Advances in Zika virus vaccines and therapeutics:A systematic review

Zika virus(ZIKV)is the causative agent of a viral infection that causes neurological complications in newborns and adults worldwide.Its wide transmission route and alarming spread rates are of great concern to the scientific community.Numerous trials have been conducted to develop treatment options for ZIKV infection.This review highlights the latest developments in the fields of vaccinology and pharmaceuticals developments for ZIKV infection.A systematic and comprehensive approach was used to gather relevant and up-to-date data so that inferences could be made about the gaps in therapeutic development.The results indicate that several therapeutic interventions are being tested against ZIKV infection,such as DNA vaccines,subunit vaccines,live-attenuated vaccines,virus-vector-based vaccines,inactivated vaccines,virus-like particles,and mRNA-based vaccines.In addition,approved anti-ZIKV drugs that can reduce the global burden are discussed.Although many vaccine candidates for ZIKV are at different stages of development,none of them have received Food and Drug Authority approval for use up to now.The issue of side effects associated with these drugs in vulnerable newborns and pregnant women is a major obstacle in the therapeutic pathway.

Characterization of the infectivity of an Indonesian Zika virus strain in mammalian cell lines

Objective:To characterize the infection patterns and growth characteristics of the Zika virus(ZIKV)strain JMB-185 from Indonesia in various mammalian cell lines.Methods:ZIKV was grown in human(A549,HEK293,HepG2,Huh7,Jurkat,and THP-1)and non-human mammalian(RAW264.7,Vero,and Vero76)cell lines.Viral replication kinetics were measured using plaque assay,while intra-and extracellular viral RNA concentrations were assessed using RT-PCR.Flow cytometry was used to quantify the infected cells and cell viability was measured using an MTT assay.The ability of ZIKV to infect cell lines was visualized using a fluorescence immunostaining assay.Results:This ZIKV strain preferentially infected the lung,kidney,and liver cell lines A549,HEK293,Huh7,Vero,and Vero76,but not the immune cells Jurkat,RAW264.7,and THP-1.By contrast,the ZIKV showed no sign of infection in HepG2 cells,while maintaining viral titer over 3 days post-infection,with no infection recorded in immunostaining,no increase in viral RNA,and no indication of cell deterioration.Conclusions:The Indonesian ZIKV strain has a similar infection profile as other strains,except for its poor infectivity on HepG2 cells.Information on the growth characteristics of Indonesia ZIKV will help expand our understanding of the biology of ZIKV which will be useful for various applications including antiviral discovery.

Polypyrimidine Tract-Binding Protein Enhances Zika Virus Translation by Binding to the 5'UTR of Internal Ribosomal Entry Site

Objectives To identify the 5'untranslated region of Zika virus(ZIKV 5'UTR)RNA-binding proteins and to investigate the impact of the binding protein on the activity of internal ribosomal entry site(IRES)located in ZIKV 5'UTR and virus production.Methods Interacting proteins in U251 cells were captured using tRSA-tagged ZIKV 5'UTR RNA and tRSA-ZIKV 5'UTR RNA-binding proteins were visualized by SDS-PAGE silver staining,Subsequently,liquid chromatographytandem mass spectrometry(LC-MS/MS),bioinformatics analysis,and Western blot were used to identify the candidate proteins binding to ZIKV 5'UTR.Dicistronic expression assay and plaque forming assay were performed to analyze the effect of the binding protein on ZIKV IRES activity and ZIKV production,respecitvely.Results tRSA RNA pull-down assay,LC-MS/MS,and Western blot analysis showed that polypyrimidine tractbinding protein(PTB)bound to the ZIKV 5'UTR.Furthermore,dual luciferase reporter assay revealed that overexpression of PTB significantly enhanced the IRES activity of ZIKV(t=10.220,P<0.001),while PTB knockdown had the opposite effect(t=4.897,P<0.01).Additionally,virus plaque forming assay demonstrated that up-regulation of PTB expression significantly enhanced viral titer(t=6.400,P<0.01),whereas reducing PTB expression level weakened virus infectivity(t=5.055,P<0.01).Conclusion PTB positively interacts with the ZIKV 5'UTR and enhances IRES activity and virus production.

Numerical Computation of SEIR Model for the Zika Virus Spreading

The purpose of this study is to present the numerical performancesand interpretations of the SEIR nonlinear system based on the Zika virusspreading by using the stochastic neural networks based intelligent computingsolver. The epidemic form of the nonlinear system represents the four dynamicsof the patients, susceptible patients S(y), exposed patients hospitalized inhospital E(y), infected patients I(y), and recovered patients R(y), i.e., SEIRmodel. The computing numerical outcomes and performances of the systemare examined by using the artificial neural networks (ANNs) and the scaledconjugate gradient (SCG) for the training of the networks, i.e., ANNs-SCG.The correctness of the ANNs-SCG scheme is observed by comparing theproposed and reference solutions for three cases of the SEIR model to solvethe nonlinear system based on the Zika virus spreading dynamics throughthe knacks of ANNs-SCG procedure based on exhaustive experimentations.The outcomes of the ANNs-SCG algorithm are found consistently in goodagreement with standard numerical solutions with negligible errors. Moreover,the procedure’s constancy, dependability, and exactness are perceived by usingthe values of state transitions, error histogram measures, correlation, andregression analysis.

Based on the risk of dengue virus transmission via blood transfusion:What about the risk in case of Zika virus?

The risk of dengue virus transmission via blood transfusion is confirmed.As a similar virus,the risk for the case of Zika virus should be mentioned.Here,the authors calculated for the risk of Zika virus transmission via blood transmission referring to the previous data on the risk in case of dengue virus.

An immunoglobulin Y that specifically binds to an in silico-predicted unique epitope of Zika virus non-structural 1 antigen

Objective:To identify unique immunogenic epitopes of Zika virus non-structural 1(NS1)antigen and produce immunoglobulin Y(IgY)for potential use in he diagnosis of of Zika virus infection.Methods:Immunogenic epitopes were identified using in silico B-cell epitope prediction.A synthetic peptide analog of the predicted epitope was used to induce antipeptide IgY production in hens which was purified using affinity chromatography.Presence of purified IgY and its binding specificity were performed by gel electrophoresis and ELISA,respectively.Results:Out of the nine continuous epitopes identified,the sequence at position 193-208(LKVREDYSLECDPAVI)was selected and used to produce anti-peptide IgY.The produced IgY was found to bind to the synthetic analog of the Zika virus NS1 immunogenic epitope but not to other flaviviruses and random peptides from other pathogens.Conclusions:In this study,we identified an immunogenic epitope unique to Zika virus that can be used to develop a serodiagnostic tool that specifically detect Zika virus infection.

Doubled dosage of sofosbuviris expected for inhibiting Zika virus infection

Sofosbuvir is a new antiviral drug that has been recommended for management of hepatitis C virus (HCV) for a few years. New researches support that sofosbuvir might he useful for the management of Zika virus infection. Based on the pharmacological activity, inhibiting the HCV RNA-dependent RNA polymerase (RdRp or NS5 protein). sofosbuvir is proposed for its effectiveness against Zika virus infection. Here, the authors used a mathematical modelling theoretical approach to predict the expected dosage of sofosbuvir for inhibiting Zika virus infection. Based on the modeling study, if sofosbuvir is assigned for management of Zika virus. infection, doubled dosage of the present dosage for hepatitis C management is recommended.

Predicting factors contributing to knowledge, attitudes and practices relating to Zika virus infection among the general public in Malaysia

Objective: To identify the predicting factors that contribute to knowledge, attitude and practices relating to Zika virus infection among the general public in Malaysia.Methods: A cross-sectional study was conducted using a validated self-administered questionnaire. Descriptive analysis was done for participants’ socio-demographic profile. Contingency table analysis was done to analyse the associations between knowledge, attitudes, and practices(KAP) scores and socio-demographic profile. A Bonferroni-corrected P-value was used to find the significance of the associations and multiple comparisons were performed in a single data set. To determine the linear relationship between each independent variable and the dependent variable, Spearman rank correlation was performed. Cohen’s correlation coefficient was evaluated to determine the strength of the effect size. Multiple correlations and regression analyses were performed to identify independent variables that predicts the dependent variable.Results: Multiple correlation analyses were conducted between respondents’ KAP score and independent variables(Age >60 years;Female gender;Selangor state;At least 1 pregnant woman per household). The independent variables such as ‘Female gender’, ‘Selangor state’ and ‘At least 1 pregnant woman per household’ were positively and significantly correlated with KAP score whereas, age >60 years was negatively and significantly correlated with the KAP scores.Conclusions: There were associations between four independent factors and the KAP scores, while only three factors contributed to changes in KAP scores among the public. Among these contributing factors, respondents’ age group was the strongest predictor.

Zika virus infection and its emerging trends in Southeast Asia

Zika virus is a mosquito-borne flavivirus that represents a public health emergency at the ongoing epidemic.Previously,this rare virus was limited to sporadic cases in Africa and Asia until its emergence in Brazil,South America in 2015,where it rapidly spread throughout the world.Recently,a high number of cases were reported in Singapore and other Southeast Asia countries.A combination of factors explains the current Zika virus outbreak although it is highly likely that the changes in the climate and high frequency of travelling contribute to the spread of Aedes vector carrying the Zika virus mainly to the tropical climate countries such as the Southeast Asia.The Zika virus is known to cause mild clinical symptoms similar to those of dengue and chikungunya and transmitted by different species of Aedes mosquitoes.However,neurological complications such as Guillain-Barrésyndrome in adults,and congenital anomalies,including microcephaly in babies born to infected mothers,raised a serious concern.Currently,there is no specific antiviral treatment or vaccine available for Zika virus infection.Therefore,international public health response is primarily focused on preventing infection,particularly in pregnant women,and on providing up-to-date recommendations to reduce the risk of non-vector transmission of Zika virus.

Serological Survey of Zika Virus in Humans and Animals in Dejiang Prefecture, Guizhou Province,China

Objective The current outbreak of Zika virus(ZIKV)poses a severe threat to human health.Two ZIKV strains were isolated from mosquitoes collected from the Dejiang prefecture in China in 2016,which was the first isolation of ZIKV in nature in China.Methods In this study,serum samples were collected from 366 healthy individuals and 104 animals from Dejiang prefecture in 2017,and the plaque reduction neutralization test(PRNT)was used to evaluate the seroprevalence of ZIKV.Results None of the 366 residents from whom the samples were collected were seropositive for ZIKV.None of the 11 pigs from whom the samples were collected were seropositive for ZIKV,while 1 of 63(1.59%)chickens and 2 of 30(6.67%)sheep were seropositive for ZIKV.Conclusions The extremely low seropositivity rate of ZIKV antibodies in animals in the Dejiang prefecture,Guizhou province in this study indicates that ZIKV can infect animals;however,there is a low risk of ZIKV circulating in the local population.

Neurological manifestations of Zika virus infection

Zika virus(ZIKV) is a flavivirus(Flaviviridae family) transmitted mainly by Aedes mosquitoes. The virus was restricted to the African continent until its spread to south-east Asia in the 1980's, the Micronesia in 2007, the French Polynesia in 2013 and, more recently in the Americas in 2015, where, up to date, the World Health Organization(WHO) has estimated about 3-4 million total cases of ZIKV infection. During outbreaks in the French Polynesia and Brazil in 2013 and 2015, respectively, national health authorities reported potential neurological complications of ZIKV disease, chiefly an upsurge in Guillain-Barré syndrome, which coincided with ZIKV outbreaks. On the other hand, the emergence of ZIKV in Brazil has been associated with a striking increase in the number of reported cases of microcephaly in fetus and newborns, twenty times higher than in that reported in previous years. While investigations are currently assessing whether there is an actual association between neurological complications and ZIKV infections, the evidence was enough worrisome for WHO to declare a public health emergency of international concern. Here we present an updated review addressing what is currently known about the possible association between ZIKV infection and the development of severe neurological disorders.

Zika virus:A review of literature

Zika virus(ZIKV) has two lineages:African and Asian.Mosquito-borne flaviviruses are thought to replicate initially in dendritic cells and then spread to lymph nodes and the blood stream.Risk for infection through blood transfusion,sexual practices and perinatal transmission exists.The possible routes of perinatal transmission are during delivery,breastfeeding and by close contact between the mother and her newborn.Also,mucocutaneous exposures to the virus by infected blood or monkey bite,organ transplantation or hemodialysis are the other routes of ZIKV transmission.There are two types of ZIKV infection;Zika fever and congenital infection.Clinical presentation of Zika fever varies from asymptomatic infections to a self-limiting febrile disease with low grade fever,conjunctivitis,maculopapular rash,headache,retro-orbital pain and arthritis/arthralgia with periarticular edema,myalgia,vertigo,vomiting and asthenia.This clinical feature could be mistaken for dengue or chikungunya fevers.Microcephaly is the most important and frequently reported clinical picture of suspected congenital Zika syndrome.Laboratory tests are needed for diagnosis of ZIKV infection,because there is no known pathognomonic clinical,biochemical or radiological features.RT-PCR is the most wellliked assay.Serum samples are tested by immunoglobulin G ELISA with ZIKV antigen.Samples are also tested by immunoglobulin M ELISA.There is no certified vaccine or therapeutic medication.In asymptomatic or uncomplicated patients,treatment is not necessary.

Advances in research on Zika virus

Zika virus(ZIKV) is rapidly spreading across the America and its devastating outcomes for pregnant women and infants have driven this previously ignored pathogen into the limelight.Clinical manifestations are fever,joint pain or rash and conjunctivitis.Emergence of ZIKV started with a first outbrcak in the Pacific arca in 2007.a second large outbreak occurred in the Pacific in 2013/2014 and subsequently the virus spread in other Pacific islands.Threat of explosive global pandemic and severe clinical complications linked with the more immediate and recurrent epidemics necessitate the development of an effective vaccine.Several vaccine platforms such as DNA vaccine,recombinant subunit vaccine.ZIKV purified inactivated vaccine,and chimeric vaccines have shown potent efficacy in ritro and in rim trials.Moreover,number of drugs such as Sofosbuvir.BCX4450.NITD008 and 7-DMA are ready to enter phase I clinical trial because of proven anti-ZIKV activity.Monoclonal based antibodies offer promise as an intervention effective for use in pregnant women.In this review,we describe the advances in research on ZIKV such as research strategies for the development of antiviral drugs & vaccines,molecular evolution,epidemiology emergence,neurological complications and other teratogenic outcomes as well as pathogenesis.

Alternate paradigms on Zika virus-related complications:An analytical review

The proportion of the reported cases of Zika virus(ZIKV) infection reached the status of a pandemic. Numerous studies are being conducted on the isolation of ZIKV strains from various epidemics, diagnosis of the infections, various animal models and cell culture designs to study the pathogenesis of ZIKV in the attempts to find an effective ZIKV vaccine. This review focuses upon the 'Off-Spectrum' body of studies which analyses the epidemiology, pathogenesis and other attributes of ZIKV in the light of various dissident hypotheses.

An updated systematic review of Zika virus-linked complications

Objective: To determine the breadth of Zika virus(ZIKV)-associated brain anomalies in neonates and adults. Methods: Systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA) statement using electronic databases ScienceDirect, Pubmed, Medline, Scopus, and Global Health Library.Only those research articles, case studies, case-control studies, case-cohort studies, crosssectional studies, and organizational survey reports were included in the study that reported any fetal outcomes for pregnant women who had infected with ZIKV during the gestational period and ZIKV-related neurological complications in adults as well. Results: Out of total 72 retrieved articles, 50 met the inclusion criteria. We estimated a significant increase in incidence of neural abnormalities such as Guillain-Barre syndrome and microcephaly in the regions that are experiencing ZIKV outbreaks. Other neurological malformations found in ZIKV patients include hydrancephaly/hydrops fetalis, myasthenia gravis,meningoencephalitis and myelitis. Conclusion: Our systematic analysis provides the broad spectrum of neurological malformations in ZIKV infected patients and these data further support the causal link of ZIKV with neurological disorders.

Healthcare workers' knowledge towards Zika virus infection in Indonesia:A survey in Aceh

Objective:To assess the knowledge on Zika virus(ZIKV) infection among healthcare providers(doctors) in Aceh province,Indonesia.Methods:A self-administered internet based survey was conducted from 3 May to 3 June 2016 among the members of doctor organizations in Aceh province.A set of validated,pre-tested questionnaire was used to measure knowledge regarding ZIKV infection and to collect a range of explanatory variables.A two-steps logistic regression analysis was employed to assess the association of participants' demographic,workplace characteristics and other explanatory variables with the knowledge.Results:A total of 442 participants included in the final analysis and 35.9% of them(159) had a good knowledge on ZIKV infection.Multivariate model revealed that type of occupation,type of workplace,availability of access to medical journals and experience made Zika disease as differential diagnose were associated with knowledge on ZIKV infection.In addition,three significant source of information regarding ZIKV were online media(60%),medical article or medical news(16.2%) and television(13.2%).Conclusion:The knowledge of the doctors in Aceh regarding ZIKV infection is relatively low.Doctors who have a good knowledge on ZIKV infection are more confident to established ZIKV disease as differential diagnosis in their clinical setting.Therefore,such program to increase healthcare providers' knowledge regarding ZIKV infection is needed to screen potential carriers of ZIKV infection.

Comparative genome analysis between Southeast Asian and South American Zika viruses

Objective:To understand the cause for the differences between potentially mild Southeast Asian and the more pathogenic ZIKV in South America.Methods:A comparative genomic analysis was performed to determine putative causations stemming from ZIKV.Results:Phylogcnctic analyses integrating geographical and time factors revealed that Southeast Asian ZIKV might not be the direct source of South American outbreaks as previously speculated.Amino acid residues unique to South American ZIKV isolates at the envelope,pr and NS1 proteins are listed and shown in the structural context.These unique residues on external viral proteins are not found in Southeast Asian ZIKV and could be responsible for the ongoing outbreak either via an intrinsic property of the virus or interactions with human immunity.Only a selected few primer/probe sets currently in clinical use were identified of being capable of detecting ZIKV strains worldwide.The envelope proteins of dengue virus(DENV) and ZIKV also showed a remarkable degree of similarity especially at the surface residues.Conclusions:findings that may help explain the cross-reactivity of DENV antibodies to ZIKV.Thus,major caveats must be exercised in using existing diagnostic tools for ZIKV.

Cleft analysis of Zika virus non-structural protein 1

The non-structural protein 1 is an important molecule of the viruses in flavivirus group including to Zika virus. Recently, the NS1 of Zika virus was discovered. There is still no complete information of the molecular interaction of NS1 of Zika virus which can be the clue for explanation for its pathogenesis and further drug search. Here the authors report the cleft analysis of NS1 of Zika virus and the result can be useful for future development of good diagnostic tool and antiviral drug finding for management of Zika virus.

Temperature and development of Zika virus infection:an Indonesian case

Distribution of Zika virus has spread throughout the world.WHO has announced that Zika virus disease is a global health problem.As a tropical country,Indonesia has the potential to spread Zika virus.This letter is to report that there was a single case of zika in Jambi province published by the Eijkman Institute for Molecular Biology.This case was analyzed with the temperature in the scene,which is considered as an appropriate factor to development of Zika virus.

Introduction of Zika virus in Bangladesh:An impending public health threat

Objective: To explore the presence of Zika virus(ZIKV) in Bangladesh and to understand the associated risk factors.Methods: A retrospective sero-surveillance was performed on stored serum samples of dengue surveillance conducted from 2013 to 2016. Real time RT-PCR was performed on randomly selected acute serum samples to detect the Zika virus nucleic acid.Results: Of 200 samples screened, one was found positive for ZIKV by real time RTPCR and further confirmed by genome sequencing. The case was a 65 years old male from a metropolitan city of Bangladesh who had no history of travel outside Bangladesh.Phylogenetic analysis of partial E gene sequences from Bangladeshi isolates demonstrated a close relationship with ZIKV from Brazil and current South American strains clustering within a monophyletic clade distinct from African lineage.Conclusions: Presence of ZIKV raises serious public health concerns in Bangladesh owing to its association with congenital anomalies/neurological-manifestations. We,therefore, recommend every suspected viral fever patient, particularly pregnant women be screened for ZIKV infection to rule out yet another emerging infection in Bangladesh.