REVIE

WS
Characteristics of SARS-CoV-2 and
COVID-19
Ben Hu 1,3
, Hua Guo 1,2,3
, Peng Zhou 1
and Zheng-Li 1 ✉
Shi
Abstract | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly
transmissible and pathogenic coronavirus that emerged in late 2019 and has
caused a pandemic of acute respiratory disease, named ‘coronavirus disease
2019’ (COVID-19), which threatens human health and public safety. In this
Review, we describe the basic virology of SARS-CoV-2, including genomic
characteristics and receptor use, highlighting its key difference from previously
known coronaviruses. We summarize current knowledge of clinical,
epidemiological and pathological features of COVID-19, as well as recent
progress in animal models and antiviral treatment approaches for SARS-CoV-2
✉e-mail: [email protected]
Coronaviruses are a diverse group of viruses infecting
https://doi.org/10.1038/ s41579-020-00459-7
many different animals, and they can cause mild to
severe respiratory infections in humans. In 2002 and
2012, respectively, two highly pathogenic coronaviruses
with zoonotic origin, severe acute respiratory syndrome
coronavirus (SARS-CoV) and Middle East respiratory
syndrome coronavirus (MERS-CoV), emerged in
humans and caused fatal respiratory illness, making
emerging coronaviruses a new public health concern in
the twenty-first century1. At the end of 2019, a novel
coronavirus designated as SARS-CoV-2 emerged in the
city of Wuhan, China, and caused an outbreak of unusual
viral pneumonia. Being highly transmissible, this novel
coronavirus disease, also known as coronavirus disease
2019 (COVID-19), has spread fast all over the world2,3.
It has overwhelmingly surpassed SARS and MERS in
terms of both the number of infected people and the
spatial range of epidemic areas. The ongoing outbreak of
COVID-19 has posed an extraordinary threat to global
public health4,5. In this Review, we summarize the cur-
rent understanding of the nature of SARS-CoV-2 and
COVID-19. On the basis of recently published findings,
this comprehensive Review covers the basic biology of
1
CAS Key Laboratory of SARS-CoV-2, including the genetic characteristics, the
Special Pathogens and
Biosafety, Wuhan Institute of
potential zoonotic origin and its receptor binding.
Virology, Chinese Academy Furthermore, we will discuss the clinical and epide-
of Sciences, Wuhan, miological features, diagnosis of and countermeasures
People’s Republic of China.
against COVID-19.
2
University of Chinese
Academy of Sciences, Beijing,
People’s Republic of China. Emergence and spread
3
These authors contributed In late December 2019, several health facilities in
equally: Ben Hu, Hua Guo. Wuhan, in Hubei province in China, reported clusters of
NATURE REVIEWS | VOLUME 19 | MARCH 2021 | 1
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patients with
and chest discomfort, and in severe cases dyspnea
pneumonia of unknown
and bilateral lung infiltration6,7. Among the first 27
cause6. Similarly to
docu- mented hospitalized patients, most cases were
patients with SARS and
epidemi- ologically linked to Huanan Seafood
MERS, these patients
Wholesale Market, a wet market located in
showed symptoms of
downtown Wuhan, which sells not only seafood but
viral pneumonia,
also live animals, including poultry and wildlife4,8.
including fever, cough
According to a retrospective study, the onset of the
first known case dates back to 8 December 2019
(REF.9). On 31 December, Wuhan Municipal Health
Commission notified the public of a pneumonia
out- break of unidentified cause and informed the
World Health Organization (WHO)9 (FIG. 1).
By metagenomic RNA sequencing and virus isola-
tion from bronchoalveolar lavage fluid samples from
patients with severe pneumonia, independent
teams of Chinese scientists identified that the
causative agent of this emerging disease is a
betacoronavirus that had never been seen before6,10,11.
On 9 January 2020, the result of this etiological
identification was publicly announced (FIG. 1). The
first genome sequence of the novel coro- navirus was
published on the Virological website on 10 January,
and more nearly complete genome sequences
determined by different research institutes were then
released via the GISAID database on 12 January7.
Later, more patients with no history of exposure to
Huanan Seafood Wholesale Market were identified.
Several familial clusters of infection were reported,
and nosocomial infection also occurred in health-care
facilities. All these cases provided clear evidence for
human-to-human transmission of the new virus4,12–14.
As the outbreak coincided with the approach of the
lunar New Year, travel between cities before the
festival facilitated virus transmission in China. This
novel coro- navirus pneumonia soon spread to other
cities in Hubei province and to other parts of China.
Within 1 month,

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8 December 2019 28 February 2020

Onset of the first recorded case in WHO risk assessment
Wuhan increased to very high on the
global level
31 December 2019 11 February 2020 2 October 2020
First report of 27 cases of ICTV named virus SARS-CoV-2 >34,000,000 cases
pneumonia with unknown cause and WHO named disease and
in Wuhan, China COVID-19 >1,000,000 deaths

Decemb Januar Februa Marc Octob

er y ry h er

9 January 2020 11 March 2020

China announced the WHO defined COVID-
identification of a novel 19 as a pandemic
coronavirus as the causative
agent of the pneumonia 29 January
13 January 2020 20 January 2020 The
Case of a traveler 2020 Human- 23 January coronavirus 30 January
from Wuhan was to-human 2020 Wuhan spread to all 2020 WHO
confirmed in transmission city was 34 provinces declared a
Thailand was confirmed locked down across China PHEIC alert
Fig. 1 | Timeline of the key events of the COVID-19 outbreak. The first recorded cases were
reported in December 2019 in Wuhan, China. Over the course of the following 10 months, more
than 30 million cases have been confirmed worldwide. COVID-19, coronavirus disease 2019; ICTV,
International Committee on Taxonomy of Viruses; PHEIC, public health emergency of international
concern; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; WHO, World Health
Organization.

it had spread massively to all 34 provinces of China. Johns Hopkins University,

The number of confirmed cases suddenly increased, as of 11 August 2020,
with thousands of new cases diagnosed daily during
late January15. On 30 January, the WHO declared the
novel coronavirus outbreak a public health emergency
of inter- national concern16. 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.17).
The outbreak of COVID-19 in China reached an
epidemic peak in February. According to the
National Health 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. To control COVID-19,
China implemented unprecedentedly strict public
health measures. 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 closed in most
cities as well as in countryside18. Owing to these
measures, the daily number of new cases in China
started to decrease steadily19.
However, despite the declining trend in China,
the international spread of COVID-19 accelerated
from late February. Large clusters of infection have
been reported from an increasing number of
countries18. The high transmission efficiency of
SARS-CoV-2 and the abun- dance of international
travel enabled rapid worldwide spread of COVID-
19. On 11 March 2020, the WHO officially
characterized the global COVID-19 out- break as a
pandemic20. Since March, while COVID-19 in China
has become effectively controlled, the case numbers
in Europe, the USA and other regions have jumped
sharply. According to the COVID-19 dash- board of
the Center for System Science and Engineering at
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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 21. High
mortality occurred especially when health-care resources were overwhelmed.
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. As some of the first reported cases in Wuhan
had no epidemiological link to the seafood market22, 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 France23. 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. To address this highly controversial issue,
further retrospective inves- tigations 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-CoV 24. Its genome organization
is shared with other betacoronaviruses. The six functional open reading frames
(ORFs) are arranged in order from 5′ to 3′: replicase (ORF1a/ORF1b), spike
(S), envelope (E), membrane (M) and nucleocapsid (N). In addition, seven
putative ORFs encoding accessory proteins are interspersed between the
structural genes25. Most of the proteins encoded by SARS-CoV-2 have a
similar

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length to the corresponding proteins in SARS-CoV. and other SARSr-CoVs (FIG. 2). Using sequences of
Of the four structural genes, SARS-CoV-2 shares more five conserved replicative domains in pp1ab (3C-like
than 90% amino acid identity with SARS-CoV except protease (3CLpro), nidovirus RNA-dependent RNA
for the S gene, which diverges11,24. The replicase gene polymerase (RdRp)-associated nucleotidyltransferase
covers two thirds of the 5′ genome, and encodes a (NiRAN), RdRp, zinc-binding domain (ZBD) and
large polyprotein (pp1ab),which is proteolytically HEL1), the Coronaviridae Study Group of the
cleaved into 16 non-structural proteins that are International Committee on Taxonomy of Viruses
involved in transcrip- tion and virus replication. Most estimated the pairwise patristic distances between
of these SARS-CoV-2 non-structural proteins have SARS-CoV-2 and known coronaviruses, and assigned
greater than 85% amino acid sequence identity with SARS-CoV-2 to the existing species SARSr-CoV 17.
SARS-CoV25. Although phyloge- netically related, SARS-CoV-2 is
The phylogenetic analysis for the whole genome distinct from all other coronaviruses from bats and
shows that SARS-CoV-2 is clustered with SARS-CoV pangolins in this species.
and SARS-related coronaviruses (SARSr-CoVs) found The SARS- CoV-2 S protein has a full size of
in bats, placing it in the subgenus Sarbecovirus of the 1,273 amino acids, longer than that of SARS-CoV
genus Betacoronavirus. Within this clade, SARS-CoV-2 (1,255 amino acids) and known bat SARSr-CoVs
is grouped in a distinct lineage together with four (1,245–1,269 amino acids). It is distinct from the S
horse- shoe bat coronavirus isolates (RaTG13, pro- teins of most members in the subgenus
RmYN02, ZC45 and ZXC21) as well as novel Sarbecovirus, sharing amino acid sequence similarities
coronaviruses recently iden- tified in pangolins, which of 76.7– 77.0% with SARS-CoVs from civets and
group parallel to SARS-CoV humans,

SARS- SARS-CoV
CoV-
relate 10 GZ02 SARS-
d 0 CoV SZ3
9 SARS-CoV
9 10 Tor2 SARS-
0
CoV BJ01
84
Bat SARSr-CoV
100 Rs4231 Bat SARSr-
100 100 CoV SHC014 Bat
75
SARSr-CoV WIV1
Bat SARSr-CoV YN2018C
100 Bat SARSr-CoV Rp3
Sarbecovirus Bat SARSr-CoV HKU3-1
Bat SARSr-CoV BM48-31
100
10 Pangolin coronavirus
88 0
Guangxi Bat coronavirus
10 ZXC21
0 Bat coronavirus ZC45
Pangolin coronavirus
Guangdong Bat coronavirus
RmYN02
Bat coronavirus RaTG13
100 SARS-CoV-2
100 China/Shenzhen/SZTH002/202001 SARS-
91 CoV-2 USA/CA1/202001
SARS- SARS-CoV-2
CoV-2-
Singapore/14Clin/202002 SARS-
relate 10
d 0 CoV-2 Japan/DP0346/202002
lineag SARS-CoV-2 Australia/VIC04/202003
e SARS-CoV-2
Germany/NRW06/202002 SARS-CoV-
2 China/Wuhan/WIV04/201912 SARS-
8 CoV-2 Vietnam/CM295/202003
Hibecovir 5 SARS-CoV-2 Italy/CDG1/202002
us
SARS-CoV-2 USA/NYUMC8/202003

Bat Hp-betacoronavirus Zhejiang2013

Nobecovir 100
us 1
0
0.05 100
010
Merbecovir 0
us

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MICROBIOLOGY
100 coronavirus
Tylonycteris
Rousettus Murine hepatitis virus
100 PipistrellusHuman Human coronavirus
coronavirus
coronavirus
Rousettus HKU1 OC43

Fig. 2 | Phylogenetic tree of the full-length genome sequences of SARS-CoV-2, SARSr-

CoVs and other betacoronaviruses. The construction was performed by the neighbour joining
method with use of the program MEGA6 with bootstrap values being calculated from 1,000 trees.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clusters with closely related viruses in
bats and pangolins and together with SARS-CoV and bat SARS-related coronaviruses (SARSr-CoVs)
forms the sarbecoviruses. The sequences were downloaded from the GISAID database and GenBank.
MERS-CoV, Middle East respiratory syndrome coronavirus.

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75–97.7% with bat coronaviruses in the same subge- SARS-CoV is only 73%. Another specific genomic
nus and 90.7–92.6% with pangolin coronaviruses11. feature of SARS-CoV-2 is the insertion of four amino
In the receptor-binding domain (RBD) of S protein, acid residues (PRRA) at the junction of subunits S1
the amino acid similarity between SARS-CoV-2 and and S2 of the S protein26 (FIG. 3a). This insertion
generates
a
1 100 200 300 400 500 600 700 800 900 1,000 1,100 1,200 1,273

S1 subunit S2 subunit
RBD
SARS-CoV
SP NTD RBM FP HR1 HR2 TM CP
1 13
292 424 494 667 770 788 894 966 1,145 1,195 1,219 1,255
SARS- 306 527 668
CoV-2
SP NTD RBM FP HR1 HR2 TM CP
1 13 305 437 508 541 685 788 806 912 984 1,163 1,213 1,237
319 686 1,273
Polybasic
Q T Q T
cleavage
N S P R R A R S V A S Q S
site
SARS-CoV-2 69
675 1
BJ01 67
H T V S L L - - - - R S T S Q K S
661 3
Q T Q T N S - - - - R S V A S Q S
RaTG13 68
675 H S M S S L - - - - R S V N Q R S 7
GX pangolin Q T Q T N S - - - - R S V S S Q A 68
671 3

SARS-CoV-2 319 R V Q P T E S I V R F P N I T N L C P F G E V F N A T R F A S V Y A WN R K R I S N C V A D Y S V L Y N S A S F S T F K C Y G V S P T K L N D L C F T N V Y A D S F V I R G D E V R Q I A P G Q T G K I A D Y N Y

K L P D 427 BJ01 . . V . S GDV . . . . . . . . . . . . . . . . . . . K . P . . . . . E . . K . . . . . . . . . . . . . . T F . . . . . . . . . . A. . . . . . . . S . . . . . . . . VK . . D. . . . . . . . . . V . . . .

. . . . . .
306
. . . . . D. . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . . . . . . .
414 . . . . . .
RaTG13 319 . . . . . I . . . . . . . . . . . . . . . . . . . . S K . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V K . . . . . . . . . . . . . V . . . . 427
. . . . . .
GX pangolin 319 427
. . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V . . . . . . . . . . . . . . R . . . .
GD pangolin 319 . . . . . . 427
RmYN02 298 409
Bat WIV1 307 415

SARS-CoV-2 428 D F T G C V I A WN S N N L D S K V G G N Y N Y L Y R L F R K S N L K P F E R D I S T E I Y Q A G S T P C N G V E G F N C Y F P L Q S Y G F Q P T N G V G Y Q P Y R V V V L S F E L L H A P A T V C G P K K

529
BJ01 415 . . M. . . L . . . T R . I . AT S T . . . . . K . . Y L. HGK . R. . . . . . . NV P F S P DGK . . T - P P AL . . . W. . ND. . . Y T . T . I . . . . . . . . . . . . . . . N . . . . . . . . . L

515
RaTG13 428 . . . . . . . . . . . K H I . A . E . . . F . . . . . . . . . A . . . . . . . . . . . . . . . . . . K . . . . Q T . L . . . Y . . Y R . . . Y . . D . . . H . . . . . . . . . . . . . N................ 529

GX pangolin 428 . . . . . . . . . . . VK Q. AL T . . - - . . . . . . . . . . K . . . . . . . . . . . . . . . . . . . . . . QV . L . . . Y . . E R . . . H. . T . . N. . . F . . . . . . . . . . NG. . . . . . . . L

529

c d
RBD Host Important residues in RBD contact with
ACE2
445 486 493 494 501
N501 T487
SARS-CoV- Human L F Q S N Human ACE2 L472
2 F486 Q493 N479 L445
SARS-CoV Human Y(442) L(472) N(479) D(480) T(487)
D480 Y442
RaTG13 RLimolopLus aflmis L L Y R N S494
GX Pangolin L L E R T SARS-CoV-2 RBD
pangolin
GD Pangolin L F Q S N SARS-related coronavirus (SARSr-CoV) WIV1. The receptor-binding
pangolin
motif (RBM) is shown in purple, and the five key residues that
RmYN02 Rhinolophus malayanus S(429) – S(453) T(454) V(461)
contact angiotensin-converting
Fig. 3 | Key differences in the spike protein of SARS-CoV-2
and related coronaviruses. a | Schematic diagram of the spike
(S) protein of severe acute respiratory syndrome coronavirus
(SARS-CoV) and SARS-CoV-2. The residue numbers of each
region correspond to their positions in the S proteins of SARS-
CoV and SARS-CoV-2. The dark blue blocks represent insertions in
the S protein. The insertions at amino acids 675–691 of the SARS-
CoV-2 S protein are shown in an enlargement at the bottom
right and aligned with those of other coronaviruses in the same
region. b | Alignment of the receptor-binding domain (RBD) in
SARS-CoV-2, SARS-CoV BJ01, RaTG13, pangolin coronavirus reported
from Guangdong, China (GD pangolin), pangolin coronavirus
reported from Guangxi, China (GX pangolin) and bat

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 SARS-CoV RBD

enzyme 2 (ACE2) directly are highlighted in green. c | Five

critical residues in the RBD of SARS-CoV-2 and other viruses. d |
Comparison of the structure of SARS-CoV-2 and SARS-CoV RBD
complexed with human ACE2 (hACE2); SARS-CoV-2 RBM in purple,
SARS-CoV RBM in yellow and hACE2 in green). Five critical
residues that are involved in the RBM–ACE2 binding are shown.
The Protein Data Bank codes are 2AJF for SARS-CoV RBD–hACE2 and
6VW1 for SARS-CoV-2 RBD–hACE2. The GenBank entries are
AY278488 for SARS-CoV BJ01, MN996532 for the bat SARSr-CoV
RaTG13, MT121216 and
MT072864 for the GD pangolin and GX pangolin coronaviruses,
respectively, and KF367457 for the bat SARSr-CoV WIV1. CP,
cytoplasmic domain; FP, fusion peptide; HR1, heptad repeat
1; HR2, heptad repeat 2; NTD, N-terminal domain; SP, signal
peptide; TM, transmembrane domain. Parts a and b adapted
from REF.26, Springer Nature Limited.

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cells and animal models.
a polybasic cleavage site (RRAR), which enables Whether this amino acid
effec- tive cleavage by furin and other proteases27. change enhanced virus
Such an S1–S2 cleavage site is not observed in all transmissibil- ity is also to be
related viruses belonging to the subgenus determined. Another marker
Sarbecovirus, except for a similar three amino acid mutation for SARS-CoV-2
insertion (PAA) in RmYN02, a bat- derived evolution is the single-
coronavirus newly reported from Rhinolophus nucleotide
malayanus in China28 (FIG. 3a). Although the insertion
in RmYN02 does not functionally represent a
polybasic cleavage site, it provides support for the
notion that this characteristic, initially considered
unique to SARS-CoV-2, has been acquired naturally28.
A structural study suggested that the furin-cleavage site
can reduce the stability of SARS-CoV-2 S protein and
facilitate the conformational adaption that is required
for the binding of the RBD to its receptor 29. Whether
the higher trans- missibility of SARS-CoV-2 compared
with SARS-CoV is a gain of function associated with
acquisition of the furin-like cleavage site is yet to be
demonstrated26.
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 pathways25. 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 outbreak30. Such ORF8 deletion may
be indicative of human adaptation after cross-species
transmission from an animal host.
To assess the genetic variation of different
SARS- CoV-2 strains, the 2019 Novel Coronavirus
Resource of China National Center for
Bioinformation aligned 77,801 genome sequences of
SARS-CoV-2 detected glob- ally and identified a total
of 15,018 mutations, including 14,824 single-
nucleotide polymorphisms (BIGD)31. In the S
protein, four amino acid alterations, V483A, L455I,
F456V and G476S, are located near the binding
interface in the RBD, but their effects on binding to the
host receptor are unknown. The alteration D614G in
the S1 subunit was found far more frequently than
other S variant sites, and it is the marker of a major
subclade of SARS-CoV-2 (clade G). Since March 2020,
SARS-CoV-2 variants with G614 in the S protein
have replaced the original D614 variants and become
the dominant form circulating globally. Compared
with the D614 variant, higher viral loads were found
in patients infected with the G614 variant, but clinical
data suggested no signif- icant link between the
D614G alteration and disease severity 32.
Pseudotyped viruses carrying the S protein with
G614 generated higher infectious titres than viruses
carrying the S protein with D614, suggesting the
altera- tion may have increased the infectivity of
SARS-CoV-2 (REF.32). However, the results of in vitro
experiments based on pseudovirus models may not
exactly reflect natural infection. This preliminary
finding should be validated by more studies using wild-
type SARS-CoV-2 variants to infect different target
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polymorphism at nucleotide position 28,144, which results in amino acid
substitution of Ser for Lys at residue 84 of the ORF8 protein. Those variants
with this muta- tion make up a single subclade labelled as ‘clade S’33,34.
Currently, however, the available sequence data are not sufficient to interpret
the early global transmission his- tory of the 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.

Animal host and spillover

Bats are important natural hosts of alphacoronavi- ruses and
betacoronaviruses. The closest relative to SARS-CoV-2 known to date is a
bat coronavirus detected in Rhinolophus affinis from Yunnan province, China,
named ‘RaTG13’, whose full-length genome sequence is 96.2% identical to
that of SARS-CoV-2 (REF.11). 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.11). Phylogenetic analysis confirms that
SARS-CoV-2 closely clusters with RaTG13 (FIG. 2). The high genetic similarity
between SARS-CoV-2 and RaTG13 supports the hypothesis that SARS-CoV-2
likely originated from bats35. Another related coronavirus has been reported
more recently in a Rhinolophus malayanus bat sampled in Yunnan. This novel
bat virus, denoted ‘RmYN02’, is 93.3% identical to SARS-CoV-2 across the
genome. In the long 1ab gene, it exhibits 97.2% identity to SARS-CoV-2,
which is even higher than for RaTG13 (REF.28). In addition to RaTG13 and
RmYN02, phyloge- netic analysis shows that bat coronaviruses ZC45 and
ZXC21 previously detected in Rhinolophus pusillus bats from eastern China
also fall into the SARS-CoV-2 lineage of the subgenus Sarbecovirus36 (FIG. 2).
The dis- covery of diverse bat coronaviruses closely related to SARS-CoV-2
suggests that bats are possible reservoirs of SARS-CoV-2 (REF.37). Nevertheless,
on the basis of current findings, the divergence between SARS-CoV-2 and
related bat coronaviruses likely represents more than 20 years of sequence
evolution, suggesting that these bat coronaviruses can be regarded only as the
likely evolu- tionary precursor of SARS-CoV-2 but not as the direct progenitor
of SARS-CoV-2 (REF.38).
Beyond bats, pangolins are another wildlife host probably linked with SARS-
CoV-2. Multiple SARS-CoV-2- related viruses have been identified in tissues of
Malayan pangolins smuggled from Southeast Asia into southern China from
2017 to 2019. These viruses from pangolins independently seized by Guangxi
and Guangdong pro- vincial customs belong to two distinct sublineages 39–41.
The Guangdong strains, which were isolated or sequenced by different research
groups from smug- gled pangolins, have 99.8% sequence identity with each
other41. They are very closely related to SARS-CoV-2, exhibiting 92.4%
sequence similarity. Notably, the RBD of Guangdong pangolin coronaviruses is
highly similar to that of SARS-CoV-2. The receptor-binding motif (RBM;
which is part of the RBD) of these viruses has only one amino acid variation
from SARS-CoV-2, and it is identical to that of SARS-CoV-2 in all five critical

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infection in two dogs from
residues for receptor binding (FIG. 3b). In comparison
40 households with human cases
with the Guangdong strains, pangolin coronaviruses of COVID-19 in Hong Kong,
reported from Guangxi are less similar to SARS-CoV- but the dogs
2, with 85.5% genome sequence identity39. The
repeated occurrence of SARS-CoV-2-related
coronavirus infec- tions in pangolins from different
smuggling events suggests that these animals are
possible hosts of the viruses. However, unlike bats,
which carry coronaviruses healthily, the infected
pangolins showed clinical signs and histopathological
changes, including interstitial pneumonia and
inflammatory cell infiltration in diverse organs40.
These abnormalities suggest that pangolins are
unlikely to be the reservoir of these coronaviruses but
more likely acquired the viruses after spillover from
the natural hosts.
An intermediate host usually plays an important
role in the outbreak of bat-derived emerging
coronaviruses; for example, palm civets for SARS-
CoV and dromedary camels for MERS-CoV. The virus
strains carried by these two intermediate hosts were
almost genetically identi- cal to the corresponding
viruses in humans (more than 99% genome sequence
identity)1. Despise an RBD that is virtually identical to
that of SARS-CoV-2, the pangolin coronaviruses
known to date have no more than 92% genome identity
with SARS-CoV-2 (REF.42). The avail- able data are
insufficient to interpret pangolins as the intermediate
host of SARS-CoV-2. So far, no evidence has shown
that pangolins were directly involved in the emergence
of SARS-CoV-2.
Currently, our knowledge on the animal origin of
SARS-CoV-2 remains incomplete to a large part. The
reservoir hosts of the virus have not been clearly
proven. It is unknown whether SARS-CoV-2 was
transmitted to humans through an intermediate host
and which animals may act as its intermediate host.
Detection of RaTG13, RmYN02 and pangolin
coronaviruses implies that diverse coronaviruses
similar to SARS-CoV-2 are circulating in wildlife. In
addition, as previous stud- ies showed recombination
as the potential origin of some sarbecoviruses such as
SARS-CoV, it cannot be excluded that viral RNA
recombination among different related coronaviruses
was involved in the evolution of SARS-CoV-2.
Extensive surveillance of SARS-CoV-2- related
viruses in China, Southeast Asia and other regions
targeting bats, wild and captured pangolins and other
wildlife species will help us to better understand the
zoonotic origin of SARS-CoV-2.
Besides wildlife, researchers investigated the sus-
ceptibility of domesticated and laboratory animals to
SARS-CoV-2 infection. The study demonstrated
exper- imentally that SARS-CoV-2 replicates efficiently
in cats and in the upper respiratory tract of ferrets,
whereas dogs, pigs, chickens and ducks were not
susceptible to SARS-CoV-2 (REF.43). The susceptibility
of minks was documented by a report from the
Netherlands on an outbreak of SARS-CoV-2 infection
in farmed minks. Although the symptoms in most
infected minks were mild, some developed severe
respiratory distress and died of interstitial
pneumonia44. Both virologi- cal and serological
testing found evidence for natural SARS-CoV-2
NATURE REVIEWS | VOLUME 19 | MARCH 2021 | 11
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appeared asymptomatic45. Another serological study detected SARS-CoV-2
neutralizing antibodies in cat serum samples collected in Wuhan after the
COVID-19 outbreak, providing evidence for SARS-CoV-2 infection in cat
populations in Wuhan, although the potential of SARS-CoV-2 transmission
from cats to humans is currently uncertain46.

Receptor use and pathogenesis

SARS-CoV-2 uses the same receptor as SARS-CoV, angiotensin-converting
enzyme 2 (ACE2)11,47. Besides human ACE2 (hACE2), SARS-CoV-2 also
recognizes ACE2 from pig, ferret, rhesus monkey, civet, cat, pan- golin, rabbit
and dog11,43,48,49. The broad receptor usage of SARS-CoV-2 implies that it may
have a wide host range, and the varied efficiency of ACE2 usage in differ- ent
animals may indicate their different susceptibilities to SARS-CoV-2 infection.
The S1 subunit of a 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 neu- tralizing antibodies50,51 (FIG. 3a). The
RBM mediates con- tact with the ACE2 receptor (amino acids 437–507 of
SARS-CoV-2 S protein), and this region in SARS-CoV-2 differs from that in
SARS-CoV in the five residues crit- ical for ACE2 binding, namely Y455L,
L486F, N493Q, D494S and T501N52 (FIG. 3b,c). Owing to these residue
changes, interaction of SARS-CoV-2 with its receptor stabilizes the two virus-
binding hotspots on the surface of hACE2 (REF.50) (FIG. 3d). Moreover, a four-
residue motif in the RBM of SARS-CoV-2 (amino acids 482–485: G-V-E-G)
results in a more compact conformation of its hACE2-binding ridge than in
SARS-CoV and ena- bles better contact with the N-terminal helix of hACE2
(REF.50). 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. 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 furin47,54,55. 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 (REFS56,57).
SARS- CoV-2 pseudovirus entry assays revealed that TMPRSS2 and cathepsin
L have cumu- lative effects with furin on activating virus entry 55. Analysis of
the cryo-electron microscopy structure of SARS-CoV-2 S protein revealed that its
RBD is mostly in the lying-down state, whereas the SARS-CoV S protein
assumes equally standing-up and lying-down conforma- tional states50,51,58,59. A
lying-down conformation of the SARS-CoV-2 S protein may not be in favour
of receptor binding but is helpful for immune evasion55.

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The pathogenesis of SARS-CoV-2 infection in lower respiratory tracts. Acute viral interstitial pneu-
humans manifests itself as mild symptoms to severe monia and humoral and cellular immune responses
respiratory failure. On binding to epithelial cells in were observed48,75. Moreover, prolonged virus shedding
the respiratory tract, SARS-CoV-2 starts replicating peaked early in the course of infection in asymptomatic
and migrating down to the airways and enters alveo- macaques69, and old monkeys showed severer intersti-
lar epithelial cells in the lungs. The rapid replication of tial pneumonia than young monkeys76, which is similar
SARS-CoV-2 in the lungs may trigger a strong to what is seen in patients with COVID-19. In human
immune response. Cytokine storm syndrome causes ACE2-transgenic mice infected with SARS-CoV-2,
acute res- piratory distress syndrome and respiratory typ- ical interstitial pneumonia was present, and viral
failure, which is considered the main cause of death in anti- gens were observed mainly in the bronchial
patients with COVID-19 (REFS60,61). Patients of older epithelial cells, macrophages and alveolar epithelia.
age (>60 years) and with serious pre-existing diseases Some human ACE2-transgenic mice even died after
have a greater risk of developing acute respiratory infection70,71. In wide-type mice, a SARS-CoV-2 mouse-
distress syndrome and death62–64 (FIG. 4). Multiple adapted strain with the N501Y alteration in the RBD of
organ failure has also been reported in some COVID- the S protein was generated at passage 6. Interstitial
19 cases9,13,65. pneumonia and inflammatory responses were found
Histopathological changes in patients with COVID-19 in both young and aged mice after infection with the
occur mainly in the lungs. Histopathology analyses mouse-adapted strain74. Golden hamsters also showed
showed bilateral diffused alveolar damage, hyaline typical symptoms after being infected with SARS-
membrane formation, desquamation of pneumocytes CoV-2 (REF.77). In other animal models, including cats
and fibrin deposits in lungs of patients with severe and ferrets, SARS-CoV-2 could efficiently replicate in
COVID-19. Exudative inflammation was also shown the upper respiratory tract but did not induce severe
in some cases. Immunohistochemistry assays detected clinical symptoms43,78. As trans- mission by direct
SARS-CoV-2 antigen in the upper airway, bronchiolar contact and air was observed in infected ferrets and
epithelium and submucosal gland epithelium, as well hamsters, these animals could be used to model
as in type I and type II pneumocytes, alveolar different transmission modes of COVID-19 (REFS77–79).
macrophages and hyaline membranes in the Animal models offer important information for
lungs13,60,66,67. understanding the pathogenesis of SARS-CoV-2
Animal models used for studying SARS-CoV-2 infection and the transmission dynamics of SARS-
infection pathogenesis include non-human primates CoV-2, and are important to evaluate the efficacy of
(rhesus macaques, cynomolgus monkeys, marmosets antiviral therapeutics and vaccines.
and African green monkeys), mice (wild-type mice
(with mouse-adapted virus) and human ACE2- Clinical and epidemiological features
transgenic or human ACE2-knock-in mice), ferrets and It appears that all ages of the population are susceptible
golden hamsters43,48,68–74. In non-human primate animal to SARS-CoV-2 infection, and the median age of
mod- els, most species display clinical features similar infection is around 50 years9,13,60,80,81. However, clinical
to those of patients with COVID-19, including virus manifesta- tions differ with age. In general, older men
shedding, virus replication and host responses to (>60 years old) with co-morbidities are more likely to
SARS-CoV-2 infection69,72,73. For example, in the develop severe respiratory disease that requires
rhesus macaque model, high viral loads were detected hospitalization
in the upper and

Age as major risk factor

<10 years <50 >60 years >68 years

years

Likely Likely Likely

COVID-19 cases (percentage of
all cases)
Critical and deceased
Asymptomatic... and mild disease (81%) Severe (14%) (5%)

Incubation period • Fever, fatigue and dry cough • Dyspnea • ARDS

• Ground-glass opacities • Coexisting illness • Acute cardiac injury
• Pneumonia • ICU needed

~5
days ~8 ~16
Disease days days
(1– onset
14) (7– (12–
14) 20)

Fig. 4 | Clinical features of COVID-19. Typical symptoms of coronavirus disease 2019 (COVID-19)
NATURE REVIEWS | VOLUME 19 | MARCH 2021 | 13
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 are fever, dry cough and fatigue and in severer cases dyspnea. Many infections, in particular in
children and young adults, are asymptomatic, whereas older people and/or people with co-
morbidities are at higher risk of severe disease, respiratory failure and death. The incubation period
is ~5 days, severe disease usually develops ~8 days after symptom onset and critical disease and
death occur at ~16 days. ARDS, acute respiratory distress syndrome; ICU, intensive care unit.

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clinical settings9. By
or even die, whereas most young people and children contrast, a high risk of
have only mild diseases (non-pneumonia or mild nosocomial transmission was
pneumonia) or are asymptomatic9,81,82. Notably, the risk reported in some other
of disease was not higher for pregnant women.
However, evidence of transplacental transmission of
SARS-CoV-2 from an infected mother to a neonate
was reported, although it was an isolated case 83,84. On
infection, the most common symptoms are fever,
fatigue and dry cough13,60,80,81. Less common symptoms
include sputum production, headache, haemoptysis,
diarrhoea, anorexia, sore throat, chest pain, chills and
nausea and vomiting in studies of patients in
China13,60,80,81. Self-reported olfac- tory and taste
disorders were also reported by patients in Italy85. 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 onset9.
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)9,86. On admission, ground-glass
opacity was the most common radiologic finding on
chest computed tomography (CT)13,60,80,81. Most patients
also developed marked lymphopenia, similar to what
was observed in patients with SARS and MERS, and
non-survivors devel- oped severer lymphopenia over
time13,60,80,81. Compared with non-ICU patients, ICU
patients had higher levels of plasma cytokines, which
suggests an immunopatho- logical process caused by a
cytokine storm60,86,87. In this cohort of patient, around
2.3% people died within a median time of 16 days
from disease onset9,86. Men older than 68 years had a
higher risk of respiratory fail- ure, acute cardiac injury
and heart failure that led to death, regardless of a
history of cardiovascular disease86 (FIG. 4). Most
patients recovered enough to be released from hospital
in 2 weeks9,80 (FIG. 4).
Early transmission of SARS-CoV-2 in Wuhan in
December 2019 was initially linked to the Huanan
Seafood Wholesale Market, and it was suggested as
the source of the outbreak9,22,60. However,
community transmission might have happened
before that88. Later, ongoing human-to-human
transmission propagated the outbreak9. It is generally
accepted that SARS-CoV-2 is more transmissible than
SARS-CoV and MERS-CoV; however, determination
of an accurate reproduction number (R0) for COVID-
19 is not possible yet, as many asymptomatic infections
cannot be accurately accounted for at this stage89. An
estimated R0 of 2.5 (ranging from 1.8 to 3.6) has been
proposed for SARS-CoV-2 recently, compared with
2.0–3.0 for SARS-CoV90. Notably, most of the SARS-
CoV-2 human-to-human transmission early in China
occurred in family clusters, and in other countries
large outbreaks also happened in other set- tings,
such as migrant worker communities, slaughter-
houses and meat packing plants, indicating the
necessity of isolating infected people9,12,91–93.
Nosocomial transmis- sion was not the main source of
transmission in China because of the
implementation of infection control measures in
NATURE REVIEWS | VOLUME 19 | MARCH 2021 | 15
MICROBIOLOGY
areas. For example, a cohort study in London revealed 44% of the frontline
health-care workers from a hospital were infected with SARS-CoV-2 (REF.94).
The high transmissibility of SARS-CoV-2 may be attributed to the
unique virological features of SARS-CoV-2. Transmission of SARS-CoV
occurred mainly after illness onset and peaked following dis- ease severity95.
However, the SARS-CoV-2 viral load in upper respiratory tract samples was
already high- est during the first week of symptoms, and thus the risk of
pharyngeal virus shedding was very high at the beginning of infection 96,97. It
was postulated that undocumented infections might account for 79% of
documented cases owing to the high transmissibility of the virus during
mild disease or the asymptomatic period89. A patient with COVID-19
spreads viruses in liquid droplets during speech. However, smaller and
much more numerous particles known as aerosol parti- cles 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 else98–100. Airborne trans-
mission was also observed in the ferret experiments mentioned above.
SARS-CoV-2-infected ferrets shed viruses in nasal washes, saliva, urine and
faeces for up to 8 days after infection, and a few naive ferrets with only indirect
contact were positive for viral RNA, suggest- ing airborne transmission78. In
addition, transmission of the virus through the ocular surface and prolonged
presence of SARS-CoV-2 viral RNA in faecal samples were also
documented101,102. Coronaviruses can persist on inanimate surfaces for days,
which could also be the case for SARS-CoV-2 and could pose a prolonged risk
of infection103. These findings explain the rapid geographic spread of COVID-
19, and public health interventions to reduce transmission will provide benefit
to mitigate the epidemic, as has proved successful in China and several other
countries, such as South Korea89,104,105.

Diagnosis
Early diagnosis is crucial for controlling the spread of COVID-19. Molecular
detection of SARS-CoV-2 nucleic acid is the gold standard. Many viral nucleic
acid detec- tion kits targeting ORF1b (including RdRp), N, E or S genes are
commercially available11,106–109. The detection time ranges from several minutes
to hours depending on the technology106,107,109–111. The molecular detection can be
affected by many factors. Although SARS-CoV-2 has been detected from a
variety of respiratory sources, including throat swabs, posterior oropharyngeal
saliva, nasopharyngeal swabs, sputum and bronchial fluid, the viral load is
higher in lower respiratory tract sam- ples 11,96,112–115. In addition, viral nucleic
acid was also found in samples from the intestinal tract or blood even when
respiratory samples were negative116. Lastly, viral load may already drop from
its peak level on disease onset 96,97. Accordingly, false negatives can be common
when oral swabs and used, and so multiple detection methods should be
adopted to confirm a COVID-19 diagnosis117,118. Other detection methods were
there- fore used to overcome this problem. Chest CT was used to quickly
identify a patient when the capacity of molecular detection was overloaded in
Wuhan. Patients

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antiviral drug against SARS-
with COVID-19 showed typical features on initial CT, CoV-2 infection, although so
including bilateral multilobar ground-glass opacities far there are not sufficient
with a peripheral or posterior distribution118,119. Thus, clinical data to support its
it has been suggested that CT scanning combined efficacy.
with repeated swab tests should be used for
individu- als with high clinical suspicion of COVID-
19 but who test negative in initial nucleic acid
screening118. Finally, SARS-CoV-2 serological tests
detecting antibodies to N or S protein could
complement molecular diagnosis, particularly in late
phases after disease onset or for retro- spective
studies116,120,121. However, the extent and dura- tion of
immune responses are still unclear, and available
serological tests differ in their sensitivity and specific-
ity, 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.

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

Inhibition of virus entry. SARS-CoV-2 uses ACE2 as

the receptor and human proteases as entry activators;
sub- sequently it fuses the viral membrane with the cell
mem- brane and achieves invasion. Thus, drugs that
interfere with entry may be a potential treatment for
COVID-19. Umifenovir (Arbidol) is a drug approved
in Russia and China for the treatment of influenza and
other respira- tory viral infections. It can target the
interaction between the S protein and ACE2 and inhibit
membrane fusion (FIG. 5). In vitro experiments showed
that it has activity against SARS-CoV-2, and current
clinical data revealed it may be more effective than
lopinavir and ritonavir in treating COVID-19
(REFS122,123). However, other clinical studies showed
umifenovir might not improve the prog- nosis of or
accelerate SARS-CoV-2 clearance in patients with mild
to moderate COVID-19 (REFS124,125). Yet some ongoing
clinical trials are evaluating its efficacy for COVID-19
treatment. Camostat mesylate is approved in Japan for
the treatment of pancreatitis and postoper- ative reflux
oesophagitis. Previous studies showed that it can
prevent SARS-CoV from entering cells by blocking
TMPRSS2 activity and protect mice from lethal
infection with SARS-CoV in a pathogenic mouse
model (wild- type mice infected with a mouse-adapted
SARS-CoV strain)126,127. Recently, a study revealed that
camostat mesylate blocks the entry of SARS-CoV-2
into human lung cells47. Thus, it can be a potential
NATURE REVIEWS | VOLUME 19 | MARCH 2021 | 17
MICROBIOLOGY
 Chloroquine and hydroxychloroquine are other potential but
controversial drugs that interfere with the entry of SARS-CoV-2. They have
been used in the prevention and treatment of malaria and autoimmune
diseases, including systemic lupus erythematosus and rheumatoid arthritis.
They can inhibit the glycosyla- tion of cellular receptors and interfere with
virus–host receptor binding, as well as increase the endosomal pH and inhibit
membrane fusion. Currently, no scientific consensus has been reached for
their efficacy in the treatment of COVID-19. Some studies showed they can
inhibit SARS-CoV-2 infection in vitro, but the clinical data are
insufficient128,129. Two clinical studies indicated no association with death rates
in patients receiving chloroquine or hydroxychloroquine compared with
those not receiving the drug and even suggest it may increase the risk of
dying as a higher risk of cardiac arrest was found in the treated patients130,131. On
15 June 2020, owing to the side effects observed in clinical trials, the US Food
and Drug Administration (FDA) revoked the emergency use authorization
for chloroquine and hydroxychloroquine for the treatment of COVID-19.
Another potential therapeutic strategy is to block bind- ing of the S protein to
ACE2 through soluble recombi- nant hACE2, specific monoclonal antibodies
or fusion inhibitors that target the SARS-CoV-2 S protein132–134 (FIG. 5). The
safety and efficacy of these strategies need to be assessed in future clinical
trials.

Inhibition of virus replication. Replication inhibitors include remdesivir (GS-

5734), favilavir (T-705), riba- virin, lopinavir and ritonavir. Except for
lopinavir and ritonavir, which inhibit 3CLpro, the other three all target
RdRp128,135 (FIG. 5). Remdesivir has shown activity against SARS-CoV-2 in vitro
and in vivo128,136. A clinical study revealed a lower need for oxygen support in
patients with COVID-19 (REF.137). Preliminary results of the Adaptive COVID-
19 Treatment Trial (ACTT) clinical trial by the National Institute of Allergy
and Infectious Diseases (NIAID) reported that remdesivir can shorten the
recovery time in hospitalized adults with COVID-19 by a couple days
compared with placebo, but the differ- ence in mortality was not statistically
significant138. The FDA has issued an emergency use authorization for rem-
desivir for the treatment of hospitalized patients with severe COVID-19. It is
also the first approved option by the European Union for treatment of adults
and adoles- cents with pneumonia requiring supplemental oxygen. Several
international phase III clinical trials are contin- uing to evaluate the safety and
efficacy of remdesivir for the treatment of COVID-19.
Favilavir (T-705), which is an antiviral drug devel- oped 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 signif- icantly
reduced the signs of improved disease signs on chest imaging and shortened
the time to viral clearance 139. 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,

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Convalescent plasma Dexamethasone

Neutralizing antibodies Inhibits inflammatory
help clear virus and cytokines and neutrophil
infected cells Lymphocyte infiltration
Neutralizin
g
antibodies
Monoclonal IL-
antibody
Neutralizes the virus
Monocyt
e
CR302
2 Tocilizumab or
Recombinant human ACE2 sarilumab
Binds to virus and inhibits • Binds IL-6 specifically
infected cell • Inhibits IL-6 signalling
SARS-CoV-2 Arbidol
Inhibits S–ACE2 Soluble IL-
interaction 6 receptor
Camostat and membrane fusion Macrophag
mesylate
Inhibits TMPRSS2 ACE2 e
Interfer
TMPRSS2 on
Expressio
Chloroquine or n of ISGs
Membrane Interfero
hydroxychloroqui n
fusion and
ne receptor
endocytosis Releas
e
Fusion inhibitor:
Uncoating EK1C4/HR2P
Inhibits membrane Assembly
fusion and
budding
(+) AAA
RNA gRNA
replicatio Non-structural proteins
n Translatio
Replicase–transcriptase Golgi
n
complex apparatus
3CLpr Inhibits
Lopinavir or ER
Polypeptides 3CLpro S
Proteolysis RdR o
p Structur
Remdesivir, al
ribavarin or proteins Nucleocapsi
UUU
favipiravir UUU d
Inhibits RdRp (–) sgRNAs UUU E
Transcription UUU Nucleu
s
AAA Translation
(–) gRNA
(+) AAA
(+) AAA
sgRNAs
AAA

Fig. 5 | SARS-CoV-2 replication and potential therapeutic targets. Potential antivirals target
the different steps of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication,
ranging from receptor binding, entry and fusion to replication. Furthermore, immunoglobulin-based
and immunomodulatory drugs are potential therapeutics as well. Note that robust data on clinical
efficacy are lacking for most of these treatments so far. 3CLpro, 3C-like protease; ACE2, angiotensin-
converting enzyme 2; CR3022, a SARS-CoV-specific human monoclonal antibody; E, envelope protein;
EK1C4, lipopeptide derived from EK1 which is a pan-coronavirus fusion inhibitor targeting the HR1
domain of the spike protein; ER, endoplasmic reticulum; gRNA, genomic RNA; HR2P, heptad repeat
2-derived peptides of SARS-CoV-2
spike protein; IL-6, interleukin-6; ISG, interferon-stimulated gene; M, membrane protein; RdRp, RNA-
dependent RNA polymerases; sgRNA, subgenomic RNA; S, spike protein; TMPRSS2, transmembrane
protease serine protease 2.

respectively140. However, this study did not include in vitro inhibitory activity
a control arm, and most of the trials of favilavir were against SARS-CoV and
based on a small sample size. For more reliable assess- MERS-CoV141,142. Alone, the
ment of the effectiveness of favilavir for treating combination of lopinavir
COVID-19, large-scale randomized controlled trials
should be conducted.
Lopinavir and ritonavir were reported to have
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and ritonavir had little therapeutic benefit in patients with COVID-19, but
appeared more effective when used in combination with other drugs, including
ribavirin and interferon beta-1b143,144. The Randomized Evaluation of COVID-
19 Therapy (RECOVERY) trial, a national clin- ical trial programme in the UK,
has stopped treatment with lopinavir and ritonavir as no significant beneficial
effect was observed in a randomized trial established in March 2020 with a total
of 1,596 patients145. Nevertheless,

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specific mon- oclonal
other clinical trials in different phases are still ongoing antibodies neutralizing SARS-
elsewhere. CoV-2 infection

Immunomodulatory agents. SARS-CoV-2 triggers a

strong immune response which may cause cytokine
storm syndrome60,61. Thus, immunomodulatory agents
that inhibit the excessive inflammatory response
may be a potential adjunctive therapy for COVID-
19. Dexamethasone is a corticosteroid often used in a
wide range of conditions to relieve inflammation
through its anti-inflammatory and
immunosuppressant effects. Recently, the
RECOVERY trial found dexamethasone reduced
mortality by about one third in hospitalized patients
with COVID-19 who received invasive mechan- ical
ventilation and by one fifth in patients receiving
oxygen. By contrast, no benefit was found in
patients without respiratory support146.
Tocilizumab and sarilumab, two types of interleukin-6
(IL-6) receptor-specific antibodies previously used to
treat various types of arthritis, including rheumatoid
arthritis, and cytokine release syndrome, showed effec-
tiveness in the treatment of severe COVID-19 by atten-
uating the cytokine storm in a small uncontrolled
trial147. Bevacizumab is an anti-vascular endothelial
growth factor (VEGF) medication that could
potentially reduce pulmonary oedema in patients with
severe COVID-19. Eculizumab is a specific
monoclonal antibody that inhibits the
proinflammatory complement protein C5.
Preliminary results showed that it induced a drop of
inflammatory markers and C-reactive protein levels,
suggesting its potential to be an option for the
treatment of severe COVID-19 (REF.148).
The interferon response is one of the major innate
immunity defences against virus invasion. Interferons
induce the expression of diverse interferon-stimulated
genes, which can interfere with every step of virus
replication. Previous studies identified type I interfer-
ons as a promising therapeutic candidate for SARS 149.
In vitro data showed SARS-CoV-2 is even more sen-
sitive to type I interferons than SARS-CoV, suggesting
the potential effectiveness of type I interferons in the
early treatment of COVID-19 (REF.150). In China, vapor
inhalation of interferon-α is included in the COVID-19
treatment guideline151. Clinical trials are ongoing
across the world to evaluate the efficacy of different
therapies involving interferons, either alone or in
combination with other agents152.

Immunoglobulin therapy. Convalescent plasma treat-

ment is another potential adjunctive therapy for
COVID-19. Preliminary findings have suggested
improved clinical status after the treatment153,154. The
FDA has provided guidance for the use of COVID-
19 convalescent plasma under an emergency
investigational new drug application. However, this
treatment may have adverse effects by causing
antibody-mediated enhance- ment of infection,
transfusion-associated acute lung injury and allergic
transfusion reactions.
Monoclonal antibody therapy is an effective
immuno- therapy for the treatment of some viral
infections in select patients. Recent studies reported
NATURE REVIEWS | VOLUME 19 | MARCH 2021 | 21
MICROBIOLOGY
in vitro and in vivo155–158. Compared with convalescent plasma, which has
limited availability and cannot be amplified, monoclonal antibodies can be
developed in larger quantities to meet clinical requirements. Hence, they
provide the possibility for the treatment and pre- vention of COVID-19. The
neutralizing epitopes of these monoclonal antibodies also offer important
infor- mation for vaccine design. However, the high cost and limited capacity
of manufacturing, as well as the prob- lem of bioavailability, may restrict the
wide application of monoclonal antibody therapy.

Vaccines
Vaccination is the most effective method for a long-term strategy for prevention
and control of COVID-19 in the future. Many different vaccine platforms
against SARS-CoV-2 are in development, the strategies of which include
recombinant vectors, DNA, mRNA in lipid nano- particles, inactivated viruses,
live attenuated viruses and protein subunits159–161. As of 2 October 2020, ~174
vac- cine candidates for COVID-19 had been reported and 51 were in
human clinical trials (COVID-19 vaccine and therapeutics tracker). Many
of these vac- cine candidates are in phase II testing, and some have already
advanced to phase III trials. A randomized double-blinded phase II trial of
an adenovirus type 5- vectored vaccine expressing the SARS-CoV-2 S protein,
developed by CanSino Biologicals and the Academy of Military Medical
Sciences of China, was conducted in 603 adult volunteers in Wuhan. The
vaccine has proved to be safe and induced considerable humoral and cel-
lular immune response in most recipients after a single immunization162.
Another vectored vaccine, ChAdOx1, was developed on the basis of
chimpanzee adenovirus by the University of Oxford. In a randomized
controlled phase I/II trial, it induced neutralizing antibodies against SARS-
CoV-2 in all 1,077 participants after a second vaccine dose, while its safety
profile was acceptable as well163. The NIAID and Moderna co-manufactured
mRNA-1273, a lipid nanoparticle-formulated mRNA vaccine candidate that
encodes the stabilized prefusion SARS-CoV-2 S protein. Its immunogenicity
has been confirmed by a phase I trial in which robust neutralizing antibody
responses were induced in a dose-dependent manner and increased after a
second dose164. Regarding inactivated vaccines, a successful phase I/II trial
involv- ing 320 participants has been reported in China. The whole-virus
COVID-19 vaccine had a low rate of adverse reactions and effectively induced
neutralizing antibody production165. The verified safety and immunogenicity
support advancement of these vaccine candidates to phase III clinical trials,
which will evaluate their efficacy in protecting healthy populations from
SARS-CoV-2 infection.

Future perspectives
COVID-19 is the third highly pathogenic human coro- navirus disease to date.
Although less deadly than SARS and MERS, the rapid spreading of this
highly conta- gious disease has posed the severest threat to global health in
this century. The SARS-CoV-2 outbreak has lasted for more than half a year
now, and it is likely that

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this emerging virus will establish a niche in humans interactions remain largely unclear. Intensive studies
and coexist with us for a long time166. Before clinically on these virological profiles of SARS-CoV-2 will
approved vaccines are widely available, there is no provide the basis for the development of preventive
bet- ter way to protect us from SARS-CoV-2 than and thera- peutic strategies against COVID-19.
personal preventive behaviours such as social Moreover, contin- ued genomic monitoring of SARS-
distancing and wearing masks, and public health CoV-2 in new cases is needed worldwide, as it is
measures, including active testing, case tracing and important to promptly iden- tify any mutation that may
restrictions on social gatherings. Despite a flood of result in phenotypic changes of the virus. Finally,
SARS-CoV-2 research published every week, current COVID-19 is challenging all human beings. Tackling
knowledge of this novel coronavirus is just the tip of this epidemic is a long-term job which requires efforts
the iceberg. The animal origin and cross-species of every individual, and international collaborations by
infection route of SARS-CoV-2 are yet to be scientists, authorities and the public.
uncovered. The molecular mechanisms of SARS-CoV-
2 infection pathogenesis and virus–host Published online 6 October 2020

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