, disseminated tuberculosis, and kidney disease, was successfully treated after transfusion of CP and tocilizumab [46] .

male patient with COVID-19, whose health condition was improved following CP administration [47] .

Presently, several clinical trials investigating the usage of CPT in COVID-19 are ongoing (as recorded in https://clinicaltrials.gov/), a number of which are summarized in Table 1 . The trials are selected according to the recruitment status of the study (recruitment or completed state), age (18 years and older), and severity of symptoms in participants (admitted to the hospital or ICU with severe symptoms). Several other publications have discussed the usage of CPT in COVID-19 [32, 33, 35] , thus no more details would not be addressed here.

All in all, CPT has demonstrated acceptable safety and in the current situation and seems a promising choice for treating severe COVID-19 patients besides other therapeutic strategies [48] . 

As mentioned before,The previous experiences and efficacy in other similar diseases, as well as its feasibility, are the important advantages of CPT. Moreover, according to different reports, CPT is welltolerated by receivers [35] , but as all treatment approaches, this method may have some minor adverse effects as well. Generally, the most common adverse effects of CPT is related to transfusion events, such as chills, fever, rash, allergic reactions, circulatory overload, and hemolysis [40, 49] .

Additionally, several other problems are attributed to the mentioned approach, including lack of plasma donors, risk of cross-contamination, inconsistency from batch to batch, non-scalability, and the possibility of host reaction [50] . These pitfalls behoove pharmaceutical companies to manufacture polyclonal or monoclonal antibodies. The first and most common targets are spike (S) proteins, which are located on the virus surface, generating its specific 'crown' shape [53] . SARS-CoV-2 starts its pathogenesis through the attachment of receptorbinding domain (RBD), located in the S1 subunit of the S protein, with angiotensin-converting enzyme 2 (ACE2). Thus, S proteins are considered as the most antigenic part of the virus with the main responsibility for the host immune responses [54] . It has been widely suggested that the previously-experimented SARS-CoV RBD neutralizing antibodies can be repurposed for SARS-CoV-2 [1, 55, 56] . The cross-neutralization capacity of antibodies relies on the conservation of the particular residues that are essential for the formation of specific bonds between RBD and the antibody, between the two types of viruses. For instance, an analysis was performed to determine which of the previously-proposed monoclonal antibodies against SARS-CoV can also cross-neutralize SARS-CoV-2. In the mentioned study, the residues for the formation of a salt bridge and electrostatic interaction between the m396 antibody and RBD were conserved between SARS-CoV and SARS-CoV-2. By contrast, antibodies, including R80 and F26G19 failed to interact with SARS-CoV-2 RBD in a similar way they did with SARS-CoV RBD due to the differences in their residues [57] .

Surprisingly, it was shown that F26G19 neutralized SARS-CoV-2 more potently than SARS-CoV through other interactions [51] . Studies including cryoelectron microscopy of SARS-CoV-2 spike and analysis of the protein-protein interactions of SARS-CoV-2 and ACE2 receptor with energy-based methods revealed the amino acids 319-591 of SARS-CoV-2 RBD as important residues; the latter study also introduced the linear and conformational epitopes within this region as antibody targets [54, 58] .

Though the RBD has been considered as the main target of interest, some neutralizing or blocking antibodies have been shown to recognize other epitopes, including domains in S1 subunit, S-ectodomain, HR1 and HR2 domains in the S2 subunit, nucleoprotein (NP), or envelope (E) protein [59] [60] [61] . For example, CR3022 cross-neutralized SARS-CoV-2 more strongly than other neutralizing antibodies against SARS-CoV, while it did not compete with ACE2 for binding to SARS-CoV-2. This observation indicates that CR3022 neutralizes SARS-CoV-2 through binding epitopes other than RBD [57] . Another study showed that the HR2 domain with an identity of 93% is highly conserved between SARS-CoV and SARS-CoV-2, and thus neutralizing antibodies that target the HR2 domain, including 2B2, 1A9, 4B12, and 1G10 potently cross-neutralized SARS-CoV-2 [62] . Similarly, the S309 monoclonal antibody, retrieved from convalescent SARS-CoV patients, potently neutralized SARS-CoV-2 through a highly conserved domain distinct from RBD and did not interfere with the binding of S protein with the ACE2 receptor [63] .

Moreover, in contrast to the above-mentioned importance of RBD in designing monoclonal antibodies, some studies have revealed the antibody-dependent enhancement of viral entry when the monoclonal antibody targets the RBD. It was shown that the binding of monoclonal antibody to the RBD triggers conformational changes that are similar to the alterations made following the binding of viral receptors to the viral RBD; hence, the binding mediates the virus entry to the cell via viral receptor-dependent pathways.

However, as stated in the mentioned study, this mechanism depends on the monoclonal antibody dosage, expression of particular viral receptors (e.g. Fc receptors), and particular features of the monoclonal antibody [64] . Although ACE2 has been introduced as the main receptor of SARS-CoV, it may not be sufficient for the interaction between the cell and the virus. Other cellular factors, such as vimentin, a cytoskeleton protein, were revealed to be important in the formation of the ACE2-SARS-CoV complex [65] . Therefore, surface vimentin was recognized as a potential target for SARS-CoV. DS-SIGN/CD209 is also a transmembrane adhesion molecule, which is mainly expressed on interstitial dendritic cells and lung alveolar macrophages. It was shown that DS-SIGN also mediates the entry of SARS-CoV. A humanized monoclonal antibody was produced to interfere with the interaction of DS-SIGN and intercellular adhesion molecule 3 (ICAM-3), and thus inhibit SARS-CoV entry to the cell [66] . Similar proteins may be identified in regards to SARS-CoV-2.

In addition to inhibiting the virus entry, antibodies can intrude into the biological activities of the virus thereby preventing its replication. Fully human antibodies, which are capable of traversing across the cell membrane of infected cells and preventing virus replication, were made against several kinds of viruses, including influenza, hepatitis C virus, and Ebola [67] . Papain-like proteases (PLpro), cysteine-like protease (3CLpro), and other non-structural proteins (nsps) can be suggested as targets of interests that hinder SARS-CoV-2 replication [1, 68] .

Besides structural parts of the virus, various steps associated with the innate and the adaptive immune responses have been proposed as the most important targets of interest. For instance, the significant rise in the level of chemokines and cytokines, including IL-1β, IFN-γ, IP-10, and MCP-1, which is called the cytokine storm, can be inhibited by antibodies [69] . The preliminary studies of critically-ill COVID-19

patients have shown that IL-6 may cause severe inflammatory responses that lead to acute respiratory distress syndrome [70] . Herein, tocilizumab, an IL-6 inhibitor monoclonal antibody, has gained significant attention. In a 21-patient clinical study recruited in China, tocilizumab resulted in the reduction of oxygen need in 75% of patients, lung lesion opacity absorption in 90.5% of patients, and correction of lymphocyte and C-reactive protein levels [70] . The significance of tocilizumab can be better explained since a noticeable number of 46 clinical trials regarding its use against SARS-CoV-2 related pneumonia and respiratory tract infections were recorded in NIH until May 27, 2020. An increase in the level of some of these proinflammatory cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) results in a positive feedback in the number of other inflammatory mediators, including IL6, IL-23, and TNF. GM-CSF along with IL6 and IL23 also induce Th1/Th17 differentiation and the polarization of macrophages to M1 phenotypes, which in turn boost the inflammatory responses [71] . Th17 immune response also can aggravate the cytokine storm by raising the level of IL17, GM-CSF, IL21, and IL22 [72] . High levels of GM-CSF and Th17 cells were observed in the plasma of severe-to critically-ill COVID-19 patients [73, 74] . Herein, harnessing the upregulation of GM-CSF can prevent a cascade of inflammatory responses, which result in acute respiratory syndrome. Since monoclonal antibodies targeting one inflammatory mediator, may fail to control the whole cytokine storm and prevent the lung injury induced by acute respiratory distress syndrome, a newer approach to prevent lung injury was proposed. It was shown that physical stress such as excessive mechanical stress caused by ventilators upregulates the expression of a gene, called nicotinamide phosphoribosyltransferase (NAMPT). As the bioavailability of NAMPT increases, Toll-like receptor 4 (TLR4), which is responsible for lung inflammation, gets activated [75, 76] .

Herein, neutralization of circulating NAMPT by monoclonal antibodies can be another viable approach in preventing the lung injury caused by SARS-CoV-2.

In addition to the role of inflammatory mediators, understanding the adaptive immune responses helps us to repurpose or invent immunomodulatory antibodies to defeat SARS-CoV-2. For example, CD4+ and CD8+ T-cells are expected to promote the proliferation of neutralizing antibodies and the destruction of infected cells, respectively. However, lymphocytopenia is identified to play a role in the pathogenesis of severely-ill COVID-19 patients [77] , which can be prevented or restored by regulating lymphocyte proliferation and apoptosis [78] . Herein, some studies have shown that sepsis may occur secondary to inflammatory responses. The immune imbalance, which occurs in sepsis, maybe as a result of T-cell depletion. PD-1 and CTLA-4 receptors are immune checkpoints that are expressed on the surface of T-cells and play a role as the negative regulator of T-cell function. Therefore, inhibiting the immune checkpoints by monoclonal antibodies is also an intriguing approach in defeating SARS-CoV-2 [79] . Furthermore, CD4+ cells express a receptor called c-chemokine receptor 5 (CCR5), which was established as a way of HIV entry to the cell [80] . This receptor could also be a potential target for SARS-CoV-2.

The level of different immunoglobulins is raised in response to SARS-CoV-2. Even though an increase in the level of immunoglobulins is attributed to pose neutralizing effect on SARS-CoV-2, a rise in anti-S IgG is associated with lung failure [81, 82] . Complement systems also play a role in conferring both humoral and natural immunity; however, they have been also attributed to the refractory inflammatory diseases.

Herein, C5a and C5a receptor, the members of the complement system, have been successfully targeted in different clinical trials of inflammatory diseases and thus can be recognized as possible targets in new diseases such as COVID-19 [83] . Additionally, TLR3, CD16, immunoreceptor tyrosin-based activation motif (ITAM), G-CSF, monocyte chemoattractant protein 1 (MCP1), TNFα, IL4, and IL10 are the other members of the immune system for which anti-SARS-CoV monoclonal antibodies were patented. These monoclonal antibodies could be reevaluated for SARS-CoV-2 [84] .

Besides the main strategies described above for designing monoclonal antibodies against SARS-CoV-2, some more novel approaches with a completely different mechanism were suggested. One of these strategies is using dewetting monoclonal antibodies. Dewetting transition is a process in which hydrophobic pores of the ion channels inhibit water transmission and thus impair the cellular performance. This phenomenon can be deployed to block viruses, bacteria, and autoimmune activities. Dewetting monoclonal antibodies are antibodies with a lipophilic fragment that target the transmembrane receptors and hinder the physiological water flow inside the channel. Such antibodies were produced against the influenza virus [85, 86] . Recently, viroporins were identified in SARS-CoV-2, the ion channel proteins that are generated by the virus E protein and are responsible for different parts of the virus life cycle, including virus entry, assembly, release, and the whole pathogenesis cycle [87] . As suggested, dewetting monoclonal antibodies could be developed against SARS-CoV-2 viroporins and administered through the nose. These antibodies can deactivate the virus by targeting viroporins even before the virus will be able to bind to the host cells [88] .

Generally speaking, tThe antibodies used for treatment could be usually produced at large-scale, either as monoclonal or polyclonal antibodies, using hybridoma cell-lines, animals, or cell-free protein synthesis either, [89] .

Monoclonal antibodies can be produced via several technologies, including the production of high-affinity human antibodies in immunized transgenic mice (e.g. XenoMouse® or HuMAB® mice), various phagedisplay systems such as generating antibodies from immunoglobulin cDNA libraries in bacteria or mammalian cells, and obtaining memory B cells of convalescent patients that are immortalized by EBV transformation. All of these techniques were previously recruited to produce monoclonal antibodies against SARS-CoV [90] . Production The production of monoclonal antibodies against SARS-CoV-2 is in its incipient phase. Currently, our data about SARS-CoV-2 antibodies greatly comes from the studies in which the antibodies derived from the plasma of convalescent patients were analyzed. A recent study of the convalescent patients' antibodies demonstrated that anti-SARS-CoV-2 antibodies were versatile among the convalescent patients and each patient represented a unique pattern of antibody biodistribution. These results explain why it may be difficult to design specific anti-SARS-CoV-2 antibodies [91] . Therefore, the introduced antibodies in this study were mainly tested against SARS-CoV or approved for other immune inflammatory diseases such as rheumatoid arthritis, cancers, and other viral infections. An extra method for designing antibodies against SARS-CoV-2 can be based on the antibody-antigen computational simulation [51] . For instance, an online docking server using the CoDockPP engine is constructed to predict the docking modes between antibodies or other peptides. This server is freely available at http://ncov.schanglab.org.cn. Identified structural parts of SARS-CoV-2 and the homologous parts of other coronaviruses were gathered to produce the mentioned docking server [92] . Table 2 consists of tThe antibodies retrieved from the previous studies on SARS-CoV or computational studies concerning SARS-CoV-2, which mainly target the virus structure or host receptors are shown in Table 2 . Despite a great homology between SARS-CoV and SARS-CoV-2, the cross-reactivity of SARS-CoV antibodies against SARS-CoV-2 is still under debate. For instance, some highly-conserved regions are found in SARS-CoV-2, which are absent in SARS-CoV. The c-terminal of SARS-CoV-2 RBD highly differs from that of SARS-CoV. Moreover, an extra furin cleavage site was found between S1 and S2 subunits in SARS-CoV-2, which is absent in SARS-CoV. These differences may not affect the ability of both viruses in interacting with the ACE2 receptor but explain the different levels of affinity among neutralizing antibodies with the two viruses [51, 57, 93, 94] . Moreover, a recent study revealed that the antibodies targeting RBD of the coronavirus family are virus species-specific, while those that target viral parts outside RBD are capable of cross recognition [91] . In an antibody epitope computational analysis, it was revealed that 85.3% of antibody epitopes in the SARS-CoV-2 spike were novel in comparison with those in SARS-CoV [95] . Therefore, antibodies suggested in Table 2 ought to be reevaluated to be used against SARS-CoV-2. Taken together, among the introduced monoclonal antibodies in these study F26G19, CR3022, and 47D11 were shown to cross-neutralize SARS-CoV and SARS-CoV-2. antibodies, including S101.1, S102.1, S103.3, S104.1, S105.2, S106.1, S107.4, S108.1, S109.2, Neutralize spike by binding to residues 318-510

Analysis of immune SARS-CoV patients' serum and in vivo study in mice [60] S132.9, S128.5, S127.6, S124.4, S159.1, S160. [111] Further information in this study concerning monoclonal antibody data against SARS-CoV-2 was retrieved from clinical trial data recorded in clinicaltrials.gov or biotechnology and pharmaceutical companies'

websites, which are summarized in Tables 3 and 4 and Harbour Biomed, are designed to neutralize SARS-CoV-2 structure. However, the mechanisms and specificities of the latter antibodies have not been elaborated to date and thus should be followed in companies' websites. Not mentioned Binds to highlyconserved epitopes within SARS-CoV and SARS-CoV-2

Vir biotechnology with WuXi biologics and Biogen

Enters clinical trial within 3-5 months Aimed to confer short-and long-term immunity and use as prophylaxis [116] Not 

For effective passive immunotherapy, several epitopes ought to be targeted rather than one epitope.

Moreover, the design of monoclonal antibodies and their testing at a clinical stage is a long pathway followed by the fact that the massive production of monoclonal antibodies might be costly, time-consuming, (Table 4 ). Polyclonal antibodies produced by immunized animals or a particular cell line technology are expected to mimic convalescent plasma therapy with a higher potency than their plasma-derived equivalents as well as better clinical outcomes. Furthermore, the risk of contamination and host reactions will be reduced compared with their plasma equivalents; dosing and kinetics also would be more predictable and scalable. Moreover, targeting more than one epitope can cause synergistic effects in neutralization and would limit the formation of escape-mutants. For instance, a recent study revealed that a cocktail of antibody noticeably enhanced SARS-CoV-2 neutralization compared with the use of one monoclonal antibody [63] .

No doubt the immune system is highly impaired in critically ill COVID-19 patients, which denotes the possibility of using immunomodulators in this disease. Monoclonal or polyclonal antibodies, interferons, and hydroxychloroquine are immunomodulators, which were widely discussed in previous sections. In this section, other Several classes of immunomodulators including tyrosine kinase inhibitors, mTOR inhibitors, calcineurin inhibitors, antimetabolites, TNF blockers, metal-based agents, and other anti-inflammatory agents are might be of value in the treatment of COVID-19.discussed Janus-associated kinase (JAK)

inhibitors are of high interest among the mentioned immunomodulators.

Although ACE2 receptors have been recognized as the main receptor for the entry of SARS-CoV-2, it was shown that SARS-CoV-2 also attacks the cells that do not have ACE2 receptors, including lymphocytes. It inhibitors have a marginal effect on IL21, which is responsible for B cell function, and do not disrupt innate immune response, since the inhibition caused by JAK2 inhibitors is transient and reversible [135] . Another member of this family, baricitinib, is of special interest due to its advantages over other JAK inhibitors and has been highly studied. Baricitinib inhibits another regulator of endocytosis, called cyclin G associated kinase, through which it can defeat the viral infection [136] . Baricitinib has been also suggested as the best choice among other JAK inhibitors due to its acceptable profile of side effects, the possibility of once-daily dosing, higher potency, and advantageous pharmacokinetics. The inhibitory doses of baricitinib were welltolerated by patients with inflammatory diseases in comparison with other kinase inhibitors [137, 138] .

Moreover, baricitinib represents low protein binding and minimal interaction with drug transporters or metabolic enzymes; thus, it is preferred over other JAK inhibitors for administration along with an antiviral regimen [138] . In contrast to the above-mentioned benefits of baricitinib, some clinical studies suggested that baricitinib may not be an ideal option for the treatment of COVID-19 due to the possibility of causing lymphocytopenia, neutropenia, viral reactivation, and enhancement of coinfection [139] . Other JAK inhibitors, including upadacitinib and filgotinib, were also shown to impair interferon-mediated antiviral responses and perpetuate SARS-CoV-2 infection. Herein, the incidence of secondary viral infections, including herpes zoster was observed, which was shown to be more prevalent in immunocompromised patients. Hence, JAK inhibitors, particularly baricitinib, should be administered with meticulous consideration, especially in susceptible and immunocompromised patients [140] . Next, ruxolitinib was listed as one of the top hit compounds in an advanced bioinformatics analysis of available medications for SARS-CoV-2. The mentioned study aimed to identify compounds that counteract the expression of SARS-CoV-2-related genes [141] . To date, only three JAK inhibitors have entered clinical studies on COVID-19 patients, including baricitinib, ruxolitinib, and tofacitinib, among which many of the studies are related to baricitinib and ruxolitinib (Table 5) . 

Bruton tyrosine kinase (BTK) inhibitors are another group of tyrosine kinase inhibitors, which has been repurposed to modulate the cytokine storm ensuing COVID-19 infection. BTK signaling leads to B cell proliferation and activation of cytokine pathway. BTK inhibitors are mainly approved for the treatment of an aggressive form of B cell lymphoma, called mantle cell lymphoma. This group includes acalabrutinib, zanubrutinib, tirabrutinib, and ibrutinib, among which ibrutinib was shown to have less efficacy and more toxicity [142] . AstraZeneca ® incorporation has designed a clinical trial to assess the efficacy of one of these BTK inhibitors, called acalabrutinib, to alleviate the cytokine storm of SARS-CoV-2 infection (Table 5 ).

In addition to BTK inhibitors, other kinase inhibitors, including erlotinib and sunitinib were also shown to interfere in viral entry through inhibiting JAK and AAK1. However, they are not classified as JAK inhibitors and are not preferred over JAK inhibitors due to less efficacy and higher toxicity [137, 138] .

Sorafenib was also hypothesized to be repurposed in COVID-19 based on a drug-gene interaction analysis [143] .

Another mechanism of immunosuppression, which has been proposed, is related to the use of mTOR inhibitors. The cytokine storm in COVID-19 patients is attributed to a mechanism, called antibodydependent enhancement, in some systematic reviews [144] . This phenomenon happens when the virus triggers the production of cross-reactive antibodies by memory B cells. These cross-reactive antibodies enhance virus delivery to the macrophages and thus contribute to the massive replication of the virus without being captured by the immune system. mTOR inhibitors were found to inhibit the activation of memory B cell and prevent the antibody-dependent enhancement mechanism. mTOR inhibitors also were shown to inhibit the replication of MERS-CoV in the in vitro studies [144] . Some mTOR inhibitors, including rapamycin or sirolimus, were hypothesized to be repurposed in COVID-19 clinical studies.

Sirolimus was shown to inhibit viral replication and release in patients with severe pneumonia and acute respiratory failure [145] . The computational analysis of protein-protein interactions and gene-enrichment network also suggested that sirolimus can be repurposed for SASR-CoV-2 [146] . Moreover, a clinical study of sirolimus on COVID-19 patients has been recently started (Table 5 ).

Papain-like protease (PLpro) is a viral protease responsible for coronavirus genome replication with deubiquitinating activity [147] . PLpro has been mainly the target of viral inhibitor class of medications.

However, antimetabolites were also shown to be effective on PLpro due to their pharmacological action.

For instance, 6-mercaptopurine (6MP) and 6-thioguanine (6TG) were shown to be the specific inhibitors of SARS-CoV PLpro [148] . Mycophenolate mofetil is another immunosuppressant that was shown to target PLpro in SARS-CoV and MERS-CoV in both in vitro and in vivo studies. However, further clinical studies are needed to assess its efficacy against SARS-CoV-2 [149] . There is no definitive evidence about the efficacy of other antimetabolites including methotrexate in COVID-19 patients [149] .

Calcineurin inhibitors such as tacrolimus might be effective against SARS-CoV-2, since they inhibit calcineurin thereby blocking T cell activation. Tacrolimus, which is mainly used in organ transplant, was shown to be effective against MERS-CoV in a renal transplant patient compared with a similar patient who did not receive tacrolimus as a part of the transplant regimen [150] . Tacrolimus was also found to be effective against SARS-CoV in a study on cell lines. However, further studies undoubtedly are required to assess its efficacy against SARS-CoV-2 [151] . There is no definitive evidence about the efficacy of other calcineurin inhibitors including cyclosporine [149] .

Metal-based agents with different metal centers, including gold, ruthenium, and bismuth were suggested to be used in COVID-19 patients [152] . The gold compound, called auranofin (Ridaura®) is an FDA approved compound, which was initially proposed for rheumatoid arthritis. The exact mechanism of auranofin is still unclear; however, it is classified as an immunomodulatory and anti-inflammatory agent. In recent years, auranofin has gained attention in viral infections, including HIV. In the case of HIV, it was revealed to be more effective than hydroxychloroquine in control of viral production, latency, and viral reactivation [153] .

It was also hypothesized that auranofin can interfere with IL-6 signaling by inhibiting JAK1 and STAT3

pathways [154] . It was shown that a low micromolar concentration of auranofin strongly inhibited SARS-CoV-2 viral replication and reduced the viral-induced cytokine expression in human cells [155] .

TNF-α was shown to be associated with SARS-CoV pulmonary injury; therefore, TNF-α blockers, which are mainly used in the treatment of autoimmune and inflammatory diseases, such as rheumatoid arthritis, ankylosing spondylitis, and psoriasis, can be suggested as a potential target for SARS-CoV-2 [156] . Besides the monoclonal antibodies that modulate the TNF-α responses, etanercept was suggested as another immunomodulator for COVID-19 patients [149] .

Lenalidomide and thalidomide, which are not specifically classified as TNF-α blockers, were hypothesized to be repurposed based on a drug-gene interaction analysis [143] . Thalidomide has antiinflammatory, anti-fibrotic, and immunoregulatory effects, which proved to be safe and effective in the treatment of lung injuries with different etiologies, including H1NI-induced lung injury [157] . It has also entered a clinical trial of COVID-19, as shown in Table 5 .

CD24Fc, which is a fusion protein constituted of human CD24 attached to the human IgG Fc region, is another biological immunomodulator. CD24Fc was demonstrated to successfully ameliorate cytokine responses in viral infections and reduce the graft versus host disease [158, 159] . Hence, CD24Fc could be effective against the SARS-CoV-2 cytokine storm and the associated pneumonia. CD24Fc has entered a clinical trial by OncImmune ® incorporation (Table 5 ).

The rationale for usinge of corticosteroids in COVID-19 patients relies on their inhibitory effects on the inflammatory factors. Corticosteroids inhibit a massive proportion of cytokines, chemokines, inflammatory enzymes, and receptors that are overexpressed in response to the viral infection [160] .

Results regarding the beneficial effects of corticosteroids against coronavirus are controversial. A metaanalysis including 5270 patients from 15 studies revealed that the use of corticosteroids resulted in higher mortality rate, the longer length of stay, a higher rate of bacterial infection, hypokalemia, and hypercalcemia [161] . Furthermore, Russell and colleagues in a comment published in The Lancet did not advocate the use of corticosteroids in COVID-19-induced lung injury or shock, except in the clinical trial settings [162] . By contrast, a retrospective analysis of 401 patients with severe SARS revealed that corticosteroids led to reduced mortality rate and shortened hospital stay [163] . Taken together, corticosteroids are indicated for critically-ill critically ill COVID-19 patients and its use in mild to moderate patients is highly disregarded. For instance, the use of corticosteroids is recommended in mechanically-ventilated COVID-19 patients with respiratory failure (with ARDS), while is inappropriate for COVID-19 patients without ARDS [164] . In fact, administering corticosteroids in the onset of disease was shown to deter the immune system and increase the viral load; thereby inducing additional complications, such as diabetes and vascular necrosis [165, 166] . The timing and dosage of corticosteroids are of special importance in the outcomes of treatment in critically-ill critically ill patients [167] . For instance, in patients with high inflammatory responses including severe deterioration of oxygenation indicators and rapid imaging progress, a short term (3-5 days) of corticosteroids doses equivalent to 1-2 mg/kg/day methylprednisolone is recommended [168] . Moreover, a recent study revealed that low doses of corticosteroids (e.g. 25-150 mg/day methylprednisolone) did not delay viral clearance and did not increase the mortality rate compared with the control group [169] .

Recently dexamethasone was introduced as the first medicine presented with a survival benefit in treating critically-ill critically ill COVID-19 patients, and WHO welcomes preliminary results regarding its use [170, 171] . According to a large, multi-center and randomized clinical trial called RECOVERY (Randomized Evaluation of COVid-19 thERapY) trial, the use of 6 mg/day dexamethasone in COVID-19 patients on mechanical ventilation or oxygen supplementation was associated with reduced mortality rate compared with those who received standard treatment. In the patients who did not need respiratory support, no improvement was observed [172, 173] . This well-known steroid is believed to support the suppression of hyperactive inflammatory responses, so-called cytokine storm [174] . Interestingly, an extra mechanism in defeating SARS-CoV-2 by dexamethasone was suggested. A computational study revealed that dexamethasone tightly binds to 3C-like protease (the main protease) in SARS-CoV-2 as remdesivir does; however, dexamethasone surprisingly forms a better contact with the enzyme active site than remdesivir [175] .

In addition to the importance of dose and timing, other considerations concerning the use of corticosteroids ought to be made according to a recent correspondence consensually made by experts in

The Lancet, including: (1) the pros and cons of corticosteroids should be carefully evaluated prior to administration;

(2) prudent consideration should be made for the further use of corticosteroids in patients who are on the regular use of corticosteroids for chronic diseases [176] .

Modulation of the immune system is obviously a major strategy in the control and treatment of COVID-19, which should be adjusted according to different stages of the disease. It can be done through vaccines, interferons, antibodies (either as convalescent plasma therapy or monoclonal and polyclonal antibodies), or potential therapeutic immunomodulators.

At the pre-disease or disease prevention stage, active immunization by vaccines could be an optimal approach. However, vaccine development is a time-consuming and complicated process. Despite enormous efforts on finding vaccines against SARS-CoV-2, there is still a fairly long way to the market availability of a proper vaccine.

Following COVID-19 disease onset, regulating the activities of the aberrant immune system may be a valuable treatment goal. At the early stages of the disease, stimulation of the immune system through passive immunotherapy is regarded as a therapeutic objective to support the patient's immune system and Despite the similarities of SARS-CoV-2 with SARS and MERS, some differences such as higher transmission rate and longer incubation period indicate its varied interaction with the immune system.

Given that most of the present data are interpreted from SARS and MERS studies, more specific data about SARS-CoV-2 immunopathogenicity and viral-mediated responses are demanded. Finally, taking into account the complexity of the immune system activities and their complicated interconnections, a systemic approach could be a key element in gaining a more complete picture of this disease and the virus pathogenicity. Such insight is urgently warranted to plan for proper interventional therapies with predictable and favorable outcomes.

Not applicable.

The authors declare no conflict of interests. Bringing  the  Total  to  10 Patients.

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

The Battle Against COVID-19: Where Do We Stand Now?

The Rise and Fall in Therapeutic Candidates for COVID-19

Therapeutic Approaches for COVID-19 Based on the Dynamics of Interferonmediated Immune Responses

Dysregulation of type I interferon responses in COVID-19

Integrated analyses of single-cell atlases reveal age, gender, and smoking status associations with cell type-specific expression of mediators of SARS-CoV-2 viral entry and highlights inflammatory programs in putative target cells

DPP4 inhibition: Preventing SARS-CoV-2 infection and/or progression of COVID-19?

Immunosuppression for hyperinflammation in COVID-19: a doubleedged sword? The Lancet

The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak

Molecular immune pathogenesis and diagnosis of COVID-19

Hypothesis for potential pathogenesis of SARS-CoV-2 infection--a review of immune changes in patients with viral pneumonia

SARS-CoV-2 nsp13, nsp14, nsp15 and orf6 function as potent interferon antagonists. Emerging Microbes & Infection

SARS-CoV-2 ORF3b is a potent interferon antagonist whose activity is further increased by a naturally occurring elongation variant

Immunopathology and immunotherapeutic strategies in severe acute respiratory syndrome coronavirus 2 infection. Reviews in Medical Virology

Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals

Type 1 interferons as a potential treatment against COVID-19

SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is enriched in specific cell subsets across tissues

Subcutaneous administration of interferon beta-1a for COVID-19: A non-controlled prospective trial

Interferon beta-1a for COVID-19: critical importance of the administration route

Evaluation of safety, efficacy, tolerability, and treatment-related outcomes of type I interferons for human coronaviruses (HCoVs) infection in clinical practice: An updated critical systematic review and meta-analysis

A World of Changes: The Inheritance of COVID-19

Developing Covid-19 Vaccines at Pandemic Speed

A review on Promising vaccine development progress for COVID-19 disease. Vacunas

Vaccines for COVID-19: The current state of play

Effectiveness of convalescent plasma therapy in severe COVID-19 patients

Treatment with convalescent plasma for critically ill patients with SARS-CoV-2 infection

Pharmacotherapy in COVID-19; A narrative review for emergency providers. The American journal of emergency medicine

Clinical trial analysis of 2019-nCoV therapy registered in China

Feasibility, safety, clinical, and laboratory effects of convalescent plasma therapy for patients with Middle East respiratory syndrome coronavirus infection: a study protocol

Cross-reactive antibodies in convalescent SARS patients' sera against the emerging novel human coronavirus EMC (2012) by both immunofluorescent and neutralizing antibody tests

Collecting and evaluating convalescent plasma for COVID-19 treatment: why and how. Vox sanguinis

TreaTment for emerging viruses: Convalescent plasma and COVID-19

Immunoglobulins or convalescent plasma to tackle COVID-19: buying time to save lives-current situation and perspectives

Convalescent plasma transfusion for the treatment of COVID-19: Systematic review

Treatment of 5 critically ill patients with COVID-19 with convalescent plasma

Convalescent plasma as a potential therapy for COVID-19. The Lancet Infectious Diseases

A short review on antibody therapy for COVID-19. New Microbes and New Infections

Effect of convalescent plasma therapy on viral shedding and survival in COVID-19 patients

Challenges of convalescent plasma therapy on COVID-19

Prospective audit of adverse reactions occurring in 459 primary antibody-deficient patients receiving intravenous immunoglobulin

Convalescent plasma in Covid-19: Possible mechanisms of action

SARS-CoV-2 infection in immunocompromised patients: humoral versus cell-mediated immunity

Development of passive immunity against SARS-CoV-2 for management of immunodeficient patients-a perspective

Convalescent plasma for persisting Covid-19 following therapeutic lymphocyte depletion: a report of rapid recovery

Convalescent (immune) plasma treatment in a myelodysplastic covid-19 patient with disseminated tuberculosis

Rapid recovery of a SARS-CoV-2 infected X-linked agammaglobulinemia patient after infusion of COVID-19 convalescent plasma. The journal of allergy and clinical immunology

Use of convalescent plasma therapy in two COVID-19 patients with acute respiratory distress syndrome in Korea

COVID-19 convalescent plasma transfusion. Hematology, Transfusion and Cell Therapy

Perspectives on monoclonal antibody therapy as potential therapeutic intervention for Coronavirus disease-19 (COVID-19)

Spike protein binding prediction with neutralizing antibodies of SARS-CoV-2. bioRxiv

A new coronavirus associated with human respiratory disease in China

The trinity of COVID-19: immunity, inflammation and intervention

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Cross-neutralization of SARS coronavirus-specific antibodies against bat SARS-like coronaviruses

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerging Microbes & Infection

Differential Antibody Recognition by Novel SARS-CoV-2 and SARS-CoV Spike Protein Receptor Binding Domains: Mechanistic Insights and Implications for the Design of Diagnostics and Therapeutics. bioRxiv

Human monoclonal antibodies against highly conserved HR1 and HR2 domains of the SARS-CoV spike protein are more broadly neutralizing

An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus

Generation and characterization of human monoclonal neutralizing antibodies with distinct binding and sequence features against SARS coronavirus using XenoMouse®. Virology

Monoclonal antibodies for the S2 subunit of spike of SARS-CoV cross-react with the newlyemerged SARS-CoV-2. Eurosurveillance

Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody

Molecular mechanism for antibody-dependent enhancement of coronavirus entry

Surface vimentin is critical for the cell entry of SARS-CoV

pH-dependent entry of severe acute respiratory syndrome coronavirus is mediated by the spike glycoprotein and enhanced by dendritic cell transfer through DC-SIGN

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

Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs

Perspectives on therapeutic neutralizing antibodies against the Novel Coronavirus SARS-CoV-2

Effective Treatment of Severe COVID-19 Patients with Tocilizumab

Aberrant pathogenic GM-CSF+ T cells and inflammatory CD14+ CD16+ monocytes in severe pulmonary syndrome patients of a new coronavirus. bioRxiv

TH17 Responses in Cytokine Storm of COVID-19: An Emerging Target of JAK2 Inhibitor Fedratinib

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Unique toll-like receptor 4 activation by NAMPT/PBEF induces NFκB signaling and inflammatory lung injury

Novel mechanism for nicotinamide phosphoribosyltransferase inhibition of TNF-αmediated apoptosis in human lung endothelial cells

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet

Lymphopenic community acquired pneumonia as signature of severe COVID-19 infection: Lymphopenia in severe COVID-19 infection

Controversies about COVID-19 and anticancer treatment with immune checkpoint inhibitors

Effects of CCR5 and CD4 cell surface concentrations on infections by macrophagetropic isolates of human immunodeficiency virus type 1

Longitudinal profile of immunoglobulin G (IgG), IgM, and IgA antibodies against the severe acute respiratory syndrome (SARS) coronavirus nucleocapsid protein in patients with pneumonia due to the SARS coronavirus. Clinical and Diagnostic Laboratory Immunology

Anti-spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection

Complement-targeted therapy: development of C5-and C5a-targeted inhibition. Inflammation and Regeneration

Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases

Interpreting thermodynamic profiles of aminoadamantane compounds inhibiting the M2 proton channel of influenza A by free energy calculations

Implications of broadly neutralizing antibodies in the development of a universal influenza vaccine. Current Opinion in Virology

Coronavirus envelope protein: current knowledge

Three options against SARS-CoV-2: pediatric sera, mithridatization, dewetting antibodies

Cell-Free Synthesis Meets Antibody Production: A Review

Neutralizing human monoclonal antibodies to severe acute respiratory syndrome coronavirus: target, mechanism of action, and therapeutic potential

Potent human neutralizing antibodies elicited by SARS-CoV-2 infection. bioRxiv

COVID-19 Docking Server: An interactive server for docking small molecules, peptides and antibodies against potential targets of COVID-19

Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein

SARS-CoV-2 and SARS-CoV spike-RBD structure and receptor binding comparison and potential implications on neutralizing antibody and vaccine development. bioRxiv

Novel antibody epitopes dominate the antigenicity of spike glycoprotein in SARS-CoV-2 compared to SARS-CoV

Molecular and biological characterization of human monoclonal antibodies binding to the spike and nucleocapsid proteins of severe acute respiratory syndrome coronavirus

Human monoclonal antibody combination against SARS coronavirus: synergy and coverage of escape mutants

Potent cross-reactive neutralization of SARS coronavirus isolates by human monoclonal antibodies

Unexpected receptor functional mimicry elucidates activation of coronavirus fusion

A human SARS-CoV neutralizing antibody against epitope on S2 protein. Biochemical and Biophysical Research Communications

Development and Characterization of a Severe Acute Respiratory Syndrome-Associated Coronavirus-Neutralizing Human Monoclonal Antibody That Provides Effective Immunoprophylaxis in Mice

Structural insights into immune recognition of the severe acute respiratory syndrome coronavirus S protein receptor binding domain

Development and characterisation of neutralising monoclonal antibody to the SARScoronavirus

Potential Neutralizing Antibodies Discovered for Novel Corona Virus Using Machine Learning. arXiv, 2020

Identification of SNAREs involved in synaptotagmin VII-regulated lysosomal exocytosis

Broadening of neutralization activity to directly block a dominant antibody-driven SARScoronavirus evolution pathway

Human antibodies from transgenic animals

A human monoclonal 1 antibody blocking SARS-CoV-2 infection

Three options against sars-cov-2: pediatric sera, mithridatization, dewetting antibodies

A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2

Roivant Announces Development of Anti-GM-CSF Monoclonal Antibody to Prevent and Treat Acute Respiratory Distress Syndrome (ARDS) in Patients with COVID-19

Biopharma Announces Development of TJM2 to Treat Cytokine Release Syndrome Associated with Severe and Critically-Ill Patients with Coronavirus Disease (COVID-19)

Humanigen Partners With CTI, A Leading Contract Research Organization, For Planned Phase III Study For Lenzilumab For Coronavirus Treatment

Vir Biotechnology Proceeding with Two Clinical Development Candidates for COVID-19

Distributed Bio optimizes anti-SARS protective antibodies to block the novel coronavirus

Tiziana Life Sciences plc To Expedite Development of its Fully Human Anti-Interleukin-6-Receptor Monoclonal Antibody, a Potential Treatment of Certain Patients Infected with Coronavirus

Aqualung Therapeutics Advances Its Investigational Monoclonal Antibody into IND-Enabling Studies of Acute Respiratory Distress Syndrome (ARDS) And Ventilator-Induced Lung Injury (VILI)

Advances-Its-Investigational-Monoclonal-Antibody-into-IND-Enabling-Studies-of-Acute-Respiratory-Distress-Syndrome-ARDS-And-Ventilator-Induced-Lung-Injury-VILI

Mount Sinai and Harbour BioMed Collaborate to Advance Novel Biotherapies for the Treatment of Cancer and Coronavirus COVID-19

Nascent biotech investigation drug product, pritumumab, to be studied as a potential therapeutic agent against (coronavirus) COVID-19

InflaRx Doses First Patient in Multicenter Randomized Clinical Trial in Severe Progressed COVID-19 Pneumonia in Europe upon Receipt of Initial Positive Human Data with InflaRx's anti-C5a Technology

Amgen And Adaptive Biotechnologies Announce Strategic Partnership To Develop A Therapeutic To Prevent Or Treat COVID-19

Identification and Characterization of a Potential Therapeutic COVID-19 Antibody by Vir Biotechnology Published in Nature

ImmunoPrecise Provides Updates on B Cell Select™ and Deep Display™ Programs for SARS-CoV-2 Antibody Discovery

Emergent BioSolutions Initiates Development of Plasma-Derived Product Candidates for the Treatment and Prevention of Coronavirus Disease

Initiates-Development-of-Recombinant-Polyclonal-Antibody-Therapy-for-COVID-19.html. 131. NuGenerex. Ii-Key-nCOV Peptide Vaccine

Anticancer kinase inhibitors impair intracellular viral trafficking and exert broadspectrum antiviral effects

The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The experience of clinical immunologists from China

Immunosuppression for hyperinflammation in COVID-19: a doubleedged sword? The Lancet

TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib

Family-wide structural analysis of human numb-associated protein kinases

Feasibility and biological rationale of repurposing sunitinib and erlotinib for dengue treatment

COVID-19: combining antiviral and anti-inflammatory treatments

Baricitinib-a januase kinase inhibitor-not an ideal option for management of covid 19

Baricitinib for COVID-19: a suitable treatment

Advanced Bioinformatics Rapidly Identifies Existing Therapeutics for Patients with Coronavirus Disease-2019 (COVID-19)

Review of Bruton tyrosine kinase inhibitors for the treatment of relapsed or refractory mantle cell lymphoma

COVID-19: A drug repurposing and biomarker identification by using comprehensive genedisease associations through protein-protein interaction network analysis

Prevent COVID-19 Severity by Repurposing mTOR Inhibitors. 2020.Preprints

Adjuvant treatment with a mammalian target of rapamycin inhibitor, sirolimus, and steroids improves outcomes in patients with severe H1N1 pneumonia and acute respiratory failure

Network-based Drug Repurposing for Human Coronavirus

The papain-like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity

Thiopurine analogue inhibitors of severe acute respiratory syndrome-coronavirus papain-like protease, a deubiquitinating and deISGylating enzyme

Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence. ecancermedicalscience

MERS CoV infection in two renal transplant recipients: case report

Replication of human coronaviruses SARS-CoV, HCoV-NL63 and HCoV-229E is inhibited by the drug FK506. Virus Research

A Role for Metal-Based Drugs in Fighting Covid-19 Infection? The Case of Auranofin

Chloroquine and beyond: exploring anti-rheumatic drugs to reduce immune hyperactivation in HIV/AIDS

Auranofin blocks interleukin-6 signalling by inhibiting phosphorylation of JAK1 and STAT3. Immunology

The FDA-approved gold drug Auranofin inhibits novel coronavirus (SARS-COV-2) replication and attenuates inflammation in human cells

TNF-[alpha] inhibition for potential therapeutic modulation of SARS coronavirus infection

Anti-inflammatory effect of thalidomide on H1N1 influenza virus-induced pulmonary injury in mice

CD24 and Siglec-10 selectively repress tissue damage-induced immune responses

CD24 and Fc fusion protein protects SIVmac239-infected Chinese rhesus macaque against progression to AIDS

One hormone, two actions: anti-and pro-inflammatory effects of glucocorticoids

The effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis

Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. The Lancet

Treatment of severe acute respiratory syndrome with glucosteroids: the Guangzhou experience

Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19)

Glucocorticoid-induced diabetes in severe acute respiratory syndrome: the impact of high dosage and duration of methylprednisolone therapy

Factors of avascular necrosis of femoral head and osteoporosis in SARS patients' convalescence. Zhonghua Yi Xue Za Zhi

The pathogenesis and treatment of theCytokine Storm'in COVID-19

Effectiveness of glucocorticoid therapy in patients with severe coronavirus disease 2019: protocol of a randomized controlled trial

Low-dose corticosteroid therapy does not delay viral clearance in patients with COVID-1

582: 469 171. WHO welcomes preliminary results about dexamethasone use in treating critically ill COVID-19 patients

COVID-19) Treatment Guidelines. National Institutes of Health

Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. medRxiv

Coronavirus breakthrough: dexamethasone is first drug shown to save lives

Deciphering the binding mechanism of Dexamethasone against SARS-CoV-2 Main Protease: Computational molecular modelling approach

On the use of corticosteroids for 2019-nCoV pneumonia