| 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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