American Journal of Translational Medicine Vol 5, Issue 4, December 2021.

ISSN 2474-7378 (P) & 2474-7386 (O)

REVIEW

Smarter virus of COVID-19, the Delta variant

B.1.617.2
Mudassar Iqbal Arain1, Xiangyang Liang2, Saira Shahanz3, Bazlah Khan Sherwani1,
Frederique Kandel4, Gang-Ming Zou4,5,6

A 1
Faculty of Pharmacy, University of Sindh, Jamshoro, Pakistan
J 2
Minnebio LLC, Saint Paul, MN 55114, USA.
T 3
Faculty of Pharmacy, Nazeer Hussain University, Karachi, Pakistan
M 4
School of Nature Science and Mathematics. Chaminade University. 3140 Waialae Ave, Honolulu, HI 96816. USA
5
School of Nursing and Dental Hygiene, University of Hawaii at Manoa, 2528 McCarthy Mall, Webster Hall 402
2 Honolulu, HI 96822, USA.
0 6
International Center of Translational Medicine, The First Affiliate Hospital, Gannan Medical University, Ganzhou,
2 Jiangxi, 34100. China
1
*Correspondence:
Gang-Ming Zou, PhD. School of Nature Science and Mathematics. Chaminade University. 3140 Waialae Ave,
Honolulu, HI 96816. USA. Email: gang-ming.zou@chaminade.edu

ABSTRACT
Pandemic of COVID-19 is still raging about the globe, with around 210 million of confirmed cases and more
than 4.4 million deaths across almost all countries. SARS-CoV-2 virus is considered as extremely
communicable and infective corona-virus, causing diseases. Variety of SARS-CoV-2 variants have been
reported worldwide. Among them, 4 variants of concern include Alpha, Beta, Gamma, and Delta. Currently,
the original virus strain was largely replaced by Delta variant, which became predominant. The current
review has highlighted the SARS-CoV-2 viruses and its few variants, focusing on their genomic structures
and viral proteins encoded. We also discussed their more fatality, rising transmissibility along with a drop of
vaccine activity against causative agent. We further explained the possible reasons for the change from the
structural points of view. This may help with developing better drugs and vaccines for preventing the
pandemic and treatment of the disease.
(Am J Transl Med 2021. 5 (4):182-189).

Keywords: SARS-CoV-2, RNA, Genome, ACE2, Spike protein.

(Manuscript received: 10/19/2021; accepted:11/19/2021; published: 12/01/2021)

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 American Journal of Translational Medicine Vol 5, Issue 4, December 2021. ISSN 2474-7378 (P) & 2474-7386 (O)
INTRODUCTION
The end of 2019 marked the era for the sequence of
continuous respiratory illness emerged with an
unrevealed source and lead to sudden loss of life in
Wuhan, China ((Lu et al., 2020). The samples prove
the evidence of a novel virus known as “severe acute
respiratory syndrome coronavirus 2” (SARS- CoV-2)
183
and it was literal cause of death as well as responsible
agent for series of pneumonia cases, confirmed after a
deep sequencing analysis (Huang et al., 2020). This
situation was considered as Pandemic and infectious
disease named as “COVID-19” by the World Health
Organization (WHO). The situation became worse
when COVID-19 rapidly spread out and almost all
countries were affected with the virus. Around
209,876,613 numbers of cases with confirmed
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 American Journal of Translational Medicine Vol 5, Issue 4, December 2021. ISSN 2474-7378 (P) & 2474-7386 (O)
diagnosis with COVID-19 with 4,400,284 deaths was
reported to WHO on August 20, 2021. Difficulty in
breathing or dyspnea, inability to taste or smell, muscle
ache or body ache, runny nose, headache, congestions,
fever, chills, diarrhea, nausea, vomiting, fatigue, sore
throat was the symptoms experienced after 2-14 days
of post exposure to the virus.
Viruses are genetically simple organisms. Viral
entity consists of protein shell named as capsid which
is genetic makeup of viral. Their DNA or RNA contain
either single or double strands in round circular or
linear shape. For replication, viruses need host and
without it cannot replication and not survive for long
period of time. For COVID-19, it has been stated that
it is a single-stranded RNA virus (Lu et al., 2020) and
when observed under an electron microscope it appears
with a crown like appearance, which is more likely to
appear due to the existence of glycoprotein spikes on
virus envelope (Perlman & Netland, 2009).
The genomic structure of SARS-CoV-2 is based on
RNA-based meta-genomic sequencing encoding 9860
amino acid and genome length is about 29,881 bp with
non-structural and structural proteins (Chen et al.,
2020). The structural components contain nucleo-
proteins and Glycoproteins as envelop (E) like spikes.
Non- structural entities are papain-like protease, RNA
dependent RNA polymerase and 3-chymotrypsin-like
protease (Jiang et al., 2020). The N-Terminus is the site
where S-Glycoprotein plus a signal peptide (amino
acid 1-13) is present with about 1273 amino acids. The
S1 subunit (14-685 residues) and the S2 subunit
(686-1273 residues) are respectively the two regions
which are accountable for membrane fusion and
receptor binding. The S1 subunit comprises of N-
Terminal Domain (14-305 residues) with a Receptor
Binding Domain (319-541 residues) along with Fusion
Peptide (788-806 residues) Hepta-peptide Repeat
Sequence, 1 (HRS1, (912–984 residues), HRS2 (1163–
1213 residues), TM Domain (1213–1237 residues) and
cytoplasm domain (1237–1273 residues) is observed in
S2 subunit of glycoprotein (Walls et al., 2020; Zhou et
184
al., 2020). The S protein of COVID-19 virus shares
98% sequence similarity with that from the bat
coronavirus RaTG13, with a furin cleavage site
between two units S1 and S2 in the COVID-19 virus
(Wu et al., 2020) (see Figure 1)
SARS-CoV-2 VARIANTS
It is believed by the researchers that the virus was first
detected and sampled in Wuhan, China is different
from a number of variants of SARS-CoV-2. However,
WHO has only listed the strains in the table as Variants
of Concerns due to an increase in fatality, rise in
transmissibility along with a drop of vaccine activity
against causative agent (Chen et al., 2020). The variant
which is gaining much attention nowadays is B.1.617.2,
identified in Maharashtra, India, also called as 21A,
labeled as Delta on 31 May, 2021 by WHO. Mutation
is present on the L452R on the spike protein that is
present in Epsilon Variants and some other mutations
as well which also have some functional consequences
for example T478K. This delta variant is highly
transmissible and is responsible for causing severe
disease, suggestive through preliminary studies (Jiang
et al., 2020) and is also responsible for displacing the
Alpha variants (B.1.1.7) and other existing variants
also known to have efficient quality of replication
compared with other alpha-variants. Both increased
transmissibility as well as immune evasion has proved
advantageous for more growth of the delta variant
which has been explained through a mathematical
modeling. The Delta variant are lesser complex and
less sensitive for neutralizing antibodies in sera when
tested in vitro. In accordance with the vaccine
breakthrough, 100 health care workers were tested in
three different centers of India. The test gave an
extraordinary result, summing up that delta variant had
capability to spread infections with more viral loads in
respiratory area and a greater transmission rate in
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 American Journal of Translational Medicine
health care workers. Increase virus activity and
neutralizing antibodies are responsible for dominance
of the delta variant. Severity of sickness was rare in
health care workers who received complete
vaccination. The Vaccine was introduced in early 2020
to overcome this deadly pandemic which showed a
significant decrease in the mortality rate. The
B.1.617.2 bears the D614G spike mutation (Walls et al.,
2020; Zhou et al., 2020).
B.1.167.1 was the first sub lineage discovered,
accelerating to B.1.167.2 with L452R spike mutation
(Wu et al., 2020). In United Kingdom, different
surveys were conducted in which delta variant was
accounting for more than 90% cases, and it was
concluded from the survey that symptoms of B.1.617.2
was a bit different when compared from the other
strains. The most common symptoms in patients who
were infected with delta variant was hyperthermia in
addition with runny nose, headache, sore throat. The
more serious symptoms associated with this variant
were hearing disorders, serious GI complains and
thrombosis plus gangrene. Results which were
obtained from Scotland, assessing about the
hospitalization, stated that unvaccinated individuals are
more prone towards hospitalization diagnosed with
delta variant when compared with alpha variant.
(Arora et al., 2021)
The “Fastest and Fittest” B.1.617.2 variant is
considered to have 1,000 times more viral load than
the infections caused by other variants, according to a
Chinese Study Report. The patients infected with delta
variant have more viral particles in their airways.
United States has reported rise in number of
hospitalizations, more prominently in the states where
delta variant is spreading quickly and vaccinated
individuals are less. “The Center for Disease Control
and Prevention (CDC)”, on July 16, 2021, reported that
35% hospitalization was increased, with 69.3%
increase in COVID-19 cases. The Director of the CDC,
Dr. Walensky considered this delta variant as “the
Pandemic of the unvaccinated” (Arora et al., 2021)
Vol 5, Issue 4, December 2021. ISSN 2474-7378 (P) & 2474-7386 (O)
In order to prevent hospitalization and death, studies
have showed that 2 doses of vaccines are effective but
levels of neutralization for vaccinated sera are more
contrary to alpha variant but less against delta variant
when compared to the original strain. New England
Journal of Medicine, conducted a study in which
neutralization activity of sera was tested specially from
those individuals who was previously infected with
SARS-CoV-2 but recovered from infection and fully
vaccinated with Moderna and Pfizer vaccines. The
results concluded that delta variant when compared
with Wuhan strain exhibited 2.9 times less vulnerable
to neutralization but all vaccination serum sample and
most convalescent serum sample showed neutralization
activity which was detectable. The study suggested the
immunity offered by the mRNA vaccines is somehow
retarded against delta variant (Arora et al., 2021).
Edara et al., (2021) conducted study by using a case
control study design for evaluating efficacy of vaccine
for the ailment caused by the delta variant in
comparison with alpha variant. The study organized in
United Kingdom clearly specified the results that there
was 88% effectiveness against the delta variant after 2
doses of the vaccines, and only 30.7% efficacy was
proven after the first dose, these results obtained were
below 50 % efficacy for COVID-19 vaccines,
specified by FDA. Different companies are looking
forward for different strategies for developing a
booster dose against B.1.617.2 for improving the
efficacy of vaccines. For instance, Pfizer is seeking for
FDA approval for its booster dose which will
ultimately show stronger neutralization against the
delta variant (Arora et al., 2021).
When scientist carried out different investigations
for testing the efficacy four monoclonal antibodies for
neutralization of delta variant, only Bamlanivimab was
unsuccessful to neutralize the delta variant
(Bamlanivimab monotherapy was not efficacious for
infections caused by B.1.617.2). Similar efficacy was
exhibited by other three antibodies in neutralizing the
virus. Similarly, antibodies, which was derived from
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 American Journal of Translational Medicine
COVID-19, recovered individuals and from the
persons who was vaccinated through BNT162b2, they
showed slight efficacy in neutralizing delta variant
(von Bartheld et al., 2021).
What makes delta variant dangerous in disease
transmissibility and severity? The ability of binding of
these variant shares ~73%–76% similarity in sequence
binding to ACE2 on the host cell surface through
which SARS-CoV-2 enter the host cells (Wan et al.,
2020). The receptor-binding motif of SARS-CoV-2
with direct contacts with ACE2 is comprised of eight
conserved residues Tyr449, Tyr453, Asn487, Tyr489,
Gly496, Thr500, Gly502, and Tyr505, while Leu455,
Phe456, Phe486, Gln493, Gln498 and Asn501 are
substituted (Ali & Vijayan, 2020). The affinity of
linkages of SARS-CoV-2 S protein and ACE2 is ~
10 nM, which is about tenfold higher than the
SARS-CoV S protein and ACE2 (Lan et al., 2020).
This change was related to five non-conserved residues
(Ali & Vijayan, 2020). Among them, SARS- CoV-2
residues Gln493 and Asn501 have more important
contribution to the great increase of binding affinity
due to their closer location to the viral binding hotspot
residues Lys31 and Lys353 on human ACE2.
SARS-CoV-2 residues Gln493 and Asn501 bind to the
hotspot residues stronger than SARS-CoV (Ali &
Vijayan, 2020; Wan et al., 2020). Alpha variant first
appeared in UK. The Alpha variant has 9 changes in
the spike-protein sequence. The mutation appears in
the RBD N501Y is closer to the Y41 and K353
remains at ACE2 protein. There is a pi-pi stack
between two aromatic rings of tyrosines and hydrogen
bonds between the phenolic oxygen on Y501 and two
NH2 group on K353 (Liu et al., 2021). The
hydrophobic interaction and hydrogen bonds
contribute to the overall binding affinity between RBD
and hACE2. The strong binding between two binding
partners can facilitates the virus entry in the cells of
hosts
The Delta variant is one 0f the most transmissible
SARS-CoV-2 variants, which is now spreading around
Vol 5, Issue 4, December 2021. ISSN 2474-7378 (P) & 2474-7386 (O)
the world (Scudellari, 2020). There are 7 mutations in
the spike protein. L452R and T478K contribute to the
RBD binding to human ACE2 and facilitate the viruses
entering the host cells. The locations of two mutations
in the RBD of Delta variant are highlighted in the
Figure The highlighted regions specifically showed the
location of two mutations in the RBD of delta variant
in the figure (Baral et al., 2020). The beta-sheet region
bearing residues 448-455 and 491-498 (Region 2),
highlighted with yellow, loop segments consisting of
residues 438-447 and 499-508 (Region 1), highlighted
in orange. Region 3 shows the receptor-binding loop
having residues 472-490 in purple. The sticks represent
the disulfide bond in the loop with mutations in the
delta variant. The mutation T478K has direct contact
with M82 and P84 of ACE2 through hydrophobic
interactions between Side chains as well as hydrogen
bonds in the Region 3 (Kim et al., 2021). The other
mutation L452R has no direct contact with ACE2, but
this mutation leads to the increase of the interactions
between two anti-parallel beta strands through
hydrogen bonding and a significantly salt-bridge
interaction between the R454 and D467 side chains in
the delta variant (Kim et al., 2021). The increased
interaction between the β strands enhances the stability
of the receptor-binding interface.
The main target for COVID-19 vaccines is the spike
protein and most serum neutralizing antibody
responses exhibited during infections are pointed at the
Receptor Binding Domain (RBD) of S protein.
Therefore, any mutation that leads to any
conformational change in S protein that are not
remembered by the former antibodies, immunity of
body which was previously developed against the
reference strain will not show any effectiveness against
the new variant. The point which should be taken into
account regarding the delta variant that it contains a
combination of “S Gene Mutation”, plus numerous
mutations in the RBD. RBD is basically a mutation
which is present near the Furin Cleavage site and any
excessive amounts of mutations in an exposed region
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 American Journal of Translational Medicine
of the N-terminal domain also called as “Antigenic
supersite” (Arora et al., 2021).
When tested, the re-grouping of disulfide bonds in a
different RBD site leads to loss of activity for all Abs
and the L452R is the variant responsible for lowering
the deactivating ability in multiple monoclonal Abs
tested. (Baral et al., 2020). After analyzing 118
antibody–RBD complexes, it was found to have beta
loop residue of Y473, A475, and E484 are commonly
affected by antibodies. However, the Delta Variant
has an increased distance between each antibody-
binding site and the receptor binding surface.
There are two domains of the spike protein S1 and
S2. The S1 is responsible for Virus-Cell attachment
while S2 is responsible for virus-cell fusion. After S1
binding to ACE2, the receptor binding subunit (SI) and
fusion subunit (S2) must split from each other at the
Furin cleavage site. The delta variant contains a proline
to arginine substitution near this cleavage site at the
position 681, more spike proteins are able to enter the
human cells when furin cleaves effectively and
efficiently. It is very surprising to know that 10% of S
proteins are present in the original strain, 50 % are
present in alpha and in delta greater than 75 % spike
protein exists. The mutation is principal factor for
transmissibility and viral infection. (von Bartheld et al.,
2021)
NTD-Antigenic Supersite is the region in the N-
Terminal Domain of S protein which is considered as
vulnerable to antibodies recognition and attack. There
are plenty of mutations occur in antigenic supersite
adding threonine to arginine substitution at position 19,
substitution at position 142 from glycine to aspartate,
deletions at position 156 and 157, substitution at
position 158 from arginine to glycine. Antigenic
supersites are absolute factors with accumulated
mutations to avoid detection from immune system.
(von Bartheld et al., 2021)
IN SUMMARY
Vol 5, Issue 4, December 2021. ISSN 2474-7378 (P) & 2474-7386 (O)
The pandemic of COVID-19 triggered many healthy
individual and caused various deaths and long-term
health complications for people who have survived the
disease. Although vaccines still appear to provide
protection against severe COVID-19, but they became
less effective as more variants emerged. Delta variant
is more common worldwide after it was first found in
India. The Variants of Concern have negative impact
on vaccine effectiveness and reduced neutralization of
the SARS-CoV-2 viruses. More research needs to be
done investigating the possible mechanism behind it.
Different companies are looking forward for different
strategies for developing a booster dose against
B.1.617.2 for improving the efficacy of vaccines.
There is also immediate demand to produce more
effective vaccines against the variants and new drugs
for the treatment of the disease.
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