As a widely used antimalarial and immunomodulatory drug, chloroquine (CQ) shows a broad-spectrum antiviral activity. Table 1 summarizes the clinical trials of CQ and HCQ for the treatment of COVID-19. Some researchers indicated that CQ is effective against SARS-CoV-2 virus in early clinical studies (Huang et al., 2020c). Of note, chloroquine phosphate is undergoing some clinical trials regarding prophylactic use in health personnel (Clinicaltrials.gov, NCT04443270) and against infection by SARS-CoV-2 (Clinicaltrials.gov, NCT04344951). Evidence from a multicenter prospective observational study indicated that patients in CQ treatment group have shorter median time to achieve an undetectable viral RNA and shorter duration of fever; also, more importantly, no severe side effects were found during CQ treatment (Huang et al., 2020b). Hydroxychloroquine (HCQ) is an analog of CQ by replacing an ethyl group in CQ with a hydroxyethyl group (Zhou et al., 1878). Nowadays, ChiCTR conducts many clinical trials in China to examine the effectiveness and safety of CQ or HCQ against COVID-19 (Gao et al., 2020). A team from Renmin Hospital of Wuhan University investigated the effects of HCQ among 62 patients suffering from COVID-19 (www.chictr.org.cn, ChiCTR2000029559). As a result, Chen et al. found that HCQ could significantly shorten time to clinical recovery (TTCR) and improve pneumonia.

However, the high-quality clinical data showing a clear and reliable benefit of CQ or HCQ remains limited. Also, the CQ or HCQ treatment could induce severe cardiac side effects, imped innate and adaptive antiviral immune responses, and cause some uncertain effects (Meyerowitz et al., 2020). Commonly, QT prolongation and torsade de Pointes (TdP) occur on patients who are administered with CQ or HCQ (Blignaut et al., 2019). Hence, before CQ and HCQ treatment, an initial cardiac evaluation is necessary for COVID-19 patients (Zhou W. et al., 2020). Also, several follow-up evaluations, such as regular ophthalmological examination and cardiac monitor, are suggested for patients with short- or long-term treatment (Knox and Owens, 1966). Thus, using CQ or HCQ as a COVID-19 treatment was controversial, which results from their ocular, cardiac, and neuro toxicities (Oren et al., 2020; Zou et al., 2020). Additionally, the certainty of evidence is low. Together, we would like to recommend monitoring the accumulative effect of long-term and/or high-dose CQ or HCQ in clinical settings. Also, researchers are not supposed to overstate or understate the clinical efficacy of CQ and HCQ on COVID-19 treatment.

Lopinavir/ritonavir tablets (brand name: Kaletra) are two structurally related protease inhibitors and works as antiretroviral agents (Cvetkovic and Goa, 2003). Table 2 summarizes the clinical trials of lopinavir/ritonavir on COVID-19 treatment. The mechanism of action of protease inhibitors is block cleavage in Gag and Gag-Pol, and result in producing immature and noninfectious virus particles (Adamson, 2012). Similar to CQ, lopinavir/ritonavir could act as potential antiviral agents against SARS in vitro and in patients with SARS infection (Chu et al., 2004). Also, lopinavir/ritonavir has favorable clinical outcome with the Middle East respiratory syndrome coronavirus (MERS-CoV) after MERS reported in 2012 (Mo and Fisher, 2016; Arabi et al., 2018). Evidence from randomized trials indicated that lopinavir/ritonavir might improve outcomes in severe and critical COVID-19 patients, but it may induce mortality (Verdugo-Paiva et al., 2020). Moreover, it is reported that lopinavir/ritonavir could only improve a minority of throat-swab nucleic acid results in hospitals (Liu et al., 2020). Also, Cao et al. revealed that no beneficial response or clinical improvement was observed after treatment with lopinavir/ritonavir in a randomized, controlled, open-label trial with 199 in hospital patients suffering from severe SARS-CoV-2 infection, even though improvement was found for some secondary endpoints (Cao et al., 2020; Stower, 2020). Together, the response of COVID-19 patients with lopinavir/ritonavir is not ideal and unfavorable. As the previous study showed, CQ had more potent effects to patients with COVID-19 than the use of lopinavir/ritonavir; hence, an ongoing clinical trial in China would like to access the effectiveness and safety of CQ and lopinavir/ritonavir for patients suffering from mild or general SARS-CoV-2 infection (www.chictr.org.cn, ChiCTR2000029741). Overall, available data on the anti-SARS-CoV-2 activity of lopinavir/ritonavir are still limited and investigational, thereby the clinical application of lopinavir/ritonavir should be considered and monitored carefully.

Remdesivir (GS-5734, brand name: Veklury), as a nucleotide analog prodrug, is a broad-spectrum antiviral drug that acts on RNA-dependent RNA polymerase (RdRp) and results in premature termination (Tchesnokov et al., 2019; Lamb, 2020). Table 3 shows the summary of clinical trials of remdesivir on COVID-19 treatment. As previously mentioned, Wang et al. showed that the EC₅₀ value of remdesivir is 1.76 μM in Vero E6 cells, which suggests that remdesivir has high effectiveness in the control of SARS-CoV-2 infection in vitro (Wang M. et al., 2020). More importantly, the intravenous remdesivir was administrated to the patient who was the first case diagnosed as SARS-CoV-2 infection in the United States (Holshue et al., 2020). No adverse effects were observed in association with the infusion; also, clinical benefits were found in patients. Another case demonstrated that remdesivir could accelerate recovery time by 4 days, which is a meaningful and optimistic progress for patients and medical systems (Jorgensen et al., 2020). Notably, remdesivir is FDA approved specifically for the treatment of COVID-19. However, as more and more clinical cases were reported, the outcome of remdesivir treatment sometimes cannot achieve the expected effects on COVID-19 patients. Many researchers (Wang Y. et al., 2020) carried out a randomized, double-blind, placebo-controlled, multicenter trial; as a result, Wang et al. found that remdesivir is not associated with statistically significant clinical improvement, even though some patients in the remdesivir treatment group had numerically faster time to improve than those in the placebo group. More importantly, remdesivir treatment was discontinued early due to the adverse events, including, but not limited to, nausea, constipation, and respiratory failure or acute respiratory distress. Overall, the certainty of evidence remains less. Since Nov. 2020, the WHO has issued a conditional recommendation against the use of remdesivir in COVID-19 patients.

The interferons (IFNs) as glycoproteins have broad-spectrum antiviral effects (Lin and Young, 2014). The IFNs can be divided into three types based on the differences in the structures of their respective receptors. In detail, the IFNs are classified into type I IFNs (IFN-α/β), type II IFNs (IFN-γ), and type III IFNs (IFN-λ). Table 4 shows the summary of clinical trials of IFNs on COVID-19 treatment. Mantlo et al. (2020) demonstrated that IFN-α (EC₅₀ = 1.35 IU/ml) and IFN-β (EC₅₀ = 0.76 IU/ml) at clinically achievable concentrations could suppress the replication of SARC-CoV-2 in Vero cells. These findings provide a valuable fundamental for the potential use of IFN-α/β to against COVID-19. Zhou et al. accessed the efficacy of IFN-α2b and arbidol involving 77 hospitalized patients; as a result, researchers revealed that IFN-α2b with or without arbidol could significantly reduce the duration for detectable virus as well as the inflammatory markers (Zhou Q. et al., 2020). Usually, the IFNs are used in combination with other antiviral therapies (Mantlo et al., 2020). Of note, a group from China examined the effectiveness and safety profile of a triple antiviral therapy including IFN-β1b, lopinavir/ritonavir, and ribavirin with 86 patients suffering from mild to moderate SARS-CoV-2 infection (Hung et al., 2020). Their results showed that the triple combination treatment is superior to lopinavir/ritonavir treatment alone with shorter viral shedding duration and hospital stay period.

However, some reports indicated that the application of IFN-λ have more advantages in COVID-19 treatment. The most outstanding profile of IFN-λ over IFN-α/β is the absence of pro-inflammatory effects (Prokunina-Olsson et al., 2020). This is because the response to IFN-λ administration localizes to epithelial cells, which could reduce side effects and inflammatory effects related to the systemic action from IFN-α/β treatment. Also, researchers showed that IFN-λ reduces the presence of virus in the lungs and prevents the induction of cytokine storm; hence, the application of IFN-λ could avoid pneumonia and acute respiratory distress syndrome (ARDS) (Andreakos and Tsiodras, 2020). Overall, IFN-λ is a promising and potential therapeutic agent for patients suffering from COVID-19. Notably, more clinical study is necessary in the future.

Umifenovir (brand name: Arbidol, ARB) is an antiviral drug, which has the ability to inhibit the replication of influenza A and B virus through impeding the early membrane fusion event (Leneva et al., 2009). Table 5 indicates the summary of clinical trials of umifenovir for the treatment of COVID-19. Zhu et al. (2020) accessed the efficacy and safety of lopinavir/ritonavir and umifenovir involving 50 COVID-19 patients, 34 cases with lopinavir/ritonavir treatment, and 16 cases with umifenovir treatment. From the results, no side effects and developed pneumonia or ARDS were observed in both groups. More importantly, patients with umifenovir treatment have shorter duration of positive RNA test compared with those with lopinavir/ritonavir treatment; thus, the authors indicated that umifenovir may be superior to lopinavir/ritonavir against COVID-19. Similarly, Deng et al. (2020) demonstrated that lopinavir/ritonavir combined with umifenovir had more favorable clinical outcomes compared with lopinavir/ritonavir only in a retrospective cohort study. Furthermore, Nojomi et al. (2020) evaluated HCQ followed by lopinavir/ritonavir or HCQ followed by umifenovir among 100 patients with COVID-19. As a result, the researchers found that patients in the umifenovir group had shorter hospitalized duration and higher peripheral oxygen saturation rate, also had improvements in requiring ICU admissions, and chest CT involvement. Moreover, some studies showed that umifenovir was well-tolerated with mild gastrointestinal tract reaction and related to the lower mortality in COVID-19 cases (Jomah et al., 2020).

However, Lian et al. (2020) indicated that umifenovir is not relative to the improved response in non-ICU COVID-19 patients in a retrospective study. In detail, the study included 81 patients suffering from COVID-19, and evaluated several baseline clinical and laboratory factors. Of note, the patients with umifenovir treatment even had longer hospital stay duration than those patients in the control group. Hence, the authors indicated that umifenovir might not improve prognosis or accelerate SARS-CoV-2 clearance in non-ICU patients with COVID-19.

Azithromycin is a macrolide antibiotic medication. Azithromycin binds to the 50S subunit of ribosome, and thereby prevents the mRNA translation and interferes with protein synthesis (Bakheit et al., 2014). Table 6 summarizes the clinical trials of azithromycin on COVID-19 treatment. Gautret et al. (2020) showed that azithromycin could reinforce the effectiveness of HCQ to clear the COVID-19 virus. Of note, the sample size was small, which only involved 20 cases. Also, researchers revealed that azithromycin combined with HCQ, or with lopinavir/ritonavir, could improve the clinical response and accelerate the COVID-19 virus clearance (Purwati et al., 2021). By contrast, Cavalcanti et al. (2020) reported that no improved clinical outcomes were observed in COVID-19 patients, suffering from mild to moderate COVID-19, treated with HCQ alone or with azithromycin compared with those with standard care in a multicenter, randomized, open-label, three-group, controlled trial involving 667 patients. Also, evidence from retrospective observational studies demonstrated that azithromycin in combination with HCQ did not induce favorable clinical outcomes for COVID-19 patients (Echeverría-Esnal et al., 2021).

It has been reported that bacterial coinfection happened in 3.5% of COVID-19 patients (Sieswerda et al., 2021). In other words, the hospitalized patients with COVID-19 have risk of bacterial infections. Sieswerda et al. (2021) recommended that the 5-day antibiotic therapy is required for the COVID-19 patients suffering with suspected bacterial respiratory infection after clinical improvements. However, their recommendation needs to be confirmed because unnecessary antibiotic treatment should be prevented. Also, some studies revealed that bacterial and fungal coinfection would occur in patients with SARS-CoV-2 infection, thereby the antimicrobial treatment regimen and stewardship interventions are necessary to control the exacerbating COVID-19 pandemic (Rawson et al., 2020). More importantly, antimicrobial resistance should be considered as the collateral effect of SARS-CoV-2 infection, and thus, proper trend for antibiotic stewardship interventions should be analyzed and prescribed in the emergency department (Pulia et al., 2020).

To date, most studies regarding stem-based therapy to SARS-CoV-2 infection have focused on mesenchymal stem cells (MSCs) (Choudhery and Harris, 2020). MSC-based therapy has the ability to suppress the cytokine storm by secreting anti-inflammatory, anti-apoptosis, and antifibrosis cytokines. Also, MSCs contribute to antibacterial activity, as well as tissue repair and regeneration (Sadeghi et al., 2020). Table 8 shows clinical trials of MSCs on COVID-19 treatment. For patients suffering from COVID-19, MSCs would repair damaged alveolar epithelial cells and blood vessels, and also prevent pulmonary fibrosis (Chen et al., 2018; Leeman et al., 2019; Zanoni et al., 2019; Afra and Matin, 2020; Li Z. et al., 2020; Golchin et al., 2020). Seven COVID-19 patients who received intravenous transplantation of MSCs had significantly improved pulmonary function in 2 days after transplantation (Leng et al., 2020). Notably, the increased peripheral lymphocytes and IL-10 level, decreased C-reactive protein (CRP) and TNF-α level, and disappeared overactivated cytokine-secreting immune cells were observed within 14 days after MSC injection. Interestingly, Jayaramayya et al. reported that MSC-derived exosomes (MSC-Exo) may be an option to improve the clinical response to COVID-19 patients (Jayaramayya et al., 2020). A phase I clinical trial investigated the use of MSC-Exo inhalation to alleviate COVID-19-induced symptoms (clinicaltrials.gov, NCT04276987). Moreover, MSC-like derivatives have acceptable safety and efficacy for COVID-19 treatment in preclinical and clinical studies (Li Z. et al., 2020).

However, some limitations remain to be considered (Sadeghi et al., 2020). First, some patients with, including, but not limited to, a history of malignant tumor, coinfections of other respiratory viruses, and pregnant woman are not eligible to evolve in clinical trials. Most clinical trials worldwide remain in phase I and II, and comprehensive results are not clear. Furthermore, it is difficult to evaluate the effectiveness of MSC therapy alone when coadministration with other conventional drugs, such as remdesivir or dexamethasone, in many cases. Importantly, the standard therapeutic protocol, such as administration route, dosage, and transplantation frequency, needs to be determined. Nevertheless, the MSC profile on the immune system provides researchers evidence that it may be a good candidate as a combination therapy of infectious diseases such as COVID-19. Overall, MSC-based therapy appears to be a potential and promising therapeutic method to overcome SARS-CoV-2 infection.

Convalescent plasma treatment provides immediate immunity by passive polyclonal antibody administration (Mair-Jenkins et al., 2015). The efficacy of convalescent plasma transfusion may result from viremia suppression (Chen L. et al., 2020). It has reported that convalescent plasma treatment can be used to improve the survival rate on patients with severe acute respiratory syndromes of viral etiology (Mair-Jenkins et al., 2015). Several studies indicated that SARS patients who were treated with convalescent plasma had a shorter hospital stay and lower mortality than those who were not treated with convalescent plasma (Soo et al., 2004; Cheng et al., 2005; Lai, 2005). Table 9 shows the clinical trials of convalescent plasma transfusion on COVID-19 treatment. Based on the findings from recent studies, initiating treatment no later than 5 days may be the most appropriate (Woelfel et al., 2020; Zhao et al., 2020b). Tiberghien et al. (2020) recommend that convalescent plasma administration at the early phases of the disease in patients at high risk of deleterious evolution may reduce the frequency of patient deterioration and, thereby, COVID-19 mortality. Also, close monitoring is necessary to detect any unintended side effects. However, a randomized trial (clinicaltrials.gov, NCT04383535) evolved in 228 COVID-19 patients to evaluate the clinical status after convalescent plasma intervention was added to standard treatment (Simonovich et al., 2021). Unfortunately, no significant differences were found in clinical outcomes or overall mortality between patients infused with convalescent plasma added to standard treatment and those who received standard treatment alone within 30 days. Similarly, an open-label, multicenter, randomized clinical trial (www.chictr.org.cn, ChiCTR2000029757) was performed in seven medical centers with 103 COVID-19 patients (Li L. et al., 2020). The results showed that convalescent plasma therapy in addition to standard treatment, compared with standard treatment alone, did not result in a significant improvement in time to clinical improvement within 28 days. Of note, it is known that other treatments, including antiviral drugs, steroids, and intravenous immunoglobulin, have the possibility to affect the relationship between convalescent plasma and antibody level (Luke et al., 2006). Thus, it is controversial whether it is worthwhile to examine the safety and efficacy of convalescent plasma intervention against SARS-CoV-2 infection in further randomized clinical trials.

An efficacious vaccine is critical to prevent morbidity and mortality caused by COVID-19. There are four categories of COVID-19 vaccines under clinical evaluation, including whole-pathogen vaccines (inactivated vaccines), subunit vaccines, and nucleic acid (DNA and mRNA) vaccines. However, defining and assessing an efficacious vaccine is complex. In the case of SARS-CoV-2 infection, an efficacious vaccine could reduce the likelihood of an infection in an individual, severity of a disease in an individual, or the degree of transmission within a population (Hodgson et al., 2021). The comprehensive understanding of SARS-Cov-2 is unclear and evolving, thereby the outcomes for a COVID-19 vaccine are critically appraised with scientific rigor to understand their generalizability and clinical significance.

Currently, three vaccines are authorized in the United States: Pfizer-BioNTech (Name: BNT162b2), Moderna (Name: mRNA-1273), and Johnson and Johnson/Janssen (Name: JNJ-78436735). Tables 10–12 summarize the clinical trials of these vaccines for the treatment of COVID-19. Of note, people under 12 years old are not eligible to receive vaccine produced by Pfizer-BioNTech, and people under 18 years old are not eligible to receive vaccines produced by Moderna and Johnson and Johnson/Janssen. Kamidani et al. (2021) indicated that children are supposed to have the opportunity to be included in clinical trials in parallel to ongoing adult phase III clinical trials. It is because the development of a pediatric COVID-19 vaccine could prevent disease and alleviate downstream effects including social isolation and interruption in education, thereby enabling children to re-engage in their world. Considering the SARS-CoV-2 variants, evidence from Polack et al. (2020) proved that BNT162b2 is 95% effective against SARS-CoV-2 infection. A 6 months of follow-up evaluation from Thomas et al. (2021) indicated that BNT162b2 has a favorable safety profile and effectively prevents COVID-19 for up to 6 months including the beta variant even though there is a gradual decline in effectiveness. Bernal et al. (Lopez Bernal et al., 2021) reported that the efficacy of the one-shot BNT162b2 vaccine is 30.7% among individuals with the delta variant, while the efficacy is 48.7% among individuals with the alpha variant. The efficacy of two shots of BNT162b2 vaccine is 88.0% among individuals with the delta variant, while the efficacy is 93.7% among individuals with the alpha variant. In other words, as CDC recommendation, vaccination against COVID-19 is the best way to stop the spread of these predominate COVID-19 strains.

Most recently, a COVID-19 vaccine booster emerged to help individuals build enough protection after vaccination. According to the information from Centers for Disease Control and Prevention (CDC, https://www.cdc.gov), individuals who have received their second dose of an mRNA COVID-19 vaccine (produced by either Pfizer-BioNTech or Moderna) for 8 months are eligible to get a booster shot. Currently, for individuals who got Johnson and Johnson/Janssen vaccine, there is not enough data to support getting an mRNA vaccine dose.