1

vaccine that can produce cross-reactive antibodies.

However, the success of such a vaccine relies greatly
on its ability to provide protection not only against
present versions of the virus but also the ones that
are likely to emerge in the future. This can be
achieved by identifying antibodies that can recognize
relatively conserved epitopes that are maintained as
such even after the occurrence of considerable
variations (362) . Even though several vaccine
clinical trials are being conducted around the world,
pregnant women have been completely excluded
from these studies . Pregnant women are highly
vulnerable to emerging diseases such as COVID-19
due to alterations in the immune system and other
physiological systems that are associated with
pregnancy . Therefore, in the event of successful
vaccine development, pregnant women will not get
a c c e s s to the v a c c i n e s (361) . Hence, it is
recommended that pregnant women be included
in the ongoing vaccine trials, since successful
vaccination in pregnancy will protect the mother,
fetus, and newborn.
The heterologous immune effects induced by
Bacillus Calmette Guérin (BCG) vaccination is a
promising strategy for controlling the COVID-19
pandemic and requires further investigations. BCG is
a widely used vaccine against tuberculosis in high-
 2

susceptible individuals . Hence , hand hygiene is

equally as important as the use of appropriate PPE,
like face masks , to break the transmission cycle of
the virus; both hand hygiene and face masks help to
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
because they are exposed directly to infected
patients . Hence, proper training must be given to all
hospital staff on methods of prevention and
protection so that they become competent enough to
protect themselves and others from this deadly
disease (316). As a preventive measure, health care
workers caring for infected patients should take
extreme precautions against both contact and
airborne transmission. They should use PPE such as
face masks (N95 or FFP3), eye protection (goggles),
gowns, and gloves to nullify the risk of infection
(299).
The human-to-human transmission reported in
SARS - CoV - 2 infection occurs mainly through
droplet or direct contact. Due to this finding,
frontline health care workers should follow stringent
infection control and preventive measures, such as
the use of PPE, to prevent infection (110) . The
mental health of the medical/health workers who are
involved in the COVID - 19 outbreak is of great
 3

aminotransferase, bilirubin, and, especially, D-dimer

(244). Middle-aged and elderly patients with primary
chronic diseases, especially high blood pressure and
diabetes, were found to be more susceptible to
respiratory failure and , therefore , had poorer
prognoses. Providing respiratory support at early
stages improved the disease prognosis and facilitated
recovery (18) . The ARDS in COVID -19 is due to the
occurrence of cytokine storms that results in
exaggerated immune response, immune regulatory
network imbalance, and, finally, multiple - organ
failure (122) . In addition to the exaggerated
inflammatory response seen in patients with
COVID-19 pneumonia, the bile duct epithelial cell-
derived hepatocytes upregulate ACE2 expression in
liver tissue by compensatory proliferation that might
result in hepatic tissue injury (123).
CORONAVIRUSES IN ANIMALS AND
ZOONOTIC LINKS--A BRIEF
VIEWPOINT
Coronavirus can cause disease in several species
of domestic and wild animals, as well as humans
(23). The different animal species that are infected
with CoV include horses, camels, cattle, swine, dogs,
cats, rodents, birds, ferrets, minks, bats, rabbits,
snakes, and various other wild animals (20, 30, 79,-
 4

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) . Efforts
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
 5

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). Efforts
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
 6

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 responses 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 were 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 to
 7

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 (183-186) . 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 severe
COVID-19 revealed no benefit of lopinavir-ritonavir
treatment over standard care (273).
The efforts to control SARS - CoV - 2 infection
utilize defined strategies as followed against MERS
and SARS, along with adopting and strengthening a
 8

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 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
 9

transmission risk ( 228 ). 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 ( 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. The majority of
Chinese cities are now facing localized outbreaks of
COVID-19 ( 231 ) . Hence, deploying efficient public
health interventions might help to cut the spread of
this virus globally.
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
disease outbreaks. Such a situation poses a
significant threat to travelers, since people from
different countries are on board, which favors the
introduction of the pathogen (320). 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. The
 10

Even though a high similarity has been reported

between the genome sequence of the new
coronavirus ( SARS-CoV-2 ) and SARS-like CoVs,
the comparative analysis recognized a furin-like
cleavage site in the SARS-CoV-2 S protein that is
missing from other SARS-like CoVs (99). The furin-
like cleavage site is expected to play a role in the life
cycle of the virus and disease pathogenicity and
might even act as a therapeutic target for furin
inhibitors. The highl y contagious nature of SARS-
CoV-2 compared to that of its predecessors might be
the result of a stabilizing mutation that occurred in
the endosome-associated-protein-like domain of
nsp2 protein.
Similarly, the destabilizing mutation near the
phosphatase domain of nsp3 proteins in SARS-CoV-
2 could indicate a potential mechanism that
differentiates it from other CoVs (100). Even though
the CFR reported for COVID-19 is meager
compared to those of the previous SARS and MERS
outbreaks, it has caused more deaths than SARS and
MERS combined (101) . Possibly related to the viral
pathogenesis is the recent finding of an 832-
nucleotide (nt) deletion in ORF8, which appears to
reduce the replicative fitness of the virus and leads to
attenuated phenotypes of SARS-CoV-2 (256).
Coronavirus is the most prominent example of a