Review COVID-19 NEJM

Acta Tropica 214 (2021) 105778
Contents lists available at ScienceDirect
Acta Tropica
journal homepage: www.elsevier.com/locate/actatropica
One year update on the COVID-19 pandemic: Where are we now?

Sanjay Kumar Mishra a, Timir Tripathi b, *
a
Department of Botany, Ewing Christian College, Prayagraj- 211003, Uttar Pradesh, India
b
Molecular and Structural Biophysics Laboratory, Department of Biochemistry, North-Eastern Hill University, Shillong 793022, Meghalaya, India
A R T I C L E I N F O A B S T R A C T
Keywords: We are living through an unprecedented crisis with the rapid spread of the new coronavirus disease (COVID-19)
SARS-CoV-2 worldwide within a short time. The timely availability of thousands of SARS-CoV-2 genomes has enabled the
Coronavirus scientific community to study the origin, structures, and pathogenesis of the virus. The pandemic has spurred
COVID-19
research publication and resulted in an unprecedented number of therapeutic proposals. Because the develop
Drug repurposing
Vaccines
ment of new drugs is time consuming, several strategies, including drug repurposing and repositioning, are being
Therapeutics tested to treat patients with COVID-19. Researchers have developed several potential vaccine candidates that
Pandemic have shown promise in phase II and III trials. As of 12 November 2020, 164 candidate vaccines are in preclinical
Pathogenesis evaluation, and 48 vaccines are in clinical evaluation, of which four have cleared phase III trials (Pfizer/Bio
Outbreak NTech’s BNT162b2, Moderna’s mRNA-1273, University of Oxford & AstraZeneca’s AZD1222, and Gamaleya’s
Sputnik V vaccine). Despite the acquisition of a vast body of scientific information, treatment depends only on
the clinical management of the disease through supportive care. At the pandemic’s 1-year mark, we summarize
current information on SARS-CoV-2 origin and biology, and advances in the development of therapeutics. The
updated information presented here provides a comprehensive report on the scientific progress made in the past
year in understanding of SARS-CoV-2 biology and therapeutics.
1. Introduction studied for COVID-19 treatment in hundreds of clinical trials worldwide.

Here, we review current knowledge related to SARS-CoV-2 gained in the
We have now been living with COronaVIrus Disease (COVID-19) for past year, including its progression, pathology, prevention, and thera
the past year. COVID-19 emerged in December 2019, and in March of peutics. We discuss what is currently known about the virus and how far
2020 was declared a pandemic by the World Health Organization. The medicine has progressed in the fight against COVID-19.
devastating effect of the causative SARS-CoV-2 virus has infected mil
lions of humans across 218 countries and terrotories and led to more 2. Origin and diversification of human CoVs
than 1.4 million deaths globally as of 24 November 2020. The pandemic
has significantly affected biomedical researchers, by first halting Coronaviruses (CoVs) are a large group of viruses that infect the
research and then resulting in the concentration of scientific resources upper respiratory tract in humans and cause common cold and flu-like
toward better understanding the SARS-CoV-2 virus and developing infections. Their name originates from the presence of club-shaped
vaccines and therapeutics (Palayew et al., 2020; Zamora-Ledezma et al., glycoprotein projections (called spikes) that arise from the surface of
2020). The advent of genomics technologies and computational ap the viral envelope and impart a crown-like appearance to the viral
proaches has accelerated scientific breakthroughs in the past year. There particles, similarly to the Sun’s corona (Fig. 1A). The CoVs belong to the
has been exponential growth in the number of scientific publications order Nidovirales of the subfamily Orthocoronaviridae in the family
related to COVID-19. The genome sequence of the virus appeared online Coronoviridae. All CoVs have zoonotic origin, and cause respiratory and
on January 10, and within weeks, the structures of several viral proteins intestinal infections in several animals, including humans. On the basis
were determined. Within months, clinical trials of vaccines and thera of genomic organization and phylogenetic relationships, CoVs are clas
peutics began, and positive reports on vaccines are currently appearing. sified into four genera: α-CoV, β-CoV, γ-CoV, and δ- CoV. The α-CoVs and
Moreover, an array of drugs approved for other viral infections are being β-CoVs infect various mammals (such as bats, cattle, domestic animals,
* Corresponding author.
E-mail address: [email protected] (T. Tripathi).
https://doi.org/10.1016/j.actatropica.2020.105778
Received 5 September 2020; Received in revised form 23 November 2020; Accepted 24 November 2020
Available online 28 November 2020
0001-706X/© 2020 Elsevier B.V. All rights reserved.
S.K. Mishra and T. Tripathi Acta Tropica 214 (2021) 105778
livestock, and humans), whereas the γ-CoVs and δ-CoVs infect avians All human CoVs have zoonotic origin and are capable of transmission
and sometimes mammals (Woo et al., 2012). among mammalian hosts; however, most CoVs originate in bats and are
CoVs were first identified as infectious bronchitis viruses in 1937, transmitted to humans through domestic animals (Forni et al., 2016; Su
infecting avian species and devastating poultry stocks. The strain of CoV et al., 2016). Thus, bats are considered the natural host and primary
responsible for 15–30% of cases of the common cold in humans was reservoir of human CoVs (Cui et al., 2019). For SARS-CoV, horseshoe
identified in 1965 (Bhargava 2020). To date, seven strains of human CoV bats (Rhinolophus) have been reported to be the natural host, and palm
have been identified as belonging to α-CoVs or β-CoVs. The four mild civets (Paguma larvata) have been reported to be the intermediate host,
strains (HCoV-NL63, HCoV-229E, HCoV-OC43, and HKU1) induce mild on the basis of the presence of antibodies in these organisms in China
respiratory disease of the upper respiratory tract in infants, older people, and European countries where the virus emerged during 2002–03. Later,
and immunocompromised individuals. In comparison, the three highly several strains of related CoVs were identified in bats (Rhinolophus) that
virulent pathogenic strains, severe acute respiratory syndrome corona emerged through the recombination of existing strains of CoVs (Shi and
virus (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), Hu, 2008; Zheng et al., 2004). MERS-CoV had camels as the primary
and SARS-CoV-2 cause acute respiratory distress syndrome, result in zoonotic host and was reported in bats of the genera Pipistrellus and
pulmonary failure and fatality in humans (Forni et al., 2016; Masters Perimyotis, thus, suggesting that bats are the key reservoir and trans
and Perlman, 2013; Su et al., 2016). The outbreak of SARS-CoV in 2002 mission agent (Cui et al., 2019; Huynh et al., 2012). The S-gene encoding
in Guangdong province in South China spread to approximately 28 spike protein is considered the hotspot of genetic recombination among
countries and infected nearly 8000 individuals, causing symptoms of different bat CoV strains (Hon et al., 2008; Huynh et al., 2012; Wu et al.,
fever, headache, and respiratory problems, such as shortness of breath, 2016). Because of the genetic variability in different CoV strains and the
taking 774 human lives (Bhargava 2020; Zhong et al., 2003). Ten years frequent genetic recombination between strains, the emergence of novel
later, in 2012, the MERS-CoV outbreak endemic in Middle Eastern variants of CoVs was predicted before 2002 (Nagy and Simon, 1997;
countries, particularly Saudi Arabia, affected nearly 2500 people Rowe et al., 1997). The progenitors of SARS-CoV evolved through
(Bhargava 2020; Wang et al., 2013; Zhong et al., 2003). Both these recombination within Rhinolophus bats and then was transmitted to farm
β-CoVs are genetically different and have been reported to originate civets (Paguma larvata) through fecal-oral transmission; infected civets
from bats (Cui et al., 2019). These outbreaks indicate the potential for then transmitted it to market civets, in which the viruses underwent
the emergence of super/lethal strains of human CoVs in the future with substantial mutation before spreading to the human population in
high transmission and mortality rates together with a long latency Guangdong, China (Cui et al., 2019). SARS-CoV-2 is the seventh member
period between infection and detectable symptoms, thus, potentially of the human CoVs (Corman et al., 2018; Wu et al., 2020b; Zhou et al.,
resulting in devastating pandemics (Patrick). The viral pneumonia-like 2020).
disease was first reported at the end of November 2019 near the wet SARS-CoV-2 was transmitted to humans from infected animals in the
seafood market in Wuhan Province, China. The CoV first reported in market and then spread rapidly throughout the world via human-to-
Wuhan was described to be a novel virus belonging to the β-CoV cate human contact involving exposure to respiratory droplets or aerosols
gory and was designated as 2019 novel coronavirus (2019-nCOV) by through nosocomial transmission. Studies have indicated that bats are
Chinese researchers (Shereen et al., 2020). However, on 11 February the natural reservoir of SARS-CoV-2, as with other human CoVs (Bane
2020, the virus was renamed SARS-CoV-2, and the disease was named rjee et al., 2019; Hampton, 2005; Li et al., 2005a; Wu et al., 2020b; Zhou
COVID-19 (Drosten et al., 2003; Fouchier et al., 2003; Zhong et al., et al., 2020). The first genome sequence of SARS-CoV-2 was compared
2003). with the bat CoV RaTG13 and human SARS-CoV, and the SARS-CoV-2
Fig. 1. Schematic representation of SARS-CoV-2 (A) virus structure and (B) genome organization.
2
genome has been found to show a nucleotide sequence identity of 96.2% 2019). The structural similarities and differences in the E and M proteins
with the bat CoV RaTG13 and 79.5% with human SARS-CoV (Naqvi of SARS-CoV-2 proteins versus bat and pangolin CoVs are responsible for
et al., 2020; Zhou et al., 2020), thus, indicating a close relationship cross-species specificity and cross-species transmission of CoVs. The
between bat and human CoVs, and suggesting that both strains might amino acid sequence variations in these structural proteins play signif
have evolved from a common ancestor strain that diversified through icant roles in the evolution and diversification of CoVs. Similar varia
genetic recombination, mutation, and natural selection during trans tions arising either from mutation or genetic recombination may result
mission. SARS-CoV-2 is thought to have originated in bats via genetic in the zoonotic origin of a new viral strain with more severe virulence
recombination of existing bat CoV strains and to have been transmitted (Bianchi et al., 2020; EA and Jones, 2019). The N protein, in association
from bats to humans either directly or through unknown intermediate with genomic RNA, forms the nucleocapsid, which maintains the
hosts, similarly to the roles of civets and camels in SARS-CoV and genome structure inside the envelope and plays significant roles in viral
MERS-CoV, respectively (Zhou et al., 2020). Recent data suggest that assembly, budding, and the host cellular response to viral infection. The
CoVs capable of infecting humans emerged in bats around 40 years ago details on the various SARS-CoV-2 proteins and their roles are shown in
and have been circulating undetected since then, thus suggesting bats as Table 1.
the primary reservoir of the SARS-CoV-2 lineage (Boni et al., 2020).
Detailed analysis of the protein sequence data has also indicated the
potential of pangolins, turtles, and snakes acting as intermediate hosts of
SARS-CoV-2, owing to the presence of ACE2 receptors in the CoVs re
ported from these animals (Guan et al., 2020). A recent study has used
protein mapping to characterize the protein interaction networks of the Table 1
three CoVs (SARS-CoV-1, MERS-CoV, and SARS-CoV-2) in humans, thus Details on the SARS-CoV-2 proteins and their roles.
revealing important molecular mechanisms and potential therapeutic Proteins Roles
interventions common to the three CoVs (Gordon et al., 2020a). Nsp1 inhibits host innate immune response; increases
proinflammatory chemokine production
3. Structure and genomic organization of SARS-CoV-2 Nsp2 acts as an Nsp3 adaptor
PLpro/Nsp3 interacts with Nsp4 and Nsp6 and forms a complex;
strips ubiquitin and blocks the host innate immune
SARS-CoV-2 is an unsegmented single-stranded positive-sense RNA response
virus. Structurally, it is a spherical or pleomorphic enveloped virus. The Nsp4 interacts with Nsp3 and Nsp6; anchors the
genome size of SARS-CoV-2 is ~29 Kb RNA, which is between the replication complex to double-membrane vesicles
genome sizes of SARS-CoV (~28 Kb) and MERS-CoV (~30 Kb) (De Wit Nsp5/3CLPro causes cleavage of viral polyproteins, thus
decreasing individual Nsps
et al., 2016; Wu et al., 2020a; Wu et al., 2020b; Zehra et al., 2020; Zhou Nsp6 interacts with Nsp3 and Nsp4; limits the expansion
et al., 2020). The genome is organized as a 5′ -leader- of autophagosome and lysosomal viral degradation
UTRs-replicase-S-E-M-N-3′ UTR-poly (A) tail sequence and is character Nsp7/primase forms the primase complex as part of the
ized by the presence of a variable number (6–12) of open reading frames replication complex (Nsp7/8/12); can perform
both de novo initiation and primer extension
(ORFs) between conserved genes (ORF1ab, S, E, M, and N) and nine
Nsp8/primase interacts with Nsp7 and the Nsp7/Nsp8 complex,
sub-genomic mRNAs, nine transcription regulatory elements and two thus forming the RNA transcriptase-replicase
terminal untranslated regions (UTRs) (Figure 1B) (Lu et al., 2020). The complex; the Nsp7/Nsp8 complex stabilizes the
5′ UTR and 3′ UTR are important for RNA-RNA interaction and binding Nsp12 regions involved in RNA binding
of viral and cellular proteins. The sizes of UTRs differ among Nsp9/RNA-binding protein interacts with the replication complex (Nsp7/8/12)
Nsp10 interacts with Nsp16, which is required for
SARS-CoV-1, SARS-CoV-2, and MERS-CoV. Two-thirds of the viral replication; stimulates Nsp16 methyltransferase
genome located at the 5′ end constitutes the first ORF (ORF1a/b); ORF1a activity; interacts with Nsp14, thus facilitating
and ORF1b contain frameshifts encoding two long polypeptides (pp1a exoribonuclease and methyltransferase activities
and pp1ab), which after priming and processing produce 16 Nsp12 (RNA-dependent RNA interacts with Nsp7 and Nsp8, thus forming an RNA
polymerase) transcriptase-replicase complex
non-structural proteins (nsp1–16), which are necessary for genome
Nsp13/NTPase/helicase initiates the capping of viral mRNA (along with
maintenance. These polypeptides are processed by viral encoded (chy Nsp14 and Nsp16) and installs the cap structure
motrypsin-like-3cLpro-/main protease-Mpro-nsp5/Papain like-nsp3) onto viral mRNA
proteases. One-third of the genome near the 3′ end (ORFs 10 and 11) methyltransferase/ repairs mutation errors during replication;
encodes four major structural proteins: the spike (S), membrane (M), exoribonuclease/NSP14 involved in viral mRNA capping
uridylate-specific required for viral RNA synthesis
envelope (E), and nucleocapsid (N). The spikes are club-shaped, halo- endoribonuclease/NSP15
like membranous glycoprotein projections that constitute peplomers, 2′ -O-methyltransferase/ forms a complex with NSP10; involved in the S-
induce neutralizing antibodies, and play the most significant role in the NSP16 adenosyl-L-methionine cap methylation of mRNA
pathogenesis of SARS-CoV-2. The M-protein is the most abundant pro NSP11 short peptide with unknown function
spike (S) protein binds the ACE2 receptor on host cells and initiates
tein, which spans the membrane bilayer and maintains the shape of the
viral fusion with the host cell membrane
virion. It plays a significant role during the budding of coronaviral envelope (E) protein involved in viral assembly
particles from host cells. It is also a conserved viral protein, with 98% membrane (M) protein involved in viral assembly
sequence similarity to bat and pangolin CoV M proteins (Bianchi et al., nucleocapsid (N) protein binds viral RNA
2020). The E-protein is a valine and leucine rich hydropathic trans ORF3a involved in the trafficking of S-protein and
apoptosis
membrane protein essential for viral pathogenesis. It is a conserved ORF3b inhibits the activities of interferons
protein of SARS-CoV-2 and has amino acid sequence similarity with ORF6 interferon I antagonist that binds karyopherins and
pangolin CoV-MP798 and bat CoV-ZXC21, CoV-ZC45, and CoV-RaTG13, decreases the interferon/antiviral response
thus, indicating a close link with bat and pangolin CoVs (Bianchi et al., ORF7a involved in virus-induced apoptosis; inhibits
CD317, which prevents the release of CoVs
2020). The proteins S, M, and E together constitute the viral envelope.
ORF7b unknown function
The E and M proteins play significant roles in viral entry, replication, ORF8 unknown function
and particle assembly within human host cells during infection (Bianchi ORF9b involved in the degradation of signalosomes; limits
et al., 2020; EA and Jones, 2019; Schoeman and Fielding, 2019). During host cell interferon responses
viral particle assembly, the M protein interacts with other structural ORF9c unknown
ORF10 unknown
proteins (S, E, and N) to constitute the complete virion (EA and Jones,
3
4. Emergence of mutations in SARS-CoV-2 designated S1-NTP and S1-CTP, respectively. The RBD is present in the
C-terminal domain of the S-protein and mediates specific binding of the
The global spread of SARS-CoV-2 has resulted in tens of thousands of S1 subunit to the ACE2 receptor. In contrast, the N-terminal domain
mutations in the native strain within a short time. To rapidly share and plays a role in transmission between hosts and modulates the host cell
disseminate the information related to virus genomes, mutations, and endoplasmic reticulum, thus, inhibiting the interferon responses in the
evolution GISAID took the initiative involving a public-private- host cell (Babcock et al., 2004; Li et al., 2003; Li et al., 2005b; Qu et al.,
partnership (Elbe and Buckland-Merrett, 2017). Subsequently, a 2005).
CoV-GLUE database was developed to interpret and analyze the The phylogenetic and genomic similarities among various CoVs,
SARS-CoV-2 virus genome sequences, with a focus on amino acid specifically in the gene encoding RBD, render CoVs more amenable to
sequence variation (http://cov-glue.cvr.gla.ac.uk/#/replacement) human transmission (Guo et al., 2020). Strains of CoV differ in binding
(Singer et al., 2020). The D614G mutation in the viral S-protein is now affinity for human ACE2, thus, resulting in variation in their infection
the most prevalent globally (Figure 2). However, it may be noted that ability, transmission rate, and pathogenicity. In the past few months,
the D614 prevalent epidemics are still prevalent in many locations when SARS-CoV-2-RBD has undergone several mutations conferring stability
G614 first began to appear. The D614G mutant virus is not associated to the viral particle (Andersen et al., 2020; Benvenuto et al., 2020; Zhou
with increased mortality or clinical severity but is more transmissible et al., 2020). The binding affinity of the S-protein of SARS-CoV-2 for the
among hosts and associated with a higher viral load (Korber et al., 2020; human receptor is much higher (~4.7 nM) than that of SARS-CoV (~31
Volz et al., 2020). It has now been shown that the substitution D614G nM) and MERS-CoV (~16.7 nM) (Wang et al., 2020c). A detailed un
enhances viral replication in the respiratory tract and increases derstanding of the mechanism and specificity of the RBD-ACE2 inter
neutralization susceptibility (Plante et al., 2020). At present, the action may aid in predicting the generation of potential strains with
SARS-CoV-2 virus has a low mutation rate; however, as the pandemic greater transmission and pathogenicity, and in monitoring future dis
progresses, it can acquire mutations with fitness advantages and ease outbreaks. In addition, the information should aid in disease
immunological and drug resistance (Callaway, 2020b; Padhi et al., management and potentially in designing specific RBD-based thera
2020c; Padhi and Tripathi, 2020). peutics (vaccines, antibodies, or drugs). Knowledge of the direction of
evolution and prediction of the residues whose mutation increases the
5. Spike protein and its role in the pathogenesis of CoVs affinity of RBD/ACE2 interactions may aid in the identification of
favorable and unfavorable target residues in the design of new thera
The S-protein of CoVs forms a trimeric clover-shaped structure that peutic strategies (Padhi et al., 2020b).
binds a range of hosts and initiates pathogenesis (Fig. 3A). The S-protein The optimization of the binding affinity of the SARS-CoV-2 S-protein
is highly glycosylated and is made up of two subunits, the S1 head and for the human ACE2 receptor may also be attributed to the presence of
the S2 filament, which protrudes as a club-shaped projection from the functional polybasic cleavage sites for proteases, such as furin. These
viral envelope (Towler et al., 2004). The receptor-binding domain (RBD) cleavage sites, also known as S1–S2 cleavage sites, occur at the interface
of the trimeric S-protein binds the human angiotensin-converting of the S1 and S2 subunits through the insertion of 12 nucleotides, thus
enzyme 2 (ACE2) receptor, thus, initiating conformational changes resulting in the acquisition of O-linked glycans at the region flanking the
that drive membrane fusion (Figure 3B) (Tortorici and Veesler, 2019). cleavage site (Walls et al., 2020). The RBD is the most variable part of
The RBD is responsible for determining the cellular tropism and host the genome of CoVs. A seven-residue stretch critical for delimiting the
range of human CoVs, whereas the S2 subunit, with the specific tandem host according to the specific affinity toward the ACE2 receptor differs
domain heptads HR1 and HR2, mediates the fusion of the viral envelope in various CoVs, and natural selection has promoted optimal binding
with the host cell membrane (Xia et al., 2020; Yu et al., 2020). The S1 affinity during the course of host shifting (Wan et al., 2020; Wrapp et al.,
subunit is differentiated into an N-terminal and a C-terminal domain 2020; Zhou et al., 2020). The furin cleavage site at the junction of the S1
Fig. 2. The D614G mutation. (A) Graph showing the increasing frequency of the D614G variant over time. (B) The virus with D614G mutation is associated with
increased transmissibility and higher viral loads in COVID-19 patients.
4
Fig. 3. (A) Schematic structure of a single CoV spike-protein, showing the receptor binding S1 subunit, membrane fusion S2 subunit, and transmembrane anchor
(TM) emerging from the viral envelope. (B) The domain structure of S-protein, containing the S1N-terminal transmembrane domain (S1NTD) S1-C terminal (S1CTD)
fusion peptide, heptad repeats (HRN and HRC), and protective cleavage sites (S1/S2 and S2). (C) Binding of CoV to the ACE2 receptor on the host cell through the S-
protein RBD.
and S2 subunits allows for furin-mediated cleavage of the two subunits could aid in controlling the entry of viral particles and subsequent
of S-protein, and enables the RBD to specifically bind the ACE2 receptor infection (Al Bari, 2017; Degtyarev et al., 2008; Inoue et al., 2007;
and facilitate the fusion of host cells and subsequent entry of the virus Schrezenmeier and Dorner, 2020; Wang et al., 2008; Yang and Shen,
into host respiratory tract cells (Follis et al., 2006; Jia et al., 2005; Zhou 2020).
et al., 2020). Moreover, O-linked glycans have a mucin-like domain that The acidic pH of the autophagosomes aids in the dissolution of the
hides the antigenic determinant sites of the S-protein of SARS-CoV-2, viral envelope and the release of the viral genomic RNA inside the host
thus, resulting in immunoevasion (Bagdonaite and Wandall, 2018). cell. Because the viral RNA is positive-sense, it can directly enter the
replication and transcription cycle; these processes occur at the cyto
6. SARS-CoV-2 pathogenesis plasmic membrane and involve coordinated synthesis of continuous and
discontinuous RNA. Two-thirds of the 5′ -end of the SARS-CoV-2 RNA,
The specific RBD-ACE2 interaction facilitates the attachment and constituting the first open reading frame (ORF 1a/b), has a frameshift
subsequent entry of viral particles into host cells. The entry of the CoVs between ORF 1a and ORF1a/b that guides the production of two large
is caused by furin-mediated cleavage and triggered by cellular proteases, polypeptides, pp1a and pp1b (de Wilde et al., 2018; Guo et al., 2020).
such as transmembrane protease serine 2 (TMPRSS2) and cathepsins These polypeptides are then processed by the virally encoded
present on the host cell surface (Bertram et al., 2011; Glowacka et al., chymotrypsin-like-3CLpro, main protease-Mpro-nsp5, and
2011). A Gln residue in the RBD (Gln479 in SARS-CoV and Gln394 in papain-like-nsp3 proteases into 16 nonstructural proteins (nsps) that
SARS-CoV-2) interacts with the Lys31 residue of the human ACE2 re constitute the viral replicase-transcriptase complex. This complex con
ceptor, thus, forming a strong interaction between the RBD and ACE2 sists of helicase (nsp13), RNA dependent RNA polymerase (RdRp, also
(Wan et al., 2020; Wu et al., 2012). After the formation of the RBD-ACE2 known as nsp12), and other nsps that are packed in membrane vesicles
ligand-receptor complex, the S2 protein activates the fusion of the viral (Sawicki and Sawicki, 2005). After ORF1, a series of multiple ORFs are
envelope with the host cell membrane. HR1 and HR2 interact, forming a preceded by a short repeated sequence called the transcription regula
six-helical bundle that juxtaposes the viral S2 protein with the C-ter tory sequence (TRS). Replication and transcription are performed by the
minus of the ectodomain of the ACE2 receptor (Xia et al., 2020; Yu et al., replicase-transcriptase complex, which organizes itself in
2020). Hypertension drugs (such as losartan) that act as ACE2 inhibitors double-membrane vesicles (ER). Transcription termination occurs at
or angiotensin receptor blockers can competitively inhibit the transcription regulatory sequences located between ORFs that serve as a
RBD-ACE2 interaction and prevent the entry of the virus into the host template for the production of RNA. The replicase-transcriptase com
cell; therefore, these drugs may be used as therapeutic agents against plex, similarly to those in other positive-sense RNA viruses, has
SARS-CoV-2 (Gurwitz, 2020). After membrane fusion, the virus uses the RNA-dependent RNA polymerase, RNA helicase, and protease activities.
clathrin-dependent or independent endocytic pathway and autophagy The transcription catalyzed by RdRP toward the 3′ -end of genome re
via lysosomes to enter host cells (Pelkmans and Helenius, 2003; Siecz sults in the production of a nested series of many sub-genomic RNAs
karski and Whittaker, 2002). The endocytic pathway used by with leader sequences at the 5′ -end. This region produces the structural
SARS-COV-2 is pH-dependent. Lysosomes are characterized by acidic proteins S, E, M, and N, which are needed for virion assembly; other
pH, and acid hydrolases play a crucial role in the degradation of the viral accessory proteins required for maintenance and replication of the viral
envelope inside the autophagosome-lysosome complex, thus, releasing genome; and several additional proteins that aid in blocking the host
the viral genome for replication, transcription, and translation. Because innate immune response (Hussain et al., 2005; Perrier et al., 2019).
the degradation of the autophagosome-lysosome complex is The replicase component of the replicase/transcriptase complex
pH-dependent, lysosomotropic drugs such as chloroquine and hydrox system encoded by ORF 1a recognizes the single-stranded positive-sense
ychloroquine (which neutralizes the pH inside the lysosomal cavity by genomic RNA and copies it into a complementary strand (genomic
blocking proton pumps), chlorpromazine (an inhibitor of minus-strand), which is used as a template to produce multiple copies of
clathrin-dependent endocytosis), and inhibitors of cathepsins (endo the positive-sense genomic RNA through continuous RNA synthesis. The
somal/lysosomal cysteine proteases that act in protein degradation) transcriptase produces a nested series of subgenomic messenger RNAs
5
via discontinuous transcription, which are translated into structural and 8. Control and management of COVID-19
non-structural viral proteins. The viral proteins are assembled at the
surfaces of the ER membrane along with the genomic RNA, thus, 8.1. Preventive approach
constituting a mature virion that is enclosed in the vesicles at the ERGIC
face of the Golgi complex. The vesicles enclosing viral particles are fused Immunization through vaccination is a preferred protection method
with the internal plasma membrane, bud out by exocytosis, and release in public health. Vaccines are developed to enhance the passive immu
vesicle-coated virus particles from infected cells (Perrier et al., 2019). nity in individuals who do not exhibit the symptoms of the disease
The released viral particles trigger the host immune system and result in against the targeted pathogen, to prevent the occurrence of the disease
the production of aggressive inflammatory responses, thus releasing an after exposure to the specific pathogen (Han, 2015). The development of
excessive amount of proinflammatory cytokines in a process called an effective vaccine is a complex process that requires a long time for
cytokine storm (Braciale and Hahn, 2013; Ragab et al., 2020). The successful optimization, production, and clinical trials to establish the
overactivated and abnormal host immune response during SARS-CoV-2 vaccine’s purity, capability, and efficacy in vaccinated individuals
pathogenesis results in the host attacking its own cells and tissues rather (Black, 2015). The most challenging issue in developing an
than targeting the viral particles (Asrani and Hassan, 2020). The pro anti-SARS-CoV-2 vaccine is achieving efficacy and clinical safety. An
duction of proinflammatory cytokines and the resulting excessive in effective vaccine promotes the development of the innate immune sys
flammatory reactions lead to acute respiratory distress syndrome tem with specific instructions for recognizing the antigenic determinant
(ARDS), which can result in lung injury, decreased oxygen saturation, of the causative pathogen (Calina et al., 2020). In classical viral vac
and widespread tissue damage, thus, causing multiorgan failure, unfa cines, the antigenic determinant epitope or attenuated viral particles are
vorable prognosis and instantaneous death in patients with COVID-19 used as vaccine antigens to activate the host immune system to produce
(Huang et al., 2020; Ragab et al., 2020; Shimizu, 2019; Thompson appropriate antibodies against the antigenic vaccine, thus, aiding in
et al., 2011). The increased levels of cytokines facilitate the influx of recognition of the specific viral pathogen upon future exposure. How
immune cells, process such as macrophages, neutrophils, and T-cells, ever, vaccine development is a time-consuming and expensive process
from the circulation toward the site of infection; this process has a with high failure rates. To produce a successful commercial vaccine,
destructive effect on human tissues by destabilizing endothelial cell to multiple candidates must be tested, and several years of high-quality
cell interactions and causing lung injury and severe ARDS, thereby research are typically required. Another challenge in the vaccine
leading to low oxygen saturation levels, which are a significant cause of development process is the rapid development of mutations in RNA vi
mortality in patients with COVID-19 (Shimizu, 2019). The patients show ruses in the genes encoding surface glycoproteins, which trigger the
lymphopenia with or without leucopenia; the lymphocyte counts antigenic immune response and lessen the effectiveness of vaccines
decline, thus resulting in high neutrophil to lymphocyte ratios, which (Kramps and Probst, 2013). Moreover, the CoVs appear to have a spe
are typically associated with the severity of the disease (Singhal, 2020). cific mechanism of being enclosed in vesicles in the host cells that lack
the receptors. This process aids in recognition of the invading virus; in
7. SARS-CoV-2 pathogenesis associated clinical complications the absence of the receptors, the viruses are not recognized by the an
and symptoms tibodies developed post-vaccination (Kikkert, 2020). If the vaccine
development process proceeds smoothly from conception to market, an
The inoculum of COVID-19 is nosocomial infection, which spreads effective and successful vaccine can be ready in approximately 12–18
primarily through respiratory droplets, secretions, and direct contact months (Amanat and Krammer, 2020). Vaccines will be essential to
with the upper respiratory tract (Li et al., 2020b). SARS-CoV-2 isolated decreasing morbidity and mortality if the SARS-CoV-2 establishes itself
from fecal and blood samples from patients with pneumonia suggests the in the population.
possibility of multiple transmission routes of the virus (Zhang et al., Serious efforts are being made worldwide to develop and launch
2020). The abundance of ACE2 receptor proteins on the epithelia of lung effective vaccines against SARS-CoV-2 through advanced molecular
alveoli and enterocytes of the small intestine supports the existence of biology and biotechnological approaches. To support the development
multiple transmission routes (Hamming et al., 2004; Zhang et al., 2020). of vaccines against SARS-CoV-2, the Coalition for Epidemic Prepared
Epidemiological reports have revealed an incubation period of 1–14 ness Innovations (CEPI) is working with global health authorities and
days with a peak at 3–7 days; during the latency period, the virus be scientists. On 11 August 2020, the first (and only) vaccine against SARS-
comes severely contagious (Jin et al., 2020). Patients show symptoms of CoV-2, Sputnik V, was approved by Russia; however, the safety and
influenza, sore throat, fever, cough, fatigue, and shortness of breath; in efficacy of the vaccine has been questioned, because it has not yet
some cases, patients develop gastrointestinal problems, such as diarrhea entered phase III clinical trials. As of 12 November 2020, 164 vaccines
and vomiting, whereas in severe cases, patients develop ARDS, thus are in different stages of clinical trials worldwide, and 48 vaccines have
resulting in multiorgan failure and death (Chen et al., 2020b; Huang already reached the crucial phase of human trials. More than 280,000
et al., 2020). Older people and those with co-morbidities, such as dia participants from at least 470 sites in 34 different countries are enrolled.
betes, hypertension, pulmonary disease, asthma, bronchitis, and car Details of the various vaccine platforms and candidate SARS-CoV-2
diovascular disorders, are prone to developing ARDS and death (Huang vaccines are shown in Table 2. The four major vaccine programs in
et al., 2020). Most people have good prognosis, but those older in age the final stages of clinical trials are Moderna’s mRNA-1273, The Uni
and/or with critical chronic disorders are adversely affected by the versity of Oxford and AstraZeneca’s AZD1222, Gamaleya Research In
disease. Recently, a connection between the virus and neurological stitute’s Sputnik V, and Pfizer & BioNTech’s BNT162; these trials are
problems has been reported (Marshall, 2020; Paterson et al., 2020). being conducted at hundreds of sites worldwide. Moderna’s mRNA-
Some people who become ill with COVID-19 develop neurological based vaccine candidate, mRNA-1273, has shown great promise and is
symptoms including confusion, disorientation, agitation, and even psy in phase III clinical trials. mRNA-1273 results in synthesis of the pre
chosis; however, the underlying mechanisms are unclear (Paterson fused form of S-protein as the antigenic determinant that is recognized
et al., 2020; Varatharaj et al., 2020). by host immune cells and generates a specific immune response against
Growing evidence suggests that about one in five people infected SARS-CoV-2 (Kramps and Probst, 2013). The second vaccine candidate,
with COVID-19 experience no symptoms. Such asymptomatic in AZD1222 (also known as ChAdOx1 nCoV-19 and Covisheild), developed
dividuals can also transmit the virus as symptomatic people, albeit at a by the University of Oxford, has also reached the phase III of clinical
far lesser rate (Nogrady, 2020). Though estimating their contribution to trials. AZD1222 is a DNA-based adenoviral vector vaccine that uses a
outbreaks is challenging, it is crucial for managing the disease spread weakened chimpanzee adenovirus, which causes the common cold in
(Bi et al., 2020). chimpanzees. The virus has been modified so that it does not multiply in
6
Table 2 in phase III trials (with more than 30,000 participants) (Callaway,
Details of the vaccine platforms and candidate SARS-CoV-2 vaccines as of WHO 2020a). Notably, Moderna’s vaccine remains stable in conventional re
data, 12 November 2020. frigerators for 1 month and in freezers for 6 months. On 18 November,
Platform Total no. of vaccine No. of vaccine candidates in the University of Oxford and Astrazeneca released the interim data from
candidates clinical trials the AZD1222 clinical trials showing that the vaccine was highly effective
RNA-based 22 6 in preventing COVID-19 with an average efficacy of 70% (with more
DNA-based 14 5 than 23,000 participants) (Ramasamy et al., 2020). The data included
Recombinant protein 56 15 people of all ages, raising hopes that it could protect age groups that are
subunit-based
at high risk. However, their finding have raised several questions as the
Inactivated virus 15 7
Virus-like particles 16 2 data were combined from two trials in two countries that used different
Replicating viral vector 17 4 protocols. On 20 November,Pfizer/BioNTech submitted a request to the
Non-replicating viral 19 9 U.S. Food and Drug Administration (FDA) for an emergency use
vector authorization (EUA) of their vaccine. Once approved, this vaccine would
Live attenuated virus 3 0
Replicating bacteria 1 0
be the first mRNA vaccine to get approval for public use. Other com
vector panies are also preparing the regulatory submission of the data for EUA
T-cell based 1 0 to authoriteis around the world. However, recent reports on reinfections
Total 164 48 have prompted questions about the long-term immunity to SARS-CoV-2
and the prospects for a vaccine (Tillett et al., 2020; To et al., 2020).
These four vaccine candidates show remarkable promise, with three
humans. The DNA encoding the SARS-CoV-2 S-protein was fused to the
exceeding 90% efficacy - an unexpectedly high rate. Notably, none re
viral vector and introduced as recombinant DNA. When the vaccine
ported significant safety issues, and one showed promise in older adults,
enters a cell, S-protein is produced and induces an immune response
a demographic that is particularly vulnerable to SARS-CoV-2 infection.
against SARS-CoV-2. The third is Pfizer’s BNT162 program evaluating
However, it is vital to continue developing more vaccines as having
four mRNA-based vaccines, all of which are combined with a lipid
multiple vaccines available for people worldwide will be essential to
nanoparticle formulation. Two vaccine candidates include a nucleoside
bring the pandemic under control. Besides, as ecouraging results
modified mRNA (BNT162b1 and BNT162b2), one includes mRNA of
emerge, the world must be prepared to address challenges linked to
optimized SARS-CoV-2 RBD (BNT162b1), and one uses mRNA of
vaccine production, storage, distribution, and pricing. The details on the
SARS-CoV-2 full-length S-protein (BNT162b2). Other than these
four vaccines are shown in Table 4.
nanoparticle-based vaccines, ankara vector-based vaccines, adjuvanted
vaccines, inactivated vaccines, fusion-protein based vaccines, recombi
nant protein, and live-attenuated vaccines are also being developed; 8.2. Curative approach
however, all these vaccines appear to be many months away from
reaching the market (Guo et al., 2020; Prompetchara et al., 2020; Roper In the absence of any clinically proven treatment strategy, the
and Rehm, 2009; Thanh Le et al., 2020). Various candidate vaccines in management and treatment of COVID-19 is mostly supportive, with the
phase II and III clinical trials are shown in Table 3. only aim being mortality reduction. Good hygiene, social distancing,
In mid-November 2020, four vaccine developers reported data sug and quarantine practices are recommended worldwide to reduce the
gesting that their vaccines are highly effective. On 9 November, Pfizer transmission of the virus. Several repurposed drugs are being used,
and BioNTech released the first compelling evidence that their including antiviral and antimalarial drugs, as tactical treatments aiming
BNT162b2 vaccine is 90% effective in phase III trials (with more than to limit the adverse effects of viral pathogenesis. Antiviral drugs target
38,000 participants) (Callaway, 2020d). On 18 November, they reported specific proteins essential for the viral life cycle and disrupt various
that the vaccine’s efficacy was more than 94% in high-risk groups and stages of viral growth. The antiviral drugs used against common RNA
was consistent across racial groups with no serious side effects (Thomas, viruses include reverse transcriptase inhibitors (nucleoside reverse
2020). However, their vaccine presents major challenges in distribution, transcriptase inhibitor and nonnucleoside reverse transcriptase in
because it must be stored at –80 ◦ C, and two doses are required for hibitors) RdRp inhibitors, and protease inhibitors (target TMPRSS2 and
effective protection. On 11 November, the controversial Russian other viral proteases that are involved in the processing of large poly
Gamaleya Research Institute’s Sputnik V vaccine was reported to be peptide coded by ORF1) (Rajarshi et al., 2020). However, no
92% effective in preventing COVID-19 in an interim efficacy analysis evidence-based and clinically demonstrated strategy has been shown for
report (with more than 16,000 participants) (Callaway, 2020c). On 16 the treatment of COVID-19. Most drugs currently in clinical trials are
November, Moderna reported 94.5% efficacy of the mRNA-1273 vaccine repurposed drugs designed for the treatment of other diseases (Dong
et al., 2020; Gordon et al., 2020b; Guy et al., 2020; Tu et al., 2020).
Several clinical trials are also underway to evaluate the suitability and
efficacy of repurposed antiviral drugs, such as remdesivir, ribavirin,
Table 3
Major candidate vaccines in phase II and III trials as of WHO data, 12 November galidesivir, favipiravir, darunavir, oseltamivir, and arbidol, for treating
2020. COVID-19 (Calina et al., 2020; Dong et al., 2020; Tu et al., 2020).
Several reports have indicated the development of resistance against
S. Vaccine candidates, Technology/platform Current stage
no. developers (participants) antiviral therapies, owing to the rapid rate of mutation leading to the
emergence of resistance in the viral strain. In such cases, a combination
1 BNT162 a1, b1, b2, c2, mRNA Phase III cleared
Pfizer/BioNTech (38,000)
of these drugs, called the highly active antiviral therapy (HAAT)
2 mRNA-1273, Moderna Nanoparticle-based Phase III cleared approach, has synergistic or additive effects of antiviral drugs, thus,
dispersion containing (30,000) delaying the progression of disease and increasing the survival rate of
mRNA the patients. Various candidate drugs in phase II and III clinical trials are
3 AZD1222, University of Modified chimpanzee Phase II-III
shown in Table 5. The few drugs currently being used for the treatment
Oxford/AstraZeneca adenovirus (ChAdOx1) (23,000)
4 COVAXIN, Bharat Inactivated SARS-CoV-2 Phase III (30,000) and management of COVID-19 are discussed below and their structures
Biotech are shown in Fig. 4.
5 Unnamed, Sinopharm Inactivated SARS-CoV-2 Phase III (15,000) In an international coalition, the WHO recently conducted a multi-
(Vero cells) center, open-label global trial, called the SOLIDARITY trial, to investi
6 CoronaVac, Sinovac Inactivated SARS-CoV-2 Phase III (10,490)
gate the potential of four repurposed drugs—remdesivir,
7
Table 4
Details of the four vaccine candidates that are in the approval stage, as of 24 November 2020.
S. Vaccine Name Developer Type Doses Efficacy Storage
no.
1 mRNA-1273 Moderna mRNA 2 95% Normal refrigerator for 1 month and in − 20

◦
C freezer for 6 months
2 BNT162b2 Pfizer & BioNTech mRNA 2 95% − 80 ◦ C
3 AZD1222 (also known as ChAdOx1 University of Oxford & DNA (chimpanzee 2 62-90% Regular refrigerator temperature
nCoV-19, Covishield) AstraZeneca adenovirus vector)
4 Sputnik V Gamaleya Research DNA (human adenovirus 2 92% Regular refrigerator temperature
Institute vector)
8.2.1. Remdesivir
Table 5
Remedesivir, the most promising antiviral drug being used for
Candidate drugs in phase II and III trials.
COVID-19 treatment, is a broad-spectrum antiviral drug, repurposed for
S. Target Drug candidates Current single-stranded RNA viruses (such as SARS, MERS, and Ebola) (Mulangu
no. stage
et al., 2019). It is an adenosine nucleoside analog prodrug that inhibits
1 RdRP Remdesivir Phase II/III the activity of the RdRp enzyme by integrating into newly synthesized
2 Favipiravir Phase III viral RNA strands, thus, delaying the chain termination of viral RNA and
3 Ribavirin Phase II
4 Oseltamivir Phase III
inhibiting the replication and synthesis of RNA (Saha et al., 2020; Wang
5 Galidesivir Phase II et al., 2020a). Recent data from a randomized, open-label, phase III
6 Sofosbuvir Phase II/III clinical trial, including 584 patients with moderate COVID-19 have
7 EIDD-2801 Phase II indicated that a 5-day course of remdesivir has statistically significantly
8 3CL protease Lopinavir/ritonavir Phase II
better results than standard care at 11 days of treatment. The clinical
9 Ivermectin Phase III
10 S-protein/ACE2 fusion Arbidol Phase III importance of this finding is uncertain (Spinner et al., 2020). Recent
11 HIV protease Darunavir Phase III data from a randomized, double-blind, placebo-controlled trial of
12 Nucleic acid synthesis Clevudine Phase II intravenous remdesivir have indicated that this treatment is statistically
13 DPP4 Brensocatib Phase III superior to placebo in shortening the time to recovery in adults (Beigel
14 Reverse transcriptase Truvada Phase III
15 Acidification of Hydroxychloroquine/ Phase III
et al., 2020). Another nucleoside analog inhibitor, EIDD-2801, has been
endosomes chloroquine found to be effective against remdesivir-resistant SARS-CoV; EIDD-2801
decreases the replication and pathogenesis of CoVs similarly to remde
sivir (Sheahan et al., 2020).
hydroxychloroquine, lopinavir/ritonavir, and interferon-β1a—for the
treatment of COVID-19. The trial enrolled approximately 12,000 pa 8.2.2. Favipiravir
tients in 500 hospital sites in more than 30 countries. The interim results Favipiravir is a prodrug with a similar mechanism of action to that of
of the SOLIDARITY trial showed that the drugs had little or no effect on remdesivir. In cells, it is converted into an active phosphoribosylated
the mortality of hospitalized patients with COVID-19 (Pan et al., 2020). form (favipiravir-RTP), which binds and inhibits viral RdRP. However,
However, because the data were not scrutinized and reviewed, several being a guanine analog, it structurally differs from remdesivir (Furuta
questions on the report remain. The trial design also prioritized broad et al., 2017). It induces mutations in the viral RdRP complex, thus
access, thereby resulting in significant heterogeneity in trial adoption, resulting in a large proportion of nonviable viruses within the total virus
implementation, controls, and patient populations. Thus, scientists population. The drug was approved as the first anti-COVID 19 drug in
believe that whether any conclusive findings can be drawn from the trial China in March 2020, after a clinical trial showed promising data with
results is unclear. The data also suggested that antiviral monotherapy for very few adverse effects. The drug causes a rapid decrease in viral load
moderately to severely ill patients with COVID-19 might not be suffi within 4 days and demonstrates up to 88% clinical improvement in
cient (Cao and Hayden, 2020). patients with mild to moderate COVID-19.
Fig. 4. 2D structures of the drugs currently used for the treatment of COVID-19.
8
8.2.3. Ivermectin agonists and immunosuppressive agents. On the basis of data from the
Ivermectin is an anti-parasitic and antiviral drug approved by the RECOVERY trial, the WHO REACT (Rapid Evidence Appraisal for
FDA for the treatment of parasitic worms, HIV, and dengue (Wagstaff COVID-19 Therapies) working group has reported that critically ill pa
et al., 2012). It suppresses host cellular processes by inhibiting nuclear tients with COVID-19 are less likely to die when administered cortico
transport by importin α/β1, thus, leading to a decrease in viral replica steroids than people who do not receive this treatment (Horby et al.,
tion (Caly et al., 2012). Ivermectin also inhibits the replication of 2020; The, 2020). A meta-analysis that pooled data from seven ran
SARS-CoV-2 in vitro, and a single dose can result in a ~5000-fold domized clinical trials conducted in 12 countries has indicated that the
reduction in viral RNA at 48 h (Caly et al., 2020). The drug is also in systemic administration of corticosteroids, such as dexamethasone, to
clinical trials for treating COVID-19. A recent observational retrospec critically ill patients with COVID-19 is associated with lower mortality,
tive study of patients with COVID-19 has reported significantly lower thus suggesting that steroids may be used as a part of the standard
mortality with ivermectin treatment (Rajter et al., 2020). treatment for people with severe COVID-19 (The, 2020). However, the
safety and efficacy of corticosteroids for the treatment of COVID-19 have
8.2.4. Lopinavir/ritonavir not been rigorously studied.
Lopinavir and ritonavir is a combination drug used for the treatment
of HIV. These compounds are aspartate protease inhibitors, and there 8.2.8. Other drugs
fore, are presumed to inhibit the SARS-CoV-2 3CLpro enzyme (Furuta Beyond the above-discussed drugs, several others are being tested for
et al., 2017). The drugs are effective against SARS-CoV and MERS-CoV in their ability to treat COVID-19, such as ribavirin, fedratinib, fluvox
vitro and animal models; however, they have not found to be useful for amine, oseltamivir, darunavir, sofosbuvir, clevudine, brensocatib, tru
treating severe COVID-19 in a randomized, controlled, open-label trial vada, galedesivir, nafamostat, lianhuaqingwen, and baricitinib (De
in hospitalized adults patients (Cao et al., 2020). Clercq, 2004; Elfiky, 2020; Koren et al., 2003; Li et al., 2020a; Runfeng
et al., 2020; Sarzi-Puttini et al., 2020; Velavan and Meyer, 2020; Wang
8.2.5. Hydroxychloroquine/chloroquine et al., 2020b; Wu and Yang, 2020).
Hydroxychloroquine/chloroquine are widely known anti-malarial
and anti-autoimmune drugs (Savarino et al., 2003). Some data suggest 8.3. Strategic management approach
that these drugs also inhibit the replication of CoVs (Vincent et al., 2005)
and cause a rapid decrease in SARS-CoV-2 viral load. In the initial stages A potential alternative, but a reliable approach to ameliorate the
of the pandemic, the drugs were widely used worldwide, because clin adverse effects of COVID-19 aims to boost and strengthen the immune
ical studies reported that the administration of hydroxychloroquine system, thus, allowing the adaptive immune component to be neutral
improves the conditions of patients with COVID-19. A further study has ized and combatting SARS-CoV-2. In this approach, several natural
confirmed that the combination of hydroxychloroquine with azi product-based formulations are used in the management of the disease,
thromycin is more effective than hydroxychloroquine alone (Arshad given that herbal medicines have the potential to treat COVID-19.
et al., 2020). Emerging preclinical and clinical data indicate that neither Several herbal formulations have been recommended for the manage
chloroquine nor hydroxychloroquine provides clinical benefit against ment of COVID-19, such as Indian giloy (Tinospora cordifolia) and ash
COVID-19 (Fatima et al., 2020; Funnell et al., 2020). The (Randomised wagandha; these have shown to be effective in the management COVID-
Evaluation of COVid-19 thERapY) trial on hydroxychloroquine, which 19 in India. Giloy/amrita in the Indian system of medicine has sub
enrolled more than 15,000 patients from 175 NHS hospitals in the UK, stantial therapeutic properties and is recognized for its immunomodu
has concluded that there is no beneficial effect of hydroxychloroquine in latory properties and ability to boost the nonspecific immune system by
patients hospitalized with COVID-19 (Horby and Landray, 2020). In acting on macrophages (Kapil and Sharma, 1997; Nair et al., 2006;
June of 2020, the FDA confirmed that hydroxychloroquine/chloroquine Sharma et al., 2012). Withania somnifera, commonly known as ashwa
alone is not effective in treating COVID-19, and their risks may outweigh gandha/Indian ginseng, has been recognized in Ayurveda for its excel
their potential benefits. Therefore, the FDA revoked the emergency use lent antioxidative, anti-inflammatory, and immunomodulatory
of hydroxychloroquine/chloroquine to treat COVID-19. activities (Bharti et al., 2016). Withanone, the active ingredient of
ashwagandha, has been shown to be a potent phytochemical for con
8.2.6. Arbidol trolling SARS-CoV-2 entry into the host cell; withanone can dock
Arbidol (umifenovir), a broad-spectrum drug, has been found to be effectively at the interface of the ACE2-RBD complex, thus, decreasing
effective against several viral diseases, such as influenza, adenovirus, the RBD-ACE2 interaction (Balkrishna et al., 2020). Withanone obtained
respiratory syncytial virus, and Ebola, and has been used for decades in from Withania somnifera and caffeic acid phenethyl ester obtained from
China and Russia for treating respiratory viral infections (Blaising et al., bee propolis have the potential to effectively interact with the
2014; Boriskin et al., 2008). It is currently being repurposed for the substrate-binding pocket of viral main protease and block the RNA
treatment of COVID-19. Arbidol is approved in China for the clinical replication machinery of SARS-CoV-2. Moreover, these natural com
treatment of COVID-19. In the influenza virus, it binds the cell surface pounds also modulate the host surface-bound protease TMPRSS2,
glycoprotein hemagglutinin and prevents the fusion of the viral mem thereby inhibiting viral entry into host cells (Kumar et al., 2020).
brane with the receptor (Kadam and Wilson, 2017). Arbidol targets the
S-protein/ACE2 interaction, thereby inhibiting viral entry by interfering 9. Conclusions
with viral binding to host cells (Padhi et al., 2020a; Wang et al., 2020d).
It also inhibits postentry stages by blocking intracellular vesicle traf The COVID-19 pandemic has sparked a research revolution, as sci
ficking (Wang et al., 2020d). Clinical trials comparing the efficacy of entists are working at breakneck speed to understand the disease and
arbidol with favipiravir are also being conducted (Chen et al., 2020a). find a cure. Scientists have demonstrated how rapidly they can adapt to
Some patients have recovered successfully from COVID-19 after re-emerging and emerging threats. Non-COVID-19 research has taken a
receiving a combination arbidol and lopinavir/ritonavir treatment (Lim back seat during the pandemic. The past year has seen rapid advances in
et al., 2020; Wang et al., 2020e). Arbidol monotherapy has been found understanding of the biology, pathogenesis, and clinical characteristics
to be superior to lopinavir/ritonavir (Zhu et al., 2020) as well as favi of the disease. There are still several unknowns about the mechanisms of
piravir (Chen et al., 2020a). SARS-CoV-2 biology and pathogenesis. Epidemiologists are predicting
short- and long-term projections to prepare for and potentially mitigate
8.2.7. Corticosteroids the spread and impact of the disease. However, the pandemic has
Corticosteroids, such as dexamethasone, are glucocorticoid receptor exposed our susceptibly to microbial pathogens and gaps in our
9
therapeutic arsenal. COVID-19 is not the first pandemic that humanity Boni, M.F., Lemey, P., Jiang, X., Lam, T.T., Perry, B.W., Castoe, T.A., Rambaut, A.,
Robertson, D.L., 2020. Evolutionary origins of the SARS-CoV-2 sarbecovirus lineage
has faced, and it will not be the last. However, it has taught us how
responsible for the COVID-19 pandemic. Nat. Microbiol. 5, 1408–1417.
unprepared the world was for such an outbreak, and provided us with Boriskin, Y.S., Leneva, I.A., Pecheur, E.I., Polyak, S.J., 2008. Arbidol: a broad-spectrum
lessons in preparing and responding to virus warnings in the future. We antiviral compound that blocks viral fusion. Curr. Med. Chem. 15, 997–1005.
hope that the continued research will lead to breakthroughs and help us Braciale, T.J., Hahn, Y.S., 2013. Immunity to viruses. Immunol. Rev. 255, 5–12.
Calina, D., Docea, A.O., Petrakis, D., Egorov, A.M., Ishmukhametov, A.A., Gabibov, A.G.,
be better prepared for future outbreaks. Shtilman, M.I., Kostoff, R., Carvalho, F., Vinceti, M., Spandidos, D.A., Tsatsakis, A.,
2020. Towards effective COVID-19 vaccines: Updates, perspectives and challenges
Authors’ Contributions (Review). Int. J. Mol. Med. 46, 3–16.
Callaway, E., 2020a. COVID vaccine excitement builds as Moderna reports third positive
result. Nature 587, 337–338.
SKM and TT conceived the idea and wrote the manuscript. Callaway, E., 2020b. Making sense of coronavirus mutations. Nature 585, 174–177.
Callaway, E., 2020c. Russia announces positive COVID-vaccine results from controversial
trial. Nature.
Declaration of Competing Interest Callaway, E., 2020d. What Pfizer’s landmark COVID vaccine results mean for the
pandemic. Nature.
The authors declare no competing financial interests. Caly, L., Druce, J.D., Catton, M.G., Jans, D.A., Wagstaff, K.M., 2020. The FDA-approved
drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res.,
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Funding Caly, L., Wagstaff, K.M., Jans, D.A., 2012. Nuclear trafficking of proteins from RNA
viruses: potential target for antivirals? Antiviral Res. 95, 202–206.
Cao, B., Hayden, F.G., 2020. Antiviral monotherapy for hospitalised patients with
The authors declare that there are no funding sources to be
COVID-19 is not enough. Lancet 396, 1310–1311.
acknowledged. Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., Ruan, L., Song, B., Cai, Y., Wei, M.,
2020. A trial of lopinavir–ritonavir in adults hospitalized with severe Covid-19. New
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One year update on the COVID-19 pandemic: Where are we now?

1. Introduction studied for COVID-19 treatment in hundreds of clinical trials worldwide.

1 mRNA-1273 Moderna mRNA 2 95% Normal refrigerator for 1 month and in − 20

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