Emerging COVID-19 Variants and Their Impact On SARS-CoV-2 Diagnosis Therapeutics and Vaccines

Annals of Medicine
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iann20
Emerging COVID-19 variants and their impact on

SARS-CoV-2 diagnosis, therapeutics and vaccines
Queenie Fernandes, Varghese Philipose Inchakalody, Maysaloun Merhi,

Sarra Mestiri, Nassiba Taib, Dina Moustafa Abo El-Ella, Takwa Bedhiafi,
Afsheen Raza, Lobna Al-Zaidan, Mona O. Mohsen, Mariam Ali Yousuf Al-Nesf,
Ali Ait Hssain, Hadi Mohamad Yassine, Martin F. Bachmann, Shahab Uddin &
Said Dermime
To cite this article: Queenie Fernandes, Varghese Philipose Inchakalody, Maysaloun Merhi,
Sarra Mestiri, Nassiba Taib, Dina Moustafa Abo El-Ella, Takwa Bedhiafi, Afsheen Raza, Lobna
Al-Zaidan, Mona O. Mohsen, Mariam Ali Yousuf Al-Nesf, Ali Ait Hssain, Hadi Mohamad Yassine,
Martin F. Bachmann, Shahab Uddin & Said Dermime (2022) Emerging COVID-19 variants and
their impact on SARS-CoV-2 diagnosis, therapeutics and vaccines, Annals of Medicine, 54:1,
524-540, DOI: 10.1080/07853890.2022.2031274
To link to this article: https://doi.org/10.1080/07853890.2022.2031274
© 2022 The Author(s). Published by Informa Published online: 08 Feb 2022.

UK Limited, trading as Taylor & Francis
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ANNALS OF MEDICINE
2022, VOL. 54, NO. 1, 524–540
https://doi.org/10.1080/07853890.2022.2031274
REVIEW ARTICLE
Emerging COVID-19 variants and their impact on SARS-CoV-2 diagnosis,

therapeutics and vaccines
Queenie Fernandesa,b, Varghese Philipose Inchakalodya, Maysaloun Merhia, Sarra Mestiria, Nassiba Taiba,
Dina Moustafa Abo El-Ellaa, Takwa Bedhiafia, Afsheen Razaa, Lobna Al-Zaidana, Mona O. Mohsena,c,
Mariam Ali Yousuf Al-Nesfd, Ali Ait Hssaine, Hadi Mohamad Yassinef, Martin F. Bachmannc,g,
Shahab Uddinh and Said Dermimea
a
Translational Cancer Research Facility, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar;
b
College of Medicine, Qatar University, Doha, Qatar; cDepartment of Biomedical Research, Immunology RIA, University of Bern, Bern,
Switzerland; dAllergy and Immunology Section, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar; eMedical
Intensive Care Unit, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar; fQatar University Biomedical Research Center,
Qatar University, Doha, Qatar; gNuffield Department of Medicine, Jenner Institute, University of Oxford, Oxford, United Kingdom;
h
Translational Research Institute and Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
ABSTRACT ARTICLE HISTORY

The emergence of novel and evolving variants of SARS-CoV-2 has fostered the need for change Received 8 November 2021
in the form of newer and more adaptive diagnostic methods for the detection of SARS-CoV-2 Revised 7 January 2022
infections. On the other hand, developing rapid and sensitive diagnostic technologies is now Accepted 12 January 2022
more challenging due to emerging variants and varying symptoms exhibited among the
KEYWORDS
infected individuals. In addition to this, vaccines remain the major mainstay of prevention and COVID-19; SARS-CoV-2;
protection against infection. Novel vaccines and drugs are constantly being developed to Omicron; Coronaviruses;
unleash an immune response for the robust targeting of SARS-CoV-2 and its associated variants. diagnostic testing; vaccine;
In this review, we provide an updated perspective on the current challenges posed by the immunological responses;
emergence of novel SARS-CoV-2 mutants/variants and the evolution of diagnostic techniques to Viral epidemic
enable their detection. In addition, we also discuss the development, formulation, working
mechanisms, advantages, and drawbacks of some of the most used vaccines/therapeutic drugs
and their subsequent immunological impact.
KEY MESSAGE
The emergence of novel variants of the SARS-CoV-2 in the past couple of months, highlights
one of the primary challenges in the diagnostics, treatment, as well as vaccine development
against the virus.
Advancements in SARS-CoV-2 detection include nucleic acid based, antigen and immuno-
assay-based and antibody-based detection methodologies for efficient, robust, and quick test-
ing; while advancements in COVID-19 preventive and therapeutic strategies include novel
antiviral and immunomodulatory drugs and SARS-CoV-2 targeted vaccines.
The varied COVID-19 vaccine platforms and the immune responses induced by each one of
them as well as their ability to battle post-vaccination infections have all been discussed in
this review.
1. Introduction
Syndrome Coronavirus 2 (SARS-CoV-2) by the
An outbreak of pneumonia that began in December International Committee on Taxonomy of Viruses [1]
2019 in Wuhan, the capital city of the Hubei Province and the WHO formally named the viral illness as the
of China was found to be associated with a novel Coronavirus Disease 2019 (COVID-19); a disease char-
strain of the Coronavirus that was tentatively named acterized by respiratory distress, fevers, coughs,
by the WHO as the 2019 novel coronavirus (2019- fatigue, pneumonia and muscle pain [2–4]. Following
nCoV). However, on the 11th of February 2020, it was the increase in the number of positive infected cases
formally renamed as the Severe Acute Respiratory in China, on the 30 January 2020, the WHO declared
CONTACT Said Dermime [email protected] Director of Translational Cancer Research Facility National Center for Cancer Care and Research,
Hamad Medical Corporation, College of Health and Life Sciences (CHLS) Hamad Bin Khalifa University, Doha, Qatar
ß 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits
unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ANNALS OF MEDICINE 525
Figure 1. The figure explains about the reported amino acid mutations in RBD region of different SARS- CoV-2 strains.
the viral epidemic a public health emergency of inter- include variants with mutations that result in changes
national concern. SARS-CoV-2 is a an enveloped, sin- to receptor binding, reduced efficacy of treatments,
gle-stranded, positive-sense RNA virus belonging to decreased neutralization by antibodies and a potential
the Betacoronavirus genus in the Coronaviridae family increase in disease severity and/or transmissibility [11].
[2,5,6]. This family of viruses was first identified in In addition, VOCs are defined as variants against which
1965 by Tyrell and Bynoe and isolated and cultivated there may be strong evidence of an increase in trans-
from patients with common colds [7]. Viral structural missibility, greater disease severity, notable reduction
proteins such as the nucleocapsid protein (N), mem- in neutralization by antibodies generated and thus
brane glycoprotein (M), and spike glycoprotein (S) are decreased response to treatments and vaccines [11].
the primary determinants of virulence and function (Table 1)
[8]. Largely like the previous zoonotic coronavirus out- Additionally, in order to synchronize a universal
breaks (SARS-CoV and MERS-CoV), the current SARS- nomenclature that facilitate a streamlined tracking of
CoV-2 virus causes lower respiratory tract infections each of the emerging SARS-CoV-2 variants, the WHO
and may lead to Acute Respiratory Distress has recommended the use of the Greek Alphabet to
Syndromes (ARDS). uniquely identify each novel variant (Figure 1).
The emergence of novel variants of the SARS-CoV-2
in the past couple of months highlights one of the pri-
2. Advancements in COVID-19 detection
mary challenges facing this pandemic. Accumulation
& diagnosis
of mutations arising out of subsequent viral replication
is a natural phenomenon. The SARS-CoV-2 virus is The emergence of novel and evolving variants of
known to evolve at a rate of approximately SARS-CoV-2 has indeed fostered the need for change
1.1 10 3 substitutions per site per year. This figure in the form of newer and more adaptive diagnostic
corresponds to nearly one substitution every 11 days methods for the detection of SARS-CoV-2 infections.
[9]. Although most mutations are found to have no On the other hand, developing rapid and sensitive
perceivable impact, few mutations were found to give diagnostic technologies is now more challenging due
rise to novel high-risk variants of the SARS-CoV-2 virus to emerging variants and varying symptoms exhibited
(Figure 1). The nomenclature and classification of in infected individuals.
these increasing number of SARS-CoV-2 variants has SARS-CoV-2 detection technologies mainly target
been a challenge to the WHO. However during late either specific viral nucleic acids (molecular testing),
2020, the WHO prompted the classification of novel proteins (antigen testing), or anti-SARS-CoV-2 antibod-
SARS- CoV-2 strains as Variants of Interest (VOIs) and ies (serological testing). The choice between each of
Variants of Concern (VOCs) [10]. Specifically, VOIs these tests depends on the selection of right test,
526 Q. FERNANDES ET AL.
Table 1. SARS Cov-2 variants and its impact on transmissibility and treatments.
Variant Variant WHO Country of Origin Spike protein
name classification label /Detection date substitutions Attributes
B.1.1.7 VOC Alpha United Kingdom/ 69del " Transmissibility (50%)
December 2020 70del
144del " Severity
E484K
S494P " Case fatality
N501Y
A570D No impact on susceptibility to EUA
D614G monoclonal antibody treatments
P681H
T716I Minimal impact on neutralization by
S982A convalescent and post-
D1118H vaccination sera
K1191N
B.1.351 VOC Beta South Africa/ D80A " Transmissibility (50%)
B.1.351.2 December 2020 D215G
B.1.351.3 241del # Susceptibility to EUA monoclonal
242del antibody treatments
243del
K417N # Neutralization to convalescent &
E484K post-vaccination sera
N501Y
D614G
A701V
P.1 VOC Gamma Brazil/ L18F # Susceptibility to bamlanivimab/
P.1.1 January 2021 T20N etesevimab monoclonal antibody
P.1.2 P26S treatments
D138Y
R190S # Neutralization to convalescent &
K417T post-vaccination sera
E484K
N501Y
D614G
H655Y
T1027I
B.1.617.2 VOI Delta India/ T19R " Transmissibility
AY.1 VOC May 2021 V70F
AY.2 VOC T95I # Susceptibility to EUA monoclonal
G142D antibody treatments
E156-
F157- # Neutralisation to post-
R158G vaccination sera
(A222V
W258L
K417N
L452R
T478K
D614G
P681R
D950N
B.1.427 VOC Epsilon California/ I4205V " Transmissibility (20%)
B.1.429 July 2020 D1183Y
S13I # susceptibility to EUA monoclonal
W152C antibody treatments
L452R
# neutralisation to convalescent &
post-vaccination sera
B.1.1.529 VOC Omicron South Africa\ A67V, del69-70, T95I, " Transmissibility
November, 2021 del142-144, Y145D,
del211, L212I, " Risk of re-infection
ins214EPE
T547K, Deletion in the S gene, leading to S
D614G, gene target failure (SGTF) in some
H655Y, PCR assays. SGTF can be used as a
N679K, proxy marker to screen
P681H, for Omicron.
N764K,
D796Y,
N856K,
Q954H,
N969K,
L981F
(continued)
Table 1. Continued.
Variant Variant WHO Country of Origin Spike protein
name classification label /Detection date substitutions Attributes
B.1.525 VOI Eta United Kingdom/Nigeria A67V # Susceptibility to EUA monoclonal
December 2020 69del antibody treatments
70del
144del # Neutralization to convalescent &
E484K post-vaccination sera
D614G
Q677H
F888L
B.1.526 VOI Iota United States/ L5F # Susceptibility to bamlanivimab/
November 2020 D80G etesevimab monoclonal antibody
T95I treatments
Y144-
F157S # Neutralisation to convalescent &
D253G post-vaccination sera
L452R
S477N
E484K
D614G
A701V
T859N
D950H
Q957R
B.1.617.1 VOI Kappa India/ T95I # Susceptibility to EUA monoclonal
December 2020 G142D antibody treatments
E154K
L452R # Neutralization to post-
E484Q vaccination sera
D614G
P681R
Q1071H
C.37 VOI Lambda Peru/ G75V Unclear data on transmissibility
August 2020 T76I
D246-252
L452Q
F490S
D614G
T859N
B.1.621 VOI Mu Colombia/ R346K " Transmissibility
January 2021 E484K
N501Y " Susceptibility to infection
D614G
P681H
P.3 VOI Theta Philippines/ E484K " Transmissibility
January 2021 N501Y
D614G " Susceptibility to infection
P681H
right sample and right time [12] as the viral nucleic of post-symptom infection (89%) and drops to nearly
acid/antigen/antibodies detection varies at different 54% at day 10 to 14. Real-time PCR technology is
time points during the infection [13]. based on detecting the presence of specific viral RNA
belonging to the viral Envelope, Nucleocapsid, Spike
and ORF1ab regions. Therefore, viral mutations can
2.1. Nucleic acid-based detection of SARS-CoV-
potentially alter the accuracy of this method, leading
2 infection
to unpredictable test performances and false-negatives
Nucleic acid-based detection is now widely used for [15]. However, such challenges could be overcome
clinical identification of SARS-CoV-2 infection. through the use of multi-target assays [14–17]. In add-
Nasopharyngeal swab samples are considered to be ition, studies are now also developing specific primers
the most reliable source for these assays, offering to enable the rapid detection of VOCs through real-
highest sensitivity (97%) as compared to samples time PCR; For example, a particular group reported
obtained from other sources like saliva (85%), nasal the development of PCR primers for the rapid detec-
swabs (86%) and throat swabs (68%) [14]. Further, the tion of the key mutations in the spike protein of the
viral RNA load is usually highest between 0 and day 4 most recent omicron variant, thus enabling it to be
distinguished from other SARS-CoV-2 variants [18]. 2.2. SARS-CoV-2 antigen and immuno-assay-based
Another study also described the development of two detection of SARS-CoV-2 infection
new PCR- based tests to identify and differentiate the
Antigen-based immuno-assays such as immunofluores-
VOCs from regular strains of SARS-CoV-2. These tests
cent assays, immunochromatographic assays, chemilu-
are claimed to be comparatively simpler and more
minescent immunoassays, and Enzyme Linked
rapid than the gold standard methods of genome
Immunosorbent Assays (ELISA) are also reliable meth-
sequencing [19]. The group also claims that these tests
ods for the detection of SARS-CoV-2 infections. These
show a strong and reliable correlation to the results commercially available kits are usually compatible with
obtained through genome sequencing. Apart from a variety of clinical specimens like nasopharyngeal
these, other groups have also reported the develop- swabs, nasal swabs, and saliva and mainly detect the
ment and use of similar PCR-based tests for detection presence of two main SARS-CoV-2 antigens (S and N
of novel VOCs [20,21]. proteins) [28]. However, the success rate of these
In addition, loop-mediated isothermal amplification assays is largely dependent on factors such as disease
(LAMP) has also been developed as a rapid, robust stage and viral load (1–3 days before to 5–7 days after
and cheap technique that is now considered as a reli- the onset of symptoms). To address these issues,
able alternative to traditional RT-PCR-based diagnosis research on incorporating novel sensor and biosensor
[22]. Interestingly, using LAMP, expensive equipment technologies, to enhance the sensitivity of these anti-
like thermocyclers may be eliminated thereby high- gen-based immunoassays is currently ongoing. [13].
lighting the portability of such rapid tests. Moreover,
this technique is also highly specific as it uses about
6–8 specific primer sequences to identify eight differ- 2.3. Anti-SARS-CoV-2 antibody-based detection of
ent regions of the target [13]. Further, Clustered SARS-CoV-2 infection
Regularly Interspaced Short Palindromic Repeats In contrast with nucleic acids and antigen-based
(CRISPR) is another novel technology that follows the detection techniques, antibody-based techniques are
principle of lateral flow assays. This assay is known to not considered suitable for the early detection of
target the E and N genes of SARS-CoV-2. The CRISPR- SARS-CoV-2 Infection. This is due to the fact that anti-
Cas13 assays are known to have a sensitivity of body responses are often generated nearly two weeks
greater than 95% and specificity of nearly 99% [23] post-infection; a time-point at which viral nucleic acid
In addition, microarray-based technology is also and antigen levels begin to decline [12]. Various bind-
currently being used to detect viral RNA. Here, ing assays like immunofluorescence, immunochroma-
labelled cDNA molecules synthesized from viral RNA tographic, chemiluminescence assays and ELISA are
hybridized with solid-phase oligonucleotides on the used for the detection of antibodies generated specific
surface of an array plate are quantified with the help to the SARS-CoV-2 viral antigen. Most of these kits tar-
of a microarray plate reader [24]. get the antibodies generated against the viral S and N
Next-generation gene sequencing (NGS) methods proteins. Various easy-to-use kits are now available
are also common for the detection of viral presence that are based on measuring the ratio between the
and helps in understanding the epidemiology of immunoglobulin M (IgM) and immunoglobulin G (IgG)
SARS-CoV-2 virus. However, although NGS platforms in the blood. [28]. In addition, humoral immune
are accurate and reliable, their practical application is responses to SARS-CoV-2 can also be detected using
often limited due the involvement of higher costs and simple blotting systems [29]. These are often auto-
expertise [13]. However, whole-genome sequence mated rapid capillary-based platforms through which
remains to be the gold standard for the detection of the reactivity of human IgGs (in serum or plasma sam-
emerging VOCs across the globe. Apparently, since ples) against five key SARS-CoV-2 viral antigens [29].
this method is more prolonged and laborious, many Evidently, the constant development of newer and
studies have come up with faster and similarly robust improved methods for the detection of novel VOCs is
PCR melting temperature assays that are largely com- of primary importance to keep pace with their rapid
parable to genome sequencing [25,26]. Interestingly, emergence. This will also play a key role in monitoring
another group has also reported the development of and curbing the spread of the new variants.
alternate sequencing platforms based on Sangers
sequencing of a single PCR fragment that is capable
of identifying and distinguishing all SARS-CoV-2 VOCs
that have been identified so far [27].
3. Advancements in COVID-19 preventive & the cytokine storm release that is a hallmark of particu-
therapeutic strategies larly critical COVID-19 infections [30,45]. These monoclo-
nal antibodies function by antagonizing both
3.1. Antiviral and immunomodulatory drugs
membrane-bound and soluble interleukin-6 receptors
Current treatment options for COVID-19 are apparently [44], thereby resulting in the blocking of the down-
stratified into two categories; being either antivirals or stream signal transduction that induces the cytokine
immune modifiers [30]. In the case of antiviral drugs, release syndrome [46]. Moreover, the clinical trials of the
Remdesivir has gained sufficient recognition for its Randomized, Embedded, Multi-factorial, Adaptive
ability to contain and manage the viral load and was Platform Trial for Community-Acquired pneumonia
approved by FDA for the treatment of COVID-19 (REMAP-CAP) showed that Tocilizumab and Sarilumab
patients with pneumonia concurrent with the shortage improved survival rate and reduced mortality in hospital-
of oxygen supply [30]. It is a broad-spectrum adeno- ized Covid-19 patients by 28 and 22.2% respectively,
sine nucleotide analogue and phosphoramidate pro- when administrated within 24 h of entering intensive
drug that can target a wide range of viruses includes care units (ICUs) [30,44,47]. According to the NHS guid-
coronaviruses. The drug mainly functions through the ance, both drugs are advocated for the treatment of
inhibition of replication in the respiratory-associated hospitalized Covid-19 patients in ICUs [47].
epithelial cells [31]. According to a recent report, Further, Casirivimab with Imdevimab forms a unique
remdesivir triphosphate, being the active form of monoclonal antibody cocktail named REGEN- COVTM.
Remdesivir, resembles the RNA of the coronavirus. These antibodies bind non-competitively to the SARS-
Therefore, it is easily integrated into nascent viral RNA CoV-2 spike protein, thus being beneficial in targeting
strands resulting in halting of viral genome replication the novel mutant SARS-CoV-2 variants and lowering
[32]. In addition, another study showed that a combin- chances of their immune escape [48]. Results of the
ation of remdesivir with baricitinib worked better in phase 3 trial showed that REGEN-COVTM decreased hos-
reducing recovery time of hospitalized patients with pitalization or death by 70% in non-hospitalized Covid-
COVID-19 pneumonia [33]. Baricitinib is a Janus 19 patients. In addition, it has also been approved by
kinase–STAT signalling inhibitor (JAK-STAT) that pos- the FDA for the treatment of mild to moderate cases in
sesses antiviral and anti-inflammatory action through adults and paediatric Covid-19 patients and in patients
the inhibition of clathrin-mediated endocytosis and at high risk of disease severity [48].
controls the elevation of cytokine levels. [34].
Moreover, certain anti-HIV drugs like lopinavir and 3.1.1. Efficacy of SARS-CoV-2 antiviral drugs on the
ritonavir that target RNA viruses (retroviruses) were emerging VOCs
reported to improve the symptoms of patients with SARS In the wake of the recent emergences of new SARS-
[35]. Therefore, they were evaluated for their potential use CoV-2 variants, it has become increasingly important
as a therapeutic agent against COVID-19. However, to evaluate whether the current therapeutics still
according to a certain report, no benefit was observed maintain efficacy against the novel variants. In fact,
with lopinavir–ritonavir treatment beyond standard care several in-vitro studies were conducted to assess the
in adult patients hospitalized with severe COVID-19 [36]. efficacy of remdesivir against new COVID- 19 variants
Similarly, chloroquine, a drug whose sulphate and phos- and more importantly to determine whether these
phate salts have been commercialized as anti-malarial VOCs expressed mutations in the RNA- Dependent
drugs was also shown to be effective against SARS-CoV-2 RNA Polymerase (RdRP) protein sequence, which is the
infections according to a few studies [37–40]. However, a main target of remdesivir. A recent study conducted
recent trial proved that post-exposure hydroxychloro- on the B.1.1.7 and B.1.351 variants proved that both
quine therapy did not prevent SARS-CoV-2 infection in variants presented a low genetic variation in the RNA
healthy individuals exposed to an infected patient [41]. In replication complex and the most frequent observed
addition, other studies have also discredited protease substitution was Nsp12 P323L. However, this substitu-
inhibitors like lopinavir and ritonavir and chloroquine to tion was not located near the polymerase active site,
model potent anti-SARS-CoV-2 therapy [42,43]. thus did not affect the inhibition function of remdesi-
Recently, two monoclonal antibodies, Tocilizumab vir [49]. In addition, according to Lee et al. the amino
and Sarilumab used as anti-inflammatory drugs for acid sequences of the B.1.1.7 and B.1.351 VOCs were
rheumatoid arthritis [44] have been repurposed for their found to possess numerous mutations in the spike
use against SARS-CoV-2 Tocilizumab was approved as an protein, when compared to the early SARS-CoV-2
immunotherapy drug by FDA for the treatment against strains [50]. However, the amino acid sequence of
NSP12, (which possesses RdRp activity), remained to central immune cells via enhanced antigen presenta-
be highly conserved among both the early and novel tion and uptake by the antigen presenting cells [59].
variants [50]. Moreover, Showers et al. also reported The safety and immunogenicity of NVX-CoV2373
no difference in the antiviral efficacy of remdesivir was initially tested in a nonhuman primate (baboons
between early SARS-CoV-2 and these new variants and cynomolgus macaque) and mice models.
[51]. Furthermore, another study that analyzed the Preliminary results showed that the vaccine elicits a T
protein sequence of RdRp among SARS-CoV-2 emer- cell and B cell response, induces a high titre of anti-S
gent variants show a high conservation in remdesivir- IgG and SARS-COV-2 neutralizing antibodies and pro-
binding residues [52]. Therefore, these reports indicate tects the upper and lower respiratory track from virus
towards the lack of evidence stating the resistance to infection and pulmonary disease [57,60]. Subsequently,
remdesivir induced by the VOCs. Phase 1-2 clinical trial were conducted to evaluate the
Similarly, molnupiravir, a recently FDA approved safety and immunogenicity of SARS-CoV-2 recombin-
antiviral drug against SARS-CoV-2 infection is also ant S nanoparticle vaccine on humans with or without
known to function through targeting the viral poly- Matrix-M adjuvant [58]. The outcomes of these trials
merase and misdirecting it to incorporate adenosine indicated that the vaccine has a reassuring safety pro-
or guanosine during viral replication, thereby leading file and is capable of inducing a robust humoral and T
to an accumulation of deleterious errors eventually cell immune response [61]. Moreover, the levels of
rendering the virus non-infectious [53–55]. Therefore, neutralizing antibodies and anti-S IgG detected in vac-
since reports have proved that the sequences respon- cinated participants was indeed found to be 4 times
sible for viral RdRp activity remains to be conserved in higher than those observed in symptomatic COVID-19
early and novel SARS-CoV-2 variants, it is unlikely that outpatient sera [61]. In addition, this vaccine also indu-
the novel VOCs could interfere in the activity of such ces a predominant CD4þ T cell response characterized
antiviral drugs. Moreover, other reports also advocate
by high production of IFN-c, IL-2, and TNF-a.
the unrestricted use of the recent FDA approved
Currently, phase 3 trials are ongoing in 5 different
Paxlovid antiviral drug against the existing VOCs and
countries (United Kingdom (UK), Northern Ireland,
especially the most recent omicron variant [56].
Mexico, Puerto Rico and United States of America)
Therefore, in the light of the above knowledge it may
[62]. However, preliminary data from the UK indicates
be safe to state that the activity of such antivirals may
that the efficacy of NVX-CoV2373 is estimated at
remain unhindered against the emerging VOCs.
89.7% among different subgroups including partici-
pants with comorbidities, with no hospitalization or
3.2. Covid-19 vaccines deaths reported in vaccinated individuals [63].
In addition to the above elucidated drugs vaccines Interestingly, the same study indicates that NVX-
remain the cornerstone of prevention and protection CoV2373 has a strong efficacy (86.3%) against the UK
against infection. Below we discuss the development, variant (B.1.1.7) [63].
formulation, working mechanisms, advantages, and
challenges of some of the most used vaccines world- 3.2.2. Adenovirus vector-based vaccines
wide (Figure 2). In addition, we also provide an over- 3.2.2.1. ZD1222. The AZD1222 (Oxford-AstraZeneca) is
view of the ongoing trials and cutting-edge research a recombinant adenovirus-based SARS-CoV-2 vaccine
focussed on vaccine efficacy and safety. constructed from the replication-deficient simian chim-
panzee adenovirus vector (ChAdOx2) expressing the
3.2.1. Protein subunit vaccines NVX-CoV2373 full- length SARS-COV-2 spike glycoprotein [64].
NVX-CoV2373 (Novavax) is a SARS-COV-2 subunit vac- Chimpanzee vectors are highly suitable for the devel-
cine constructed from the full-length SARS- COV-2 opment of human vaccines due to their high immuno-
spike glycoprotein and is produced in the established genicity and genome stability that prevents the
baculovirus-Spodoptera frugiperda (Sf9) insect cell deletion or mutation of foreign genes [65]. These vec-
expression system [57]. This vaccine is formulated tors have been tested in clinical trials of 5000 vaccines
through the use of nanoparticles containing trimeric (including vaccines for Ebola, malaria, HIV and Crohn
full-length SARS-CoV-2 S glycoprotein adjuvant with disease [66] in which their efficacy to induce a potent
saponin based Matrix-M [58]. Studies have shown that CD8þ T cell and antibody responses even with a sin-
this Matrix-M can enhance immune responses by pro- gle dose of the vaccine was reported. [67,68]. In par-
moting the recruitment, activation, and maturation of ticular, the chimpanzee adenovirus vectors are safe as
Figure 2. The figure explains about the different COVID-19 vaccine platforms, the immune response to the vaccine and the pro-
tective immune response during the post-vaccination infection. (A) Different COVID-19 vaccine platforms. a. DNA vaccine in which
SARS-CoV-2 spike open reading frame (ORF) is cloned into a plasmid DNA which will be injected intramuscularly; b. Viral vector
platforms in which, the spike protein ORF is cloned into adenovirus genome to form an infectious recombinant virus which will
be injected intramuscularly; c. mRNA vaccine, in which SARS-CoV-2 spike mRNA is chemically synthesized and enclosed with lipid
nanoparticles then it is injected into human body; d. Protein vaccine in which total or subunit part of spike protein is mixed with
specific adjuvant before being injected into human system; e. Inactivated virus vaccine whereby SARS-CoV-2 virus is chemically
inactivated, mixed with specific adjuvant then injected intramuscularly. (B) Immune response to the SARS-CoV-2 vaccine: Once in
the human body, the different vaccine platforms will synthesize or deliver SARS-CoV-2 total or subunit spike protein which will
induce specific memory immune response against SARS-CoV-2 virus. (C) SARS-CoV-2 virus neutralization during post-vaccination
infection. 1. If an infection occurs after vaccination, anti-SARS-COV-2 antibodies bind to the SARS-CoV-2 virus and inhibit its
attachment to the host cell. 2. Antibody Dependent Cellular Cytotoxicity: The anti-spike antibodies recognize the spike antigen on
the infected cells. Four major immune effector cells (neutrophils, eosinophils, macrophages, and NK cells) will recognize the cell
bounded antibodies and infected cells and the killing is achieved by cytolytic processes. 3. The memory T cells are quickly con-
verted into cytotoxic T cells and eliminate the infected cells.
they avoid issues with pre-existing immunity to arterial and venous thromboses occurring within days
human adenoviruses. to weeks after vaccination [73]. According to the
The AZD1222 vaccine has been approved by the European Medicines Agency (EMA), the number of
WHO and is used now in 102 countries [69]. Clinical trials thromboembolic events in vaccinated people is no
tested on over 60,000 adult participants (aged higher than the numbers seen among the general
18–55 years) in UK, Brazil, South Africa, Kenya, the USA, population [74]. However, rates for venous thrombo-
India and Japan show that the vaccine has a well-toler- embolism events observed 28 days after vaccination in
ated safety profile with no serious adverse events related Denmark were higher than the expected incidence
to the vaccine [70]. After the second dose, most partici- rates among the general population (50 versus 30)
pants were shown to elicit neutralizing antibody [75]. Altogether, the safety, immunogenicity, and effi-
responses correlating strongly with anti-spike IgG anti- cacy outcomes of the AZD1222 vaccine are reassuring
body levels [64,71]. However, the Phase 3 clinical trial but these side effects need to be investigated through
interim results from the USA showed that the efficacy of a large-scale study in different populations to further
the vaccine could vary according to the immunization understand its utility.
regimes (1 or 2 doses) and the length of the interval
between the doses (12 or 6 weeks). Such findings sup- 3.2.2.2. Gam-COVID-Vac. Gam-COVID-Vac (Sputnik V)
port the recent decision in the UK to prioritize use of a is a heterologous adenoviral vector based vaccine
12- week interval between doses [72]. against SARS-CoV-2 constructed from two vector com-
Recently, several European countries suspended the ponents, recombinant adenovirus type 26 (rAd26) and
use of the AZD1222 vaccine due to reports linking it recombinant adenovirus type 5 (rAd5) carrying both
to episodes of thrombocytopenia, bleeding, and the SARS-CoV-2 full-length glycoprotein S gene
(rAd26-S and rAd5-S) [76]. Recombinant adenoviruses mRNA vaccines was found to be effective against sev-
have been widely used for vaccine development such eral viral infections. It has been reported that mRNA
as hepatitis B, Ebola virus, RSV, HIV and Zika vaccines vaccines are able to induce potent innate and adap-
with an excellent safety profile confirmed in many tive immune reactions against Rabies, Zika and
clinical studies [77–80]. Moreover, recombinant adeno- Influenza A infections in animal models and in humans
virus vectors elicit robust long-lasting immune [87–90]. Therefore, it is not surprising that mRNA vac-
response without the need of adjuvant after one or cines have now emerged as an effective preventive
two doses of vaccine [81,82]. The use of 2 different strategy against SARS-CoV-2 infections. This technol-
viral vectors will help to overcome any prior anti- ogy is based on the principle that mRNA is an inter-
adenovirus immunity in the body that may destroy mediate messenger that can be easily delivered into
the vector of the second dose [83]. host cells and translated into antigen of interest that
Phase 1/2 clinical trials were conducted to assess will trigger a protective antigen-specific immune
safety and immunogenicity of two formulations (fro- response in the human body. Within a year from the
zen and lyophilized) of this vaccine on 76 healthy onset of the COVID-19 pandemic, two mRNA vaccines,
adult volunteers aged between 18 and 60 years [76]. namely, BNT162b2 (Pfizer-BioNTech) and mRNA-1273
In Phase 1, participants received a single intramuscular (Moderna biotechnologies Inc.) were approved by the
dose of rAd26-S or rAd5-S on day 0 [76]. However, in FDA for emergency use as a prevention against SARS-
phase 2, which began no earlier than 5 days after the CoV-2 infection.
phase 1 vaccination, participants were administrated a Both vaccines, BNT162b2 and mRNA-1273, carry a
single intramuscular dose of rAD26-S on day 0 fol- nucleoside-modified messenger RNA encoding the
lowed by another dose of rAD5-S on day 21 [76]. full-length SARS-CoV-2 spike protein (S) stabilized in
Preliminary data from the phase 1 trials show that no the pre-fusion conformation and formulated in lipid
severe adverse reactions were detected in participants nanoparticles (LNPs). These LNPs form a solid lipid
after vaccination [76]. Also, the frozen formulation was complex that encapsulate and stabilize the mRNA and
found to be induce a higher IgG titre (14.703 versus promotes its intracellular uptake [88,91]. While both
11.143) and neutralizing antibodies (49.25 versus vaccines are administered intramuscularly in two
45.95) while eliciting higher CD4 (2.5 versus 1.3) and shots, the second dose is administered after 21 days
CD8 (1.3 versus 1.1) T cell proliferation rates as com- for BNT162b2 and 28 days for mRNA-1273.
pared to the lyophilized formulation indicating the fro- Phase III clinical trials have demonstrated that
zen formulation to be more effective than the BNT162b2 and mRNA-1273 vaccines have exhibited
lyophilized one [76]. more than 90% protection efficacy in people with no
Phase 3 clinical trials were performed on a larger prior known infection [92–95]. In fact, Polack et al.
scale (nearly 22,000 adults aged at least 18 years) [84]. demonstrated that the BNT162b2 vaccine conferred
Participants received 2 doses of the vaccine (dose 1 95% protection against COVID-19 in persons 16 years
rAD26-S and dose 2 rAD5-S) or a placebo, 21 days apart of age and older, with only mild adverse effects that
[84]. Results of this phase showed that the vaccine effi- were similar to those observed with other known viral
cacy was estimated at 91.6%. In addition, 94% of the vaccines (short-term fatigue, headache, mild-to-moder-
participants presented mild adverse reactions, while a ate pain at the injection site) [93]. Moreover, the COVE
minority (less than 0.5%) exhibited severe adverse events study group in the USA has reported that the mRNA-
[84]. Though four deaths were reported among partici- 1273 vaccine has presented 94.1% efficacy in prevent-
pants, the cause of death was linked to the vaccine but ing COVID-19 illness with no patterns of safety con-
rather to severe comorbidities [84]. Interestingly, a recent cerns [92]. In another recent study, Thompson et al.
study showed that sera from a donor vaccinated with have shown that, for both mRNA vaccines, full immun-
Gam-COVID-Vac efficiently neutralized the spike protein ization with 2 doses of vaccine provides 90% effective-
from B.1.1.7 and B.1.351 strains [85]. This data suggest ness against COVID-19 at 14 days following the
that this vaccine may offer protection against different second dose [96]. However, while the mRNA-1273 vac-
SARS-CoV-2 variants. cine is only approved for use in people aged 18 years
and older, the BNT162b2 vaccine has been recently
3.2.3. mRNA vaccines granted authorization by the FDA to be used in ado-
Since more than a decade, mRNA based therapeutics lescents aged 12 to 15 years old [97]. Moreover, recent
have raised major interest in cancer and infectious dis- studies have reported that the BNT162b2 vaccine pro-
eases likewise [86]. Particularly, immunization through vides strong protection (95%) against the COVID-19
variants detected in the United Kingdom (B.1.1.7) and diseases including influenza, poliomyelitis and human
South Africa (B.1.351) [98,99]. Interestingly, a pre-print papillomavirus infections [104–106]. In comparison to
report has revealed that the effectiveness of other whole pathogen-containing vaccines, such as
BNT162b2 was reduced to 87.9% with the B.1.617.2 live attenuated virus vaccines, the use of inactivated
COVID-19 variant that has lately emerged in India virus vaccines pose fewer safety concerns, since the
[100]. As for the mRNA-1273 vaccine, further studies pathogen cannot revert to its original state and cause
are needed to confirm its effectiveness against the diseases in immunocompromised individuals [107].
emerging COVID-19 variants. Moreover, since they contain the killed pathogen, they
Evidently, the immunogenic potential of COVID-19 can be easily stored and shipped.
mRNA vaccines have already been documented According to WHO’s draft landscape of SARS-CoV-2
through various preclinical and clinical trials candidate vaccines, 12 inactivated virus vaccines (14%)
[89,92,93,101]. Interestingly, a phase I clinical trial on are currently in the clinical phase testing. For instance,
47 participants demonstrated that the mRNA-1273 pharmaceutical companies like Sinovac and
induces a robust immune response which was time Sinopharm, both arising from China have produced
and dose-dependent [101]. Additionally, while CD4 T inactivated viral vaccines that are currently in phase 3
cells expression was upregulated in response to the and 4 of clinical trials respectively [108].
vaccination, only low level of CD8 T cells were
detected at the highest tested concentration and after 3.2.4.1. COVID-19 vaccine (Vero cell) inactivated.
the second vaccination dose [101]. Moreover, another COVID-19 Vaccine (Vero Cell) Inactivated (CoronaVac
study showed that BNT162b2 induces a broad (formerly PiCoVacc)) developed by Sinovac Biotech
immune response with SARS-CoV-2 spike-specific neu- Ltd, is an inactivated SARS-CoV-2 (CN2 strain) vaccine
tralizing antibodies and poly-specific CD4þ and CD8þ adjuvant containing aluminium hydroxide (Al (OH)3)
T cells [102]. Interestingly, the same study has and is administrated through a two-dose regimen
reported a strong memory T cell response up to nine (3 mg at day 0 and 28). The virus was extracted from
weeks after the booster dose [102]. the bronchoalveolar lavage fluid (BALF) of 11 infected
Apparently, in comparison to other approved vac- patients, cultured in a large- scale Vero cells factories,
cines platforms, mRNA-based vaccines have several inactivated with b-propiolactone for 24 h, purified with
advantages. For example, in the situation of a wide- Ion-Exchange Chromatography (IEC) and Size exclusion
spread global pandemic such as COVID-19, mRNA vac- Chromatography (SEC) methods and finally adsorbed
cine production is rapid and can be manufactured on onto an aluminium hydroxide adjuvant [109]. The vac-
larger scales at relatively lower costs. Moreover, mRNA cine’s safety evaluation has been performed in rhesus
vaccines are considered safe since they do not contain macaques (Macaca mulatta) monkeys that are known
the full pathogen (unlike vaccines integrating live-vec- to mimic COVID-19-like symptoms after SARS- CoV-2
tors or inactivated viruses), and do not carry the viral infection [110]. Preclinical results using two doses
DNA material that might be associated to genotoxic (3 mg and 6 mg) with two immunization schedules (at
concerns (like DNA-based vaccines) [88,103]. days 0 and 14 or days 0 and 28) indicated extensive
However, the major problem with mRNA vaccines is evidences for safety and efficacy, with a complete pro-
the stability of the formulation since they require a tection against COVID-19 infection.
strict temperature control for shipment and storage to In April 2020, the COVID-19 Vaccine (Vero Cell)
avoid the degradation of the mRNA. Moreover, the Inactivated vaccine entered its phase I clinical trial
induced activation of the immune system would with 144 healthy participants aged between 18 and
potentially lead to side effects associated with 59 years old. In most subjects, antibody seroconversion
enhanced inflammatory processes. Therefore, although was slightly higher than 75%. These results have been
mRNA vaccines project a powerful strategy to contain improved to more than 95% in 600 participants
the COVID-19 outbreak, more studies are needed to enrolled in phase 2 clinical trials [111], with no signifi-
confirm the long-term effectiveness and safety of cant side effects reported . Similar results have been
these vaccines. reported in healthy participants older than 60 years
old [112]. These results supported the extension of the
3.2.4. Whole virus vaccines study to phase III clinical trial using a two-dose regi-
Historically, whole viral inactivation is one of the old- men (3 mg at day 0 and 28). The clinical trials have
est strategies that have been successfully used to pro- been launched in seven countries including Brazil,
duce vaccines to prevent/treat a variety of viral Indonesia, Turkey, China,
Philippines, Hong Kong, and Chile. Furthermore, and 100% effective against severe cases [121]. In add-
two randomized double-blinded placebo control stud- ition, UAE previously announced interim results showing
ies have been performed in Brazil and Turkey to deter- that the vaccine provided 86% efficacy [122].
mine the efficacy of the vaccine. These trials Additionally, Sinopharm has started a phase III trial in
demonstrated that the COVID-19 Vaccine (Vero Cell) several countries in Africa [123,124], Asia and Europe
Inactivated efficacy rate for COVID-19 prevention was [125]. Reports from a randomized, double blind, placebo
up to 53% in Brazil and 83% in Turkey [113,114]. In parallel-controlled phase III clinical trial in Argentina
addition, these studies also report that vaccination showed that the vaccine portrayed a lower effectiveness
with COVID-19 Vaccine (Vero Cell) Inactivated induces (79%) as compared to other approved COVID-19 mRNA
a humoral response 28 days post-vaccination i.e. 97% vaccines. However, this vaccine has an advantage stor-
neutralizing antibodies against SARS-COV-2 and 99% age and shipment protocols at regular refrigeration
against RBD-IgG [111,112]. Although only a small num- temperatures.
ber of studies have been published for the COVID-19
Vaccine (Vero Cell) Inactivated vaccine, very few cases 3.2.5. Efficacy of COVID-19 vaccines on the emerg-
of hypersensitivity, including severe allergic reactions ing VOCs
(0.009%) have been reported [115,116]. Given the alarming frequency of the emergence of
SARS-CoV-2 variants, the efficacy of the existing vac-
3.2.4.2. Covilo; BIBP-CorV. Covilo; BIBP-CorV cines remains in question. In the light of this, it may
(Sinopharm BIBP COVID-19 vaccine) is one of two inac- be encouraging to state that in addition to the gen-
tivated virus COVID-19 vaccines developed by eral public, even patients with co-morbidities like can-
Sinopharm. Few studies have investigated the cer and other immuno-compromised individuals like
immunogenicity and efficacy of BBIBP-CorV. The first solid organ transplant recipients (SOTRs) have also
study on BBIBP-CorV has showed that the vaccine shown the development of neutralizing antibodies
induces high levels of neutralizing antibodies in six upon vaccination with most conventional vaccines, as
mammalian species including mice, rats, guinea pigs, discussed in the following reports. According to cer-
rabbits, and nonhuman primates (cynomolgus mon- tain studies, SOTRs may be more commonly associated
keys and rhesus macaques). Interestingly, this study with breakthrough disease despite being fully vacci-
reported that two doses of immunization of BBIBP- nated as compared to the general population
CorV at 2 mg/dose, is able to provide high protection [126,127]. Other studies have also reported that most
against SARS- CoV-2 without detectable antibody SORTs often develop weak antibody responses against
dependent enhancement of infection [117]. In add- SARS-CoV-2 m-RNA vaccines [128–130]. However,
ition, all macaques in the low and high dose groups according to another subsequent study even such vul-
did not show a detectable viral load in any lung lobe nerable populations are reported to show an increase
at 7 days after inoculation of BBIBP-CorV. Also in com- in neutralizing antibodies against novel VOCs after the
parison to the AZD1222 vaccine, both vaccines were third dose of a
found to confer effective protection by preventing the SARS-CoV-2 vaccine [131]. In addition, the CAPTURE
development of viral interstitial pneumonia in all vac- study also reported the presence of neutralizing anti-
cinated macaques [118]. bodies against the novel COVID-19 VOCs in patients
Phase I (192 adults) and phase II (448 adults) clin- with both solid and hematological cancers, upon
ical trials for the BBIBP-CorV vaccine, have shown that immunization with the BNT162b2 or AZD1222 vaccine.
the vaccine is safe and well tolerated at all tested Although these studies report that the vaccination-
doses. Antibodies were elicited against SARS- dependent stimulation of an immune response against
CoV-2 in all vaccine recipients at 42 days after the the novel VOCs in such vulnerable populations is
second dose. These trials included individuals older than much lowered as compared to normal healthy individ-
60 that showed significantly high neutralizing antibody uals; yet these results are indeed promising and prove
titres [119]. Moreover, a particular report also stated that the potency of the currently available vaccines to
the vaccine had a low rate of adverse reactions and combat the existing and emerging VOCs.
showed high immunogenicity. Yet, however, long-term In addition, the utilization of computational
assessment of safety and efficacy would require phase III approaches to predict the impact of the VOCs on the
trials [120]. The first peer- reviewed data obtained in vaccines has also proven useful. For example, certain
United Arab Emirates (UAE) and Bahrain showed that computational approaches like epitope prediction that
BBIBP-CorV is 78.1% effective against symptomatic cases enables the identification of structural vaccinology
targets may also help in modelling the effects of the future [145]. Therefore, close monitoring of the novel
mutations in the spike proteins observed in the coronavirus is essential to keep the pandemic in check.
emerging VOCs [132,133]. Moreover, another study Finally, the greatest challenge of the current
has also provided a reliable model for epitope loss in COVID-19 pandemic is the transmission of the virus to
VOCs and their predicted escape from vaccine- healthcare workers. Studies report that although strin-
induced SARS-CoV-2 antibodies [134]. Such computa- gent isolation and quarantine measures are ensured at
tional approaches prove to be highly useful in foresee- medical facilities, yet human-to-human transmission of
ing the impact of the emerging VOCs on the efficacy the SARS-CoV-2 is highly common [146,147].
of COVID-19 vaccines. According to recent reports, nearly 41% of the
patients were found to be infected in hospital settings,
out of which 29% were medical staff [148]. Such trans-
4. Challenges mission in healthcare settings poses a very serious
Since the SARS-CoV-2 is a novel virus, its invasive threat and requires rigorous monitoring.
properties have not yet been well studied or under-
stood. However, some studies have highlighted a new 5. Conclusion
potential threat in the form of identifying the possible
neuro-invasive properties of the novel virus. For The outbreak of the COVID-19 pandemic has unques-
example, although the SARS-CoV and SARS-CoV-2 are tionably raised a major public health emergency all
both known to enter and infect host cells through over the world. The threatening concern is attributed
ACE2 expressed in the lung cells; according to some to the transmissibility of the virus and its capacity to
studies, ACE2 is not the only receptor that makes host rapidly evolve and mutate leading to the emergence
cells susceptible to viral infection. For example, human of new uncommon strains.
The leap in advancement of better diagnosis, tar-
endothelial and intestinal cells that express ACE2
geted vaccines and therapeutic remedies is sound evi-
failed to be infected by SARS-CoV in vivo [135,136] On
dence that scientific understanding, research, and
the other hand, cells with comparatively undetectable
technology is evolving at the pace of the pandemic.
levels of ACE2 (like hepatocytes) were found to be
Evidently, continued, and consistent research is
infected by SARS-CoV [137]. Likewise, SARS-CoV and
required to improve our knowledge of key aspects of
MERS-CoV are known to enter the central nervous sys-
the viral pathogenesis that can lead to enhanced pre-
tem where the ACE2 and DDP430 receptors are very
ventive and therapeutic strategies.
low [138]. Similarly, studies on patients have shown
the presence of SARS-CoV particles in the brain of
infected individuals thus supporting the neuro-invasive Acknowledgement
potential of this virus [139–141]. Since SARS-CoV and We acknowledge Qatar National Library for supporting the
the SARS-CoV-2 are like each other, it is possible that publication of this manuscript.
the latter may also possess such a neuro-invasive
potential. Furthermore, in the case of COVID-19, the
Author contributions
latency period may be sufficient for SARS-CoV-2 to
invade the CNS and destroy the medullary neurons QF, MM, SM, NT, DM, TB wrote the initial draft and VP pre-
pared the figures a graphical illustration. AR, critically revised
[138]. In support of this theory, some studies
and organised the manuscript. LZ, MOM, MAN, AA, HM, MB,
[4,142,143] have reported that a few of the COVID-19 SU and SD provided intellectual input and an overall review
patients did have mild neurologic symptoms like of the manuscript. All authors contributed to manuscript
headaches and nausea, while another recent study revision, read, and approved the submitted version.
reported that an estimated 88% of severe COVID-19
cases displayed neurologic manifestations such as Disclosure statement
acute cerebrovascular disease and impaired conscious-
No potential conflict of interest was reported by
ness [144].
the author(s).
The rapidly mutating virus has also emerged as a
matter of great concern. There is sufficient evidence to
state that the SARS-CoV-2 virus is capable of rapidly Funding
evolving to invade human immune responses as well as Open Access funding provided by the Qatar
gaining the ability to adapt to other hosts in the near National Library.
ORCID viral detection using a commercial reverse transcrip-

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ORCID viral detection using a commercial reverse transcrip-

Med. 2021;385(13):1172–1183. doi:10.1056/ randomized clinical trial in Uganda and Tanzania. J

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