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HERACLES Report Summary

Project ID: 602051
Funded under: FP7-HEALTH
Country: Italy

Periodic Report Summary 2 - HERACLES (Human cystic Echinococcosis ReseArch in CentraL and Eastern Societies)

Project Context and Objectives:
Cystic Echinococcosis (CE), a chronic helminthic disease caused by the infection with the larval stage (metacestode) of the tapeworm Echinococcus granulosus complex (Egc), is one of the most widespread zoonotic diseases. In the EU, two forms of echinococcosis are clinically recognized in humans: CE, caused by E. granulosus complex and alveolar echinococcosis caused by Echinococcus multilocularis. However, human CE is by far the most prevalent and probably accounts for more than 95% of the estimated 2-3 million global cases with 200,000 new cases diagnosed annually.
In many parts of the world, however, CE causes severe healthcare and economic losses due to treatment costs, lost wages, and livestock-associated production losses. In the European Union (EU) and adjacent countries (AC), CE is endemic and highly endemic in southern and eastern countries such as Spain, Italy, Greece, Macedonia, Bulgaria, Moldova, Romania and Turkey. In Eastern Europe, the number of CE human cases has dramatically increased in recent years, with high endemicity in pastoral communities. Thus, within EU, some southern countries (such as Spain and Italy) and eastern countries (such as Bulgaria, Romania and Turkey) are those where human CE is still a major health and economic problem.

The main objectives of HERACLES are:
• Identify by ultrasound screening the population affected by CE in endemic rural areas of eastern European countries, such as Romania, Bulgaria and Turkey;
• Create national registries in eastern European countries for the surveillance of CE to provide baseline data for risk calculations and to establish a prospective case retrieval;
• Establish a representative collection of genetic Egc isolates and blood/serum/plasma samples from animal and human CE patients and related databases;
• Validate new molecular-based POC-LOC kits for immunological surveillance, rapid diagnosis and follow-up in humans and animals;
• Identify factor/s associated with CE response to therapy or lack thereof through host-parasite interplay (parasite virulence vs human immunity);
• Increase drug bioavailability in an in vivo model, to shorten the course of antiparasitic (ABZ based) treatment in CE and to synthesize a new enantiomeric drug based on ABZ.

These activities will improve our understanding of the biological mechanisms underpinning pathogenesis, in accordance with the aims of this biomedical call, and will translate this understanding into easy-to-use molecular based kits (Immuno-chromatographic and Lab-on-a-chip kits) for the diagnosis, clinical management and follow-up. The results from HERACLES will support governments, the European Commission and related European agencies such as ECDC to harmonize data collection, monitoring and reporting of CE, according to the EU legislation.
HERACLES is designed to investigate the host-parasite interplay while at the same time mapping the epidemiology of the infection and improving its diagnosis, clinical management and follow-up. HERACLES will address all these aspects at the same time thanks to the interdisciplinary expertise of its members thus making a direct impact on the health care system of the CEE countries involved in the project. Any lessons learned are likely to be applicable and useful for other countries where CE represents an important health problem such as the North African countries (e.g. Morocco, Algeria, Tunisia, Libya). Indeed, given the peculiar pathogenesis of CE and the lack of effective control programs, patients suffering from CE will be seen for many decades to come.

Project Results:
WP1. The prevalence of CE was assessed in rural areas, by means of ultrasound screening in Bulgaria, Romania and Turkey. The surveys preparation was carried out according to study protocols, each individualized to meet the particular needs and local situation in each country (logistics and availability of treatment procedures) while maintaining an homogeneous structure. Data collection during screening activities and coding of samples and ultrasound records are the same for each team.
The organization of the surveys has been supported by UNIPV (WHO CC for the clinical management of CE). All screening campaigns were carried out within the scheduled timeframe and exceedingly reached the planned population size, thanks to the excellent work that teams’ PIs did with local authorities and press agencies. Biological samples were collected as per protocol by each team.
In the first 36 months, 16 ultrasound surveys have been conducted in Romania, Turkey and Bulgaria.
In 2014-2015, 24,696 people were screened in Bulgaria (n=8,602), Romania(n=7,470) and Turkey (n=8,624). We identified 248 positive/possible cases that will be evaluated on follow-up. As suspected, really variable prevalence was detected within countries. Total CE detected by imaging was 0.36%, 0.46% and 0.64% of the rural population from Bulgaria, Romania and Turkey, respectively. Rural population affected by CE has been preliminary estimated (data not corrected by age and gender) at 175,000 (95% CI 128,000-233,000) in these three countries.

WP2. Protocols for the collection, storage and treatment (DNA extraction from cyst material, serum separation, etc.) of samples have been described and delivered to the partners. Clinical protocols for the definition of cohorts and samples have been already elaborated. A bio-bank facility has been built up and hosted by Partner 3 which is currently filled with 1,500 samples.
Two databases have been developed: the European Register of Cystic Echinococcosis (ERCE; and the CYSTRACK ( database for the collection of clinical data from retrospective patients. During the first 36 months, 947 patients were enrolled in ERCE.
Regarding the work on serological detection of CE, 2B2t and five additional recombinant antigens have been produced in an automated fermentor and purified in a cost effective manner. An ELISA protocol has been produced and preliminary tested with a panel of human sera to evaluate their usefulness. The first trials in Immunochromatography have been already undertaken for the antigen 2B2t by partners 3 and 9, resulting in a prototype preliminarily validated. A new recombinant AgB1B2Ag5 has been produced and it is currently under testing in ELISA and VirClia®.

WP3. Thanks to the biological samples available from the surveys, this gives for the first time the possibility to collect accurate clinical data and related parasitic samples that can be genotyped. A methodology on CE genotyping has been implemented, standardised and five-hundred parasitic samples of human origin are under analysis. A suitable and sensible method to efficiently separate exosomes from plasma and distinguish proteins specifically enriched in exosomes has been recently optimized. Quantitative proteomic analysis will follow.

WP4. Animal model has been successfully established via intraperitoneal injection of protoscoleces. After 9 months developed hydatid cysts has been detected. A patent on salts of benzimidazole has been obtained and drugs were synthetized.

WP5. Intense and very focused disseminating and training activities have been implemented by all the partners targeting the population screened during the Surveys in Romani, Bulgaria and Turkey (n=24,696). The main tools were flyers, posters, seminars and other graphical material. The project web site is updated with a lot of material and information on the activities of HERACLES.

Potential Impact:
CE is a neglected parasitic disease that urgently needs attention. For this reason the impact of HERACLES will be:
• Decrease the human burden of CE in high endemic rural areas of eastern European countries as a result of the public health measures implemented after the screening and follow-up activities;
• Provide baseline data for risk assessment and establish a prospective case retrieval by setting-up national registries for the surveillance of CE;
• Validate new molecular-based kits with impact on the immunological surveillance, rapid diagnosis and follow-up;
• Identify factor/s associated with CE response to therapy or lack thereof, which will lead to savings in monetary and healthcare costs;
• Increase ABZ bioavailability in an in vivo model and synthesize a new enantiomeric drug based on ABZ, with impact on CE treatment.

The results are expected to shed light on the biological mechanisms of host-parasite relationship and their role in the CE pathogenesis to ultimately improve the diagnosis and treatment of a puzzling condition. The results from HERACLES will support governments, the European Commission and related European agencies such as ECDC in their effort to harmonize data collection, monitoring and reporting of CE, according to EU legislation. One of the most effect will be the reduction of the disease burden in humans and saving money for the health system in the CEE.

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