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Received: 19 May 2021
-
Revised: 8 August 2021
-
Accepted: 9 August 2021
DOI: 10.1002/rmv.2287
REVIEW
The global emergence of Chikungunya infection: An
integrated view
Khanzadi Nazneen Manzoor
1
|Farakh Javed
2
|Muhammad Ejaz
3
|
Mubashar Ali
3
|Neelam Mujaddadi
3
|Abid Ali Khan
4
|Aamer Ali Khattak
5
|
Assad Zaib
5
|Ibrar Ahmad
6
|Waqar Khalid Saeed
2
|Sobia Manzoor
7
1
Department of Biosciences, COMSATS
institute of Information Technology,
Islamabad, Pakistan
2
Department of Biomedical Sciences, Pak‐
Autria Fachhochschule: Institute of Applied
Sciences & Technology, Haripur, Pakistan
3
Department of Microbiology, The University
of Haripur, Haripur, Pakistan
4
Institute of Precision Medicine, Hochschule
Furtwangen University, Furtwangen im
Schwarzwald, Germany
5
Department of Medical Lab Technology, The
University of Haripur, Haripur, Pakistan
6
Center for Human Genetics, Hazara
University, Mansehra, Pakistan
7
Atta‐ur‐Rehman school of applied
biosciences, National University of science and
Technology, Islamabad, Pakistan
Correspondence
Farakh Javed, Department of Biomedical
Sciences, Pak‐Autria Fachhochschule:
Institute of Applied Sciences & Technology,
Mang, Haripur, Pakistan.
Email: Farakh.javed@fbse.paf-iast.edu.pk and
farukhbbt@gmail.com
Summary
Chikungunya virus (CHIKV) is one of the emerging viruses around the globe. It
belongs to the family Togaviridae and genus Alphavirus and is an arthropod borne
virus that transmits by the bite of an infected mosquito, mainly through Aedes
aegypti and Aedes albopcitus. It is a spherical, enveloped virus with positive single
stranded RNA genome. It was first discovered during 1952‐53 in Tanganyika, after
which outbreaks were documented in many regions of the world. CHIKV has two
transmission cycles; an enzootic sylvatic cycle and an urban cycle. CHIKV genome
contains 11,900 nucleotides and two open reading frames and shows great
sequence variability. Molecular mechanisms of virus host‐cell interactions and the
pathogenesis of disease are not fully understood. The disease involves three phases;
acute, post‐acute and chronic with symptoms including high‐grade fever, arthralgia,
macupapular rashes and headache. There is no licensed vaccine or specific treat-
ment for CHIKV infection. This lack of specific interventions combined with diffi-
culties in making a precise diagnosis together make the disease difficult to manage.
In this review we aim to present the current knowledge of global epidemiology,
transmission, structure, various aspects of diagnosis as well as highlight potential
antiviral drugs and vaccines against CHIKV.
KEYWORDS
Aedes aegypti,Aedes albopictus, alpha virus, Chikungunya virus
1
|
INTRODUCTION
Chikungunya virus (CHIKV) is an arthropod borne virus, transmitted
via the bite of infected mosquito. It was first discovered in epidemic
of dengue like fever in 1952–1953 in Tanganyika (now called
Tanzania) and was isolated from the serum of the patient in acute
febrile phase of illness.
1–3
The word Chikungunya derived from local
Kimakonde or Kiswahili language spoken in some regions of Tanzania
and Mozambique that means ‘that which bends up’, refers to the post
symptoms of Chikungunya viral infection.
4
CHIKV outbreaks
occurred in many regions but its large epidemic reemerged in La‐
Reunion island of Indian Ocean in early 2000s, infecting thousands
of people.
5
CHIKV belongs to genus Alphavirus of Togaviridae family
that has enveloped positive single stranded RNA genome and belongs
Abbreviations: CHIKV, Chikungunya virus; NTR, non‐translated region; NSAID, non‐steroidal anti‐inflammatory drugs; ORF, open reading frames; UTR, untranslated region.
Khanzadi Nazneen Manzoor & Farakh Javed equally participated to this study
Rev Med Virol. 2021;e2287. wileyonlinelibrary.com/journal/rmv © 2021 John Wiley & Sons Ltd.
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https://doi.org/10.1002/rmv.2287
to Semiliki Forest Virus antigenic serocomplex.
6,7
Genome size is
approximately 11.8 kb with two open reading frames (ORFs) that are
separated by an untranslated junction region. ORF1 encodes for
polyproteins that are precursor for non‐structural protein while
ORF2 encodes for structural protein.
8,9
After an incubation period of 1–12 days, averaging of 2–4 days
disease is characterized by high‐grade fever, arthralgia, macupapular
rashes and headache.
10
Neonates and people aged more than
60 years, having higher viral load were at higher risk of acute CHIKV
infection. The case fatality is 1:1000; mostly cases involved were
elderly in the Reunion outbreak.
11
Currently, there is no antiviral
drug therapy for treatment or vaccine to prevent CHIKV infection,
treatment is based on clinical symptoms such as use of non‐steroidal
anti‐inflammatory drugs to reduce the symptoms.
12–14
2
|
HISTORY AND EPIDEMIOLOGY
CHIKV first recognized in 1952–1952 in Tanzania; since then, CHIKV
cases were documented in over 60 countries of Asia, Africa, Europe
and America Figure 1. In 1958 Bangkok (Thailand) outbreak of
CHIKV fever was the first significant urban outbreak of CHIKV.
15
Few epidemics of CHIKV occurred in India between 1963 and 1973,
including Kolkata outbreak in 1963, followed by Maharashtra, Tamil
Nadu and Andhra Pradesh (1964–1965) and Barsi (1973)
outbreaks.
16–19
Between 1998–1999 and 2001–2003 outbreaks
were reported in Malaysia and Indonesia respectively.
20,21
In May
2004, Lamu district, Kenya outbreak caused 13,500 infections. After
that a modest outbreak in nearby Mombasa district was thought to
be associated with pervious outbreak in Lamu district, Kenya.
16,22
In January 2005, another CHIKV outbreak in Grande Comore
Island had 215,000 reported cases.
23
In 2005–2006, severe CHIKV
outbreak in La Reunion Island of Indian Ocean infected almost
266,000 people (total population of 770,000 people) with 213
deaths.
11,24,25
Later, Aedes albopictus infection was also reported in
the outbreak of La Reunion island.
5
Prenatal transmission of CHIKV
infection at the time of delivery was observed in the epidemic of La
Reunion island of Indian Ocean.
26
After about 32 years, CHIKV
outbreak occurred in the several states of India; Andhra Pradesh
being the first state to report in December 2005. Later, the infection
spread to other 12 Indian states including Karnataka, Kerala,
Maharashtra, Tamil Naidu, Gujarat and Madhya Pradesh in which
about 1.3 million peoples were infected with CHIKV.
27–29
In
December 2006, infection spread to neighbouring countries caused
an epidemic in Maldives (3500 confirmed cases) and in Sri Lanka with
60,000 people infected and 80 deaths.
30,31
In July 2007, outbreak of CHIKV occurred in two villages of
Northern Italy, Castiglione di Cervia and Castiglione di Ravenna of
Romagna region in which 205 patients were diagnosed with CHIKV.
This outbreak was autochthonous, due to a single viremic patient
FIGURE 1 World map showing the most common outbreaks of Chikungunya virus (CHIKV) around the globe. Outbreaks of Chikungunya
virus had observed in all subcontinents
2 of 13
-
MANZOOR
ET AL.
from Kerala state of India.
32–34
In 2010, about 253 suspected and
129 laboratory confirmed CHIKV cases were reported in Guangdong
province of China, indicating the maiden outbreak of CHIKV.
35
Two
autochthonous cases were documented in Southeastern France in
2010
36,37
while in October 2014, 12 autochthonous (11 confirmed)
cases of Cameroon origin were reported in Montpelier, France.
38
Republic of Congo documented the CHIKV epidemic in 2011 in which
317 cases (37 RT‐PCR confirmed) were reported.
39–41
In 2011,
CHIKV antibodies were detected in 460 blood samples in Pool and
7014 samples in Brazzaville, while representative of Integrated
Regional Information Networks reported approximately 8000 sus-
pected cases, with no mortality.
39,41,42
CHIKV detected in Feb 2011 in New Caledonia, where 33
autochthonous cases indicated the entry of CHIKV in Pacific Ocean
43
while in June 2012, the epidemic appeared in Papua New Guinea
where more than 1500 cases were reported until 2013.
43
Until 2015,
CHIKV had been detected in 8 out of 22 Pacific island Territories or
countries.
44
In 2014, about 318 laboratory confirmed cases reported
in French Polynesia.
45
In Brazil, the first CHIKV case was diagnosed
in a patient returning from Indonesia (endemic country) in Rio de
Janiero on 18 August 2010
46
while until 2015 about 20,661 sus-
pected cases (7823 confirmed cases) reported by Brazilian ministry
of health
47
and in 2016, 3394 cases were reported.
42
In November 2013, the first reported CHIKV case in Saint Martin
caused an epidemic in which 26 suspected cases (20 confirmed) were
identified.
48
Later, infection spread to other territories of Caribbean
regions including Martinique, French, Guiana, Guadeloupe and Haiti
and Dominican Republic.
49
In 2013–2014, about 17,000 cases were
documented.
50
CHIKV spread to about 45 territories or countries of
South, central and North America causing more than 2.9 million sus-
pected cases with 296 deaths until July 2016.
51
US National Institute of
Allergy and Infectious Diseases in 2008 categorized CHIKV as Cate-
gory C priority agent due to high risk of spread in the different areas.
51
In Pakistan, the first large epidemic of CHIKV was reported in
Karachi city in December 2016 in which 1018 cases were reported in
Lyari, Malir, Keamari and Ibrahim Hyderi regions.
52
On 26th
December, Ministry of Health Services, Regulation and Coordination
officially reported the first CHIKV outbreak to WHO (World Health
Organization). Approximately 30,000 suspected cases and 4000
confirmed cases were reported by Armed Forces Institute of Pathology
and National Institute of Health (NIH) in Karachi.
52–54
In July 2017,
second CHIKV outbreak was reported in District of Haripur and 18
cases were confirmed as CHIKV positive by NIH Islamabad.
55,56
Next
outbreak was observed in District Manshera but no officially published
data regarding number of suspected or confirmed cases is available.
57
3
|
VECTOR AND TRANSMISSION
CHIKV, a mosquito‐borne disease, is mainly transmitted via mainly
bite of infected Aedes aegypti and Aedes albopcitus mosquitos.
16,58
Two CHIKV transmission cycles namely enzootic sylvatic cycle and
urban cycle. An enzootic sylvatic cycle (animal‐mosquito‐human),
maintained in Africa; between forest dwelling Aedes species (Aedes
taylori,Aedes furcifer,Aedes luteocephalus,Aedes africanus and Aedes
neoafricanus) and other in non‐human primates (rodents, monkeys,
birds and some unidentified vertebrates).
59–63
The virus occasionally
spreads to human population that live close to sylvatic environment
while sylvatic cycle have also been also reported in Asia.
64,65
Humans
are the main reservoir during epidemic while rodents, monkeys and
birds are reservoirs outside epidemic.
59
Urban cycle (human‐mosquito‐human) is maintained by CHIKV
transmission between human and urban mosquitoes.
59,66
Aedes
aegypti is the major vector of CHIKV in urban outbreaks. Besides
Aedes aegypti, the other vector Aedes albopictus was observed as
vector of transmission in virus and this strain is also find associated
in Indian Ocean Island outbreak with harbouring the substitution in
alanine to valine of E1 glycoprotein (E1‐A226V), results in
enhanced transmitting ability.
59,67–70
In addition to Aedes aegypti
and Aedes albopictus, some other vectors found in endemic areas are
Aedes stephensi and Aedes vittatus.
71
Transmission of virus from
infected male mosquito (Aedes aegypti) to female via venereal route
have been reported.
72
Vertical transmission from mother to child
has also been analysed, causing foetal death and congenital
illness.
73
The breeding habitat of Aedes aegypti and Aedes albopictus
is mainly fresh water. The mosquito's eggs remain resistant until
rainy season giving rise to larvae.
4
Main transmission vector of
CHIKV infection, Aedes aegypti is mostly adapted to urban envi-
ronment while Aedes albopictus is well amended to both rural and
urban environment.
4,59
4
|
VIRUS VARIABILITY AND SEQUENCE
ANALYSIS
CHIKV genome contains 11,900 nucleotides and two ORFs code for
nonstructural and structural proteins.
74
CHIKV genome shows great
sequence variability but cross protection against different genotype
has been observed in patients who has been infected by one geno-
type.
75
There are three geographically related genotype of CHIKV.
One from West Africa, another from Asia and one contains all iso-
lates from Eastern, Central and South Africa (ECSA).
76
However,
genome length among these lineages varies, as ECSA lineage is
shorter than West African and Asian isolates Figure 2. Almost all
genes show nucleotide differences including 26s junction regions and
50and 30UTRs. Along with distinct genotypes, novel variants such as
quasispecies have been identified in patients infected with CHIKV as
shown in Figure 2.
77
Some sites such as E1, E2 and nsp3 show
intergenomic genetic differences that are associated with host
adaptability in alpha virus.
78
Currently intensive sequencing of
CHIKV genome is conducted and nearly 394 CHIKV sequences
including 51 full length genomes reported so far in generic data
banks (Genbank, European Molecular Biology Laboratory and DNA
Data Bank of Japan).
MANZOOR ET AL.
-
3 of 13
FIGURE 2 Evolutionary relationships of taxa. The evolutionary history was inferred using the Neighbour‐Joining method and Tamura Nei
method. The optimal tree with the sum of branch length =0.27860208 is shown. The percentage of replicate trees in which the associated
taxa clustered together in the bootstrap test (1000 replicates) is shown next to the branches. The tree is drawn to scale, with branch lengths in
the same units as those of the evolutionary distances used to infer the phylogenetic tree. The evolutionary distances were computed using the
Maximum Composite Likelihood method and are in the units of the number of base substitutions per site. The analysis involved 35 nucleotide
sequences. Codon positions included were 1st +2nd +3rd +Noncoding. All positions containing gaps and missing data were eliminated. There
were a total of 1096 positions in the final data set. Evolutionary analyses were conducted in MEGA5
4 of 13
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MANZOOR
ET AL.
5
|
GENOME ORGANIZATION
CHIKV belongs to the family Togaviridae and genus Alphavirus. CHIKV
is small, enveloped virus, spherical in shape with diameter up to
70 nm.
79
Genome of CHIKV is a single and positive stranded RNA
molecule which contains about 11,900 nucleotides whose organiza-
tion is 50NTR‐cap‐nsP1‐nsP2nsP3‐nsP4‐(junctional region)‐C‐E3‐E2‐
6K‐E1‐poly (A)‐NTR3’ Figure 3. Three segments are present in non‐
translated (NTR) region that are 50NTR whose length is almost 76
nucleotides, 30NTR which is of 526 nucleotides in length while the
junctional region of 68 nucleotides long (Table 1).
5.1
|
Nonstructural protein
CHIKV have two ORFs like other alpha viruses. ORF contains 7424
nucleotides at 50terminal responsible for encoding non‐structural
proteins nsP1‐4 and these proteins are involved in virus replica-
tion
80
Table 1.
5.1.1
|
nsP1
The nsP1 is 1605 bp in length; its N‐terminal region is a methyl-
transferase and guanylyltransferase engaged with topping and
methylation of recently incorporated viral genomic and subgenomic
RNAs. Additionally, nsP1 is a noteworthy part of the infection
replicase complex and capacities to stay replication buildings to have
cell layers amid RNA replication.
81,82
5.1.2
|
nsP2
The nsP2 protein has large net positive charge on it (+21) and con-
sists of 2394 nucleotides. The nsP2 protein consists of three do-
mains, the main containing helicase domain, RNA triphosphatase
domain and nucleoside triphosphatase domain.
83
Though, the second
and third domains are a papain‐like protease and are nonfunctional
methyltransferase. In addition, nsP2 contains a nuclear localization
sequence that made an interpretation of nsP2 to be translocated into
the nucleus.
84,85
It displays RNA triphosphatase/nucleoside triphos-
phatase and helicase exercises inside its N‐terminal area, the C‐end
encodes the viral cysteine protease important for preparing of
nonstructural polyprotein.
86,87
5.1.3
|
nsP3
The nsp3 consist of about 1590 bp in length and no exact capacity or
movement has been credited to this protein. It is made of two do-
mains; the first being a novel macro domain situated in the moder-
ated N terminal region. The C‐terminal domain is less moderated and
is phosphorylated in up to 16 positions on serines and
threonines.
88,89
The part of phosphorylation is not all around recor-
ded be that as it may, cancellation of the phosphorylated residues
and diminishes the RNA synthesis level. The C end of nsP3 is in this
manner thought to have a superfluous regulatory part.
90
5.1.4
|
nsP4
The nsP4 is of 1833 bp long and contains the RNA‐dependent RNA
polymerase, engaged with genome replication and interpretation.
91
It
works as RNA‐dependent RNA‐polymerase and could likewise as-
sume a platform part for connection with different nsPs or host
proteins through its N terminal end. It is the most conserved
protein.
92
All of these ns proteins are involved in formation of RNA repli-
case along with some proteins from host cell.
93
5.2
|
Structural proteins
ORF contain 3732 nucleotides fragment at its 30‐terminal and these
nucleotides are responsible for encoding five structural polyproteins
(sPs), that is, capsid, E3, E2, 6K/TF and E1 protein.
5.2.1
|
Capsid
Capsid consists of 783 nucleotides and contains two domains. First,
the amino terminal domain, is not involved in formation of structural
architecture but takes part in nucleocapsid formation as well as
interaction with RNA to enclose the genome. While the second is
carboxyl terminal domain that serves as serine protease.
94–96
5.2.2
|
E3
This protein is 192 bp long and it is basically α/βprotein which
regulates the spike assembly and interacts with E2 glycoprotein.
97
5.2.3
|
E2
E2 protein is about 1269 bp long. It is outer most region of spike
protein and have three immunoglobulin domains that is, A, B and C
domains as well as two glycosylation sites positions at 263 and 345.
98
The C domain is near to the viral membrane and function as a linker to
the transmembrane region. The B domain is present at the membrane
distal end which allows the contact with E3 protein. While the A
domain is present in the centre of protein.
99
E2 protein involved in
facilitating the virus to enter cells via A and B domains by two
mechanisms which are glycosaminoglycan GAG‐independent and
GAG‐dependent.
100
While E2 is also the main target of neutralizing
antibodies.
98
MANZOOR ET AL.
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5 of 13
TABLE 1Structural and non‐structural proteins of CHIKV
Protein name Symbol Size (aa) Location in cell Function
Structural
Capsid C 261 Cytoplasm Nucleocapsid formation as well as interacts with RNA to enclose the genome
Envelope 3 E3 64 Cytoplasm Regulates the spike assembly and interacts with E2 glycoprotein
Envelope 2 E2 423 Cytoplasm Involved in facilitating the virus to enter into cells
6K transframe 6K/TF 61 Cytoplasm Enhancing the virus assembly and release
Envelope 1 E1 436 Cytoplasm Involved in pre and post fusion events
Nonstructural
nsP1 protein nsp1 535 Cytoplasm Methylation of recently incorporated viral genomic and sub genomic RNAs
nsP2 protein nsP4 799 Cytoplasm Helicase exercises inside its N‐terminal area, viral cysteine protease
nsP3 protein nsP3 530 Cytoplasm Cancellation of the phosphorylated residues and diminishes the RNA synthesis level
nsP4 protein nsP4 61 Cytoplasm Engaged with genome replication and interpretation
FIGURE 3 Genome of Chikugunya virus (CHIKV). CHIKV possess +ssRNA with an open reading frame about 12 kb, encoding five
structural protein that is, capsid, E3, E2, 6K/TF and E1 protein and four non‐structural protein np1 to np5 are coloured in green. The amino
acid lengths of all encoding proteins are indicated in black. Red, black, dark green and purple arrow indicate the cleavage site of viral nsp2
protease, signal peptidase capsid and furin, separately
6 of 13
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MANZOOR
ET AL.
5.2.4
|
6K/TF
6K/TF is 183 bp in length. During the translation of 6K gene the
protein is produced by a frame shift although it is transframe (TF)
protein that is involved in enhancing the virus assembly and release.
5.2.5
|
E1
E1 protein is 436 bp in length and consists of three β‐sheet rich
domains (domains I, II and III), involved in pre and post fusion events
of replicating cycle.
101
6
|
PATHOGENESIS AND CLINICAL
MANIFESTATIONS
Molecular mechanisms of virus host‐cell interactions and pathogen-
esis of disease are not fully understood. Infected female mosquitoes
suck the blood from person infected with CHIKV and then allow viral
replication in the midgut for some days and then transmit that virus
to another host by biting. Epithelial and endothelial cells, primary
fibroblasts and macrophages are vulnerable to the virus and allow for
its replication.
16
There are three phases of disease and infected
person suffers with at least one of these three phases which are
acute, post‐acute and chronic stage.
102
6.1
|
First acute phase
Acute phase is comprising of first three weeks of infection. Signs and
symptoms arise after incubation period which is on average about 4–
7 days (in range of 1–12 days). Symptoms do not appear in all
infected persons. Asymptomatic infections are reported in about 3%–
25% patients with antibodies to CHIKV.
16,103
Signs and symptoms
then last for 5–10 days. In 99.5% cases, arthritis with severe pain,
pyrexia and inflammatory arthralgia are typical clinical presentations
of infection. Fever is very high, which is even not controlled by an-
tipyretics, along with painful and swollen peripheral joints. Other
signs and symptoms include headache, macular to maculopapular
rash, myalgia oedema of face and other extremities. In children, there
may be epistaxis and gingival bleeding, but it is not common in adults.
During acute phase, some unusual symptoms also appear which are
neurological and gastrointestinal, damaging of mucus membrane,
malaise, renal and respiratory failure, and pancreatitis.
104–106
Despite
all these, most patients have clinical improvement within 1–
2 weeks.
106
6.2
|
Second post‐acute phase
This phase commences from 4th week till the end of 3rd month. Sign
and symptoms of this phase are periarticular and synovial
inflammation along with severe arthritis, neuropathy, neuropsychi-
atric disorders and peripheral vascular disorders.
107
6.3
|
Third chronic phase
This phase appears after 3rd month when clinical symptoms still
exist.
107
In Reunion Island from 2005–2006 chronic phase lasted from
few months to several years in some infected patients and in Angola it
lasted up to 15 years.
102,108
Chronic disease was observed in 80%–
93% of patients in Reunion Island, from these patients 57% had it for
15 months and 47% for about 2 years.
104,109
It was observed in a study
that 76 patients suffered with chronic disease for about 3 years and
only 31% of these fully recovered while remaining patients suffered
from intermittent arthralgia due to which these patients were unable
to lift heavy objects and even not walk.
110
Mental health problems
have also been reported in many patients. It was estimated that eco-
nomic burden is about €250.00 per patient every year.
110,111
CHIKV
infections are mostly confused with dengue viral infection because in
both infections there is high fever along with myalgia and same mos-
quito specie transmit both viruses. But despite all this arthralgias in
multiple joints is more common in case of CHIKV only.
112–116
7
|
DIAGNOSIS
7.1
|
Genetic method
Samples taken from patient, RNA of virus or antibodies to CHIKV can
be detected for the confirmation of infection. In past, diagnosis was
based on serological techniques but with the advance molecular
techniques now RNA of virus can be detected in serum by the
reverse transcriptase‐polymerase chain reaction (RT‐PCR) specif-
ically when infection is in acute phase. There is high level of viremia
by CHIKV infection which usually lasts for 4–6 days and persist up to
12 days from disease onset.
117,118
Due to this reason viral culture or
RT‐PCR during an acute phase can be used for confirmation of
infection. Virus can be easily isolated from serum that is collected
during first 7 days of disease while the nucleic acid of virus can be
detected after few days with the help of real time RT‐PCR.
117,119
For
detection of CHIKV RT loop‐mediated isothermal amplification can
also be used.
120
There is an advantage of this technique that no
specialized equipment like thermocyclers is required in it. Isolation of
virus requires 48 h and molecular assays are completed within 1 day.
7.2
|
Virological method
CHIKV infection can be confirmed virologically by isolation of
virus from plasma, sera and tissue or whole blood. That diagnosis
is very specific but not sensitive. Viral antigens can be detected
with help of enzyme‐linked immunosorbent assay (ELISA) or
immunochromatographic assay. But only some antigen detection
MANZOOR ET AL.
-
7 of 13
kits are available with different sensitivity level towards different
genotypes of virus.
121
7.3
|
Serological method
Anti‐CHIKV immunoglobulin IgM and IgG antibodies can be detected
by ELISA.
117,119
ELISA is very specific for detection of infection
because it has very little cross reactivity with other alpha viruses. For
diagnosis of CHIKV infection, rapid dipstick variations of CHIKV
ELISA were developed recently but availability of these limited
worldwide.
120
Despite these techniques, plaque reduction neutrali-
zation test (PRNT) and immunofiuorescence assays are also used for
detecting antibodies to CHIKV in the serum.
16
PRNTs are very useful
for diagnosis because of their specificity to alpha viruses and are
thought to be gold standard to confirm the results of serological
tests. The use of live virus is required for PRNTs which is its major
drawback. Immunofiuorescence assays are very specific and sensi-
tive, but these are unable to quantify antibodies as well as requires
special equipment and training. But still these tests are available
commercially and are optionally used in those laboratories where
other infectious agents are to be detected.
16
8
|
PROSPECTIVE TREATMENT AND VACCINES
There are no antiviral drugs or vaccines for treatment and prevention
of CHIKV infection. Antipyretics, analgesics and anti‐inflammatory
agents may be used for treatment of different symptoms. IgGs anti-
bodies obtained from patients infected with CHIKV show protection
against CHIKV infection in mice.
122
This method becomes very
effective in neonates for treatment and prevention from CHIKV
infection whose mothers are viremic. However, this method is very
costly, and it is very difficult to develop CHIKV antiviral drugs and
vaccines. But due to recent outbreaks of CHIKV in Africa, La Réunion
island and Asia different research avenues have been started for
development of CHIKV antiviral drugs and vaccines (Table 2).
127
It
was reported that chloroquine phosphate is effective for treating
chronic CHIKV arthritis.
128
For treatment of CHIKV induced
arthritis, ribavirin which is an antiviral agent was used and it was
reported to be effective in reducing the swelling of joint and soft
tissue.
129
Bindarit, which is an anti‐inflammatory drug, has been re-
ported to be effective for treatment of arthritis caused by CHIKV
infection.
130
Two compounds harrington and cephalotoxine alkaloid
inhibited CHIKV replication in early stages.
131
Controlling mosquitoes can be helpful in prevention of disease
but it is very difficult strategy. Most effective way of disease control
would be vaccination. For development of vaccine against CHIKV,
infection different approaches have been used. The first vaccine
against CHIKV was formalin inactivated vaccine.
132
ECSA genotype of
2006 Indian outbreak strain was used for development of formalin
inactivated vaccine which was whole virus vaccine.
133
In 1986, Levitt
and colleagues developed the first live attenuated vaccine. It was
developed by plaque‐purified CHIKV in MRC‐5 (human foetal lung
fibroblast) cell line.
134
At US Army Medical Research Institute of In-
fectious Diseases, live‐attenuated CHIKV vaccine was also developed.
That vaccine was safe to be used as well as very well tolerated.
123
Other than these, DNA based vaccine using envelope (structural
protein) sequences was also developed.
135
By using a combined E1, E2
and E3 genes construct was found to be helpful in generating cell
mediated as well as humoral immune response.
124
VLP vaccines were
also developed that have ability of producing high tittered neutral-
izing antibodies.
136
But there was a drawback of all these vaccines.
Multiple immunizations were required for these vaccines and
TABLE 2Vaccines for CHIKV under process and clinical trials
Vaccine Description Trial Developer References
TSI‐GSD‐218 Live attenuated virus vaccine developed by United States
Army Medical Research Institute of infectious Diseases.
Produced by serial passage in MRC‐5 cells. Further
development stops due to funding issues
Phase II US Army Medical Research
Institute of Infectious
Diseases, The Salk Institute
for Biological Studies
[123]
VRC‐CHKV Chikungunya VLPs that are composed of the E1, E2, and
capsid proteins from the chikungunya virus strain 37997.
Manufactured at VRC, NIAID, Vaccine Pilot Plant
operated by Leidos Biomedical Research. It was safe with
good immunogenicity profile
Phase II National Institute of Allergy and
infectious Diseases (Vaccine
Pilot Plant operated by
Leidos Biomedical Research)
[124]
MVCHIK Live recombinant measles‐virus based chikungunya vaccine.
Live attenuated recombinant viral vectored vaccine based
on the Schwarz strain of measles vaccine. First measles‐
virus based candidate vaccine for humans
Phase I Themis Bioscience GmbH/
Institut Pasteur
[125]
CHIKV/IRES Live‐attenuated vaccine based on the insertion of a
picornavirus IRES sequence into the genome of CHIKV.
Induces strong neutralizing antibody response and
protects mice after a single dose
Phase I Takeda Pharmaceuticals U.S.A.,
Inc./University of Texas
Medical Branch
[126]
Abbreviations: CHIKV, Chikungunya virus; IRES, internal ribosome entry site.
8 of 13
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ET AL.
manufacturing was also expensive. This problem was overcome by the
development of live attenuated vaccine. CHIK‐IRES vaccine that
proved to be safe as well as efficient.
126
Chimeric viruses that contain
CHIKV structural proteins, Eastern equine encephalitis virus and
Venezuelan equine encephalitis virus induced neutralizing antibodies
and thus help in protection of mice from CHIKV infection.
9
9
|
CHIKV AND HEALTH COMMUNICATION IN
THE 21ST CENTURY
Different social networks play crucial role in spreading awareness
about CHIKV and its consequences such as Facebook, Instagram and
Twitter. Moreover, Facebook is main information source that contain
different posts which could be reliable and relevant to disease.
137
CHIKV related contents at twitter is under different themes and
hashtags such as (i) Aedes Aegypti, (ii) Chikungunya, (iii) Preventing
Mosquito Borne Disease and (iv) Health Care Services. Apart from
that, different news channels are the second most important source
for CHIKV‐related information such as Science Daily, Dawn News
and The Star Online. Main concern of Science Daily was to investi-
gate the cause of persistent joint pain after months of infection while,
Dawn News showed the epidemiology of disease in different areas of
Pakistan and its severity compared to last year.
138
The Star News
indicated the new cases in traders and merchants in Simbang Kuala
that was investigated by Kedah Health Department Malaysia.
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐
CoV‐2), also named as the 2019 novel Coronavirus (2019‐nCoV), is a
newly emerging zoonotic agent that come into sight in December
2019 and is the causative agent of the Coronavirus Disease 2019
(COVID‐19) pandemic.
139
Wide spread of virus is due to its ability of
person‐to‐person transmission. People get infected via direct contact
or by droplets that are produced through sneezing or coughing of
infected person.
140
CHIKV is an arthropod borne virus and spread via
infected mosquito.
16
These attributes of CHIKV reduce likelihood of
its epidemics to develop into a pandemic.
To control pandemic in future it is required to take various pre-
cautionary measures. Quick and accurate method are required for
rapid diagnose and reliable results. Widely used standard method for
viral diagnosis is quantitative reverse polymerase chain reaction.
MALDI‐TOF MS and IR spectroscopy are also introduced for routine
identification of bacteria, viruses and fungi.
141
It is required to conduct
epidemiological surveillance and puts pressure on health care units.
142
10
|
CHIKV, URBANIZATION AND GEOGRAPHIC
EXPANSION
The habitat which is created by us allows Aedes mosquitoes to live with
us. In urban areas, high population densities are of major concern
regarding disease transmission that are of mosquito borne. In urban
zones from 1960 to 2014 population increased from 34% to 54%.
143
As
hypothesized by LaDeau regarding mosquito population there are two
effects of urbanization: buffer temperature fluctuations and mean
temperatures are raised by the urban heat islands. This in turn facili-
tates the growth and viral replication rates. Immature mosquito life
stages are further supported by creation of additional container habi-
tats.
144
In urban environments, the population is increasing which is
creating good habitats for vectors. The risk of new emergence of CHIKV
epidemics increases due to movements of international population and
dissemination of mosquito worldwide progressively. This threat can be
limited in susceptible regions by international collaboration. In
epidemic countries, it can be controlled by controlling the vector as well
as isolating infectious people.
135
11
|
CONCLUSION
CHIKV is a re‐emerging virus that is known to infect millions of
people worldwide. CHIKV is a major health concern. The main
chronic symptom of CHIKV infection is persisting arthralgia.
Continuous viral surveillance is needed and will help in gathering
data related to viral genotype which could be helpful in development
of viral drugs and vaccines.
ACKNOWLEDGEMENTS
None.
CONFLICT OF INTEREST
There is no conflict of interest exists among the authors.
AUTHOR CONTRIBUTIONS
Farakh Javed conceived the idea and design the flow of manuscript.
Farakh Javed, Nazneen Manzoor, Muhammad Ejaz, Mubashir Ali and
Neelam Mujaddadi wrote the first draft of the manuscript. Farakh
Javed, Nazneen Manzoor, Sobia Manzoor, Waqar Saeed, Aamer Ali
Khattak. Ibrar Ahmad, Abid Ali Khan and Asad Zaib revised the
manuscript. Farakh Javed, Nazneen Manzoor and Mubashir Ali pro-
duced the figures. All authors reviewed and approved the final version
of the manuscript.
DATA AVAILABILTY STATEMENT
Data sharing not applicable to this article as no datasets were
generated or analysed during the current study.
ORCID
Farakh Javed
https://orcid.org/0000-0003-1305-7834
Muhammad Ejaz https://orcid.org/0000-0002-1339-5537
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How to cite this article: Manzoor KN, Javed F, Ejaz M, et al.
The global emergence of Chikungunya infection: An integrated
view. Rev Med Virol. 2021;e2287. doi:10.1002/rmv.2287
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