the legacy of zikaplan a transnational research consortium addressing zika CORD-Papers-2022-06-02 (Version 1)

Title: The legacy of ZikaPLAN: a transnational research consortium addressing Zika
Abstract: Global health research partnerships with institutions from high-income countries and low- and middle-income countries are one of the European Commissions flagship programmes. Here we report on the ZikaPLAN research consortium funded by the European Commission with the primary goal of addressing the urgent knowledge gaps related to the Zika epidemic and the secondary goal of building up research capacity and establishing a Latin American-European research network for emerging vector-borne diseases. Five years of collaborative research effort have led to a better understanding of the full clinical spectrum of congenital Zika syndrome in children and the neurological complications of Zika virus infections in adults and helped explore the origins and trajectory of Zika virus transmission. Individual-level data from ZikaPLAN`s cohort studies were shared for joint analyses as part of the Zika Brazilian Cohorts Consortium the European Commission-funded Zika Cohorts Vertical Transmission Study Group and the World Health Organization-led Zika Virus Individual Participant Data Consortium. Furthermore the legacy of ZikaPLAN includes new tools for birth defect surveillance and a Latin American birth defect surveillance network an enhanced Guillain-Barre Syndrome research collaboration a de-centralized evaluation platform for diagnostic assays a global vector control hub and the REDe network with freely available training resources to enhance global research capacity in vector-borne diseases.
Published: 2022-04-04
Journal: Global health action
DOI: 10.1080/16549716.2021.2008139
DOI_URL: http://doi.org/10.1080/16549716.2021.2008139
Author Name: Wilder Smith Annelies
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wilder_smith_annelies
Author Name: Brickley Elizabeth B
Author link: https://covid19-data.nist.gov/pid/rest/local/author/brickley_elizabeth_b
Author Name: Ximenes Ricardo Arraes de Alencar
Author link: https://covid19-data.nist.gov/pid/rest/local/author/ximenes_ricardo_arraes_de_alencar
Author Name: Miranda Filho Demcrito de Barros
Author link: https://covid19-data.nist.gov/pid/rest/local/author/miranda_filho_demcrito_de_barros
Author Name: Turchi Martelli Celina Maria
Author link: https://covid19-data.nist.gov/pid/rest/local/author/turchi_martelli_celina_maria
Author Name: Solomon Tom
Author link: https://covid19-data.nist.gov/pid/rest/local/author/solomon_tom
Author Name: Jacobs Bart C
Author link: https://covid19-data.nist.gov/pid/rest/local/author/jacobs_bart_c
Author Name: Pardo Carlos A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/pardo_carlos_a
Author Name: Osorio Lyda
Author link: https://covid19-data.nist.gov/pid/rest/local/author/osorio_lyda
Author Name: Parra Beatriz
Author link: https://covid19-data.nist.gov/pid/rest/local/author/parra_beatriz
Author Name: Lant Suzannah
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lant_suzannah
Author Name: Willison Hugh J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/willison_hugh_j
Author Name: Leonhard Sonja
Author link: https://covid19-data.nist.gov/pid/rest/local/author/leonhard_sonja
Author Name: Turtle Lance
Author link: https://covid19-data.nist.gov/pid/rest/local/author/turtle_lance
Author Name: Ferreira Maria Lcia Brito
Author link: https://covid19-data.nist.gov/pid/rest/local/author/ferreira_maria_lcia_brito
Author Name: de Oliveira Franca Rafael Freitas
Author link: https://covid19-data.nist.gov/pid/rest/local/author/de_oliveira_franca_rafael_freitas
Author Name: Lambrechts Louis
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lambrechts_louis
Author Name: Neyts Johan
Author link: https://covid19-data.nist.gov/pid/rest/local/author/neyts_johan
Author Name: Kaptein Suzanne
Author link: https://covid19-data.nist.gov/pid/rest/local/author/kaptein_suzanne
Author Name: Peeling Rosanna
Author link: https://covid19-data.nist.gov/pid/rest/local/author/peeling_rosanna
Author Name: Boeras Deborah
Author link: https://covid19-data.nist.gov/pid/rest/local/author/boeras_deborah
Author Name: Logan James
Author link: https://covid19-data.nist.gov/pid/rest/local/author/logan_james
Author Name: Dolk Helen
Author link: https://covid19-data.nist.gov/pid/rest/local/author/dolk_helen
Author Name: Orioli Ieda M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/orioli_ieda_m
Author Name: Neumayr Andreas
Author link: https://covid19-data.nist.gov/pid/rest/local/author/neumayr_andreas
Author Name: Lang Trudie
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lang_trudie
Author Name: Baker Bonny
Author link: https://covid19-data.nist.gov/pid/rest/local/author/baker_bonny
Author Name: Massad Eduardo
Author link: https://covid19-data.nist.gov/pid/rest/local/author/massad_eduardo
Author Name: Preet Raman
Author link: https://covid19-data.nist.gov/pid/rest/local/author/preet_raman
sha: 6f2d2ee28a7d4dec009a9dfc2ec5cbb6c7e0fcd0
license: cc-by
license_url: https://creativecommons.org/licenses/by/4.0/
source_x: Medline; PMC
source_x_url: https://www.medline.com/https://www.ncbi.nlm.nih.gov/pubmed/
pubmed_id: 35377284
pubmed_id_url: https://www.ncbi.nlm.nih.gov/pubmed/35377284
pmcid: PMC8986226
pmcid_url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986226
url: https://www.ncbi.nlm.nih.gov/pubmed/35377284/ https://doi.org/10.1080/16549716.2021.2008139
has_full_text: TRUE
Keywords Extracted from Text Content: https://rede.tghn.org/ WHO/PAHO Aedes-borne her oligodendrocyte cells T cells Neuroviruses endocrine mosquitoes Culex-borne antigenic complex III flaviviruses human tissue Polynesia human Nile Culex-borne flavivirus proteins derived mouse axonal cryptorchidism GBD blood samples South-East Asia Network' RegLAMC flaviviruses Travellers Brazil, Argentina peripheral nervous system disease ZIKVexposed DENV peripheral nervous cell lines ReLAMC GBDDC Ae. field-derived Ae specimens Umeå human Zika virus participants Zika [105] . pregnant persons mice Australasian flaviviruses gangliosides BAF T-cell GVH patients embryonic foetal neural progenitor cells centre central nervous system lethal Zika virus oropharyngeal networks low-passage ZIKV strains Culex-borne flaviviruses human samples DENV immune COVID-19 neural tissues Cohorts Consortium [56 flavivirus IGOS brain infections DengueTools neuronal cell bodies Zika ZikaPLAN Brazil, Cuba Zika Cohorts Vertical Transmission Study Group Pernambuco arboviruses https://globalvectorhub.lshtm.ac.uk/ herd peripheral nerve AWS CRISPR/Cas9 [3] . Brazil and 7 Women mothers Covid Neuro Network adult mice globe chikungunya virus Colombia DENV-endemic Americas brain human water-storage BAF45b nerve glycolipids Brazil very ECLAMC lymphocytes joint UNICEF Guillain-Barré SARS-CoV-2 Umeå Centre TGHN body myelin-forming oligodendrocytes humans larvicide NEAS quality-assured clearances REDe adenoid GBS women Practice/ mouse embryos Duane Gubler Zika-specific adolescents Zika vaccine travellers Zika [69] peripheral nerve cultures tissue tissues Culex-borne flavivirus Koren Wolman-Tardy [106] [ [107] [108] [109] co-twins App-based https://www. £2.3 M Margaux Luciani glial cells patient myelin PNS Aedes aegypti https://gbsstudies.erasmusmc.nl/ dengue virus ZIKV-GBS Nile virus children T cell CNS App GeoSentinel Health Organization-led Zika Virus Latin-American network myelinating cultures infants Prof Laura Rodrigues cell [1] placental Brain Infections UK persons Umeå Sweden
Extracted Text Content in Record: First 5000 Characters:Global health research partnerships are increasingly taking the form of consortia of institutions from highincome countries and low-and middle-income countries that undertake programs of research. These partnerships differ from collaborations that carry out single projects in their manifold variety of goals, activities, including the nature of their management [1] . Such consortia primarily aim to enhance research collaboration between and within countries and continents by facilitating access to patient cohorts for shared data analyses, levering upon the strength of multidisciplinary and international research approach, and building up collaborative networks between research institutions across the globe. After a cluster of children born with abnormally small head circumferences was detected in northeast Brazil in late 2015, and a public health emergency declared in early 2016 [2] , the European Commission awarded three research consortia with global health research partnerships to urgently address the knowledge gaps related to Zika virus infections, and form a research network with Latin America. ZikaPLAN stands for 'Zika Preparedness Latin American Network' and was one of the three consortia [3] . ZikaPLAN is a consortium with more than 100 researchers from 26 institutions from Belgium, Brazil, The etiologic agent triggering the epidemic of microcephaly cases was initially an open question [5, 6] . A series of epidemiological studies advanced scientific thought by connecting the microcephaly cases to Zika virus (ZIKV) infections in pregnancy [7] [8] [9] , ruling out alternative hypotheses, such as larvicide [10] and providing the first clinical description of a new disease, congenital Zika Syndrome [11, 12] . As part of the response to the epidemic, teams of investigators based in the Brazilian states of Pernambuco, Rio de Janeiro, and Goiás initiated, with support from the ZikaPLAN Consortium and the Brazilian government, a series of prospective cohort studies of pregnant persons with rash and children with Congenital Zika Syndrome (CZS) to elucidate the risks associated with maternal ZIKV infections. To identify cases of acute maternal Zika virus (ZIKV) infections, the Microcephaly Epidemic Research Group (MERG) in Pernambuco State described the serological markers of ZIKV and dengue virus (DENV) among mothers and neonates [7, 8, 13] and tested participants in the MERG Pregnant Women Cohort. The former study showed a high frequency of ZIKV exposure among mothers of microcephalic neonates and distinct patterns of ZIKV and DENV immune responses, as discernible by the neutralization test [13] . In the latter, women were tested at up to three timepoints during and after pregnancy using a combination of molecular and serologic assays, and the results were integrated in an evidence-graded diagnostic algorithm [14] . Among the pregnancies with suspected or confirmed ZIKV infections, 20% of ZIKV-exposed offspring presented with at least one clinical feature compatible with CZS, with absolute risks for microcephaly of 3%, neuroimaging abnormalities of 7%, neurologic abnormalities of 5%, and ophthalmologic abnormalities of 7% [15] . Interestingly, vertical transmission of ZIKV, placental features, and neurodevelopmental outcomes can be discordant between co-twins [16] . ZikaPLAN found low sensitivity of both ultrasonography [17] and amniocentesis [18] for prenatal CZS screening and affirmed the importance of comprehensive clinical assessment of neonates with suspected and confirmed ZIKV exposure during pregnancy. Sixty-five per cent of evaluable infants born to PCR-positive mothers were found to have serologic or molecular evidence of vertical transmission when tested within the first three months of life, with decreasing vertical transmission rates over the three trimesters (78% in first, 64% in second, and 48% in third) [19] . A similar temporal pattern was apparent in the frequency of children born small for gestational age and/or with symptoms consistent with CZS, with the highest rates of adverse outcomes in children born to women reporting rash (i.e. a common sign of acute ZIKV infection) in the first trimester [20] . Relative to ZIKV-negative neonates, ZIKVpositive neonates have a 5-times higher risk of presenting with microcephaly [21] . Lower socioeconomic position (i.e. indicated by lower maternal education, lower household income, and higher household crowding) was associated with increased odds of a child being born with congenital microcephaly [22] . Families residing in areas with poor living conditions had a higher prevalence of microcephaly compared with populations with better living conditions [23] . The ZikaPLAN studies provided unique insights regarding the natural history of CZS. Of note, the MERG pediatric cohort is one of the largest single cohort studies of children with CZS in the world. The MERG pediatric cohort study published several case series reporting on microcephaly [24] , prenat
Keywords Extracted from PMC Text: central nervous system Sweden body REDe infants human water-storage women DENV immune co-twins WHO/PAHO Zika vaccine endocrine Culex-borne flavivirus pregnant travellers Colombia https://www.youtube.com/watch?v=Mdf7F8i7azg&t=5s UNICEF ReLAMC Polynesia Covid Neuro Network Neuroviruses lethal Brazil, Colombia COVID-19 human learnings https://globalbirthdefects.tghn.org/ Nile foetal mosquitoes GBD children 's DENV https://gbsstudies.erasmusmc.nl/ Culex-borne flaviviruses GBDDC adenoid globe UK adolescents South-East Asia Australasian flaviviruses Americas [88–91 Zika [105]. App Zika ZikaPLAN Cohorts Consortium [56 [106] [107–109] Americas humans Women Zika-specific participants mothers cryptorchidism [30,31] DENV-endemic Brazil and 7 Pernambuco IGOS peripheral nervous T-cell low-passage ZIKV strains mouse Health Organization-led Zika Virus https://rede.tghn.org/ SARS-CoV-2 £2.3 M NEAS Culex-borne antigenic complex III flaviviruses placental Aedes aegypti arboviruses brain quality-assured mouse embryos Aedes-borne Zika- oropharyngeal France specimens DengueTools brain infections dengue virus Brazil, Argentina patients patient Pernambuco State Ae. RegLAMC Zika Cohorts Vertical Transmission Study Group TGHN GBS Guillain-Barré ECLAMC peripheral nervous system disease GeoSentinel Zika virus App-based Umeå field-derived Ae persons [1] Travellers GVH https://globalvectorhub.lshtm.ac.uk/ Culex-borne flavivirus proteins derived centre joint herd https://zikaplan.tghn.org/zikaplan-tools/webinars/ chikungunya virus Umeå Centre adult mice human Zika virus embryonic Nile virus https://rede.tghn.org/gbs-flowchart-sample/ travellers Brain Infections
Extracted PMC Text Content in Record: First 5000 Characters:Global health research partnerships are increasingly taking the form of consortia of institutions from high-income countries and low- and middle-income countries that undertake programs of research. These partnerships differ from collaborations that carry out single projects in their manifold variety of goals, activities, including the nature of their management [1]. Such consortia primarily aim to enhance research collaboration between and within countries and continents by facilitating access to patient cohorts for shared data analyses, levering upon the strength of multidisciplinary and international research approach, and building up collaborative networks between research institutions across the globe. After a cluster of children born with abnormally small head circumferences was detected in northeast Brazil in late 2015, and a public health emergency declared in early 2016 [2], the European Commission awarded three research consortia with global health research partnerships to urgently address the knowledge gaps related to Zika virus infections, and form a research network with Latin America. ZikaPLAN stands for 'Zika Preparedness Latin American Network' and was one of the three consortia [3]. ZikaPLAN is a consortium with more than 100 researchers from 26 institutions from Belgium, Brazil, Colombia, Cuba, France, Senegal, Switzerland, The Netherlands, UK, and USA, coordinated by the University of Umeå in Sweden. It is interlinked with the other two EU funded consortia ZIKAlliance and ZIKAction through co-managed and cross-cutting three joint work packages related to communication, management, ethics, networking and cohort studies. A detailed description on the geographic distribution and work packages was published at the beginning of the project [3] with a further mid-term update [4]. The ZikaPLAN project started in October 2016 and came to an end in May 2021. In this article, we exemplify the key learnings, achievements and impact of ZikaPLAN with a focus on the clinical and public health work, drawing upon the networks and resources as well as more than one hundred ZikaPLAN publications to date (available at the project website https://zikaplan.tghn.org/publications/). To identify cases of acute maternal Zika virus (ZIKV) infections, the Microcephaly Epidemic Research Group (MERG) in Pernambuco State described the serological markers of ZIKV and dengue virus (DENV) among mothers and neonates [7,8,13] and tested participants in the MERG Pregnant Women Cohort. The former study showed a high frequency of ZIKV exposure among mothers of microcephalic neonates and distinct patterns of ZIKV and DENV immune responses, as discernible by the neutralization test [13]. In the latter, women were tested at up to three timepoints during and after pregnancy using a combination of molecular and serologic assays, and the results were integrated in an evidence-graded diagnostic algorithm [14]. Among the pregnancies with suspected or confirmed ZIKV infections, 20% of ZIKV-exposed offspring presented with at least one clinical feature compatible with CZS, with absolute risks for microcephaly of 3%, neuroimaging abnormalities of 7%, neurologic abnormalities of 5%, and ophthalmologic abnormalities of 7% [15]. Interestingly, vertical transmission of ZIKV, placental features, and neurodevelopmental outcomes can be discordant between co-twins [16]. ZikaPLAN found low sensitivity of both ultrasonography [17] and amniocentesis [18] for prenatal CZS screening and affirmed the importance of comprehensive clinical assessment of neonates with suspected and confirmed ZIKV exposure during pregnancy. Sixty-five per cent of evaluable infants born to PCR-positive mothers were found to have serologic or molecular evidence of vertical transmission when tested within the first three months of life, with decreasing vertical transmission rates over the three trimesters (78% in first, 64% in second, and 48% in third) [19]. A similar temporal pattern was apparent in the frequency of children born small for gestational age and/or with symptoms consistent with CZS, with the highest rates of adverse outcomes in children born to women reporting rash (i.e. a common sign of acute ZIKV infection) in the first trimester [20]. Relative to ZIKV-negative neonates, ZIKV-positive neonates have a 5-times higher risk of presenting with microcephaly [21]. Lower socioeconomic position (i.e. indicated by lower maternal education, lower household income, and higher household crowding) was associated with increased odds of a child being born with congenital microcephaly [22]. Families residing in areas with poor living conditions had a higher prevalence of microcephaly compared with populations with better living conditions [23]. The ZikaPLAN studies provided unique insights regarding the natural history of CZS. Of note, the MERG pediatric cohort is one of the largest single cohort studies of children with CZS in the world. The MERG pediatric cohort study publ
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