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.

A Model for the Risk of Microcephaly Induced by the Zika Virus (ZIKV)

It has been introduced and analyzed a mathematical model based on integral equations, which turns into a dynamical system of non-linear differential equations to account for the risk of microcephaly incidence caused by the Zika virus. A specific pregnant women susceptible group has been accounted for. The epidemic threshold (basic reproduction number) has been obtained by implementing the next generation matrix method. A sensitivity analysis with respect to each parameter has been applied to that threshold. Finally, the incidence to the exposure is obtained by performing several system simulations.

Immunological evidence of Zika virus transmission in Thailand

Objective: To identify immunological evidence of Zika virus transmission in Thailand. Methods: To undertake a preliminary serosurvey of possible exposure to Zika virus, 21 serum samples from cohort of acute undifferentiated fever patients were examined for immunoreactivity to Zika, Dengue, Japanese encephalitis and Chikungunya envelope antigens by Western blot analysis. Results: Twenty of the 21 serum samples showed immunoreactivity to at least one of the antigens, with seven samples showing immunoreactivity to all antigens. Of particular note, two serum samples showed immunoreactivity only to Zika envelope antigen, with no immunoreactivity to other envelope antigens. Conclusions: This study presents the first evidence of Zika virus transmission in Thailand, although as yet the relationship between transmission and possible cases of Zika fever in Thailand requires further investigation.

Afebrile, asymptomatic and non-thrombocytopenic Zika virus infection: don't miss it!

Zika virus infection is the present problematic arboviral disease. Classically, this disease cause febrile illness and can result in low platelet count. However, there are some new obervations on atypical clinical presentations of Zika virus infection that can make the diagnosis more difficult. The afebrile, asymptomatic and non-thrombocytopenic Zika virus infection can be seen in clinical practice and can lead to missed or delayed diagnosis.

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.

Zika virus,a pathway to new challenges

The current Zika outbreak is largest of its kind with 1.4 million cases in Brazil alone.World Health Organization declared the current outbreak as the public health emergency of international concerns.The major route of Zika virus transmission is mosquito bites.Sexual transmission and monkey bites are also observed in few cases.There is dire need to evaluate the other routes of transmission like blood transfusion,lactation and contact with body fluids.Zika virus is infecting infants,not only causing microcephaly but also creating number of complications resulting in bad outcomes of pregnancy.In Brazil alone,4 000 cases of microcephaly have observed during the current outbreak.The incidence of Guillian-Barre(GB) syndrome is also observed during the current Zika virus outbreak.GB syndrome is acute medical condition leading the patients to death due to weakness of respiratory muscles or can cause the life time disability.There is no anti-viral drug or vaccine available for Zika virus.Zika infection can be prevented by using mosquito repellents,mosquito nets,cooling rooms by air conditions and wearing full sleeves or permethrin treated clothes.The current outbreak of Zika has not only affected the health care but also caused great economic loss.Estimated loss in Latin America and Caribbean is US$3.5 billion.United Nation's sustainable development goal 3.d stresses the strengthening of early warning,risk reduction and management of national and global health risks.The world will keep on facing new challenges in the form of Ebola or Zika;there is strong need to prepare ourselves for any disease outbreak.

Knowledge, attitudes and practice survey on Zika virus infection among pregnant women in Brunei Darussalam

To assess the knowledge, attitudes, and practices(KAP) on Zika virus infection among pregnant women in Brunei Darussalam by a cross-sectional survey. Methods: Between February and June 2017, we recruited 234 pregnant women from all government healthcare centres at Brunei-Muara district, using a modified systematic sampling approach. A pre-tested and self-administered questionnaire was used and data analysis was conducted using descriptive statistics and multiple logistic regression analyses. Results: The study participants were mainly Malay(87.2%) and their mean age was 28.0 years. The median knowledge score was 13, out of a possible score of 28. Most participants(92.7%) knew that Zika virus was transmitted by mosquito bites whereas some(34.6%) knew that sexual transmission was also possible. Media(radio, television or newspapers) was the preferred source of updated information on Zika virus, followed by healthcare workers(44.0%), government announcements(43.2%), and social media(38.0%). Pregnant women who were 25 years old or older [Adj. OR=3.62(95% CI: 1.57, 9.51)], not Malays [Adj. OR=3.32(95% CI: 1.35, 8.55)], and had an average monthly household income of more than BND $3 000 [Adj. OR=4.06(95% CI: 1.81, 19.44)] were more likely to score higher for knowledge on Zika virus. The median prevention practice score was 23, out of a possible score of 36. Most participants reported wearing covering clothes(98.3%) and kept their living surroundings clean(99.6%). Most participants(88.0%) agreed that Zika is an important issue in their community. Conclusion: We found a lack of knowledge on Zika virus infection among pregnant women attending government maternal and child healthcare centres in Brunei Darussalam, in particular that Zika virus can be sexually transmitted. Such information could be well disseminated at the healthcare centre level. Health literacy studies should be conducted to understand the facilitators and barriers of KAP on Zika virus infection among pregnant women.

Zika virus infection, transmission, associated neurological disorders and birth abnormalities: A review of progress in research, priorities and knowledge gaps

On February 1, 2016, the World Health Organization declared that the cluster of microcephaly cases and other neurological disorders constitute public health emergency of international concern. Furthermore, few studies demonstrated that there was an increased evidence of causal relationship of Zika virus(ZIKAV) infection and microcephaly, birth abnormalities and neurological disorders such as Guillain–Barre′ syndrome.ZIKAV transmission occurs mainly by the bite of infected mosquitos(Aedes species), but there are also reports that infections could occur via the placenta, breast milk, saliva,blood transfusion and sex. This article reviews the global efforts, progress in scientific research to understand the pathogenesis of ZIKAV infection & disease, clinical presentations, congenital transmission and autoimmune neurological disorders. The paper further explores the knowledge gaps, future priority research agenda for strategic response including vector control and prevention. We conducted a systematic literature review to synthesise available evidence on ZIKAV infection and its vector and host interaction from electronic databases.

Epitope finding in Zika virus molecule:The first world report

Zika virus infection is a new problematic virus infection that becomes the present public health problem. Now this mosquito borne infectious disease can be seen worldwide and can cause dengue-like infection. In addition, it can also induce transplacental infection and result in congenital neurological defect. To prevent this infection, there is still no specific vaccine. To find a new vaccine, finding epitope is the first step. Here, the authors report the study to find epitope within Zika virus molecule.According to this study, the appropriate epitopes can be seen. This is the fi rst world report on epitope finding for Zika virus. The data can be useful for further vaccine development.

Predicted pattern of Zika virus infection distribution with reference to rainfall in Thailand

Zika virus infection is the present global medical problem.The disease appears in several countries around the world.The relationship between rainfall and occurrence of Zika virus infection was previously mentioned.Here,the authors use the mathematical modeling technique to reappraise on the previous data on immunoreactivity rate of Zika virus,dengue virus and Ckikungunya virus in Thailand and the reported interrelationship between arboviral infections and rainfall in Thailand for constructing of the predicted pattern of Zika virus distribution in Thailand.This data can be a useful tool for further disease surveillance in this area.

ZIKA-How fast does this virus mutate?

The World Health Organization has declared the present Zika virus epidemic to be a ＇Public Health Emergency of International Concern＇. The virus appears to have spread from Thailand to French Polynesia in 2013, and has since infected over a million people in the countries of South and Central America. In most cases the infection is mild and transient, but the virus does appear to be strongly neurotropic and the presumptive cause of both birth defects in fetuses and Guillain-Barr6 syndrome in some adults. In this paper, the techniques and utilities developed in the study of mitochondrial DNA were applied to the Zika virus. As a result, it is possible to show in a simple manner how a phylogenetic tree may be constructed and how the mutation rate of the virus can be measured. The study showed the mutation rate to vary between 12 and 25 bases a year, in a viral genome of 10 272 bases. This rapid mutation rate will enable the geographic spread of the epidemic to be monitored easily and may also prove useful in assisting the identification of preventative measures that are working, and those that are not.

Zika virus spreading in South America: evolutionary analysis of emerging neutralizing resistant Phe279Ser strains

Objective: To investigate the genetic diversity of Zika virus(ZIKV) and the relationships existing among these circulating viruses worldwide. To evaluate the genetic polymorphisms harboured from ZIKV that can have an influence on the virus circulation. Methods: Three different ZIKV dataset were built. The first dataset included 63 E gene sequences, the second one 22 NS3 sequences and the third dataset was composed of 108 NS5 gene sequences. Phylogenetic and selective pressure analysis was performed. The edited nucleic acid alignment from the Envelope dataset was used to generate a conceptual translation to the corresponding peptide sequences through UGene software. Results: The phylogeographic reconstruction was able to discriminate unambiguously that the Brazilian strains are belonged to the Asian lineage. The structural analysis reveals instead the presence of the Ser residue in the Brazilian sequences(however already observed in other previously reported ZIKV infections) that could suggest the presence of a neutralization-resistant population of viruses. Conclusions: Phylogenetic, evolutionary and selective pressure analysis contributed to improve the knowledge on the circulation of ZIKV.

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.

Biological and historical overview of Zika virus

The recent outbreak of the Zika virus attracts worldwide attention probably because the most recently affected country(Brazil) will host the 2016 Olympic Game. Zika virus infected cases are now spreading to many other countries and its infection might be linked to some severe medical sequelae. Since its first isolation from the infected monkey in 1947 in Uganda, only a few studies had been taken until recent outbreak. According to the history of referenced publications, there is a 19-year gap from 1989 to 2007. This might be because only mild diseases were diagnosed from Zika virus infected populations. Obviously, the recent reports that Zika virus infection is probably associated with microcephaly of the neonates makes us reevaluate the medical significance of the viral pathogen. It can be transmitted sexually or by mosquito biting. Sexual transmission of the Zika virus distinguishes it from other members of the Genus Flavivirus. Detailed information of the Zika virus is needed through a thorough investigation covering basic, epidemical, subclinical and clinical studies. Here, we reviewed the published information 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.

Identification of various cell culture models for the study of Zika virus

AIM To identify cell culture models supportive for Zika virus(ZIKV) replication.METHODS Various human and non-human cell lines were infected with a defined amount of ZIKV Polynesia strain. Cells were analyzed 48 h post infection for the amount of intracellular and extracellular viral genomes and infectious viral particles by quantitative real-time PCR and virus titration assay. The extent of replication was monitored by immunofluorescence and western blot analysis by using Env and NS1 specific antibodies. Innate immunity was assayed by luciferase reporter assay and immunofluorescence analysis.RESULTS All investigated cell lines except CHO cells supported infection, replication and release of ZIKV. While in infected A549 and Vero cells a pronounced cytopathic effect was observed COS7, 293 T and Huh7.5 cells were most resistant. Although the analyzed cell lines released comparable amounts of viral genomes to the supernatant significant differences were found for the number of infectious viral particles. The neuronal cell lines N29.1 and SH-SY5 Y released 100 times less infectious viral particles than Vero-, A549-or 293 T-cells. However there is no strict correlation between the amount of produced viral particles and the induction of an interferon response in the analyzed cell lines.CONCLUSION The investigated cell lines with their different tissue origins and diverging ZIKV susceptibility display a toolbox for ZIKV research.

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.

The Global Impact of the Zika Virus Pandemic: The Importance of Emergency Preparedness

The 2015 outbreak of Zika virus in Brazil led to a significant increase of neonatal microcephaly. While Zika virus was identified in Africa in the 1940s and was noted to be present in Asia, it was not until 2007 that there was a significant shift in the behavior of the virus. Reasons for this change in Zika virus behavior and pathogenesis could be due to a change in the virulence of the virus, and a new ability to infect the human host. Additionally, the changing habitat of mosquitoes along with increasing urbanization and changes of human habitats has increased the risk of Zika virus exposure. This review summarizes the response to the Zika pandemic and recommendations for interventions through the lens of the Sendai Framework for disaster risk reduction. Emergency preparedness focuses on lessening the likelihood and the impact of disasters. Preparedness encompasses the actions of mitigation, prevention, response, and recovery.