ZikaPLAN: addressing the knowledge gaps and working towards a research preparedness network in the Americas

Figures & data

Table 1. Overview of work packages and their short and long-term impact.

Work Packages	Partners involved in the work package	Addressing urgent gaps and creating the evidence base	Implications for immediate interventions	Long-term research network	Foundation
WP1 MERG	Universidade Federal de Goiás, Universidade Federal de Pernambuco, Umeå University, London School of Hygiene and Tropical Medicine, Associação Técnica–Científica de Estudo Colaborativo Latino Americano de Malformações Congênitas, Fundação Oswaldo Fiocruz and University of Pernambuco.	Determining the attack rate, the case definition of congenital Zika syndrome and the extent of disability and health care impact	Harmonized Latin-American wide guidelines for the management of severe illness caused by Zika	Platform for intervention (vaccine and drug studies)	Research network against any future emerging severe infectious threats
WP2 NEURO-Zika: clinical	Umeå University, University of Glasgow, University of Oxford, Erasmus University, Universidad del Valle, University of Liverpool, Fundação de Apoio à Universidade de São Paulo, and Fundação Oswaldo Fiocruz.	Investigating neurological complications of Zika
WP3 Non-vector transmission	University of Leuven, Antwerp Institute of Tropical Medicine, Swiss Tropical and Public Health Institute.	Mice models developed to study potential interventions to sexual and vertical transmission; semen studies in ZIKV patients	Potential for additional studies to develop specific therapeutic interventions to mitigate severe complications of Zika infections	Platform for evidence- based public health responses Platform for deployment of large scale pathogenesis studies
WP4 NEURO-ZIKA: pathogenesis	Umeå University, University of Glasgow, University of Leuven, University of Liverpool, La Jolla Institute for Allergy and Immunology and Fundação Oswaldo Fiocruz.	Pathomechanisms of neuroinvasion and immune mediated response
WP6 INVADE: Investigating Vaccines in Antibody Dependent Enhancement (ADE)	London School of Hygiene and Tropical Medicine, Fundación Universidad del Norte, La Jolla Institute for Allergy and Immunology and The University of North Carolina at Chapel Hill.	ADE as cause for more severe Zika disease either confirmed or excluded; T and B cell epitopes defined for vaccine and diagnostic applications
WP5 Platform for diagnostics innovation and evaluation	London School of Hygiene and Tropical Medicine, University, Fondation Mérieux, University of North Carolina at Chapel Hill, Antwerp Institute of Tropical Medicine, Fundação Oswaldo Fiocruz, Instituto de Medicina Tropical Pedro Kourí, Institut Pasteur de Dakar and contributions by Swiss Tropical and Public Health Institute,	Biobank and virtual platform for diagnostics evaluation	Platform for evaluation of diagnostic assays developed within ZikaPLAN and beyond (commercial companies, academia)	Global laboratory platform to evaluate diagnostics for flavivirus infections
WP7 Contemporary versus historical viral fitness of ZIKV	University of Leuven, Institut Pasteur and Fundación Universidad del Norte.	Determining the phenotypic differences of the current Zika viruses with historical Zika viruses	Designing evidence-informed public health responses	Platform for evidence- based public health responses
WP8 Disease burden and Risk Assessment	Umeå University, London School of Hygiene and Tropical Medicine, Queen Mary University of London, University of Ulster, Fundação de Apoio à Universidade de São Paulo, Instituto Butantan, Associação Técnica–Científica de Estudo Colaborativo Latino Americano de Malformações Congênitas and Swiss Tropical and Public Health Institute.	Establishing burden of disease and risk of further spread; tools for birth defect surveillance,
WP9 Mathematical modelling to inform public health policies	Umeå University, London School of Hygiene and Tropical Medicine, University of Oxford, Institut Pasteur, and Fundação de Apoio à Universidade de São Paulo.	Modelling vector control strategies; vaccine strategies; transmission dynamics
WP10 WEAR: WEarable Aedes Repellant Technologies	London School of Hygiene and Tropical Medicine and Universidad del Valle.	Wash-in detergent formulations and impregnated clothing technologies for the protection against Aedes mosquito bites	Personal protective measures for affected communities	Rapidly scalable intervention
WP11 PLAN: Preparedness Latin-American Network	Umeå University, London School of Hygiene and Tropical Medicine, University of Oxford, Fondation Mérieux, Fundação Oswaldo Fiocruz, University of Pernambuco, with contributions from all other partners.	Online curriculum and education website, engaging with affected communities, stakeholders and policymakers, adaptable study protocols, resolving regulatory and administrative bottlenecks, coordinating actions within the consortium and other consortia.	Network prepared for rapid support of designing clinical and public health responses	Platform for a Latin American research network for birth defect surveillance, hospital based research, and cohort studies
WP12 Dissemination and Communication	Fondation Mérieux and Umeå University with contributions from all other partners.
WP13 Consortium Coordination	Umeå University is coordinator of the consortium.
WP 14 Zika Data Share	This is a shared WP amongst ZikaPLAN, ZIKAlliance and ZIKAction. Led by the London School of Hygiene and Tropical Medicine for ZikaPLAN.	Enhance outreach through and along the work of the other EU funded consortia, ZIKAction and ZIKAlliance			Network beyond ZikaPLAN
WP 15 ZIKA-COLLAB	This is a shared WP amongst ZikaPLAN, ZIKAlliance and ZIKAction. Led by Umeå University for ZikaPLAN.

Figure 1. Microcephaly Epidemic Research Group (MERG), Neuro-Zika, and the clinical sites of the Butantan Phase 3 trial for dengue vaccine.

Figure 2. Birth defect surveillance network (RELAMC).

Figure 3. Neuro Emerging Viruses in the Americas Study (NEAS).

Table 2. Scientific publications by the Microcephaly Epidemic Research Group (MERG) in North-East Brazil and ZikaPLAN Work Package 1 Partners, from 2015 to present.

1. Castanha, P. M. S. et al. Perinatal analyses of Zika- and dengue virus-specific neutralizing antibodies: A microcephaly case-control study in an area of high dengue endemicity in Brazil. PLoS Neglected Tropical Diseases, 13:1–17, 2019.

2. Souza, W. V. et al. Microcephaly epidemic related to the Zika virus and living conditions in Recife, Northeast Brazil. BMC Public Health, 18:130–136, 2018.

3. Araujo, T. V. B. et al. Association between microcephaly, Zika virus infection, and other risk factors in Brazil: final report of a case-control study. Lancet Infectious Diseases, 18:328–336, 2018.

4. Albuquerque, M. F. P. M. et al. The microcephaly epidemic and Zika virus: building knowledge in epidemiology. Cadernos de Saúde Pública, 34: 1–13, 2018.

5. Pires, P. et al. Neuroimaging findings associated with congenital Zika virus syndrome: case series at the time of first epidemic outbreak in Pernambuco State, Brazil. Childs Nervous System, 34:957–963, 2018.

6. Miranda-Filho, D. B. et al. Initial Description of the Presumed Congenital Zika Syndrome. American Journal of Public Health, 106:598–600, 2016.

7. Albuquerque, M. F. P. M. et al. Microcephaly in Infants, Pernambuco State, Brazil, 2015. Emerging Infectious Diseases, 22:1090–1093, 2016.

8. Araujo, T. V. B. et al. Association between Zika virus infection and microcephaly in Brazil, January to May, 2016: preliminary report of a case-control study. Lancet Infectious Diseases, 16:1356–1363, 2016.

9. Albuquerque, M. F. P. M. et al. Pyriproxyfen and the microcephaly epidemic in Brazil – an ecological approach to explore the hypothesis of their association. Memórias do Instituto Oswaldo Cruz, 111:774–776, 2016.

10. Souza, W. V. et al. Microcephaly in Pernambuco State, Brazil: epidemiological characteristics and evaluation of the diagnostic accuracy of cutoff points for reporting suspected cases. Cadernos de Saude Publica, 32(4):e00017216, 2016.

11. Leal, M. C. et al. Hearing Loss in Infants with Microcephaly and Evidence of Congenital Zika Virus Infection – Brazil, November 2015–May 2016. Morbidity and Mortality Weekly Report, 65(34):917–919, 2016.

12. Franca, R. F. O. et al. First International Workshop on Zika Virus Held by Oswaldo Cruz Foundation (Fiocruz) in Northeast Brazil March 2016 – A Meeting Report. PLOS Neglected Tropical Diseases, 10(6):e0004760, 2016.

13. Cordeiro, M. T. et al. Results of a Zika Virus (ZIKV) Immunoglobulin M–specific diagnostic assay are highly correlated with detection of neutralizing anti-ZIKV antibodies in neonates with congenital disease. The Journal of Infectious Diseases, 214:1897–1904, 2016.

14. Poretti, A. et al. Zika virus infection during pregnancy and small heads: What is the connection and what can be seen by imaging. Atlas of Science. 2016. Avaliable in: <http://atlasofscience.org/zika-virus-infection-during-pregnancy-and-small-heads-what-is-the-connection-and-what-can-be-seen-by-imaging/>

15. Hazin, A. N. et al. Computed tomographic findings in microcephaly associated with Zika Virus. The New England Journal of Medicine, 374(22):2193–2195, 2016.

16. Einspieler C, Utsch F, Brasil P, Panvequio Aizawa CY, Peyton C, Hydee Hasue R, et al. Association of Infants Exposed to Prenatal Zika Virus Infection With Their Clinical, Neurologic, and Developmental Status Evaluated via the General Movement Assessment Tool. JAMA Netw Open. 2019;2(1):e187235. Epub 2019/01/19. doi: 10.1001/jamanetworkopen.2018.7235. PubMed PMID: 30657537; PubMed Central PMCID: PMCPMC6431234.

17. Brickley EB, Rodrigues LC. Further pieces of evidence in the Zika virus and microcephaly puzzle. Lancet Child Adolesc Health. 2018;2(3):162–4. Epub 2018/09/01. doi: 10.1016/S2352-4642(18)30021-X. PubMed PMID: 30169250.

18. Lopes Moreira ME, Nielsen-Saines K, Brasil P, Kerin T, Damasceno L, Pone M, et al. Neurodevelopment in Infants Exposed to Zika Virus In Utero. N Engl J Med. 2018;379(24):2377–9. Epub 2018/12/24. doi: 10.1056/NEJMc1800098. PubMed PMID: 30575464.

19. Devakumar D, Bamford A, Ferreira MU, Broad J, Rosch RE, Groce N, et al. Infectious causes of microcephaly: epidemiology, pathogenesis, diagnosis, and management. Lancet Infect Dis. 2018;18(1):e1-e13. Epub 2017/08/29. doi: 10.1016/S1473-3099(17)30398-5. PubMed PMID: 28844634.

20. Lowe R, Barcellos C, Brasil P, Cruz OG, Honorio NA, Kuper H, et al. The Zika Virus Epidemic in Brazil: From Discovery to Future Implications. Int J Environ Res Public Health. 2018;15(1). Epub 2018/01/10. doi: 10.3390/ijerph15010096. PubMed PMID: 29315224; PubMed Central PMCID: PMCPMC5800195.

21. Paixao ES, Teixeira MG, Costa M, Barreto ML, Rodrigues LC. Symptomatic Dengue during Pregnancy and Congenital Neurologic Malformations. Emerg Infect Dis. 2018;24(9):1748–50. Epub 2018/08/21. doi: 10.3201/eid2409.170361. PubMed PMID: 30124410; PubMed Central PMCID: PMCPMC6106414.

22. Paixao ES, Leong WY, Rodrigues LC, Wilder-Smith A. Asymptomatic Prenatal Zika Virus Infection and Congenital Zika Syndrome. Open Forum Infect Dis. 2018;5(4):ofy073. Epub 2018/05/08. doi: 10.1093/ofid/ofy073. PubMed PMID: 29732381; PubMed Central PMCID: PMCPMC5925427.

23. Paixao ES, Teixeira MG, Rodrigues LC. Zika, chikungunya and dengue: the causes and threats of new and re-emerging arboviral diseases. BMJ Glob Health. 2018;3(Suppl 1):e000530. Epub 2018/02/13. doi: 10.1136/bmjgh-2017-000530. PubMed PMID: 29435366; PubMed Central PMCID: PMCPMC5759716.

24. Paixao ES, Costa M, Teixeira MG, Harron K, de Almeida MF, Barreto ML, et al. Symptomatic dengue infection during pregnancy and the risk of stillbirth in Brazil, 2006–12: a matched case-control study. Lancet Infect Dis. 2017;17(9):957–64. Epub 2017/08/29. doi: 10.1016/S1473-3099(17)30366-3. PubMed PMID: 28845800; PubMed Central PMCID: PMCPMC6205624.

25. Rodrigues LC, Paixao ES. Risk of Zika-related microcephaly: stable or variable? Lancet. 2017;390(10097):824–6. Epub 2017/06/26. doi: 10.1016/S0140-6736(17)31478-2. PubMed PMID: 28647174.

26. Rodrigues LC. Zika’s Long Haul: Tackling the Causes of Human Vulnerability to Mosquito-Borne Viruses. Am J Public Health. 2017;107(6):831–3. Epub 2017/05/13. doi: 10.2105/AJPH.2017.303792. PubMed PMID: 28498761.

27. Wilder-Smith A, Wei Y, Araújo TVB, VanKerkhove M, Turchi Martelli CM, Turchi MD, et al. Understanding the relation between Zika virus infection during pregnancy and adverse fetal, infant and child outcomes: a protocol for a systematic review and individual participant data meta-analysis of longitudinal studies of pregnant women and their infants and children. BMJ Open. 18 June 2019;9(6):e026092. doi: 10.1136/bmjopen-2018-026092

28. Moreira MCN, Nascimento M, Mendes CHF, Pinto M, Valongueiro S, Moreira MEL, Lyra TM, Kuper H; SEIZ Research Group. Emergency and permanence of the Zika virus epidemic: an agenda connecting research and policy. Cad Saude Publica. 2018;34(8):e00075718.

29. Kuper H, Lyra TM, Moreira, MEL, Albuquerque MSV, Araujo, TVB, Fernandes, S, Jofre-Bonet, M, Larson, H, de Melo, APL, do Nascimento, MAF, Penn-Kekana, L, Pimentel, C, Pinto, M, Simas, C, Valongueiro, S.  Social and economic impacts of congenital Zika syndrome in Brazil: Study protocol and rationale for a mixed-methods study [version 2; peer review: 1 approved, 1 approved with reservations] Wellcome Open Research.  2019;3:127

Table 3. Web-based information that ZikaPLAN has made publicly available.

Website	What is the website about!	URL
REDe	REDe is an international network focused on building research capacity and preparedness to tackle emerging infectious disease outbreaks in Latin America and Caribbean.	https://rede.tghn.org/
Global Birth Defects	The Global Birth Defects website is an initiative by the International Committee for Congenital Anomaly Surveillance Tools to provide specific and pragmatic resources that can improve surveillance systems and research projects in low-resource communities and areas where congenital anomaly diagnosis expertise is scarce.	https://globalbirthdefects.tghn.org/
Brain Infections Global	Improving the Management of Acute Brain Infections	https://braininfectionsglobal.tghn.org/
Global Vector Hub	The Global Vector Hub is an open access, interactive resource that not only has the capacity to transform vector research and vector control programmes, but also revolutionise our preparedness and ability to respond quickly and effectively to vector-borne disease outbreaks, around the world.	https://www.lshtm.ac.uk/research/centres-projects-groups/globalvectorhub
IGOS International Guillain-Barré syndrome outcome study	The study aims to identify clinical and biological determinants and predictors of disease course in Guillain-Barré syndrome.	https://gbsstudies.erasmusmc.nl/
IGOS-Zika	The International Zika virus related Guillain-Barré syndrome Outcome Study (IGOS-Zika)	https://igoszika.erasmusmc.nl/