The spike proteins of SARS-CoV-2 play a major role in the interaction between the virus and the ACE2 receptor expressed by the host cell. The binding of the spike protein to ACE2 leads to membrane fusion and the initiation of the viral life cycle. To inhibit SARS-CoV-2 binding to ACE2, several neutralizing monoclonal antibodies (MAbs) targeting the spike protein of SARS-CoV-2 have been developed. Among them, the 80R MAb binds to the S1 fragment of SARS-CoV at the conformational epitope (amino acid residues 426–492) and blocks the binding of the viral S1 subunit to the ACE2 receptor, thereby preventing the entry and spread of the virus (44). These findings have been demonstrated by in vitro and in vivo studies (27, 45). Other MAbs targeting different epitopes of the S1 subunit have also been developed and tested by in vitro and in vivo studies, such as CR3022, F26G18, F26G19, m396, 1A9, and CR3014 (27–32).

A recent study suggested the involvement of similar mechanisms of host entry in infection with SARS-CoV-2, and consequently, different studies are currently investigating single MAbs or combinations of different MAbs. Such antibodies recognize different epitopes on the SARS-CoV-2 surface, which should be assessed first by in vitro and in vivo (mouse) approaches prior to different clinical trials. However, several neutralizing MAbs also bind to IgG Fc receptors (FcγR). The antibody/FcγR interaction might lead to virus entry that could infect other cells expressing this receptor independently of the ACE2-specific virus receptor. Recently, it has been demonstrated that FcγRIIA plays a major role in viral entry via antibody-dependent enhancement (ADE) using in vitro strategies (46). However, the signaling pathway associated with the MAbs/virus/receptor interaction is not yet clear. ADE viral entry in the presence of neutralizing MAbs has been demonstrated for many viruses, especially for those expressing the coronavirus spike protein. Understanding the effect of this interaction on the activation of human cells expressing the Fc receptor and viral proliferation may help to establish new vaccination strategies in the future.

Chloroquine (CQ) or hydroxychloroquine (HCQ) (a more soluble and less toxic metabolite of CQ) are antimalarial products that have been tested in humans (56). CQ and HCQ are also used in the treatment of several autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis. Additionally, CQ inhibits autophagy, favoring the apoptosis of cancer cells (57).

Promising studies have demonstrated that the CQ/HCQ compounds have the ability to inhibit certain coronaviruses, such as SARS-CoV-1 (58). Additional in vitro studies have shown that CQ and HCQ have antiviral activity against SARS-CoV-2, with more side effects being observed for CQ than for HCQ (58). In contrast, others have demonstrated that HCQ has greater antiviral activity than CQ during SARS-CoV-2 infection (18). Basically, CQ or HCQ exert their effects on eukaryotic cells by increasing the vacuolar pH of organelles such as endosomes and lysosomes. The increase in pH neutralizes the acidic lysosomal pH, decreasing autophagosome-lysosome fusion and autophagic degradation (59, 60). Autophagosome-lysosome fusion is essential for virus/cell fusion and immune-modulating activity (61). CQ and HCQ can also modify the glycosylation of ACE2, which binds to the spike protein S of SARS-CoV. This may interfere with the virus-receptor interaction (19). Additionally, an in vitro approach demonstrated that CQ inhibits COVID-19 virus infection (62). Some studies have indicated that HCQ also reduces the levels of some proinflammatory cytokines, such as IL-6, IL-18, and TNF-α (63). Indeed, CQ and HCQ inhibit endosomal TLRs and have anti-inflammatory effects by inhibiting prostaglandin synthesis or lipid peroxidation (64).

Hence, it was suggested that CQ and HCQ represent a potential new drug treatment for COVID-19. However, there are some limitations in performing clinical trials in patients owing to the restrictions on research studies using cell culture or animals and side effects, such as cardiotoxicity and liver cytotoxicity, due to the half-life of these compounds of ~3.1 days (65). However, the risk of toxicity in patients treated for 10 years with HCQ for systemic lupus erythematosus was shown to be approximately 7.5% and to be higher in patients treated for longer periods (66). In COVID-19-associated acute infection, CQ and HCQ are used for a very short time (~5 days). Nevertheless, acute adverse events, such as hypersensitivity and gastrointestinal intolerance, require attention, especially in critically ill patients who may develop similar clinical manifestations due to COVID-19. Additionally, CQ and HCQ can be safely used during pregnancy (67). Recently, a clinical trial with a small sample size showed that HCQ treatment is associated with a decrease in viral load in COVID-19 patients, and the effect is reinforced by azithromycin (39). Because of the low number of patients and the lack of some group controls during this recent study, new national and international clinical trials are being conducted to confirm the authenticity of these findings. A current clinical trial of CQ and HCQ therapy in the treatment of COVID-19 in Europe may reveal new possibilities for antiviral therapy for COVID-19 to stop the pandemic. Although the antiviral activity of hydroxychloroquine remains uncertain, there have been several controversies regarding the clinical benefits of this drug in patients with COVID-19. Recently, a new publication showed the beneficial effects of hydroxychloroquine or chloroquine when used alone or with a macrolide on in-hospital outcomes for COVID-19. Each of the drug regimens was associated with a decrease in in-hospital survival and an increased frequency of ventricular arrhythmias when used for the treatment of COVID-19. However, this study was retracted from the Lancet journal (https://doi.org/10.1016/S0140-6736(20)31174-0). In contrast, an approved study by the Ethics Committee of Shanghai Public Health Clinical Center under the number NCT04261517 demonstrated that the prognosis of COVID-19 patients with moderate cases is good. However, a large sample size study is needed to investigate the effects of HCQ in the treatment of COVID-19 (68). A new study is ongoing and can be found on ClinicalTrials.gov under the identifier NCT04303507 with the official title “Chloroquine/Hydroxychloroquine Prevention of Coronavirus Disease (COVID-19).” This study is a double-blinded, randomized, and placebo-controlled trial that will be conducted in a healthcare setting. A total of 40,000 participants will be recruited, and the investigators predict an average of 400–800 participants per site at 50–100 sites. However, the estimated completion date is April 2021.

Since recent findings revealed that most COVID-19 patients with severe cases admitted to the intensive care unit for respiratory failure present predominantly with hypercoagulation, anticoagulant drugs could a potentially prevent a state that could lead to arterial and venous thromboembolic complications (69). Antithrombin and activated protein C for the treatment of classical acute respiratory distress syndrome can be used as anticoagulants for inflammatory thrombus prevention. Platelets may be involved in systemic and local thrombotic responses. Antiplatelet therapies may present a new therapeutic approach. This is a known phenomenon in acute coronary syndromes, where anticoagulant therapy along with antiplatelet therapy decreases arterial thrombosis, but it is associated with an increase in bleeding risk (42).

Remdesivir is an antiviral molecule with a chemical formula of C27H35N6O8P. Remdesivir prevents viral replication by inhibiting viral DNA polymerase. Its antiviral activity has been demonstrated against Ebola virus in multiple human cell types, including primary macrophages and human endothelial cells, with low half-maximal effective concentration (EC₅₀) values of 0.06–0.14 μM (33). It has also been shown that remdesivir inhibits SARS-CoV in primary human airway epithelial cell cultures, which are a biologically relevant in vitro model of pulmonary infection (70). Moreover, remdesivir has exhibited antiviral activity against the Marburg virus (33). SARS-CoV and SARS-CoV-2 present 82% RNA sequence homology, and their RNA-dependent RNA polymerase (RdRp) sequences share 96% sequence similarity. Therefore, drugs targeting the viral RdRp proteins of SARS-CoV are also suspected to be effective against SARS-CoV-2. According to the in vitro antiviral activity of remdesivir, the in vivo tests showed the suppression of Ebola virus replication and the protection of all infected animals against lethal infection (33). In addition, remdesivir decreased the viral load in the lungs and preserved the pulmonary function of mice during SARS-CoV infection (70). These findings suggest that remdesivir can be used as a potential new therapeutic approach for human infections caused by coronaviruses, including SARS-CoV-2. In fact, the first case of COVID-19 in Washington, USA, was treated with intravenous remdesivir. During the treatment, no obvious adverse effects were observed (71). However, we cannot comment yet on the efficiency of the treatment effect of remdesivir during the COVID-19 outbreak.

There are four clinical trials currently enrolling patients in the United States. Moreover, two clinical trials in China have been registered on ClinicalTrials.gov: NCT04257656 for severe disease and NCT04252664 for mild-to-moderate disease (72). Recently, Yeming et al. published the results of the NCT04257656 clinical trial, which showed no clear outcome because of the death or discharge of patients (73). Moreover, in another clinical trial, the benefit in terms of the time to clinical improvement was not statistically significant (21 vs. 23 days), even though the study was underpowered (74). There are limited safety data for remdesivir, which should be obtained in further studies.

Ribavirin is a broad-spectrum nucleoside antiviral drug that is phosphorylated in virus-infected cells. Basically, the entry of the product into virus-infected cells leads to its phosphorylation. This product acts as a competitive inhibitor of the viral synthetase, interfering with early viral transcription events and thereby hindering the synthesis of ribonucleoproteins and subsequent viral spread. Several controversial in vitro studies investigating ribavirin have been conducted. While a few of them have demonstrated that ribavirin has an antiviral effect on SARS, others have revealed no evidence of its antiviral role (75, 76). Additionally, a clinical trial reported no significant antiviral effects on SARS-infected patients (77). In fact, the same study reported side effects, such as haemolytic anemia, resulting from the clinical administration of ribavirin (77). During the COVID-19 pandemic, ribavirin combined with interferon was used based on the Chinese treatment guidelines.

The Bacillus Calmette-Guerin (BCG) vaccine against tuberculosis has been demonstrated to reduce mortality during other infections. The protective mechanism involved in tuberculosis infection has been explored in vivo. It was demonstrated that BCG vaccination increased IFN-γ production by CD4+ cells (78). T cells play a crucial role in viral infections; CD4 T cells provide B cell help for antibody production and control the response of other immune cell subsets, whereas CD8 T cells kill infected cells to reduce the viral burden. To better understand the role of T cell responses in SARS-CoV-2 infection, some studies are beginning to be conducted. During SARS-CoV-1 infection, the occurrence of lymphopenia with drastically reduced numbers of both CD4 and CD8 T cells in moderate and severe COVID-19 cases has been described in several current reports (79). Th1 and Th17 cells play a crucial role in the induction of CD4+ and CD8+ memory cells that are involved in the control of the immune system response during non-mycobacterial secondary infections. Interestingly, BCG vaccination continued to increase Th1 and Th17 responses at least 1 year after vaccination in healthy subjects (80). COVID-19 infection severity is associated with a sharp decrease in the frequency of CD4+ and CD8+ cells and the expression of INF-γ on the surface of CD4+ cells (78). The nonspecific effects of the BCG vaccine present a potential therapeutic method to increase memory responses and enhance the immune system during viral infections that might aid in combating the COVID-19 pandemic.