Periodic Reporting for period 4 - ZIKAction (ZIKAction: Preparedness, research and action network on maternal-paediatric axis of ZIKV infection in Latin America and the Caribbean)
Periodo di rendicontazione: 2020-10-01 al 2021-09-30
ZIKAction had the complementary goals of 1) developing a multinational ready-to-act network capable of rapidly addressing maternal and paediatric health research needs arising from the Zika virus (ZIKV) outbreaks and 2) conducting an interdisciplinary programme of research studies to address key knowledge gaps relating to ZIKV epidemiology, natural history and pathogenesis, with an emphasis on maternal and child health. This research is important because, whilst sufficient evidence exists to infer a causal relationship between prenatal ZIKV infection and severe brain anomalies, much remains uncertain regarding the natural history of ZIKV infection in pregnancy and childhood and the medium and long term sequelae of exposure in utero.
To accomplish these goals we developed four interconnected science-based platforms. In ZIKA-VT we conducted prospective cohort studies of pregnant women and their infants in Jamaica and Haiti to generate knowledge on ZIKV (and DENV, CHIKV) infection in pregnancy and the associated outcomes, alongside objectives to pilot a smartphone app for monitoring arbovirus symptoms in pregnant women and to develop methods for investigating outcomes of maternal ZIKV infection. A key objective in ZIKA-PED was to define the clinical spectrum and natural history of congenital ZIKV infection and to assess the role of host genetic factors in susceptibility to ZIKV infection. ZIKA-PATHO was focused on elucidating the pathogenesis of vertical transmission and on developing animal models, including a timed gestation model of ZIKV infection in sheep to better understand the timing and mechanisms of vertical transmission. The objectives of ZIKA-VID included the evaluation of ZIKV diagnostics, with a focus on DENV-experienced populations and the analysis of host responses to ZIKV infection through transcriptomics. A further objective was to prepare for a Latin-American and Caribbean (LAC) emerging infectious disease preparedness and response network common to all EU-funded ZIKV consortia.
To accomplish these goals we developed four interconnected science-based platforms. In ZIKA-VT we conducted prospective cohort studies of pregnant women and their infants in Jamaica and Haiti to generate knowledge on ZIKV (and DENV, CHIKV) infection in pregnancy and the associated outcomes, alongside objectives to pilot a smartphone app for monitoring arbovirus symptoms in pregnant women and to develop methods for investigating outcomes of maternal ZIKV infection. A key objective in ZIKA-PED was to define the clinical spectrum and natural history of congenital ZIKV infection and to assess the role of host genetic factors in susceptibility to ZIKV infection. ZIKA-PATHO was focused on elucidating the pathogenesis of vertical transmission and on developing animal models, including a timed gestation model of ZIKV infection in sheep to better understand the timing and mechanisms of vertical transmission. The objectives of ZIKA-VID included the evaluation of ZIKV diagnostics, with a focus on DENV-experienced populations and the analysis of host responses to ZIKV infection through transcriptomics. A further objective was to prepare for a Latin-American and Caribbean (LAC) emerging infectious disease preparedness and response network common to all EU-funded ZIKV consortia.
The ZIKA-VT prospective cohort studies enrolled a cumulative total of 1147 women. The dramatic decline in ZIKV incidence in 2017 meant that few incident ZIKV infections were identified, but incident DENV cases were documented and followed. Seroprevalence of ZIKV IgG and CHIKV IgG in pregnancy in Jamaica was 15.6% and 83.6% respectively. The pilot of the ZIKApp in Jamaica demonstrated its feasibility and acceptability among 173 pregnant women, with good participant retention (91%) and adherence to daily symptom diary completion up to delivery. An evidence synthesis using Bayesian Latent Class models to estimate the risk of vertical transmission of ZIKV by trimester of maternal infection using published data reported estimated average risks of transmission in the 1st, 2nd and 3rd trimesters to be 46%, 28% and 25%.
ZIKA-PED established a Paediatric Registry to characterize the features of children antenatally exposed to ZIKV and/or presenting with suspected Congenital Zika Syndrome, and including longitudinal data to assess longer-term sequelae and management. Overall 192 children were enrolled in Brazil, Jamaica and Argentina, with most children now aged 5-6 years. Most Registry participants have microcephaly (in Brazil 65% had severe microcephaly) and associated brain abnormalities, whilst prevalence of ocular abnormalities varied by country (62% in Brazil versus 28% in Jamaica). In the Spanish PEDZIKARED birth cohort study, 152 children have been followed to assess long-term effects of in utero ZIKV exposure. The ZIKA-HOST sub-study used a ZIKV vaccine and gene expression approach to explore ZIKV infection from the host perspective, utilising a host biobank of mother-child samples from Brazil and Spain to identify host genes regulated after ZIKV infection.
In ZIKA-PATHO, activities included investigation of ZIKV replication in human placental explants, including the role of antibody dependent enhancement and comparison of the replication profile and infectivity of African and Asian ZIKV lineages. Experiments were also conducted to assess how the viral lipid profile may impair the placental barrier in pregnant women . An ovine model of ZIKV infection was developed to explore the kinetics of placental infection and pathogenesis, and potential for sexual transmission, the first to do so in a large animal outbred host other than non-human primates. This has involved immunological, endocrinological and pathological characterization of a timed gestation model, as well as development of a model of in vitro placental infection which showed that cortisol and reproductive hormones enhance viral susceptibility of fetal cells.
A major activity in ZIKA-VID was a comprehensive comparative analysis of the accuracy of second generation ZIKV diagnostic assays for use in LAC populations, which informed a theoretical model to address uncertainty in diagnosis that could prove useful not only in ZIKV but also in future emerging infections. Other work included seroprevalence studies of ZIKV, DENV and CHIKV in adults, pregnant women and children in Brazil and Jamaica, plus a study of the metabolomic profiles of ZIKV-exposed infants, which showed significant changes in the plasma lipidome in exposed versus control newborns.
With the other EU-funded ZIKV consortia, joint work on harmonization and data sharing has included partcipation in the WHO individual patient data meta-analysis. REDe provides an online hub for knowledge sharing across the regions impacted by ZIKV.
ZIKA-PED established a Paediatric Registry to characterize the features of children antenatally exposed to ZIKV and/or presenting with suspected Congenital Zika Syndrome, and including longitudinal data to assess longer-term sequelae and management. Overall 192 children were enrolled in Brazil, Jamaica and Argentina, with most children now aged 5-6 years. Most Registry participants have microcephaly (in Brazil 65% had severe microcephaly) and associated brain abnormalities, whilst prevalence of ocular abnormalities varied by country (62% in Brazil versus 28% in Jamaica). In the Spanish PEDZIKARED birth cohort study, 152 children have been followed to assess long-term effects of in utero ZIKV exposure. The ZIKA-HOST sub-study used a ZIKV vaccine and gene expression approach to explore ZIKV infection from the host perspective, utilising a host biobank of mother-child samples from Brazil and Spain to identify host genes regulated after ZIKV infection.
In ZIKA-PATHO, activities included investigation of ZIKV replication in human placental explants, including the role of antibody dependent enhancement and comparison of the replication profile and infectivity of African and Asian ZIKV lineages. Experiments were also conducted to assess how the viral lipid profile may impair the placental barrier in pregnant women . An ovine model of ZIKV infection was developed to explore the kinetics of placental infection and pathogenesis, and potential for sexual transmission, the first to do so in a large animal outbred host other than non-human primates. This has involved immunological, endocrinological and pathological characterization of a timed gestation model, as well as development of a model of in vitro placental infection which showed that cortisol and reproductive hormones enhance viral susceptibility of fetal cells.
A major activity in ZIKA-VID was a comprehensive comparative analysis of the accuracy of second generation ZIKV diagnostic assays for use in LAC populations, which informed a theoretical model to address uncertainty in diagnosis that could prove useful not only in ZIKV but also in future emerging infections. Other work included seroprevalence studies of ZIKV, DENV and CHIKV in adults, pregnant women and children in Brazil and Jamaica, plus a study of the metabolomic profiles of ZIKV-exposed infants, which showed significant changes in the plasma lipidome in exposed versus control newborns.
With the other EU-funded ZIKV consortia, joint work on harmonization and data sharing has included partcipation in the WHO individual patient data meta-analysis. REDe provides an online hub for knowledge sharing across the regions impacted by ZIKV.
The interdisciplinary research conducted in ZIKAction has resulted in new evidence being generated, a greater understanding of arboviral infections in pregnancy and childhood and a strengthened capacity for conducting preparedness research against emerging pathogens. The launching of new studies over these 5 years allowed collection of key data and conduct of important translational research to ensure impact despite the changing epidemiology of ZIKV infection.
Innovations include the first demonstration of the feasibility of an mhealth intervention (ZIKApp) for monitoring arbovirus symptoms in pregnancy, supporting its future development to contribute to surveillance and diagnosis of infections as well as use by clinical teams to optimise maternal care. Other novel approaches used in our studies can be applied in the future: e.g. in Haiti we used dried blood spot technology for infant sampling, alongside use of hand-held ultrasound machines by research nurses in the community, with cloud technology allowing remote assessment by radiologists. The integration of ‘omics approaches to evaluate the host responses and phenotypic outcomes of ZIKV infection in the placenta is a further example of progress beyond the state of the art, and paves the way for future translational research.
The recent ZIKV outbreaks in India underscore an ongoing acute need for accurate diagnostics for clinical, research and surveillance purposes. This illustrates the potential impact of our work to compare the accuracy of second generation ZIKV IgG assays, which will inform choices around testing algorithms for studies in different populations, including those with prior DENV exposure.
Innovations include the first demonstration of the feasibility of an mhealth intervention (ZIKApp) for monitoring arbovirus symptoms in pregnancy, supporting its future development to contribute to surveillance and diagnosis of infections as well as use by clinical teams to optimise maternal care. Other novel approaches used in our studies can be applied in the future: e.g. in Haiti we used dried blood spot technology for infant sampling, alongside use of hand-held ultrasound machines by research nurses in the community, with cloud technology allowing remote assessment by radiologists. The integration of ‘omics approaches to evaluate the host responses and phenotypic outcomes of ZIKV infection in the placenta is a further example of progress beyond the state of the art, and paves the way for future translational research.
The recent ZIKV outbreaks in India underscore an ongoing acute need for accurate diagnostics for clinical, research and surveillance purposes. This illustrates the potential impact of our work to compare the accuracy of second generation ZIKV IgG assays, which will inform choices around testing algorithms for studies in different populations, including those with prior DENV exposure.