Periodic Reporting for period 4 - ZIKAlliance (A global alliance for Zika virus control and prevention)
Berichtszeitraum: 2021-04-01 bis 2021-09-30
ZIKAlliance is a multinational, multi-disciplinary research consortium comprised of 54 partners worldwide. It investigates clinical, fundamental, environmental & social aspects of Zika virus (ZIKV) infection, in particular the impact during pregnancy (including short & medium term effects on newborns). The objectives are to (i) improve the scientific knowledge about ZIKV natural history, mechanisms of infection, immune response, diagnostic methods, potential antiviral treatments & societal impact and (ii) build preparedness capacity for future epidemic threats in Latin America and the Caribbean.
A multidisciplinary integrated approach of ZIKV epidemiology in Latin America
Combining epidemiology data & modelling research we built a pan-continental ZIKV model to project realistic case numbers; ZIKV genetic & phylogeny studies allowed specifying the date on which ZIKV reached the Americas, discovering the recombinant nature of ZIKV genome and proposing a new disruptive hypothesis for ZIKV long-term evolution & epidemiology. We improved the understanding of non-vectored transmission by identifying the mechanisms underlying ZIKV persistence in testis & sexual transmission.
Regarding mosquito-borne transmission, detection of ZIKV in field-collected mosquitoes using mass screening methods combined with experimental vector competence studies contributed to establish the pivotal role of aedes mosquitoes. We showed that co-infections of ZIKV with other arboviruses modify viral evolution and mosquito antiviral responses. Since main ZIKV vectors are resistant to most commonly used insecticides in the Americas, we investigated the development of promising bio-tools to improve vector control, e.g. we produced the first Genetic Sexing Strain in Ae. albopictus for rapid mass sex separation dedicated to Wolbachia-based sterile male control strategy.
Environmental studies (i.e. collecting and testing for ZIKV >4000 animal specimens from >20 wild and domestic animal species) and experimental infections of monocyte-derived cells from diverse animal species provided limited evidence for ZIKV sylvatic cycles in the Americas. In contrast, sylvatic cycles for yellow fever virus were described in non-human primates, and new animal reservoirs were identified for other arboviruses.
Preclinical and clinical research to better understand infection in pregnant women (PW) and children (CH)
We have set-up a clinical research program with PW and CH cohorts in 8 countries (14 sites) in Latin America & the Caribbean. We benefited from early inclusion programs in the French West Indies (FWI, funded by the French INSERM) and Brazil (FIOCRUZ). In total, we included 8893 PW and 2594 CH. In the FWI, we found low rates of fetal severe abnormalities and confirmed that the risk is maximal during the first trimester of pregnancy. Results from other sites will be part of a WHO moderated ‘Individual Patient Data Meta-Analysis’.
Complementary preclinical research on ZIKV‐associated fetal pathology and neurodevelopmental defects in animal models and humans identified major factors involved in the entry of the virus in the cells, a human host factor essential for ZIKV infection of placental cells and, importantly, the major determinants of ZIKV-induced microcephaly.
Diagnosis laboratory capacity was examined and the main barriers reported in a lessons learned paper. Initial procedures were adapted to ease pooled analysis from different sites and reference laboratory support was implemented to harmonize laboratory results.
The partners initiated the developmental evaluation within CH cohorts and put together a guidelines manuscript on monitoring of at-risk pregnancies and policies regarding abortion in the context of the ZIKV epidemic.
In response to the COVID-19 pandemic, partners rapidly repurposed their cohorts, first within the remits of ZIKAlliance and then as part of a new EC funded initiative (ORCHESTRA) to support investigations related to SARS-CoV-2 infection in PW and adverse pregnancy outcomes in CH. Additional research activities beyond ZIKV are initiated (e.g. on TORCHS pathogen prevalence), using the cohorts infrastructure. Cohorts' sustainability implies bringing additional research groups on board and nesting their scientific questions in the established PW and CH cohorts (e.g. the successful repurposing of PW cohorts for SARS-CoV-2 studies in Venezuela, Brazil, Colombia, and Peru).
Promoting interaction between research and society through social sciences and communication
We developed a historical, epistemological & political timeline of Zika epidemic and response in Brazil through interviews, public documents, epidemiological and socio-economic data analysis, and investigated the public understanding of Zika infection and social imaginary in social media. We concluded that arguments framed in terms of social justice and socio-economic impact failed to make the transition into concrete sanitary or political interventions. Scientific production, media and public controversies related to Zika epidemic were investigated in Brazil, including fieldwork in PW from Manaus-Amazonas. A survey conducted in French Guiana about public’s beliefs, attitudes & behaviours in response to the ZIKV epidemic showed the predominant role of mothers as children main caregivers.
Communication to the scientific community and dissemination to the public was ensured through the publication of >200 scientific articles but also through press releases, a consortium newsletter, a website, a twitter channel and an open access repository with all articles published by the consortium. We ensured that all ZIKAlliance-related external activities and scientific outputs have received maximum exposure and public acknowledgement.
Combining epidemiology data & modelling research we built a pan-continental ZIKV model to project realistic case numbers; ZIKV genetic & phylogeny studies allowed specifying the date on which ZIKV reached the Americas, discovering the recombinant nature of ZIKV genome and proposing a new disruptive hypothesis for ZIKV long-term evolution & epidemiology. We improved the understanding of non-vectored transmission by identifying the mechanisms underlying ZIKV persistence in testis & sexual transmission.
Regarding mosquito-borne transmission, detection of ZIKV in field-collected mosquitoes using mass screening methods combined with experimental vector competence studies contributed to establish the pivotal role of aedes mosquitoes. We showed that co-infections of ZIKV with other arboviruses modify viral evolution and mosquito antiviral responses. Since main ZIKV vectors are resistant to most commonly used insecticides in the Americas, we investigated the development of promising bio-tools to improve vector control, e.g. we produced the first Genetic Sexing Strain in Ae. albopictus for rapid mass sex separation dedicated to Wolbachia-based sterile male control strategy.
Environmental studies (i.e. collecting and testing for ZIKV >4000 animal specimens from >20 wild and domestic animal species) and experimental infections of monocyte-derived cells from diverse animal species provided limited evidence for ZIKV sylvatic cycles in the Americas. In contrast, sylvatic cycles for yellow fever virus were described in non-human primates, and new animal reservoirs were identified for other arboviruses.
Preclinical and clinical research to better understand infection in pregnant women (PW) and children (CH)
We have set-up a clinical research program with PW and CH cohorts in 8 countries (14 sites) in Latin America & the Caribbean. We benefited from early inclusion programs in the French West Indies (FWI, funded by the French INSERM) and Brazil (FIOCRUZ). In total, we included 8893 PW and 2594 CH. In the FWI, we found low rates of fetal severe abnormalities and confirmed that the risk is maximal during the first trimester of pregnancy. Results from other sites will be part of a WHO moderated ‘Individual Patient Data Meta-Analysis’.
Complementary preclinical research on ZIKV‐associated fetal pathology and neurodevelopmental defects in animal models and humans identified major factors involved in the entry of the virus in the cells, a human host factor essential for ZIKV infection of placental cells and, importantly, the major determinants of ZIKV-induced microcephaly.
Diagnosis laboratory capacity was examined and the main barriers reported in a lessons learned paper. Initial procedures were adapted to ease pooled analysis from different sites and reference laboratory support was implemented to harmonize laboratory results.
The partners initiated the developmental evaluation within CH cohorts and put together a guidelines manuscript on monitoring of at-risk pregnancies and policies regarding abortion in the context of the ZIKV epidemic.
In response to the COVID-19 pandemic, partners rapidly repurposed their cohorts, first within the remits of ZIKAlliance and then as part of a new EC funded initiative (ORCHESTRA) to support investigations related to SARS-CoV-2 infection in PW and adverse pregnancy outcomes in CH. Additional research activities beyond ZIKV are initiated (e.g. on TORCHS pathogen prevalence), using the cohorts infrastructure. Cohorts' sustainability implies bringing additional research groups on board and nesting their scientific questions in the established PW and CH cohorts (e.g. the successful repurposing of PW cohorts for SARS-CoV-2 studies in Venezuela, Brazil, Colombia, and Peru).
Promoting interaction between research and society through social sciences and communication
We developed a historical, epistemological & political timeline of Zika epidemic and response in Brazil through interviews, public documents, epidemiological and socio-economic data analysis, and investigated the public understanding of Zika infection and social imaginary in social media. We concluded that arguments framed in terms of social justice and socio-economic impact failed to make the transition into concrete sanitary or political interventions. Scientific production, media and public controversies related to Zika epidemic were investigated in Brazil, including fieldwork in PW from Manaus-Amazonas. A survey conducted in French Guiana about public’s beliefs, attitudes & behaviours in response to the ZIKV epidemic showed the predominant role of mothers as children main caregivers.
Communication to the scientific community and dissemination to the public was ensured through the publication of >200 scientific articles but also through press releases, a consortium newsletter, a website, a twitter channel and an open access repository with all articles published by the consortium. We ensured that all ZIKAlliance-related external activities and scientific outputs have received maximum exposure and public acknowledgement.
Creating new research tools for the scientific community and implementing a policy of harmonization & data sharing
A large number or diagnostic & research tools (e.g. antigens, antibodies, innovative baited traps for mosquitoes, protocols for reverse genetics methods, animal or organ infections..) was created. We have developed a pipeline for identifying ZIKV inhibitors using screening methods & animal models. Despite the evaluation of hundreds of thousands of molecules, it has not identified a convincing ZIKV treatment candidate; however, its repositioning for dengue virus has recently resulted in qualifying a leading antiviral molecule.
Collaboration and data harmonization efforts have been implemented with the 2 other EC-funded research projects ZIKAction & ZIKAPlan. Harmonized protocols, data management platforms & external quality assessment procedures were shared. Common governance boards were created for data sharing & biobanking, as well as common Scientific Advisory Board, Ethics Advisory Committee and Communication Oversight Board. The consortia shared an educational programme with an Open Access Community Platform, webinars, reciprocal monitoring & online distance learning modules. Challenges faced in the 3 consortia with regard to harmonization and data sharing led ZIKAlliance researchers to secure additional funding from the EC H2020 program in a personalized medicine call with the project ‘ReCoDID’ – Reconciliation of Cohort Data for Infectious Diseases.
A large number or diagnostic & research tools (e.g. antigens, antibodies, innovative baited traps for mosquitoes, protocols for reverse genetics methods, animal or organ infections..) was created. We have developed a pipeline for identifying ZIKV inhibitors using screening methods & animal models. Despite the evaluation of hundreds of thousands of molecules, it has not identified a convincing ZIKV treatment candidate; however, its repositioning for dengue virus has recently resulted in qualifying a leading antiviral molecule.
Collaboration and data harmonization efforts have been implemented with the 2 other EC-funded research projects ZIKAction & ZIKAPlan. Harmonized protocols, data management platforms & external quality assessment procedures were shared. Common governance boards were created for data sharing & biobanking, as well as common Scientific Advisory Board, Ethics Advisory Committee and Communication Oversight Board. The consortia shared an educational programme with an Open Access Community Platform, webinars, reciprocal monitoring & online distance learning modules. Challenges faced in the 3 consortia with regard to harmonization and data sharing led ZIKAlliance researchers to secure additional funding from the EC H2020 program in a personalized medicine call with the project ‘ReCoDID’ – Reconciliation of Cohort Data for Infectious Diseases.