This section highlights publications on research conducted by ZikaPLAN consortium members and partners as part of the initiative.

Favipiravir inhibits in vitro Usutu virus replication and delays disease progression in an infection model in mice

Nidya A. Segura Guerrero et al – Antiviral Research, October 29, 2018

The ZikaPLAN and ZIKAlliance authors of this study show that the Usutu virus (USUV) infection model in mice is suitable for assessing the potential in vivo efficacy of novel USUV/flavivirus inhibitors.

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Cutting Edge: Transcriptional Profiling Reveals Multifunctional and Cytotoxic Antiviral Responses of Zika Virus–Specific CD8+ T Cells

Alba Grifoni et al – The Journal of Immunology, October 12, 2018

In this study, the authors characterized the quality and phenotypes of human CD8+ T cells responding to ZIKV infection, providing what they believe to be the first in-depth characterization of such a response.

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Projecting the end of the Zika virus epidemic in Latin America: a modelling analysis

Kathleen O’Reilly et al – BMC Medicine, October 3, 2018

Despite the decline in the number of Zika cases in 2017, future incidence in Latin America and the Caribbean remains uncertain. The findings of this study suggest the ZIKV epidemic is by and large over in the region, with incidence projected to be low in most cities in 2018.

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A cross-sectional analysis of Zika virus infection in symptomatic and asymptomatic non-pregnant travellers: Experience of a European reference center during the outbreak in the Americas

Dr. Ralph Huits et al - Travel Medicine and Infectious Disease, September 12, 2018

Zika virus (ZIKV) infection is of concern to travellers because of potential sexual transmission and adverse pregnancy outcomes. In this article, the authors describe their experience in diagnosing ZIKV in travellers returning from endemic territories.

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Symptomatic Dengue during Pregnancy and Congenital Neurologic Malformations

Paixão et al. - Emerging Infectious Diseases, September 2018

This research letter provides an overview of the authors’ findings that dengue virus infection during pregnancy increased the risk for any neurologic congenital anomaly in the infant by roughly 50% and for other congenital malformations of the brain 4-fold.

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Is vaccinating monkeys against yellow fever the ultimate solution for the Brazilian recurrent epizootics?

Eduardo Massad et al. - Epidemiology & Infection, August 14, 2018

In this article, the authors propose that vaccinating monkeys in relatively small green areas of the urban centers is perhaps the ultimate solution for the Brazilian recurrent yellow fever epizootics.

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A Note on the Risk of Infections Invading Unaffected Regions

Amaku et al. - Computational and Mathematical Methods in Medicine, July 4, 2018

The authors present two probabilistic models to estimate the risk of introducing infectious diseases into previously unaffected countries/regions by infective travelers, looking at both direct transmission of infection and vector-borne infection.

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Zika in travellers 1947-2017: a systematic review

Wilder-Smith A. et al. - The National Center for Biotechnology Information, July 2018

The authors of this article performed a systematic review of travel-associated ZIKV infections from 1947 to April 2017. Published reports on autochthonous ZIKV transmission in Asia were also compared with published reports on exportations from travellers in Asia.

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Dengue vaccine: reliably determining previous exposure

Kevin K Ariën et al. – The Lancet Global Health, June 22,2018

In this article, the authors highlight the challenges in establishing dengue serostatus.

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Zika vaccines and therapeutics: landscape analysis and challenges ahead

Annelies Wilder-Smith et al. - BMC Medicine, June 6, 2018

Several Zika virus (ZIKV) vaccine candidates are currently in development. In this paper, the authors describe the various vaccine platforms, with a discussion on their advantages and disadvantages in the context of use scenarios and provide an overview of the current status of vaccine development.

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The risk of urban yellow fever resurgence in Aedes-infested American cities

Eduardo Massad et al. - Epidemiology and Infection, May 30, 2018

In this article, the authors present a method to estimate the risk of urban yellow fever resurgence in dengue-endemic cities.

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Zika Virus IgG in Infants with Microcephaly, Guinea-Bissau, 2016

Maiken Worsøe Rosenstierne et al. – Emerging Infectious Diseases, May 2018

In this research letter, the authors report an in-depth investigation of pathogens commonly associated with birth defects in 15 infants born with microcephaly in Guinea-Bissau in 2016.

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Re-visiting the evolution, dispersal and epidemiology of Zika virus in Asia

Pettersson et al. Emerging Microbes & Infections, May 2018

The authors of this article trace the phylogenetic history and spatiotemporal dispersal pattern of ZIKV in Asia prior to its explosive emergence in the Pacific region and the Americas. Their findings reveal new features of the evolution and dispersal of ZIKV that may benefit future disease control strategies.

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Can Zika virus antibodies cross-protect against dengue virus?

K. Ariën et al. – The Lancet, May 2018

This correspondence looks back at findings reported by Ribeiro GS, Kikuti M, Tauro LB, et al. in The Lancet Global Health (Does immunity after Zika virus infection cross-protect against dengue? - Feb 2018) and shares findings from an in vitro investigation of dengue virus neutralization potential in samples from dengue virus-naïve patients with a documented Zika virus infection or virus neutralization.

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Asymptomatic Prenatal Zika Virus Infection and Congenital Zika Syndrome

Paixão et al. – Open Forum Infectious Diseases, April 7, 2018

In this article, the authors investigate to what extent asymptomatic vs symptomatic prenatal Zika virus infections contribute to birth defects.

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Zika virus infection in the returning traveller: what every neurologist should know

Leonhard SE et al. – Practical Neurology, March 18, 2018

This review provides an overview of Zika virus-associated neurological disease and aims to support neurologists in areas without current active transmission of the virus who may encounter patients returning from endemic areas.

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Estimating the probability of dengue virus introduction and secondary autochthonous cases in Europe

E. Massad et al. – Nature Scientific Reports, March 15, 2018

This report estimates the risk of dengue virus introductions via travelers into Europe and number of secondary autochthonous cases as a result of the introduction. The authors apply mathematical modeling to estimate the number of dengue-viremic air passengers and find that the risk of onward transmission in Europe is reassuringly low, except where Aedes aegypti is present.

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Diverse laboratory colonies of Aedes aegypti harbor the same adult midgut bacterial microbiome

Dickson et al. – Parasites & Vectors, March, 2018

This article looks at the nature, biogenesis, and mechanism of vDNA synthesis. The authors suggest that, analogous to mammalian RIG-I-like receptors, Dicer-2 functions like a pattern recognition receptor for DVGs to modulate antiviral immunity in insects.

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Dicer-2-Dependent Generation of Viral DNA from Defective Genomes of RNA Viruses Modulates Antiviral Immunity in Insects

E. Poirier et al. – Cell Host & Microbe, March 1, 2018

This article looks at the nature, biogenesis, and mechanism of vDNA synthesis. The authors suggest that, analogous to mammalian RIG-I-like receptors, Dicer-2 functions like a pattern recognition receptor for DVGs to modulate antiviral immunity in insects.

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The spectrum of neurological disease associated with Zika and chikungunya viruses in adults in Rio de Janeiro, Brazil: A case series

R. Mehta et al. – PLOS Neglected Tropical Diseases, February 12, 2018

The authors studied adults who had developed a new neurological condition following suspected Zika virus infection between 1st November 2015 and 1st June 2016. They found that chikungunya virus appears to have an equally important association with neurological disease in Brazil as Zika virus, and many patients had dual infection. To understand fully the burden of Zika the authors suggest looking beyond GBS, and also investigating for other co-circulating arboviruses, particularly chikungunya.

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Aedes Mosquitoes and Aedes-Borne Arboviruses in Africa: Current and Future Threats

David Weetman et al. – International Journal of Environmental Research and Public Health, January 28, 2018

The authors review available data on the distribution of yellow fever, dengue, chikungunya and Zika in Africa, their Aedes vectors, transmission potential, and challenges and opportunities for Aedes control. They identify key knowledge gaps and future research areas, and in particular, highlight the need to improve knowledge of the distribution of disease, major vectors, and insecticide resistance.

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Microcephaly epidemic related to the Zika virus and living conditions in Recife, Northeast Brazil

Souza et al. – BMC Public Health, January 12, 2018

The study analyzes the spatial distribution of microcephaly cases in Recife (2015–2016) and shows that populations residing in areas with precarious living conditions had a higher prevalence of microcephaly compared with populations with better living conditions.

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The Zika Virus Epidemic in Brazil: From Discovery to Future Implications

Lowe R, Barcellos C, Brasil P, Cruz OG, Honório NA, Kuper H, Carvalho MS - International Journal of Environmental Research and Public Health, January 9, 2018

This article provides an overview of the discovery of Zika virus in Brazil, including its emergence and spread, epidemiological surveillance, vector and non-vector transmission routes, clinical complications, and socio-economic impacts. The authors discuss gaps in the knowledge and the challenges ahead to anticipate, prevent, and control emerging and re-emerging epidemics of arboviruses in Brazil and worldwide.

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Further pieces of evidence in the Zika virus and microcephaly puzzle

Elizabeth B Brickley et al. – The Lancet, Child & Adolescent Health, January 12, 2018

In this article, the authors present more evidence of the links between Zika virus infection in pregnancy and microcephaly.

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Development of envelope protein antigens to serologically differentiate Zika from dengue virus infection

Premkumar L et al. – Journal of Clinical Microbiology, December 29, 2017

The authors designed two recombinant antigens displaying unique antigenic regions on domain I (Z-EDI) and domain III (Z-EDIII) of ZIKV envelope protein. They found that the Z-EDIII antigen has much potential as a diagnostic antigen for population level surveillance and for detecting past infections in patients.

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Innovative and new approaches to laboratory diagnosis of Zika and dengue: a meeting report

Goncalves A, Peeling RW, Chu MC, Gubler DJ, de Silva AM, Harris E, Murtagh M, Chua A, Rodriguez W, Kelly C, Wilder-Smith A. – Journal of Infectious Diseases, December 25, 2017 [Epub ahead of print]

This meeting report, from a workshop organized by the Partnership for Dengue Control, reviews the current landscape of Flavivirus diagnostics and makes recommendations for facilitating the development and evaluation of new diagnostic tools.

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Ontogeny of the B- and T-cell response in a primary Zika virus infection of a dengue-naïve individual during the 2016 outbreak in Miami, FL

Ricciardi MJ et al. - PLoS Neglected Tropical Diseases, December 21, 2017

The authors present one of the first cases of ZIKV infection, in a dengue-naïve individual, which had been locally acquired in the United States. It is the first study to establish the timing of the ontogeny of the immune response against ZIKV.

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Association between microcephaly, Zika virus infection, and other risk factors in Brazil: final report of a case-control study

Thalia Velho Barreto de Araújo et al. – The Lancet Infectious Diseases, December 2017

This is the final report of the first case-control study evaluating the potential causes of microcephaly: congenital Zika virus infection, vaccines, and larvicides. The study confirms the association between microcephaly and congenital Zika virus infection and provides evidence of the absence of an effect of other potential factors, such as exposure to pyriproxyfen or vaccines during pregnancy.

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ZikaPLAN: Zika Preparedness Latin American Network

A. Wilder-Smith, R. Preet, K. E. Renhorn, R. A. Ximenes, L. C. Rodrigues, T. Solomon, J. Neyts, L. Lambrechts, H. Willison, R. Peeling, A. K. Falconar, A. R. Precioso, J. Logan, T. Lang, H. P. Endtz & E. Massad – Global Health Action, December 2017

This study design article describes the ZikaPLAN consortium and how it is working to address research gaps around ZIKV and build long-term emerging infectious disease response capacity in Latin America and the Caribbean.

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Zika virus in semen: a prospective cohort study of symptomatic travellers returning to Belgium

Huits, De Smet, Ariën, Van Esbroeck, Bottieau, Cnops - Bulletin of the World Health Organization, December 2017

The majority of men in this study of Belgian travellers with confirmed Zika virus infection had detectable Zika virus RNA in their semen. Based on the study results, the authors recommend that semen from Zika virus-infected men should be analysed with RT-PCR and that health professionals should advise infected men, even if they are vasectomized, about current recommendations for prevention of sexual transmission of the virus.

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Prevalence and clinical profile of microcephaly in South America pre-Zika, 2005-14: prevalence and case-control study

I. Orioli et al. – BMJ, November 21, 2017

This study describes the prevalence and clinical spectrum of microcephaly in South America for the period 2005-14, before the start of the Zika epidemic in 2015. The authors establish a baseline for the prevalence of diagnosed microcephaly before the Zika epidemic that can serve for future surveillance and show that, even in non-Zika times, the potential effects of infectious and non-infectious causes of abnormal brain development should not be ignored.

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Lineage-Specific Real-Time RT-PCR for Yellow Fever Virus Outbreak Surveillance, Brazil

Carlo Fischer et al. – Emerging Infectious Diseases, November 2017

The authors describe novel multiplex real-time reverse transcription PCRs that differentiate between vaccine and American wild-type YFV. Such assays could address the need to discriminate between potential vaccination-associated events and wild-type virus infection in symptomatic patients for large-scale deployment of vaccines.

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Behavioral, climatic, and environmental risk factors for Zika and Chikungunya virus infections in Rio de Janeiro, Brazil, 2015-16

Trevon L. Fuller et al. – PLOSone, November 16, 2017

The study aimed to identify environmental drivers of arbovirus epidemics to predict where the next epidemics will occur and prioritize municipalities for vector control and eventual vaccination. The findings show that rainfall appears to precede ZIKV and CHIKV epidemics and this suggests that an early warning system based on weather that predicts these outbreaks a few weeks in advance would help policy-makers and clinicians to prepare countermeasures.

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Prior Dengue virus exposure shapes T cell immunity to Zika virus in humans

Alba Grifoni et al. – Journal of Virology, October 2017

The authors of this accepted manuscript investigate the kinetics and viral epitopes targeted by T cells responding to ZIKV and address the critical question of whether pre-existing dengue virus (DENV) T cell immunity modulates these responses. The data show that memory T cell responses elicited by prior infection with DENV recognize ZIKV-derived peptides and that DENV exposure prior to ZIKV infection influences the timing, magnitude and quality of the T cell response. The findings also show that ZIKV-specific responses target different proteins than DENV-specific responses.

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Symptomatic dengue infection during pregnancy and the risk of stillbirth in Brazil, 2006–12: a matched case-control study

Enny S Paixão, Maria da Conceição N Costa, Maria Glória Teixeira, Katie Harron, Marcia Furquim de Almeida, Mauricio L Barreto, Laura C Rodrigues - The Lancet Infectious Diseases, September 17, 2017

Maternal infections during pregnancy can increase the risk of fetal death. Dengue infection is common, but little is known about its role in fetal mortality. The authors aimed to investigate the association between symptomatic dengue infection during pregnancy and fetal death.

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Structural investigation of C6/36 and Vero cell cultures infected with a Brazilian Zika virus

Debora Ferreira Barreto-Vieira et al. - PLOSone, September 12, 2017

The study demonstrated the susceptibility of C6/36 and Vero cells to ZIKV infection and showed that part of the replicative cycle may occur within viroplasm-like structures, which has not been previously demonstrated in other flaviviruses.

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Zika genomics urgently need standardized and curated reference sequences

Kristof Theys et al. - PLOS Pathogens, September 7, 2017

In this article, it is demonstrated that, while the proliferation of genomic data offers new opportunities for comparative and evolutionary genomics of ZIKV, the rapid advance in ZIKV genomics has resulted in inconsistencies that complicate the interpretation, reproducibility, and comparison of findings from and across studies.

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Extensive Genetic Differentiation between Homomorphic Sex Chromosomes in the Mosquito Vector, Aedes aegypti

Albin Fontaine, Igor Filipović, Thanyalak Fansiri, Ary A. Hoffmann, Changde Cheng, Mark Kirkpatrick, Gordana Rašić, and Louis Lambrechts - Genome Biology and Evolution, September 2017

Mechanisms and evolutionary dynamics of sex-determination systems are of particular interest in insect vectors of human pathogens like mosquitoes because novel control strategies aim to convert pathogen-transmitting females into nonbiting males, or rely on accurate sexing for the release of sterile males. This study’s results lay a new foundation for the mapping and population genomic studies in Aedes aegypti, and for the control strategies that rely on accurate sexing and sex reversal in this important mosquito vector.

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Rapid antigen tests for dengue virus serotypes and Zika virus in patient serum

Irene Bosch et al. - Science Translational Medicine, September 27, 2017

The authors describe how incorporating monoclonal antibodies into an immunochromatography format yielded a rapid diagnostic assay that identified the four dengue serotypes and Zika viral infections without cross-reaction when testing human serum samples from endemic areas in Central and South America and in India. This approach could be useful for developing rapid diagnostics for other emerging pathogens.

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Replication of the Zika virus in different iPSC-derived neuronal cells and implications to assess efficacy of antivirals

Kristina Lanko et al. - Science Direct, September 2017

In this article, the authors highlight the need to assess the potential antiviral activity of novel ZIKV inhibitors in stem cell derived neuronal cultures.

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Uncovering the Repertoire of Endogenous Flaviviral Elements in Aedes Mosquito Genomes

Yasutsugu Suzuki, Lionel Frangeul, Laura B. Dickson, Hervé Blanc, Yann Verdier, Joelle Vinh, Louis Lambrechts, Maria-Carla Saleh - Journal of Virology, August 2017

Endogenous viral elements derived from nonretroviral RNA viruses have been described in various animal genomes. The authors investigated the repertoire of endogenous flaviviral elements (EFVEs) in Aedes mosquitoes, the vectors of arboviruses such as dengue and chikungunya viruses.

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Infectious causes of microcephaly: epidemiology, pathogenesis, diagnosis, and management

Dr Delan Devakumar, PhD, Alasdair Bamford, PhD, Prof Marcelo U Ferreira, PhD, Jonathan Broad, MBChB, Richard E Rosch, BMBCh, Prof Nora Groce, PhD, Prof Judith Breuer, MD, Prof Marly A Cardoso, PhD, Prof Andrew J Copp, DPhil, Paula Alexandre, PhD, Prof Laura C Rodrigues, PhD, Prof Ibrahim Abubakar, PhD - The Lancet Infectious Diseases, August 22, 2017

In this Review, the authors summarize important aspects of major congenital infections that can cause microcephaly, and describe the epidemiology, transmission, clinical features, pathogenesis, management, and long-term consequences of these infections. They highlight potential issues with classification of microcephaly and show how some infants affected by congenital infection might be missed or incorrectly diagnosed.

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Risk of Zika-related microcephaly: stable or variable?

Laura C. Rodrigues and Enny S Paixao - The Lancet, August 26, 2017

The authors comment on the important question of whether the risk of microcephaly (and congenital Zika syndrome) after infection with Zika virus during pregnancy varies according to setting and highlight the role of cohort studies of pregnant women to provide robust answers.

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How do biting disease vectors behaviourally respond to host availability?

Laith Yakob - BioMed Central, August 16, 2017

A novel formula that accounts for vectors’ diverse feeding behaviour is presented and nested into a vector-borne disease transmission model. This coupled structure offers a flexible framework that can be applied to any vector-borne disease to assess the epidemiological importance of the availability of multiple blood host species.

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Characteristics of Dysphagia in Infants with Microcephaly Caused by Congenital Zika Virus Infection, Brazil 2015

Mariana C. Leal, Vanessa van der Linden, Thiago P. Bezerra, Luciana de Valois, Adriana C.G. Borges, Margarida M.C. Antunes, Kátia G. Brandt, Catharina X. Moura, Laura C. Rodrigues, and Coeli R. Ximenes – Emerging Infectious Diseases, August 2017

In this article, the characteristics of dysphagia in 9 infants in Brazil with microcephaly caused by congenital Zika virus infection are summarized. They show that dysphagia resulting from Congenital Zika Syndrome microcephaly is severe and has onset after 3 months of age.

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Zika virus tropism and interactions in myelinating neural cell cultures: CNS cells and myelin are preferentially affected

Stephanie L. Cumberworth†, Jennifer A. Barrie†, Madeleine E. Cunningham, Daniely Paulino Gomes de Figueiredo, Verena Schultz, Adrian J. Wilder-Smith, Benjamin Brennan, Lindomar J. Pena, Rafael Freitas de Oliveira França, Christopher Linington, Susan C. Barnett, Hugh J. Willison, Alain Kohl† and Julia M. Edgar† - Acta Neuropathologica Communications Neuroscience of Disease, June 23, 2017
†Contributed equally

The recent global outbreak of Zika virus (ZIKV) infection has been linked to severe neurological disorders affecting the peripheral and central nervous systems (PNS and CNS, respectively). Here CNS and PNS myelinating cultures from wild type and Ifnar1 knockout mice are used to examine neuronal and glial tropism and short-term consequences of direct infection with a Brazilian variant of ZIKV.

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On the Origin and Timing of Zika Virus Introduction in Brazil

Eduardo Massad, Marcelo Nascimento Burattini, Kamran Khan, Claudio Jose Struchiner, Francisco Antonio Bezerra Coutinho, Annelies Wilder-Smith – Epidemiology & Infection, June 15, 2017

In this study, mathematical models are applied to determine the most likely time window of ZIKV introduction in Brazil.

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The complex relationship between the emerging flaviviruses: dengue and Zika

Tan et al. – The Biochemist, June 2017

In this article, the authors examine the effects of dengue and Zika sero-cross-reactivity, the similarities and differences between them and the common and unique characteristics of mosquito-borne flaviviruses.

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Zika’s Long Haul: Tackling the Causes of Human Vulnerability to
 Mosquito-Borne Viruses

Laura C. Rodrigues - American Journal of Public Health, June 2017

“WHO, and affected countries, need to manage Zika not as an emergency but in the same sustained way we manage other established, epidemic-prone pathogens like dengue and chikungunya. We are here for the long haul.”

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Aedes aegypti Control Through Modernized, Integrated Vector Management

Laith Yakob, Sebastian Funk, Anton Camacho, Oliver Brady, W. John Edmunds – PLOS Current Outbreaks, January 30, 2017

Despite identifying important disadvantages of Wolbachia and SIT, this initial analysis demonstrates potential for good synergy when combining novel mosquito approaches in a modernized, integrated vector control program.

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Comparative Analysis of Dengue and Zika Outbreaks Reveals Differences by Setting and Virus

Sebastian Funk , Adam J. Kucharski, Anton Camacho, Rosalind M. Eggo, Laith Yakob, Lawrence M. Murray, W. John Edmunds - PLOS Currents: Outbreaks, December 6, 2016

Fitting models to data from dengue and Zika outbreaks in Micronesia showed that transmission is similar for both viruses. Dengue models that have been developed for decades can and should be exploited in the current context of the Zika pandemic.

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Low risk of a sexually-transmitted Zika virus outbreak

Laith Yakob, Adam Kucharski, Stephane Hue, W John Edmunds - The Lancet Infectious Diseases, October 2016

Although Zika virus is a mosquito-borne flavivirus, reports have begun to emerge of its possible sexual transmission leading to concern that this alternative transmission route will expand the at-risk population beyond the tropical confines of the mosquito vectors and the current outbreak.

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Zika and Other Emerging Viruses: Aiming at the Right Target

Kai Dallmeier and Johan Neyts, Cell Host & Microbe 20, October 12, 2016

Kai Dallmeier and Johan Neyts from the Rega Institute for Medical Research, Department of Microbiology & Immunology, University of Leuven Leuven, Belgium look at the in vitro screens conducted by Barrows et al. (2016) and Xu et al. (2016) with the goal of identifying FDA-licensed drugs and drug-like small molecules that could potentially be repurposed to prevent and treat ZIKV infections.

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How did Zika virus emerge in the Pacific Islands and Latin America?

Pettersson JH et al. – mBio, September-October, 2016

Based on comparative ZIKV complete genome phylogenetic analyses and temporal estimates, the article identifies amino acid substitutions that may be associated with increased viral epidemicity, CZVS, and GBS. Reverse genetics, vector competence, and seroepidemiological studies test the hypothesis that these amino acid substitutions are determinants of epidemic and neurotropic ZIKV emergence.

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In this study, the authors characterized the quality and phenotypes of human CD8+ T cells responding to ZIKV infection, providing what they believe to be the first in-depth characterization of such a response.