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A review of SARS-CoV-2 virology, vaccines, variants
and their impact on the COVID-19 pandemic
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Tetsuyuki Hirahata, Reeshan ul Quraish, Afraz ul Quraish
and Shahan ul Quraish
A novel coronavirus, named severe acute respiratory syndrome-coronavirus-2 (SARSCoV-2) has spread in Wuhan, China, and caused the global pandemic infectious
disease. This disease has been known as coronavirus disease 2019 (COVID-19). It
continued to spread around the world and created outrageous effects on the healthcare
and economic system throughout the world. Various strategies have been designed todiminish the morbidity and mortality of this infectious disease. Among them, thedevelopment of vaccines is the most effective method to prevent and treat the viral
infection. Novel vaccines have been developed and proved to be effective in multiple
clinical reports indicating a significant decline in the risk of COVID-19 infection.
However, the emergence of new variants of SARS-CoV-2 with immune-evasive characteristics raised questions concerning the effectiveness of the vaccines. This review
provides a brief introduction to developed vaccines, as well as emerging variant strains
and vaccine effectiveness against these variants. In this article, we also reviewed thegeneral biological features of SARS-CoV-2 and its pathogenesis and explained theclinical symptoms, transmission, diagnostic and treatment approaches to monitor andcontrol emerging COVID-19 infection.
Copyright ß 2024 The Author(s). Published by Wolters Kluwer Health, Inc.

Reviews and Research in Medical Microbiology 2024, 35:000–000
Keywords: coronavirus disease 2019, severe acute respiratory syndromecoronavirus-2 virus, three waves of coronavirus disease 2019, vaccines, variants

Introduction
The outbreak of pneumonia in December 2019 occurredin China’s Hubei province, raising global health concerns
due to its rapid transmission to other areas. After researchon numerous cases, a novel coronavirus was identified as
the cause of the disease and, On February 11 of thefollowing year, that causative pathogen was named by theinstitutional Virus Classification Commission as severe
acute respiratory syndrome-coronavirus-2 (SAR-CoV-2)
due to its high homology (80%) to SARS-CoV (whichcaused acute respiratory syndrome during 2002–2003)[1] and the resulting disease was named by the World
Health Organization (WHO) as coronavirus disease 2019
(COVID-19) [2,3]. As infection has spread globally withdeadly effects, the World Health Organization declared

COVID-19 a global pandemic on March 11; 2020 [4,5].
The first case of the novel coronavirus (SARS-CoV-2)
was released in December 2019. Since then, this virus has
continuously caused global health calamities and caused
drastic impacts in all fields including; environmental,social, political, cultural, and economic. The mosteffective method to reduce the drastic effects of viral
infectious disease is vaccination. Several vaccines havealready been developed and marketed worldwide atunprecedented speed and scale, while a number ofvaccines are in the process of being developed and morethan 200 different candidate vaccines are in different
stages of development [6]. As of 2 December 2022, 11different vaccines have been granted Emergency Use
Listing (EUL) by the WHO. These include two mRNA
vaccines (Pfizer–BioNTech-Comirnaty and Moderna-

Hirahata Gene Therapy Laboratory, HIC Clinic, Tokyo, Japan.
Correspondence to Tetsuyuki Hirahata, Hirahata Gene Therapy Laboratory, HIC-Clinic #1105. Itocia Office Tower 11F, 2-7-1,
Yurakucho, Chiyoda-ku, Tokyo 100-0006, Japan.
E-mail: hirahata@hicc.jp
Received: 4 September 2023; revised: 22 October 2023; accepted: 8 November 2023
DOI:10.1097/MRM.0000000000000393
ISSN 2770-3150 Copyright Q 2024 The Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under theterms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download andshare the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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Spikevax), two protein subunits vaccines (Novavax and
COVOVAX), four adenoviral vector vaccines (CanSinoConvidecia, Johnson & Johnson, Oxford–AstraZeneca,
and COVISHIELD), and 3 inactivated vaccines (Sinopharm, Sinovac, and COVAXIN) [7]. Globally, as of 21
September 2023, there have been 770 778 396 confirmed
cases of COVID-19, including 6958 499 deaths, reported
to WHO. 70.5% of the world population has received atleast one dose of a COVID-19 vaccine. As of 18
September 2023, a total of 13 505 089 801 vaccine doses
have been administered. 20 739 are now administeredeach day. 32.6% of people in low-income countries havereceived at least one dose [8]. In this review, we discussed
developed vaccines and the impacts of variants on theeffectiveness of these vaccines as well as challenges
regarding the development of vaccines and the vaccination process to curb this pandemic. In this report, we alsopresent the clinical work performed in our laboratory(Hirahata Gene Therapy Laboratory, HIC-Clinic) regarding the treatment of this infection and review it withthe current research.

respiratory infections [17]. Among seven human CoVs
(HCoVs), two betaCoV (HCoV-229E and HCoVHKU1) and two alphaCoV (HCoV-NL63 and HCoVOC43) genera have been circulating in human anddeveloped upper respiratory disease [18,19]. Threecoronaviruses (beta coronavirus/ betaCoV genus) thatcause serious respiratory disease are SARS-CoV, MERSCoV, and SARS-CoV-2 which are responsible for highmortality rates in humans. In the 21st century, three CoVs
named SARS-CoV, MERS-CoV, and SARS-CoV-2
outbreaks emerged from their reservoirs to cause serious
respiratory disease in humans. Among them, severe acuterespiratory syndrome coronavirus (SARS-CoV) emergedin late 2002, and Middle East respiratory syndrome
coronavirus (MERS-CoV), emerged in 2012, whichhave been previously implicated in epidemics withmortality rates up to 10% and 35% respectively, [20,21]
and SARS-CoV-2 emerged in 2019 in China as a threat
to the human lives and caused COVID-19 disease.
SARS-CoV-2 has become a major public health concern
after the outbreak of the MERS-CoV and SARS-CoV[15,16,20].

Etiology of coronavirus
A human coronavirus was isolated for the first time fromthe nasal secretions of a male child with a common cold in1965 [9]. Coronaviruses (CoVs) are nonsegmented,
enveloped, single-strand, positive-sense RNA viruses
ranging from 60 to 140 nm in diameter with spike-likeprojections on their surface giving them a crown-likeappearance therefore, coronaviruses (CoVs) are named
due to their Sun’s corona or crown-like surface
projections [10,11]. CoVs are the largest group ofhost-specific RNA viruses infecting birds, snakes, bats,and mammals including humans. They belong to thefamily Coronaviridae (order Nidovirales), which is
divided into subfamilies Coronavirinae and Torovirinae.
The subfamily Coronavirinae is further divided into four
genera: Alphacoronavirus (alphaCoV), Betacoronavirus(BetaCoV), Gammacoronavirus (GammaCoV), andDeltacoronavirus (deltaCoV) [12,13]. CoVs grouped
into Alphacoronaviruses and Betacoronaviruses, which
are mostly found in mammals like bats, civets, rodents,and humans while Gammacoronaviruses and Deltacoronaviruses are mostly found in birds. It is reported thatbeta-coronaviruses cause severe disease while alphacoronaviruses cause asymptomatic or mildly symptomatic
disease [14]. To date, seven human CoVs (HCoVs)
capable of infecting humans have been identified
including HCoV229E, HCoV-OC43, HCoV-NL63,
HKU1, SARS-CoV, MERS-CoV and SARS-CoV-2[15,16]. Some of the HCoVs were identified in the mid1960s, while others were only detected in the 21st
century. In general, estimates suggest that 2% of the
population is healthy carriers of CoVs and that theseviruses are responsible for about 5% to 10% of acuteRole of spike protein in the pathogenesis of
SARS-CoV-2 infection
Phylogenic analysis revealed that SARS-CoV-2 is closely
related to the beta-coronaviruses. Similar to othercoronaviruses, the genome of SARS-CoV-2 is positive-sense single-stranded RNA [(þ) ssRNA] with a cap
at the 50 end, and a polyadenylated (polyA) tail at the 3end’ [22]. The genome of SARS-CoV-2 has a length ofabout 30K nucleotides. It has other 5–8 accessory
proteins (ORF3a, ORF6, ORF8, ORF7, and ORF9),
nonstructural proteins (NSPs), structural proteins, andaccessory proteins. Nonstructural proteins such as RNA
polymerase, RdRp; papain-like protease, PLpro; coronavirus main protease, 3CLpro) are encoded by the ORF
region [21]. Nonstructural proteins (NSPs) such as(NSP3, NSP9, NSP10, NSP12, NSP13, NSP15, and
NSP16) play important roles in viral replication, cleavageof host mRNA, membrane rearrangement, assembly
processes, capping, tailing, and methylation, etc. which
are vital for viral life cycle and pathogenesis [23–25]. Fourstructural proteins of the SARS-CoV-2 virus named Sspike Protein (outer spiky glycoprotein), envelope
protein (E), Membrane/matrix glycoprotein (M), andnucleocapsid protein (N) share high sequence similarity
to those from SARS-CoV and MERS-CoV [20,24,25].
These proteins help the coronavirus-host cell interactions
to create an optimal condition for viral entry in host cells,viral replication, and induction of the immune system byeliciting neutralizing antibodies. Thus, coronavirus-hostinteraction plays a vital role in the viral disease
pathogenesis [26]. Amongst the four structural proteins,CE: ; RMM-D-23-00071; Total nos of Pages: 24;

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the S protein (a transmembrane glycoprotein) that covers
the surface of the SARS-CoV-2 virus, plays the vital roleof virus binding to the receptor (angiotensin-converting
enzyme 2-ACE2), which is expressed on the host cell,
antigenic recognition, viral fusion, and virus entry into
the host cell [23,27]. The S protein has two subunits S1and S2. The subunit S1 is responsible for the binding ofviral envelops to the host cell receptor, while the S2
subunit contains a fusion peptide, a transmembrane
domain, and a cytoplasmic domain that facilitates thefusion of the virus-cell membrane to the host cell [28,29].
Further, the S1 subunit is split into different functional
domains, receptor binding domain (RBD) and Nterminal domain (NTD) which facilitates viral entry
into the host cell and serves as a potential target forneutralization in response to vaccines [30]. Structural andfunctional analysis showed that the RBD of the S1subunit (SARS-CoV-2 spike or S protein) is afundamental peptide domain in the pathogenesis ofinfection as it represents a binding site for the humanangiotensin-converting enzyme 2 (ACE2) receptors [31–33]. Following the binding of the S protein to the (ACE2)
receptor on the host cell surface, the spike protein
activated via undergoing protease cleavage by enzyme
trans-membrane protease serine 2 ‘TMPRSS2’, which islocated on the host cell membrane and promotes virus
entry into the cell by activating the S protein. Once thevirus enters the cell, the viral genome is released into thehost cell, replication and transcription of the viral RNA is
occurred, structural protein is synthesized and assembled
in the host cell, then viral particles are released from hostcells by the exocytic pathway [34,35].

Symptoms of SARS-CoV-2 infection
SARS-Cov-2 virus primarily affects the respiratory
system although other organ systems such as the lung,brain, kidneys, immune system, and heart are affected
directly or indirectly [36]. Acute COVID-19 infection
symptoms vary from asymptomatic/mild symptoms tocritical illness with acute respiratory disease and death.
Most common symptoms are very similar to seasonal flu
such as fatigue, headache, cough, fever, shortness ofbreath, and other symptoms reported in acute conditions
include vomiting, muscle pain, diarrhea, myalgia, sputum
production, dyspnea, and hemoptysis. Patients withserious symptoms such as difficulty breathing, chest pain,
and loss of speech or movement need urgent medical
attention [37–40].

Clinical diagnosis of SARS-CoV-2 infection
Reliable and early diagnosis of infection plays a pivotal
role in combating the pandemic COVID-19. A reliable

and specific diagnostic test is the most effective approach
to identify the infected patients in the mass population
during this pandemic infection. Three types of diagnostic
tests are available to identify the infection; molecular or
nucleic acid amplification tests (e.g., PCR tests) that
detect viral RNA; antigen tests that detect viral proteins(e.g., nucleocapsid or spike proteins); and serology-based
tests that detect viral antigen or host antibodies in tissues,
secretions, or eliminations from individuals with ongoingor past infections [41]. The use of the quantitative
reverse-transcription polymerase chain reaction (RTPCR) assays for the detection of viral nucleic acid is themost valuable assay in terms of its specificity, reliability,
high capacity, and speed. It has been shown to be very
sensitive for accurately detecting the viral genome, andable to detect a single copy of the viral RNA [42]. Threehighly conserved regions (RdRp, E, and N gene) havebeen found in the SARS-CoV-2 viral genome, and areusually selected as the reliable targets for the design ofprimers and probes [43]. It is essential to update thesequences of primers and probes to ensure the detectionof newly emerged variants.
A novel antigen-based rapid test for diagnosis of SARSCoV2 showed high sensitivity and specificity mainly inthe first week among symptomatic patients and samples
with high viral load [44].
Serological assays such as enzyme-linked immunosorbent
assay (ELISA), chemiluminescent immunoassay (CLIA),
and immunofluorescent assay (IFA) are based on targeting
S protein and N protein antigens for the rapid detection of
SARS-CoV-2 through measure immunoglobulin M(IgM) and/or immunoglobulin G (IgG) antibodies inserum or body fluid samples [45].
All three types of tests are available as laboratory-based
assays that can be performed by lay health-care providers
outside of laboratory settings and with minimal training.
Although sensitivity and specificity are important
attributes of a diagnostic test, they differ between
populations and the types of equipment employed [46].
A correct diagnosis in a patient also depends on the timeof sampling relative to the stage of infection, the quality ofthe specimen collection, proficiency to perform a test,
and correct interpretation of the results.

Transmission of SARS-CoV-2 virus
Animal-to-human transmission
The source of origination and transmission are essential to
be determined in order to prevent transmission of disease.
In the case of SARS-CoV, initially, researchers foundpalm civets as a key reservoir of infection. The samples
isolated from the civets at the food market showed
positive results for viral RNA detection [47]. Further,3

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wide-reaching investigations of farmed and wild-caught
civets revealed that the SARS-CoV strains found in
market civets were transmitted to them by other animals[48] suggesting that the palm civet might be the secondary
host of infection. Another report revealed the discovery
of novel coronaviruses related to human SARS-CoV,which were named SARS-CoV-related viruses or SARSlike coronaviruses, in horseshoe bats (genus Rhinolophus)[49,50]. These discoveries also suggested that civets were
only intermediate hosts and bats may be the original hostfor SARS-CoV. Due to similarities between SARS-CoVand SARS-CoV-2, a group of scientists and researchers
believed that like SARS-CoV, another animal might bepresent as an intermediate host to transmit SARS-CoV-2
to humans. Therefore, finding the intermediate host ispivotal to developing preventive strategies to stop
interspecies transmission of SARS-CoV-2. In this regard,some studies also revealed that SARS-CoV2 have beentransmitted to humans through other intermediate
animals potentially sourced from the Huanan wholesale
seafood market which sells bats, snake, and other poultryin Wuhan City, Hubei province, China [51–53].
Furthermore, phylogenetic analysis of the SARS-CoV2 genome indicates that the virus is closely related (with
88% identity) to two bat-derived SARS-like coronaviruses collected in 2018 in eastern China (bat-SLCoVZC45 and bat-SL-CoVZXC21). Moreover, after
genomic similarity findings of novel coronavirus with
SARS-like bat viruses, some researchers suggested that
only bats could be the key reservoirs of this infection[51,54]. Later on, further study found that the virus is
more related to BatCoV RaTG13, a bat coronavirus
detected in Rhinolophus affinis bat which has 96.2%
whole-genome sequence similarity [55]. Another study
based on relative synonymous codon usage (RSCU) on avariety of animal species also revealed that bats are themost probable wildlife reservoir of SARS-CoV-2 [56].
Altogether, these findings suggest that bats might be theoriginal host of this virus [57]. However, bat-derived
coronavirus (CoVs) rarely infect humans therefore anintermediate host must be there for transmission of
SARS-CoV-2 to humans. Therefore, further research
was performed to find out that intermediate host, andaccording to one study, pangolins have been suggested as
an intermediate host for SARS-CoV-2, Malayan wild
pangolins were tested for SARSCoV-2-like coronaviruses, with major amino acid identity with SARSCoV-2 in the E, M, N and S proteins, respectively. In
particular, the receptor-binding domain (RBD) of the
spike protein of the Pangolin-CoV was found to have aminor difference in only one amino acid from that of
SARS-CoV-2. Comparative genomic analysis further
indicated that the SARS-CoV-2 may have potentiallyoriginated from the viral recombination to PangolinCoV with Bat-nCoV (RaTG13) before transmitting tohumans [58]. Nonetheless, finding the intermediate
SARS-CoV-2 host is pivotal to developing preventive
strategies to stop interspecies transmission, and more

research work is required to perform in the aspects of theidentification of the intermediate source that caused thetransmission of the virus to humans.

Human-to-human transmission
The principal mode by which people are infected with
SARS-CoV-2 is through exposure to respiratory fluids
carrying infectious viruses. Infectious exposures occur inthree different ways (1). Direct inhalation of air carrying
very fine respiratory droplets and aerosol particles released
into the environment by sneezing or coughing. (2)Deposition of respiratory droplets and particles on
exposure with oral, nose, or eye mucous membranes.
(3) Touching mucous membranes with hands that havebeen soiled either directly by respiratory fluids containing
the virus or indirectly by touching inanimate surfaces
contaminated with the virus. Therefore, COVID-19 canbe transmitted through direct contact with infected
people or indirectly, through the surface contaminated by
infected person [59–63].

Variants of SARS-CoV-2 virus
Like other RNA viruses, the SARS-Cov2 virus isunstable and prone to genetic evaluation caused bygenetic mutations or viral recombination resulting in thedevelopment of variants that have different characteristics
compared to its ancestral strain (the original SARS-CoV2 virus). Throughout the COVID-19 pandemic, many
variants of SARS-CoV-2 have been found globally.
Though coronaviruses such as SARS-CoV-2 are relatively stable as they possess a genetic proofreadingmechanism due to the presence of a nonstructuralprotein (nsp) with 30 -50 exoribonuclease activity (nsp14)[64]. Therefore, the rate of variant accumulation is slower
than for other RNA viruses such as HIV-1 or influenza A.
However, Korber et al., with the analysis of accumulating
GISAID sequence data developed a bioinformatics
approach identifying specific viral variants carrying theD614G mutation in the Spike protein of SARS-CoV2
which rapidly became the dominant widespread variantof SARS-CoV2 across the world [65]. Another variant
was identified in humans, attributed to transmission from
infected farmed mink in Denmark [66]. Since then, many
genomic studies have revealed changes in the genome of
SARS-CoV-2, and multiple variants have been definedby diffident lineage based on the sequences of the spike
protein. However, the mutation also occurs in regions
beyond spike proteins that contribute to the variant’s
distinct features [67]. These viral variants cause anincrease in the efficiency of viral transmission, enhancing
viral replication, disturbing viral fitness, cell tropism,disease severity, drug resistance, pathogenicity, and escapeimmune recognition [68].

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With the continued emergence of multiple variants, inlate 2020, the WHO defined variants as variants ofinterest (VOIs), variants of concern (VOCs), and variants
under monitoring (VUMs) in the function of theirgenome mutations, their properties of spreading between
susceptible hosts, the disease severity produced, and by
the evasion of the immune response elicited by currently
available vaccines. Among them, two major types of viralvariants, VOIs and VOCs are identified to fight against
the pandemic [69].
Alpha (B.1.1.7 or 20I/501Y.V1)/UK variant: The
B.1.1.7 variant, the first variant of concern, is known as
the Alpha variant or GRY. It was first reported in thesoutheast of the United Kingdom in September 2020 andbecame the dominant variant and circulated worldwide
and designated as a VOC and labeled Alpha by the WHO
on December 18, 2020. (https://www.who.int/en/
activities/tracking-SARS-CoV-2-variants/)[70,71].
This variant is characterized by the presence of approx.
17 mutations in the viral genome. Most of them including(H69-V70 deletion, Y144 deletion, N501Y, A570D,
D614G, P681H, T716I, S982A, and D1118H) are foundin the spike protein as compared with the original virus
isolated in China [72]. Among the mutations, N501Y’s
protruding protein mutation plays an extremely important role in enhancing the binding affinity of S proteinwith hACE-2 receptors and enhancing the ability to enter
host cells [73–75]. Compared with other VOCs, it has a
50% higher transmissibility [76]. According to one trial
report, AstraZeneca’s vaccine has been shown to be 70%
effective against alpha VOCs [77]. Another trial study
reported that the Pfizer-BioNTech (BNT162b2) vaccine
was 89.5% effective against the Alpha variant after
receiving two doses [78].
Beta (B.1.351 or 20H/501Y.V2)/South Africa
variant: B.1.351, also known as 501Y.V2 was firstdetected in South Africa in May 2020 after the first
epidemic wave in Nelson Mandela Bay and spread rapidly
in Eastern Cape, Western Cape, and KwaZulu-Natalprovinces in just a few weeks, causing the second wave of
epidemic in South Africa [79]. It was designed as a VOC
and labeled Beta by the WHO on December 18, 2020
(https://www.who.int/en/activities/tracking-SARSCoV-2-variants/). This variant contains nine mutations(L242_L244 deletion, D80A, D215G, K417N, E484K,
N501Y, D614G, and A701V) in the spike protein ascompared with the original SARS-CoV-2 virus [72]. Of
which 3 mutations (K417N, E484K, and N501Y) arelocated in the receptor binding domain (RBD),
increasing the binding affinity with hACE-2 receptors,
resulting in a higher risk of transmission [80]. The
mutation E484K in this variant mediates the antibody
escape is the main reason for the reduced sensitivity tovaccines [81]. According to the findings of a trial, thePfizer-BioNTech vaccine has been shown to be 75%
effective against this viral variant after two doses [78]. And

Novavax vaccine showed 86% efficacy against Beta
variants in the UK and 60% in South Africa, respectively[82], the trial results for the ChAdOx1 nCoV-19 vaccine
from Oxford-AstraZeneca revealed low efficacy (10%)
after two doses against this variant [83].
Gamma (P.1 or 20J/501Y.V3)/Brazilian variant: theP.1 variant, also known as the Gamma variant or GR/
501Y. V3. It was primarily found in North Brazil in thecity of Manaus in the Amazonas state in December 2020and caused the second wave of the epidemic in thiscountry [84]. By January 2021, it was identified at the
National Institute of Infectious Diseases (NIID) in Japan
during analysis of samples of four travelers/passengers
from Brazil and was designated as VOC and labeled
Gamma by the WHO on January 11, 2021. (https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/). This variant arose from lineage B.1.1.28 and has
12 mutations in its spike protein (L18F, T20N, P26S,
D138Y, R190S, K417T, E484K, N501Y, D614G,
H655Y, T1027I, and V1176F) [72]. L18F, K417N/T,
E484K, N501Y, and D614G are located in the RBD,
similar to the B.1.351 variant [84,85]. These mutations
have been shown to have important implications, both in
the transmissibility of the virus and the rate of reinfection[86]. When compared to the other prevalent variants inthe country, it was found 1.7–2.4 times more transmissible [82] In another report, it was observed that this variant
is 2.2 times higher transmissible and led to a few cases ofreinfection recovered from COVID-19 [87,88]. According to one study, 50% efficacy of two doses of Pfizer orOxford-AstraZeneca vaccines against this variant wasobserved [89]. In the case of CoronaVac, the vaccine
showed 37–59% efficacy against this variant [90,91]. In
contrast, Moderna (mRNA-1273/Moderna) showed areduced efficacy of protection (61%) after two doses [92].
Another clinical trial demonstrated that the CoronoVacvaccine is 50% effective against the Gamma variant inBrazil [93].
Delta (B.1.617.2)/India variant: B.1.617.2, also
referred to as the Delta variant or GK was first detectedin Maharashtra, India in October 2020, causing a second
wave of deadly COVID-19 infections in India [69]. Thisvariant was designated as VOC and labeled Delta by the
WHO on May 11, 2021, (https://www.who.int/en/
activities/tracking-SARS-CoV-2-variants/). VOC Delta
was a worldwide circulating variant after the Alphavariant and was reported by at least 169 countries(https://outbreak.info). In comparison to other VOCs,
this variant has had deadly global impacts [94]. Thisvariant is characterized as highly transmissible and has
spread worldwide between fully vaccinated as well as inunvaccinated individuals [95]. According to reports fromUK studies, this variant is 60% more transmissible
compared to the Alpha variant [82]. There were ten
mutations in the S protein of Delta variant: T19R, T95I,
G142D, E156G, Del157/158, L452R, T478K, D614G,

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P681R, D950N (https://outbreak.info) [96]. The current vaccines on the market have shown to be less efficientagainst Delta VOCs than the Alpha variant. The Pfizer
vaccine has been shown to be 88% and 93% effective
against the Delta and Alpha VOCs, respectively, after a full
dose. The AstraZeneca vaccine has been shown to be 60%
and 66% effective against Delta and Alpha strains after two
doses, respectively [82]. The mutations like L452R, andT478K have not been reported in previous VOC Alpha,Beta, and Gamma, these mutations gave VOC Delta astronger transmission ability and immune escape ability,
which made the Delta variant quickly become adominant variant and reduced the efficacy of approved
vaccines. The emergence of this variant despitewidespread vaccination raised questions about theefficacy of current SAR-CoV-2 vaccines (https://aci.
health.nsw.gov.au/covid-19/critical-intelligence-unit/
sars-cov-2-variants).

Omicron (B.1.1.529): first reported inSouth Africa in November 2021
This variant (B.1.1.529 lineage) was identified on
November 11, 2021 in Botswana, Africa, and was
designated as VOCs and labeled Omicron by the WHO
on November 26, 2021 (https://www.who.int/en/
activities/tracking-SARS-CoV-2-variants/). Omicron
consists of four genetically related viral sub-lineages(BA.1, BA.1.1, BA.2, and BA.3) that diverged from the
B.1.1.529 lineage [97]. It has more than 30 mutations,
including T95I, K417N, N501Y, T478K, N679K,
G142D/143–145del, and P681H. These mutations are
already reported in previous VOC (alpha, beta, gamma,
and delta) [98]. Six of these mutations (G339D, N440K,
S477N, T478K, Q498R, and N501Y) enhance thebinding affinity to the human hACE-2 receptor, while
seven mutations (K417N, G446S, E484A, Q493R,
G496S, Q498R, and N501Y) are associated with areduction in neutralization [99]. Omicron has mutationsuch as N501Y, which is present in the B.1.1.7, B.1.351,
P.1, and P.3 lineages, and associated with improved
binding of the RBD domain of the spike protein to theACE2 receptor, resulting in higher transmissibility[100,101]. It also shares the K417N and E484K mutations(E484A in the Omicron variant) with the B.1.351 and P.1
lineages, which are linked to evasion of the immune
response [102]. One study demonstrated that the
Omicron variant is more contagious as the reproductive
number of the Omicron variant is higher than that of the
Delta variant [103,100]. However, the results of recent
hospitalizations from the United States found that the
Omicron variant was associated with less severe disease
compared to Delta [104,105]. In addition, Omicron ischaracterized by its potential to evade the humoral
immune response in individuals who have a full

vaccination scheme (including the booster dose)[106,107] and therefore, Omicron is considered more
infectious (2.7–3.7 times higher) than the Delta variant[108]. As mentioned, Omicron has so many common
mutations described in other VOCs, that it is expectedthat available vaccines may help control the further
prevalence of SARS-CoV-2 cases, but still more researchis required in this regard. According to one study, theefficacy of the Pfizer vaccine against this variant decreases
28.2-fold, however, a third dose increases the effectiveness of the Pfizer vaccine 23.4-fold [106,107], suggestingthat the third boost of the Pfizer vaccine can efficiently
neutralize this variant. As well as the combination of theJohnson and Johnson (Ad26.COV2) vaccine with abooster of Pfizer, also crucially increases the activity ofneutralizing antibodies against Omicron [107]. Omicronassociated lineages, such as BA.1, BA.1.1, BA.2, BA.3,
and XE (BA.1 and BA.2 recombinant), are still emerging.
Moreover, new variants such as the Deltacron a newrecombinant variant that originated from the recombination in the Delta and Omicron coinfected patients haveappeared in many countries like France and America,
although the detected sequence of Deltacron was lower
than Omicron [109,110].
Conclusively, the emergence of new variants in the
SARA-CoV-2 genome has become one of the primarychallenges facing coronavirus disease because a genetic
mutation in the SARS-CoV-2 genome could alter its
pathogenic potential, and would increase the difficulty inthe diagnosis and treatment of infection and also create
trouble in drug and vaccine development against thecoronavirus [111,112]. The investigation of the variantsof SARS-CoV-2 has suggested that the coronavirus canevolve with high resistance to immune system neutralization. There is variability observed among different
individuals as a response to S-protein. Therefore, athorough study is required to investigate the efficacy ofantibody neutralization in the licensed vaccines against
SARS-CoV-2 variants [113,114]. New Variants of
SARS-CoV-2 not only cause increased transmissibility,
morbidity, and mortality rate but also can escape fromdetection by currently available diagnostic tests, which
can potentially delay the diagnosis and treatment,
therefore encouraging the need for improvement in
the form of more adaptive diagnostic techniques for
detection of COVID-19 infection [115].

Three waves of SARS-CoV-2 infection
People from different countries all over the world have
faced three waves of COVID-19 infection to date. Thesewaves of SARS-CoV-2 are driven by its variants which
continuously set aside the accomplishments achieved
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variants result from mutations in the SARS-CoV-2
genome has introduces auger ably extreme challenges incontrolling the threat of COVID-19.

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First wave
The first case of COVID-19 in China was reported in
December 2019 and within a week; it had spreadthroughout the entire world. However, first wave of
COVID-19 was detected internationally in March 2020
(spring) and affected almost every corner of the world,
due to atmosphere changes the southern hemisphere wasaffected later [116,117]. Interestingly, except in South
Africa, cases and death rates with lower numbers werereported in Africa. The reason behind this may be theshort average age and Ebola disease experience years agothat helped to minimize the effect of COVID-19 [118].
The 1st wave is considered a global catastrophe thatdrastically impacts every aspect of life including health,social life, and economy [119,120]. The economies ofdifferent societies were significantly affected globally,
resulting in a sharp decline in the production of various
items; consequently, unemployment rates and other social
problems (violence in the family) were increased. The
first wave affected multiple nations all over the world, andseveral experts predicted that the second wave might bestronger than the first wave [117].

Second wave
The second wave occurred at the end of summer andautumn in July 2020. Some parts of society thought thatthe pandemic was over and disregarded the initial
announcement of the incoming second wave due tothe minimum number of infection cases reported in thesummer months [116]. Like other viral infections such as
influenza blaze up seasonally, COVID-19 returned inautumn and the second wave hit many countries with amuch higher force than the first one as predicted bymultiple experts. More infection cases were reported
increased number of patients in ICUs and in somecountries, more deaths were recorded during the second
wave [116,121,122]. During the second wave, thepolitician in many countries changed their priorities
after the first wave faded away. In most countries,
particularly in Germany, the instructions were very sharpin the 1st wave of this pandemic. Now in the second
wave, the economy of society has become the firstpriority on the list, businesses remained open rather thanstrictly decreasing contacts thus infections and death rates
have risen [116]. The second wave of SARs-CoV-2
showed more potential threats than the first wave andaffected India very severely, as well as other countries suchas the United Kingdom, Brazil, and France [123].

According to one report, the main cause of the second
wave in Europe was not the relaxation of interventions
during the summer, but rather the failure to enforce
interventions in the fall [124]. Moreover, experts gave
predictions about the third wave that would be more
deadly than previous waves as the virus emerged with a
new mutation.

Third wave
A third wave of COVID-19 occurred after Christmas
2020 worldwide and differential features to previous
waves were observed, Such as a large proportion of cases
were linked to household contacts, most likely because
Christmas gatherings were the major trigger of this newwave [125]. The proportion of clinically severe cases of
SARS-CoV-2 infection and mortality rates were low ascompared to prior COVID-19 waves because diagnosesof asymptomatic or mildly symptomatic individuals haveincreased over time. Therefore, rapid antigen test
availability to prompt diagnosis and then isolation[126], better clinical monitoring, and treatment of
COVID-19 patients play crucial parts in controllingthe spread of the third wave [127,128]. Anotherinteresting feature in the third wave was the moretransmissible B.1.1.7 strain was observed; that have higher
transmissibility; therefore, re-infections became morecommon. Since Christmas, a growing proportion of new
SARS-CoV-2 infections have been observed due to theB.1.1.7 strain. These mutations that appeared within the
SARS-CoV2 virus genome and the social activities/
contacts between people without obligatory precautions
may be the main cause of the third wave [129]. There is aneed to increase the vaccination rate to combat thispandemic and adhere to other precautionary publichealth measures like wearing a mask, using sanitizer, andcreating awareness among people regarding social
distancing, etc.

Vaccines platform for SARS-CoV-2
infection
The first step regarding managing this viral infection is toensure adequate isolation to prevent transmission toanother individual as transmission rates of SARS-CoV-2
are shown to be higher than other coronaviruses,
therefore considered a concern for public health; themajority of countries worldwide adopted different
precautionary measures including lockdown policy to
reduce the transmission rate via reducing social activities
and contacts, that causing a significant negative impact on
the economics of different societies all over the world,
therefore, there was an urgency to develop safe and7CE: ; RMM-D-23-00071; Total nos of Pages: 24;

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efficacious vaccines to mitigate the current viral disease.
In this regard, clinical researchers throughout the world
performed intense research and significant progress has
been made in the development of efficacious vaccines
against SARS-CoV-2 to combat the pandemic.
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Currently, several platforms are being utilized globally for
vaccine development, and multiple vaccines against
SARS-CoV-2 have either been developed or are in theprocess of being developed in various countries aroundthe world including the USA, Germany, Australia, UK,
China, Austria, France, India and Hong Kong (WHO2020).

Protein subunit
Protein subunit vaccines based on limited fragments ofpathogen-drive protein (antigen) to elicit an immune
response against pathogen [130], are therefore consideredsafer than full pathogen-based vaccines. This vaccine ismanufactured by DNA recombinant technology but
requires an adjuvant to enhance antigenic-specificimmunity [131–133]. Many research institutes developed
the protein subunit vaccine against SARS-CoV-2 byusing spike S-glycoprotein of SARS-CoV-2, and its
fragments S1, S2, and RBD as prime targets antigen forsubunit vaccine to induce neutralizing antibodies against
pathogen [133,134]. Considering the advantages of safety
and cost-effectiveness, subunit vaccines are the best
option in conjunction with other approaches of vaccine.
However, their limitation includes the need for multiple
booster administration and adjuvants to potentiate longterm vaccine-induced immune responses [131,132,135].

Novavax NVX-CoV2373
It is a subunit vaccine that was co-developed by theAmerican biotechnology Novavax and the Coalition for
Epidemic Preparedness Innovations Foundation. Thisvaccine contains a recombinant full-length SARS-CoV-2
spike glycoprotein adjuvant with saponin based MatrixM and manufactured in the established baculovirusSpodoptera Fruiperda (sf9) insect cell expression system[136–139]. This vaccine is capable of producing a strong
antibody response and activating the T cells [140]. Resultsof phase 3 clinical trials showed that Novavax provided
96.4% protection against symptomatic COVID-19 and86.3% against the Alpha variant [141]. Clinical trials
conducted in the UK indicated that the efficacy of
Novavax was 89.7% [142]. On 12 March 2021, Novavax
revealed that the COVID-19 vaccine was found to be
96.4% and 86% effective against the original strain andLineage B.1.1.7, respectively [143].
EpiVacCorona vaccine
This subunit vaccine was manufactured by the VECTOR
Institute based on three chemically synthesized peptidesof the S glycoprotein, expressed as a chimeric protein[144,145]. Rout of administration of this vaccine isintramuscularly in two doses 3 weeks apart. A person aged
18 years and above is eligible for this vaccine [140]. The
phase 1/2 clinical trials showed that EpiVacCorona is safe
and immunogenic. The immunological effectiveness of
the EpiVac corona vaccine was found to be 100% [144].

Anhui Zhifei (ZF 2001) COVID-19 vaccine
ZF2001 was co-developed by the Chinese Anhui Zhifei
Longcom and the Academy of Military Medical Sciences[145]. This subunit vaccine contains the dimeric form of
the RBD of the S protein and a conventional alum
adjuvant [146]. This vaccine is administered intramuscularly in three doses after every four weeks. Results ofphases I and II showed that the vaccine protein subunit
was well tolerated and highly immunogenic [145].
Another report showed that RBD-vaccine retained
neutralizing effects against Beta and Gamma variants
and maintained its neutralizing activity against the Delta
strain [147].

mRNA vaccine
mRNA vaccines contain RNA molecules that encode thepathogen’s protein or antigen to trigger a protective
antigen-specific immune response in the human body.
This vaccine has emerged as a noninfectious andnonintegrating platform for vaccine development withno potential risk of infection or insertional mutagenesis.
mRNA vaccine is a promising alternative to traditional
vaccine approaches due to their safety, potency, strong
immunogenicity, low-cost production, fast manufacturing, inherent adjuvant qualities, and unique administration system [148,149]. Unlike DNA vaccines that need toenter the nucleus, this vaccine only needs to enter thecytoplasm to achieve target antigen expression. RNA
molecules are delivered via lipid nanoparticles (LNPs)
directly into the host cell and mRNA sends instructions
to the ribosome in the cytoplasm of the human body cellthat is translated into the target protein [150,151]. Oncethe process is complete, mRNA is digested byribonuclease [152,153]. As mRNA does not crossthrough the nuclear membrane, therefore, the risk ofunanticipated long-term expression and genetic integration is eliminated [150,154].
Currently two mRNA vaccines, namely, BNT162b2(Pfizer-BioNTech) and mRNA-1273 (Moderna biotechnologies Inc.) were approved by the FDA for
emergency use as a prevention against SARS-CoV-2
infection. Both vaccines, BNT162b2 and mRNA-1273
are novel lipid nanoparticle (LNP)-encapsulated mRNAbased vaccine that encodes for a full-length, prefusion
stabilized spike (S) protein of SARS-CoV-2. These LNPs
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the mRNA and promotes its intracellular uptake[155,156].

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BioNTech-Pfizer COVID-19 vaccine(BNT162b2)
BNT162b2 was prepared by BioNTech with support
from the pharmaceutical company Pfizer [157]. The
mRNA is packaged in a lipid nanoparticle and encodes
the entire spike protein [157,158]. The preliminary datafrom phase 2/3 clinical trials demonstrated that
BNT162b2 had 95% efficacy in preventing symptomatic
SARS-CoV-2 infections [157]. Moreover, recent studies
reported that the BNT162b2 vaccine provides strong
protection (95%) against the COVID-19 variants
detected in the United Kingdom (B.1.1.7) and South
Africa (B.1.351) [159,160]. According to another study,
the vaccine effectiveness of two doses of the BNT162b2
was found to be 93.7% and 88.0% against the reported
infection for the Alpha and Delta variants, respectively[161]. Another study from the United Kingdom foundthat the Pfizer BioNTech-Comirnaty vaccine had 90%
effectiveness against infection for Delta 14 days following the second dose [162]. Moreover, this vaccine is 75%
effective against documented infection for the Beta
variant and retains broad efficacy against the Gamma
variant in people 80–96 years of age [159,163].
Moderna vaccine-mRNA-1273
The mRNA-1273 vaccine was developed by Moderna
Biotechnologies Inc. and the National Institute of Allergy
and Infectious Diseases. The mRNA is encapsulated inlipid nanoparticles (LNPs) and encodes the entire 1273
amino acid sequence of protein spike (S) protein of
SARS-CoV-2 virus and is therefore named mRNA-1273
vaccine. The results of a phase III clinical trial showed thattwo doses of the Moderna-mRNA-1273 vaccine were
94.1% (95% CI: 89.3–96.8) effective against COVID-19
infection [164]. Another study from Spain also demonstrated that the effectiveness of the Moderna-mRNA1273 vaccine was 86% (95% CI: 56–95) against infection
with Alpha variants [165] the vaccine was found toprovide continuous protection against infection for the
Beta variant [166]. According to the results of anotherstudy, the vaccine effectiveness of the second dose wasfound to be 95.5% (95% CI: 90.9–97.8) against infection
14 days for the Gamma variant. Whereas, the results of anegative test case-control study demonstrated that thevaccine was found to be highly effective against infection
for the Delta variant 14 to 60 days following the second
dose (VE: 94.1%, 95% CI: 90.5–96.3), while it declined
to 80.0% (95% CI: 70.2–86.6) for 151–180 days
following the second dose [167]. According to theretrospective cohort study from the Czech Republic, thevaccine effectiveness of two doses was found to be 47%(95% CI: 45–49) against reported infection for the
Omicron variant [168]. Further studies are needed toconfirm vaccine effectiveness against the emerging
COVID-19 variants.

CureVac N.V. CureVac/CVnCoV vaccine
Another vaccine named CVnCoV Vaccine is manufactured by CureVac biotech firm in association with Bayer
Pharmaceutical Company. This vaccine competes with
the Moderna and Pfizer-BioNTech vaccines and has anatural, nonchemically modified synthetic mRNA that
encodes the full-length S glycoprotein [142]. Data fromphase 1 clinical trials showed that CVnCoV was safe andtolerable in all participants [169]. Results of the phase 2b/
3 clinical trials indicated that the vaccine is 48.2%
effective against symptomatic coronavirus infection cases,
70.7% effective against moderate-to-severe infection, and100% against hospitalization and death [170].

DNA vaccine
DNA-based vaccine inserts delivering gene or its
fragment (encoding a viral antigen) into the host cells
especially the antigen-presenting cells (APC) by using a
DNA-plasmids vector. Once, genetic material deliveredby this vaccine is translocated to the host’s cell nucleus; themammalian promotor present in the vector is thenactivated and elicits the transcription and translation of
the target translocated gene into protein through host cellmachinery [171,172]. The method used to inject plasmid
DNA (as a vector) into the cell is electroporation which
produces brief electrical pulses to reversibly open small
pores in the cell membrane to allow the entrance ofplasmid DNA into the cell. This vaccine approachstimulates humoral as well as cell-mediated immune
responses efficiently [171,173]. DNA vaccines arenoninfectious, easy to produce, cost-effective, and stable.
However, DNA vaccine needs to cross the nuclear
membrane to become translated which is a major
limitation of this vaccine. It may produce antibodies
against itself which is another disadvantage of thisapproach [174]. Recently DNA vaccines have beendeveloped against the SARS-CoV-2 virus by different
research groups.

INO-4800 vaccine
Inovio Pharmaceuticals developed a DNA vaccine named
INO-4800 that encodes the S protein of the SARS-CoV2 virus which is used as an antigen of DNA vaccine.
Moreover, to improve the DNA vaccine potency, Inovio’s
DNA medicines deliver plasmids intradermally byelectroporation device (CELLECTRA). An electricpulse is then applied to reversibly open small pores in
the cell membrane so that the plasmid can enter the cells[175,176]. The preliminary data demonstrated INO4800 as a potential COVID-19 vaccine candidate,
supporting further translational study [177]. On December 14, 2021, Inovio released Clinical Data on Phase 1
and 2 trials that demonstrated INO-4800 appears safe andtolerable as a primary series and as a booster with theinduction of both humoral and cellular immune

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responses. In addition to eliciting neutralizing antibodies,
INO-4800 also induced T-cell immune responses as
demonstrated by IFNg ELISpot [178].

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Zydus Cadila ZyCoV-D COVID-19 vaccine(ZyCoV-D)
It is the first plasmid DNA vaccine for human use,
prepared by Zydus Cadila, India. It comprises a DNA
plasmid vector pVAX1 carrying the gene encoding the S
glycoprotein and the sequence encoding for the IgE
signal peptide. ZyCoV-D is the first COVID-19 vaccine
approved for young adults older than 12 years [179–183].
The DNA vaccine candidate was found to be safe andtolerable during the phase 1 part of the phase 1/2 clinical
trials [183]. Further, Interim data from the phase 3 clinical
trial reported an efficacy of 66.6% against symptomaticcases [180].

preventing mild cases, and 100% protective efficacy inthe prevention of severe cases [193]. Recent studies
revealed that the vaccine is highly effective in neutralizing
and nAb activity was significantly reduced against B.1.351
and P1 by a factor of 5.27 and 3.92, respectively[194,195]. Another study revealed the nAb activity was
found to be reduced against the P1 lineage [196].
According to one report, CoronaVac has an estimatedeffectiveness of 59% against Delta [197]. One retrospective cohort study from Chile demonstrated that theefficacy of the Sinovac-CoronaVac vaccine was 37.9%
against the Omicron variant among children aged 3–
5 years 14 days following the second dose [198].
According to another study conducted in Colombia,
the vaccine was found to be 67.2% effective at preventing
hospitalization and 77.1% effective at preventing death[199].

Currently, several inactivated virus vaccines are being
developed to treat COVID-19. According to the WHO
draft landscape of SARS-CoV-2 candidate vaccines, 12
inactivated virus vaccines (14%) are currently in theclinical phase of testing. For instance, pharmaceuticalcompanies like Sinovac and Sinopharm, have produced
inactivated viral vaccines that are currently in phase 3 and
4 of clinical trials respectively [187].

Covaxin vaccine (Bharat Biotech BBV 152)
BBV 152 is a vero cell-based whole- virion inactivated
SARS-CoV-2 vaccine that was developed by Bharat
Biotech from an isolated NIV-2020-770 strain of a patientwith COVID-19 sequenced in India [200]. BBV152
showed substantial neutralizing antibody responses in thephase 1 study, which persisted up to 3 months following
the second vaccination. In contrast to the phase 1 study,
the results of phase 2 trials showed good reactogenicity,
safety, and enhanced humoral and cell-mediated immune
responses [201]. Phase 3 efficacy study reported that thevaccine efficacy was found to be 81%. Covaxin also shows
promising results in neutralizing the new UK strain
B.1.1.7 [201,202]. Other studies also demonstrate that thevaccine has a neutralizing effect approx. 3 and 2.7 fold forthe new variants B.1.351 and B.1617.2 respectively[203,204]. According to phase III analysis of Covaxin on
127 symptomatic cases, the vaccine showed 81% efficacy
against mild and moderate COVID-19 disease and against
severe COVID-19 disease was 100%. Although theefficacy against asymptomatic COVID-19 infection was
found to be 70% [205]. Phase 3 trial conducted in India
showed that the vaccine was 77.8% efficacious against
symptomatic cases and confers 65.2% protection against
the Delta variant [206].

Sinovac-CoronaVac COVID-19 vaccine
The Sinovac-CoronaVac vaccine, developed by Sinovac
Research and Development Co., Ltd, is an inactivatedvaccine created from Vero cells that have been inoculatedwith SARS-CoV-2 [188]. To determine the efficacy ofthe vaccine, two double-blinded placebo control studies
have been performed in Brazil and Turkey. These trials
demonstrated that the vaccine efficacy rate for COVID19 prevention was 53% in Brazil and 83% in Turkey[189,190]. Further, Phase 3 studies in Turkey andIndonesia showed a protective efficacy of 83.5% and65.3%, respectively [191,192]. Another phase 3 study in
Brazil showed a 50.4% protective efficacy in preventing
symptomatic infections, 78% protective efficacy in

Sinopharm vaccine (BBIBP-CorV COVID-19
vaccine)This vaccine is developed by the Sinopharm’s Beijing
Institute of Biological Products (China). China hasapproved the Sinopharm multivariant vaccine (Sinopharm’s BBIBP-CorV) for widespread use, which is a
WHO-approved inactivated virus vaccine. In thistechnology, vero-cell cultivated and inactivated formsof the virus are used. Phase I and phase II randomized
clinical trials for the BBIBP-CorV vaccine, have shownthat the vaccine is safe and well tolerated at all tested doses[207]. According to the data provided by the WHO
regarding phase III, the vaccine is 78.1% effective against
COVID-19 (symptomatic) [208]. UAE’s MOHAP

Inactivated whole-virus vaccine
Inactivate virus vaccine contains a complete virus that isinactivated by chemical, radiation, or heat. These
vaccines are fully recognized by the immune system
resulting in a powerful immune response. Vaccines against
hepatitis A, flu, polio, and rabies are examples ofinactivated virus-based vaccines [184,185]. As contains
inactivated or killed virus, this vaccine cannot replicate
and is noninfectious and safer. These vaccines are lesspotent and provide weaker immunity than live vaccines,
so the use of adjuvants and multiple boosters ofinactivated vaccines are required to achieve an effusive
immune response [186].

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previously announced interim results that revealed thevaccine provided 86% efficacy [209]. According to one
study conducted in China, the efficacy of the vaccine is79.34%, and it is 100% effective in suppressing moderate
to severe COVID-19 cases [152]. In addition, Sinopharmhas started a phase III trial in several countries in Africa,
Asia, and Europe [210–212].

Viral vector vaccine
A viral vector vaccine contains a safe modified virus as aviral vector, either replicating or nonreplicating thatdelivers the genetic code into the body to stimulate boththe cell-mediated and humoral immune response. These
vaccines have a great potential for prophylactic solution
against pathogens as these vaccines trigger the cytotoxic
T-cell which leads to the elimination of infected cells[213]. Adenovirus (different from SARS-CoV-2) is being
used in these vaccines as a viral vector to introduce
transcribed DNA segments of SARS-CoV-2 encoding
for the spike glycoprotein (antigen) into the host cells[152,214]. After vaccination, an injected vector
delivers genetic code into the body cell to make spikeglycoprotein and further activate the immune system[215]. Once spike protein is recognized by the immune
system, it starts generating specific neutralizing antibodies
followed by T cell activation which in turn destroys
spike protein and eliminates the infected cell [150,214].
Various viral vector vaccines are developed to treat
coronavirus infection such as Oxford-AstraZeneca
vaccine (AZD1222, ChAdOx1 nCoV-19), Sputunik-V
vaccine (Gam-COVID-vac), Johnson and Johnson
vaccine (Ad26.CoV-2-S) and AD5-nCoV vaccine(Convidacia) [216].

Oxford–AstraZeneca vaccine (AZD1222
COVID-19 vaccine)This vaccine is a recombinant vaccine, often referred to as
ChAdOx1 nCoV-19, manufactured by Oxford University in association with AstraZeneca [145,150,214]. Thisvaccine is constructed from a nonreplicated chimpanzee
adenoviruses vector (ChAdOx1) to transmit SARS-CoV2 spike proteins to induce an immune response [217]. The
AZD1222 vaccine has been approved by the WHO and isused in many countries worldwide [218]. Clinical trials
performed on over 60,000 adult participants in the UK,
Brazil, South Africa, Kenya, the USA, India, and Japandemonstrate that the vaccine has a safety profile with noserious adverse effects related to the vaccine [219].
According to analysis data from four ongoing blinded,
randomized, controlled trials done across the United
Kingdom, Brazil, and South Africa, the vaccine showed
an overall efficacy of 70.4% (95% CI: 54.8–80.6) for
symptomatic COVID-19. According to another analysis
in the United Kingdom, Brazil, and South Africa, theefficacy of the AZD1222 vaccine was found to be 81.3%

in participants who received two doses spaced within
12 weeks [220]. A report from the UK study showedthat the AstraZeneca vaccine is 74.5% and 67.0% effective
against the Alpha and Delta variants, respectively [221].
Further, results of the study from the United Kingdom
showed the vaccine efficacy of AZD1222 against
documented infection was found to be 73% (95% CI:
66–78) [222]. Another report showed the effectiveness ofa double-dose AZD1222 vaccine was 70.4% (95% CI:
43.6–84.5) against symptomatic infection for the Beta
variant (B.1.351) [223]. For gamma variants, theeffectiveness of a double-dose of this vaccine was foundto be 88.1% (95% CI: 82.8–91.7) in a study from Brazil[224] and results of another study showed its effectivenessis 77.9% against gamma variant [225]. Another study fromthe Czech Republic revealed that the VE of AZD1222
was 51% (95% CI: 23–69) against documented infection
for the Omicron variant [226].

Sputnik V vaccine (Gam-COVID-Vac)
Sputnik V was manufactured by the Gamaleya ResearchInstitute of Epidemiology and Microbiology (Russia’s
Ministry of Health). This is a heterologous adenoviral
vector-based vaccine constructed from two vector
components, recombinant adenovirus type 26 (rAd26)
and recombinant adenovirus type 5 (rAd5) which carry-CoV-2 gene for SARS-CoV-2 full-length glycoprotein
S [227]. The gene encoding the S-protein of SARSCoV-2 carried a rAd26 vector (first dose) that provides
humoral and cellular immunity, and the rAd5 vector(second dose) induces the formation of memory cells.
From the results of phase 3 trials, the efficacy after 3 weeksof the first dose of the vaccine was found to be 92% [228].
Recently, results of neutralizing activity analysis of
Sputnik V vaccine sera against SARS-CoV-2 variants
showed that Sputnik V vaccine efficiently neutralized the
S protein of the B.1.1.7 variant and the B.1 lineage [229],
another report indicated that the vaccine was around 90%
effective against the Delta variant [230]. An Interim
analysis of the phase 3 study showed that the efficacy of
Sputnik V was 91.6% against symptomatic COVID-19[227]. According to another report, the vaccine showed aprotective efficacy of 91.6% against COVID-19 after acomplete dose which is comprised of 2 doses given
3 weeks apart intramuscularly [228].
Janssen-Ad26.COV 2.S vaccine
The Janssen-Ad.26.COV2.S vaccine developed by the
Janssen Pharmaceutical Companies of Johnson & Johnson
is a recombinant adenoviral vector vaccine. It contains a
recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length andstabilized SARS-CoV-2 spike protein [231,232]. It
induced powerful neutralizing antibody responses andprovided almost complete protection following SARSCoV-2 infection [232,233]. This vaccine is 66% effective
in preventing disease after a single dose and is capable of
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28 days postvaccination [150,152]. An interim analysis of
the phase 3 trial showed that vaccine efficacy was 66%
against symptomatic disease [234]. A study from Spain
also demonstrated the effectiveness of Janssen-Ad26.
COV2.S vaccine was estimated to be 77% (95% CI: 27–93) against infection among close contacts with Alphainfected patients [166]. The vaccine is also highly effective
against the B.I.351 lineage observed in South Africa[142]. According to one report, one dose of the JanssenAd26.COV2.S vaccine provides effective protection
against COVID-19 when the Beta variant is predominant[235]. Results of one study also revealed that the efficacy
of Janssen-Ad26.COV2.S vaccine against the symptomatic disease, hospitalization, and death due to the Gamma
variant in Brazil was found to be 50.9%, 72.9%, and90.5% respectively [236]. The efficacy of the vaccine
against infection for the Delta variant demonstrated by astudy from Spain was estimated at 42% which is lower
than that of the Alpha variant [166]. Moreover, the study
from the Czech Republic showed that the Janssen-Ad.26.
COV2.S vaccine was 60% effective against documented
infection for the Omicron variant 14 days following thesecond dose [226].

AD5-nCoV vaccine (Convidecia/CanSino)
AD5-nCOV, trade name Convidecia, was developed by
CanSino Biologics in cooperation with the Academy of
Military Medical Sciences. It is a single-dose viral vector
vaccine for COVID-19 [237]. It consists of a recombinant, replication- defective adenovirus type-5 vector(Ad5) expressing the full-length spike protein of SARSCoV-2 [150]. Data collected from the phase 1 clinical trial
suggested that this vaccine is safer and can induce both
humoral and cellular responses [238]. CanSino Biologics
announced that the interim analysis data of the phase III
clinical trial of Convidecia demonstrated that the efficacy
vaccine was found to be 65.28% in preventing all
symptomatic COVID-19 disease 28 days after single-dose
vaccination and an efficacy of 90.07% in preventing
severe disease 28 days after single-dose (https://www.
precisionvaccinations.com/vaccines/convidicea-vaccine). Moreover, results from the Pakistan subset trial
demonstrated that AD5-nCOV is 65.7% effective inpreventing symptomatic cases and 100% effective inpreventing severe disease [239].

Live attenuated vaccine
These vaccines are developed from attenuated, weakened,or less virulent forms of pathogen to induce strong andlong-lasting cellular and humoral immunity. LAV is themost immunogenic vaccine that does not require an
adjuvant to achieve optimal response due to its
effectiveness in mediating immunity by mimicking
natural infection [240]. This vaccine cannot be given
to immunocompromised patients, infants, and elderly

people due to the risk of reversion of virulent strain [241].
Currently, a live attenuated vaccine named COVI-VAC
using deoptimization technology developed by Codagenix Biotech Inc. in collaboration with Serum Instituteof India [242]. This is also reported; the University ofHong Kong developed an LAV influenza-based vaccine
strain with the deletion in the NS1 gene [243].

Virus-like particle based vaccine
Virus-like particle (VLP) are virus particles that areformed by structural viral protein which are selfassembled into protein nanoparticles and mimic theoverall structure of a virus/pathogen. They are noninfectious and nonreplicative as they lack genomic
components [244–246]. Because no viral inactivation
step or live viruses are involved in the production of the
VPL vaccine, VPL can be easily developed in a lowcontainment production facility [247]. Particle size andthe repetitive antigenic surface of the VPL vaccine elicits arobust antibody response by cross-linking the B-cellsurface receptor [248–250]. VLP vaccine technology wasutilized to develop against SARS-CoV-2. Currently,
there are 9 VLP vaccines have been developed against
SARS-CoV-2, among which five are being evaluated inclinical trials. The main antigenic component of thesevaccines is the S protein, specifically the RBD, which is
involved in viral entry and antibody neutralization[251,252]. Recently, the Central Committee on Research Involving Human Subjects in the Netherlands
approved an ABNCoV2 capsid virus-like particle-based
COVID-19 vaccine developed by AdaptVac, a PREVENT-nCoV consortium member [253].

COVID-19 pandemic in JapanThe first case of COVID-19 in Japan was recognized by
the government on January 16, 2020 and the first death
was recorded on 14 Feb of the same year. The vaccination
was started on February 17, 2021, Japan approved Pfizer–
BioNTech, Moderna, and Oxford–AstraZeneca for use.
The number of confirmed cases of COVID-19 in Japan
reached 33 803 574 with 74 694 deaths and 33 728 878
recovered [254]. According to the medical task-force
advice to the government, three important issues to deal
with are; early detection and response to clusters, earlypatient diagnosis and intensive care for the severely ill, andbehavior modification of citizens [255]. Cluster Response Team (Ministry of Health, Labor and Welfare) wasestablished in February 2020 to identify small-scale
clusters of COVID-19 infections before they grow intomega-clusters. The Japanese government also focuses on
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work style changes such as remote work, avoidance of
close contact settings, wearing masks, refraining fromtalking on public transportation, and long-distancetraveling were also taken into consideration. In May
2023, Japan decided to downgrade the status of thecoronavirus from strict category 2 (which includes
tuberculosis) to category 5 of common infectious diseases
and seasonal flu [257]. The number of new patients has
been on a gradual upward trend since early April 2023
and has continued to increase, while in Okinawa
Prefecture the numbers have been declining since earlyJuly. The number of new patients across the country by
age group is increasing in all age groups except for thosein their teens. As for the mutant strains, XBB.1.9 strains
are unchanged, XBB.1.16 strains and XBB.2.3 strains
increasing, and XBB.1.5 strains decreasing [258].

Designed a plasmid-based nasal COVID-19
vaccine at HIC clinic, Japan
Nasal vaccines offer new benefits for use and efficacy, as
they are easy to deliver and can be used by the individual
without medical staff assistance by using a suitable device
for the nasal application, with minimum discomfort[259]. Another advantage is that nasal vaccination induces
both mucosal and systemic immunity while intramuscular
vaccination primarily induces systemic immune response[260].
We in our molecular biology laboratory at HIC-Clinic
construct a plasmid-based COVID-19 vaccine that can beadministrated via the nasal route. SARS-CoV-2 can betransmitted by respiratory particles released from aninfected subject, aerosol from the infected subjects, due totheir smaller diameter (<5 mm) can infect subjects at
higher distances via the nasal entry [261]. The mucous
membrane of the nose and throat is an importantcomponent of the immune system, one of the first lines ofdefense against germs entering from outside the body. It
contains antibacterial enzymes found in the mucus, cilia
move out the mucus from the airway and they also
contain antibodies most important of which is IgA. The
SARS-CoV-2 virus first infects the nose and throat before
spreading to the lungs, where severe COVID-19 candevelop. This entry gate of the nose and throat is always
exposed to the fresh attacker virus from the environment,even after the development of the blood antibodies after
the usual injected vaccines, these entry points are difficult
to reach, and the injected vaccines often fail to prevent thevirus infection through the upper respiratory tract [262].
Nasal vaccine application can induce both mucosal andsystemic immune responses [263]. Secretory IgA (dimericform) is the main immunoglobulin found in mucous
secretions and also in small amounts in blood [264]. In

response to luminal stimulation by vaccines, antigenpresenting cells in epithelial cells, Peyer’s patches, andlymph follicles will produce cytokines and stimulate theB-cells to produce IgA [265]. Helper T Cells and NKT
cell-derived cytokines play an important role in the
production of high-affinity IgA [259]. Spike (S)glycoprotein has a crucial role in virus attachment andentry by binding angiotensin-converting enzyme 2(ACE2) receptors through its receptor-binding domain,
and this S protein is being widely used as a target for
vaccine development. Based on our experience in thedevelopment of anticancer gene therapy and plasmidbased cancer vaccines [266], we designed recombinant
COVID-19 vaccines and tested them for their efficacy.
The plasmid construction for the expression of SARSCoV2 spike protein was performed under an enhanced
Human cytomegalovirus immediate-early (CMV) promoter for high-level expression of recombinant proteinsin mammalian cells. Here the ampicillin resistance gene
plasmid was used, and the gene insert sequence for surface
glycoprotein was selected as is available from the NCBI
database (GenBank: MN908947.3). Following Fig. 1
demonstrates the cellular and humoral response elicited
after the coronal nasal DNA vaccine.

Delivery device of HIC clinic nasal
COVID-19 vaccine
We developed a delivery device for nasal vaccines withalready-in-use clinical-grade components and rapping.
The components are shown in Fig. 2, and the main fillingbody is one ml syringe of the NIPRO Japan.

Challenges and future perspectives
The COVID-19 pandemic has spread globally andbecome the world’s most lethal threat and contagious
disease to the health of the global population, especiallywith the emergence of variants of the SARS-CoV-2
virus. These immune evasive variants integrate themutation to the spike protein which could affect immune
recognition of antibodies derived from existing vaccinesand hinder the therapeutic antibody function thus
affecting the degree of protection by vaccines [267].
Hence, questions have been raised concerning theeffectiveness of developed vaccines against new variants.
Moreover, previous studies on coronaviruses also showedthat various mutations in the target proteins of thecoronaviruses can be associated with drug resistance andchanges in the structures of target proteins that may leadto vaccine inefficacy [23]. Therefore, the uncertainty overlong-lasting protection against COVID-19 has also risen.
It is crucial to determine how long a protective immune

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Fig. 1. Demonstration of local effect and systemic after coronal nasal DNA vaccine.

response can be maintained in an individual after
vaccination [268,269]. Because some cases of patientswith reinfection have been reported who had recoveredfrom COVID-19. Ideally, vaccination should induce
long-term immunity, but annual vaccination would befeasible based on experiences with the annual influenza
vaccine [270,271]. To induce long-lasting protective
immunity, the additional boosting dose of an updated
vaccine is required especially for those who are
immunocompromised, and have concomitant comorbidities to enhance antigen-specific immunity [131]. To
improve the vaccine’s protective efficacy adjuvant with
better immunogenicity may play an important role [272].
In addition, vaccine effectiveness affected by immuneevasive variants could improve with the development ofmultiple epitope-based vaccines, so in case one epitope

does not respond the other could take over andconclusively vaccine efficacy could enhance [253].
Nevertheless, considering the continuous emergence of
new variants, pursuing research on variants, developing
long-term studies, and clinical trials on a large scale arepivotal in determining the efficacy of existing vaccines
against variants and the currently authorized vaccines mayneed to be updated periodically to avoid clinical efficacy
loss (Figs. 3–5).
Another great challenge due to the mutation in spike
protein is the increase in the transmissibility of virus
variants. Human-to-human transmission of SARS-CoV2 is highly observed even in hospital settings, althoughstrict isolation and quarantine measures are ensured at
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Fig. 2. Nasal COVID-19 vaccine delivery device components. Photograph of an un-filled nasal vaccine device to show its
components in a clean bench. The upper device is a complete and final form with all three components attached. Below is an
exploded image of the device with all three components separated.

were found to be infected in hospital settings, out of
which 29% were medical staff [274]. Transmission in
hospital and healthcare settings poses a very serious threat
and requires strict vigilance to control virus transmission.
It is crucial to track the SARS-CoV-2 mutations/variants,
and countries all around the world should increase theattention to disease surveillance systems and scale up
response operations to control the spread of the SARSCoV-2 virus and keep strict attention on following all thepreventive measures must be continued by every
individual to control the spread of SARS-CoV-2 virus.

Most importantly, advocates vaccinating unvaccinatedindividuals as a priority in suppressing the transmission
and mutation of SARS-CoV-2 and guiding them tofollow hygiene guidelines after vaccination is a vital
strategy that may contribute to better limiting SARSCoV-2 spread [275].
Another challenge that may become a matter of concern
for the prevention of diseases by vaccination is theantibody-dependent enhancement (ADE) phenomenon.
ADE exists in several kinds of viruses. Viral infection

Fig. 3. Nasal COVID-19 vaccine delivery device in packaging envelope. Photograph of a filled device in its sterilized envelopewith a label for the description and date of the drug inside.

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Fig. 4. Nasal COVID-19 vaccine delivery device unpacking from the packaging. Photograph of a filled device before use. The
surface or table used should be clean and sterilized, as well as the hands of the person involved.

initiates with the attachment of the virus particle to thecytoplasm membrane on the cell surface, to block thisviral attachment, antibodies are secreted that target theviral surface proteins specifically, and control infections byneutralizing the viruses, weakening their infective ability.
However, in ADE incidence, the binding of specificantibodies to viral surface proteins can promote viralinvasion into the cell through Fc receptors, thus
enhancing viral infection [276]. Previous studies demonstrate that neutralizing antibodies against RBD of MERSCoV and SARS-CoV facilitated virus entry into Fc

Fig. 5. Nasal COVID-19 vaccine delivery device self-application by the person. Photograph of a filled device during theself-application of nasal vaccine by the person.

receptor-expressing human cells in vitro [277]. In thecurrent pandemic, several specialists have suggested that
immune responses against SARS-CoV-2 could lead to
ADE [279]. However, the incidence of SARS-CoV-2
ADE has not yet been proven [278]. An alternative target
to overcome ADE may be the nonsurface proteins, suchas the nucleocapsid (N) protein. Because the N protein is
not on the virus surface, its antibodies cannot promotevirus entry. Nucleic acid based vaccines such as DNA andRNA-based platforms could quickly provide solutions to
bypass such issues, as motifs of the vaccine antigen thatcause ADE could be easily engineered or removed [279].
Moreover, another issue is the vaccine development
process (up to licensing of the vaccine) which in itself is along and expensive process and generally, it takes nearabout 10 years to develop a novel vaccine and requires ahuge amount of money [280]. It has been estimated that
almost US$31–68 million is required to bring a vaccine
candidate to the end of phase-II trials [281]. Most
importantly, collaboration is the most significant strategy
for therapeutic development and new research [282].
Therefore, collaborations between different representatives from academia and biopharmaceutical companies
might help to develop effective vaccines very quickly.
Another important concern about vaccines is that vaccine
candidates are tested on certain numbers of a population
instead of all population groups, therefore different
population groups such as elderly, young, special patients,
and immunocompromised individuals, pregnant andbreastfeeding women are not considered in the initial
vaccine research, hence, unwarranted adverse effects may
observe in these groups during general and universal useof the vaccine [283]. Another greater challenge regarding
vaccination is vaccine hesitancy which is extensively
prevalent not only in developing countries but also intechnologically advanced countries with a high literacy

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rate. Vaccine refusal has been an issue physicians have had
to deal with even in prepandemic times. Regarding the
COVID-19 pandemic, there has been growing COVID19 vaccine hesitancy [284,285]. Understanding thevaccine hesitancy is essential to achieve the desired levelof immunization. When a vaccine with a high percentage
of efficacy, is introduced/used in public, but it does notshow the desired effect as expected, peoples erodes
confidence in that vaccine. As a result, fewer people
accept the vaccine, which makes the pandemic worse.
Another reason for developing vaccine hesitancy inpublic is the spreading of scientific-sound misinformation
regarding vaccines. As COVID-19 vaccines have only
been recently introduced worldwide, in a much fasterperiod compared to a typical vaccine development [286],
acceptance of vaccines against SARS-CoV-2 presented apublic health challenge due to false information throughsocial media platforms that vaccine trial participants havedied after taking a candidate COVID-19 vaccine.
Reduced available data on safety and efficiency also
contributed to this issue [287]. Therefore, it is very
important to improve vaccine acceptance and reduce
vaccine hesitancy, the scientific community and healthcare staff build trust and establish effective communication between the people and the public health system andprovide them with transparent information regarding
vaccine safety and effectiveness [288].
One of the important challenges of vaccination is the issue
of inequality in the distribution of vaccines which has
affected many people’s lives around the world, especiallyin poor and less developed countries [289]. Developed
countries continue to sign agreements with the world’s
largest pharmaceutical companies to purchase vaccines
more than their requirements at prices that are notpossible for most countries. Therefore, developing
countries face acute problems in obtaining vaccines[290,291]. To overcome the existence of these inequalities, WHO with other international organizations suchas the Global Alliance for Vaccines and Immunizations(GAVI) and Coalition for Epidemic Preparedness
Innovations (CEPI) have made efforts to establish asystem to ensure the right and equitable distribution of
vaccine named the COVID-19 Vaccines Global Access(COVAX). In September 2020, the WHO under
COVAX outlined the vaccine distribution policy[292]. Though these efforts significantly contributed tobuilding a fair vaccination distribution plan [293], but it
has been witnessed globally during the pandemic that
income has been an important factor i.e., high-income
countries have achieved the fastest vaccine [294].
Another important issue is related to vaccine storage, andtransportation, which puts an extra financial burden on
developing countries. Most of the vaccines store significantly at low storage temperatures that are below thefreezing point, which is difficult to maintain for longer
durations and poses a huge limitation in developing

countries. Further, vaccines must be protected from direct
exposure to sunlight and ultraviolet light which makes theirhandling more difficult [227]. Despite the rapid development and global distribution of vaccines in various
countries, the number of individuals vaccinated still
represented a small proportion of the world [295].
Investments in vaccine developments against new variants
must be accompanied by investments in planned immunization infrastructure, disease surveillance, and public healthto mitigate the devastating effects of COVID-19 pandemic.
Public health measures, such as introducing mandatory
masks to reduce viral transmission, and creating awarenessamong people regarding social distancing play a basic rolein controlling the spread of infection.

Conclusion
COVID-19 has been a dreadful threat in this era for
mankind. To date, several vaccines with high efficacy havebeen developed in various countries all over the world.
Despite the availability of the highly effective vaccine, thispandemic is still causing a high mortality rate, and therecent hit by devastating multiple waves of coronavirus
places a significant concern on the state, government,
healthcare services, scientists, and researchers in establishing successful and effective vaccines, therapeutics andstrategies to cope with coming waves. Evidently, more
research is required to improve the efficacy and safety ofdeveloped vaccines by increasing neutralizing antibodies
because the emergence of multiple variants of the SARSCoV-2 virus causes an increase in their infectivity, ability
to escape host immune response, and decreased
neutralization from vaccination. Nevertheless, adherence
to precautionary hygiene measures (including handwashing, wearing masks, and social distancing), continuous monitoring, and high throughput sequencing of the
SARS-CoV-2 virus genome, and vaccination are crucial
steps in the prevention of virus transmission and early
detection of variants to combat this pandemic.

Acknowledgements
Funding: The author(s) received no financial support for
the research, authorship, and/or publication ofthis article.
Authors contributions: R.Q. conceptualized, researched,
and wrote this manuscript. All authors have read andagreed to the published version of the final manuscript.

Conflicts of interest
The author(s) declared no potential conflicts of interest
concerning the authorship, and/or publication ofthis article.

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