Accepted Manuscript Title: An updated review of Zika virus Author: Abdelrahman Ibrahim Abushouk Ahmed Negida Hussien Ahmed PII: DOI: Reference:
S1386-6532(16)30545-5 http://dx.doi.org/doi:10.1016/j.jcv.2016.09.012 JCV 3701
To appear in:
Journal of Clinical Virology
Received date: Revised date: Accepted date:
15-3-2016 27-9-2016 30-9-2016
Please cite this article as: Abushouk Abdelrahman Ibrahim, Negida Ahmed, Ahmed Hussien.An updated review of Zika virus.Journal of Clinical Virology http://dx.doi.org/10.1016/j.jcv.2016.09.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
An updated review of Zika virus
1
Abdelrahman Ibrahim Abushouk1, 2, Ahmed Negida3, 4, 5, Hussien
2
Ahmed3, 4, 5
3
1
Faculty of Medicine, Ain Shams University, Cairo, Egypt
4
2
NovaMed Medical Research Association, Cairo, Egypt
5
3
Medical Research Group of Egypt, Cairo, Egypt
6
4
Faculty of Medicine, Zagazig University, Zagazig, El-Sharkia, Egypt
7
5
Student Research Unit, Zagazig University, Zagazig, El-Sharkia, Egypt
8 9
Correspondence to: Abdelrahman Ibrahim Abushouk; Faculty of Medicine, Ain
10
Shams University, Cairo, Egypt; Postal code 11566; Tel: +201014295780; Email:
11
[email protected]
12 13
1
HIGHLIGHTS
2
1. RT PCR of urine samples seem to be the most reliable diagnosis for ZIKV. 2. A recent report described successful treatment by intravenous Xiyanping. 3. Vector control is the most effect prevention against ZIKV. 4. Future research should develop broad spectrum antivirals. 5. The association between ZIKV and microcephaly needs further investigation.
3 4 5 6 7 8 9 10 11
Abstract
1
The current outbreak of Zika virus (ZIKV) in South America is one of the most
2
serious public health emergencies since the Ebola outbreak of West Africa (2014).
3
ZIKV belongs to flaviviridae family and has two lineages (Asian and African). The
4
virus was first discovered in Uganda (1947) and the first human infection was
5
identified in Nigeria (1952). The current epidemic is the third of its type after that of
6
Yap Island, Micronesia (2007) and French Polynesia (2013). Phylogenetic studies
7
revealed that the current strain shares about 99.7% of nucleotides and 99.9% of amino
8
acids with the strain of French Polynesia epidemic (2013), suggesting that it has
9
spread across the Pacific Ocean to invade South America. Aedes Aegypti mosquito is
10
the main vector for ZIKV and there are some reports describing possible sexual and
11
maternal to fetal transmission. ZIKV infection is known to be self-limited. However,
12
recent reports suggested that it can be associated with neurological manifestations as
13
Guillan-Barrè Syndrome and microcephaly in the newborn population. Currently,
14
vector control seems to be the most effective available preventive measure against
15
ZIKV spread. The development of broad spectrum antivirals and ZIKV vaccines
16
should be a priority of future research.
17
Keywords
18
Zika virus; Epidemic; Public health; Microcephaly
19 20
1 2
1. Zika Virus Morphology
3
ZIKV is a predominantly single RNA stranded virus, belonging to the flaviviridae
4
family (1,2), a viral family in which the yellow fever virus is considered the
5
prototype, most lethal and most historically relevant member. Zika virus (ZIKV) is a
6
positive-sense RNA virus with a 10.7-kb genome encoding a single polyprotein that is
7
cleaved into three structural proteins (C, PrM/M, and E) and seven nonstructural
8
proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) (3).
9
It is believed that the virus initially developed in Uganda probably between 1892 and
10
1943. Phylogenetic studies indicated the presence of two lineages of ZIKV: the Asian
11
and African lineages (1). In 2007, the full length of ZIKV genome was identified and
12
published (4) and till then, the virus was primarily infecting wild primates causing
13
sporadic "Spillover" infections in humans. However, it is believed that the virus
14
recently adapted to humans by losing an NS1 codon of its genome (5).
15
2. Historical Overview
16
During a research on jungle yellow fever virus in ZIKA forest, Uganda 1947, a rhesus
17
monkey contracted an arthropod borne virus that was later isolated and identified as
18
ZIKV. However, it was not reported in humans until 1952 when it was first detected
19
in Nigeria (6). All over the following 60 years, it was known that ZIKV causes benign
20
sporadic infections in both Africa and Asia. Therefore, when the first epidemic
21
appeared in Yap Island, Micronesia, in 2007, it was initially misdiagnosed as Dengue
22
fever. During this outbreak (Micronesia, 2007), Forty-nine ZIKV infected cases were
23
confirmed, while serological evidence of infection was obtained from 73% of the
24
individuals older than 3 years (2). In 2013, it caused another epidemic in French
1
Polynesia (with > 400 laboratory confirmed cases) before spreading across the Pacific
2
Ocean to invade Brazil, Suriname, and Columbia (7). A summary of ZIKV history
3
and previous outbreaks is shown in table 1 and the CDC map of current ZIKV-
4
infected areas is shown in figure 1.
5
Phylogenetic analyses revealed that the current strain belongs to the Asian subtype
6
and shares more than 99.7% of nucleotides and 99.9% of amino acid identity with the
7
strain of French Polynesian outbreak in 2013 (1). These results suggested that the
8
current ZIKV epidemic reached South America from the epidemic of French
9
Polynesia in 2013 by spreading across the Pacific Ocean.
10
3. Pathogenesis and Transmission
11
The pathogenesis of ZIKV infection remains largely unknown, but most arboviruses
12
are thought to replicate within the skin dendrites at the primary inoculation site before
13
spreading to the regional lymph nodes and then to the blood stream (8). The virus is
14
claimed to spend an intrinsic incubation period of 4 to 5 days within the human host,
15
infecting another vector during blood feeding where it spends an extrinsic incubation
16
period of 8 to 12 days and disseminates to the vector's saliva to infect another host as
17
illustrated in Figure 2 (9).
18
3.1.
Mechanical transmission
19
Like most Arboviruses, Zika virus maintains a complex cycle of transmission between
20
arthropods and vertebrate animals (1). The virus was first isolated from Aedes
21
Africanus mosquito in 1948 in Zika forest (10). However, Ae. Aegypti mosquito was
22
identified as the main vector, feeding on blood from infected individuals and
23
transmitting the virus to healthy ones (9). Other Aedes mosquito species are suggested
24
to be involved in viral transmission as Ae. Albopictus, a highly invasive vector
1
presenting a threat to urban as well as rural areas (11,12). The global distribution of
2
both Ae. Aegypti and Albopictus is growing, increasing the risk of arbovirus
3
pandemics (13). A molecular study, performed in 2014 on 37 isolated samples of the
4
virus, showed that the virus has acquired a molecular change to adapt to the Ae.
5
Dalzieli vector by losing a glycosylation site (N154) in its protein envelope (2). In
6
2013, researchers have noted an analogous pattern of spread between ZIKV and
7
Chikungunya, another member of the flaviviridae family transmitted by Aedes
8
mosquito species (14).
9
3.2.
Sexual transmission
10
In 2011, a case report suggested a non-vector borne route of viral transmission
11
through sexual contact (15). In December 2015, another case report was published
12
confirming the presence of viral particles in the semen of a 44 year old man who had
13
been diagnosed with ZIKV infection two weeks earlier (16). In February 2016, the
14
center of disease control (CDC) in the USA announced possible sexual transmission
15
in 14 cases, but the mode of transmission was not confirmed (17). Sexual
16
transmission of Zika virus through infected semen is now well established (18).
17
Despite the fact that the RNA of ZIKV can persist in semen for up to 62 days, cases
18
usually present before 19 days of sexual contact and only one case has been reported
19
of a woman presenting with a ZIKV infection 44 days after the onset of symptoms in
20
her partner (19). Also, a case report indicated that ZIKV can be transmitted through
21
anal sex, as well as vaginal sex (20).
22
3.3.
Maternal fetal transmission
23
Pregnant women are susceptible to ZIKV during all trimesters of pregnancy and
1
maternal-fetal transmission has been confirmed. Also perinatal mode of transmission
2
has been reported in two cases in French Polynesia and was associated with mild
3
disease in newborn infants (21).
4
3.4.
Blood transfusion
5
During the outbreak of ZIKV in French Polynesia, Musso et al., demonstrated the risk
6
of potential transmission through blood transfusion obtained from infected individuals
7
(22).
8
4. Clinical Picture
9
When the virus was initially reported in human in 1952, the infection was known to
10
be asymptomatic or mildly symptomatic starting with mild fever, small joint pain,
11
retro-orbital headache, and conjunctivitis (23). Three to five days following the rise in
12
temperature, the patient develops a widely spread maculopapular rash (15,23–25).
13
Although ZIKV is known to cause a self-limited infection in adults, the
14
documentation of 73 cases of Guillan-Barrè Syndrome (GBS) during the French
15
Polynesian outbreak raised concerns about a possible association between the virus
16
and serious neurological complications (26). Similarly, in the Brazilian outbreak in
17
April 2015, the Brazilian ministry of health reported increased frequency of GBS and,
18
moreover, a 20 fold increase in the rate of microcephaly within the newborn
19
population (27). However, the causality link between ZIKV infection and
20
development of GBS has not been formally established so far and the strongest
21
evidence in the literature about it comes from a case control study that identified 42
22
cases of GBS of which 88% of them reporting a recent history of acute viral infection
23
during the French Polynesia outbreak (28).
24
The causality association between ZIKV infection in the first trimester of pregnancy
1
and development of microcephaly or other congenital anomalies has been formally
2
established (29,30). Most reported cases in the literature are for women who gave
3
birth to newborns with microcephaly and reported symptoms of contracting ZIKV
4
(mostly rash) in their first or second trimester of pregnancy (31–33). Recently, four
5
fetuses with microcephaly were born in Columbia to women who did not report
6
symptoms of contracting ZIKV, but had a lab evidence of ZIKV infection (34). A
7
recent report described ophthalmic findings as macular pigment mottling and loss of
8
foveal reflex associated with microcephaly and intracerebral calcifications in newborn
9
infants whose mothers showed clinical manifestations matching the criteria for ZIKV
10
diagnosis (35). In addition, RNA particles of ZIKV were detected in amniotic fluid
11
analysis of two women with radiological evidence of microcephaly. This finding
12
suggests that the virus crossed the placenta and may be incriminated in producing
13
congenital anomalies (36).
14
5. Diagnosis
15
5.1.
16
Clinical presentation
In the absence of other arbovirus epidemics, diagnosis can be solely made on clinical
17
grounds; however, as mentioned earlier, ZIKV outbreaks are usually associated with
18
other arbovirus epidemics making diagnostic investigations a necessity for clarifying
19
the clinical presentation (14).
20
5.2.
Serological analysis
21
Detecting IgM in the patient's serum by ELISA technique is an effective method, but
22
not available in most laboratories. Moreover, the cross reactivity with antibodies to
23
other arboviruses decreases the specificity of this technique (25,37,38). In a recent
24
study, serum samples from 21 patients with acute undifferentiated fever in Thailand
1
were examined for immunoreactivity against ZIKV, Dengue, Japanese encephalitis
2
and Chikungunya envelope antigens. The study showed evidence of immunoreactivity
3
against ZIKV envelope, suggesting that the ZIKV outbreak might have transmitted to
4
Thailand (39). However, due to the cross reactivity of serological analysis, more
5
specific diagnostic methods (e.g. molecular diagnosis using real time PCR) are
6
required.
7
5.3.
Molecular diagnosis (RT-PCR)
8
Molecular diagnosis can be performed using Reverse Transcriptase Polymerase Chain
9
Reaction (RT-PCR) (40). Diagnostic studies suggested that serum can test positive for
10
viral particles as soon as the illness and fever appear, but when the rash occurs,
11
viremia starts to drop. However, viral nucleic acids remain detectable for about 20 to
12
60 days from the onset of symptoms (41,42).
13
During the French Polynesia epidemic, Kutsuna et al. reported positive viral RNA in
14
urine, while serum samples from the same patients were negative (43). Gourinat et al.
15
reported that the virus can be detected in the urine of infected individuals with higher
16
titers after 20 days from the onset of the disease (38). These data are consistent with
17
former studies which suggested prolonged detection of viral RNA of other
18
flaviviruses as dengue virus (44) and West Nile virus (45) in urine samples. These
19
reports highlight the role of viral detection in urine as a diagnostic method for ZIKV
20
infection during epidemics.
21 22 23
6. Treatment
1
Because the infection is self-limited, management is usually based on supportive
2
treatment and bed rest. When epidemics of multiple viruses coexist, differentiation
3
between these types may be valuable for prompt treatment because Dengue fever
4
requires monitoring of the patient hematocrit value and cessation of aspirin use to
5
reduce the risk of hemorrhage, while Chikungunya infection requires management of
6
post-chronic arthritis which occurs after the infection resolves (14). Aspirin should be
7
avoided in children below 10 years to avoid the occurrence of Reye's Syndrome,
8
while Acetaminophen can be used instead (46). A recent in-vitro study suggested that
9
ZIKV infection could respond to interferon therapy; however, further investigations
10
are essential to confirm this finding (47). Recently, a report has described a case of
11
ZIKV infection that was cured using an integrated approach of traditional Chinese
12
medicine and western medicine. This patient was admitted into the infectious isolation
13
wards and daily intravenous drip of 250 mg xiyanping injection was prescribed as an
14
antiviral therapy. Then, Ibuprofen was administered to reduce fever and
15
chloramphenicol eye drops were prescribed to relieve conjunctival congestion. After
16
few days, the urine and blood tests for ZIKV were negative (48).
17
Currently, there are no approved drugs for treatment of ZIKV or any other flavivirus
18
(49). Shan et al. suggested utilizing two strategies to develop a treatment for ZIKV
19
including: 1) repurposing the use of existing drugs, used for other clinical indications,
20
as potential therapeutic agents for ZIKV, mimicking what was attempted with the
21
Ebola virus, 2) Developing de novo inhibitors of ZIKV infection and replication,
22
using viral enzyme assays to identify potential inhibitors from compound libraries
23
(50).
24
7. Prevention
1
7.1.
2
Vaccination
To moment, no vaccines have been developed yet. But it is expected that the ZIKV
3
vaccine would encounter the same problems of arbovirus vaccines owing to the
4
sporadic and unexpected eruption of epidemics; therefore, vaccinating a large
5
population for fear of its outbreak might not be cost-effective (14,51). In March 2016,
6
eighteen academic institutions and pharmaceutical companies were working to
7
develop different types of vaccines for ZIKV including purified inactivated vaccine,
8
live attenuated vaccines, DNA vaccines, and viral vectored vaccines (52). Each of
9
these vaccines has its advantages and drawbacks. For instance, live attenuated
10
vaccines can elicit a strong, long-lasting immune response after few doses; however,
11
safety concerns arise, especially in case of pregnant women and children. On the other
12
hand, subunit vaccines are safe and can be developed in a shorter timeline, but they
13
require multiple doses to induce an immune response (50).
14
To accelerate the timeline of vaccine production, all of these vaccines should be
15
pursued concurrently. We are aware that most of these vaccines are in the preclinical
16
trials phase and some of them have shown a promising efficacy in animal studies.
17
Recently, an animal study has been published showing that intramuscular injection of
18
a DNA vaccine, encoding the full length of PrM and E structural proteins, elicited a
19
stronger humoral immune response in mice than other vaccines that did not encode
20
the PrM protein (53). Another DNA vaccine, developed by Invoice Pharmaceuticals,
21
could induce an immune response against ZIKV in monkeys and rabbits (54,55).
22
We are aware of four phase 1 studies registered on clinicaltrials.gov at the time of
23
publishing this article (NCT02840487, NCT02887482, NCT02809443, and
24
NCT01967238) and are expected to start in the second half of 2016. Although the
1
timeline to provide an effective vaccine for ZIKV is being condensed, the pathway to
2
licensure of an effective vaccine may take four to five years at a minimum (56). In a
3
recent article by Durbin et al., the authors highlighted five considerations for ZIKV
4
vaccine development including 1) the target population for immunization. The
5
ultimate goal of vaccination is providing this vaccine to children residing in endemic
6
areas as a part of their routine immunization, 2) which vaccine is safe for use in
7
pregnancy and what is the best timing for vaccination as congenital anomalies due to
8
ZIKV infection occur very early in pregnancy, 3) The needed number of doses to
9
elicit an immune response, 4) The safety and immunogenicity of the vaccine in
10
persons with former flavivirus exposure; therefore, developed vaccines should be
11
tested in both flavivirus-naive and flavivirus-exposed individuals, and 5)
12
sustainability of the protective effect of the vaccine (55).
13
7.2.
14
Vector control
Other preventive measures can be learnt from the Yellow fever virus; vector control is
15
suggested to be the most efficient preventive strategy by using insect repellents and
16
house screens, wearing long sleeved shirts, sleeping in air conditioned rooms, and
17
clearing up household debris which act as breading sites for mosquitos. The World
18
Health Organization (WHO) recommends the use of repellents containing DEET (N,
19
N-diethyl-3-methylbenzamide), IR3535 (3-[N-acetyl-N-butyl]-aminopropionic acid
20
ethyl
2-(2-hydroxyethyl)-1-
21
methylpropylester) (57). Recently, the WHO’s vector control advisory group is
22
discussing the use of genetically modified mosquitos to control Ae. Aegypti, the main
23
vector of Zika virus (58). The OX513A male mosquito was used successfully before
24
to tackle dengue fever in Brazil through competing with the wild Ae. Aegypti males.
25
ester)
or
icaridin
(1-piperidinecarboxylic
acid,
7.3.
Travel and pregnancy measures
1
Before the association between ZIKV and congenital malformations in newborn
2
infants could be established, the CDC adopted the presumption of “guilty until proved
3
innocent” and developed guidelines for pregnant women and their caregivers (59).
4
These guidelines imply that all pregnant women should consider postponing their
5
travel to areas with ZIKV ongoing transmission. If necessary, adhering to the
6
previously mentioned vector control guidelines is strongly advised. For women with a
7
history of travel to infected areas, they should be examined for ZIKV infection as well
8
as Dengue and Chikungunya due to the similar geographical distributions of these
9
viruses. Symptomatic pregnant women or those with ultrasound evidence of
10
microcephaly should be tested for ZIKV infection using RT-PCR (60). Pregnant
11
women with established diagnosis of ZIKV should perform serial ultrasound every 3
12
to 4 weeks with referral to a maternal-fetal medicine unit for further management
13
(59).
14
The CDC recently recommended sexual abstinence or condom use for men who are
15
residing or recently returning from an area with active ZIKV transmission (61).
16
Because of the potential risks associated with Zika virus infection during pregnancy,
17
the CDC has recommended health care providers to discuss prevention of unintended
18
pregnancy with women who reside in areas of active Zika virus transmission and do
19
not want to become pregnant (62). However, limitations in access to contraception in
20
some of these areas might affect the ability to prevent an unintended pregnancy (63).
21 22 23
8. Future research
1
Zika virus infection is a threat, not only to public health, but also to global security
2
and economy. From a preventive view, future research should focus on developing an
3
effective vaccine against ZIKV. In terms of treatment, the development of a broad
4
spectrum antiviral drug has been recently recommended because the "One Bug- One
5
Drug" approach is no longer practical (14). The association between ZIKV and
6
neurological manifestation require further verification. In addition, the underlying
7
pathological process and identification of population whom are at risk of these
8
neurological manifestations should be investigated in the future.
9
Abbreviations: GBS: Guillan-Barrè Syndrome, RT-PCR: Reverse Transcriptase
10
Polymerase Chain Reaction, ZIKV: Zika virus.
11
Conflict of interest: None to declare
12
Acknowledgement: None
13
Funding source: None to declare
14 15
1
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2
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1
Figure 1 shows areas of active transmission of ZIKV, in the current outbreak,
2
according to CDC reports. Left circle indicates viral transmission in Pacific
3
islands as Samoa and Tonga. Right circle indicates viral transmission in Cape
4
Verde, West Africa (obtained 10th, February, 2016).
5 6
Figure 2 shows the life cycle of ZIKV between the Aedes Mosquito and the human host.
7 8 9 10
1
Table
2
Table 1 summarizes the history of VIKV discovery and epidemics
3
1947
ZIKV was first discovered
1952 2007 2013
ZIKV first human infection in Nigeria. First epidemic Yap island, Micronesia 49 cases Second epidemic French Polynesia >400 cases >1.5 million cases (in Brazil; Third epidemic South America according to Brazil Ministry of health)
2015
4 5 6 7
The author has requested enhancement of the downloaded file. All in-text references underlined in blue are linked to publications on ResearchG
