INTRODUCTION Of COVID-19

Over the past 2 decades, coronaviruses have been associated with significant
disease outbreaks in East Asia and the Middle East. The severe acute respiratory
syndrome (SARS) and the Middle East respiratory syndrome (MERS) began to
emerge in 2002 and 2012, respectively.
Recently, a novel coronavirus, severe acute respiratory syndrome coronavirus 2
(SARS - CoV - 2), causing coronavirus disease 2019 (COVID - 19), emerged in
late 2019, and it has posed a global health threat, causing an ongoing pandemic
in many countries and territories

(1) . Health workers worldwide are currently making efforts to control further
disease outbreaks caused by the novel CoV (originally named 2019 -
nCoV), which was first identified in Wuhan City, Hubei Province, China,
on 12 December 2019. On 11 February 2020, the World Health
Organization (WHO) announced the official designation for the current
CoV - associated disease to be COVID - 19, caused by SARS - CoV - 2.
The primary cluster of patients was found to be connected with the Huanan
South China Seafood Market in Wuhan
(2). CoVs belong to the family Corona viridae (subfamily Corona virinae), the
members of which infect abroad.

Diagnosis [ 21 ]
A suspect case is defined as one with fever, sore throat and cough who has history
of travel to China or other areas of persistent local transmission or contact with
patients with similar travel history or those with confirmed.
CoV - 2 is considered a new Betacoronavirus belonging to the subgenus
Sarbecovirus (3). A few other critical zoonotic viruses (MERS - related CoV and
SARS - related CoV) belong to the same genus. However, SARS - CoV - 2 was
identified as a distinct virus based on the percent identity with other
Betacoronavirus; conserved open reading frame la / b (ORF1a / b) is below 90 %
identity (3). An overall 80 % nucleotide identity was observed between SARS -
CoV - 2 and the original SARS - CoV, along with 89 % identity with ZC45 and
ZXC21 SARS related CoVs of bats (2, 31, 36).
In addition, 82 % identity has been observed between SARS - CoV - 2 and human
SARS - CoV Tor2 and human SARS - CoV BJ01 2003 (31). A
sequence identity of only 51.8 % was observed between MERS - related CoV and
the recently emerged SARS - CoV - 2 ( 37 ) . Phylogenetic analysis of the
structural genes also revealed that SARS - CoV - 2 is closer to bat SARS - related
CoV . Therefore , SARS - CoV - 2 might have originated from bats , while other
amplifier hosts might have played a role in disease transmission to humans ( 31 )
ote , the other two zoonotic CoVs ( MERS - re V and SARS - related CoV ) also
originated from bats ( 38 , 39 ) . Nevertheless, for SARS and MERS, civet
SARS is a viral respiratory disease caused by a formerly unrecognized animal
CoV that originated from the wet markets in southern China after adapting to the
human host, thereby enabling transmission between humans (90).
The SARS outbreak reported in 2002 to 2003 had 8,098 confirmed cases with 774
total deaths (9.6 %) (93). The outbreak severely affected the Asia Pacific region,
especially mainland China (94). Even though the case fatality rate (CFR) of
SARS - CoV - 2 (COVID - 19) is lower than that of SARS - CoV, there exists a
severe concern linked to this outbreak due to its epidemiological similarity to
influenza viruses (95, 279).
This can fail the public health system, resulting in a pandemic (96). MERS is
another respiratory disease that was first reported in Saudi Arabia during the year
2012.
The disease was found to have a CFR of around 35 % (97). The analysis of
available data sets suggests that the incubation period of SARS - CoV - 2, SARS
- CoV, and MERS - CoV is in almost the same range. The longest predicted
incubation time of SARS - CoV - 2 is 14 days. Hence, suspected for 14 days
Specimen collection and storage
A Nasopharyngeal and oropharyngeal swab should be collected using Dacron or
polyester flocked swabs. It should be transported to the laboratory at a
temperature of 4 ° C and stored in the laboratory between 4 and -70 ° C on the
basis of the number of days and, in order to increase the viral load,
both nasopharyngeal and oropharyngeal swabs should be placed in the same tube.
Bronchoalveolar lavage and nasopharyngeal aspirate should be collected in a
sterile container and transported similarly to the laboratory by maintain a
temperature of 4 ° C.
Sputum samples, especially from the lower respiratory tract, should be collected
with the help of a sterile container and stored, whereas tissue from a biopsy or
autopsy should be collected using a sterile container along with saline.
However, both should be stored in the laboratory at a temperature that ranges
between 4 and -70 ° C. Whole blood for detecting the antigen, particularly in the
first week of illness, should be collected in a collecting tube and stored in the
laboratory between 4 and -70 ° C. Urine samples must also be collected using a
sterile container and stored.

with SARS and MERS (117).

SARS - CoV - 2 invades the lung parenchyma, resulting in severe interstitial
inflammation of the lungs. This is evident on computed tomography (CT) images
as ground - glass opacity in the lungs. This lesion initially involves a single lobe
but later expands to multiple lung lobes (118).
The histological assessment of lung biopsy samples obtained from COVID - 19 -
infected patients revealed diffuse alveolar damage, cellular fibromyxoid
exudates, hyaline membrane formation, and desquamation of pneumocytes,
indicative of acute respiratory distress syndrome (119).
It was also found that the SARS - CoV - 2 - infected patients often have
lymphocytopenia with or without leukocyte abnormalities. The degree of
lymphocytopenia gives an idea about disease prognosis, as it is found to be
positively correlated with disease severity (118).
Pregnant women are considered to have a higher risk of getting infected by
COVID - 19. The coronaviruses can cause adverse outcomes for the fetus, such
as intrauterine growth restriction, spontaneous abortion, preterm delivery, and
perinatal death.
Nevertheless, the possibility of intrauterine maternal - fetal transmission (vertical
transmission) of CoVs is low and was not seen during either the SARS or MERS
- CoV outbreak (120). However,
All of these therapeutic approaches have revealed both in vitro and in vivo anti -
CoV potential. Although in vitro research carried out with these therapeutics
showed efficacy, most need appropriate support from randomized animal or
human trials. Therefore, they might be of limited applicability and require trials
against SARS - CoV - 2 to gain practical usefulness.
The binding of SARS - CoV - 2 with ACE2 leads to the exacerbation of
pneumonia as a consequence of the imbalance in the renin angiotensin system
(RAS). The virus - induced pulmonary inflammatory redness may be reduced by
the administration of ACE inhibitors (ACEI) and angiotensin type - 1 receptor
(AT1R) (207).
Several investigations have suggested the use of small - molecule inhibitors for
the potential control of SARS - CoV infections.
Drugs of the FDA - approved compound library was screened to identify four
small - molecule inhibitors of MERS - CoV (chlorpromazine, chloroquine,
loperamide, and lopinavir) that inhibited viral replication. These compounds also
hinder SARS - CoV and human CoVs
(208) .
Therapeutic strategies involving the use of specific antibodies or compounds that
neutralize cytokines and their receptors will help to restrain the host inflammatory
responses. Such drugs acting specifically in the respiratory tract will help.
Abstract

There is a new public health crisis threatening the world with the emergence and
spread of 2019 novel coronavirus (2019 - nCoV) or the severe acute respiratory
syndrome coronavirus 2 (SARS - CoV - 2). The virus originated in bats and was
transmitted to humans through yet unknown intermediary animals in Wuhan,
Hubei province, China in December 2019.
There have been around 96,000 reported cases of coronavirus disease 2019
(COVID - 2019) and 3300 reported deaths to date (05/03/2020). The disease is
transmitted by inhalation or contact with infected droplets and the incubation
period ranges from 2 to 14 d.

The symptoms are usually fever, cough, sore throat, breathlessness, fatigue,
malaise among others. The disease is mild in most people; in some (usually the
elderly and those with comorbiditiae) it may nrograce. (173, 174). Hence,
knowledge and understanding of S protein - based vaccine development in SARS
- CoV will help to identify potential S protein vaccine candidates in SARS - CoV
- 2.
Therefore, vaccine strategies based on the whole S protein, S protein subunits, or
specific potential epitopes of S protein appear to be the most promising vaccine
candidates against coronaviruses.
The RBD of the S1 subunit of S protein has a superior capacity to induce
neutralizing antibodies.
This property of the RBD can be utilized for designing potential SARS - CoV
vaccines either by using RBD - containing recombinant proteins or recombinant
vectors that encode RBD (175).
Hence, the superior genetic similarity existing between SARS - CoV - 2 and
SARS CoV can be utilized to repurpose vaccines that have proven in vitro
efficacy against SARS - CoV to be utilized for SARS - CoV - 2. The possibility
of cross protection in COVID - 19 was evaluated by comparing the S protein
sequences of SARS - CoV - 2 with that of SARS - CoV. The comparative analysis
confirmed that the variable residues were found concentrated on the S1 subunit
of S protein, an important vaccine target of the virus (150).
Hence, the possibility of SARS - CoV - specific neutralizing antibodies providing
cross - protection to COVID - 19 might be lower. Further genetic analysis is
required 42. mice, and hDPP4 - Tg mice (transgenic for expressing hDPP4) for
MERS - CoV infection (221). The CRISPR - Cas9 gene - editing tool has been
used for inserting genomic alterations in mice, making them susceptible to MERS
- CoV infection (222).
Effort: 44 are under way to recognize suitable animal models for SARS - CoV2 /
COVID - 19, identify the receptor affinity of this virus, study pathology in
experimental animal models, and explore virus - specific immune responses and
protection studies, which together would increase the pace of efforts being made
for developing potent vaccines and drugs to counter this emerging virus.
Cell lines, such as monkey epithelial cell lines (LLC - MK2 and Vero - B4), goat
lung cells, alpaca kidney cells, dromedary umbilical cord cells, and advanced ex
vivo three - dimensional tracheobronchial tissue, have been explored to study
human CoVs (MERS - CoV) (223, 224).

Vero and Huh - 7 cells (human liver cancer cells) have been used for isolating
SARS - CoV - 2 (194). Recently, an experimental study with rhesus monkeys as
animal models revealed the absence of any viral loads in nasopharyngeal and anal
swabs, and no viral replication was recorded in the primary tissues at a time
interval of 5 days post - reinfection in reexposed monkeys (274). The subsequent
virological, radiological, and pathological
Coronavirus is the most prominent example of a virus that has crossed the species
barrier twice from wild animals to humans during SARS and MERS outbreaks
(79, 102). The possibility of crossing the species barrier for the third time has also
been suspected in the case of SARS - CoV - 2 (COVID - 19).
Bats are recognized as a possible natural reservoir host of both SARS - CoV and
MERS - CoV infection. In contrast, the possible intermediary host is the palm
civet for SARS - CoV and the dromedary camel for MERS - CoV infection (102).
Bats are considered the ancestral hosts for both SARS and MERS (103).
Bats are also considered the reservoir host of human coronaviruses like HCoV -
229E and HCoV - NL63 (104). In the case of COVID - 19, there are two
possibilities for primary transmission:
it can be transmitted either through intermediate hosts, similar to that of SARS
and MERS, or directly from bats (103).
The emergence paradigm put forward in the SARS outbreak suggests that SARS
- CoV originated from bats (reservoir host) and later jumped to civets
(intermediate host) and incorporated changes within the receptor - binding
domain (RBD) to improve binding to civet ACE2.
This civet - adapted virus, during their subsequent exposure to humans at live
markets, promoted further adaptations that resulted in the epidemic strain (104).

CLINICAL DIAGNOSIS
The symptoms of COVID - 19 remain very similar to those of the other
respiratory epidemics in the past, which include SARS and MERS, but here the
range of symptoms includes mild rhinitis to septic shock.
Some intestinal disturbances were reported with the other epidemics, but COVID
- 19 was devoid of such symptoms. When examined, unilateral or bilateral
involvement compatible with viral pneumonia is observed in the patients,
and bilateral multiple lobular and sub - segmental consolidation areas were
observed in patients hospitalised in the intensive care unit.
Comorbid patients showed a more severe clinical course than predicted from
previous epidemics.
Diagnosis of COVID - 19 includes the complete history of travel and touch, with
laboratory testing. It is more preferable to choose serological screening, which
can help to analyse even the asymptomatic infections; several serological tests
are in progress for SARS - CoV - 2.14, 30 risk regions. It is derived from a live
attenuated strain of Mycobacterium bovis. At present, three new clinical trials
have been registered to evaluate the protective role of BCG vaccination against
SARS CoV - 2 (363).

Recently, a cohort study was conducted to evaluate the impact of childhood BCG
vaccination in COVID - 19 PCR positivity rates. However, childhood BCG
vaccination was found to be associated with a rate of COVID - 19 - positive test
results similar to that of the nonvaccinated group (364).
Further studies are required to analyze whether BCG vaccination in childhood
can induce protective effects against COVID – 19 in adulthood. Population
genetic studies conducted on 103 genomes identified that the SARS - CoV - 2
virus has evolved into two major types, L and S. Among the two types, L type is
expected to be the most prevalent ( -70 %), followed by the S type ( -30 %) (366).
This finding has a significant impact on our race to develop an ideal vaccine, since
the vaccine candidate has to target both strains to be considered effective.
At present, the genetic differences between the L and S types are very small and
may not affect the immune response.
However, we can expect further genetic variations in the coming days that could
lead to the emergence of new strains (367).
plasma cytokines, which suggests an immunopatho logical process caused by a
cytokine storm 60,8687. In this cohort of patient, around 2.3 % people died within
a median time of 16 days from disease onset % 86.
Men older than 68 years had a higher risk of respiratory failure, acute cardiac
injury and heart failure that led to death, regardless of a history of cardiovascular
diseases (FIG. 4).
Most patients recovered enough to be released from hospital in 2 weeks 280 (FIG.
4). Early transmission of SARS - CoV - 2 in Wuhan in December 2019 was
initially linked to the Huanan Seafood Wholesale Market, and it was suggested
as the source of the outbreak 22.60.
However, community transmission might have happened before that “. Later,
ongoing human - to - human transmission propagated the outbreak.
It is generally accepted that SARS - CoV - 2 is more transmissible than SARS -
CoV and MERS - CoV; however, determination of an accurate reproduction
number (RO) for COVID - 19 is not possible yet, as many asymptomatic
infections cannot be accurately accounted for at this stage. An estimated R0 of
2.5 (ranging from 1.8 to 3.6) has been proposed for SARS - CoV - 2 recently,
compared with 2.0-3.0 for SARS - CoV⁹. Notably, most of the SARS - CoV - 2
human - to - human transmission early in China occurred in family clusters, and
in other countries large outbreaks also happened in other set things, such as
migrant worker communities, slaughter houses and meat packing plants,
indicating the necessity of isolating infected people1291-93.
Nosocomial transmission was not the main source of transmission in China
because of the implementation of infection control measures in clinical settings.
By contrast, a high risk of nosocomial transmission was reported in some other.
Currently, our knowledge on the animal origin of SARS - CoV - 2 remains
incomplete to a large part. The reservoir hosts of the virus have not been clearly
proven.
It is unknown whether SARS - CoV - 2 was transmitted to humans through an
intermediate host and which animals may act as its intermediate host. Detection
of RaTG13, RmYN02 and pangolin coronaviruses implies that diverse
coronaviruses similar to SARS - CoV - 2 are circulating in wildlife.
In addition, as previous studies showed recombination as the potential origin of
some sarbecoviruses such as SARS - CoV, it cannot be excluded that viral RNA
recombination among different related coronaviruses was involved in the
evolution of SARS - CoV - 2.
Extensive surveillance of SARS - CoV - 2 related viruses in China, Southeast
Asia and other regions targeting bats, wild and captured pangolins and other
wildlife species will help us to better understand the zoonotic origin of SARS -
CoV - 2.
Besides wildlife, researchers investigated the sus ceptibility of domesticated and
laboratory animals to SARS - CoV - 2 infection. The study demonstrated exper
imentally that SARS - CoV - 2 replicates efficiently in cats and in the upper
respiratory tract of ferrets, whereas dogs, pigs, chickens and ducks were not
susceptible to SARS - CoV - 2 (REF.).

The susceptibility of minks was documented by a report from the Netherlands on

an outbreak of SARS - CoV - 2 infection in farmed minks. Although the
symptoms in most infected minks were mild, some developed severe respiratory
distress and died of interstitial pneumonia¹.
Both virologi cal and serological testing found evidence for natural SARS - CoV
- 2 infection in two dogs from households with human cases of COVID - 19 in
Hong Kong,

CLINICAL PATHOLOGY OF SARS - CoV - 2 (COVID - 19)

The disease caused by SARS - CoV - 2 is also named severe specific contagious
pneumonia (SSCP), Wuhan pneumonia, and, recently, COVID 19 (110).
Compared to SARS - CoV, SARS - CoV - 2 has less severe pathogenesis but has
superior transmission capability, as evidenced by the rapidly increasing number
of COVID - 19 cases (111).

The incubation period of SARS - CoV - 2 in familial clusters was found to be 3

to 6 days (112). The mean incubation period of COVID - 19 was found to be 6.4
days, ranging from 2.1 to 11.1 days (113).
Among an early affected group of 425 patients, 59 years was the median age, of
which more males were affected (114). Similar to SARS and MERS, the severity
of this CoV is high in age groups above 50 years (2, 115).
Symptoms of COVID - 19 include fever, cough, myalgia or fatigue, and, less
commonly, headache, hemoptysis, and diarrhea (116, 282). Compared to the
SARS - CoV - 2 - infected patients in Wuhan during with COVID - 19 showed
typical features on initial CT, including bilateral multilobar ground - glass
opacities with a peripheral or posterior distribution¹18,119.
Thus, it has been suggested that CT scanning combined with repeated swab tests
should be used for individuals with high clinical suspicion of COVID - 19 but
who test negative in initial nucleic acid screening¹¹.
Finally, SARS - CoV - 2 serological tests detecting antibodies to N or S protein
could complement molecular diagnosis,
particularly in late phases after disease onset or for retro spective studies
¹16,120,121. However, the extentantion of immune responses are still unclear,
and serological tests differ in their sensitivity and spity, all of which need to be
taken into account when one is deciding on serological tests and interpreting their
results or potentially in the future test for T cell responses .

Therapeutics
To date, there are no generally proven effective thera pies for COVID - 19 or
antivirals against SARS - CoV - 2, although some treatments have shown some
benefits in certain subpopulations of patients or for certain end points (see later).
Researchers and manufacturers are conducting large - scale clinical trials to
evaluate various therapies for COVID - 19. As of 2 October 2020, there were
about 405 therapeutic drugs in development for COVID - 19, and nearly 318 in
human clinical trials (COVID - 19 vaccine and therapeutics tracker).
In the following sections, we summarize potential therapeutics against SARS -
CoV - 2 on the basis of published clinical data and experience.

Epidemiology and Pathogenesis

All ages are susceptible.
Infection is transmitted through large droplets generated during coughing and
sneezing by symptomatic patients but can also occur from asymptomatic people
and before onset of symptoms [9]. Studies have shown higher viral loads in the
nasal cavity as compared to the throat with no difference in viral.
burden between symptomatic and asymptomatic people [12]. Patients can be
infectious for as long as the symptoms last and even on clinical recovery.
Some people may act as super spreaders; a UK citizen who attended a conference
in Singapore infected 11 other people while staying in a resort in the French Alps
and upon return to the UK [6].
These infected droplets can spread 1-2 m and deposit recovered patients and used
for plasma transfusion twice in a volume of 200 to 250 ml on the day of collection
(310).
At present, treatment for sepsis and ARDS mainly involves antimicrobial
therapy, source control, and supportive care.
Hence, the use of therapeutic plasma exchange can be considered an option in
managing such severe conditions. Further randomized trials can be designed to
investigate its efficacy (311).

Potential Therapeutic Agents

Potent therapeutics to combat SARS - CoV - 2 infection include virus binding
molecules, molecules or inhibitors targeting particular enzymes implicated in
replication and transcription process of the virus,
helicase inhibitors, vital viral proteases and proteins, protease inhibitors of host
cells, endocytosis inhibitors, short interfering RNA (siRNA), neutralizing
antibodies, MAbs against the host receptor,

MAbs interfering with the S1 RBD, antiviral peptide aimed at S2, and natural
drugs / medicines (7, 166, 186).
The S protein acts as the critical target for developing CoV antivirals, like
inhibitors of S protein and S cleavage, neutralizing antibodies, RBD - ACE2
blockers, siRNAs, blockers of the fusion core, and proteases (168).
All of these therapeutic approaches have revealed infected by human beings.
However, evidence of cat to - human transmission is lacking and requires further
studies (332).
Rather than waiting for firmer evidence on animal - to - human transmission,
necessary preventive measures are advised, as well as following social distancing
practices among companion animals of different households (331).
One of the leading veterinary diagnostic companies, IDEXX, has conducted large
- scale testing for COVID - 19 in specimens collected from dogs and cats.
However, none of the tests turned out positive (334).
In a study conducted to investigate the potential of different animal species to act
as the intermediate host of SARS - CoV - 2, it was found that both and cats can
be infected via experimental inoo of the virus. In addition, infected cats efficiently
transmitted the disease to naive cats (329).
CoV - 2 infection and subsequent transmission in ferrets were found to
recapitulate the clinical aspects of COVID - 19 in humans.
The infected ferrets also shed virus via multiple routes, such as saliva, nasal
washes, feces, and urine, post infection, making them an ideal animal model for
studying disease transmission (337).
Experimental inoculation was also done in other animal species and found that
the dogs have low susceptibility, while the chickens, Splits Tree phylogeny
analysis.
In the unrooted phylogenetic tree of different beta coronaviruses based on the S
protein, virus sequences from different subgenera grouped into separate clusters.
SARS - CoV - 2 sequences from Wuhan and other countries exhibited a close
relationship and appeared in a single cluster (Fig. 1).
The CoVs from the subgenus Sarbecovirus appeared jointly in SplitsTree and
divided into three subclusters, namely, SARS - CoV - 2, bat - SARS - like CoV
(bat - SL - CoV), and SARS - CoV (Fig. 1).
In the case of other subgenera, like Merbecovirus, all of the sequences grouped
in a single cluster, whereas in Embecovirus, different species, comprised of
canine respiratory CoVs, bovine CoVs, equine CoVs, and human CoV strain
(OC43), grouped in a common cluster.
Isolates in the subgenera Nobecovorus and Hibecovirus were found to be placed
separately away from other reported SARS - CoVs but shared a bat origin. chest
discomfort, and in severe cases dyspnea and bilateral lung infiltration. Among the
first 27 documented hospitalized patients, most cases were epidemi ologically
linked to Huanan Seafood Wholesale Market.
A wet market located in downtown Wuhan, which sells not only seafood but also
live animals, including poultry and wildlife. According to a retrospective study,
the onset of the first known case dates back to 8 December 2019 (REF.).
On 31 December, Wuhan Municipal Health Commission notified the public of a
pneumonia outbreak of unidentified cause and informed the World Health
Organization (WHO) (FIG. 1). By metagenomic RNA sequencing and virus
isolation from bronchoalveolar lavage fluid samples from patients with severe
pneumonia, independent teams of Chinese scientists identified that the causative
agent of this emerging disease is a betacoronavirus that had never been seen
before. On 9 January 2020, the result of this etiological identification was
publicly announced (FIG. 1).
The first genome sequence of the novel coro navirus was published on the
Virological website on 10 January, and more nearly complete genome sequences
determined by different research institutes were then released via the GISAID
database on 12 January, Later, more patients with no history of exposure tc
Huanan Seafood Wholesale Market were identified.
Several familial clusters of infection were reported. and nosocomial infection also
occurred in health - care facilities. All these cases provided clear evidence for
human - to - human transmission of the new virus, 12-14, As the outbreak
coincided with the approach of the lunar New Year, travel between cities before
the festival facilitated virus transmission in China.
This novel coro navirus pneumonia soon spread to other cities in Hubei province
and to other parts of China. Within 1 month.
Animal host and spillover
Bats are important natural hosts of alphacoronavi ruses and betacoronaviruses.
The closest relative to SARS - CoV - 2 known to date is a bat coronavirus detected
in Rhinolophus affinis from Yunnan province, China, named ' RaTG13 ‘, whose
full - length genome sequence is 96.2 % identical to that of SARS - CoV - 2
(REF.¹).
This bat virus shares more than 90 % sequence identity with SARS - CoV - 2 in
all ORFs throughout the genome, including the highly variable S and ORF8
(REF.¹). Phylogenetic analysis confirms that SARS - CoV - 2 closely clusters
with RaTG13 (FIG. 2).
The high genetic similarity between SARS - CoV - 2 and RaTG13 supports the
hypothesis that SARS - CoV - 2 likely originated from bats³5.

Another related coronavirus has been reported more recently in a Rhinolophus

malayanus bat sampled in Yunnan This novel hat virus denoted ' RmYN02 '
involved in the COVID - 19 outbreak is of great importance, because the strain
on their mental well-being will affect their attention, concentration, and decision
- making capacity.
Hence, for control of the COVID - 19 outbreak, rapid steps should be taken to
protect the mental health of medical workers (229). Since the living mammals
sold in the wet market are suspected to be the intermediate host of SARS CoV -
2, there is a need for strengthening the regulatory mechanism for wild animal
trade (13). The total number of COVID - 19 confirmed cases is on a continuous
rise and the cure rate is relatively low, making disease control very difficult to
achieve.
The Chinese government is making continuous efforts to contain the disease by
taking eme control and prevention measures.
They have built a hospital for patients affected by this virus and are currently
building several more for accommodating the continuously increasing infected
population (230).
Coronavirus S protein is a large, multifunctional class I viral transmembrane
protein. The size of this abundant S protein varies from 1,160 amino acids (IBV,
infectious bronchitis virus, in poultry) to 1,400 amino acids (FCoV, feline
coronavirus) (43).
It lies in a trimer on the virion surface, giving the virion a corona or crown - like
appearance. Functionally it is required for the entry of the infectious virion
particles into the cell through interaction with various host cellular receptors (44).
Furthermore, it acts as a critical factor for tissue tropism and the determination of
host range (45). Notably, S protein is one of the vital immunodominant proteins
of CoVs capable of inducing host immune responses (45).
The ectodomains in all CoVs S proteins have similar domain organizations,
divided into two subunits, S1 and S2 (43). The first one, S1, helps in host receptor
binding, while the second one, S2, accounts for fusion.

The former (S1) is further divided into two subdomains, namely, the N - terminal
domain (NTD) and C - terminal domain (CTD). Both of these subdomains act as
receptor - binding domains, interacting efficiently with various host receptors
(45). The S1 CTD contains the receptor - binding motif (RBM). In each
coronavirus spike protein, the trimeric S1 locates itself on top of the trimeric S2.

8 PREVENTIONS
The WHO and other agencies such as the CDC have published protective
measures to mitigate the spread of COVID - 19. This involves frequent hand
washing with handwash containing 60 % of alcohol and soap for at least 20
seconds.
Another important measure is avoiding close contact with sick people and
keeping a social distance of 1 metre always to everyone who is coughing and
sneezing.
Not touching the nose, eyes and mouth was also suggested. While coughing or
sneezing, covering the mouth and nose with a cloth / tissue or the bent elbow is
advised. Staying at home is recommended for those who are sick, and wearing a
facial mask is advised when going out among people. Furthermore, it is
recommended to clean and sterilise frequently touched surfaces such as phones
and doorknobs on a daily basis.51,52 Staying at home as much as possible is
advisable for those who are at higher risk for severe illness, to minimise the risk
of exposure to COVID - 19 during outbreaks.53

Inhibition of virus entry.

SARS - CoV - 2 uses ACE2 as the receptor and human proteases as entry
activators; sub sequently it fuses the viral membrane with the cell mem brane and
achieves invasion.
Thus, drugs that interfere with entry may be a potential treatment for
COVID - 19. Umifenovir (Arbidol) is a drug approved in Russia and China for
the treatment of influenza and other respira tory viral infections.
It can target the interaction between the S protein and ACE2 and inhibit
membrane fusion (FIG. 5). In vitro experiments showed that it has activity against
SARS - CoV - 2, and current clinical data revealed it may be more effective than
lopinavir and ritonavir in treating COVID - 19 (REFS 122,123).
However, other clinical studies showed umifenovir might not improve the prog
nosis of or accelerate SARS - CoV - 2 clearance in patients with mild to moderate
COVID - 19 (REFS124.125).
Yet some ongoing clinical trials are evaluating its efficacy for COVID - 19
treatment. Camostat mesylate is approved in Japan for the treatment of
pancreatitis and postoper ative reflux oesophagitis.
Previous studies showed that it can prevent SARS - CoV from entering cells by
blocking TMPRSS2 activity and protect mice from lethal infection with SARS -
CoV in a pathogenic
mouse model (wild type mice infected with a mouse - adapted SARS - CoV
strain) 126,127. Recently, a study revealed that camostat mesylate blocks the
entry of SARS - CoV - 2 into human lung cells 47.
Thus, it can be a potential antiviral drug against SARS - CoV - 2 infection,
although so far there are not sufficient clinical data to support its efficacy.

Coronaviruses in Humans SARS, MERS, and COVID – 19

Coronavirus infection in humans is commonly associated with mild to severe
respiratory diseases, with high fever, severe inflammation, cough, and internal
organ dysfunction that can even lead to death (92).

Most of the identified coronaviruses cause the common cold in humans.

However, this changed when SARS - CoV was identified, paving the way for
severe forms of the disease in humans (22).
Our previous experience with the outbreaks of other coronaviruses, like SARS
and MERS, suggests that the mode of transmission in COVID - 19 as mainly
human - to - human transmission via direct contact, droplets, and fomites (25).
Recent studies have demonstrated that the virus could remain viable for hours in
aerosols and up to days on surfaces; thus, aerosol and fomite contamination could
play potent roles in the transmission of SARS - CoV - 2 (257).

The immune response against coronavirus is vital to control and get rid of the
infection.
However, maladjusted immune responses may contribute to the
immunopathology of the disease, resulting in impairment of pulmonary gas
exchange. Understanding the interaction between CoVs.
Coronaviruses in Humans SARS, MERS, and COVID - 19 Coronavirus infection
in humans is commonly associated with mild to severe respiratory diseases, with
high fever, severe inflammation, cough, and internal organ dysfunction that can
even lead to death (92).
Most of the identified coronaviruses cause the common cold in humans.
However, this changed when SARS - CoV was identified, paving the way for
severe forms of the disease in humans (22).
Our previous experience with the outbreaks of other coronaviruses, like SARS
and MERS, suggests that the mode of transmission in COVID - 19 as mainly
human - to - human transmission via direct contact, droplets, and fomites (25).
Recent studies have demonstrated that the virus could remain viable for hours in
aerosols and up to days on surfaces; thus, aerosol and fomite contamination could
play potent roles in the transmission of SARS - CoV - 2 (257).
The immune response against coronavirus is vital to control and get rid of the
infection. However, maladjusted immune responses may contribute to the
immunopathology of the disease, resulting in impairment of pulmonary gas
exchange.
Understanding the interaction between CoVs and host innate immune systems.
Prevent further spread of disease at mass gatherings, functions remain canceled
in the affected cities, and persons are asked to work from home (232).
Hence, it is a relief that the current outbreak of COVID - 19 infection can be
brought under control with the adoption of strategic preventive and control
measures along with the early isolation of subsequent cases in the coming days.
Studies also report that since air traffic between China and African countries
increased many times over in the decade after the SARS outbreak, African
countries need to be vigilant to prevent the spread of nove coronavirus in Africa
(225).
Due to fear of virus spread, Wuhan City was completely shut down (233). The
immediate control of the ongoing COVID - 19 outbreaks appear a mammoth task,
especially for developing countries, due to their inability to allocate quarantine
stations that could screen infected individuals ' movements (234).
Such underdeveloped countries should divert their resources and energy to
enforcing the primary level of preventive measures, like controlling the entry of
individuals from China or countries where the disease has flared up,
isolating the infected individuals, and quarantining individuals with suspected
infection. Most of the sub - Saharan African countries have a fragile health
system.
COVID - 19 patients showing severe signs are treated symptomatically along
with oxygen therapy. In such cases where the patients progress toward respiratory
failure and become refractory to oxygen therapy, mechanical ventilation is
necessitated.
The COVID - 19 - induced septic shock can be managed by providing adequate
hemodynamic support (299). Several classes of drugs are currently being
evaluated for their potential therapeutic action against SARS - CoV - 2.
Therapeutic agents that have anti - SARS - CoV - 2 activity can be broadly
classified into three categories: drugs that block virus entry into the host cell,
drugs that block viral replication as well as its survival within the host cell, and
drugs that attenuate the exaggerated host immune response (300).
An inflammatory cytokine storm is commonly seen in critically ill COVID - 19
patients. Hence, they may benefit from the use of timely anti - inflammation
treatment. Anti - inflammatory therapy using drugs like glucocorticoids, cytokine
inhibitors, JAK inhibitors, and chloroquine / hydroxychloroquine should be done
only after analyzing the risk / benefit ratio in COVID - 19 patients (301).
There have not been any studies concerning the application of nonsteroidal anti -
inflammatory drugs (NSAID) to COVID - 19 - infected patients. However,
reasonable pieces of evidence are available that link NSAID.
Repurposed broad - spectrum having proven uses against other viral pathogens
can be employed for SARS - CoV - 2 - infected patients. These possess benefits
of easy accessibility and recognized pharmacokinetic and pharmacodynamic
activities, stability, doses, and side effects (9).
Repurposed drugs have been studied for treating COV infections, like lopinavir
/ ritonavir, and interferon - 13 revealed in vitro anti - MERS - CoV action.
The in vivo experiment carried out in the nonhuman primate model of common
marmosets treated with lopinavir / ritonavir and interferon beta showed superior
protective results in treated animals than in the untreated ones (190).
A combination of these drugs is being evaluated to treat MERS in humans
(MIRACLE trial) (191).
These two protease inhibitors (lopinavir and ritonavir), in combination with
ribavirin, gave encouraging clinical outcomes in SARS patients, suggesting their
therapeutic values (165).
However, in the current scenario, due to the lack of specific therapeutic agents
against SARS CoV - 2, hospitalized patients confirmed for the disease are given
supportive care, like oxygen and fluid therapy, along with antibiotic therapy for
managing secondary bacterial infections (192). Patients with novel coronavirus
or COVID - 19 pneumonia who are mechanically ventilated often require
sedatives. analgesics. possible origin of SARS - CoV - 2 and the first mode of
disease transmission are not yet identified (70). Analysis of the initial cluster of
infections suggests that the infected individuals had a common exposure point, a
seafood market in Wuhan, Hubei Province, China (Fig. 6).
The restaurants of this market are well - known for providing different types of
wild animals for human consumption (71). The Huanan South China Seafood
Market also sells live animals, such as poultry, bats, snakes, and marmots (72).
This might be the point where zoonotic (animal - to human) transmission occurred
(71). Although SARS - CoV - 2 is alleged to have originated from an animal host
(zoonotic origin) with further human - to human transmission (Fig. 6), the
likelihood of foodborne transmission should be ruled out with further
investigations, since it is a latent possibility (1).

Additionally, other potential and expected routes would be associated with

transmission, as in other respiratory viruses, by direct contact, such as shaking
contaminated hands, or by direct contact with contaminated surfaces (Fig. 6).
Still, whether blood transfusion and organ transplantation (276), as well as
transplacental and perinatal routes, are possible routes for SARS - CoV - 2
transmission needs to be determined (Fig. 6).
Initially, the epicenter of the SARS - CoV - 2 pandemic was China, which
reported a significant number of deaths associated with COVID - 19, with 84,458
laboratory - confirmed cases and 4,644 deaths as of 13 May 2020 (Fig. 4).
As of 13 May 2020, SARS - CoV - 2 confirmed cases have been reported in more
than 210 countries apart from China (Fig. 3 and 4) (WHO Situation Report 114)
(25, 64).
COVID - 19 has been reported on all continents except Antarctica. For many
weeks, Italy was the focus of concerns regarding the large number of cases, with
221,216 cases and 30,911 deaths, but now, the United States is the country with
the largest number of cases, 1,322,054, and 79,634 deaths.
Now, the United Kingdom has even more cases (226,4671) and deaths (32,692)
than Italy. A John Hopkins University web platform has provided daily updates
on the basic epidemiology of the COVID - 19 outbreak.
Viewpoint on SARS - CoV - 2 Transmission, Spread, and
Emergence
The novel coronavirus was identified within 1 month (28 days) of the outbreak.
This is impressively fast compared to the time taken to identify SARS CoV
reported in Foshan, Guangdong Province, China (125 days) (68).
Immediately after the confirmation of viral etiology, the Chinese virologists
rapidly released the genomic sequence of SARS - CoV - 2, which played a crucial
role in controlling the spread of this newly emerged novel coronavirus to other
parts of the world (69).
The possible origin of SARS - CoV - 2 and the first mode of assays, like assays
offer high accuracy in the diagnosis of SARS CoV - 2, but the current rate of
spread limits its use due to the lack of diagnostic assay kits.
This will further result in the extensive transmission of COVID - 19, since only a
portion of suspected cases can be diagnosed. In such situations, conventional
serological enzyme - linked immunosorbent assay (ELISA), that are specific to
COVID - 19 IgM and IgG antibodies can be used as a high - throughput
alternative (149).
At present, there is no diagnostic kit available for detecting the SARS CoV - 2
antibody (150). The specific antibody profiles of COVID - 19 patients were
analyzed and it was found that the IgM level lasted more than 1 month, indicating
a prolonged stage of virus replication in SARS - CoV - 2 - infected patients. The
IgG levels were found to increase only in the later stages of the disease.
These findings indicate that the antibody profiles of SARS - CoV - 2 and SAR
were similar (325). These findings can be utilized for the development of specific
diagnostic tests against COVD-19.

Laboratory testing for coronavirus disease 2019 (COVID 19) in

suspected human cases
The assessment of the patients with COVID - 19 should be based on the clinical
features and also epidemiological factors. The screening protocols must be
prepared and followed per the native context. 31 Collecting and testing of
specimen samples from the suspected individual is considered to be one of the
main principles for controlling and managing the outbreak of the disease in a
country. The suspected cases must be screened thoroughly in order to detect the
virus with the help of nucleic acid amplification tests such as reverse transcription
polymerase chain reaction (RT PCR). If a country or a particular region does not
have the facility to test the specimens, the specimens of the suspected individual
should be sent to the nearest reference laboratories per the list provided by
WHO.32

It is also recommended that the suspected patients be tested for the other
respiratory pathogens by performing the routine laboratory investigation per the
local guidelines, mainly to differentiate from other viruses that include influenza
virus, parainfluenza virus, adenovirus, respiratory syncytial virus, rhinovirus,
human. anti - SARS - CoV - 2 activity is far higher than the maximum plasma
concentration achieved by administering the approved dose (340). However,
ivermectin, being a host - directed agent, exhibits antiviral activity by targeting a
critical cellular process of the mammalian cell. Therefore, the administration of
ivermectin, even at lower doses, will reduce the viral load at a minor level. This
slight decrease will provide a great advantage to the immune system for mounting
a large - scale antiviral response against SARS - CoV - 2 (341). Further, a
combination of ivermectin and hydroxychloroquine might have a synergistic
effect, since ivermectin reduces viral replication, while hydroxychloroquine
inhibits the entry of the virus in the host cell (339).
Further, in vivo studies and randomized clinical control trials are required to
understand the mechanism as well as the clinical utility of this promising drug.
Nafamostat is a potent inhibitor of MERS - CoV that acts by preventing
membrane fusion. Nevertheless, it does not have any sort of inhibitory action
against SARS - CoV - 2 infection (194).

Recently, several newly synthesized halogenated triazole compounds were

evaluated, using fluorescence resonance energy transfer (FRET) based helicase
assays, for their ability to inhibit.

12 EARLY SUPPORTIVE THERAPY AND MONITORING

Management of patients with suspected or documented COVID - 19 consists of
ensuring appropriate infection control and supportive care.
WHO and the CDC posted clinical guidance for COVID - 19.59 Immediate
therapy of add - on oxygen must be started for patients with severe acute
respiratory infection ( SARI ) and respiratory the initial stages of the outbreak ,
only mild symptoms were noticed in those patients that are infected by human -
to - human transmission (14).
The initial trends suggested that the mortality associated with COVID - 19 was
less than that of previous outbreaks of SARS (101). The updates obtained from
countries like
China, Japan, Thailand, and South Korea indicated that the COVID - 19 patients
had relatively mild manifestations compared to those with SARS and MERS (4).
Regardless of the coronavirus type, immune cells, like mast cells, that are present
in the submucosa of the respiratory tract and nasal cavity are considered the
primary barrier against this virus (92). Advanced in - depth analysis of the
genome has identified 380 amino acid substitutions between the amino acid
sequences of ARS - CoV - 2 and the SARS / SARS - like coronaviruses. These
differences in the amino acid sequences might have contributed to the difference
in the
pathogenic divergence of SARS - CoV - 2 Further research is required to evaluate
the differences in tropism, pathogenesis, transmission of this novel agent
associated with this change in the amino acid sequence. With the current observed
through both in vivo and in vitro experiments. There is an enhanced nasal
secretion observed along with local oedema because of the damage of the host
cell, which further stimulates the synthesis of inflammatory mediators.
In addition, these reactions can induce sneezing, difficulty breathing by causing
airway inhibition and elevate mucosal temperature. These viruses, when released,
chiefly affect the lower respiratory tract, with the signs and symptoms existing
clinically.
Also, the virus further affects the intestinal lymphocytes, renal cells, liver cells.
and T - lymphocytes. Furthermore, the virus induces T - cell apoptosis, causing
the reaction of the T - cell to be erratic, resulting in the immune system's complete
collapse. 24, 25

Mode of transmission
In fact, it was accepted that the original. transmission originated from a seafood
market, which had a tradition of selling live animals, where the majority of the
patients had either worked or visited, although up to now the understanding of
the COVID - 19 transmission risk remains incomplete. 16 In addition, while the
newer patients had no exposure to the market and still got the virus from the
humans present there, there is an increase in the outbreak.
CEPI has also funded Moderna to develop a vaccine for COVID - 19 in
partnership with the Vaccine Research Center (VRC) of the National Institute of
Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health
(NIH) (182). By employing mRNA vaccine platform technology, a vaccine
candidate expressing SARS - CoV - 2 spike protein is likely to go through clinical
testing in the coming months (180).
On 16 March 2020, Jennifer Haller became the first person outside China to
receive an experimental vaccine, developed by Moderna, against this pandemic
virus. Moderna, along with China's CanSino Biologics, became the first research
group to launch small clinical trials of vaccines against COVID - 19.
Their study is evaluating the vaccine's safety and ability to trigger immune
responses (296).
Scientists from all over the world are trying hard to develop working vaccines
with robust protective immunity against COVID - 19. Vaccine candidates, like
mRNA - 1273 SARS - CoV - 2 vaccine, INO - 4800 DNA coronavirus vaccine,
and adenovirus type 5 vector vaccine candidate (Ad5 - nCoV), are a few examples
under phase I clinical trials, while self-amplifying RNA vaccine, oral
recombinant COVID 19 vaccines, BNT162, plant - based COVID - 19 vaccine,
and li - Key peptide COVID - 19 vaccine are
Immunomodulatory agents.
SARS - CoV - 2 triggers a strong immune response which may cause cytokine
storm syndrome 60,61. Thus, immunomodulatory agents that inhibit the
excessive inflammatory response may be a potential adjunctive therapy for
COVID - 19.
Dexamethasone is a corticosteroid often used in a wide range of conditions to
relieve inflammation through its anti - inflammatory and immunosuppressant
effects.
Recently, the RECOVERY trial found dexamethasone reduced mortality by
about one third in hospitalized patients with COVID - 19 who received invasive
mechanical ventilation and by one fifth in patients receiving oxygen.
By contrast, no benefit was found in patients without respiratory support¹46.
Tocilizumab and sarilumab, two types of interleukins - 6 (IL - 6) receptor -
specific antibodies previously used to treat various types of arthritis , including
rheumatoid arthritis , and cytokine release syndrome , showed effec tiveness in
the treatment of severe COVID - 19 by atten uating the cytokine storm in a small
uncontrolled trial¹47 .
Bevacizumab is an anti - vascular endothelial growth factor (VEGF) medication
that could potentially reduce pulmonary oedema in patients with severe COVID
- 19.
Eculizumab is a specific monoclonal antibody that inhibits the proinflammatory
complement protein C5. Preliminary results showed that it induced a drop of
inflammatory markers and C - reactive protein levels, suggesting its potential to
be an option for the treatment of severe COVID - 19 (REF.¹48).

performance (Table 2) (80, 245, 246). The viral loads of SARS - CoV - 2 were
measured using N - gene specific quantitative RT - PCR in throat swab and
sputum samples collected from COVID - 19 - infected individuals.
The results indicated that the viral load peaked at around 5 to 6 days following
the onset of symptoms, and it ranged from 104 to 107 copies / ml during this time
(151).
In another study, the viral load was found to be higher in the nasal swabs than the
throat swabs obtained from COVID - 19 symptomatic patients (82). Although
initially it was thought that viral load would be associated with poor outcomes,
some case reports have shown. asymptomatic individuals with high viral loads
(247). Recently, the viral load in nasal and throat swabs of 17 symptomatic
patients were determined, and higher viral loads were recorded soon after the 92
onsets of symptoms, particularly in the nose compared to the throat. The pattern
of viral nucleic acid shedding of SARS - CoV - 2 - infected patients was similar
to that of influenza patients but seemed to be different from that of SARS - CoV
patients. The viral load detected in asymptomatic patients resembled that of
symptomatic patients as studied in China, which reflects the transmission
perspective of asymptomatic or symptomatic patients having minimum signs and
symptoms (82). Another study, A suspected case of COVID - 19 infection is said
to be confirmed if the respiratory tract aspirate or blood samples test positive for
SARS - CoV - 2 nucleic acid using RT - PCR or by the identification of SARS
CoV - 2 genetic sequence in respiratory tract aspirate or blood samples (80) .
The patient will be confirmed as cured when two subsequent oral swab results are
negative (153). Recently, the live virus was detected in the self - collected saliva
of patients infected with COVID - 19.
These findings were confirmative of using saliva as a noninvasive specimen for
the diagnosis of COVID - 19 infection in suspected individuals (152).
It has also been observed that the initial screening of COVID - 19 patients infected
with RT - PCR may give negative results even if they have chest CT findings that
are suggestive of infection. Hence, for the accurate diagnosis of COVID - 19, a
combination of repeated swab tests using RT - PCR and CT scanning is required
to prevent the possibility of false - negative results during disease screening (154).
RT - PCR is the most widely used test for diagnosing COVID - 19. However, it
has some significant limitations from the clinical perspective, since it will not
give any clarity regarding disease progression. Droplet digital PCR ( ddPCR ) can
be used for the quantification of viral load in the samples obtained from lower
respiratory tracts .
in vitro and in vivo 155-158. Compared with convalescent plasma, which has
limited availability and cannot be amplified, monoclonal antibodies can be
developed in larger quantities to meet clinical requirements.
Hence, they provide the possibility for the treatment and prevention of COVID
- 19. The neutralizing epitopes of these monoclonal antibodies also offer
important information for vaccine design. However, the high cost and limited
capacity of manufacturing, as well as the problem of bioavailability, may restrict
the wide application of monoclonal antibody therapy.

Vaccines
Vaccination is the most effective method for a long - term strategy for
prevention and control of COVID - 19 in the future. Many different vaccine
platforms against SARS - CoV - 2 are in development, the strategies of which
include recombinant vectors, DNA, mRNA in lipid nano particles, inactivated
viruses, live attenuated viruses and protein subunits 159-161. As of 2 October
2020, ~ 174 vac cine candidates for COVID - 19 had been reported and 51 were
in human clinical trials (COVID - 19 vaccine and therapeutics tracker). Many
of these vac cine candidates are in phase II testing, and some have already
advanced to phase III trials. A randomized double - blinded phase II trial of an
adenovirus type = vectored vaccine expressing the SARS - CoV - 2 S protein,
developed by CanSino Biologicals and the Academy of Military Medical
Sciences of China, was conducted in 603 adult volunteers in Wuhan.
The vaccine has proved to be safe and induced considerable humoral and cel lular
immune response in most recipients after a single immunization 162. Another
vectored vaccine, ChAdOx1, 101.

Origin and Spread of COVID - 19 [ 1, 2, 6]

In December 2019, adults in Wuhan, capital city of Hubei province and a major
transportation hub of China started presenting to local hospitals with severe
pneumonia of unknown cause.
Many of the initial cases had a common exposure to the Huanan wholesale
seafood market that also traded live animals. The surveillance system (put into
place after the SARS outbreak) was activated and respiratory samples of patients
were sent to reference labs for etiologic investigations.
On December 31st 2019, China notified the outbreak to the World Health
Organization and on 1st January the Huanan Sea food market was closed. On 7th
January the virus was identified as a coronavirus that had > 95 % homology with
the bat.
Inhibition of virus replication. Replication inhibitors include remdesivir (GS -
5734), favilavir (T - 705), riba virin, lopinavir and ritonavir. Except for lopinavir
and ritonavir, which inhibit 3CLpro, the other three all target RdRp128,135 (FIG.
5). Remdesivir has shown activity against SARS - CoV - 2 in vitro and in vivo
¹28.136. A clinical study revealed a lower need for oxygen support in patients
with COVID - 19 (REF.137).
Preliminary results of the Adaptive COVID - 19 Treatment Trial (ACTT) clinical
trial by the National Institute of Allergy and Infectious Diseases (NIAID)
reported that remdesivir can shorten the recovery time in hospitalized adults with
COVID - 19 by a couple days compared with placebo, but the difference in
mortality was not statistically significant ¹3. The FDA has issued an emergency
use authorization for rem desivir for the treatment of hospitalized patients with
severe COVID - 19. It is also the first approved option by the European Union
for treatment of adults and adoles cents with pneumonia requiring supplemental
oxygen.
Several international phase III clinical trials are contin uing to evaluate the safety
and efficacy of remdesivir for the treatment of COVID - 19. Favilavir (T - 705),
which is an antiviral drug developed in Japan to treat influenza, has been
approved in China, Russia and India for the treatment of COVID - 19.
A clinical study in China showed that favilavir significantly reduced the signs of
improved disease signs on chest imaging and shortened the time to viral
clearance¹³9.
A preliminary report in Japan showed rates of clinical improvement of 73.8 %
and 87.8 % from the start of favilavir therapy in patients with mild COVID - 19
at 7 and 14 days, respectively, and 40.1 % and 60.3 % in patients with severe
COVID - 19 at 7 and 14 days, residues for receptor binding (FIG. 3b). In
comparison with the Guangdong strains, pangolin coronaviruses reported from
Guangxi are less similar to SARS - CoV - 2, with 85.5 % genome sequence
identity “.
The repeated occurrence of SARS - CoV - 2 - related coronavirus infec tions in
pangolins from different smuggling events suggests that these animals are
possible hosts of the viruses.
However, unlike bats, which carry coronaviruses healthily, the infected
pangolins showed clinical signs and histopathological changes, including
interstitial pneumonia and inflammatory cell infiltration in diverse organs 40.
These abnormalities suggest that pangolins are unlikely to be the reservoir of
these coronaviruses but more likely acquired the viruses after spillover from the
natural hosts.
An intermediate host usually plays an important role in the outbreak of bat -
derived emerging coronaviruses; for example, palm civets for SARS - CoV and
dromedary camels for MERS - CoV.
The virus strains carried by these two intermediate hosts were almost genetically
identical to the corresponding viruses in humans (more than 99 % genome
sequence identity) ¹.
Despise an RBD that is virtually identical to that of SARS - CoV - 2, the pangolin
coronaviruses known to date have no more than 92 % genome identity with SARS
- CoV - 2 (REF. 2).
The available data are insufficient to interpret pangolins as the intermediate host
of SARS - CoV - 2. So far, no evidence has shown that pangolins were directly
involved in the emergence of SARS - CoV – 2 able data are insufficient to
interpret pangolins as the intermediate host of SARS - CoV - 2. So far, no
evidence has shown that pangolins were directly involved in the emergence of
SARS - CoV - 2. absence of this protein is related to the altered virulence of
coronaviruses due to changes in morphology and tropism ( 54 ) . The E protein
consists of three domains , namely , a short hydrophilic amino terminal , a large
hydrophobic transmembrane domain , and an efficient C - terminal domain ( 51 )
. The SARS - CoV - 2 E protein reveals a similar amino acid constitution without
any substitution (16) .

N Protein
The N protein of coronavirus is multipurpose. Among several functions, it plays
a role in complex formation with the viral genome, facilitates M protein
interaction needed during virion assembly, and enhances the transcription
efficiency of the virus (55, 56). It contains three highly conserved and distinct
domains, namely, an NTD, an RNA - binding domain or a linker region (LKR),
and a CTD (57). The NTD binds with the 3 ' end of the viral genome, perhaps
via electrostatic interactions, and is highly diverged both in length and sequence
(58 ) .
The charged LKR is serine and arginine rich and is also known as the SR ( serine
and arginine ) domain ( 59 ) . The LKR is capable of direct interaction with in
vitro RNA interaction and is responsible for cell signaling ( 60 , 61 ) .
It also modulates the antiviral response of the host by working as an antagonist
for interferon

Princess , Celebrity Apex , and Ruby Princess . The number of confirmed COVID
- 19 cases around the world is on the rise . The success of preventive measures
put forward by every country is mainly dependent upon their ability to anticipate
the approaching waves of patients .
This will help to properly prepare the health care workers and increase the
intensive care unit ( ICU ) capacity ( 321 ) . Instead of entirely relying on
lockdown protocols , countries should focus mainly on alternative intervention
strategies , such as large - scale testing , contract tracing , and localized quarantine
of suspected cases for limiting the spread of this pandemic virus . Such
intervention strategies will be useful either at the beginning of the pandemic or
after lockdown relaxation ( 322 ) .
Lockdown should be imposed only to slow down disease progression among the
population so that the health care system is not overloaded
.
The reproduction number ( Ro ) of COVID - 19 infection was earlier estimated
to be in the range of 1.4 to 2.5 ( 70 ) ; recently , it was estimated to be 2.24 to 3.58
( 76 ) . Compared to its coronavirus predecessors, COVID - 19 has an Ro value
that is greater than that of MERS ( Ro < 1 ) ( 108 ) but less than that of SARS (
Ro value of 2 to 5 ) ( 93 ) . Still, to prevent further spread of disease at mass
gatherings, rom experience with several outbreaks associated with known
emerging viruses, higher pathogenicity of a virus is often associated with lower
transmissibility. Compared to emerging viruses like Ebola virus, avian H7N9,
SARS - CoV, and MERS - CoV , SARS - CoV - 2 has relatively lower
pathogenicity and moderate transmissibility ( 15 ) . The risk of death among
individuals infected with COVID - 19 was calculated using the infection fatality
risk ( IFR ) . The IFR was found to be in the range of 0.3 % to 0.6 % , which is
comparable to that of a previous Asian influenza pandemic ( 1957 to 1958 ) (73,
277 ) . Notably, the reanalysis of the COVID - 19 pandemic curve from the initial
cluster of cases pointed to considerable human - to - human transmission.
It is opined that the exposure history of 112 SARS - CoV - 2 at the Wuhan seafood
market originated from human - to - human transmission rather than animal - to -
human transmission (74); however, in light of the zoonotic spillover in COVID -
19, is too early to fully endorse this idea (1).
Following the initial infection, human - to - human transmission has been
observed with a preliminary reproduction number (Ro) estimate of 1.4 to 2.5 (70,
75), and recently it is estimated to be 2.24 to 3.58 (76). In another study, the
average reproductive number of vitro antiviral potential of FAD - approved drugs,
viz., ribavirin, penciclovir, nitazoxanide, nafamostat , and chloroquine , tested in
comparison to remdesivir and favipiravir ( broad - spectrum antiviral drugs )
revealed remdesivir and chloroquine to be highly effective against SARS - CoV
- 2 infection in vitro ( 194 ) .
Ribavirin, penciclovir, and favipiravir might not possess noteworthy in vivo
antiviral actions for SARS - CoV - 2, since higher concentrations of these
nucleoside analogs are needed in vitro to lessen the viral infection. Both
remdesivir and chloroquine are being used in humans to treat other diseases,
and such safer drugs can be explored for assessing their effectiveness in COVID
- 19 patients. Several therapeutic agents, such as lopinavir / ritonavir,
chloroquine, and hydroxychloroquine, have been proposed for the clinical
management of COVID - 19 (299).
 A 113 molecular docking study, conducted in the RNA dependent RNA
polymerase (RdRp) of SARS - CoV - 2 using different commercially available
antipolymerase drugs, identified that drugs such as ribavirin, remdesivir,
galidesivir , tenofovir, and sofosbuvir bind RdRp tightly , indicating their vast
potential to be used against COVID - 19 ( 305 ) . A broad - spectrum antiviral
drug that was developed in the United States, tilorone dihydrochloride (tilorone),
Bovine coronaviruses (BoCoVs) are known to infect several domestic and wild
ruminants (126). BoCoV inflicts neonatal calf diarrhea in adult cattle, leading to
bloody diarrhea (winter dysentery) and respiratory disease complex (shipping
fever) in cattle of all age groups (126). BoCoV – like viruses have been noted in
humans, suggesting its zoonotic potential as well (127). Feline enteric and feline
infectious peritonitis (FIP) viruses are the two majors feline COVs (128), where
feline CoVs can affect the gastrointestinal tract, abdominal cavity (peritonitis),
respiratory tract, and central nervous system (128).
Canines are also affected by CoVs that fall under different genera, namely,
canine enteric coronavirus in Alphacoronavirus and canine respiratory
coronavirus in Betacoronavirus, affecting the enteric and respiratory tract,
respectively (129, 130).
IBV, under Gammacoronavirus, causes diseases of respiratory, urinary, and
reproductive systems, with substantial economic losses in chickens (131, 132).
In small laboratory animals, mouse hepatitis virus, rat sialodacryoadenitis
coronavirus, and guinea pig and rabbit coronaviruses are the major CoVs
associated with disease manifestations like enteritis, hepatitis, and respiratory
infections ( 10 , 133 ) . Swine acute diarrhea syndrome coronavirus.

13 CONVALESCENT PLASMA THERAPY

Guo Yanhong, an official with the National Health Commission (NHC), stated
that convalescent plasma therapy is a significant method for treating severe
COVID - 19 patients.
Among the COVID - 19 patients currently receiving convalescent plasma therapy
in the virus - hit Wuhan, one has been discharged from hospital, as reported by
Chinese science authorities on Monday, 17th February 2020 in Beijing.
The first dose of convalescent plasma from a COVID - 19 patient was collected
on 1st and 9th February 2020 from a severely ill patient who was given treatment
at a hospital in Jiangxia District in Wuhan.
The presence of the virus in patients is minimised by the antibodies in the
convalescent plasma.
Guiqiang stated that donating plasma may cause minimal harm to the donor and
that there is nothing to be worried about. Plasma donors must be cured patients
and discharged from hospital. Only plasma is used, whereas red blood cells
(RBC), white blood cells (WBC) and blood platelets are transfused back into the
donor's body. Wang alleged that donor's plasma will totally improve to its initial
state after one or 2 weeks from the day of plasma donation of around 200 to 300
millilitres.61 115
Chloroquine and hydroxychloroquine are other potential but controversial drugs
that interfere with the entry of SARS - CoV - 2. They have been used in the
prevention and treatment of malaria and autoimmune diseases, including
systemic lupus erythematosus and rheumatoid arthritis.
They can inhibit the glycosylation of cellular receptors and interfere with virus -
host receptor binding, as well as increase the endosomal pH and inhibit membrane
fusion. Currently, no scientific consensus has been reached for their efficacy in
the treatment of COVID - 19. Some studies showed they can inhibit SARS - CoV
- 2 infection in vitro, but the clinical data are insufficient 128,129.
Two clinical studies indicated no association with death rates in patients receiving
chloroquine or hydroxychloroquine compared with those not receiving the drug
and even suggest it may increase the risk of dying as a higher risk of cardiac arrest
was found in the treated patients 130,131.
On 15 June 2020, owing to the side effects observed in clinical trials, the US Food
and Drug Administration (FDA) revoked the emergency use authorization for
chloroquine and hydroxychloroquine for the treatment of COVID - 19.
Another potential therapeutic strategy is to block bind ing of the S protein to
ACE2 through soluble recombinant hACE2, specific monoclonal antibodies or
fusion inhibitors that target the SARS - CoV - 2 S protein ¹32-134 (FIG. 5).
The safety and efficacy of these strategies need to be assessed in future clinical
trials.
Chloroquine and hydroxychloroquine are other potential but controversial drugs
that interfere with the entry of SARS - CoV - 2. They have been used in the
prevention and treatment of malaria and autoimmune diseases, including
systemic lupus erythematosus and rheumatoid arthritis.
They can inhibit the glycosylation of cellular receptors and interfere with virus -
host receptor binding, as well as increase the endosomal pH and inhibit membrane
fusion. Currently, no scientific consensus has been reached for their efficacy in
the treatment of COVID - 19. Some studies showed they can inhibit SARS - CoV
- 2 infection in vitro, but the clinical data are insufficient 128,129.
Two clinical studies indicated no association with death rates in patients receiving
chloroquine or hydroxychloroquine compared with those not receiving the drug
and even suggest it may increase the risk of dying as a higher risk of cardiac arrest
was found in the treated patients 130,131.
On 15 June 2020, owing to the side effects observed in clinical trials, the US Food
and Drug Administration (FDA) revoked the emergency use authorization for
chloroquine and hydroxychloroquine for the treatment of COVID - 19.
Another potential therapeutic strategy is to block binding of the S protein to
ACE2 through soluble recombinant hACE2, specific monoclonal antibodies or
fusion inhibitors that target the SARS - CoV - 2 S protein ¹32-134 (FIG. 5).
The safety and efficacy of these strategies need to be assessed in future clinical
trials.
Chloroquine and hydroxychloroquine are other potential but controversial drugs
that interfere with the entry of SARS - CoV - 2. They have been used in the
prevention and treatment of malaria and autoimmune diseases, including
systemic lupus erythematosus and rheumatoid arthritis.
They can inhibit the glycosylation of cellular receptors and interfere with virus -
host receptor binding, as well as increase the endosomal pH and inhibit membrane
fusion.
Currently, no scientific consensus has been reached for their efficacy in the
treatment of COVID - 19. Some studies showed they can inhibit SARS - CoV - 2
infection in vitro, but the clinical data are insufficient 128,129.
Two clinical studies indicated no association with death rates in patients receiving
chloroquine or hydroxychloroquine compared with those not receiving the drug
and even suggest it may increase the risk of dying as a higher risk of cardiac arrest
was found in the treated patients 130,131.
On 15 June 2020, owing to the side effects observed in clinical trials, the US Food
and Drug Administration ( FDA ) revoked the emergency use authorization for
chloroquine and hydroxychloroquine for the treatment of COVID - 19.
 Another potential therapeutic strategy is to block binding of the S protein to
ACE2 through soluble recombinant hACE2, specific monoclonal antibodies or
fusion inhibitors that target the SARS - CoV - 2 S protein ¹32-134 (FIG. 5).
The safety and efficacy of these strategies need to be assessed in future clinical
trials.
N Protein
The N protein of coronavirus is multipurpose. Among several functions, it plays
a role in complex formation with the viral genome, facilitates M protein
interaction needed during virion assembly, and enhances the transcription
efficiency of the virus (55, 56).

It contains three highly conserved and distinct domains, namely, an NTD, an

RNA - binding domain or a linker region (LKR), and a CTD (57). The NTD binds
with the 3 ' end of the viral genome, perhaps via electrostatic interactions, and is
highly diverged both in length and sequence (58).

The charged LKR is serine and arginine rich and is also known as the SR (serine
and arginine) domain (59). The LKR is capable of direct interaction with in vitro
RNA interaction and is responsible for cell signaling (60, 61).
It also modulates the antiviral response of the host by working as an antagonist
for interferon (IFN) and RNA interference (62). Compared to that of SARS -
CoV, the N protein of SARS - CoV - 2 possess five amino acid mutations, where
two are in the intrinsically dispersed region (IDR; positions 25 and 26), one each
in the NTD (position 103), LKR (position 217), and CTD (position 334) (16).
other emerging viral diseases. Several therapeutic and preventive strategies,
including vaccines, immunotherapeutics, and antiviral drugs, have been exploited
against the previous CoV outbreaks (SARS - CoV and MERS - CoV) (8, 104,
164-167).
These valuable options have already been evaluated for their potency, efficacy,
and safety, along with several other types of current research that will fuel our
search for ideal therapeutic agents against COVID - 19
(7, 9, 19, 21, 36).
The primary cause of the unavailability of approved and commercial vaccines,
drugs, and therapeutics to counter the earlier SARS - CoV and MERS - CoV
seems to owe to the lesser attention of the biomedicine and pharmaceutical
companies , as these two CoVs did not cause much havoc , global threat , and
panic like those posed by the SARS - CoV - 2 pandemic ( 19 ) . Moreover, for
such outbreak situations, the requirement for vaccines and therapeutics / drugs
exists only for a limited period, until the outbreak is controlled. The proportion
of the human population infected with SARS - CoV and MERS - CoV was also
much lower across the globe, failing to attract drug and vaccine manufacturers
and producers. Therefore, by the time an effective drug or vaccine is designed
against such disease outbreaks, the virus would have been controlled by adopting
appropriate and strict health emergency on 31 January 2020; subsequently, on 11
March 2020, they declared it a pandemic situation. At present, we are not in a
position to effectively treat COVID - 19, since neither approved vaccines nor
specific antiviral drugs for human CoV infections are available (7-9 nations are
currently making efforts to prev further spreading of this potentially deadly virus
by implementing preventive and control strategies other emerging viral diseases.
Several therapeutic and preventive strategies, including vaccines,
immunotherapeutic, and antiviral drugs, have been exploited against the previous
CoV outbreaks (SARS - CoV and MERS - CoV ) (8, 104 , 164-167 ) .
These valuable options have already been evaluated for their potency, efficacy,
and safety, along with several other types of current research that will fuel our
search for ideal therapeutic agents against COVID – 19 (7, 9, 19, 21, 36).
The primary cause of the unavailability of approved and commercial vaccines,
drugs, and therapeutics to counter the earlier SARS - CoV and MERS - CoV
seems to owe to the lesser attention of the biomedicine and pharmaceutical
companies, as these two CoVs did not cause much havoc, global threat, and panic
like those posed by the SARS - CoV - 2 pandemic (19). Moreover, for such
outbreak situations, the requirement for vaccines and therapeutics / drugs exists
only for a limited period, until the outbreak is controlled.
The proportion of the human population infected with SARS - CoV and MERS -
CoV was also much lower across the globe, failing to attract drug and vaccine
manufacturers and producers. Therefore, by the time an effective drug or vaccine
is designed against such disease outbreaks, the virus would have been controlled
by adopting appropriate and strict health emergency on 31 January 2020;
subsequently, on 11 March 2020, they declared it a pandemic situation.
At present, we are not in a position to effectively treat COVID - 19, since neither
approved vaccines nor specific antiviral drugs for human CoV infections are
available (7-9 nations are currently making efforts to prev further spreading of
this potentially deadly virus by implementing preventive and control strategies
there has been concern regarding the impact of SARS - CoV - 2 / COVID - 19 on
pregnancy. Researchers have mentioned the probability of in utero transmission
of novel SARS - CoV - 2 from COVID 19 - infected mothers to their neonates in
China based upon the rise in IgM and IgG antibody levels and cytokine values in
the blood obtained from newborn infants immediately postbirth ; however , RT -
PCR failed to confirm the presence of SARS - CoV - 2 genetic material in the
infants ( 283 ).
Recent studies show that at least in some cases, preterm delivery and its
consequences are associated with the virus. Nonetheless, some cases have raised
doubts for the likelihood of vertical transmission (240-243). COVID - 19
infection.
was associated with pneumonia, and some developed acute respiratory distress
syndrome (ARDS). The blood biochemistry indexes, such as albumin, lactate
dehydrogenase, C reactive protein, lymphocytes (percent), and neutrophils
(percent) give an idea about the disease severity in COVID - 19 infection (121).
During COVID - 19, patients may present leukocytosis leukopenia with
lymphopenia (244), hypoalbuminemia, and an increase of lactate dehydrogenase,
aspartate transaminase, alanine aminotransferase, bilirubin, and, especially, D -
dimer GOAN M 1 11 1 significance of frequent and good hand hygiene and
sanitation practices needs to be given due emphasis (249-252). Future explorative
research needs to be conducted with regard to the fecal - oral transmission of
SARS - CoV - 2, along with focus in environmental investigations to find out if
they could stay viable in situations and atmosp facilitating such potent routes of
transmission.

Children and elderly population

On the basis of the available reports, COVID - 19 among children accounted for
1-5 % of the confirmed cases, and this population does not seem to be at higher
risk for the disease than adults.
There is no difference in the COVID - 19 symptoms between adults and children.
However, the available evidence indicated that children diagnosed with COVID
- 19 have milder symptoms than the adults, with a low mortality rate.
 2.48, 49 On the contrary, older people who are above the age of 65 ars are at
higher risk for a severe course of disease. In the United Stated, approximately 31-
59 % of those with confirmed COVID - 19 between the ages of 65 and 84 years
old required hospitalisation, 11-31 % of them required admission to the intensive
care unit, and 4-11 % died.50 primary anti - genic epitopes mainly those
recognised by neutralising antibodies.
The spike S - protein being in a spike form is subjected to a structural
rearrangement process so that fusing the outer membrane of the virus with the
host cell membrane becomes easier. 19, 20 Recent SARS - CoV work has also
shown that the membrane exopeptidase ACE enzyme (angiotensin - converting
enzyme) functions as a COVID - 19 receptor to enter the human cell 21
respiratory infection (SARI) and respiratory distress, shock or hypoxaemia.
Patients with SARI can be given conservative fluid therapy only when there is no
evidence of shock. Empiric antimicrobial therapy must be started to manage
SARI.
For patients with sepsis, antimicrobials must be administered within 1 hour of
initial assessments. The WHO and CDC recommend that glucocorticoids not be
used in patients with COVID - 19 pneumonia except where there are other
indications (exacerbation of chronic obstructive pulmonary disease). 5⁹ Patients '
clinical deterioration is closely observed with SARI; however, rapidly
progressive respiratory failure and sepsis require immediate supportive care
interventions comprising quick use of neuromuscular blockade and sedatives,
hemodynamic management, nutritional support, maintenance of blood glucose
levels, prompt assessment and treatment of nosocomial pneumonia, and
prophylaxis against deep venous thrombosis (DVT) and gastrointestinal (GI)
bleeding. 60 Generally, such patients give way to their primary illness to
secondary complications like sepsis or multiorgan system failure.48 countries.
Large - scale screening programs might help us to control the spread of this virus.
However, this is both challenging as well as time - consuming due to the present
extent of infection (226 current scenario demands effective implem of vigorous
prevention and control strategies to the prospect of COVID -19 for nosocomial
infaationa ( 68 ) anitation practices needs to be given due emphasis ( 249-252 ) .
Future explorative research needs to be conducted with regard to the fecal - oral
transmission of SARS - CoV - 2, along with focusing on environmental
investigations to find out if this virus could stay viable in situations and
atmospheres facilitating such potent routes of transmission. The correlation of
fecal concentrations of viral RNA with disease severity needs to be determined,
along with assessing the gastrointestinal symptoms and the possibility of fecal
SARS - CoV - 2 RNA detection during the COVID - 19 incubation period or
convalescence phases of the disease (249-252). The lower respiratory tract
sampling techniques, like bronchoalveolar lavage fluid aspirate, are considered
the ideal clinical materials, rather than the throat swab, due to their higher positive
rate on the nucleic acid test (148).
The diagnosis of COVID 19 can be made by using upper - respiratory - tract
specimens collected using nasopharyngeal and oropharyngeal swabs. However,
these techniques are associated with unnecessary risks to health care 127 workers
due to close contact with patients (152). Similarly, a single patient with a high
viral load was reported to contaminate an entire endoscopy room by shedding the
virus, which may remain viable for at rates, disease outbreaks , community spread
, clustered transmission events , hot spots , and super spreader potential of SARS
- CoV - 2 / COVID warrant full exploitation of real - time mapping by employing
geographical info systems ( GIS ) , such as the GIS software Kosm web - based
real - time tools and dashboards, apps , and advances in information technology
( 356-359 ).

Animal Models and Cell Cultures

For evaluating the potential of vaccines and therapeutics against CoVs , including
SARS - CoV , MERS - CoVs , and the presently emerging SARS CoV - 2,
suitable animal models that can mimic the clinical disease are needed ( 211 , 212).
Various animal models were assessed for SARS- and MERS CoVs, such as mice,
guinea pigs, golden Syrian hamsters, ferrets, rabbits, nonhuman primates like
rhesus macaques and marmosets, and cats (185, 213-218).
The specificity of the virus to hACE2 (receptor of SARS - CoV) was found to be
a significant barrier in developing animal models. Consequently, a SARS - CoV
transgenic mouse model has been developed by inserting the hACE2 gene into
the mouse genome (219). The inability of MERS - CoV to replicate in the
respiratory tracts of animals (mice, hamsters, and ferrets) is another limiting
factor. However, with genetic engineering , a 288-330 ++ MERS - CoV
genetically modified mouse model was developed and now is in use for the
assessment of novel drugs and vaccines against MERS - CoV ( 220 ) . In the past,
small animals ( mice or hamsters ) have been targeted for being closer to a
humanized structure , such as mouse DPP4 altered with human DPP4 ( hDPP4 )
, hDPP4 – transduced mice , and hDPP4 - Tg mice ( transgenic for expressing a
polybasic cleavage site ( RRAR ), which enable tive cleavage by furin and other
proteases " . S1 - S2 cleavage site is not observed in all related belonging to the
subgenus Sarbecovirus, except for a similar three amino acid insertion (PAA) in
RmYN02, a polybasic cleavage site (RRAR), which enables effec tive cleavage
by furin and other proteases 27. Such an S1 - S2 cleavage site is not observed in
all related viruses belonging to the subgenus Sarbecovirus, except for a similar
three amino acid insertion (PAA) in RmYN02, a bat - derived coronavirus newly
reported from Rhinolophus malayanus in China (FIG. 3a). Although the insertion
in RmYN02 does not functionally represent a polybasic cleavage site, it provides
support for the notion that this characteristic, initially considered unique to SARS
- CoV - 2, has been acquired naturally 28. A structural study suggested that the
furin - cleavage site can reduce the stability of SARS - CoV - 2 S protein and
facilitate the conformational adaption that is required for the binding of the RBD
to its receptor ".
Whether the higher trans missibility of SARS - CoV - 2 compared with SARS -
CoV is a gain of function associated with acquisition of the furin - like cleavage
site is yet to be demonstrated ²6.
An additional distinction is the accessory gene orf8 of SARS - CoV - 2, which
encodes a novel protein showing only 40 % amino acid identity to ORF8 of SARS
- CoV. Unlike in SARS - CoV, this new ORF8 protein does not contain a motif
that triggers intracellular stress pathways 25. Notably, a SARS - CoV - 2 variant
with a 382 - nucleotide deletion covering the whole of ORF8 has been discovered
in a number of patients in Singapore, which resembles the 29- or 415 - nucleotide
deletions in the ORF8 region observed in human SARS - CoV variants from the
late phase of the 2002-2003 outbreak 30. Such ORF8 deletion may be indicative
of human adaptation after cross - species transmission from an animal host.
To on the constic variation of different CADS peutics, and regimens to counter
emerging viruses (161-163, 280).
Several attempts are made to design and develop vaccines for infection, mostly
by targeting the spike glycopre Nevertheless, owing to extensive diversity.

4 VIROLOGY

Coronaviruses, a family of viruses within the nidoviruses superfamily, are

further classified according to their genera, alpha-, beta-, gamma and delta
coronaviruses (a-, B-, y- and 8-). Among those, alpha and beta species are
capable of contaminating only mammals, whereas the other two genera can
infect birds and could also infect mammals.
13, 14 Two of these genera belong to human coronaviruses (HCOVs): a -
coronaviruses, which comprise human coronavirus 229E (hcov229E) and human
coronavirus NL63 (hcovNL63), and B coronaviruses, which are human
coronavirus HKU1, human coronavirus OC43, MERS - COV (known as Middle
East respiratory syndrome coronavirus) and SARS - CoV (referred to as severe
acute respiratory syndrome coronavirus).
15 The severe acute respiratory syndrome CoV - 2 (SARS - CoV - 2) is now
named novel COVID - 19 (coronavirus disease 2019).
16 Genome sequencing and phylogenetic research revealed that the COVID - 19
- causing coronavirus is a beta - coronavirus that belongs to the same subtypes as
SARS virus, but still lists a variant group. The receptor - binding gene region 147

4 VIROLOGY
Coronaviruses, a family of viruses within the nidoviruses superfamily, are
further classified according to their genera, alpha-, beta-, gamma and delta
coronaviruses (a-, B-, y- and 8- ).
Among those, alpha and beta species are capable of contaminating only
mammals, whereas the other two genera can infect birds and could also infect
mammals. 13, 14 Two of these genera belong to human coronaviruses (HCOVs):
a - coronaviruses, which comprise human coronavirus 229E (hcov229E) and
human coronavirus NL63 (hcovNL63 ) , and B coronaviruses , which are human
coronavirus HKU1, human coronavirus OC43 , MERS - COV ( known as Middle
East respiratory syndrome coronavirus ) and SARS - CoV ( referred to as severe
acute respiratory syndrome coronavirus ) .
15 The severe acute respiratory syndrome CoV - 2 (SARS - CoV - 2) is now
named novel COVID - 19 (coronavirus disease 2019).
Genome sequencing and phylogenetic research revealed that the COVID - 19 -
causing coronavirus is a beta - coronavirus that belongs to the same subtypes as
SARS virus, but still lists a variant group. The receptor - binding gene region 147
Serological testing
Serological surveys are also considered to be one of the most effective ones in
facilitating outbreak investigation and it also helps us to derive a retrospective
assessment of the disease by estimating the attack rate.32 According to the recent
literature , paired serum samples can also help clinicians to diagnose COVID - 19
in case of false negative results in NAAT essays.37 The literature also declared
that the commercial and non - commercial serological tests are under
consideration in order to support the practising clinicians by assisting them in
diagnosis . Similarly, there are studies published on COVID - 19 which are
comprised of the serological data on clinical samples.

Viral sequencing
Apart from confirming the presence of virus in the specimens, viral sequencing
is also quite useful in monitoring the viral genomic mutations, which plays a very
significant role in influencing the performance of the medical countermeasures
inclusive of the diagnostic test. Genomic sequencing of the virus can also help
further in developing several studies related to molecular epidemiology, 32 in
asymptomatic patients. These abnormalities progress from the initial focal
unilateral to diffuse bilateral ground - glass opacities and will further progress to
or coexist with lung consolidation changes within 1 to 3 weeks (159).
The role played by radiologists in the current scenario is very important.
Radiologists can help in the early diagnosis of lung abnormalities associated with
COVID - 19 pneumonia.
They can also help in the evaluation of disease severity, identifying its
progression to acute respiratory distress syndrome and the presence of secondary
bacterial infections (160). Even though chest CT is considered an essential
diagnostic tool for COVID - 19, the extensive use of CT for screening purposes
in the suspected individuals might be associated with a disproportionate risk -
benefit ratio due to increased radiation exposure as well as increased risk of cross
infection.
Hence, the use of CT for early diagnosis of SARS - CoV - 2 infection in high -
risk groups should be done with great caution (292). More recently, other
advanced diagnostics have been designed and developed for the detection of
SARS - CoV - 2 (345, 347, 350-352). A reverse transcriptional loop - mediated
isothermal amplification (RT - LAMP), namely, iLACO, has been developed for
rapid and colorimetric detection of this administration of the recombinant
adenovirus - based vaccine in BALB / c mice was found to induce l lasting
neutralizing immunity against MER pseudotyped virus, characterized by the
induc systemic IgG , secretory IgA , and lung - resident memory T - cell responses
( 177 ) .
We assessed the nucleotide percent similarity using the MegAlign software
program, where the similarity between the novel SARS - CoV -
2 isolates were in the range of 99.4 % to 100 %. Among the other Serbecovirus
CoV sequences, the novel SARS - CoV 2 sequences revealed the highest
similarity to bat SL - CoV, with nucleotide percent identity ranges between 88.12
and 89.65 %. Meanwhile, earlier reported SARS - CoVs showed 70.6 to 74.9 %
similarity to SARS - CoV - 2 at the nucleotide level. Further, the nucleotide
percent similarity was 55.4 %, 45.5 % to 47.9%, 46.2 % to 46.6 %, and 45.0 %
to 46.3 % to the other four subgenera, namely, Hibecovirus, Nobecovirus,
Merbecovirus, and Embecovirus, respectively. The percent similarity index of
current outbreak isolates indicates a close relationship between SARS - CoV - 2
isolates and bat SL - CoV, indicating a common origin. However, particular
pieces of evidence based on further complete genomic analysis of current isolates
are necessary to draw any conclusions, although it was ascertained that the current
novel SARS - CoV - 2 isolates belong to the subgenus Sarbecovirus in the diverse
range of betacoronaviruses. Their possible ancestor was hypothesized to be from
bat CoV strains, wherein bats might have played a crucial role in harboring this
class of viruses. dogs have low susceptibility, while the chickens, ducks, and pigs
are not at all susceptible to SARS CoV - 2 (329). Similarly, the National
Veterinary Services Laboratories of the USDA have reported CO in tigers and
lions that exhibited respirator like dry cough and wheezing. The zoo animals are
suspected to have been infected by an asymptomatic 88.
We assessed the nucleotide percent similarity using the MegAlign software
program, where the similarity between the novel SARS - CoV - 2 isolates was in
the range of 99.4 % to 100 %.
Among the other Serbecovirus CoV sequences, the novel SARS - CoV 2
sequences revealed the highest similarity to bat SL - CoV, with nucleotide percent
identity ranges between 88.12 and 89.65 %.
Meanwhile, earlier reported SARS - CoVs showed 70.6 to 74.9 % similarity to
SARS - CoV - 2 at the nucleotide level. Further, the nucleotide percent similarity
was 55.4 %, 45.5 % to 47.9 %, 46.2 % to
46.6 %, and 45.0 % to 46.3 % to the other four subgenera, namely, Hibecovirus,
Nobecovirus, Merbecovirus, and Embecovirus, respectively. The percent
similarity index of current outbreak isolates indicates a close relationship between
SARS - CoV - 2 isolates and bat SL - CoV, indicating a common origin. However,
particular pieces of evidence based on further complete genomic analysis of
current isolates are necessary to draw any conclusions, although it was
ascertained that the current novel SARS - CoV - 2 isolates belong to the subgenus
Sarbecovirus in the diverse range of betacoronaviruses. Their possible ancestor
was hypothesized to be from bat CoV strains, wherein bats might have played a
crucial role in harboring this class of viruses. dogs have low susceptibility, while
the chickens, ducks, and pigs are not at all susceptible to SARS CoV - 2 (329).
Similarly, the National Veterinary Services Laboratories of the USDA have
reported CO in tigers and lions that exhibited respirator like dry cough and
wheezing. The zoo animals are suspected to have been infected by an
asymptomatic 88 animal species is necessary to prevent the possibility of virus
spread and initiation of an outbreak due to zoonotic spillover (1) . Personal
protective equipment (PPE), like face masks, will help to prevent the spread of
respiratory infections like COVID - 19.
Face masks not only protect from infectious aerosols but also prevent the
transmission of disease to other susceptible individuals while traveling through
public transport systems (313).
Another critical practice that can reduce the transmission of respiratory diseases
is the maintenance of hand hygiene. However, the efficacy of this practice in
reducing the transmission of respiratory viruses like SARS - CoV - 2 is much
dependent upon the size of droplets produced.
Hand hygiene will reduce disease transmission only if the virus is transmitted
through the formation of large droplets (314).
Hence, it is better not to overemphasize that hand hygiene will prevent the
transmission of SARS - CoV - 2, since it may produce a false sense of safety
among the general public that further contributes to the spread of COVID - 19.
Even though airborne spread has not been reported in SARS - CoV - 2 infection,
transmission can occur through droplets and fomites, especially when there is
close, unprotected contact between infected and susceptible individuals. health
emergency on 31 January 2020; subsequently, on 11 March 2020, they declared
it a pandemic situation. At present, we are not in a position to effectively treat
COVID - 19,
since neither approved vaccines nor specific antiviral drugs for treating human
CoV infections are available (7-9). Most nations are currently making efforts to
prevent the further spreading of this potentially deadly virus by implementing
preventive and control strategies.
In domestic animals, infections with CoVs are associated with a broad spectrum
of pathological conditions. Apart from infectious bronchitis virus, canine
respiratory CoV, and mouse hepatitis virus, CoVs are predominantly associated
with gastrointestinal diseases (10). The emergence of novel CoVs
may have become possible because of multiple CoVs being maintained in their
natural host, which could have favored the probability of genetic recombination
(10).
High genetic diversity and the ability to infect multiple host species are a result
of 123 high - frequency mutations in CoVs , which occur due to the instability of
RNA - dependent RNA polymerases along with higher rates of homologous RNA
recombination ( 10 , 11 ) . Identifying the origin of SARS - CoV - 2 and the
pathogen's evolution will be helpful for disease surveillance (12), development
of RBD, indicating its potential as a therapeutic agent in the management of
COVID - 19.
It can be used alone or in combination with other effective neutralizing antibodies
for the treatment prevention of COVID - 19 (202).
Furthermore, CoV - specific neutralizing antibodies, like m396 and CR3014,
failed to bind the S protein of SARS – CoV hamsters) have been targeted for
being closer to a humanized structure, such as mouse DPP4 altered with
human DPP4 (hDPP4), hDPP4 - transduced mice, and hDPP4 - Tg mice
(transgenic for expressing a polybasic cleavage site (RRAR), which enables
effec tive cleavage by furin and other proteases ²7. Such an S1 - S2 cleavage
site is not observed in all related viruses belonging to the subgenus
Sarbecovirus, except for a similar three amino acid insertion (PAA) in
RmYN02, a bat - derived coronavirus newly reported from Rhinolophus
malayanus in China28 (FIG. 3a). Although the insertion in RmYN02 does
not functionally represent a polybasic cleavage site, it provides support for
the notion that this characteristic, initially considered unique to SARS - CoV
- 2 , has been acqui naturally28 . A structural study suggested that the furin -
cleavage site can reduce the stability of SARS - CoV - 2 S protein and
facilitate the conformational adaption that is required for the binding of the
RBD to its receptor “.
Whether the higher trans missibility of SARS - CoV - 2 compared with SARS -
CoV is a gain of function associated with acquisition of the furin - like cleavage
site is yet to be demonstrated 26. An additional distinction is the accessory gene
orf8 of SARS - CoV - 2, which encodes a novel protein showing only 40 % amino
acid identity to ORF8 of SARS - CoV. Unlike in SARS - CoV, this new ORF8
protein does not contain a motif that triggers intracellular stre. 132 pathways 25.
Notably, a SARS - CoV - 2 variant with a 382 - nucleotide deletion covering the
whole of ORF8 has been discovered in a number of patients in Singapore, which
resembles the 29- or 415 - nucleotide deletions in the ORF8 region observed in
human SARS - CoV variants from the late phase of the 2002-2003 outbreak.
Such ORF8 deletion may be indicative of human adaptation after cross - species
transmission from an animal host. To as the constic variation of diffamant CADO
therapeutics, and drug regimens to counter er viruses (161-163, 280).
Several attempts ar made to design and develop vaccines for Cov infection,
mostly by targeting the spike glycoprotein.

Therapeutics and Drugs

There is no currently licensed specific antiviral treatment for MERS- and SARS
- CoV infections, and the main focus in clinical settings remains on lessening
clinical signs and providing supportive care (183186).
Effective drugs to manage COVID 19 patients include remdesivir, lopinavir /
ritonavir alone or in a blend with interferon beta, convalescent plasma, and
monoclonal antibodies (MAbs); however, efficacy and safety issues of these
drugs require additional clinical trials (187, 281).
A controlled trial of ritonavir - boosted lopinavir and interferon alpha 2b
treatment was performed on COVID - 19 hospitalized patients
(ChiCTR2000029308) (188).
In addition, the use of hydroxychloroquine and tocilizumab for their potential role
in modulating inflammatory responses in the lungs and antiviral effect has been
proposed and discussed in many research articles.
Still, no fool - proof clinical trials have been published (194, 196, 197, 261-272).
Recently, a clinical trial conducted on adult patients suffering from COVID - 19
revealed no benefit of lopinavir - r treatment over standard care (273). The efforts
to control SARS - CoV - 2 infection utilize defined strategies as followed against
MERS proteins without the presence of S protein would not confer any noticeable
protection, with the absence of detectable serum SARS - CoV - neutralizing
antibodies (170).
Antigenic determinant sites present over S and N structural proteins of SARS -
CoV - 2 can be explored as suitable vaccine candidates (294).
In the Asian population, S, E, M, and N proteins of SARS CoV - 2 are being
targeted for developing subunit vaccines against COVID - 19 (295).
The identification of the immunodominant region among the subunits and
domains of S protein is critical for developing an effective vaccine against the
coronavirus.
The C - terminal domain of the S1 subunit is considered the immunodominant
region of the porcine deltacoronavirus S protein (171). Similarly, further
investigations are needed to determine the immunodominant regions of SARS
CoV - 2 for facilitating vaccine development.
However, our previous attempts to develop a universal vaccine that is effective
for both SARS CoV and MERS - CoV based on T - cell epitope similarity pointed
out the possibility of cross reactivity among coronaviruses (172).
That can be made possible by selected potential vaccine targets that are common
to both viruses. SARS - CoV - 2 has been reported to be closely related to SARS
- CoV (173, 174).
Hence, knowledge and understanding o 175 turtles, ducks, fish, Siamese
crocodiles, an animal meat without any fear of COVID Chinese government is
encouraging people to el they can return to normalcy. 93.3 % identical to SARS
- CoV - 2 across the genome. In the long lab gene, it exhibits 97.2 % identity to
SARS - CoV - 2, which is even higher than for RaTG13 (REF.28).
In addition to RaTG13 and RmYN02, phyloge netic analysis shows that bat
coronaviruses ZC45 and ZXC21 previously detected in Rhinolophus pusillus bats
from eastern China also fall into the SARS - CoV - 2 lineage of the subgenus
Sarbecovirus (FIG. 2).
The dis covery of diverse bat coronaviruses closely related to SARS - CoV - 2
suggests that bats are possible reservoirs of SARS - CoV - 2 (REF.). Nevertheless,
on the basis of current findings, the divergence between SARS - CoV - 2 and
related bat coronaviruses likely represents more than 20 years of sequence
evolution, suggesting that these bat coronaviruses can be regarded only as the
likely evolu tionary precursor of SARS - CoV - 2 but not as the direct progenitor
of SARS - CoV - 2 (REF.38). Beyond bats, pangolins are another wildlife host
probably linked with SARS - CoV – 2.
Multiple SARS - CoV - 2 related viruses have been identified in tissues of
Malayan pangolins smuggled from Southeast Asia into southern China from 2017
to 2019.

These viruses from pangolins independently seized by Guangxi and Guangdong

pro vincial customs belong to two distinct sublineages 3941. The Guangdong
strains, which were isolated or sequenced by different research groups from smug
gled pangolins, have 99.8 % sequence identity with each other. They are very
closely related to SARS - CoV - 2, exhibiting 92.4 % sequence similarity.
Notably, the RBD of Guangdong pangolin coronaviruses is highly similar to that
of SARS - CoV - 2.

The receptor - binding motif (RBM; which is part of the RBD) of these viruses
has only one amino acid variation from SARS - CoV - 2, and it is identical to that
of SARS - CoV - 2 in all five critical differs from that in SARS - CoV in the five
residues crit ical for ACE2 binding, namely Y455L, L486F, N493Q, D494S and
T501N52 (FIG. 3b, c).

Owing to these res changes, interaction of SARS - CoV - 2 with its re stabilizes
the two virus - binding hotspots on the s of hACE2 (REF.5 %) (FIG. 3d).
Moreover, a four - residue mic in the RBM of SARS - CoV - 2 (amino acids 482-
485: G - V - E - G) results in a more compact conformation of (RBM; which is
part of the RBD) of these only one amino acid variation from SARS - CoV - 2,
and it is identical to that of SARS - CoV - 2 in all five critical differs from that in
SARS - CoV in the five residues crit ical for ACE2 binding, namely Y455L,
L486F , N493Q , D494S and T501N2 ( FIG . 3b, c). Owing to these residue
changes, interaction of SARS - CoV - 2 with its receptor stabilizes the two virus
- binding hotspots on the surface of hACE2 (REF.50) (FIG. 3d).

Moreover, a four - residue motif in the RBM of SARS - CoV - 2 (amino acids
482-485: G - V - E - G ) results in a more compact conformation of its hACE2 -
binding ridge than in SARS - CoV and ena bles better contact with the N -
terminal helix of hACE2 ( REF.5 ) .
Biochemical data confirmed that the structural features of the SARS - CoV - 2
RBD has strengthened its hACE2 binding affinity compared with that SARS -
CoV 50,52,53 Similarly to other coronaviruses, SARS - CoV –2 needs proteolytic
processing of the S protein to activate the endocytic route. It has been shown that
host proteases participate in the cleavage of the S protein and activate the entry
of SARS - CoV - 2, including transmembrane protease serine protease 2
(TMPRSS2), cathepsin L and furin¹7.5455.
Single - cell RNA sequencing data showed that TMPRSS2 is highly expressed in
several tissues and body sites and is co - expressed with ACE2 in nasal epithelial
cells, lungs and bronchial branches, which explains some of the tissue tropism of
SARS - CoV - 2 (REFS 56,57).
SARS - CoV - 2 pseudovirus entry assays revealed that TMPRSS2 and cathepsin
L have cumu lative effects with furin on activating virus entry. Analysis of the
cryo - electron microscopy structure of SARS - CoV - 2 S protein revealed that
its RBD is mostly in the lying - down state, whereas the SARS - CoV S protein
assumes equally standing - up and lying - down conforma tional states $
0,51,58,59.
A lying - down conformation of the SARS - CoV - 2 S protein may not be in
favour of rece binding but is helpful for immune evasion $ 5. article gives a bird's
eye view about this new virus. Since knowledge about thievirne is rapidly
evolving readers specimens, like bronchoalveolar lavage fluid, sputum, nasal
swabs, fibro bronchoscope brush biopsy specimens, pharyngeal swabs, feces, and
blood (246).
The presence of SARS - CoV - 2 in fecal samples has posed grave public health
concerns. In addition to the direct transmission mainly occurring via droplets of
sneezing and coughing, other routes, such as fecal excretion and environmental
and fomite contamination, are contributing to SARS - CoV - 2 transmission and
spread (249-252).
Fecal excretion has also been documented for SARS - CoV and MERS - CoV,
along with the potential to stay viable in situations aiding fecal - oral transmission.
Thus, SARS - CoV - 2 has every possibility to be transmitted through this mode.
Fecal - oral transmission of SARS CoV - 2, particularly in regions having low
standards of hygiene and poor sanitation, may have grave consequences with
regard to the high spread of this virus. Ethanol and disinfectants containing
chlorine or bleach are effective against coronaviruses (249-252). Appropriate
precautions need to be followed strictly while handling the stools of patients
infected with SARS - CoV - 2.
Biowaste materials and sewage from hospitals must be adequately disinfected,
treated, and disposed of properly. The significance of frequent and good hand
hygiene and comprised a small population and hence, the possibility of
misinterpretation could arise. However, in another case study, the authors raised
concerns over the efficacy of hydroxychlorog azithromycin in the treatment of
COVID - 19 since no observable effect was seen when the used.

In some cases, the treatment was discontinued due to the prolongation of the QT
interval (307). 181 since no observable effect was seen when they were used. In
some cases, the treatment was discontinued due to the prolongation of the QT
interval (307).
Hence, further randomized clinical trials are required before concluding this
matter. Recently, another FDA - approved drug, ivermectin, was reported to
inhibit the in vitro replication of SARS - CoV - 2.

The findings from this study indicate that a single treatment of this drug was able
to induce an -5,000 - fold reduction in the viral RNA at 48 h in cell culture. (308).
One of the main disadvantages that limit the clinical utility of ivermectin is its
potential to cause cytotoxicity. However, altering the vehicles used in the
formulations, the pharmacokinetic properties can be modified, thereby having
significant control over the systemic concentration of ivermectin (338).
Based on the pharmacokinetic simulation, it was also found that ivermectin may
have limited therapeutic utility in managing COVID - 19 since the inhibitory
concentration that has to be achieved for effective anti - SARS - CoV - 2 activity
is far higher than the susceptible individuals. Hence, hand hygiene is equally as
important as the use of appropriate PPE, like face masks, to break the
transmission cy the virus; both hand hygiene and face masks lessen the risk of
COVID - 19 transmission (315 Medical staff are in the group of individuals most
at risk of getting COVID - 19 infection. This is chest discomfort, and in severe
cases dyspnea and bilateral lung infiltration. Among the first 27 documented
hospitalized patients, most cases were epidemiologically linked to Huanan
Seafood
Wholesale Market a wet market located in downtown Wuhan, which sells not
only seafood but also live animals, including poultry and wildlife.
According to a retrospective study, the onset of the first known case dates back
to 8 December 2019 (REF.). On 31 December, Wuhan Municipal Health
Commission notified the public of a pneumonia outbreak of unidentified cause
and informed the World Health Organization (WHO) (FIG. 1). By metagenomic
RNA sequencing and virus isolation from bronchoalveolar lavage fluid samples
from patients with severe pneumonia, independent teams of Chinese scientists
identified that the causative agent of this emerging disease is a beta coronavirus
that had never been seen before.10.11.
On 9 January 2020, the result of this etiological identification was publicly
announced (FIG. 1). The first genome sequence of the novel coronavirus was
published on the Virological website on 10 January, and more nearly complete
genome sequences determined by different research institutes were then released
via the GISAID database on 12 January.

Later, more patients with no history of exposure to Huanan Seafood Wholesale

Market were identified. Several familial clusters of infection were reported, and
nosocomial infection also occurred in health - care facilities.
All these cases provided clear evidence for human - to - human transmission of
the new virus + 12-14 As the outbreak coincided with the approach of the lunar
New Year, travel between cities before the festival facilitated virus transmission
in China. This novel coronavirus pneumonia soon spread to other cities in Hubei
province and to other parts of China.

Within 1 month. route warrants the introduction of negative fecal viral nucleic
acid test results as one of the additional discharge criteria in laboratory -
confirmed cases of COVID - 19 (326). The COVID - 19 pandemic does not ha
novel factors, other than the genetically pathogen and a further possible reservoir.
CONCLUDING REMARKS
Several years after the global SARS epidemic, the current SARS - CoV - 2 /
COVID - 19 pandemic has served as a reminder of how novel pathogens can
rapidly emerge and spread through the human population and eventually cause
severe public health crises.
Further research should be conducted to establish animal models for SARS -
CoV-2 to investigate replication, transmission dynamics, and pathogenesis in
humans.
This may help develop and evaluate potential therapeutic strategies against
zoonotic CoV epidemics.
Present trends suggest the occurrence of future outbreaks of CoVs due to changes
in the climate, and ecological conditions may be associated with human - animal
contact.
Live animal markets, such as the Huanan South China Seafood Market, represent
ideal conditions for interspecies contact of wildlife with domestic birds, pigs, and
mammals, which substantially increases the probability of interspecies
transmission of CoV infections and could result in high risks to humans due to
adaptive genetic recombination in these viruses (323-325).
The COVID - 19 - associated symptoms are fever, cough, expectoration,
headache, and myalgia or fatigue.
Individuals with asymptomatic and atypical identified angiotensin receptor 2
(ACE₂) as the receptor through which 87 the virus enters the respiratory mucos
[11].
S Glycoprotein
Coronavirus S protein is a large, multifunctional class I viral transmembrane
protein. The size of this that remdesivir has to be further evaluated for its efficacy
in the treatment of COVID - 19 infection in humans.
The broad - spectrum activity exhibited by remdesivir will help control the spread
of disease in the event of a new coronavirus outbreak. Chloroquine is an
antimalarial drug known to possess antiviral activity due to its ability to block
virus - cell fusion by raising the endosomal pH necessary for fusion.
It also interferes with virus receptor binding by interfering with the terminal
glycosylation of SARS - CoV cellular receptors, such as ACE2 (196).
In a recent multicenter clinical trial that was conducted in China, chloroquine
phosphate was found to exhibit both efficacy and safety in the therapeutic
management of SARS - CoV - 2 - associated pneumonia
(197).
This drug is already included in the treatment guidelines issued by the National
Health Commission of the People's Republic of China. The preliminary clinical
trials using hydroxychloroquine, another aminoquinoline drug, gave promising
results. The COVID - 19 patients received 600 mg of hydroxychloroquine daily
along with azithromycin as a single - arm protocol.
This protocol was found to be associated v noteworthy reduction in viral load.
Find resulted in a complete cure (271); however, the comprised a small
population and, hence, the snakes, and various other wild animals (20, 30, 79, 93,
124, 125, 287).
Coronavirus infection is linked to different kinds of clinical manifestations,
varying from enteritis in cows and pigs, upper respiratory disease in chickens,
and fatal respiratory infections in humans (30).
Among the CoV genera, Alphacoronavirus and Beta coronavirus infect
mammals, while Gamma coronavirus and Delta coronavirus mainly infect birds,
fishes, and sometimes, mammals (27, 29, 106). Several novel coronaviruses that
come under the genus
Delta coronavirus have been discovered in the past from birds, like Wigeon
coronavirus HKU20, Bulbul coronavirus HKU11, Munia coronavirus HKU13,
white - eye coronavirus HKU16, night - heron coronavirus HKU19, and common
moorhen coronavirus HKU21, as well as from pigs (porcine coronavirus HKU15)
(6, 29). Transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea
virus (PEDV), and porcine hemagglutinating encephalomyelitis virus (PHEV)
are some of the coronaviruses of swine.
Among them, TGEV and PEDV are responsible for causing severe gastroenteritis
in young piglets with noteworthy morbidity and mortality. Infection with PHEV
also causes enteric infection but can cause encephalitis due to its ability to infect
the nerveus the SARS - CoV. Environmental sample from the Huanan Sea food
market also tested positive, signifying that the virus.

The capsular membrane WHICH represents the outer envelope usually has
glycoprotein projection and covers the nucleus, comprising a matrix protein
containing a positive - strand RNA.
Since the structure possesses 5 ' - capped and 3 ' - polyadenylated ends, it remains
identical to the cellular mRNAs. 18 The structure is comprised of hemagglutinin
esterase (HE) (present only in some beta - coronaviruses), spike (S), small
membrane ( E ) , membrane ( M ) and nucleocapsid ( N ), as shown ( Figure 1).
The envelope containing glycoprotein is responsible for attachment to the host
cell, which possesses the primary anti - genic epitopes mainly those virological,
radiological , and pathological observations indicated that the monkeys with
reexposure had no recurrence of COVID - 19 , like the SARS - CoV - 2 - infected
monkeys without rechallenge .
These findings suggest that primary infection with SARS - CoV - 2 could protect
from later exposures to the virus, which could help in defining disease prognosis
and crucial inferences for designing and developing potent vaccines against
COVID - 19 (274).
PREVENTION, CONTROL AND MANAGEMENT
In contrast to their response to the 2002 SARS outbreak, China has shown
immense political openness in reporting the COVID - 19 outbreak promptly.
They have also performed rapid sequencing of COVID - 19 at multiple levels and
shared the findings globally within days of identifying the novel virus ( 225 ).
The move made by China opened a new chapter in global health se and
diplomacy.
Even though complete lock does declare following the COVID - 19 outbreak
Wuhan, the large - scale movement of people has 90 resulted in a radiating spread
of infections in the air. liquid droplets during speech. However, smaller and much
more numerous particles known as aerosol particles can also be visualized, which
could linger in the air for a long time and then penetrate deep into the lungs when
inhaled by someone else 98-100.
Airborne trans mission was also observed in the ferret experiments mentioned
above. SARS - CoV - 2 - infected ferrets shed Swine acute diarrhea syndrome
coronavirus (SADS - CoV) was first identified in suckling piglets having severe
enteritis and belongs to the genus Alphacoronavirus (106).
The outbreak was associated with considerable scale mortality of piglets (24,693
deaths) across four farms in China (134). The virus isolated from the piglets was
almost identical to and had 95 % genomic similarity with horseshoe bat
(Rhinolophus species) coronavirus HKU2, suggesting a bat origin of the pig virus
(106, 134, 135). It is also imperative to note that the SADS - CoV outbreak started
in Guangdong province, near the location of the SARS pandemic origin ( 134 ).
Before this outbreak, pigs were not known to be infected with bat - origin
coronaviruses.
This indicates that the bat - origin coronavirus jumped to pig by breaking the
species barrier. The next step of this jump might not end well, since pigs are
considered the mixing vessel for influenza A viruses due to their ability to be
infected by both human and avian influenza A viruses (136).
Similarly, they may act as the mixing vessel for coronaviruses, since they are in
frequent contact with both humans and multiple wildlife.
Additionally, pigs are also found to be suscept infection with human SARS - CoV
and MERS - C making this scenario a nightmare ( 109 , 137 ).

CONCLUDING REMARKS
Several years after the global SARS epidemic, the current SARS - CoV - 2 /
COVID - 19 pandemic has served as a reminder of how novel pathogens can
rapidly emerge and spread through the human population and eventually cause
severe public health crises.
Further research should be conducted to establish animal models for SARS - CoV
- 2 to investigate replication, transmission dynamics, and pathogenesis in humans.
This may help develop and evaluate potential therapeutic strategies against
zoonotic CoV epidemics.
Present trends suggest the occurrence of future outbreaks of CoVs due to changes
in the climate, and ecological conditions may be associated with human - animal
contact. Live animal markets, such as the Huanan South China Seafood Market,
represent ideal conditions for interspecies contact of wildlife with domestic birds,
pigs and mammals, which substantially increases the probability of interspecies
transmission of CoV infections and could result in high risks to humans due to
adaptive genetic recombination in these viruses ( 323-325 ) .
The COVID - 19 - associated symptoms are fever, cough, expectoration,
headache, and myalgia or fatigue. Individuals with asymptomatic and atypical
identified angiotensin receptor 2 ( ACE₂ ) as the receptor through whic the virus
enters the respiratory mucosa [ 11 ].
Differential Diagnosis [ 21 ]
The differential diagnosis includes all types of respiratory viral infections
[influenza , parainfluenza , respiratory syncytial virus ( RSV ) , adenovirus ,
human metapneumovirus , non-COVID 19 coronavirus ] , atypical organisms
(mycoplasma , chlamydia ) and bacterial infections .
It is not possible to differentiate COVID - 19 from these infections clinically or
through routine lab tests . Therefore travel history becomes important.
However, as the epidemic spreads. the travel history Cases continued to increase
exponentially and modelling studies reported an epidemic doubling time of 1.8 d
[ 10 ] .
In fact on the 12th of February, China changed its definition of confirmed cases
to include patients with negative / pending molecular tests but with clinical,
radiologic and epidemiologic features of COVID - 19 leading to an increase in
cases by 15,000 in a single day [ 6 ] .
As of 05/03/2020 96,000 cases worldwide (80,000 in China) and 87 other
countries and 1 international conveyance (696, in the cruise ship Diamond
Princess parked off the coas of Japan) have been reported [ 2].
The COVID - 19 patients received 600 mg of hydroxychloroquine daily along
with azithromycin as a single - arm protocol. This protocol was found to be
associated with a noteworthy reduction in viral load.
Finally, it resulted in a complete cure ( 271 ) ; however , the study comprised a
small population and , hence , the snakes , and various other wild animals (20 ,
30 , 79 , 93 , 124 , 125 , 287 ) .
Coronavirus infection is linked to different kinds of clinical manifestations,
varying from enteritis in cows and pigs, upper respiratory disease in chickens,
and fatal respiratory infections in humans (30).
Among the CoV genera, Alphacoronavirus and Betacoronavirus infect mammals,
while Gammacoronavirus and Deltacoronavirus mainly infect birds, fishes, and,
sometimes, mammals ( 27 , 29 , 106 ) .
Several novel coronaviruses that come under the genus Delta coronavirus have
been discovered in the past from birds , like Wigeon coronavirus HKU20 , Bulbul
coronavirus HKU11 , Munia coronavirus HKU13 , white - eye coronavirus
HKU16 , night - heron coronavirus HKU19 , and common moorhen coronavirus
HKU21 , as well as from pigs ( porcine coronavirus HKU15 ) ( 6 , 29 ).
Transmissible gastroenteritis virus ( TGEV ) , porcine epidemic diarrhea virus
(PEDV ) , and porcine hemagglutinating encephalomyelitis virus ( PHEV ) are
some of the coronaviruses of swine .
Among them, TGEV and PEDV are responsible for causing severe gastroenteritis
in young piglets with noteworthy morbidity and mortality.
Infection with PHEV also causes enteric infection but can cause encephalitis due
to its ability to infect the nervous the SARS - CoV. Environmental sample from
the Huanan Sea food market also tested positive, signifying that the virus
originated from there [ 71. The number
14 ANTIVIRAL THERAPY
COVID - 19 is an infectious disease caused by SARS - CoV - 2 , which is also
termed the novel coronavirus and is diligently associated with the SARS virus .
The Ministry of Science and Technology from the People's Republic of China
declared three potential antiviral medicines suitable for treating COVID - 19 .
Those three medicines are, namely, Favilavir , chloroquine phosphate and
remdesivir . A clinical trial was conducted to test the efficacy of those three drugs,
and the results proved that out of the three medicines above only Favilavir is
effective in treating the patients with novel coronavirus . The remaining two drugs
were effective in treating malaria.62 | Likewise a study carried out in the United
States by the National Institute of Health proved that remdesivir is effective in
treating the Middle East respiratory syndrome coronavirus ( MERS CoV ) , which
is also a type of coronavirus that was transmitted from monkeys .
The drug remdesivir was also used in the United States for treating the patients
with COVID - 19. There has been a proposal to use the combination of protease
inhibitors lopinavir - ritonavir for treating the patients affected by COVID - 19.62
glass opacities and sub segmental consolidation. It is also abnormal in
asymptomatic patients / patients with no clinical evidence of lower respiratory
tract involvement. In fac abnormal CT scans have been used to diagnose COVID
- 19 in suspect cases taken by the healthcare professional, such as contact
precautions and airborne precautions with eye protection .
"56 Individuals with a mild clinical presentation may not require primary
hospitalization. Close monitoring is needed for the persons infected with COVID-
19.
Elderly patients and those with prevailing chronic medical conditions such as as
an entry receptor while exhibiting an RBD similar to that of SARS - CoV (17, 87,
254, 255).
Several countries have provided recommendations to their people traveling to
China ( 88 , 89 ) . Compared to the previous coronavirus outbreaks caused by
SARS CoV and MERS - CoV , the efficiency of SARS - CoV 2 human - to -
human transmission was thought to be less .
This assumption was based on the finding that health workers were affected less
than they were in previous outbreaks of fatal coronaviruses ( 2 ) .
Superspreading events are considered the main culprit for the extensive
transmission of SARS and MERS ( 90 , 91 ) . Almost half of the MERS - CoV
cases reported in Saudi Arabia are of secondary origin that occurred through
contact with infected asymptomatic or symptomatic individuals through human -
to - human transmission ( 92 ) . The occurrence of superspreading events in the
COVID - 19 outbreak cannot be ruled out until its possibility is evaluated .
Like SARS and MERS , COVID - 19 can also infect the lower respiratory tract ,
with milder symptoms ( 27 ) . The basic reproduction number of COVID - 19 has
been found to be in the range of 2.8 to 3.3 based on real - time reports and 3.2 to
3.9 based on predicted infected cases ( 84 ) .

The COVID - 19 patients received 600 mg of hydroxychloroquine daily along

with azithromycin as a single - arm protocol . This protocol was found to be
associated with a noteworthy reduction in viral load . Finally , it resulted in a
complete cure ( 271 ) ; however , the study comprised a small population and ,
hence , the snakes , and various other wild animals ( 20 , 30 , 79 , 93 , 124 , 125 ,
287 ) .
Coronavirus infection is linked to different kinds of clinical manifestations ,
varying from enteritis in cows and pigs , upper respiratory disease in chickens ,
and fatal respiratory infections in humans ( 30 ) . Among the CoV genera ,
Alphacoronavirus and Betacoronavirus infect mammals , while
Gammacoronavirus and Deltacoronavirus mainly infect birds , fishes , and ,
sometimes , mammals ( 27 , 29 , 106 ) .

Several novel coronaviruses that come under the genus Delta coronavirus have
been discovered in the past from birds , like Wigeon coronavirus HKU20 , Bulbul
coronavirus HKU11 , Munia coronavirus HKU13 , white - eye coronavirus
HKU16 , night - heron coronavirus HKU19 , and common moorhen coronavirus
HKU21 , as well as from pigs ( porcine coronavirus HKU15 ) ( 6 , 29 ) .

Transmissible gastroenteritis virus ( TGEV ) , porcine epidemic diarrhea virus

(PEDV ) , and porcine hemagglutinating encephalomyelitis virus ( PHEV ) are
some of the coronaviruses of swine .
Among them, TGEV and PEDV are responsible for causing severe
gastroenteritis in young piglets with noteworthy morbidity and mortality .
Infection with PHEV also causes enteric infection but can cause encephalitis due
to its ability to infect the nervous the SARS - CoV . Environmental sample from
the Huanan sea food market also tested positive , signifying that the virus. snakes,
and various other wild animals ( 20 , 30 , 79 , 93 , 124 , 125 , 287) . Coronavirus
infection is linked to different kinds of clinical manifestations, varying from
enteritis in cows and pigs, upper respiratory disease in chickens, and fatal
respiratory infections in humans (30).
Among the CoV genera, Alphacoronavirus and Beta coronavirus infect
mammals, while Gamma coronavirus and Delta coronavirus mainly infect birds,
fishes, and, sometimes, mammals (27, 29, 106 ) .
Several novel coronaviruses that come under the genus Deltacoronavirus have
been discovered in the past from birds, like Wigeon coronavirus HKU20, Bulbul
coronavirus HKU11, Munia coronavirus HKU13, white - eye coronavirus
HKU16 , night - heron coronavirus HKU19 , and common moorhen coronavirus
HKU21 , as well as from pigs ( porcine coronavirus HKU15 ) ( 6 , 29 ).
Transmissible gastroenteritis virus (TGEV ) , porcine epidemic diarrhea virus
(PEDV ) , and porcine hemagglutinating encephalomyelitis virus ( PHEV ) are
some of the coronaviruses of swine .
Among them, TGEV and PEDV are responsible for causing severe
gastroenteritis in young piglets with noteworthy morbidity and mortality.
Infection with PHEV also causes enteric infection but can cause encephalitis due
to its ability to infect the nervous.
The exploration of fully human antibodies (human single - chain antibodies;
HuscFvs) or humanized nanobodies ( single - domain antibodies ; sdAb , VH /
VHH ) could aid in blocking virus replication , as these agents can traverse the
virus infected cell membranes ( trans bodies ) and can interfere with the biological
characteristics of the replicating virus proteins .
Such examples include trans bodies to the influenza virus, hepatitis C virus, Ebola
virus, and dengue virus (206). Producing similar trans bodies against intracellular
proteins of coronaviruses, such as papain - like proteases ( PLpro ) , cysteine -
like protease ( 3CLpro ) , or other nsps , which are essential for replication and
transcription of the virus , might formulate a practical move forward for a safer
and potent passive immunization approach for virus - exposed persons and
rendering therapy to infected patients .
In a case study on five grimly sick patients having symptoms of severe pneumonia
due to COVID - 19, convalescent plasma administration was found to be helpful
in patients recovering successfully. The convalescent plasma containing a SARS
- CoV - 2 - specific ELISA (serum) antibody titer higher than 1: 1,000 and
neutralizing antibody titer more significant than 40 was collected from the
recovered patients and used for plasma transfusion.