Archives of Microbiology (2022) 204:8

https://doi.org/10.1007/s00203-021-02606-x

MINI-REVIEW

COVID‑19: comprehensive review on mutations and current vaccines

Ananda Vardhan Hebbani1 · Swetha Pulakuntla2 · Padmavathi Pannuru3 · Sreelatha Aramgam2,4 ·
Kameswara Rao Badri5,6 · Vaddi Damodara Reddy2 

Received: 3 August 2021 / Revised: 9 November 2021 / Accepted: 22 November 2021 / Published online: 6 December 2021
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
Viral outbreaks had been a threat for the human race for a long time. Several epidemics and pandemics have been reported
in the past with serious consequences on human health and subsequent social and economic aspects. According to WHO,
viral infections continue to be a major health concern globally. Novel coronavirus, SARS-CoV-2 (Severe acute respiratory
syndrome coronavirus-2) causes the most recent infectious pandemic disease, COVID-19 (Coronavirus disease-19). As of
now, there were 249 million infections of COVID-19 worldwide with a high mortality of more than 5 million deaths reported;
and the number of new additional cases is drastically increasing. Development of therapies to treat the infected cases and
prophylactic agents including vaccines that are effective towards different variants are crucial to curtail the COVID-19
pandemic. Owing to the fact that there is a high mortality and morbidity rate along with the risk of virus causing further
epidemic outbursts, development of additional effective therapeutic and preventive strategies are highly warranted. Preven-
tion, early detection and treatment will reduce the spread of COVID-19 pandemic. The present review highlights the novel
mutations and therapeutic updates associated with coronaviruses along with the clinical manifestations—diagnosis, clinical
management and, prophylactic and therapeutic strategies of COVID-19 infection.

Keywords  SARS-CoV-2 · Mutations · COVID-19 · Clinical management · Therapeutic strategies

Introduction
Communicated by Erko Stackebrandt.
An incidence of unidentified pneumonia caused by 2019-
Ananda Vardhan Hebbani and Swetha Pulakuntla contributed nCoV/SARS-CoV-2 (Severe Acute Respiratory Syndrome
equally.
Coronovirus-2) was reported in the Wuhan city, China in
* Kameswara Rao Badri the final months of 2019 (Zhou et al. 2020). The uniden-
[email protected] tified pneumonia was termed as COVID-19 (Coronavirus
* Vaddi Damodara Reddy disease-19) considered to have spread from bats to humans.
[email protected] The mode of spreading from human to human is predomi-
1
nantly, through airborne respiratory droplet contact. The
Department of Biochemistry, Indian Academy Degree
College, Bengaluru 560 043, India basic reproduction number (R0) of the virus is analyzed
2
to be in between 1.4 and 6.47 across different countries,
Department of Biochemistry, REVA University,
Bengaluru 560064, India which is not just of wider range when compared to the other
3
corona viral infections, but also stands at a position very
DR Biosciences, Research and Development Institute,
Bettahalasur, Bengaluru 562157, India
near after the other well-known infectious diseases such as
4
Measles, Chickenpox, Mumps, Polio and Rubella (Liu et al.
Department of Radiation Oncology, Emory University
School of Medicine, Atlanta, GA 30322, USA
2020; Tang et al. 2020). Genetic and phylogenetic analysis
5
revealed that SARS-CoV-2 belongs to β-coronaviruses along
Department of Pharmacology and Toxicology,
Cardiovascular Research Institute, Morehouse School
with the other two predominant members, i.e., MERS-CoV
of Medicine, Atlanta, GA 30310, USA (Middle East respiratory syndrome-related coronavirus)
6
Clinical Analytical Chemistry Laboratory, Clinical Research
and SARS-CoV (severe acute respiratory syndrome coro-
Center, Morehouse School of Medicine, Atlanta, GA 30310, navirus) (Leao et al. 2020). All the recent viral infection
USA

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threat includes SARS of 2003 being caused by SARS-CoV, family of Coronaviruses (CoVs) belongs to the suborder
MERS of 2012 being caused by MERS-CoV and COVID- Cornidovirineae, order Nidovirales, phylum Incertae sedis
19 of 2019 being caused by SARS-CoV-2; belongs to the and realm Riboviria. The Coronaviridae family has 2 sub-
same family, Coronaviridae (Gorbalenya et al. 2020). Over families, 5 genera, 27 subgenera and 46 species, based on
20 different viral families are being clinically characterized serologic and genetic analysis (de Groot et al. 2013; Pas-
for their disease causing potential and transmission pattern carella et al. 2020).The detailed genetic lineages are pre-
amongst which Coronaviridae family is being investigated sented in Figs. 1 and 2. There are similarities either in the
quite significantly, but still a long way to go given the mor- perspective of disease caused or viral receptor type/distribu-
bidity and mortality associated (Gorbalenya and Siddell tion amongst the human coronaviruses and the details are
2021). Though initiated and appeared as a simple unidenti- summarized in Table 1.
fied form of pneumonia, COVID-19 is one of the very few
viral infections which transformed into a global pandemic
in a very short span of time. Globally, the wavy pattern of Structure and epidemiology of SARS‑CoV‑2
COVID-19 infection and mortality rate is certainly attribut-
able to the rate of its mutation and this review is an attempt CoVs are roughly spherical, moderately pleomorphic
to understand the same. and a typical virion has been reported to be of an average
COVID-19 has a wavy pattern of infection / mortality diameter of 80–125 nm, enveloped, with single stranded
rates, understanding the mutations and their associated epi- positive (-sense) RNA viruses with a nucleocapsid. The
demiology will be interesting. RNA genome is of 26–32 kb in size with 7–10 translatable
ORFs (open reading frames). ORF1a and b are translated
into proteins, pp1a and pp1ab (polyprotein 1a and 1ab).
Viral lineage These polyproteins will be processed by viral proteases
to synthesize 16 non-structural proteins. Among those,
According to the Coronaviridae study group of Animal RNA-dependent RNA-polymerase enzyme (RdRp) is one
ssRNA + viruses subcommittee of the ICTV (International that aids in replicating viral RNA through transcription of
Virus Taxonomy committee), Coronaviridae is the largest a minus strand template, during which CoVs generate 6

Coronaviridae
Family

Letovirinae Orthocoronavirinae
Subfamily Subfamily

Alphaletovirus Alphacoronavirus Betacoronavirus Deltacoronavirus Gammacoronavirus

Genus Genus Genus Genus Genus

1 subgenera with 1 14 subgenera with 5 subgenera with 26 3 subgenera with 7 3 subgenera with 5
species species species species
19 species out of which
2 species are known to
affect humans

Human coronavirus
229E of subgenus
Duvinacovirus

Human coronavirus
NL63 of subgenus
Setracovirus

Fig. 1  Genetic lineage of Corona family

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Betacoronavirus
Genus

Embecovirus
Hibecovirus Merbecovirus Nobecovirus Sarbecovirus
Subgenus

Bat Hp- Severe acute

Hedgehog coronavirus Eidolon bat
Betacoronavirus 1 betacoronavirus respiratory syndrome-
1 coronavirus C704
Zhejiang2013 related coronavirus

Middle East
China Raus Rouseus bat
respiratory syndrome-
coronavirus HKU24 coronavirus GCCDC1
related coronavirus

Human coronavirus Pipistrellus bat Rouseus bat

HKU1 coronavirus HKU5 coronavirus HKU9

Tylonycteris bat
Murine coronavirus
coronavirus HKU4

Myodes coronavirus
2JL14

Fig. 2  Genetic lineage of Corona viruses

Table 1  Comparison of the viral host receptor and its distribution in humans

Human disease Corona virus Viral host receptor Receptor distribution in the body

Mild respiratory infections HCoV-NL63 ACE2 Epithelial lining in nose, mouth and lungs
Also in heart, blood vessels, kidneys, liver and GI tract
Mild respiratory infections HCoV-229E ANPEP Small intestine, renal microvillar membrane and other
plasma membranes
Mild respiratory infections HCoV-OC43 9-O-Ac-Sia Unknown
Mild respiratory infections HCoV-HKU1 9-O-Ac-Sia Unknown
Mild respiratory infections or SARS SARS-CoV ACE2 Epithelial lining in nose, mouth and lungs
Also in heart, blood vessels, kidneys, liver and GI tract
Mild or severe MERS MERS-CoV DPP4 Epithelial lining of lungs and kidneys
Mild or severe COVID-19 SARS-CoV-2 ACE2 Epithelial lining in nose, mouth and lungs
Also in heart, blood vessels, kidneys, liver and GI tract

to 9 sub-genomic mRNAs (sgmRNAs) that help in trans- Mutation types and frequency

lation of the accessory and structural proteins from the in SARS‑CoV‑2 genomes
downstream ORFs. Viral genome also codes for all the
necessary viral structural and functional proteins (viral We have reported different global mutations of SARS-
infection and replication) including envelope protein (E), CoV-2 presented globally during Dec 2019 to June 2021.
nucleocapsid protein (N), membrane protein (M) and spike This data were collected from multiple resources including
protein (S) (Ahn et al. 2020).

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PubMed (https://​p ubmed.​n cbi.​n lm.​n ih.​g ov/), Genbank proteins (nsps) that are important for the viral replications.
(https://​w ww.​n cbi.​n lm.​n ih.​g ov/​genba​n k/) database and NSPs has the highest number of missense mutations in
GISAID (https://​www.​gisaid.​org/) genomic database. In the ORF1ab region found in 1905 mutations. Out of total
this review, we have reported maximum number of iden- mutations 3328, 1344 are synonymous mutations 57 are
tified mutations; non-synonymous, synonymous, point deletion mutations, 2 are insertion mutations, 7 are frame
mutations, deletions, and silent mutations of the whole shift deletion mutations, and 13 are stop-gained (Koyama
genome from multiple sources and the data are presented et al. 2020). The most frequent mutations E191G, G76S,
in Table 2. K61N, V259L, T176I, L140V, T269M and V88L are in the
Non-structural proteins of the coronavirus whole- ORF region. We have reported multiple mutations in nsp,
genome encodes 6 ORFs, the largest occupied by ORF1ab RdRp including P323L and 11 deletions in the conserved
polyproteins which can produce the 16 non-structural region that may be useful for the drug target for antiviral
drugs (Yang et al. 2020).

Table 2  Global SARS-CoV-2 viral mutations

Country Mutations References

India D614G, P323L, G1124V, R203K and G204R, Q271R, R78M, E583D, L54F, Maitra et al. (2020); Baner-
K77M, A520S, A706S, G1251V, T22I, E471Q, S494P, G1124V, Q271R, jee et al. (2020)
L5F, F2L, G261S,M177I, L7I, E156D, S162I, T572I, Q6771H, L18F,
E224G, A243S, T299I, P82L, D290Y, K558N, D574H, R634S, I402L,
Y28H, T274I, T323I, T1027I, H49Y, T602I, A879S, V1104L, P1263L,
M731R, F797C, T761S, L828P, A831S, G857C, A930T, H1101Y, K1191N,
A771V,T1027I, C1243F, G769V, C1250F, G125V, V1068V, S1021F, A892V
Worldwide (Europe, China, S-protein:D614G,L752F, F32I, H655Y, V483A, F157L, V615L, K202N, Yang et al. (2020)
North America, Asia, South S939F, F797C, A930V, R408I, V367F, Q409E, S254F, A435S, D1146E,
America) S247R and P1143L
ORF Region:E191G, G76S, K61N, V259L, T176I, L140V, T269M and V88L
N: K247I, S194L, P46S, S327L, E378Q, and D343V
ORF8:T11I, L84S, S97N, and S67F
ORF7a: P34S, Q62*, and H73Q
ORF10: P10S and I13M
E:S6L
Globe wise Non-Synomous:L84S, D614G, G251V, P214L, R203K, G204R, Q57H, Kim et al. (2020)
N679Y, S680P, Q677H, Q675H, T175M and D3G
Synonymous: D467V, I468F, I468T, I472V, G476S, S477G, V483A, P491R,
Y508H, R509K and V510L
Multiple countries L54F, A27V, T29I, H49I, H49Y, E96D, D111N, T240I, G176V, A348T, Mercatelli and Giorgi (2020)
G476S, V483A, A520S, H519Q, D614G, D936Y, A1078V and D1259H,
F106F, P314L, Q57H, G203K&R, T85I,L37F, Y446Y, G251V, S76S, L84S,
L7L, M54K, P504L, P585S, I559V, R337R, D268*, G212D,S247R, V378I,
L84S, G392D, A376T, P334S, L3606F, G251V
India T19R, K77T, T95I, G142D, E154K, N440K, L452R, T478K, E484Q, D614G, Cherian et al. (2021)
P681R, D950N, Q1071H, H1101D
China F2L, Q14S, V16L, T29S, K41T, V42I, S46N T51S, D53G, F59Y, I62L, S65N, Pulakuntla et al. (2021)
F73V, N81K, V84I, S91A, I101V, T114S, V127I, E132N, F140Y, Q173K
L176M, M177L, L179M, Q183S, K187D, N188T, I210V, N211D, L212V,
D215N, D228E, L229I, R237K, Q239R, A243T, L244I, A262S, L276M,
E281Q, A292S, T299A, F306L, T345S, A371T, I402V, R403K, N440K,
S443A, V445T, G447D, N460K, A61T, N68G, R72K, K147N, S151T,
F489Y, Q492E, Q497H, N500T, G503N, Y507F, H528N, A520G, V171I,
I197V, N531T, N555K, K557Q, A569S,D614G V 622M, D627E,T632A,
T638A, S640A I651V, I666V, Q675H, T676S, T678S, S708A, L752F,
A1078T, G1093A S221A, S255E, A260T, K278S, S689Q, Q690R, V1104I,
V1228I
RUSSIA D138H, D614G
ITALY L5F, Q239K, D614G, T630S
USA L5F, V367F, D614G, A892S

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Mutations associated with coronavirus structural SARS‑CoV‑2 variants and Delta variant

proteins
There are multiple SARS-CoV-2 variants that include Alpha
Spike Glycoprotein mutations (B.1.1.7, Q.1–Q.8), Beta (B.1.351, B.1.351.2, B.1.351.3),
Delta (B.1.617.2, AY.1, AY.2, AY.3), Gamma (P.1, P.1.1,
The spike (S) region is a large multifunctional and trans- P.1.2), Epsilon (B.1.427, B.1.429), Eta (B.1.525), Iota
membrane protein. In spike protein, the receptor-binding (B.1.526), Kappa (B.1.617.1), 1.617.3, Mu (B.1.621,
domain (rbd) has an affinity to bind with ACE2 (Angioten- B.1.621.1), Zeta (P.2), Lambda (C.37). b.1.1.7 and Q
sin-converting enzyme 2) of the host cells and facilitates lineages (alpha), B.1.351, B.1.351.2, B.1.351.3 (beta),
the corona viral entry into the host cell, leading to the rapid B.1.617.2, AY.1, AY.2, AY.3 (delta) and P.1. P.1.1, P.1.2
transmission for the infection of the SARS-CoV-2. Com- (gamma) were categorized initially as variants of concern
parison of various global strains with Wuhan sequence based on increases transmissibility and increased disease
revealed 394 missense mutations, 260 synonymous, 5 dele- severity and evidence of impact on diagnosis, treatment and
tions 1framshift and 1 stop-gained 6 overall all mutations protectiveness against vaccines. Even though, Alpha, Beta,
in spike region 687 (Yang et al. 2020). Among the two Gamma and Epsilon variants were categorized variants of
sub-regions of spike protein, S1 and S2 domain, the S1 concern until recently, but now they were categorized as
domain having the highest number of mutations D614G, variants being monitored (VM). The other variants that fall
Y28H, H49Y, R78M, K77M, Q271R, T22I G261S, E471, under VM are Eta, Iota, Kappa, B.1.617.3, Zeta and Mu.
S494, A520S and I402L responsible for the pathogenicity B.1.427, B.1.429, B.1.525 (Eta), B.1.526 (Iota),
of the SARS-CoV-2 (Maitra et al. 2020; Pulakuntla et al. B.1.617.1 (kappa) and B.1.616.3 were categorized by Center
2021). Our studies also identified high-frequency combi- for Disease Control as variants of interest (VI) until recently
nation mutations like D614G + I472V, D614G + K458R, however based on latest developments currently there are
D614G + V341I, D614G + Q675H, D614G + Q675H, no variants under VI category. Until recently there were no
D614G + S939F, D614G + D936Y and D614G + L5F are SARS-CoV-2 variants higher than the prior category (VI)
responsible for increased infectivity (Li et al. 2020). This that falls under variants of high consequence (VH) category.
may potentially reorganize S protein with loss of hydrogen However, Delta (B.1.617.2 and AY lineages) were catego-
bonds with adjacent residues there by enhancing binding rized under this group recently based on increased transmis-
of S1 region with ACE2 enhancing viral entry and host sibility, increased disease severity and evidence of impact of
to host transmission. These mutations and these areas of diagnosis, treatment and/or vaccine (https://​www.​cdc.​gov/​
spike protein must be investigated. The D614G is a strong coron​avirus/​2019-​ncov/​varia​nts/​varia​nt-​info.​html).
non-synonymous mutation along with these few other fre- SARS-CoV-2 B.1.617.2 also termed as delta variant was
quent mutations in the S region including L84S, D614G, reported to have got identified in October 2020 predomi-
G251V, P214L, R203K, G204R, Q57H, N679Y, S680P, nantly in India and further supposed to have spread to the
Q677H, Q675H, T175M and D3G. Out of these 11 muta- UK and many other countries by December 2020. SARS-
tions, V510L, R509K, Y508H, P491R, V483A, S477G, CoV-2 Delta variant is one among the three major subtypes
G476S, I472V, I468T, I468F and D467V are synonymous viz., B1.617.1, B1.617.2 and B1.617.3 which contain muta-
and located near to ACE2 receptor binding site (Pulakuntla tions predominantly in the N-terminal and the receptor bind-
et al. 2021). The association of V483H and G476S muta- ing domains of S-proteins. Since mutations are associated
tions on human ACE2 receptor binding capacity in MERS with S-protein (T19R, V70F*, T95I, F142D, E156-, F157-,
and SARS research have been demonstrated (Cherian et al. R158G, A222V*, W258L*, K417N*, L452R, T478K,
2021). Novel mutations of SARS-CoV-2 started showing D614G, P681R, D950N) in delta variant is understood to
up leading to the second wave of infections during Decem- be much more infectious with very fast rate of infectivity
ber 2020 to March 2021. Among these most frequent triple when compared to other variants. Thus, SARS-CoV-2 Delta
mutations are T19R, K77T, T95I, G142D, E154K, N440K, variant is being classified as variant of concern (VOC) by
T478K, E484Q, D614G, P681R, D950N, Q1071H and Centres for Disease Control and Prevention (CDC), USA;
H1101D (Cherian et al. 2021). with enhanced (> 60%) transmissibility potential in compari-
Aforementioned D614G mutations are generally asso- son to the other variants (Planas et al. 2021).
ciated with B.1 lineage of viruses, which has many sub-
lineages and all of them are established to show multiple Envelope (E) protein mutations
changes in spike proteins. The sublineage B.1.617.2 lineage
is referred to as SARS-CoV-2 Delta variant, which has been Corona envelope protein is the smallest and important struc-
the latest mutational variant observed globally (Planas et al. tural protein key in the assembly and budding of the virus.
2021). Deletion of E-protein led to attenuated virus production. The

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membrane peptide works as a viroporin and inactivation or antagonist to interferon the host response. N protein of SARS-
lack of this protein, the structural changes can take place CoV showed frequent mutations, P46S, S194L, K247I, S327L,
in the virus leading to transmission. It has three domains, D343V and E378Q. Koyama et al. (2020) reported a total of
C-terminal domain (functional), amino-terminal (hydro- 378 mutations out of which 246 are missense mutations, 126
phobic) and transmembrane domain (hydrophobic). The are synonymous mutations and 6 deletion mutations viz.,
E-protein of SARS-CoV-2 is being considered as one of ORF3a, ORF6, ORF7, ORF8 and ORF10 of the viral genome
the highly conserved proteins. E protein has a limited num- have relatively fewer mutations, i.e., 344 missense mutations,
ber of mutations while comparing with other proteins and 149 synonymous, 9 deletion, 3 frame shift mutations and 17
about 43 synonymous and missense mutations were reported stop-gained mutations compared to other proteins.
(Koyama et al. 2020). Studies showed that enhanced amino
acid variations were observed in the C-terminal domain of Mutations associate with other non‑structural (nsp)
the E protein that were playing a key role in COVID-19 and accessory proteins
pathogenesis (Rahman et al. 2021). Transmembrane domain
mutation (V25A) and many triple cysteine motif harbouring The SARS-CoV-2 genome has 15 non-structural proteins
mutations (L39M, A41S, A41V, C43F, C43R, C43S, C44Y nsp1-10 and nsp12-16 (total 16 nsps including nsp11) along
and N45R) are being reported as the major variants of E with 8 auxillary protein ORF3a, ORF3b, ORFp6, ORF7a,
protein mutations, which control conformational and binding ORF7b, ORF8b, ORF9b and ORF14. These proteins play
characteristics of E-protein (Rahman et al. 2021). Though a key role in viral amplification. Mutations in these aux-
highly conserved, the observed mutations in E protein have iliary/accessory proteins were not found so far (Banerjee
got a lot of biological relevance and importance, especially et al. 2020; Kim et al. 2020; Mercatelli and Giorgi 2020; Wu
to design a therapeutic intervention. et al. 2020). It is important to verify for and analyze these
mutations to understand the pathogenicity and to improve
‑ Membrane (M) protein mutations the host immunity. SARS-CoV-2 mutational data were col-
lected from existing literature as well as our lab reports.
Membrane viral protein of the coronavirus is the most abun-
dant envelope protein of coronaviruses. M-Protein play a Diagnosis
key role in viral assembly, morphogenesis and antigenecity.
It shapes the envelope and it could bind with nucleocapsid According to WHO, diagnosis of COVID-19 infection at
and be involved in coronavirus assembly. It has three trans- appropriate time after initial observation of symptoms play
membrane domains, with an amino terminus (short) that a crucial role in the control of pandemic. As of now, many
projects out and c-terminus (long) that projects inside of the commercial kits are available using nasal, nasopharyngeal
virus. In silico studies reported that the M-protein of SARS- and saliva samples. In India, multiple kits were available
CoV-2 is > 98% similar to that of bat and pangolin SARS- using saliva swab samples including IgG/IgM antibodies by
CoV, which demonstrates its evolutionarily conserved nature myLAB Box, gold nanoparticles-based colorimetric detec-
(Thomas 2020). Though relatively uncommon, M protein tion kit by Oxford Suzhou center for advanced research
gene mutations are being newly observed especially in the and gold nanoparticles coated with glucans-based colori-
USA patient pool, which is reported to be the reason behind metric detection by Iceni Diagnostics (Amawi et al. 2020).
the hike in the number of COVID positive cases (Shen et al. Additionally, real-time PCR amplification of viral E gene
2021). Emergence of novel M182T and V70L are being assay confirmatory testing and RdRp/nsp7-8-12 gene assay,
reported across the globe and the present evidence suggests based on collection of respiratory samples from hospitalized
that so far 71 synonymous mutations associated with M gene patients is also being developed and used for the detection
are being identified (Koyama et al. 2020). Mutations associ- of COVID-19 (Corman et al. 2020). Globally various PCR-
ated with M proteins seem to be more alarming because of based (single gene and multiple gene amplification, real-
the observation that the average age of the patient pool asso- time based, LAMP based) and antigen–antibody interaction-
ciated with M mutation is 4.6–6.3 years (Shen et al. 2021). based assays are available using various clinical samples.

Nucleocapsid protein mutations

Clinical manifestations
The nucleocapsid protein is multifunctional majorly facilitates
genome packing and assembles the viral RNA with mem- As SARS-CoV can infect all the general population in
brane proteins. It can enhance the transcription efficiency of various ways, infection rate can be classified into mild,
the virus. N protein has conserved N-terminal and C-terminal moderate and severe. Mild and moderate infections are
domains. N-protein also modulates the antiviral function as an with asymptomatic and/or few symptoms (fever, cold, dry

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Cough, tiredness, headache, pains, loss of smell and taste) including usage of traditional medicines. Studies have
and potentially get cured by home isolation (da Rosa et al. shown that SARS-CoV-2 viral loads are significantly com-
2021). In case of severe infections of COVID due to high parable to the disease intensity and progression (Horby et al.
viral titers that leads to hypoxia especially in individuals 2021), which highlights the importance of having a thera-
with co-morbidities like obesity, diabetes, cardiovascular peutic strategy not only to treat the symptoms of infection,
and neurological diseases. There are 27 clinical manifesta- but also to be able to deal with the reduction in the viral
tions and few were summarised in Table 3. Vahey et al. 2020 loads. Known anti-viral and other drugs including remde-
reported that COVID-19-infected patients symptoms like siver, IFN-α, Lopinavir/ritonavir, Ribavirin, Chloroquine
fever, cough, malaise, dyspnoea, fatigue, sputum/secretion, phosphate and hydroxychloroquine along with azithromy-
dermatological manifestations, anorexia, sneeze, neurologi- cin and Arbidol, were used initially that were claimed to
cal, symptoms, rhinitis, myalgia, goose bumps, sore throat, have a encouraging response in the preliminary treatment
headache, diarrhoea, chest pain, rhinorrhoea, palpitation, of COVID-19 (Vahey et al. 2020; Cyranoski 2020; Shen
dizziness, nausea or vomiting, shivering, confusion, nasal et al. 2020; Dong et al. 2020; McKee et al. 2020; Lai et al.
congestion, nasal congestion, abdominal pain and haemop- 2020; Gautret et al. 2020). Later many research groups and
tysis. Clinical manifestation that presented in the highest pharmaceutical giants throughout the world started research-
number (58%) of infected patients was fever followed by ing extensively on development of more specific therapeutic
cough (55%). Neurological symptoms (20%) are also other strategies to curtail COVID-19 infection and spread (Alijotas
main clinical manifestations causing anosmia and hyposmia, et al. 2020). Recently in India, the Drug Controller General
mechanism/s of which are poorly understood. At present, of India approved the drug 2-Deoxy d-Glucose (2-DG), for
most of the cases are suffering from respiratory diseases and emergency usage for moderate to severe COVID-19 patients
it is difficult to identify and differentiate respiratory prob- (Verma et al. 2020). Besides, many candidate drugs viz.,
lems from COVID. To identify the respiratory disease clini- baricitinib, fedratinib, and ruxolitinib, JAK-STAT signaling
cal manifestations of COVID-19 are helpful to characterize inhibitors were being proposed to deal with elevated lev-
COVID-19 (da Rosa et al. 2021). els of cytokines during the infection (Stebbing et al. 2020).
Parallel, due to the global demand for development of a
permanent cure to the problem, many vaccines, drug and
Therapeutic strategies immunotherapeutic candidates were being proposed which
started making their way into the clinical trials, the current
Sheahan et al. (2020) report describes the clinical proto- status of which are being summarized in Tables 4 and 5.
cols for the diagnosis and treatment of COVID-19, in which Moreover, vaccines are the most effective prophylactic/ther-
many therapeutic strategies to treat COVID-19 are being apeutic strategies for the protection of global health (Cun-
mentioned. The strategies predominantly include conva- ningham et al. 2020). Since passive immunization had been
lescent plasma therapy, circulatory and blood purification successfully used to treat infectious diseases, convalescent
support, antiviral therapy, oxygen therapy, mechanical ven- plasma therapy was anticipated to show effective therapeutic
tilation (invasive), immunotherapy, rescue therapy, renal potential in treating COVID-19 it became one of the treat-
replacement/transplant, and additional treatment options ment options initially (Lai et al. 2020). Moreover, immediate

Table 3  Clinical manifestations of the COVID-19

Disease category Clinical features Clinical manifestations (may occur in Proportion
patients belonging to any of the last of patients
three disease categories) (Globally)

Mild disease Non/mild pneumonia – 75–85%

Moderate disease Pneumonia Gastro intestinal symptoms such as
Severe disease Severe pneumonia, Dyspnea, Respiratory frequency ≥ 30/min, Blood diarrhea and cramps; 10–15%
oxygen saturation ≤ 93%, P/F ratio < 300, Lung infiltrates > 50% Neurological symptoms such as
(within 24–48 h) headache, altered mental status,
Guillain–Barre syndrome (GBS)
Critical disease Acute respiratory distress syndrome, Respiratory failure, Sepsis 5–10%
and Stroke;
(multiple organ dysfunction / failure)
Cardiovascular events such as
Septic shock
myocarditis, arrhythmias and heart
failure;
Ocular manifestations such as con-
junctival hyperemia, chemosis
Anosmia and dysgeusia

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Table 4  Drug candidates against COVID-19

Drug candidate Medication class Description Phase References/link

13
Remdesvir Antiviral Intravenous/Inhalable drug that interferes Phase 3 Sheahan et al. (2020)
Page 8 of 17

with the activity of RdRp, thereby

tampering viral replication
Dexamethasone Glucocorticoid Drug to reduce inflammation associated Phase 2 Horby et al. (2021)
with cytokine release syndrome https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
381936
Avigan (favilavir/ favipiravir) Antiviral Per-oral drug that interferes with the Phase 3 Ahn et al. (2020)
activity of RdRp, thereby tampering
viral replication
Kaletra (Lopinavir-ritonavir) Antiviral Per-oral drug that interferes with the Phase 3 Lai et al. (2020)
activity of viral proteases
EIDD-2801 Broad spectrum antiviral Oral drug that interferes with the activ- Phase 2 https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
ity of RdRp, thereby tampering viral 405739
replication
CD24FC Recombinant fusion protein acting as a Intravenous infusion that targets a novel Phase 2/3 https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
non-antiviral biological modifier immune pathway checkpoint and 317040
modulates immune responses
INOpulse Nitric oxide Inhaled NO therapeutic for improving Phase 3 https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
arterial oxygenation in affected patients 398290
RLF-100 (aviptadil) Synthetic human vasoactive intestinal Anti-inflammatory drug that can improve Fast-track approval from FDA https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
peptide oxygenation in the blood of the 453839
affected patients
Losmapimod Mitogen activated protein kinase Anti-inflammatory drug, particularly IND approved to test in phase 3, by FDA https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
(MAPK) inhibitor reducing C-reactive protein and IL-6 264442
AdMSCs Autologous adipose derived stem cells ACE2-mesenchymal stem cell therapeu- IND approved to test in phase 2, by FDA https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
tics to treat pneumonia associated with 362189
the infection
PTC299 Dihydroorotate dehydrogenase Therapeutic that inhibits viral replication Phase 2/3 https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
(DHODH) inhibitor and inflammatory reposes 439071
Calquence (aclabrutinib) Kinase inhibitor Drug acting as an inhibitor of enzyme Clinically tested on patients https://​www.​astra​zeneca.​com/​media-​
Bruton’s tyrosine kinase (BTK) associ- centre/​press-​relea​ses/​2020/​calqu​
ated with production of TNF-α, IL-6, ence-​showed-​promi​sing-​clini​cal-​impro​
IL-10 and MCP-1, thereby reducing vement-​in-​major​ity-​of-​19-​hospi​talis​ed-​
respiratory distress covid-​19-​patie​nts.​html
Farxiga (dapagliflozin) Sodium-glucose co-transporter 2 Drug that promotes glucosuria and a Phase 3 https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
(SGLT2) inhibitor treatment for COVID patients with 350593
conditions such as hypertension, type
2 diabetes and atherosclerotic CVD,
heart failure, chronic kidney disease
Pepcid (famotidine) H2 blocker Drug that inhibits 3-chymotripsin-like Phase 3 https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
proteases, that controls viral replication 370262
Archives of Microbiology (2022) 204:8
Archives of Microbiology (2022) 204:8 Page 9 of 17  8

and simultaneous ambulatory and medical care along with and multiple bio-pharmaceutical companies in the success-
randomized clinical trials is the only way to find effective ful discovery and manufacture of various vaccines. Accord-
and safe treatments for COVID-19 (Kalil 2020; Shree et al. ing to WHO and the COVID-19 vaccine tracker, 74 vaccine
2020; Badri et al. 2021). candidates are being developed or under development world-
wide. Among these few vaccines successfully completed
Phytomedicine therapy 3rd phase trials and now those are in use and the data were
shown in Table 7.
By virtue of their multi-targeted and less toxic features,
phytomedicines have attracted attention for prevention of mRNA Vaccines
many viral infections including COVID19. The increasing
scientific proof of rich phytoconstituents in phytomedicine BNT162b2  BNT162b2 mRNA-based vaccine was devel-
and ensuing treatment/prophylactic potentials have cre- oped by the Pfizer BioNtech, Fousun pharma. BioNtech is
ated remarkable confidence in the society (Girija and Sivan the first company to register for the FDA approval of their
2020). This led to a rise in confidence towards alternative candidate COVID-19 vaccine. BNT162b2 is a lipid nano-
traditional medicine. According to WHO reports, traditional particle-based RNA vaccine (with nucleoside-modifica-
medicine (TM) which includes Indian Ayurveda, Chinese tions), encoding the SARS-CoV-2 full-length spike protein.
medicine, and Arabic Unani medicinal therapies that use Two proline mutations locks the spike protein confirmation
herbs/natural products are widely and rapidly growing health in the prefusion conformation (Polack et al. 2020). After its
systems with plenty of economic advantage. Rich local tradi- development and testing, the vaccine has been designated
tional/cultural adaptations in countries like Belgium (38%), to be administered in two doses, 21 days apart. After entry
China (40%), USA (42%), Australia (48%), Canada (70%), into the host cell, it makes multiple copies of viral full
India (70%), France (75%) and Africa (80%) are leaning length spike protein through immune cells. It shows 95%
more towards TM. In multiple geographical areas including efficiency by encoding the viral spike protein for immune
Asia and Latin America, people prefer to use TM due to response. Total number of participants that participated in
cultural beliefs and ancient traditions. TM is not only seen the study were 43,448 around the world (Sadoff et al. 2021).
in developing and underdeveloped countries but in many BNT162b2 administered doses have depended on neutral-
developed countries it is increasingly accepted and growing izing antibodies higher against the SARS-CoV-2. The sig-
rapidly. Potential of Ayurveda-based rasayana botanicals, nificant immunogenicity and activation of the CD8+ and
which includes Withania somnifera, Tinospora cordifolia CD4+ T-cells was found (Clinical Trial id: NCT04368728).
and Asparagus racemosus, in COVID-19 treatment is being
postulated (Ang et al. 2020) using in-silico approaches by mRNA‑1273  mRNA-1273 COVID-19 vaccine is the first
therapeutic potential of Ayurvedic preparations viz., Sudar- vaccine to be enrolled for clinical trials after complete
shana Churna, Dhanvantara Gutika and Talisadi Churna SARS-CoV-2 genome sequencing and was developed by
along with proper diet and self-quarantining, in a self- US-based start-up company, Moderna (Wang et al. 2021).
detected COVID-19 case is being reported by (DU et al. mRNA-1273 is a novel lipid nanoparticle (LNP)-encap-
2020). As per the Chinese and Korean guidelines, frequency sulated mRNA-based vaccine that uses/delivers prefusion
of commonly used plant formulations for COVID-19 treat- stabilized spike (S) protein of SARS-CoV-2. The mRNA
ments is being extensively reviewed by use of traditional translates to produce SARS-CoV-2 viral spike protein (full
Chinese medicines in prevention of COVID-19 infection length), thereby allowing the body to generate an immune
in healthy population and also treating the symptoms for response and retain that information in memory immune
patients at all stages of corona-viral/entero-viral infections cells. Efficacy shown in study participants who received
were reported (Ren et al. 2020; Luo et al. 2020; Ni et al. the 2 doses of vaccine with negative baseline SARS-CoV-2
2020). Details of the different phytotherapeutic interventions status, was approximately 94% for the follow-up period of
that are being proposed/recommended/already attempted 9 weeks. The data reviewed concludes that the benefits of
until now in literature to treat corona/entero viral infections mRNA-1273 vaccine outweigh the known and potential
in specific are being summarized in Table 6. risks (Wu et al. 2021).

Current vaccines for COVID‑19 Inactivated vaccine

From January 2020, many studies and publications on SARS Covaxin (BBV152)  India's first indegenous COVID19 vac-
CoV-2 whole genome sequences analysis and mutational cine BBV152/Covaxin was developed by Bharat Biotech
analysis have been initiated and many are underway with in collaboration with Indian Council of Medical Research
spectacular collaborations among scientists from academia and National Institute of Virology. This vaccine used

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Table 5  Immunotherapeutic candidates against COVID-19

13
Immunotherapy Medication class Description Clinical phase/Details References/link
Page 10 of 17

Convalescent plasma Immunoglobulin Passive immunotherapy by giving eIND approval by FDA Shen et al. (2020); Dong et al. (2020)
plasma from COVID recovered
patients to the newly affected, to neu-
tralize the virus more efficiently
Tocilizumab Monoclonal antibody Recombinant humanized antihuman Clinically tested at Anhui Provincial McKee et al. (2020)
IL-6 receptor monoclonal antibody Hospital, China
that prevents IL-6 induced damage to
target cells
Mavrilimumab Monoclonal antibody Intravenous drug that antagonize Clinically tested at San Raffaele Hos- Lai et al. (2020)
GM-CSF signaling by binding to α— pital, Italy
subunit of GM-CSF receptor
Lenzilumab Humanized monoclonal antibody (class Intravenous infusion that targets pro- Clinically tested on a hospitalized Alijotas et al. (2020)
IgG1 kappa) inflammatory cytokine GM-CSF 68 year old man
PRO 140 (lenornlimab) Humanized monoclonal antibody (class Subcutaneous injection acting as a Phase 2/3 https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
IgG4) CCR5 antagonist that blocks CCR5 343651
co-receptor on the surface of CD4
cells
Gimsilumab Human monoclonal antibody Intravenous infusion that targets pro- Phase 2 https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
inflammatory cytokine GM-CSF 351243
Otilimab Monoclonal antibody Intravenous infusion that targets inflam- Phase 2 https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
matory cytokine GM-CSF 376684
JS016 Monoclonal antibody Therapeutic that binds to the spike Phase 1 https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
protein receptor in SARS-CoV-2 and 441918
block viruses form binding to the
ACE2 host cell surface receptor
LY-CoV555 Monoclonal antibody Therapeutic that binds to the spike Phase 1 https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
protein receptor in SARS-CoV-2 and 427501
block viruses form binding to the
ACE2 host cell surface receptor
Kevzara (sarilumab) IL-6 receptor antagonist Anti-inflammatory drug for patients Phase 3 https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
with acute respiratory distress syn- 327388
drome associated with COVID-19
Ilaris (canakinumab) Human monoclonal antibody Monoclonal antibody-based drug tar- Phase 2 https://​clini​caltr​ials.​gov/​ct2/​show/​NCT02​
geting interleukin (IL-1β) 059291
Ultomiris (ravulizumab) Human monoclonal antibody Monoclonal antibody-based drug inhib- IND approved to test in phase 2, by https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
iting C5 complement FDA 369469
Remicade (infliximab) Chimeric monoclonal antibody TNF inhibitor, that can be a poten- Phase 2 https://​clini​caltr​ials.​gov/​ct2/​show/​NCT04​
tial treatment for cytokine release 425538
syndrome
Archives of Microbiology (2022) 204:8
 Table 6  Phytotherapeutic interventions proposed against different types of corona viral / entero viral infections
Phytoconstituents/Herbal medicines Type Mode of action Proposed therapeutic against Model References

Caflanone, Equivir, Hesperetin, Myri- Flavonoid Bind to spike protein, helicase and SARS-CoV-2 In silico Stebbing et al. (2020)
cetin and Linebacker protease sites on ACE2 receptor
with high affinity
Astragali Radix (Huangqi), Glycyr- Traditional Majorly by inhibiting inflammation SARS-CoV-2 Recommendations as per Chinese Cunningham et al. (2020)
Archives of Microbiology (2022) 204:8

rhizae Radix Et Rhizoma (Gancao), Chinese condition associated with COVID- guidelines and official government
Saposhnikoviae Radix (Fangfeng), Medicines 19 websites of 31 provinces in main-
Atractylodis Macrocephalae land China
Rhizoma (Baizhu), and Lonicerae
Japonicae Flo
Luteolin Flavonoid Alleviates NLRP3 inflammasome SARS-CoV In vitro Kalil (2020)
activation
Myricetin Flavonoid Inhibits NLRP3 inflammasome SARS-CoV In vivo Badri et al. (2021)
activation
Apigenin Flavonoid Reduces induction of LOX-1 and SARS-CoV In vitro Girija and Sivan (2020)
NLRP3 expression
Quercetin Flavonoid Suppresses fructose-induced NLRP3 SARS-CoV In vitro Ang et al. (2020)
inflammasome activation
Kaempferol Flavonoid Interferes with NLRP3 inflamma- SARS-CoV In vivo Du et al. (2020)
some activation
Baicalin Flavonoid Suppresses NLRP3 inflammasome SARS-CoV Ex vivo and in vitro Ren et al. (2020)
and NF-κB signaling Dengue viral infection
Wagonoside Flavonoid Inhibit NF-κB signaling and NLRP3 SARS-CoV In vivo Du et al. (2020)
inflammasome
Apigenin, Flavonoids Undisclosed Enterovirus 71 In silico
Luteolin,
Kaempferol, Quercetin, Isorhamnetin,
Formononetin, Chrysosplenetin and
Penduletin
Emodin Anthraquinone Inhibit interaction of SARS-CoV SARS-CoV In vitro Ni et al. (2020)
spike protein with ACE2 receptor Kremsner et al. (2020)
Resveratrol Stilbenoid Inhibition of viral replication and host MERS-CoV In vitro
cell apoptosis along with prolong-
ing cellular survival after viral
infection

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Page 12 of 17 Archives of Microbiology (2022) 204:8

SARS-CoV2 whole-virion inactivated by β-propiolactone. ance of the variants could be neutralized by this vaccine
The strain used, NIV-2020-770 contains the Asp614Gly (Tanriover et al. 2021). As an assessment of the WHO’s, the
mutation. It showed 50% efficiency with safe and immune advisory group approved this vaccine for emergency use.
response in the clinical trial with recruited 25,800 par- The phase 3 clinical trials were conducted internationally on
ticipants. However, the inactivation of SARS-CoV2 by 9000 participants (clinical id: NCT04456595).
β-propiolactone was reported to cause aggregation of the
viral particles leading to loss of antigenic potential. This BBIBP‑CorV  BBIBP-CorV developed by Sinopharm, it is an
vaccine is also effective against the UK B.1.1.7 variants and inactivated vaccine. Study reports revealed that the vaccine
specific to neutralizing IgG antibodies. The Drug controller have efficiencies upto 79.3% by neutralizing the antibod-
general of India has approved after three phase clinical tri- ies with two doses after 21  days vaccination (Wang et  al.
als successfully present it has huge production in India (Ella 2020). This vaccine works the same as coronaVac and is
et al. 2021). made based on the UK strains, and WHO advised its usage
only upon emergency. The sample size for this clinical trial
CoronaVac  CoronaVac COVID-19 Vaccine  developed by was 1300 (Clinical id NCT04560881).
Sinovac Biotech Ltd. is an inactivated pathogen. The virus
is inactivated by β-propiolactone and then adjuvanted with Viral vectors
aluminum hydroxide to make the vaccine, which is generally
administered on a 0/14–28-day schedule to prevent the dis- AZD1222  The ChAdOx1 nCoV-19 vaccine (AZD1222)
ease. This vaccine is also potent/protects against B.1.351, a was developed at Oxford University. AZD1222 contains
South African variant and B.1.1.7, a UK variant. The resist- SARS-CoV-2 structural spike protein gene delivered by

Table 7  Current list of available vaccines and their efficiency

S. no. Vaccine Name Devel- Time line doses % efficiency (%) Ag type Study evolution Status References
clinical Trail id oped
countries

1 Pfizer (BNT162b2) USA 21 days b/w to 95 mRNA Tolerability and In use Polack et al. (2020)
NCT04368728 doses immunogenicity
from different
strain
2 Moderna USA 28 days 94 mRNA Neutralization In use Wu et al. (2021)
(mRNA-1273) against UK
NCT04470427 variant strain
B.1.351varient
3 Covaxin India 28 days 50 In activated Neutralization In use Ella et al. (2021)
(BBV152) against UK vari-
NCT04471519 ant strain
4 Covishiled UK 28 days 65 Viral vector Neutralization In use Voysey et al. (2021)
AZD1222 against B.1.1.7
NCT04516746 variant
5 Sputnik V Russian 21 days 91 Viral vector Immune system In use Jones and Roy
NCT04530396) (2021)
6 Jassen (Johnson & USA 28 days 66 Viral vector Effective against In Use Sadoff et al. (2021)
Johnson) Ad26. severe condition
CoV2.S
NCT04505722
7 Corona Vac China 14 days 50.4 Inactivated Effective against In use Wang et al. (2021)
NCT04456595 UK, South Afri-
can variants
8 BBIBP China 21 days 79.3 Inactivated Variant neutraliza- In use Wang et al. (2020)
NCT04560881 tion
9 EpiVacCorona Russia 21 days 90 Peptide Increased immune In use Doroftei et al.
NCT04527575 response (2021)
10 Convidecia China 21 days 65 Viral Vector Tolerability and In use Zhu et al. (2020)
NCT04526990 immunogenicity
from different
strain

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Archives of Microbiology (2022) 204:8 Page 13 of 17  8

replication-deficient adenoviral vector ChAdOx1 (chimpan- clinical trials, 40,000 participants are involved (Clinical trial
zee) (Voysey et al. 2021). As per reports, this vaccine has id NCT04526990. After vaccination elevated IFN-α levels
65% efficiency against COVID-19 after 28 days of 2 dose and T-cell response were observed.
vaccination and has shown blood clotting issues after vac-
cination. Due to this reason, 12 countries across the globe Peptide vaccine
rejected the use of this vaccine. After the safety commu-
nity confirmed the vaccine benefits more than the risks and EpiVacCorona  EpiVacCorona is a chemically synthesized
its non-association with high risk of blood clotting, on 31 peptide (three short fragments/epitopes of viral spike
March 2021. AstraZeneca, TGA, WHO and MHRA have protein)-based vaccine developed by the federal budgetary
issued statements for the safety use and efficiency (Madhi and state research center of virology, Russia. These short
et al. 2021). This vaccine worked against UK variants and peptides represent the immunogenic B-cell epitopes that
induced antibodies were low with neutralisation. 32,000 should be recognized by the human immune system. The
participants participated in clinical trials (Clinical trial id peptides are subsequently conjugated to a chimeric carrier
NCT04516746). protein and given as a vaccine. The vaccine showed 90%
efficiency as per reports after administration of two doses
Sputnik V  Gamaleya research institute, A Russian Medical in 21  days. Reports also revealed the vaccine tolerability,
Research Institute of the Russian Health Ministry developed safety, immunogenicity against COVID-19 (Ryzhikov et al.
a recombinant adenovirus vaccine called Sputnik V/Gam- 2021). The total 3000 study participants participated (Clini-
COVID-Vac. This vaccine delivers SARS-CoV-2 spike cal id NCT04527575) in this clinical trial.
protein using a novel heterologous recombinant adenovirus
approach. This heterologous adenoviral vector has adenovi- Effective under trial vaccines
rus 26 (Ad26) and adenovirus 5 (Ad5) components (Jones
et al. 2021). This vaccine is administered in two doses within Novavax is developing a vaccine called NVX-CoV2373 with
21 days and has an efficiency of 91% against SARS-CoV-2. a prefusion protein nanoparticles against COVID-19. This
It shows high humoral and cellular immune response along vaccine has the highest efficiency against COVID-19. This
with good tolerability, immunogenicity and high efficiency, is under a third phase clinical trial and soon it will come
40,000 participants participated in the clinical trials (Clini- into use. NVX-CoV2373 (Clinical trials id NCT04368988)
cal id NCT04530396) of Sputnik V. induced immunogenicity and showed protective response
against respiratory diseases (Poland et al. 2020; Cheryl et al.
JNJ‑78436735  JNJ-78436735 is a monovalent vaccine com- 2020; Shinde et al. 2021). Another vaccine, ZyCoV-D is a
posed of a replication incompetent recombinant Ad26 vec- plasmid based DNA Vaccine, under phase 3 clinical trials,
tor that encodes SARS-CoV-2 viral spike protein. The vac- with approval from Drug Control General of India. It exhib-
cine was developed by Johnson & Johnson, administered in ited an efficient immune response. Abdala (CIGB 66), a
two doses in 28 days’ time gap, and showed 66% efficiency protein-based vaccine, is under phase 3 clinical trial (Yadav
against COVID-19 severe conditions (Logunov et al. 2021). et al. 2020; Ward et al. 2020). Medicago is an influenza
Rare incidences of cerebral venous sinus thrombosis was vaccine that is under trial. When tested after 20 days, viral-
observed after taking this vaccination, US had paused the like particles were working against the COVID-19. Under
administration of the vaccine while FDA, CDC and ACIP fast track FDA approved to release vaccine for emergency
investigated the risks. On 20 April EMA approved by saying use. VLA2001 is an inactivated vaccine developed with sup-
that, thrombosis is rare and common with decreased num- port from the UK national institute of health research. This
bers of blood platelets. The total number of clinical trial vaccine is safer and well tolerated to neutralize antibodies
participants is 43,783 and it is an effective vaccine against in study participants (Peter et al. 2020; Cecilia et al. 2020;
moderate and severe COVID-19 in the United States (Clini- Smith et al. 2020; Pablo et al. 2020; Elizabeth et al. 2020;
cal id NCT04505722). Capone et al. 2020; Richmond et al. 2021). In addition,
there are about 60 vaccines under trials. Few vaccines are
Ad5‑nCoV  This vaccine is developed by China-based in phase-3 trials and many are in phase-1 or -2 trial shown
CanSino Biologics using adenovirus vector, Canvidicea. in Table 8.
Ad5-nCoV is an Ad5 vector based (E1 and E3 deleted, Many more vaccines are under development viz: Cvn-
replication defective) vaccine expressing the full-length CoV, BCG, INO-4800, UB-612, GRAd-COV2, SCB-2019,
spike protein of COVID19 virus (Wuhan-Hu-1 strain, Nanocovax, BNT162, Soberana1 and 2, AdCLD-CoV19,
YP_009724390) with the tissue plasminogen activator sig- ABNCoV2, EuCorVac-19, Mambisa (CIGB-669), IIBR-
nal peptide gene (Zhu et al. 2020). This vaccine has an effi- 100, AGO301-COVID-19, GX-19N, ARCT-021-COVID-19,
ciency of 65% with two doses of vaccination in 21 days. In HGCO-19, MRT5500, AV-COVID-19, SpFN, KBP-201,

13
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Page 14 of 17 Archives of Microbiology (2022) 204:8

Table 8  Vaccine Trials of SARS-CoV-2

S. no. Name Ag type Developing Countries Trail phase Clinical trial id References

1 Novovax Nanoparticle UK Phase3 NCT04368988 Cheryl et al. (2020); Shinde

NVX-CoV2373 NCT04533399 et al. (2021)
NCT04611802
2 ZyCoV-D DNA (plasmid) India Phase3 NA Yadav et al. (2020)
3 Abdala (CIGB66) Protein Subunit Cuba phase3 NA Zimmer et al. (2021)
4 Medicago Plant based protein/VLP Canada phase3 NCT04450004 Ward et al. (2020)
NCT04636697
5 VLA2001 Inactivated UK Phase3 NCT04671017 https://​valne​va.​com/​press-​
NCT04864561 relea​se/​valne​va-​repor​
ts-​posit​ive-​phase-1-​2-​
data-​for-​its-​inact​ivated-​
adjuv​anted-​covid-​19-​vacci​
ne-​candi​date-​vla20​01/
6 Un named Adjuvant protein US, India phase3 NA http://​ctri.​nic.​in/​Clini​caltr​
ials/​pdf_​gener​ate.​php?​
trial​id=​48329​&​EncHid=​
&​modid=​&​compi​d=%​
27,%​27483​29det%​27
7 CvnCov mRNA based Multinational phase2b/3 NCT04449276 Peter et al. (2020)
NCT04515147
NCT04652102
NCT04674189
8 BCG Vaccine Live attunated Australia Pahse 2/3 NCT04328441 Cecilia et al. (2020)
9 INO-4800 DNA vaccine US Phase2/3 NCT04336410 Smith et al. (2020); Pablo
NCT04447781 et al. (2020)
NCT04642638
10 No name Adenovirus US Phase2/3 NCT04591717 Elizabeth et al. (2020)
11 UB-612 Multi peptide US Phase2/3 NCT04545749 https://​www.​busin​esswi​
NCT04683224 re.​com/​news/​home/​
20210​20800​5198/​en/​
COVAXX%​E2%​80%​99s-​
COVID-​19-​Vacci​ne-​UB-​
612-​Induc​ed-​Neutr​alizi​
ng-​Antib​odies-​in-​100-​
of-​Parti​cipan​ts-​During-​
Phase-1-​Clini​cal-​Trial
12 GRAd-COV2 Adenovirus Italy, Germany and Phase2/3 NCT04528641 Capone et al. (2020)
Belgium
13 SCB-2019 Protein Part China Phase2/3 NCT04405908 Richmond et al. (2021)
NCT04672395
14 Unname Recombinant protein UK Phase2 NCT04537205 https://​www.​gsk.​com/​
NCT04762680 en-​gb/​media/​press-​relea​
ses/​sanofi-​and-​gsk-​initi​
ate-​phase-​12-​clini​cal-​
trial-​of-​covid-​19-​adjuv​
anted-​recom​binant-​prote​
in-​based-​vacci​ne-​candi​
date/#
15 Soberana Monovalent /conjugate Cuba Phase 1/2/3 SOBERANA 01A https://​www.​emerg​
SOBERANA 02 ency-​live.​com/​health-​
and-​safety/​cuba-​minis​
try-​of-​health-​annou​nces-​
phase-3-​for-​abdala-​cigb-​
66-​and-​sober​ana-​02-​its-​
two-​covid-​19-​vacci​nes/
16 AdCLD-CoV19 Adenovirus Korea Phase 1/2a NCT04666012 https://​clini​caltr​ials.​gov/​ct2/​
show/​NCT04​666012

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