History:

Coronaviruses are enveloped positive sense RNA viruses ranging from 60 nm to 140 nm in
diameter with spike like projections on its surface giving it a crown like appearance under
the electron microscope; hence the name coronavirus [3]. Moreover, a four-residue motifin
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 enables better contact
with the N- terminal helix of hACE2 (REFS). All the patients were either asymptomatic
(9%) or had mild disease. Tackling this epidemic is a long-term job which requires efforts
of every individual, and international collaborations by scientists, authorities and the public
a polybasic cleavage site (RRAR), which enables effective cleavage by furin and other
proteases". In addition to RaTG13 and RmYN02, phylogenetic 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.
Acute viral interstitial pneumonia and humoral and cellular immune responses were
observed. The computerized tomographic chest scan is usually abnormal even in those with
no symptoms or mild disease. Treatment is essentially supportive; role of antiviral agents is
yet to be established. CDC (Table 1) (258, 259) consolidation. The six functional open
reading frames (ORFs) are arranged in order from 5 to 3': replicase (ORFla/ORF1b), spike
(S), envelope (E), membrane (M) and nucleocapsid (N). All patients recovered with
symptomatic therapy and there were no deaths. Advanced in-depth analysis of the genome
has identified 380 amino acid substitutions between the amino acid sequences of SARS-
CoVv-2 and the SARS/SARS-like coronaviruses. 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). 4).

Historia:

Los coronavirus son virus de ARN de sentido positivo que presentan un rango que varían
de 60 nm a 140 nm de diámetro con forma de púas en su superficie que les dan una
apariencia de corona bajo el microscopio electrónico; de ahí el nombre de coronavirus [3].
Además, un motivo de cuatro residuos en la RBM del SARS-CoV-2 (aminoácidos 482-
485:G-V-E-G)µ da como resultado una conformación más compacta de su cresta de unión a
hACE2 que en el SARS-CoV y permite un mejor contacto con el N-terminal. hélice de
hACE2 (REFS). Todos los pacientes eran asintomáticos (9%) o tenían enfermedad leve.
Abordar esta epidemia es un trabajo a largo plazo que requiere el esfuerzo de cada
individuo y la colaboración internacional de científicos, autoridades y el público en general
para crear un sitio de escisión polibásico (RRAR), que permite una escisión eficaz mediante
furina y otras proteasas". Además de RaTG13 y RmYN02, el análisis filogenético muestra
que los coronavirus de murciélago ZC45 y ZXC21 detectados previamente en murciélagos
Rhinolophus pusillus del este de China también pertenecen al linaje SARS-CoV-2 del
subgénero Sarbecovirus" (FIG. Se observaron neumonía intersticial viral aguda y
respuestas inmunes humorales y celulares La tomografía computarizada de tórax suele ser
anormal incluso en aquellos sin síntomas o con enfermedad leve. El tratamiento es
esencialmente de apoyo; el papel de los agentes antivirales aún no se ha establecido (Tabla
1) (258, 259). Los marcos de lectura (ORF) están ordenados de 5 a 3': replicasa
(ORFla/ORF1b), espiga (S), envoltura (E), membrana (M) y nucleocápside (N). Todos los
pacientes se recuperaron con terapia sintomática y allí. no hubo muertes. Un análisis
avanzado en profundidad del genoma ha identificado 380 sustituciones de aminoácidos
entre las secuencias de aminoácidos del SARS-CoVv-2 y los coronavirus similares al
SARS/SARS. Inmediatamente después de la confirmación de la etiología viral, los
virólogos chinos publicaron rápidamente la secuencia genómica del SARS-CoV-2, que
desempeñó un papel crucial en el control de la propagación de este nuevo coronavirus
recién surgido a otras partes del mundo (69). 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 outbreak260.
4). Currently, however, the available sequence data are not sufficient to interpret the early
global transmision history ofthe virus, and travel patterns, founder effects and public health
measures also strongly influence the spread of particular lineages, irrespective of potential
biological differences between different virus variants. Since March, while COVID-19 in
China has become effectively controlled, the case numbers in Europe, the USA and other
regions have jumped sharply. The city of Wuhan was shut down on 23 January, and all
travel and transportation connecting the city was blocked. In the following couple of weeks,
all outdoor activities and gatherings were restricted, and public facilities were dosed in
most cities as well as in countryside". So far, no evidence has shown that pangolins were
directly involved in the emergence of SARS- COV-2. The SARS-CoV, Transmission of
SARS-CoV occurred mainly after illness onset and peaked following disease severity,
However, the SARS-CoV-2 viral load in upper respiratory tract samples was already
highest during the first week of symptoms, and thus the risk of pharyngeal virus shedding
was very high at the beginning of infection%. Except for lopinavir and ritonavir, which
inhibit 3CLpro, the other three all target RdRp2515 (FIG. 2). An estimated RO 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-CoV. By 23rd January, the 11 million population of Wuhan was placed under
lock down with restrictions of entry and exit from the region. The neutralizing epitopes of
these monoclonal antibodies also offer important information for vaccine design. The
outbreak of COVID-19 in China reached an epidemic peak in February. (3a). Hence,
deploying efficient public health interventions might help to cut the spread of this virus
globally.

Animal host and spillover:

Bats are important natural hosts of alphacoronaviruses and betacoronaviruses. (5). A lying-
down conformation of the SARS-CoV-2 S protein may not be in favour of receptor binding
but is helpful for immune evasion". The possible origin of SARS-CoV-2 and the first mode
of polymorphism at nucleotide position 28,144, which results in amino acid substitution of
Ser for Lys at residue 84 of the ORF8 protein. The possibility of eross protection in
CoVID-19 was comparing the S protein sequences of SARS-CoV-2 evaluated by with that
of SARS-CoV. Food and Drug Administration (FDA) had granted 22 in vitro diagnostics
Emergency Use Authorizations (EUAs), including for the RT- PCR diagnostic panel for the
universal detection of SARS-like betacoronaviruses and specific detection of SARS-CoV-
2, developed by the U.S. Many people are asymptomatic. 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
___________________________

disease. Non-essential international travel should be avoided at this time. People should
stop spreading myths and false information about the disease and try to allay panic and
anxiety of the public.

Antiviral Drugs:

Several classes of routinely used antiviral drugs, like oscitamivir (neuraminidase inhibitor),
acyclovir, ganciclovir, and ribavirin, do not have any effect on COVID-19 and, hence, are
not recommended (187). Oseltamivir, a neuraminidase inhibitor, has been explored in
Chinese hospitals for treating suspected COVID-19 cases, although proven efficacy against
SARS-CoV-2 is still lacking for this drug (7). 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. It is opined that the exposure history of 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). Further genetic analysis is required.

Vaccines:

Vaccination is the most effective method for a long-term strategy for prevention and control
of COVID-19 in the future. Although nearly 30 cruise ships from different countries have
been found harboring COVID-19 infection, the major cruise ships that were involved in the
COVID-19 outbreaks are the Diamond Princess, Grand Princess, Celebrity Apex, and Ruby
Princess. Canines are also affected by CoVs that fall under different genera, namely, canine
enteric coronavirus in Alphacoronavirus coronavirus in Betacoronavirus, affecting the
enteric and canine respiratory and respiratory tract, respectively (129, 130). High mortality
occurred especially when health-care resources were overwhelmed. Multiple organ failure
has also been reported in some COVID-19 cases 1365. Histopathological changes in
patients with COVID-19 occur mainly in the lungs. Four corona viruses namely HKU1,
NL63, 229E and OC43 have been in circulation in humans, and generally cause mild
respiratory disease. There have been two events in the past two decades wherein crossover
of animal betacorona viruses to humans has resulted in severe disease. The 51 subunit ofa
corona-virus is further divided into two functional domains, an N-terminal domain and a C-
terminal domain. Structural and biochemical analyses identified a 211 amino acid region
(amino acids 319-529) at the S1 C-terminal domain of SARS-CoV-2 as the RBD, which has
a key role in virus entry and is the target of neutralizing antibodiess051 (FIG. 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)'.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), Prevention
entails home isolation of suspected cases and those with mild illnesses and strict infection
control measures at hospitals that include contact and droplet precautions. The patients
infected with COVID-19 had elevated plasma angiotensin 2 levels. The level of angiotensin
2 was found to be linearly associated with viral load and lung injury, indicating its potential
as a diagnostic biomarker (121). Up to 30 March 2020, the U.S. Later, ongoing human-to-
human transmission propagated the outbreak". Most of the proteins encoded by SARS-
CoV-2 have a similar with COVID-19 showed typical features on initial CT, including
bilateral multilobar ground-glass opacities with a peripheral or posterior distribution1,
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 screening" 1, Finally, SARS-CoV-2 serological tests detecting antibodies
to Nor S protein could complement molecular diagnosis, particularly in late phases after
disease onset or for retrospective studies16,120121, However, the extent and duration of
immune responses are still unclear, and available serological tests differ in their sensitivity
and specificity, 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 therapies 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). (3d). A
structural study suggested that the furin-cdeavage site can reduce the stability of SARS-
CoV 25 protein and facilitate the conformational adaption that is required for the binding of
the RBD to its receptor". These differences in the amino acid sequences might have
contributed to the difference in the pathogenic divergence of SARS-CoV-2 (16). Further
research is required to evaluate the possible differences in tropism, pathogenesis, and
transmission of this novel agent associated with this change in the amino acid sequence.
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.

genome sequence is 96.2% identical to that of SARS-CoV-2 (REF "). Cytokine storm
syndrome causes acute respiratory distress syndrome and respiratory failure, which is
considered the main cause of death in patients with COVID-19 (REFSO), and deaths. By
contrast, a high risk of nosocomial transmission was reported in some other. The
pathogenesis of SARS-CoV-2 infection in humans manifests itself as mild symptoms to
severe respiratory failure. Regardless of the coronavirus type, immune cells, like mast cels,
that are present in the submucosa of the respiratoryy tract and nasal cavity are considered
the primary barrier against this virus (92). Virus may also be detected in the stool and in
severe cases, the blood. 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 evolutionary precursor of SARS-CoV-2 but not as the direct progenitor of SARS-
CoV-2 (REF35). Beyond bats, pangolins are another wildlife host probably linked with
SARS-CoV-2. Biochemical data confirmed that the structural features of the SARS-CoV-2
RBD has strengthened its hACE2 binding affinity compared with that of SARS-
CoV50,52.53. Similarly to other coronaviruses, SARS-CoV-2 needs proteolytic processing
of the S protein to activate the endocytic route. The USA is the country with the largest
number of cases so far. Although genetic evidence suggests that SARS-CoV-2 is a natural
virus that likely originated in animals, there is no conclusion yet about when and where the
virus first entered humans. 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 place, but the difference in mortality was not
statistically significant, The FDA has issued an emergency use authorization for rem desivir
for the treatment of hospitalized patients with severe COVID-19. Most people showed
signs of diseases after an incubation period of 1-14 days (most commonly around 5 days),
and dyspnoea and pneumonia developed within a median time of 8 days from illness onset.
In a report of 72,314 cases in China, 81% of the cases were classified as mild, 14% were
severe cases that required ventilation in an intensive care unit (ICU) and a 5% were critical
(that is, the patients had respiratory failure, septic shock and/or multiple organ dysfunction
or failure, On admission, ground-glass opacity was the most common radiologic finding on
chest computed tomography (CT). . On 30 January, the WHO declared the novel
coronavirus outbreak a public health emergency of inter-national concern". It must be
remembered that the multiplex PCR panels currently available do not include the COVID-
19. Intensive studies on these virological profiles of SARS-CoV-2 will provide the basis for
the development of preventive and therapeutic strategies against COVID-19. The case
fatality rate is estimated to range from 2 to 3%. Diagnosis is by demonstration of the virus
in respiratory secretions by special molecular tests. Replication inhibitors include
remdesivir (GS-5734), favilavir (T-705), ribavirin, lopinavir and ritonavir. The majority of
Chinese cities are now facing localized outbreaks of COVID-19 (231). The receptor-
binding motif (RBM; which is part of the RBD) of these viruses hasonly one amino acid
variation from SARS-CoV-2, and it is identical to that of SARS-CoV-2 in all five critical
lower respiratory tracts. Moreover, continued genomic monitoring of SARS-CoV-2 in new
cases is needed worldwide, as it is important to promptly identify any mutation that may
result in phenotypic changes of the virus. In another study, the average reproductive
number of major problem associated with this diagnostic kit is that it works only when the
test subject has an active infection, limiting its use to the earlier stages of infection.
Commercial tests are also not available at present. 3a). Convalescent plasma treatment is
another potential adjunctive therapy for COVID-19. Moreover, prolonged virus shedding
peaked early in the course of infection in asymptomatic macaques, and old monkeys
showed severer interstitial pneumonia than young monkeys", which is similar to what is
seen in patients with OVID-19. The recent increase in the number of confirmed critically ill
patients with COVID-19 has already surpassed the intensive care supplies, limiting
intensive care services to only a small portion of critically ill patients (67). Before choosing
the ideal therapeutic agent for the management of COVID-19, randomized clinical control
studies should be performed with a sufficient study population.

Vaccines:

Vaccination is the most effective method for a long-term strategy for prevention and control
of COVID-19 in the future. Although nearly 30 cruise ships from different countries have
been found harboring COVID-19 infection, the major cruise ships that were involved in the
COVID-19 outbreaks are the Diamond Princess, Grand Princess, Celebrity Apex, and Ruby
Princess. Canines are also affected by CoVs that fall under different genera, namely, canine
enteric coronavirus in Alphacoronavirus coronavirus in Betacoronavirus, affecting the
enteric and canine respiratory and respiratory tract, respectively (129, 130). High mortality
occurred especially when health-care resources were overwhelmed. Multiple organ failure
has also been reported in some COVID-19 cases 1365. Histopathological
changes in patients with COVID-19 occur mainly in the lungs. Four corona viruses namely
HKU1, NL63, 229E and OC43 have been in circulation in humans, and generally cause
mild respiratory disease. There have been two events in the past two decades wherein
crossover of animal betacorona viruses to humans has resulted in severe disease. The 51
subunit ofa corona-virus is further divided into two functional domains, an N-terminal
domain and a C- terminal domain. Structural and biochemical analyses identified a 211
amino acid region (amino acids 319-529) at the 51 C-terminal domain of SARS-CoV-2 as
the RBD, which has a key role in virus entry and is the target of neutralizing antibodiess051
(FIG. 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)'. 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). Prevention entails home isolation of suspected cases and those with mild illnesses
and strict infection control measures at hospitals that include contact and droplet
precautions. The patients infected with COVID-19 had elevated plasma angiotensin 2
levels. The level of angiotensin 2 was found to be linearly associated with viral load and
lung injury, indicating its potential as a diagnostic biomarker (121). Up to 30 March 2020,
the U.S. Later, ongoing human-to-human transmission propagated the outbreak". Most of
the proteins encoded by SARS-CoV-2 have a similar with COVID-19 showed typical
features on initial CT, including bilateral multilobar ground-glass opacities with a
peripheral or posterior distribution1, 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 screening"1, Finally,
SARS-CoV-2 serological tests detecting antibodies to Nor S protein could complement
molecular diagnosis, particularly in late phases after disease onset or for retrospective
studies16,120121, However, the extent and duration of immune responses are still unclear,
and available serological tests differ in their sensitivity and specificity, 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 therapies 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). (3d). A structural study
suggested that the furin-cdeavage 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". These differences in the amino acid sequences might have contributed to the
difference in the pathogenic divergence of SARS-CoV-2 (16). Further research is required
to evaluate the possible differences in tropism, pathogenesis, and transmission of this novel
agent associated with this change in the amino acid sequence. 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. In comparisonwith 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 infections in pangolins from
different smuggling events suggests that these animals are possible hosts of the viruses.
This property of the RBD can be utilized for designing potential SARS- COV RBD-
containing vaccines either by using recombinant proteins or recombinant vectors that
encode RBD (175). 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
caleulated using the infection fatality risk (IFR). Researchers and manufacturers are
conducting large-scale clinical trials to evaluate various therapies for COVID-19. They are
very closely related to SARS-CoV-2, exhibiting 92.4% sequence similarity. Finally,
COVID-19 is challenging all human beings. Common laboratory findings include
normal/low white cell counts with elevated C reactive protein (CRP). Most of these SARS-
CoV-2 non-structural proteins have greater than 85% amino acid sequence identity with
SARS-CoV25. The phylogenetic analysis for the whole genome shows that SARS-CoV-2 is
clustered with SARS-CoV and SARS-related coronaviruses (SARSr-CoVs) found in bats,
placing it in the subgenus Sarbecovirus of the genus Betacoronavirus. The receptor-binding
gene region (173, 174). On binding to epithelial cells in the respiratory tract, SARS-CoV-2
starts replicating and migrating down to the airways and enters alveolar epithelial cells in
the lungs. The comparative analysis confirmed that the variable residues were found
concentrated on the Si subunit of S protein, an important vaccine target of the virus (150).
Recent studies reported specific monoclonal antibodies neutralizing SARS-CoV-2
infection.

Inhibition Of Virus Replication:

The massive migration of Chinese during the Chinese New Year fuelled the epidemic.
Cases in other provinces of China, other countries (Thailand, Japan and South Korea in
quick succession) were reported in people who were returning from Wuhan. 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 furint"5455. Environmental samples from the Huanan sea food market
alsotested positive, signifying that the virus originated from there [7]. The virus spreads
faster than its twn ancestors the SARS-CoV residues for receptor binding (FIG). However,
this individual early report cannot give a solid answer to the origin of SARS-CoV-2 and
contamination, and thus a false positive result cannot be excluded. More so, future
outbreaks of viruses and pathogens of zoonotic origin are likely to continue. Therefore,
apart from curbing this outbreak. Bovine coronaviruses (BoCoVs) are known to infect
several domestic and wild ruminants (126). The first fatal case was reported on 11th Jan
2020. Several laboratories around the world are currently developing antibody-based
diagnostic tests against SARS-CoV-2 (157). Chest CT is an ideal diagnostic tool for
identifying viral pneumonia. With the current outbreak of COVID-19, there is an
expectancy of a significant increase in the number of published studies about this emerging
coronavirus, as occurred require sedatives, analgesics, and even muscle relaxation drugs to
prevent ventilator-related lung injury incoordination (122). The discovery of diverse bat
coronaviruses closely related to SARS-CoV-2 suggests that bats are possible reservoirs of
SARS-CoV-2 (RE.*"). Within this clade, SARS-CoV-2 is grouped in a distinct lineage
together with four horseshoe bat coronavirus isolates (RaTG13, RmYN02,ZC45 and
ZXC21) as well as novel coronaviruses recently identified in pangolins, which group
parallel to SARS-CoV in vitro and in vivo5- 135, Compared with convalescent plasma,
which has limited availability and cannot be amplified, monoclonal antibodies can be
developed in larger quantities to meet clinical requirements. As the epidemic progresses,
commercial tests comorbidities), it may progress to pneumonia, acute respiratory distress
syndrome (ARDS) and multi organ dysfunction. The vaccine has proved to be safe and
induced considerable humoral and cellular immune response in most recipients after a
single immunization', Another vectored vaccine, ChAdOxl, and other SARSr-CoVs (FIG).
At present, nucleic acid detection techniques, like RT-PCR, are considered an effective
method for confirming the diagnosis in clinical cases of COVID-19 (148). Those variants
with this mutation make up a single subclade labelled as clade 5'3,34. The most common
symptoms were fever (50%) and cough (38%). Histopathology analyses showed bilateral
diffused alveolar damage, hyaline membrane formation, desquamation of pneumocytes and
fibrin deposits in lungs of patients with severe COVID-19. This might also have
contributed to the increased case fatality rate observed in the COVID-19 outbreak.

VIROLOGY:
Coronaviruses, a family of viruses within the nidoviruses superfamily, are further classified
according to their genera, alpha-, beta-, gamma-and deltacoronaviruses (a, B, y- and 8-).
Among those, alpha and beta species are capable of Cov (referred to as severe acute
respiratory syndrome coronavirus). contaminating only mammals, whereas the other two
genera can infect birds and could also infect mammals. 15, 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-COVV (known as Middle
East respiratory syndrome coronavirus) and SARS- cov (referred to as severe acute
respiratory syndrome coronavirus).
The severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is now named novel COVID-
19 (coronavirus disease 2019). 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). It was postulated that undocumented infections might account for 79%
of vaccines that have proven in vitro efficacy against SARS-CoV to be utilized for SARS-
CoV-2. The number of cases documented cases owing to the high transmissibility of the
virus during mild disease or the asymptomatic period. Hence, the superior genetic similarity
existing between SARS-CoV-2 and SARS-CoV can be utilized to repurpose started
increasing exponentially, some of which did not have exposure to the live animal market,
suggestive of the fact that human-to-human transmission was occurring [8]. 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". According to
the COVID-19 dashboard of the Center for System Science and Engineering at Johns
Hopkins University, as of 111 August 2020, was linked to a family member and 26 children
had history of travel/residence to Hubei province in China. In the following sections, we
summarize potential therapeutics against SARS-CoV-2 on the basis of published clinical
data and experience. Using sequences of five conserved replicative domains in pplab (3C-
ike protease3CLpro), nidovirus RNA-dependent RNA polymerase (RdRp)- associated
nucleotidyltransferase (NIRAN), RdRp, zinc-binding domain (ZBD) and HEL1), the
Coronaviridae Study Group of the International Committee on Taxonomy of Viruses
estimated the pairwise patristic distances between SARS-CoV-2 and known coronaviruses,
and assigned SARS-CoV-2 too the existing species SARSr-CoV", Although
phylogenetically related, SARS-CoV-2 is distinct from all other coronaviruses from bats
and pangolins in this species. The SARS-CoV-2 S protein has a full size of 1,273 amino
acids, longer than that of SARS-CoV (1,255 amino acids) and known bat SARSr-CoVs
(1,245-1,269 amino acids). Remdesivir has shown activity against SARS-CoV-2 in vitro
and in vivo2136, A clinical study revealed a lower need for oxygen support in patients with
COVID-19 (REF 137). Therefore travel history becomes important. However, as the
epidemic spreads, the travel history 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 available data are insufficient to interpret pangolins
as the intermediate host of SARS- CoV-2. It is not possible to differentiate COVID-19 from
these infections clinically or through routine lab tests. To address this highly controversial
issue, further retrospective investigations involving a larger number of banked samples
from patients, animals and environments need to be conducted worldwide with well-
validated assays.

Genomics, Phylogeny and Taxonomy:

As a novel betacoronavirus, SARS-CoV-2 shares 79% genome sequence identity with

SARS-CoV and 50% with MERS- CoV4, Its genome organization is shared with other
betacoronaviruses. 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.
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). A patient with COVID-19 spreads viruses in liquid droplets during speech. On 11
February, the International Committee on Taxonomy of Viruses named the novel
coronavirus 'SARS-CoV-2, and the WHO named the disease 'COVID-19 (REF"). In human
ACE2-transgenic mice infected with SARS-CoV-2, typical interstitial pneumonia was
present, and viral antigens were observed mainly in the bronchial epithelial cells,
macrophages and alveolar epithelia. In China, vapor inhalation of interferon-a is included in
the COVID-19 treatment guidelinels, Clinical trials are ongoing across the world to
evaluate the efficacy of different therapies involving interferons, either alone or in
combinationwith other agents.

Immunoglobulin Therapy:

An ideal therapeutic option suggested need to be. The U.S. for SARS-CoV-2 (COVID-19)
is the combination therapy comprised of MAbs and the drug remdesivir (COVID-19) (201).
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,
length to the corresponding proteins in SARS-CoV. Of the four structural genes, SARS-
CoV-2 shares more than 90% amino acid identity with SARS-CoV except for the S gene,
which diverges24, The replicase gene covers two thirds of the 5 genome, and encodes a
large polyprotein (pplab), which is proteolytically cleaved into 16 non-structural proteins
that are involved in transcription and virus replication. Many different vaccine platforms
against SARS-CoV-2 are in development, the strategies of which include recombinant
vectors, DNA, mRNA in lipid nanoparticles, inactivated viruses, live attenuated viruses and
protein subunits-lo. The chest CT findings associated with COVID-19 infected patients
include characteristic patchy drugs, viz., All clinicians should keep themselves updated
about recent developments including global spread of the infiltration that later progresses to
ground-glass capacities (158). The in vitro antiviral potential of FAD-approved drugs, viz.,
All clinicians should keep themselves updated about recent developments including global
spread of the

(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. In
comparisonwith 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 infections in pangolins from different
smuggling events suggests that these animals are possible hosts of the viruses. This
property of the RBD can be utilized for designing potential SARS-CoV RBD-containing
vaccines either by using recombinant proteins or recombinant vectors that encode RBD
(175). Compared to emerging viruses like Ebolavirus, 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
caleulated using the infection fatality risk (IFR). Researchers and manufacturers are
conducting large-scale clinical trials to evaluate various therapies for COVID-19. They are
very closely related to SARS-CoV-2, exhibiting 92.4% sequence similarity. Finally,
COVID-19 ischallenging all human beings. Common laboratory findings Include
normal/low white cell counts with elevated C reactive protein (CRP). Most of these SARS-
CoV-2 non- structural proteins have greater than 85% amino acid sequence identity with
SARS-CoV25. The phylogenetic analysis for the whole genome shows that SARS-CoV-2 is
clustered with SARS-CoV and SARS-related coronaviruses (SARS- CoVs) found in bats,
placing it in the subgenus Sarbecovirus of the genus Betacoronavirus. The receptor-binding
gene region (173, 174). On binding to epithelial cells in the respiratory tract, SARS-CoV-2
starts replicating and migrating down to the airways and enters alveolar epithelial cells in
the lungs. The comparative analysis confirmed that the variable residues were found
concentrated on the Sl subunit of S protein, an important vaccine target of the virus (150).
Recent studes reported specific monoclonal antibodies neutralizing SARS-CoV-2 infection
Inhibition of virus replication. The massive migration of Chinese during the Chinese New
Year fuelled the epidemic. Cases in other provinces of China, other countries (Thailand,
Japan and South Korea in quick succession) were reported in people who were returning
from Wuhan. 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 furint 5455. Environmental samples from the
Huanan sea food market alsotested positive, signifying that the virus originated from there
[7]. The virus spreads faster than its twn ancestors the SARS-CoV residues for receptor
binding (FIG). However, this individual early report cannot give a solid answer to the
origin of SARS-CoV-2 and contamination, and thus a false positive result cannot be
excluded. More so, future outbreaks of viruses and pathogens of zoonotic origin are likely
to continue. Therefore, apart from curbing this outbreak. Bovine coronaviruses (BoCoVs)
are known to infect several domestic and wild ruminants (126). The first fatal case was
reported on 11th Jan 2020. Several laboratories around the world are currently developing
antibody-based diagnostic tests against SARS-CoV-2 (157). Chest CT is an ideal diagnostic
tool for identifying viral pneumonia. With the current outbreak of COVID-19, there is an
expectancy ofa significant increase in the number of published studies about this emerging
coronavirus, as occurred require sedatives, analgesics, and even muscle relaxation drugs to
prevent ventila tor-related lung injury incoordination (122). The discovery of diverse bat
coronaviruses closely related to SARS-CoV-2 suggests that bats are possible reservoirs of
SARS-CoV-2 (RE.*"). Within this clade, SARS-CoV-2 is grouped in a distinct lineage
together with four horseshoe bat coronavirus isolates (RaTG13, RmYN02,2C45 and
ZXC21) as well as novel coronaviruses recently identified in pangolins, which group
parallel to SARS-CoV in vitro and In vivo5- 135, Compared with convalescent plasma,
which has limited availability and cannot be amplified, monocional antibodies can be
developed in larger quantities to meet clinical requirements. As the epidemic progresses,
commercial tests comorbidities), it may progress to pneumonia, acute respiratory distress
syndrome (ARDS) and multi organ dysfunction. The vaccine has proved to be safe and
induced considerable humoral and cellular immune response in most recipients after a
single immunization', Another vectored vaccine, ChAdOxl, and other SARS-CoVs (FIG).
At present, nucleic acid detection techniques, like RT-PCR, are considered an effective
method for confirming the diagnosis in clinical cases of COVID-19(148). Those variants
with this mutation make up a single subclade labelled as clade 53,34. The most common
symptoms were fever (50%) and cough (38%). Histopathology analyses showed bilateral
diffused alveolar damage, hyaline membrane formation, desquamation of pneumocytes and
fibrin deposits in lungs of patients with severe COVID-19. This might also have
contributed to the Increased case fatality rate observed in 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. One case of
severe pneumonia and

multiorgan dysfunction in a child has also been reported [19]. 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). A confirmed case is a suspect case with a
positive molecular test.

Specific diagnosis is by specific molecular tests on respiratory samples (throat

swab/nasopharyngeal swab/sputum/ endotracheal aspirates and bronchoalveolar lavage).
The SARS-CoV-specifie human MAb CR3022 is found to bind with SARS-CoV-2 RBD,
indicating its potential as a therapeutic agent. From experience With several outbreaks
associated with known emerging viruses, higher pathogenicity of a virus is often associated
with lower transmissibility. Some human ACE2-transgenic mice even died after infection.
In wide-type mice, a SARS-CoV-2 mouse-adapted strain with the N501Y alteration in the
RBD of the S protein was generated at passage 6. Whether the higher transmissibility 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. 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, 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 in Yunnan. In addition, seven putative
ORFS encoding accessory proteins are interspersed between the structural genes. As of 2
October 2020, -174 vaccine candidates for COVID-19 had been reported and 51 were in
human clinical trials (CoVID-19 vaccine and therapeutics tracker). Hence, they provide the
possibility for the treatment and prevention of COVID-19. 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-, Airborne transmission was also observed in the ferret experiments
mentioned above. It is difficult to evaluate the therapeutie potential of a drug or a
combination of drugs for managing a disease based on such a limited sample size. Golden
hamsters also showed typical symptoms after being infected with SARS-CoV-2 (REF7).
Animal models offer important information for understanding the pathogenesis of SARS-
CoV-2 infection and the transmission dynamics of SARS-CoV-2, and are important to
evaluate the efficacy of antiviral therapeutics and vaccines.

Clinical And Epidemiological Features:

It appears that all ages of the population are susceptible to SARS-CoV-2 infection, and the
median age of infection is around 50 years13608081, However, clinical manifestations
differ with age. Swine acute diarrhea syndrome coronavirus it had spread massively to all
34 provinces of China. SARS-CoV-2 pseudovirus entry assays revealed that TMPRSS2 and
cathepsin Lhave cumulative effects with furin on activating virus entrys3, Analysis of the
cryo-electron about this virus is rapidly evolving, readers are urged to update themselves
regularly. 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 conformational states 051.5859. Since knowledge

DIAGNOSIS OF SARS-CoV-2 (COVID-19):

RNA tests can confirm the diagnosis of SARS-CoV-2 (COVID-19) cases with real-time RT-
PCR or next-generation sequencing (148, 149, 245, 246). Considering the zoonotic links
associated with SARS-CoV-2, the One Health approach may play a vital role in the
prevention and control measures being followed to restrain this pandemic Virus patients
had positive molecular tests on repeat testing [22]. (317-319). The substantial importation
of COVID-19 presymptomatic cases from Wuhan has resulted in independent, self-
sustaining outbreaks across major cities both within the country and across the globe.
However, community transmission might have happened before that". IBV, under Gamma
coronavirus, causes diseases of respiratory, urinary, and reproductive systems, with
substantial economic losses in chickens (131, 132). In fact, abnormal CT scans have been
used to diagnose COVID-19 in suspect cases with negative molecular diagnosis; many of
these patients had positive molecular tests on repeat testing [22].´

__________-

shed of persistent local transmission or contact with patients with similar travel history or
those with confirmed COVID-19 infection. The chest CT imaging abnormalities associated
with COVID-19 pneumonia have also been observed even in asymptomatic patients.
The occurrence of COVID-19 infection on several cruise ships gave us a preliminary idea
regarding the transmission pattern of the disease. Cruise ships act as a closed environment
and provide an ideal setting for the occurrence of respiratory. Such a situation poses a
disease outbreaks. Significant threat to travelers, since people from different countries are
on board, which favors the introduction of the pathogen (320). Time alone will tell how the
virus will impact our lives here in India (2). Another related coronavirus has been reported
more recently in a Rhinolophus malayanus bat sampled in Yiunnan Thic novel hat virnc
denoted 'RmYN02 system (30). Similarly the neonatal cases that have been reported have
been mild [20].

Diagnosis:
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 considerable protection in mice against a MERS-
CoV lethal challenge. Interstitial pneumonia and inflammatory responses were found in
both young and aged mice after infection with the mouse-adapted strain. To control
COVID- 19, China implemented unprecedentedly strict public health measures. The RBD
of the S1 subunit of S protein has a superior capacity to induce neutralizing antibodies. The
rapid replication of SARS-CoV-2 in the lungs may trigger a strong immune response. It is
also abnormal in asymptomatic patients/ patients with no clinical evidence of lower
respiratory tract involvement. 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 settings, such as migrant worker communities, slaughter-
houses and meat packing plants, indicating the necessity of isolating infected people.
Nosocomial transmission was not the main source of transmission in China because of the
implementation of infection control measures in clinical settings. 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(REFS563). It is also the first
approved option by the European Union for treatment of adults and adolescents with
pneumonia requiring supplemental oxygen. Several international phase III clinical trials are
continuing 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 clearance. Such antibodies may play a crucial
role in enhancing protective humoral responses against the emerging CoVs by aiming
appropriate epitopes and functions of the S protein, The cross-neutralization ability of
SARS-CoV RBD-specific neutralizing MAbs considerably relies on the resemblance
between their RBDs; therefore, SARS-CoV RBD-specific be recognized by a relative
analysis of RBD of SARS-CoV-2 to that of SARS-CoV, and cross-neutralizing SARS-CoV
but did not induce severe clinical symptoms8, As transmission by direct contact and air was
observed in infected ferrets and hamsters, these animals could be used to model different
transmission modes of COVID-19 (REFS7-7). The first such instance was in 2002-2003
when a or even die, whereas most young people and children have only mild diseases (non
pneumonia or mild pneumonia) or are asymptomatic" 81.3, Notably, the risk of disease was
not convalescent plasma under an emergency investigational new drug application.
According to the National Health antibodies could cross-neutralized SL CoVs, i.e., bat-SL-
CoV strain WIVI (RBD with eight amino acid differences from SARS-CoV) but not bat-
SL-CoV strain SHC014 (24 amino acid differences) (200), Appropriate RBD-specific Mabs
can RBD-specific MAbs could be explored for their effectiveness against COVID-19 and
further assessed clinically. Biotechnology company Regeneron is attempting to recognize
potent and specific MAbs to combat COVID-19. In other animal models, including cats and
ferrets, SARS-CoV-2 could efficiently replicate in the upper respiratory tract higher for
pregnant women. However cases may be asymptomatic or even without fever. Notably, the
RBD of Guangdong pangolin coronaviruses is highly similar to that of SARS-CoV-2.
Preliminary findings have suggested improved clinical status after the treatment 5,154, The
FDA has provided guidance for the use of COVID-19 Commission of China, the total
number of cases continued to rise sharply in early February at an average rate of more than
3,000 newly confirmed cases per day. 2). The updates obtained from countries like China,
Japan, Thailand,

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 organismsn(mycoplasma, chlamydia) and bacterial
infections. The sensitivity of chest CT is far superior to that of X- ray screening. 4). Most
patients also developed marked lymphopenia, similar to what was observed in patients with
SARS and MERS, and non-survivors developed severer lymphopenia over time compared
with non-ICU patients, ICU patients had higher levels interactions remain largely unclear.
Soon this lock down was of plasma cytokines, which suggests an immunopathological
process caused by a cytokine storm 86857, 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 disease (FIG. 36). The high genetic similarity
between SARS-CoV-2 and RaTG13 supports the hypothesis that SARS- CoV-2 likely
originated from bats5. In general, older men (>60 years old) with co-morbidities are more
likely to developsevere respiratory disease that requires hospitalization differs from that in
SARS-CoV in the five residues critical for ACE2 binding, namely Y455L, L486F, N493Q,
D494S and T501NS" (FIG). As some of the first reported cases in Wuhan had no
epidemiological link to the seafood market, it has been suggested that the market may not
be the initial source of human infection with SARS-CoV-2. One study from France detected
SARS-CoV-2 by PCR in a stored sample from a patient who had pneumonia at the end of
2019, suggesting SARS-CoV-2 might have spread there much earlier than the generally
known starting time of the outbreak in France. Most patients recovered enough to be
released from hospital in 2 weeks(FIG). The result obtained from a associated with human-
machine clinical study of four patients infected with COVID-19 claimed that combination
therapy using lopinavir/itonavir, arbidol, and Shufeng Jiedu capsules (traditional Chinese
medicine) was found to be effective in managing COVID-19 pneumonia (193). 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). Hence, the possibility of SARS-CoV-specific neutralizing antibodies
providing cross-protection to COVID-19 might be lower. Patients of older age (>60 years)
and with serious pre-existing diseases have a greater risk of developing acute respiratory
distress syndrome and death-6 (FIG). Less common symptoms include sputum production,
headache, haemoptysis, diarrhoea, anorexia, sore throat, chest pain, chills and nausea and
vomiting in studies of patients in Chinal3,60,80,31, Self-reported olfactory and taste
disorders were also reported by patients in Italys. Early manifestations of COVID-19
pneumonia might not be evident in X-ray chest radiography. 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 exists in a variant
group. Owing to these measures, the daily number of new cases in China started to decrease
steadily", However, despite the declining trend in China, the international spread of
COVID-19 accelerated from late February. Such an $1-$2 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). In a suspect case in India, the appropriate sample
has to be sent to designated reference labs in India or the National Institute of Virology in
Pune. It is distinct from the S proteins of most members in the subgenus Sarbecovirus,
sharing amino acid sequence similarities of 76.7-77.0% with SARS-CoVs from civets and
humans, article gives a bira's eye View about this new virus. 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 naturally2". Immunohistochemistry assays detected SARS-CoV-2 antigen in the
upper airway, bronchiolar epithelium and submucosal gland epithelium, as well as in type I
and type II pneumocytes, alveolar macrophages and hyaline membranes in the lungs.
Animal models used for studying SARS-CoV-2 infection pathogenesis include non-human
primates rhesus macaques, cynomolgus mankeys, marmosets and African green monkeys,
mice wild-type mice with mouse-adapted virus and human ACE2-transgenic or human
ACE2-knock-in mice), ferrets and golden hamsters.ab- 7, In non-human primate animal
models, most species display clinical features similar to those of patients with COVID-19,
including virus shedding, virus replication and host responses to SARS-CoV-2 infection,
For example, in the rhesus macaque model, high viral loads were detected in the upper and
216 countries and regions from all six continents had reported more than 20 million cases
of COVID-19, and more than 733,000 patients had died. Exudative inflammation was also
shown in some cases. The number of confirmed cases suddenly increased, with thousands
of new cases diagnosed daily during late January". Interferons induce the expression of
diverse
interferon-stimulated genes, which can interfere with every step of virus replication. SARS-
CoV-2-infected ferrets
_______