key: cord-0727843-ps44te5y
authors: Li, Chang-Xing; Noreen, Sobia; Zhang, Li-Xue; Saeed, Muhammad; Wu, Pei-Feng; Ijaz, Muhammad; Dai, Dong-Fang; Maqbool, Irsah; Madni, Asadullah; Akram, Faizan; Naveed, Muhammad; Li, Jian-Hua
title: A critical analysis of the SARS-CoV-2 (COVID-19) pandemic, emerging variants, therapeutic interventions, and vaccination strategies
date: 2021-12-15
journal: Biomed Pharmacother
DOI: 10.1016/j.biopha.2021.112550
sha: b09d5f94805a31b1d98937fcff8a3b1d1bad7c83
doc_id: 727843
cord_uid: ps44te5y

Coronavirus is a family of viruses that can cause diseases such as the common cold, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS). The universal outbreak of coronavirus disease 2019 (COVID-19) caused by SARS coronaviruses 2 (SARS-Cov-2) has become a global pandemic. The β-Coronaviruses, which caused SARS-CoV-2 (COVID-19), have spread in more than 213 countries, infected over 81 million people, and caused more than 1.79 million deaths. COVID-19 symptoms vary from mild fever, flu to severe pneumonia in severely ill patients. Difficult breathing, acute respiratory distress syndrome (ARDS), acute kidney disease, liver damage, and multi-organ failure ultimately lead to death. Researchers are working on different pre-clinical and clinical trials to prevent this deadly pandemic by developing new vaccines. Along with vaccines, therapeutic intervention is an integral part of healthcare response to address the ongoing threat posed by COVID-19. Despite the global efforts to understand and fight against COVID-19, many challenges need to be addressed. This article summarizes the current pandemic, different strains of SARS-CoV-2, etiology, complexities, surviving medications of COVID-19, and so far, vaccination for the treatment of COVID-19.

The current outbreak of infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is termed coronavirus disease 2019 (COVID-19) [1] . The World Health Organization (WHO) characterized the illness as a pandemic, spreading rapidly and considerably in many people [2, 3] . To date, SARS-CoV-2 has infected the highest number of people, 81+ million (81, 475, 053) , and has been declared a global emergency (pandemic) by the WHO [4] . Unlike epidemics, pandemics are worldwide and can spread over several countries. Previously, the H1N1 influenza outbreak was declared as a pandemic The mode of transmission of COVID-19 outbreak initially was through the animals, after a few initially infected individuals reported from Seafood Market; subsequently, all other transmissions are said to be human to human [6] . Furthermore, the outbreak emerged so rapidly due to transmission from humans to humans that it flew from China to other countries within a few days. There are copious ways through which virus transfers from human to human, i.e., via coughing or sneezing droplets, surfaces of public transport, restaurants, and other public places like toilets, elevators, and bus stops, etc. [7, 8] .

Some therapeutic moieties used previously for viral infections are being tried for COVID-19 patients [9, 10] . New drug candidates are also in the development phase but are subject to certain limitations [11, 12] . More than 80 companies and academic research groups are J o u r n a l P r e -p r o o f currently working on 3,370 registered trials for drug testing and vaccine development for COVID-19, and the Drug Regulatory Authority of Pakistan (DRAP) also approved five clinical studies on COVID-19 patients. Additionally, more than 75 therapeutic agents based on RNAi, recombinant proteins, and peptides are under 600 planned clinical trials [13, 14] , most of them are monoclonal antibodies, and a few are polyclonal antibodies [15, 16] . UK has become the first to approve Pfizer/BioNTech COVID-19 vaccine. Some trials with umbilical cord immunoglobulin G (IgG) and stem cell therapy are at the stage of early development, and researchers are testing them against COVID-19 symptoms; however, the debate continues over the best approach.

In this review, we summarize the historical background and emergence of different SARS CoV variants in 2020, recurrence in 2021, and highlight the evidence for viral recombination between the other coronaviruses (CoVs) present in animal populations, which may have resulted in the evolution and emergence of novel CoVs that are transmissible and lethal to humans. Our primary focus was an outbreak of SARS-CoV-2, etiology, and complications of COVID-19. Finally, we summarize the possible treatment and prevention options, challenges, and future perspectives of COVID-19 in detail.

Human coronaviruses were first identified in the mid-1960s. Until now, seven coronaviruses' types have been documented. Three recent examples of such coronaviruses are SARS-CoV-1, MERS-CoV, and 2019-nCoV, which are involved in the pathogenesis of severe respiratory infections. COVID-19 is manifested by high-grade fever, dry cough, and pneumonia of unknown causes in people with an inadequate immune system [17] . A recent study identified that animal-to-human transmission could be halted more quickly than the transfer from humans to humans [18] . Still, experts warn that the COVID-19 should not be downplayed or J o u r n a l P r e -p r o o f linked to the seasonal flu. Relatively, respiratory disease due to COVID-19 is analogous to severe pneumonia, and in severely ill cases, patients experience difficulty breathing and need to be hospitalized and put on ventilators in some critical cases. Seasonal flu has a mortality rate of 0.1%, while COVID-19 mortality rate so far is >2 %, making it 20 times more lethal than the seasonal flu [19] . People infected with COVID-19 had experienced multiple symptoms, including fever, cough, sore throat, and chest pain, and sputum production.

Additionally, muscle ache, respiratory symptoms, headache, and renal injury are also observed by various research groups working on COVID-19. COVID-19 pandemic is a complex problem, and significant complications of COVID-19 include acute respiratory distress [20] , arrhythmia, shock, acute kidney injury (AKI), or acute renal failure (ARF), acute cardiac injury, liver dysfunction, and secondary infection. A new, bizarre symptom includes pink eye (conjunctivitis), blue-tinged lips, anosmia, confusion, delirium, inability to wake or stay awake, skin rashes, and "Covid-toes [21] .

Historically, the contagious maladies have been considered the highest menace to the community health and resulted in added years of life lost from untimely death than any other malady [22, 23] . In 2005, WHO established an Emergency Committee due to the rapid developments in the appearance of novel contagious diseases with a pandemic perspective.

Within one decade, four severe infectious public health disasters of transnational trepidation have been publicized. The possible reasons behind the amplified frequency of these pandemics might be the snowballing international trade and expedition, interruption of ecosystems from confrontations or economic advances that brings humans into interaction with beforehand unrecognized infectious microbes, and humans are confronted with eternal contagious encounter and an amassed occurrence of pandemic menaces to global health [24] .

Generally, infectious public health hazards are caused by microbes, which are either zoonotic or vector-borne. Since the beginning of the 21 st century, various infectious outbreaks have J o u r n a l P r e -p r o o f occurred; out of these, the most prominent is Ebola [25] , Influenza 

J o u r n a l P r e -p r o o f Almost 50 years ago, HCoV-OC43 and HCoV-229E were recognized, which mainly cause the common cold in humans. HCoV-OC43 was isolated in 1967 from volunteers at the Common Cold Unit in Salisbury, United Kingdom. The nasopharyngeal swab of a patient suffering from common cold was collected, and strain OC43 was isolated from that specimen [45] . Although there is no serological cross-reactivity between 229E and OC43 but HCoV- 

Human Coronavirus HKU1 was discovered in 2005 from patients with pneumonia symptoms in Hong Kong. HCoV-HKU1 was detected from the nasopharyngeal aspirates of patients by RT-PCR of the pol gene of coronaviruses [49] . In another article, Woo et al. reported the discovery of HCoV-HKU1 in January 2005 from nasopharyngeal aspirates of a 71-year-old man who had just come back from Shenzhen, China. This man suffered from pneumonia, and quantitative RT-PCR results showed that the amount of HCoV-HKU1 RNA was 8.5 to 9.6 × 106 copies per ml in his sample [50] . HCoV-HKU1 belongs to species of coronavirus which originated from infected mice and differentiated from other members of the genus betacoronavirus and subgenus embecovirus due to the presence of the hemagglutinin esterase (HE) gene [51] . HCoV-HKU1 coronavirus employed an N-acetyl-9-O-acetylneuraminic acid receptor to enter the host. These are enveloped, positive-sense, single-stranded RNA viruses. J o u r n a l P r e -p r o o f Symptoms related to HCoV-HKU1 are the common cold, asthma, bronchitis, pneumonia exacerbation, and chronic obstructive pulmonary disease (COPD) [52] .

SARS coronavirus is also known as SARS-related coronavirus, and severe acute respiratory syndrome coronavirus (SARS-CoV)-1 transmit the infection to bats, humans, and palm civets [53, 54] . SARS-CoV-1 belongs to the genus beta-coronavirus that infects the epithelial cells within the lungs. ACE2 is the primary human receptor for the attachment of this virus [55] . 

MERS-related coronavirus belongs to genus beta-coronavirus and subgenus merbecovirus. It is the first beta-coronavirus belonging to lineage C that infects humans. MERS-CoV genomes were phylogenetically classified into two clades, clade A and B. Initial cases of MERS were of clade A clusters, while new cases that were genetically distinct belong to clade B clusters [60] . MERS-CoV is initially known as the 2012 novel coronavirus (2012-nCoV) or simply novel coronavirus (nCoV), belong to species of coronavirus which infects humans, bats, and camels [54, 61] . MERS is a respiratory infection caused by MERS CoV first identified in the 2012 outbreak in Saudi Arabia. MERS-CoV infection globally spread to over 25 countries with high fatalities leading to high-level public health threats [62] . It was found that bats were the reservoirs for MERS-CoV, which make it zoonotic, but the humanto-human transmission was also observed. MERS-CoV transmission from camels to humans J o u r n a l P r e -p r o o f SARS-CoV-2 fluctuates from a few hours to a few days based on temperature, humidity, and type of residing surface. SARS-CoV-2 possibly remained viable on plastic and steel for up to 03 days, cardboard surface for 01 days, on copper for 04 hours [79] . SARS-CoV-2 has also been found in stool samples from infected people [80] . 

The variant of concern (VOC) is a variant with indications of higher transmissibility, more severe disease (e.g., more hospitalizations or deaths), considerable reduction in neutralization by antibodies developed after previous infection or vaccination, reduced efficiency of therapies or vaccinations, or diagnostic detection failures [84] .

Another variant, the B.1.1.7 lineage, often termed as 20I/501Y.V1 or VOC 202012/01, was identified by the WHO working evolution group collaborating with UK medical authorities. This strain has been found in the Netherlands, Denmark, and Australia, and it is expected to play a role in the upcoming pandemic [85] . 

Variant having specific genetic markers associated with alterations in receptor binding, lower neutralization by antibodies developed against recent infection or vaccination, the impaired success of treatments, potential diagnostic effects, or projected increase in transmissibility or disease severity. They are classed as such since there is data that they transmit fastly, induce more severe infections, or circumvent previously acquired immunity better than circulating disease variants. Earlier this month, the UK government classified the B.1.617.2 subtype as a variation of concern in the United Kingdom. There has been an increase from 202 to 520 B.1.617.2 infections in just one week [89] .

It is not uncommon for a variety of significant consequences to continue spreading despite  Currently, there are no SARS-CoV-2 variants that rise to the level of high consequence.

While discussing the origin of SARS-CoV-2, it is assumed that bats are the cause of this infection, as the sequences of SARS-related CoVs have been identified in Chinese horseshoe bats. Two bats were found to have the SARS-CoVs with a genomic sequence similar to SARS-CoV-2 than any other virus identified to date. They also act through the same ACE2 receptors as the human coronavirus, confirming that SARS-CoV-2 originated from bats [42] .

The expression of ACE2 is significantly increased in patients with diabetes mellitus and hypertension being treated with ACE inhibitors, which produces an up-regulation of ACE2 receptors. Contrary to initial reports, the American College of Cardiology (ACC) has reported no data to support the claim that ACE inhibitors increase the risk of COVID-19 infection [90] . Human lung epithelial cells are severely infected when the virus attacks the respiratory system. The virus can invade macrophages and dendritic cells but only leads to mild infection [91] . Despite this mild nature of the infection, various pro-inflammatory cytokines and chemokines are activated that may contribute to disease and can be identified in the blood of SARS-CoV-2 infected individuals [92] . The precise mechanism of lung injury and the cause of severe disease in humans is still unknown [93] . The symptoms may appear from 2-14 days after the exposure. Based on current epidemiological findings, the incubation period is 1-14 days and, in some cases, 3-7 days. The virus can spread through direct contact during the incubation period [94] . Most people with robust immune systems recover without treatment, while older people and patients with pre-existing diseases like cardiovascular disease (CVD), diabetes, chronic respiratory disease, and cancer are more prone to develop serious illnesses

A study reported by Rasmussen and co-workers described 23-32% of patients with severe pneumonia were admitted to the intensive care unit (ICU) while 17-29% of patients developed acute respiratory distress [96] . COVID-19 has been classified as mild, moderate, severe, and critical based on clinical symptoms [97] . Mild disease patients suffer from upper respiratory tract viral infection with mild fever, dry cough, sore throat, headache, muscle pain, and nasal congestion. 81% of cases of COVID-19 are mild with no sign of severe disease like dyspnea [98] . Moderate disease patients present with cough, shortness of breath, tachypnea with no severe symptoms. Severe disease symptoms include pneumonia, acute respiratory distress syndrome, sepsis, and septic shock [99] . However, patients also experience a decrease in lymphocytes circulating in the blood [100] . About 5% of severe disease patients develop respiratory failure, septic shock, and multiple organ failure. Data from the Chinese Centers for Disease Control and Prevention (China CDC) [57] suggest that the mortality rate for severely diseased patients is 49% [98] . COVID-19 also has affected pregnant women, and clinical manifestations were the same as in the non-pregnant adults. A clinical case report described 18 cases of COVID-19 infection in pregnant women in the third trimester with symptoms of fetal distress and preterm delivery. Another study of 12 pregnant women reports a 25 % mortality rate. Clinical complications include acute respiratory distress in four patients, three with disseminated intravascular coagulopathy, three with renal failure, and two with secondary bacterial pneumonia and sepsis [96] .

Previous studies reported that SARS-CoV-1 infection caused male infertility. SARS-CoV-2 also binds the same ACE2 receptors as SARS-CoV-1, and the expression of ACE2 is upregulated in testicular cells [101] . The findings suggested that orchitis is the complication J o u r n a l P r e -p r o o f of SARS-CoV-1, and spermatogenesis could be affected after the infection. SARS-CoV-2 also infects children, and clinical data confirmed pediatric patients have mild symptoms.

Current data reports that the mean age of onset in children is from 1.5 months to 17 years, mainly with no fever and pneumonia symptoms. Most pediatric patients recover from the disease within 1-2 weeks [102] .

COVID-19 pandemic is a complex problem, and it should not be considered a single unit but as a heterogeneous group of infections. Several disease-related and patient-related factors are involved in the development of COVID-19. Complications of COVID-19 include acute respiratory distress (ARD) [20] , arrhythmia, shock, AKI, acute cardiac injury, liver dysfunction, and secondary infection. The poor clinical outcome was related to disease severity [103] .

The pathophysiology of unusual high-risk acute respiratory distress syndrome (ARDS) in SARS-CoV-1 or MERS-CoV infection has not been completely understood. Previous studies have indicated that high levels of pro-inflammatory cytokines in serum (e.g., IL6, IL12, IFNγ, IP10, and MCP1) were associated with pulmonary inflammation and extensive lung damage in SARS patients [104] . The progression to ARDS shows worsening of respiratory symptoms and ultimately leads to respiratory failure. ARDS occurs as a complication within 

Levels of aspartate transaminase (AST) and alanine transaminase (ALT) at the time of admission correlate with clinical worsening of symptoms to ARDS. Therefore, higher levels at admission result in rapid respiratory deterioration to ARDS [98] . A research group from China studied the pathological features of a patient who died from severe infection with SARS-CoV-2 by postmortem biopsies. The patient was a 50-year-old man admitted with fever, chills, dry cough, and difficulty breathing. After oxygen therapy, the patient was not stable and died due to sudden cardiac arrest. Biopsy samples were taken from the lungs of the patient. Left lung tissue biopsy showed pulmonary edema and hyaline membrane formation indicative of ARDS. Inflammatory infiltrates of interstitial mononuclear cells were observed in both lungs [105] .

Although ARDS is the main complication of COVID-19, the involvement of other organs needs to be considered. After respiratory infection, the infiltrated virus may go into the bloodstream, accumulate in the kidney and cause damage to renal resident cells. RNAaemia, characterized by a positive result for RT-PCR in the plasma sample, was found in 15% COVID-19 patients. It was reported that 6.7% of patients with SARS in 2003 developed acute renal impairment, and death due to SARS in patients with AKI was 91.7%. Thus, the kidney impairment and outcome in patients infected by SARS-CoV-2, which resembles SARS in 2003, were urgently warranted [106] . A study of Wuhan General Hospital, China, reported that 27.06% of patients with COVID-19 had abnormal glomerular filtration rate (GFR) and patients who are aged or have comorbidities more commonly developed acute renal failure. They performed the autopsy of six COVID-19 subjects and observed renal function. Different degrees of acute tubular necrosis, luminal brush border damage, and vacuole degeneration were found in different areas of all six renal tissue samples. Severe J o u r n a l P r e -p r o o f infiltration of lymphocytes in the tubulointerstitium was seen in two cases, and moderate infiltration was observed in three patients, and the remaining patient showed an absence of lymphocyte infiltration impairment. It is indicated that the SARS-CoV-2 virus can directly infect human renal tubules and, as a result, lead to acute renal tubular injury. Moreover, improved estimated GFR (eGFR) would increase the survival of COVID-19 patients with acute renal failure. Therefore, it is strongly recommended that applying potential interventions, including continuous renal replacement therapies to protect kidney function in COVID-19 patients, particularly for acute respiratory failure (ARF) cases, maybe a key approach to reducing mortality [107] .

With the outbreak of COVID-19, patients with severe infection seem to have higher rates of China, indicate that 2-11% of patients with COVID-19 had liver comorbidities, and 14-53% cases reported abnormal levels of alanine aminotransferase and AST during disease progression [108] . In a study published in The Lancet by Huang and colleagues, the elevation of AST was observed in eight (62%) of 13 patients in the ICU compared with seven (25%) of 28 patients who did not require care in the ICU [109] . Another large cohort, including 1099 patients from 552 hospitals in 31 provinces or provincial municipalities, had more severe J o u r n a l P r e -p r o o f patients with disease and abnormal liver aminotransferase levels than less severe patients [110] . Moreover, patients with liver cirrhosis or liver cancer are at risk of SARS-CoV-2 infection because of their systemic immuno-compromised status. The severity, mortality, and incidence of complications in these patients, including secondary infection, hepatic encephalopathy, upper gastrointestinal bleeding, and liver failure, need to be examined in large-cohort clinical studies.

Patients with severe SARS-CoV-2 infection can develop a coagulopathy state with fulminant activation of the coagulation cascade, resulting in widespread microvascular thrombosis and depletion of coagulation factors. This is characterized by thrombocytopenia, prolongation of the partial thromboplastin time, the elevation of D-dimer, and decreased fibrinogen levels [111] . A study reports a 69-year-old man with a history of hypertension, diabetes, and stroke presented with fever, cough, dyspnea, diarrhea, and the headache were diagnosed COVID-19 on RT-PCR. There were clinically significant coagulopathy and antiphospholipid antibodies in the patient's blood. Patient examination showed ischemia in the lower limbs as well as in the digits of the left hand. Patient laboratory reports indicated leukocytosis, thrombocytopenia, and elevated prothrombin time and partial thromboplastin time with high levels of fibrinogen and d-dimer. Serological test analysis revealed the presence of anticardiolipin IgA antibodies as well as anti-β 2 -glycoprotein I IgA and IgG antibodies. The presence of these antibodies may lead to thrombotic events in COVID-19 patients [112] .

Clinicians have become more concerned that the pandemic will result in many individuals suffering from long-term illnesses and disabilities [113] . The neurological dysfunction is getting worse as the pandemic has progressed. Stroke, brain hemorrhage, and memory loss J o u r n a l P r e -p r o o f have all been added to the list recently. Host defense mechanisms can be activated by cerebrovascular inflammation, which can contribute to neurological disorders [114] . As the pandemic ramped up, many experts, including Alysson Muotri, a La Jolla-based neuroscientist at the University of California, San Diego, Michael, and his colleagues, began accumulating case reports of neurological problems connected to COVID-19 [115] .

A study published in Brain (a Journal of Neurology) suggests that SARS-CoV-2 infection is related to neurological and neuropsychiatric diseases. The patients are separated into five categories based on their clinical, neurological, and laboratory aspects, and the results are summarized. COVID-19 has a broad spectrum of neurological consequences, including CNS disorders such as encephalitis, acute disseminated encephalomyelitis (ADEM) with hemorrhage and necrotic change, transverse myelitis, ischemic stroke, and Guillain-Barré syndrome (GBS). Acute hemorrhagic leukoencephalopathy (AHLE) is a kind of ADEM that requires a decompressive craniectomy [116] . In another study, He and his colleagues analyzed clinical details for 125 persons in the United Kingdom who reported COVID-19related neurological or mental problems in a study published in Psychiatry (The Lancet).

Sixty-two percent had suffered damage to the brain's blood supply, such as strokes and hemorrhages, and 31% had altered mental states, such as disorientation or prolonged unconsciousness, which was occasionally accompanied by encephalitis, or brain tissue swelling. Psychosis developed in ten patients who had changed mental states [117] . In a recent paper, Wan et al. explain typical signs of neurological dysfunctions linked with SARS-CoV-2, including encephalopathy, aphasia, meningitis, prosopoplegia, encephalitis, sensory loss, GBS, dysarthria, skeletal, muscular symptoms, and acute confusion [118] .

To date, several research have looked into the relationship between SARS-CoV-2 and neurological illnesses like schizophrenia [119] , dysphoria [120] , delirium [121] , epilepsy J o u r n a l P r e -p r o o f [122] , depression [123, 124] , bipolar disorder [125] , Alzheimer's disease (AD) [126, 127] , Parkinson's disease (PD) [128] , and obsessive-compulsive disorder (OCD) [129] .

COVID-19 can induce cardiovascular events such as myocardial damage, arrhythmias, myocardial infarction, and pulmonary embolism. Many individuals with coronavirus disease 2019 (COVID-19) have pre-existing CVD or suffer from acute myocardial injury even during illness [120] . Though severe acute pulmonary edema is the hallmark of severe COVID-19 disease, cardiac events can appear in a variety of ways, each posing its own set of treatment problems. Myocardial infarction and right ventricular failure are the most prevalent signs, but heart failure, cardiovascular shock, encephalopathy, arrhythmia, and vascular thrombosis have also been reported [121] . Though severe acute pulmonary edema is the hallmark of severe COVID-19 disease, cardiac events can appear in a variety of ways, each posing its own set of treatment problems. Myocardial infarction and right ventricular failure are the most prevalent signs, but heart failure, cardiovascular shock, encephalopathy, arrhythmia, and vascular thrombosis have also been reported [122] .

The current clinical management of the COVID-19 consists of preventive measures and control of infection and supportive care, including oxygen therapy and mechanical ventilatory support when indicated. [131] . Antibiotics' probable mechanism of action against SARS-CoV-2 infection is depicted in Figure 1 (a) .

Chloroquine has been used globally for more than 70 years as an antimalarial drug, and it is part of the WHO model list of essential medicines. It is less costly and has an approved clinical safety profile. Chloroquine's potential mechanism of action against SARS-CoV-2 infection has been depicted in Figure 1 (b) . Researchers have repositioned chloroquine and hydroxychloroquine as a therapeutic regimen to hunt for new pharmacologic drugs that would be effective against the SARS-CoV-2 virus [132] . A group of Chinese researchers investigated the effect of chloroquine in vitro by using Vero E6 cells infected by SARS-CoV-2. The results indicated that chloroquine was highly influential in decreasing viral replication, with an effective concentration (EC) of 6.90 μM that is easily attainable with standard dosing due to its better penetration in lung tissues. The authors demonstrated that chloroquine blocks virus infection by increasing endosomal pH and interfering with the glycosylation of the cellular receptor of SARS-CoV-1. The authors also speculated that the known immunomodulant action of the drug might improve the antiviral effect in vivo [133] .

Additionally, chloroquine repurposing was investigated in two different hospitals in China.

Preliminary data suggested that approximately 100 COVID-19 infected patients treated with chloroquine showed a more rapid decrease in fever and improved lung computed tomography images [134] . Patients recovered in a short period compared with control groups, with control groups no noticeable adverse severe effects. The Chinese medical advisory board has suggested chloroquine inclusion in the COVID-19 treatment guidelines on seeing these results. As a result, chloroquine is probably the first molecule used in China and abroad as a first-line agent for treating severe COVID-19 infections [135] .

Another Chinese research group conducting multicenter trials on the efficacy of chloroquine in COVID-19 associated pneumonia reported that chloroquine phosphate had proven efficacy and acceptable safety in more than 100 patients enrolled in the trials [136] . According to the risk-benefit ratio, the high security and the low expenditure of chloroquine in the context of the current COVID-19 outbreak make it a suitable candidate in the highly stressed health care system [137] . Hydroxychloroquine (an analog of chloroquine) has been demonstrated to have an anti-SARS-CoV-1 activity in vitro [139] . Hydroxychloroquine's clinical safety profile is better than that of chloroquine (during long-term use) and allows a higher daily dose with fewer concerns about drug-drug interactions. Study results showed that hydroxychloroquine is efficient in clearing a viral nasopharyngeal load of SARS-CoV-2 in COVID-19 patients in only three to six days, in most patients. A significant difference was observed between hydroxychloroquine-treated patients and controls starting even on day 3 post-infection. These results are of great importance because a recent study in China has shown that the mean duration of viral shedding in patients suffering from COVID-19 was 20 days (even 37 days for the most extended duration) [131] . As of March 30, 2020, the US FDA has given emergency approval of antimalarial drugs chloroquine and hydroxychloroquine to treat COVID-19 [140] .

According to the National Health Commission (NHC) of the People's Republic of China guidelines, IFN-α, lopinavir/ritonavir are recommended as antiviral therapy in COVID-19 treatment [141] . Remdesivir may be the best option for treating COVID-19 as it has proven efficacy in treating MERS-CoV compared with lopinavir/ritonavir in animal studies [142] .

On May 7, 2020, remdesivir was approved for use in Japan [143] . The research was conducted on the first Korean COVID-19 patient from China on January 20, 2020. He presented the symptoms of chills and muscle pain. He developed a fever and dry cough on days 5 and 7, respectively. Lopinavir/ritonavir was started on10th day of illness.

Interestingly, viral load started to reduce from the next day of lopinavir/ritonavir administration, and no detectable coronavirus titers have been observed [144] . Another study reported that the ribonucleoside analog, β-D-N4-hydroxycytidine (NHC, EIDD-1931), had shown broad-spectrum antiviral activity against SARS-CoV-2, MERS-CoV, SARS-CoV-1, and other related Bat-CoVs, as well as showed increased efficacy against the coronavirus resistant to any other nucleoside analog inhibitor. In a study, mice infected with SARS-CoV-its potential application as an effective antiviral agent against SARS-CoV-2 and any other zoonotic coronaviruses [145] .

Favipiravir is a member of RNA polymerase inhibitor antiviral drugs. It blocks the replication of RNA viruses by converting them to the active phosphoribosylated form in cells Figure   1(c) . This active form is recognized as a substrate by viral RNA polymerase, thus inhibiting RNA polymerase activity [146] . However, evidence regarding their use in the treatment of COVID-19 is lacking [142] .

Molnupiravir is Covid's first oral antiviral medication to see positive outcomes in clinical trials. Molnupiravir is the first antiviral medicine for Covid that can be taken as a tablet instead of injection, according to Merck, Sharp, and Dohme (MSD) and Ridgeback Biotherapeutics. The UK medicine regulator has given its approval to the first oral treatment designed to treat symptomatic Covid. It will first be administered to both vaccinated and unvaccinated patients in countrywide research, with additional data on its usefulness gathered before any decision to order more. To be most effective, the medicine must be taken within five days of the onset of symptoms [148] . Table 2 .

Corticosteroids are used extensively to treat various respiratory system disorders due to their anti-inflammatory, and immune suppression properties Figure 2 . Despite their established use in respiratory disorders, there is debate over their role in managing respiratory symptoms associated with COVID-19 [150] . Various studies have been conducted on the use of corticosteroids in COVID-19 management and demonstrated a reduction in mortality rate compared to patients who did not receive corticosteroids [151] . Along with their therapeutic potential, corticosteroids use has adverse effects. A study reported immunity suppression and increased viral load, and delayed clearance of coronavirus from the body [152] . [153] . The Oxford RECOVERY Trial tested various therapeutic options, including low dose corticosteroid (dexamethasone), antivirals, hydroxychloroquine, and azithromycin, in a randomized manner. Out of all tested therapeutic moieties, the only dexamethasone succeeded in reducing the COVID-19 associated death rate [154] .

Dexamethasone is an anti-inflammatory and immunosuppressive corticosteroid drug that the FDA has licensed. Dexamethasone has been declared a "significant development" for the COVID-19 in the present epidemic. The use of steroidal dexamethasone has been highlighted as a recent breakthrough in lowering the mortality rate in severe COVID-19 cases [153] .

Early findings showed that this drug could decrease the mortality risk from 40% to 28% in ventilated patients and from 25% to 20% for patients on oxygen therapy. Dexamethasone use did not produce any significant side effects, and use was ineffective in mild COVID-19 cases [155] . The current administration of corticosteroids should be reserved for patients with severe conditions related to cytokine storm, including ARDS, renal failure, acute cardiac injury, and elevated serum levels of D-dimers [156] .

According to the researchers of the latest analysis on using an antidepressant for COVID-19, the medicine significantly lowers hospitalizations and mortality. Selective serotonin reuptake inhibitors (SSRIs) include fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram, escitalopram [157] , and serotonin-norepinephrine reuptake inhibitors (SNRIs) and Dopamine Reuptake Inhibitors, e.g., Bupropion has been used for SARS CoV-2 [158] . The drug, called fluvoxamine, is a medication that is used to treat depression and obsessive-compulsive disorder. It is an SSRI and agonist of the serotonin-1 receptor (S1R) [159] . Fluvoxamine has a J o u r n a l P r e -p r o o f number of potential pathways for treating COVID-19 disease, including anti-inflammatory and antiviral properties Figure 3 . However, it is also known to reduce immunological responses and tissue damage, and researchers attribute its success in the new experiment to these features. COVID-19-related mortality was reduced by about 90% among trial participants who took medicine as advised and did so in the early stages of the condition, while the requirement for intense COVID-19-related medical treatment dropped by roughly 65%. A huge win for medicine repurposing!" Vikas Sukhatme, a drug repurposing researcher at Emory University School of Medicine in Atlanta, Georgia, said in an e-mail to Nature.

Those at high risk of collapse and are unable to receive monoclonal antibodies should be treated with fluvoxamine [160] .

According to the latest clinical-trial results, a low-cost, high-effective, and widely available medicine used to treat mental illness reduces the chance of death from COVID-19 and the demand for patients with the condition to need intense medical care. For this investigation, the research team assessed 9803 potential volunteers. Fluvoxamine was given to 741 participants and a placebo to 756. A randomized, placebo-controlled, adaptive platform trial in Minas Gerais, Brazil, was conducted to see if fluvoxamine could prevent COVID-19 progression and hospitalization in outpatients with laboratory-confirmed SARS-CoV-2. This is only the second trial to indicate that a repurposed medicine had a significant therapeutic benefit in the early treatment population. Fluvoxamine may minimize the risk of clinical deterioration in COVID-19 outpatients, according to a small placebo-controlled, randomized experiment, indicating the need for larger randomized, placebo-controlled research. In highrisk outpatients with early diagnosed COVID-19, treatment with fluvoxamine (100 mg twice daily for 10 days) reduced the requirement for hospitalization, defined as retention in a COVID-19 emergency setting or transfer to a tertiary hospital [161] .

Zimniak et al. discovered that compared to other SSRIs such as escitalopram and paroxetine, fluoxetine has antiviral effects toward SARS-CoV-2. Fluoxetine also stops cytokines from being released. Consequently, the 5-HT reuptake receptor has no relevance to the antiviral effect. The studies state that fluoxetine therapy decreased viral protein expression, signaling that the drug works proximal to gene expression. Fluoxetine successfully suppressed SARS-CoV-2 replication at a dose of 0.8 g/mL, with an EC50 of 0.38 g/mL [162] .

Antidepressants also worked as strong inhibitors of an enzyme called acid sphingomyelinase. This enzyme works by breaking down a few of the fatty molecules on cell surfaces, making them highly susceptible; the COVID-19 virus uses this enzyme to help it invade cells. Hence, the antidepressants effectively prevented the virus from entering [163] .

Besides these, other medical treatments, including benzodiazepines [164] , a potent pan-AKTkinase drug (Capivasertib), have a role in SARS-CoV-2 S protein pseudo-type virus and VSV-dG in Vero cells [165] . Lithium has been demonstrated to: a) impede the reproduction of numerous types of viruses, including ones that are related to the SARS-CoV-2 virus; b) boost the immune response by lowering lymphopenia, and c) fight inflammation via avoiding the cytokine storm [166] . Besides, antiepileptic's include carbamazepine, valproic acid, and gabapentin [158] . Attempts have also been made to evaluate clozapine therapy and its link to an increased risk of COVID-19 infection and severe outcomes [167] .

Current therapy of COVID-19 with the existing practice of antivirals and antimalarial drugs mainly focused on symptomatic treatment and respiratory maintenance. Given the lack of effective antiviral and antimalarial therapy against COVID-19, researchers have stressed the need for novel development and manufacturing platforms that can be readily adapted to this J o u r n a l P r e -p r o o f new pathogen. So, we would need a system that links genotype to phenotype to keep up with the sequence data generation. In pharmaceutical research, everything takes time, and it takes longer if you have to start from zero. Several platforms are under development for COVID- 19 . Vaccine development is a lengthy, expensive process. Attrition is high, and it typically takes multiple candidates and many years to produce a licensed vaccine [168] . As reported by the WHO, vaccines are one of the most effective ways to prevent diseases by boosting the body's immune system to defend the body against infectious pathogens like bacteria and viruses.

The projections on the surface of COVID-19 enable the virus to enter human cells. In developing a vaccine that targets SARS-CoV-2, scientists are looking at these projections intensely. In creating a vaccine for SARS-CoV-2, scientists need to find a viable antigen to stimulate the body's immune system against the infection. Many companies worldwide are working on a SARS-CoV-2 vaccine, developing different ways to boost the immune system summarized in Table 3 . Adjuvants are also employed for elderly patients to amplify their immune system, and it is expected that by studying adjuvants to boost a vaccine, the elderly can be vaccinated with a mix of ingredients that would supercharge their immunity [169] .

For the development of vaccines, various technologies are being used, both well-known and brand new for human vaccines, such as viral vector vaccine, protein-based vaccine, virus vaccine, and nucleic acid vaccine.

Inserting a pathogen protein gene into another virus can infect a person without producing disease. The safe virus serves as a platform or "vector" to deliver the protein that stimulates an immune response. The safe virus is then administered as a vaccination. Some organisms replicate (reproduce) in the body, whereas others do not.

J o u r n a l P r e -p r o o f

Like a vaccination, a pure protein is taken from the virus (either living or inactivated).

Coronaviruses use this protein as their "spike" in just the same way as virus-like particles.

Hepatitis B, shingles, and other viral illnesses can be prevented with protein vaccinations that have been in use for decades. As a means of eliciting an immune response, these vaccines deliver proteins, together with immunotherapy that stimulate the immune system of the body, straight to the cells of a person. [170] 

In this technique, a virus is chosen, changed (weakened), or inactivated totally to prevent disease transmission.

This is a new techniqueno other vaccinations for human use have employed thisand it's less stable than DNA. It is possible to use nucleic acid rather than just the virus, protein antigen, or virus that expresses protein. DNA plasmid: penetrates the nucleus, is translated to mRNA for protein expression, and injected or mRNA [171] .

Traditional Chinese remedies (TCM) have a key role in preventing and controlling COVID-19, with a successful cure rate. TCM includes decoctions, Chinese patent medicine, acupuncture, and other characteristic therapies that can reduce inflammation and alleviate immune response by regulating immune-related pathways and cytokine action-related pathways [172, 173] . Ideally, SARS-CoV-2 infection can be stopped by the blockade of ACE2, and fortunately, TCM-derived compounds could interact with ACE2 receptors, i.e., protease), which are very effective against SARS [177] . Additionally, baicalin, a Chinese herbal compound, also had anti-SARS activity (123) . Water extract of most TCM such as Houttuynia cordata (also known as fish mint, fish leaf, rainbow plant, chameleon plant, heartleaf, fish wort, Chinese lizard tail, or bishop's weed) exhibits several antiviral mechanisms against SARS by inhibiting the viral 3CL protease and also by blocking the viral RNA-dependent RNA polymerase activity [178] . In a study, Luo and colleagues have reported 10 most commonly used Chinese herbs that played a substantial role in the fight against COVID-19 to consist of; Astragalus membranaceus, Atractylodis Rhizoma, Agastache rugosa, Cyrtomium fortune, Fructus forsythia, Glycyrrhizae uralensis, Lonicerae Japonicae Flos, Rhizoma Atractylodis Macrocephalae, Radix platycodonis, and Saposhnikoviae divaricate [179] . Another research reported that the most frequently used Chinese herb, licorice root, which contains glycyrrhizin, potently inhibits the replication of SARS viruses [180] . Though there are scads of publications on TCM treatments for SARS J o u r n a l P r e -p r o o f yet HNC's guideline did not recommend TCM products owing to the shortage of safety data and trials [181] . Toxicological studies are also insufficient for Chinese herbal medicines, yet some reported that some herbs used in TCM contain nephrotoxins and mutagens [182, 183] .

To date, 05 ongoing clinical trials of COVID-19 drugs have not demonstrated positive results, as reported by Global Data [184] . Thus far, hydroxychloroquine or chloroquine is one of the most prominent examples that recently failed to benefit hospitalized patients, and even developed side effects in a retrospective study (Phase II clinical trial). Patients treated with hydroxychloroquine also had a higher mortality rate in clinical trials. In the US clinical trials, Patients treated with hydroxychloroquine also had a higher mortality rate [185] . The other clinical trial drug is darunavir (HIV treatment) and cobicistat (phase III clinical trial) for COVID-19 pneumonia. These trials have the expected end date of August 31, 2020."Pharma company Johnson & Johnson claimed that darunavir presented no evidence of activity against the COVID-19 testing thus far [186] . Additionally, WHO also discontinue the trials of lopinavir/ritonavir for the treatment of COVID-19. These drug trial results show little or no reduction in the mortality of hospitalized COVID-19 patients when compared to the standard of care [187] . Remdesivir (antiviral drug) also reported failure in its first randomized clinical trial and was halted early due to poor statistical acceptance [188] . However, this does not spell the end of the road for the drug discovery towards COVID-19 treatment, and many ongoing trials will offer a clear representation of therapy soon. 

The authors report no conflicts of interest. [134, [199] [200] [201] [202] J o u r n a l P r e -p r o o f Jian-Hua Li: Supervision. The group of people is working on different articles and their names have been added and deleted by mutual consent based on their contribution to this and other articles. All the added authors made a significant contribution to the interpretation of the data and drafting the manuscript and/or revising it critically for intellectual content. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

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