Pandemic coronavirus disease (COVID-19): challenges and a global perspective

The technology-driven world of the 21st century is currently confronted with a major threat to humankind in the form of the coronavirus disease (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). As of April 22, 2020, COVID-19 has claimed 169, 006 human lives and had spread to over 200 countries with more than 2,471,136 confirmed cases. The perpetually increasing figures associated with COVID-19 are disrupting the social and economic systems globally. The losses are unmatched and significantly higher compared to those from previously encountered pathogenic infections. Previously, two CoVs (SARS-CoV and Middle East respiratory syndrome-CoV) affected the human population in 2002 and 2012 in China and Saudi Arabia, respectively. Based on genomic similarities, animal-origin CoVs, primarily those infecting bats, civet cats, and pangolins, were presumed to be the source of emerging human CoVs, including the SARS-CoV-2. The cohesive approach amongst virologists, bioinformaticians, big data analysts, epidemiologists, and public health researchers across the globe has delivered high-end viral diagnostics. Similarly, vaccines and therapeutics against COVID-19 are currently in the pipeline for clinical trials. The rapidly evolving and popular technology of artificial intelligence played a major role in confirming and countering the COVID-19 pandemic using digital technologies and mathematical algorithms. In this review, we discuss the noteworthy advancements in the mitigation of the COVID-19 pandemic, focusing on the etiological viral agent, comparative genomic analysis, population susceptibility, disease epidemiology, animal reservoirs, laboratory animal models, disease transmission, diagnosis using artificial intelligence interventions, therapeutics and vaccines, and disease mitigation measures to combat disease dissemination.


Introduction
The ongoing global threat, declared a pandemic by the international health agencies, originated from the novel coronavirus (CoV) and named as the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [1]. A live animal market in the Hubei Province of Wuhan in Mainland China was identified as the hotspot of this outbreak [2]. The outbreak was suspected when a cluster of patients started admitting the local health care facilities with complaints of fever, cough, dyspnea, and fatigue, resembling symptoms common to viral pneumonia [3].  Major events starting from the first report of novel CoV from Wuhan, China, the declaration of COVID-19 as a worldwide pandemic by the WHO, and the situation as on April 11 th , 2020, has been depicted in the timeline format.
As per the WHO observations, the COVID-19 epidemic has peaked and plateaued between January 23 rd and February 2 nd , 2020, in China, and then followed a declining trend, paving a path for the elimination of the epidemic. However, the WHO has simultaneously stated that other countries are reporting a continuous increase in the number of cases, with the USA reporting the highest increase in daily deaths (n = 37,602). The definitive origin of the SARS-CoV-2 remains undetermined.
However, initial estimations implicate Wuhan as the epicenter and the live animal seafood market as the source of this outbreak, owing to the involvement of animals [10]. The postulation was primarily based on the significant genomic similarity between SARS-CoV-2 and bat or pangolin CoVs. The first patient to be reported in Wuhan did not visit the seafood market, and molecular dating analyses of SARS-CoV-2 genomic sequences suggest its origin in late November [11,12]. These findings raised specific questions pertinent to the COVID-19 epidemic and the Wuhan seafood market. The wellestablished human transmission in the outbreak emphasizes the likelihood of better adaptability of the virus in transmission dynamics [3,11,13].
The events leading to the emergence of a virus capable of infecting a new host have occurred previously in the case of CoVs [14]. Earlier reports suggested the emergence of the SARS-CoV by recombination between bat SARS-like CoVs, followed by mutations in civet CoVs prior to its spillover. Similarly, the Middle East respiratory syndrome (MERS)-CoV also circulated and acquired mutations in camels for approximately 30 years before the incidence of MERS in the Middle East [15,16], indicating the adaptation of CoVs to different hosts before their spillover to humans [17]. The SARS-CoV-2 is suggested to be a chimera of two different viruses, a bat-CoV (RaTG13) and a pangolin-CoV [18].
Researchers have put forth their best efforts in developing effective treatments and vaccine candidates, and have succeeded to a significant extent in identifying several repurposed drugs and vaccine candidates. However, many such treatment options are in the different stages of pre-clinical and clinical development. To date, no approved, effective antiviral agent or vaccine against SARS-CoV-2 is available for human use. The development of next-generation effective diagnostics has undergone a great leap. This review highlights the significant progress made in the measures for the resolution of the COVID-19 pandemic using virus genomic analysis, assessment of global epidemiological trends, transmission patterns, the present-day status of therapeutics, and public health preparedness plans for controlling the wider dissemination of the disease.

Previous human CoV epidemics
Usually, infections caused by the Betacoronaviruses are mild to asymptomatic in nature [19,20]. Since the first report of CoV in 1960's, humans are affected by CoV infection. To date, six strains of CoVs, causing mild to severe respiratory illnesses in humans, have been identified [21]. Of these, four CoVs (HCoV-NL63, HCoV-229E, HCoV-OC43, and HCoV-HKU1) cause mild symptoms in humans. Contrarily, two outbreaks of severe respiratory illness due to the zoonotic transmission of CoVs were noted in humans, namely the severe acute respiratory syndrome (SARS) and MERS.

SARS-CoV
The first incidence of SARS-CoV was reported on November 16 th , 2002, in the coastal Guangdong province of southeast China bordering Hong Kong and Macau. This infection spread across 31 countries at a moderate speed. The virus was predicted to originate from bats and civet cats with animal-to-human (zoonotic) and human-to-human modes of transmission (Table 1). A winter season predilection was also noted in the pattern of this epidemic. After adopting strict public health measures consisting of quarantine and lockdown of air traffic, the disease could finally be contained by July 5, 2003 [22]. During this period, the SARS-CoV infected 8,422 people and caused 916 deaths at a CFR of 10.87%. Since then, the SARS-CoV infection has phased out, and the outbreak was managed.

MERS-CoV
Since the first occurrence of MERS in Saudi Arabia in June 2012, sporadic cases are still reported, primarily in the Arabian Peninsular region, and MERS has spread to more than 27 countries worldwide. Notably, the CFR in MERS is the highest (34.77 %) among all CoVs. To date, it has infected 2,496 people with the death of 868 patients. The disease was primarily restricted to Saudi Arabia, followed by the UAE and the Republic of Korea (Table 1). A few travel-related cases have been reported in Europe in individuals with a travel history to the Arabian Peninsular countries. The source of viral origin was traced to bats, and the camels were the intermediate host for the virus, which followed animal-to-human (zoonotic disease) and human-to-human mode of virus transmission [19,23].

Novel coronavirus (SARS-CoV-2)
The in the 5′-UTR were more identical to that of SARS-CoV than to the bat SARS-like CoV; however, the 3′-UTR was more conserved compared to other related Betacoronaviruses [26].  Figure 2. At the genomic level, the sequence homology of SARS-CoV-2 with MERS-CoV is lower (50-51.8%) than that with SARS-CoV (79%) [32]. Phylogenetically, the SARS-CoV-2 is most similar to the bat SARS-like-CoVZC45

Supplementary
concerning most genes [33,34]. Even at the amino acid level, the SARS-CoV-2 is relatively similar bat SARS-like-CoVZC45, although there exist certain notable differences. For example, the 6, 7b, and 10 proteins are present in SARS-CoV-2, whereas these are absent in bat SARS-like CoVZC45. Compared to the SARS-CoV, the sequence for 8a is absent in the SARS-CoV-2 genome; the sequence for 3b is shorter, while that for 8b has an extra 73 amino acids in SARS-CoV-2 [29].  The trimeric spike (S) glycoprotein, the most important determinant of host tropism and transmission capability, is functionally composed of two subunits, the S1 (receptor binding) and S2 (cell membrane fusion) [33,35]. The SARS-CoV-2 S2 subunit is comparatively conserved and closely related to that in bat SARS-like-CoVZC45, while the S1 subunit had only 70% identity with that of bat SARS-like-CoVZC45 [26,34]. During infection, the S protein is proteolytically processed by host cell proteases at the S1/S2 cleavage site, and following cleavage, the S protein is cleaved into the Nterminal S1 subunit and C-terminal S2 subunit. The S1 subunit comprises a signal peptide, an Nterminal domain, and a receptor-binding domain (RBD). In contrast, the S2 subunit comprises a conserved fusion peptide, a second proteolytic site (S2'), followed by an internal fusion peptide, heptad repeats 1 and 2, a transmembrane domain, and a cytoplasmic domain [36]. The cleaved S protein remains in the metastable pre-fusion conformation [37,38]. After the virus enters the host cell, a second cleavage (at the S2' cleavage site) occurs for membrane fusion, mediated by the endolysosomal proteases [33]. Since furin is highly expressed in the lungs, the furin-like cleavage sites (S1/S2 and S2') appear to be critical for the activation of the S protein and, therefore, for the efficient entry of virus [36,39]. On comparing these sites, we observed a typical furin-like cleavage site rich in basic amino acid residues (SPRRARSVAS) in SARS-CoV-2 that is absent in bat SARS-like-CoVZC45

CoV receptors
Host cell receptors and viral surface glycoprotein/ligand binding serve as the most important determinants of host range, cross-species transmission, and antiviral targeting inventions [41,42].
CoVs can infect a wide range of host species, including humans, animals, and birds (Table 2). CoVs from four genera recognize at least five different receptors and, therefore, exhibit an intricate host receptor recognition pattern. The differential usage of host receptors by different CoVs indicates the structural diversity in the RBDs of the S glycoprotein. However, CoV infections in humans are primarily driven by interactions between envelope-anchored spike glycoprotein (S protein) of CoV and the host cell receptor, the angiotensin-converting enzyme 2 (ACE2) [43,44]. Viruses from the same genus can recognize different receptors (for example, SARS-ACE2 and MERS-DPP4), while CoVs from different genera can bind to the same receptor as well, such as ACE-2 (HCoV-NL63 and SARS). The key features of the external subdomain of RBDs need to be investigated further to elucidate its role in receptor usage, transmission, and pathogenesis of SARS-CoV-2.

SARS-CoV-2 surface persistence/susceptibility
With the exponential increment in SARS-CoV-2 cases globally, the non-availability of effective and specific antiviral treatment, and the lack of specific vaccines, the prime focus has been on minimizing contact with infected persons, asymptomatic carriers, or contaminated surfaces to contain the spread of the virus. Given this, we reviewed the available literature on viral persistence on different contaminated surfaces that we commonly come in contact with daily. The SARS-CoV-2 has been shown to persist in aerosols for up to 3 hours, with a decline in the infectious virus titer from 10 3.5 to 10 2.7 TCID50 per liter of air [45]. Meanwhile, the SARS-CoV-2 was found to be retained more stably on plastic and stainless steel and could retain infectivity for up to 72 hours when present on these contaminated surfaces. However, the infective titer reduced significantly from 10 3.7 to 10 0.6 TCID50 on plastic surfaces and from 10 3.7 to 10 0.6 TCID50 on stainless steel surfaces. On copper surfaces, both SARS-CoV-2 and SARS-CoV-1 were rendered non-viable after 4 and 8 hours, whereas on cardboard surfaces, no viable viruses were detected after 24 and 8 hours, respectively [46]. Other CoVs, such as MERS-CoV, remained viable for up to 48 hours on plastic and stainless steel surfaces [47]. A limited number of low pathogenicity human CoVs, such as the HCoV-229E and HCoV-OC43, were found to be viable from 2-9 hours up to 6 days on different surfaces such as aluminum, glass, plastic, PVC, silicon rubber, latex gloves, ceramic, and Teflon [48][49][50].
Owing to the significant number of COVID-19 cases worldwide and the lack of effective remedies for this disease, the WHO is constantly endorsing and promoting better personal hygiene practices. Social distancing and self-isolation are being encouraged to contain the spread of the virus.
Therefore, the WHO recommended two hand rub formulations based on ethanol and 2-propanol [51].
Such alcohol-based hand rub formulations were found to be effective in inactivating the SARS-CoV-2 [52].

Phylogenomic analysis of SARS-CoV-2 and related CoVs
We analyzed the spike gene sequences (n = 38) of SARS-CoV-2, which were retrieved from the NCBI database. The spike gene sequences of CoVs representing different subgenera of Betacoronavirus, including the SARS-CoV and MERS-CoV, were also retrieved. Based on the BLASTn analysis, certain strains similar to bat SARS-like-CoVs and bat-CoVs were also included in this analysis. The nucleotide and amino acid percent similarities between these CoVs were calculated using the MegAlign software from DNASTAR. The phylogenetic analyses of spike genes from different CoVs were conducted using the GTR + G substitution model and the Maximum Composite Likelihood method. The tree was visualized using iTOL, an online tree visualization tool [53].
The whole-genome sequence of SARS-CoV-2 derived from isolates from different countries showed a high similarity of 99 to 100% at both nucleotide and amino acid levels, suggesting the stability of the viral genome. To determine the similarity index between SARS-CoV-2 and other members of Betacoronavirus, we analyzed the spike protein sequences of all subgenera. The reference SARS-CoV-2 strain (Wuhan-Hu-1/NC_045512) was closely associated with a bat-CoV (RaTG13) from Yunnan, China, with 93.1 and 97.67% nucleotide and amino acid sequence similarity, respectively (Table 3). A pangolin-CoV strain MP789 from China also had a similarity index of 89.7 and 89.78% in nucleotide and amino acid sequences with the reference strain, respectively. Besides, two bat SARSlike-CoVs (bat-SL-CoVZC45/MG772933 and bat-SL-CoVZXC21/MG772934) were also closely related to the novel SARS-CoV-2 ( Table 3).
The clustering of SARS-CoV-2 with the bat and pangolin CoVs provided evidence of its possible origin from these animals. Another member of the subgenus Sarbecovirus, the SARS-CoV, was distantly related to the SARS-CoV-2 (Table 3).  Figure 4).

Epidemiology of SARS-CoV-2 infection
The Wuhan seafood market in China was implicated as the epicenter of the COVID-19 pandemic, and China was marked as the index country. Seven cases of pneumonia of unknown etiology were reported in Wuhan from December 8 th to 18 th , 2019. The first cluster of such patients was identified on December 21 st , 2019. Pneumonia of unknown etiology is defined as an illness without an identified causative pathogen that fulfills the following criteria: fever (≥ 38 °C), radiographic evidence of pneumonia, low or average white-cell count or low lymphocyte count, and no symptomatic improvement after antimicrobial treatment for 3 to 5 days following standard clinical guidelines [11,54]. The patients presented with a severe acute respiratory infection, with some developing acute respiratory distress syndrome (ARDS) and associated complications [55].

Transmission
The information about the mode of transmission of SARS-CoV-2 is limited and continuously evolving. Transmission primarily occurs via the person-to-person route through respiratory droplets (>5-10 μm in diameter) and fomites. Droplet infection is associated mainly with coughing, sneezing, and talking to an infected person, and the virus is transmitted to humans through direct contact with mucus membranes. Transmission can also occur by touching an infected surface, followed by contact with eyes, nose, or mouth. The travel range of the droplets is less than six feet (approximately two meters), and these are not retained in the air for long. Satisfactory evidence of the airborne transmission of SARS-CoV-2 remains unavailable [45]. Although clinically infected patients readily transmit the virus [14], asymptomatic infected patients can also transmit the virus, and therefore, these carriers should be tested to effectively contain the spread [11,56,57].
There is evidence of intestinal infection from SARS-CoV-2, and subsequent excretion through feces [56,58]. In China, out of ten pediatric COVID-19 patients without respiratory symptoms, eight were positive for fecal SARS-CoV-2 shedding; however, the nasopharyngeal samples from these subjects tested negative for the virus [59]. These findings were further supported by a study in which the virus was successfully cultured from feces samples [59,60]. However, there have been no reports of fecal-oral transmission of SARS-CoV-2 to date. Some reports also suggested SARS-CoV-2 infection in newborns; however, there is no evidence for vertical transmission or intrauterine infection in a COVID-19 patient during the late pregnancy stage [55].

Incubation period
The incubation period for SARS-CoV-2 ranged from 2 to 14 days in human-to-human transmission, while, in some cases, it extended up to 24 days [57]. However, a median incubation period of 5-6 days has been reported by the WHO recently [61].

Basic Reproduction number (R0)
The basic reproduction number plays a pivotal role in infectious disease epidemiology and indicates the risk a pathogen carries with respect to its spread. In other words, R0 provides information about the transmissibility of a virus and represents the number of new infections originating from an infected individual in a population. A recent comparison of different studies on the estimation of R0 for COVID-19 revealed that the estimated mean R0 for COVID-19 is 3.28, with a median of 2.79, which is higher than the WHO estimate of 1.95 [62]. However, considerable variability was noted owing to the use of different methods, insufficient data, and short onset time of the disease.

Population susceptibility
There is no age limit for vulnerability to SARS-CoV-2 infection. However, cases with higher morbidity and chances of mortality have been reported in older adults. Individuals above 65 years of

Socio-economic impact
The

Clinical Profile
CoVs include viruses infecting humans and other animal species such as birds, camels, cattle,

Clinical Pathology
Based on the time of occurrence and intensity of symptoms, the infection has been categorized into three stages; mild, severe, and critical stage [69,70]. In the mild stage, mild pneumonia/no pneumonia develops, although symptoms of upper respiratory tract viral infection marked by mild fever, dry cough, sore throat, nasal congestion, malaise, headache, and muscle pain prevail [71]. In severely affected patients, the rate of respiration is above 30/min due to dyspnea, respiratory symptoms such as cough and shortness of breath or tachypnea are common, oxygen saturation in the blood is below 93%, indicating hypoxia, and these developments are observed within a time period of 24-48 hours. The critical stage is marked by symptoms such as severe pneumonia, septic shock, respiratory failure, cardiac arrest, and/ or multiple organ failure, which may eventually lead to the death of the patient [72,73].
Radiological images indicate that two to five lobes of the lungs may be affected. The most common and pronounced lesions are marked by patchy ground-glass opacities and patchy consolidation in the mid, external, and sub-pleural areas of the lung [74]. A chest radiograph, computer tomographic (CT) scan, and/ or lung ultrasound indicate the presence of bilateral opacities [55,75,76]. Thoracic CT scan imaging depicted bilateral ground-glass opacity and bilateral multiple lobular and sub-segmental areas of consolidation [77][78][79]. The pathological image of a COVID-19 patient presented bilateral diffuse alveolar damage with cellular fibromyxoid exudates. The cytopathic effects were marked by the presence of interstitial mononuclear inflammatory infiltrates, with a majority of lymphocytes and multinucleated syncytial cells along with atypical enlarged pneumocytes containing large nuclei and amphophilic granular cytoplasm in the intra-alveolar spaces. In some infected patients, microvascular steatosis and mild lobular and portal activity were recorded in hepatic tissues, while interstitial mononuclear inflammatory infiltrates were d in the cardiac tissues [8].

Immunopathobiology
Existing literature documents that patients suffering from severe SARS-CoV-2 infection might suffer from the cytokine storm syndrome that could eventually lead to death [80,81]. In a viral infection, cell-mediated immunity is triggered to overcome the infection; however, owing to the overproduction of cytokines, interferons, and other factors, such events can have drastic effects in certain patients [82]. Evidently, respiratory failure due to the ARDS is the leading cause of mortality, and apart from this, secondary hemophagocytic lymphohistiocytosis is also induced in a limited Increasing evidence suggests that fatalities resulting from SARS-CoV-2 infection could be primarily attributed to the ARDS [88,89], which may be associated with comorbidities and followed by multiple organ failure, leading to death [90]. ARDS is an immunopathological feature common to SARS-CoV-1, MERS-CoV, and the more recent SARS-CoV-2 infections [87,91]. CoV-2 infection [89,[91][92][93][94][95]96]. In this context, the increased levels of IL-6 were considered a reliable indicator of poor prognosis in the severe stage of the disease [96]. The cytokine storm triggers a severe attack by the immune system on the lung and the body, inducing ARDS and multiple organ failure, and finally leading to death in severe cases of SARS-CoV-2 infections, similar to that in SARS-CoV and MERS-CoV infections [87,92]. A recent study also supported the proposition that the SARS-CoV-2 acts on lymphocytes and leads to a cytokine storm and a series of immune dysregulation events in the body [92,93,95].

Identification of animal reservoirs or intermediate host(s) and the evolution of SARS-CoV-2 is
critical to our understanding of the molecular mechanism underlying interspecies transfer, and hence, devising effective control measures to prevent its further spread.
The preliminary whole-genome analyses of SARS-CoV-2 denoted a high genetic identity (96.2%) with a bat (BetaCoV/bat/Yunnan/RaTG13/2013) virus, detected in Rhinolophus affinis in the Yunnan province of China [97], leading to speculation that bats might act as a possible reservoir host.
Notably, the homology modeling studies of RBD of SARS-CoV-2 suggest that it has a structure similar to that of SARS-CoV RBD, with few differences in the key residues at the amino acid level [33]. Another study based on synonymous codon usage bias suggested snakes as an intermediate host; however, this virus has not been detected in any snake species yet [98]. Later on, pangolins were found to be a potential intermediate host. The recent detection and whole-genome sequence analysis of the SARS-CoV-2 from Malayan pangolins indicated a sequence identity of 85.5 to 92.4% with pangolin SARS-CoV-2, which is lower compared to that with bat CoV RaTG13 (96.2%). However, the RBD of the S protein from pangolin SARS-CoV-2 exhibited 97.4% amino acid similarity to that of SARS-CoV-2, higher compared to that of RaTG13 (89.2%) [99]. Furthermore, the SARS-CoV-2 RBD shares five identical key residues with that of pangolin-CoV, while it shares only one residue with that of RaTG13 [99]. This finding suggests that pangolins may act as a potential intermediate host.

However, studies suggesting bats as a reservoir host and pangolins as an intermediate host for SARS-
CoV-2 need to be investigated further.
The susceptibility in different animals has recently been evaluated through an experiment on SARS-CoV-2 infection, where SARS-CoV-2 was found to replicate efficiently in cats and ferrets, while it replicated poorly in pigs, dogs, chickens, and ducks [100]. Viral transmission via respiratory droplets was also noted in cats in this study. A dog and a tiger tested were reported to test positive for the SARS-CoV-2 [101]. of SARS-CoV-2 transmission from pet animals to the human population; however, further investigation is warranted

Animal models in SARS-CoV-2 research
There is an ongoing search for a suitable animal model to study SARS-CoV-2 infection [102].
After the SARS outbreak, numerous inbred mouse strains were evaluated as models for the SARS-CoV disease with varying levels of results [103][104][105]. The genetically engineered mouse model, known as the humanized ACE2, was developed in response to the SARS outbreak; this model could be infected by SARS-CoV-2 and develop mild pneumonia. The other promising animal models for SARS-CoV-2 vaccine research could include hamsters and monkeys [106]. Recently, ferrets have been identified as an infection and transmission animal model for studying the SARS-CoV-2; this finding may facilitate the development of SARS-CoV-2 drugs and vaccines [107].

Sample collection
For However, depending upon available resources, certain modifications can be incorporated in the Standard Operating Procedures to minimize the risk. Lately, saliva samples have been found to test positive for SARS-CoV-2 in 91.7% of the symptomatic cases, and a declining trend in viral load has also been reported. This finding is of immense importance as the collection of saliva is a non-invasive technique, requiring less stringent conditions, and this can also be used as a screening tool [112].
Zhang et al. used anal swabs in addition to respiratory samples and found a higher number of positive cases using anal swabs than respiratory swabs, especially in the later stages of infection [60].

Diagnostic technologies
Sensitive and specific diagnostic methods are always preferred, especially in cases of epidemics or pandemics, for rapid and accurate diagnosis of viruses. Molecular (RT-PCR) assays are fast, highly sensitive, and specific, and are gradually replacing the conventional methods. worldwide [113]. Among these, 22 kits have already been assigned for emergency use authorization (EUA) by the U.S. Food and Drug Administration (FDA). The details of the selected kits are provided in Table 4. Table 4. A summary of selected molecular diagnostic tests that received emergency use authorization (EUA) from regulatory bodies. rapid point-of-care tests (POCTs) can act as a breakthrough in the current scenario [114]. In this context, a recent breakthrough in COVID-19 diagnosis was marked by the Xpert® Xpress SARS-CoV-2 test (an RT-qPCR test) developed in the USA and reported as a rapid diagnostic test that provides result in 45 minutes. Moreover, it is an automated POCT with EUA from the FDA and enables the detection of the SARS-CoV-2 in the nasal wash, nasopharyngeal swab, and aspirated samples [115]. technique has been used to diagnose COVID-19 in less than an hour without using multiple instruments [117]. A study employed the combination of RT-PCR, CRISPR, and metagenomic nextgeneration sequencing (mNGS) for the detection of SARS-CoV-2 and confirmed the effective clinical diagnosis of COVID-19 [118].

Artificial intelligence in COVID-19 diagnosis
Artificial intelligence (AI) tools are being tested and applied for preliminary screening of possible early infections of SARS-CoV-2 among individuals. Based on the AI-based learning framework, individuals are being categorized as high, moderate, or minimal risk individuals [108].
However, multiple experts differ in their opinion over the data collected by these AI tools, as it is often considered sensitive owing to concerns of national security [109].
The chest CT-based diagnosis, usually in COVID-19, has certain limitations in terms of differentiation between COVID-19 and community-acquired pneumonia. Therefore, a deep learning model for COVID-19 was developed and employed to distinguish the common community-acquired pneumonia from COVID-19 [110]. With a lack of point-of-care diagnostics, AI-driven tools can prove useful in determining the risk involved and the transmission dynamics among different population groups. Presently, owing to the involvement of active learning processes in AI tools, the rate of confidence in decision-making processes has increased [28,111]. Therefore, there is an urgent need to standardize protocols to develop AI-based devices that can be used during such disasters.

Vaccine development
The most common preventive and effective approach to decelerate the COVID-19 pandemic is the use of vaccines in humans. Currently, there are significant research efforts being made globally to develop safe and effective vaccines against the SARS-CoV-2 [119]. Approximately 78 vaccine Inc. and Beijing Advaccine Biotechnology Co. Ltd [13], is undergoing phase I clinical trials. The globally coordinated efforts to combat the SARS-CoV-2 have led to the development of potential vaccine candidates in the shortest possible time; however, these candidates need to be subjected to rigorous clinical trials to prove their efficacy and safety before being considered for global immunization. Therefore, in the current situation, the therapeutic drugs are the most effective alternative for the containment of the virus and restoration of public health. Recently, two more vaccine candidates also entered phase I clinical trials, the details of which are summarized in Table 5.

Development of antiviral therapeutics
The rapid spread of the SARS-CoV-2 demands the immediate development of effective and safe therapeutic strategies. In the absence of licensed vaccines and approved antiviral drugs, the most promising approach adopted by researchers is the repurposing of drugs (identifying new uses for approved drugs to deliver effective treatment in the shortest possible time) [12,123]. However, no specific anti-SARS-CoV-2 treatment has been recommended by the US FDA, yet owing to the lack of concrete evidence.
Favilavir (Favipiravir), the first antiviral drug tested against SARS-CoV-2, approved by the National Medical Products Administration of China in February 2020, is commonly used to treat influenza infection in China and Japan and has shown promising results in shortening the course of SARS-CoV-2 infection [12,123,124]. This drug acts by inhibiting the RNA-dependent RNA polymerase activity (RdRp) of SARS-CoV-2. Despite its potential effectiveness, the drug is yet to be approved by the U.S. FDA. Remdisivir has also been reported to treat COVID-19 patients to full recovery [125,126]. In fact, remdisivir is also a repurposed drug that was initially developed for the treatment of Ebola virus infection. Remdisivir is reported to prevent viral replication by the premature termination of RNA transcription. Currently, remdisivir is under clinical trials for the treatment of COVID-19 patients. Furthermore, a combination of lopinavir and ritonavir has been reported to improve the condition of a COVID-19 patient significantly in South Korea [126]. Similar to remdisivir, a combination of lopinavir and ritonavir was developed to treat HIV-1 infections in adults. However, the combination of lopinavir and ritonavir failed to serve its initial purpose when used for the treatment of COVID-19 patients in recent clinical trials in China [127].
Hydroxychloroquine, an anti-malarial drug, in combination with azithromycin, has shown promising results in an open-label non-randomized clinical trial in reducing the viral load in COVID-19 patients [128]. However, its associated side-effects could be more severe in COVID-19 patients with preexisting chronic medical conditions.
Apart from these drugs, convalescent plasma therapy (plasma from recovered COVID-19 patients that contains antibodies against SARS-CoV-2) could also be used as an alternative treatment strategy to improve the survival rate of COVID-19 patients [129]. Recently, the FDA allowed the use of plasma therapy for critically ill patients under an emergency investigational new drug protocol (FDA, 2020). The treatment strategies must focus on curbing hyper inflammation, and the existing readily available therapies may prove beneficial in patients with severe SARS-CoV-2 infection. A humanized monoclonal antibody viz. tocilizumab competitively binds to IL-6 receptors and subsequently prevents the binding of IL-6 to its receptor [130]. Notably, the blocking of the IL-6 receptor by tocilizumab may prove to be crucial and reduce the number of deaths associated with severe stage COVID-19. In this context, a clinical trial (ChiCTR2000029765) using tocilizumab

Mitigation strategies
In the absence of approved antiviral agents and vaccines, the most effective strategies are based on the disruption of the transmission cycle of the virus (human-to-human) via droplets or close contact. To achieve this, the most critical step would involve maintaining strict hand hygiene and adherence to basic cough etiquettes, across all strata from children to the elderly. A study reported the employment of prevention and control strategies at three levels: case-related population, general population, and national level [131]. Additionally, the National Health Commission of China issued protocols for the mitigation of COVID-19 in order to contain further spread of the virus by a ‚big isolation and big disinfection‛ policy during the Chinese spring festival [132]. A national-level mitigation strategy has also been adopted for the elderly population and in rural areas [133,134].
Awareness regarding the connotations of hand hygiene amongst the general public, instead of stressing on the usage of masks, is the need of the hour in view of the multiple modes of transmission.
The use of sanitizers or soaps is one of the essential components of the prevention and control of COVID-19. Sanitizers with 60% ethanol or 70% isopropanol are effective against SARS-CoV-2.
Similarly, household detergents or soaps are also useful in sanitization. While sanitizers are sufficient for relatively clean hands, soiled hands would need to be washed using soap and water for 20 seconds. Additionally, the WHO issued guidelines on the use of face masks during care at home and in the community, along with health care settings in the context of COVID-19 [135]. Moreover, the use of particulate respirators, such as certified N95 or FFP2, is recommended for health care workers who perform aerosol-generating procedures.
In contrast, medical masks are recommended while providing clinical care to the suspected or confirmed COVID-19 cases [135]. The WHO has approved the use of N95 masks for patients at all times for source control and for healthcare providers only in certain situations, such as when they are in close vicinity of a patient (within 3 feet) or are performing aerosol-generating procedures on symptomatic patients; these masks are not recommended for use by the general public. In situations of close contact (within three to six feet) with a suspected or confirmed case, a facemask ought to be used instead of an N95 or powered, air-purifying respirator, whereas if the patient is not using a facemask, the health care provider should wear an N95 mask even when at a distance of three to six feet from the patient. In low-resource outbreak settings, the reuse of N95 masks after ethylene oxide  [136,137]. Smartphones and internet services can also be utilized to disseminate information regarding the presentation and prevention of the infection.
Disposable protective clothing, eye gear, gloves, masks, and shoe covers should be used while handling animal and animal products, and the same should be restricted to the workplace to prevent the spread to family members. Consumption of undercooked and raw meat should strictly be avoided. Proper heating of food to a temperature of 60 °C for thirty minutes, mimicking thermal shock conditions, practice a common in India, is sufficient to kill the virus. Breath analyzers and other public sharing equipment should use a disposable mouthpiece to prevent the human-to-human transfer of the virus. Proper cleaning of all surfaces should be practiced in hospitals, airports, at workplaces, and in domestic settings to allow the appropriate action of detergents since the SARS-CoV is an enveloped virus. The virus has been found to persist on inanimate surfaces from two hours up to nine days at room temperature, depending upon the type of surface and at temperatures, 4 °C and certain strains remain viable for up to 28 days. Surface disinfection with 0.1% hypochlorite or 62-71% ethanol was found to be effective in reducing the infectivity of a surface within an exposure time of one minute [138].
Unfortunately, this is the third event of the spillover of a zoonotic respiratory virus to humans in this decade, highlighting the necessity of prerequisite multidisciplinary coordination for curbing the emergence of novel viruses and controlling such apocalyptic events [139][140][141]. The 'One health approach' is one such initiative that incorporates the preventive strategies for the emergence of zoonosis in all three arms; humans, animals, and the environment [142,143].

Conclusions and prospects
The