












































Journal of Enam Medical College
Vol 11 No 2 May 2021

64

Editorial 

SARS-CoV-2 Variants and Vaccines: 
What We Learn and What We Can Forecast?

Received: 18 February 2021        Accepted: 28 March 2021
doi: https://doi.org/10.3329/jemc.v11i2.65187

The COVID-19 pandemic has had devastating health, 
social and economic consequences around the world. 
In the absence of effective medical countermeasures, 
preventing disease and minimizing the spread of 
infection has required exceptional public health 
measures. 

We are still dealing with COVID-19 and surprisingly 
not finished yet, despite the efforts of public health 
officials to curtail infections and the work done by 
scientists to provide vaccinations in record time. The 
increase in new cases around the world after a period 
of sharp decreases makes that much abundantly 
obvious.

The emergence of SARS-CoV-2 in late 2019 was 
followed by a period of relative evolutionary stasis 
lasting about 11 months. Since late 2020, however, 
SARS-CoV-2 evolution has been characterized by 
the emergence of sets of mutations, in the context 
of variants of concern (VOC), that impact virus 
characteristics, including transmissibility and 
immunogenicity, probably in response to the changing 
immune profile of the human population.1 There is 
emerging evidence of reduced neutralization of some 
SARS-CoV-2 variants by post vaccination serum; 
however, a greater understanding of correlates of 
protection is required to evaluate how this may impact 
vaccine effectiveness.

Coronaviruses have a novel exoribonuclease (ExoN) 
encoded in their genomes, which is correcting many 
of the errors that occur during replication.2 Genetic 
inactivation of the exonuclease in SARS-CoV 
increases mutation rates by 15 to 20-folds. The 
molecular basis of this CoV proofreading complex is 
being investigated as a possible therapeutic target 
for SARS-CoV-2. Importantly, nucleotide deletions, 
unlike substitutions, cannot be corrected by this 
proofreading mechanism, which is a factor that may 

accelerate adaptive evolution to some extent. 
The tremendous progress has been made with the 
authorization and deployment of vaccines and 
antibody therapies. These strategies are directed at the 
viral spike protein, but the emergence of viral variants, 
particularly in the S gene, threatens their continued 
efficacy.3 The mutations in the S gene, particularly 
those that affect portions of the protein that are critical 
for pathogenesis and normal function such as the 
receptor binding domain (RBD) or furin cleavage 
site or those that cause conformational changes to the 
S protein, are of the utmost interest. If these changes 
are not recognized by first-wave antibodies, these 
mutations may provide an avenue for the virus to 
escape from immunity to the original SARS-CoV-2 
strain.  
Initial reports that a mutation had been identified 
in the SARS-CoV-2 genome began circulating 
in March 2020, and by the end of June, D614G, which 
constitutes replacement of aspartate (D) with glycine 
(G) at the 614th amino acid of S protein, was found 
in nearly all SARS-CoV-2 samples worldwide. 
D614G has been found to enhance viral replication in 
human lung epithelial cells and primary human 
airway tissues by increasing infectivity and stability 
of virions.2

Additional research has suggested that the increased 
infectivity may be the result of enhanced functional 
S protein assembly on the surface of the virion. In 
addition, several other studies have reported that 
D614G may be associated with higher viral loads. 

According to the Centers for Disease Control and 
Prevention (CDC), deletion of amino acids 69 and 
70 in B.1.1.7 is likely to cause a conformational 
change in the spike protein. The creation of a Δ69Δ70 
deletion mutant via site-directed mutagenesis and 
lentiviral pseudotyping resulted in 2-fold higher 



May 2021J Enam Med Col Vol 11 No 2

65

infectivity than the WT (D614G background), 
indicating that this linked pair of amino acid deletions 
may improve SARS-CoV-2 fitness. Deletion of 
amino acid 144 in B.1.1.7 and amino acids 242-244 
in B.1.351 have also been associated with reduced 
binding capacity of certain neutralizing antibodies.

The first reported SARS-CoV-2 mutation, D614G, 
which has now become common to nearly all sequenced 
SARS-CoV-2 genomes worldwide, followed by analysis 
of key S protein mutations associated with SARS-
CoV-2 variants of interest (VOI) and VOC, including 
B.1.1.7, B.1.351, P.1., B.1.427/B.1.429, B.1.526 and 
multiple lineages of variants that contain mutations at 
amino acid position 677.4

The receptor binding domain (RBD) of S protein is 
comprised of amino acids 319-541. It binds directly to 
ACE2 receptors on human cells. Therefore, mutations 
in this portion of the genome are particularly significant 
to SARS-CoV-2 fitness and antigenicity.

Currently, there are four main types of COVID-19 
vaccine: nucleic acid (mRNA and DNA), viral vector, 
protein subunit, and inactivated virus. Two COVID-19 
mRNA vaccines (BNT162b2 developed by Pfizer-
BioNTech and mRNA-1273 by Moderna) have been 
authorized by the U.S. Food and Drug Administration 
(FDA) and European Medicines Agency (EMA). In 
addition, Ad26.COV2.S (Johnson & Johnson) was 
approved by the FDA and EMA and ChAdOx1 nCoV-
19 (AstraZeneca) was authorized by the EMA, both of 
which are viral vector vaccines.

Vaccination with various vaccine platforms, 
including mRNA and viral vectors, has been shown 
to elicit SARS-CoV-2-specific CD4+ and CD8+ T-cell 
responses. In principle, it is more difficult to evade 
T-cell responses than a neutralizing antibody response 
because multiple T-cell epitopes are scattered across 
viral proteins, whereas neutralizing antibody targets 
a narrow region in the viral protein. Although SARS-
CoV-2 mutations that abrogate binding to major 
histocompatibility complex have been reported, 
researchers reported an insignificant impact of 
SARS-CoV-2 variants on both CD4+ and CD8+ T-cell 
responses in COVID-19 convalescents and recipients 
of COVID-19 mRNA vaccines.5  T-cell responses 

to the variants B.1.1.7, B.1.351, P.1, and CAL.20C 
were not different from those to the ancestral strain of 
SARS-CoV-2. 

B.1.1.7, B.1.351 and P.1 all have a mutation that 
replaces asparagine (N) with tyrosine (Y) at position 
501 of the RBD. N501Y has been shown to increase 
binding capacity of SARS-CoV-2 to human ACE2 
receptors, disrupt antibody binding to RBD and has 
been implicated in reduced antibody production via 
impaired T and B cell cooperation. Together, these 
findings suggest that SARS-CoV-2 variants possessing 
the N501Y mutation may have an increased potential 
for immunological escape.

The SARS-CoV-2 B.1.617 lineage was identified 
in October 2020 in India. It has since then become 
dominant in some Indian regions and UK and further 
spread to many countries including Bangladesh.6 
The lineage includes three main subtypes (B1.617.1, 
B.1.617.2 and B.1.617.3), harboring diverse spike 
mutations in the N-terminal domain (NTD) and the 
receptor binding domain (RBD) which may increase 
their immune evasion potential. B.1.617.2, also 
termed variant Delta, is believed to spread faster than 
other variants. The delta variant spread is associated 
with an escape to antibodies targeting non-RBD and 
RBD spike epitopes.

According to current estimates, the Delta variant 
could be more than twice as transmissible as the 
original strain of SARS-CoV-2 and also replicates 
much faster.7 Individuals infected with Delta also 
had viral loads up to 1,260 times higher than those in 
people infected with the original strain. But evidence 
is mounting that the Delta variant, first identified in 
India, is capable of infecting fully vaccinated people 
at a greater rate than previous versions, and concerns 
have been raised that they may even enhance the 
spread of the virus. A study in China found that people 
infected with the Delta variant carry 1,000 times more 
virus in their noses compared with the original version 
first identified in Wuhan in 2019.

Preliminary reports show that the 501Y.V2 variant 
has complete immune-escape in South African 
convalescent serum samples and reductions in 
neutralizing activity in vaccinee serum samples for all 



May 2021J Enam Med Col Vol 11 No 2

66

four vaccines tested.8 Extrapolating vaccine efficacy 
against pre-existing variants to new variants could be 
seriously misleading. Adequate genomic surveillance 
standardized variant nomenclature, and a repository 
of variants and vaccinee serum samples are needed to 
deal with the challenges of repeatedly emerging new 
SARS-CoV-2 variants.9

Virus genomic sequences are being generated and 
shared at an erratic rate, with more than one million 
SARS-CoV-2 sequences available via the Global 
Initiative on Sharing All Influenza Data (GISAID), 
permitting near real-time surveillance of the unfolding 
pandemic.10 The use of pathogen genomes on this 
scale to track the spread of the virus internationally, 
study local outbreaks and inform public health policy 
signify a new age in virus genomic investigations. 

As highly deleterious mutations are rapidly purged, 
most mutations observed in genomes sampled from 
circulating SARS-CoV-2 are expected to be either 
neutral or mildly deleterious. Such mutations may alter 
various aspects of virus biology, such as pathogenicity, 
infectivity, transmissibility and antigenicity. 

The extent to which mutations affecting the antigenic 
phenotype of SARS-CoV-2 will enable variants to 
circumvent immunity conferred by natural infection or 
vaccination remains to be determined. However, there 
is growing evidence that mutations that change the 
antigenic phenotype of SARS-CoV-2 are circulating 
and affect immune recognition to a degree that requires 
immediate attention. The spike protein mediates 
attachment of the virus to host cell-surface receptors 
and fusion between virus and cell membranes.11 It 
is also the principal target of neutralizing antibodies 
generated following infection by SARS-CoV-2, and 
is the SARS-CoV-2 component of both mRNA and 
adenovirus-based vaccines licensed for use and others 
awaiting regulatory approval.12 

The people of Bangladesh are highly vulnerable to 
COVID-19 as evident by a number of circulating 
variants in different regions of this country.13 
In a global response, many countries, including 
Bangladesh, acted decisively and rapidly to restrict 
population movement and introduce additional social 
and behavioral interventions, all designed to slow the 

spread of the virus. SARS-CoV-2 genomic diversity 
and mutation rate in Bangladesh is comparable to 
strains circulating globally. Notably, the data on the 
genomic changes of SARS-CoV-2 in Bangladesh is 
reassuring, suggesting that immunotherapeutic and 
vaccines being developed globally should also be 
suitable for this population.14 

It is worth noting that research works evaluating 
neutralization potency against the P.1, B.1.427/B.1.429 
and B.1.526 lineages are still needed, and new 
information about SARS-CoV-2 variants is being 
produced daily. 

This ongoing mutation threat emphasizes 
the necessity of genomic surveillance programs that 
will track SARS-CoV-2 evolution, help contain the 
spread of disease and inform public health practices, 
including diagnostics and vaccine development with 
distribution.3  Together, these observations provide 
support for current strategies to monitor multiple 
variables proactively. These strategies include viral 
testing of symptomatic and asymptomatic persons, 
sequencing of viral RNA, and monitoring of 
neutralizing antibody titers, particularly in vaccinated 
persons who subsequently become infected. 

Given the short time since the COVID-19 vaccines 
have become available, it is not surprising that many 
scientific uncertainties persist and are the subject 
of intense ongoing research. They include i) the 
ability of vaccines to reduce/eliminate SARS-CoV-2 
transmission, ii) duration of immunity, iii) correlates 
(indicators) of protection, iv) vaccine efficacy/
effectiveness in specific populations and in individuals 
with prior infection, and v) protection against 
infection/reinfection by different virus variants.

Iftikhar Ahmed 
Professor, Department of Microbiology 
Enam Medical College, Savar, Dhaka 
Email: ia65831@gmail.com

References

1.  Harvey WT, Carabelli AM, Jackson B, Gupta RK, 
Thomson EC, Harrison EM et al. SARS-CoV-2 



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variants, spike mutations and immune escape. Nat Rev 
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2.  Hagen A.  SARS-CoV-2 Variants vs Vaccines. 
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M, Conlon EG et al. Vaccine Breakthrough Infections 
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384(23): 2212−2218.

4.  Bhattacharya M, Chatterjee S, Sharma AR, 
Agoramoorthy G, Chakraborty C. D614G mutation 
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5.  Tarke A, Sidney J, Methot N, Jhang Y, Dan JM, 
Goodwin B et al. Negligible impact of SARS-CoV-2 
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6.  Planas D, Veyer D, Baidaliuk A, Staroploli I, Guivel-
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7.  Hummel S, Burpo FJ, Hershfield J, Kick A, 
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8.  Wibmer CK, Ayres F, Hermanus T, Madzivhandila M, 
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escapes neutralization by South African COVID-19 
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9.  Fontanet A, Autran B, Lina B, Kieny MP, Abdool 
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14.  Cowley LA, Afrad MH, Rahman SI, Mahfuz-
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