Forskningsprojekt ZikaPLAN ska dels producera kunskap om och visa på möjliga åtgärder mot zikavirus-infektion, dels bygga upp ett bestående latinamerikanskt nätverk för beredskap och motåtgärder mot smittsjukdomsepidemier.
ZikaPLAN, som är ett latinamerikanskt nätverk för att bekämpa epidemier av smittsamma sjukdomar, har ett omfattande fokus på att adressera kunskapsluckor och behov kring pågående zikautbrott för att bättre diagnosticera och förstå sjukdomen och dess följdverkningar, förhindra spridning och utbilda drabbade befolkningar, samt att bygga en hållbar latinamerikansk responskapacitet mot zika och andra kommande infektionssjukdomar, så kallade emerging infectious diseases (EID).
European Commission, 2016: 15 300 000 kr
The ZikaPLAN initiative combines the strengths of 25 partners in Latin America, North America, Africa, Asia, and various academic centres in Europe and their collaborators around two related purposes:
A. Addressing ZIKA: we will address the current knowledge gaps in Zika as requested in the call topic: association with congenital syndromes and neurological complications, clinical spectrum of disease, determinants of severe disease, pathogenesis and in particular neuropathogenesis, non-vector and vector transmission, diagnostics innovation and evaluation, burden of disease and risk factors for geographic spread; birth defect surveillance, social science for communication strategies with affected communities, novel personal preventive measures, and modelling on vector control and vaccine strategies for evidence-informed policies.
B. Prepare for beyond Zika: Whilst addressing Zika, we will position the various activities and results as a springboard towards building a sustainable Latin-American network capable of rapidly launching concerted, large scale research responses to emerging infectious diseases outbreaks of significant (potential) impact to the region. This way we can leverage the Zika response towards building a long term emerging infectious diseases (EID) response capacity in the region beyond the four year project period.
The project, the consortium and its main components have been designed with these dual, complementary purposes in mind. Parts of our planned activities will primarily address Purpose A (Addressing Zika), yet will also contribute to Purpose B (Beyond Zika). Vice versa, the components of our programme geared towards Purpose B (Beyond Zika) will also have a positive impact on the current Zika outbreak response.
The initiative will collaborate and closely work with two other EU funded consortia, ZIKAction and ZikAlliance.
A. Addressing ZIKA: tackling knowledge gaps and needs in key areas of interest to the current Zika Outbreak
Objective 1: To determine the attack rate and full clinical spectrum of Congenital Zika Syndrome (CZS).
The research in pursuit of this objective builds on the MERG (Microcephaly Epidemic Research Group) and is organised into three research lines:
1A CZS implications for pregnant women
Here we will aim to determine the absolute risk of miscarriage, still birth, microcephaly and other manifestations in neonates of pregnant women with ZIKV infection by gestational age. We will also define the full spectrum of CZS at birth and thirdly we will develop an improved case definition of CZS for surveillance purposes and birth defect registries.
1B CZS implications for neonates
We will characterize the clinical spectrum of CZS for neonates and validate simple tools for assessing deficiencies in other low resources-settings.
1C Social and economic impact of CZS
We will estimate the social impact and the economic costs of having a child with CZS on the women´s and the family´s life (e.g. on livelihood, occupation, mental health, health service needs) and impact on public services.
Objective 2: To define the spectrum of neurological diseases associated with Zika virus (ZIKV) infection, in the central nervous system (CNS) and peripheral nervous system (PNS) of adults and children (excluding neonates).
This includes immunologically mediated illness, for example Guillain-Barré syndrome (GBS) or acute disseminated encephalomyelitis (ADEM), and direct viral invasion of the nervous system for example meningoencephalitis. Here we will conduct retrospective and prospective cohort studies of neurological Zika disease across Brazil and Colombia, establishing a biobank of materials derived (including control samples). Thereby we aim to enhance our understanding of disease mechanisms of neurological Zika disease and improve clinical management of neurological Zika disease.
Objective 3: To investigate the extent of and factors associated with sexual transmission of Zika in humans and animal models.
We will establish a ZIKV mouse model for (i) studying sexual transmission and entry pathways of the virus via the vaginal route and (ii) for vertical transmission. The frequency of ZIKV persistence as well as the kinetics of ZIKV in semen samples will be assessed by means of RT-PCR, after acute ZIKV infection. Replication fitness of ZIKV in semen will be assessed by isolation of ZIKV virions in culture. Finally, we will evaluate targets and pathways in virus-host interactions in ex vivo and in vitro human tissue models of sexual transmission.
Objective 4: To discover and characterise the mechanistic pathways of ZIKV infection in the pathogenesis of CNS and PNS injury, focusing on a) direct viral invasion, and b) immune and autoimmune responses to viral infection.
We will define ZIKV tropism in CNS and PNS, in vitro and in vivo. Second, we will determine the consequences for PNS and CNS cell health, function and survival of direct ZIKV infection, in vitro and in vivo. We will investigate intra- and intercellular trafficking of ZIKV within and between the periphery and the PNS and CNS and characterize the nature of ZIKV main cellular receptors on human neural cells, screening proteins, glycoproteins, proteoglycans, glycolipids. Hereby we aim to identify candidates used by ZIKV to attach to neural cells. Furthermore, we will determine if humoral factors from Zika-GBS patient and control sera are pathogenic to PNS and CNS cells in vitro and ex vivo. Using sensitive immunoassays we will examine sera from Zika-GBS cases and controls for antigen targets known to be associated with conventional GBS, principally peripheral nerve glycolipids. Differential immune responses in patients with (i) non-neurological ZIKV infection, (ii) viral invasion of the CNS (e.g. encephalitis) and (iii) with autoimmune neurological disease will be examined.
Objective 5: To develop and validate tools for the diagnosis, surveillance and research on ZIKV.
We will develop novel ZIKV diagnostic tests in accordance with WHO Target Product Profiles and determine the utility of novel ZIKV diagnostic tools for patient management, disease control and epidemiologic research. The validation of the performance and operational characteristics of diagnostic tests will be accelerated by setting up a biobank of specimens and a network of laboratory and clinical sites, pre-approved for clinical trial protocols.
Objective 6: To identify the major T-cell epitopes and cross reactive B-cell epitopes on ZIKV and assess the role of flavivirus antibodies in protective and pathogenic immunity following ZIKV through antibody dependent enhancement (ADE).
This objective addresses the question of whether pre-existing immunity to other co-circulating flaviviruses (or flavivirus vaccines) plays a protective or detrimental role. More than 2000 T cell epitopes and epitopes targeted by type-specific and neutralizing antibodies will be identified. This information is critical to developing vaccines, serological diagnostic assays as well as understanding potential mechanisms of immune pathogenesis responsible for severe neurological and fetal defects
Objective 7: To determine whether the contemporary ZIKV is associated with a higher viral fitness in Aedes mosquitoes and more severe neurological disease and testicular involvement in mice compared with historical Zika viruses.
This objective addresses the role of mosquito vectors in the emergence of ZIKV in Latin America using an experimental approach. It will investigate whether ZIKV emergence is associated with adaptive viral evolution in the vector, i.e. viral fitness differences that may explain the observed recent increase in ZIKV transmission by mosquitoes among humans. We also will address whether contemporary ZIKV result in more severe neurological disease, different tissue tropism and higher viral loads in mice compared with historical Zika virus isolates.
Objective 8: To assess the evolution of the ZIKV outbreak in Brazil, document, anticipate and model regional and global geographic spread of ZIKV infections and model the relative contribution of sexual transmission in ZIKV transmission dynamics.
In this objective we will build on an existing cohort of 17,000 subjects aged 2-59 in 14 different locations in Brazil. Using this cohort, we will determine the incidence of ZIKV infection over 3 years (active febrile episode surveillance). Seroprevalence data will be documented, stratified by age, gender, prior dengue exposure, and geographic distribution at baseline in the year 2016. Force of force of infection, Basic Reproduction Number, average age of ZIKV infection, and the optimum vaccination age will be calculated in the study. We will describe the spatio-temporal and demographic factors associated with ZIKV infections in Brazil as well as the full spectrum from mild to severe disease and the ratio of asymptomatic to symptomatic ZIKV infections.
B. Beyond ZIKA: Building a sustainable Latin-American EID Preparedness and Response capacity
Objective 9: To develop mathematical models to inform public health policies on how best to mitigate the Zika outbreak in Latin America and beyond (vaccines, vector control) and to anticipate and prepare for the Zika impact on health care systems.
Using data obtained from the MERG study (see also objective I) we will model various aspects of the Zika outbreak in Latin America including the extent and estimate DALY of CZS, the extent of neurological complications and their impact on health care utilisation (based on our studies under objective II), the role of non-vector transmission in Zika virus dynamics (based on the evolving literature and findings of our studies on sexual transmission), vector parameters based on viral fitness (linked to our studies on viral fitness), vector control strategies (Wolbachia/genetically modified mosquitoes) for Brazil, optimal control bundles to mitigate future outbreaks, in particular in Latin American cities and burden of disease by age group and location to inform vaccine developers (based on results of our studies on burden of disease). The results of these efforts will be translated into policy-briefs and health-policy recommendations.
Objective 10: To develop novel, wash-in detergent formulations and long-lasting plastic technologies containing repellents for the treatment of clothing and other wearable repellent technologies for the protection of pregnant women against Aedes mosquito bites.
This part of the programme zooms in on protective clothing as a fast and generic preventive strategy against Aedes mosquitoes transmitted diseases. In several cohorts, including pregnant women we will assess the acceptance of proposed wearable repellent technologies. We will investigate and develop novel detergents containing repellents that can be used during laundry to allow active repellents to be applied to clothing for protection and we will investigate new wash-resistant technologies, including novel silica-shell, polymer fibres and microencapsulated formulations to determine whether repellent active ingredients can be retained in fabrics for multiple washes. New plastic wearable repellent technologies will be developed and tested including flip flops, wrist bands, necklaces using a plastic silica technology for protection against Aedes mosquitoes. Finally, this part of the programme also includes a modelling study to determine what level of protection (i.e. reduction in biting rate) is required to reduce Zika transmission in pregnant women.
Objective 11: To establish a Latin-American and Caribbean network together with other EU funded Zika consortia for emerging infectious diseases preparedness and response equipped to support a rapid and coherent research response to the Zika outbreak in the short term, and to other vector-borne and emerging infectious disease outbreaks in Latin America in the long-term.
This objective is specifically included to ensure that the consortium, the networks built, activities performed and results obtained are leveraged into establishing a Latin-American EID Preparedness and Response network in the region beyond Zika. To this purpose, we will together with ZikAlliance and ZIKAction collaborate with regional and international networks in order to leverage synergies, share knowledge and tackle regulatory bottlenecks. Where possible, we will make use of input and data from peer networks and research databases with the aim to speed up evidence generation and improve research efficiencies. This includes GLOPID-R, PREPARE, the Global Health Network, PAHO, et cetera. Under this objective, we will also include the development of a sustainability plan that will allow PLAN to continue to be impactful during and beyond the funding period of ZikaPLAN and the other EU Zika projects.
Objective 12: To promote and exploit the ZikaPLAN project results and those from the other EC funded Zika consortia associated Latin American and European RTD efforts and make research results available to the external stakeholders of the network.
Objective 12 deals with our activities aimed at promoting awareness and uptake of the (intermediate) results generated by the project at the level of our most important stakeholders. Here, we will engage into dialogue with patients, policymakers, health authorities, peer researchers and networks, pharma and biotech industry etc. Using various targeted communication media and tools we will create and maintain links and communications with our (envisaged) partners and potential future collaborators within Latin-America, and globally. Together with ZIKAlliance and ZIKAction we will from a powerful collaboration as envisaged by the Call Topic.