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Brussels, 17 October 2006
IP/06/1413 announces €28.3 million of new funding for research projects in the field of avian and pandemic influenza. This MEMO outlines the 17 projects selected for funding. Final budget figures (EU contribution) and project details are subject to the final signature of contracts, and so may change. A glossary of terms used in the project descriptions is found at the end of the document.
a) Animal health research projects
The primary aim of this project is to develop better avian influenza vaccines through live or vector vaccines that could be mass applicable through spray, drinking water or eye drop. These vector vaccines would offer considerable advantages: mass applicable, less labour intensive and animal friendly application, protection by local and systemic immunity and less interference with eventual maternal antibodies, more complete protection through cellular and humoral immunity, faster onset of immunity when used in face of an outbreak and cheaper production methods. The project exploits recently acquired knowledge concerning the molecular characterization of the viruses resulting in the construction of candidate strains with highly interesting efficacy and safety profile. Safety and efficacy with Newcastle disease (NDV) vectors and infectious laryngotracheitis (ILT) vectors both for H5 and for H7 inserts have already been demonstrated in vivo. Such vaccines would also have marker aspects which will allow differentiation of vaccinated from infected animals (DIVA principle). Sensitive, specific and easy to use marker diagnostic tests that will be compatible with the vaccines will also be developed.
The project focuses on technology transfer and training and will: i) Organise technical workshop to facilitate technology transfer particularly in the field of molecular diagnostic tools for pathogen detection and differentiation, to reinforce epidemiological analysis for monitoring and modelling of Avian influenza especially and to respond to outbreaks with infectious diseases of livestock in general. ii) Provide training through organization of seminars and short term courses in well qualified laboratories of a number of member states of European Union and iii)
Organize technical workshops, courses and training in the partner countries to improve the technical experimental level of the staff and laboratories in charge of livestock infectious diseases. The consortium includes seven European and seven developing countries as well as FAO/IAEA, OIE and FAO animal health programmes.
FLU-LAB-NET provides new opportunities for enhancement and reinforcement of the Community Reference Laboratory and National Reference Laboratory network for avian influenza (AI) within the EU. This will strengthen harmonisation and development of laboratory and diagnostic methods, coordination of research efforts and sharing of expertise. Rapid responses to national and global emergencies with data sharing will be key areas of exploitation, contributing to a European laboratory task force capability for AI in animal species. Rapid, formal interactive communications will be addressed through web-based forums. Laboratories involved in influenza research in domestic mammals will also participate. FLU-LAB-NET will also foster formal links and coordinate with corresponding human, swine and equine influenza networks. FLU-LAB-NET provides opportunities for identification and development of the complementarities of global, multi-disciplinary influenza research programmes. Strategically important third country and INCO partners are also included in this network, in order to raise laboratory standards and benefit from knowledge sharing. This will promote greater trust, understanding and early access to information that may be of importance to both veterinary and public health in the EU.
Highly pathogenic avian influenza viruses (HPAIV) have acquired the unprecedented and alarming capability to infect humans. The presence of HPAIV in wild birds poses a continuous risk for poultry and fatal human infections. Due to the lack of sufficient knowledge, attempts to avoid or contain HPAIV outbreaks have been largely unsuccessful. Full understanding of the ecology and pathogenesis of HPAIV requires a multidisciplinary approach determining host-pathogen interactions and the role played by the host immune response. To this end, the FLUPATH consortium was established. FLUPATH is composed of 6 National Reference Laboratories for avian influenza, 5 academic institutions and 2 institutions specialized in animal science and health. The participants, with expertise in chicken genomics, micro-array technology, pathology, receptors, innate immunity and chicken immunology, will use multidisciplinary and complementary approaches to address key problems and unanswered questions with respect to the ecology and pathogenesis of avian influenza.
FLUPATH will provide knowledge and tools for new strategies which will be tailored for the control and management of avian influenza at the European and International level.
Avian influenza (AI) represents one of the greatest concerns for public health that has emerged in recent times. The ongoing Asian H5N1 outbreak is a serious concern for food security and human health world-wide. Evidence is growing that highly pathogenic H5N1 is not only spreading by poultry trade but is also carried by wild birds. Recently, H5N1 infected wild birds, mainly waterfowl, have been detected in several countries in the European Union. These findings indicate that H5N1 is becoming more and more endemic in wild birds. The finding of a cat, a stone marten and raptors that died as a result of H5N1 infection, highlight the consequences of this development. Questions are being raised about the risk of contamination of surface water for animals and humans.
At present there is a lack of scientific data on the survival of AI viruses in fresh and processed poultry products, in feathers and down, and in poultry manure and litter. Because of the lack of data, a proper assessment of the risk posed by these materials for spreading or reintroduction of disease is impossible. The objective of this proposal is to generate data on AI virus stability and the effect of biological, chemical and physical parameters there upon. Moreover, it will provide knowledge about virus survival under different physical conditions. This will enable proper risk assessment of the trade in treated and fresh poultry commodities and poultry litter.
The primary goal of this project will be the development and application of technologies to combat avian influenza (AI) infections. A study will be conducted to establish the effectiveness of the current EU surveillance and early warning systems for AI and then to develop blueprints for improvements to these programmes in disease free periods and during outbreaks. The model will include criteria for harmonised diagnostic tests for on-farm outbreak investigation. To complement this study a range of diagnostic tools will be developed, evaluated and validated alongside the evaluation of a range of commercially available tests. This will include high throughput techniques for molecular and serological testing, penside testing and simplified tests for use in laboratories with limited resources or experience. Efforts will particularly focus on the validation of tests for use on clinical materials derived from Anseriformes, other wild birds species and some selected mammalian species.
The present world wide avian influenza crisis has highlighted the need for comprehensive training and the transfer of technology to accession and INCO countries with the clear goal of aiding these countries in combating AI with the most up-to-date diagnostic and disease management procedures. The FLUTRAIN project aims to at two levels. It will firstly approach the need for training by providing three workshops over the duration of the project (3 years) that will call on experts in the AI field to pass on their valuable expertise in the diagnosis and management of AI to participants from accession and INCO countries. Training opportunities will also be provided in partner labs in order to consolidate the information and practical experience gained during the workshops. In addition a CD-ROM will also be prepared containing essential information provided during the workshops. A website will be developed which will enable participants and the general public to access the training programs and will include on-line discussion fora between trainees and trainers. The second goal of FLUTRAIN will be the transfer of technology to accession and INCO countries. This will include the provision of new, simplified and cost effective diagnostic methods and reagents. It will also involve the transfer of deliverables, both for serological and virological diagnosis that have been (or will be) developed in three European projects namely AVIFLU, Lab-on-site and FLUAID. The consortium is made up of 19 members which includes 2 SMEs. The participants can be identified as trainers (12) or recipients (7). Given the rapid evolution of AI on a worldwide level, remaining recipient countries will be identified.
INN-FLU will increase the understanding of host susceptibility and disease pathogenesis of hpAIV in chickens. The project is based on four columns: (i) characterization of the virulence of an hpH5N1 strain isolated from a Thai eagle in several species, (ii) determination of host factors influenced by AIV infection during the very early phase of infection, (iii) research on whether different lines of chicken breeds show differences in resistance to hpH5N1 infection, and (iv) investigation of contact points between wild birds and domestic free range poultry and migratory behaviour of birds based on satellite tracking. The objective is to better understand disease pathogenesis, virulence determinants, and host-pathogen interactions and to define the molecular basis for host specificity in chickens. The major focus with regard to host-pathogen interactions will be on the innate immune response in birds and the role of individual influenza virus proteins involved. Experiments will also address the question whether HA molecules from non-H5 and non-H7 strains can give low pathogenic viruses the potential to become highly pathogenic. The scientifically outstanding partners of the consortium know each other well and have already collaborated successfully in earlier research projects. It is to be expected that the project will deepen our knowledge of influenza virus infection and transmission in birds substantially.
NEW-FLUBIRD will establish a European network of virologists and ornithologists, data managers, epidemiologists and modellers, in order to provide “early warning and risk assessment systems” in real time for the threat posed to animal and human health by avian influenza (AI) viruses from migratory birds. The network will largely build on, and extend existing collaborations between AI virologists in Europe and international ornithological organizations active within and outside Europe including Africa, Middle East and Eastern Europe. Epidemiological assessments will thus cover the major flyways of migratory birds over Europe and the areas from which migratory birds in Europe migrate. Furthermore it will focus on experimental infection of selected migratory bird species with HPAI virus H5N1 and possibly other relevant HPAI viruses, to determine pathogenesis and excretion profiles. In turn, the ornithological studies will construct migratory route maps and set up systematic sampling from healthy wild migratory birds thus providing insight in volume and timing of migration as well as key sites of those migratory bird species that pose the highest risk of transmitting HPAI viruses to poultry in Europe. Finally, NEW-FLUBIRD will seek integration with global early warning systems developments like GLEWS of FAO and WHO (Global Early Warning System) and GNAIS of WCS (Global 3 Network for Avian Influenza Surveillance).
Ducks play a major role in the epidemiology of AI since wild waterfowl, including ducks, constitute the natural reservoir of all subtypes of influenza and is considered as the “Trojan horse” of Asian H5N1 HPAI. The NOVADUCK project brings together both private (2 companies, 1 SME) and public sector stakeholders (European reference laboratories and agencies on AI) from 4 European countries towards the aim of developing and evaluating new highly protective and cost-effective avian influenza live vaccines for ducks, based on live viral vectors and in line with the DIVA strategy (Differentiating between Infected and Vaccinated Animals). Viral vectors will be engineered to optimise both their immunogenicity and protective capacities. Vaccine candidates will be pre-screened for safety and immunogenicity using newly developed duck-specific immunological tools. The best vaccine candidates will be evaluated for efficacy in a HPAI challenge-model in ducks. Serological DIVA test able to detect infection in vaccinated duck flocks will be generated and the effect of vaccination on genetic and antigenic drift of H5N1 will be assessed.
The RIVERS project aims 1/ to gather data on the survival of avian influenza viruses, in particular A(H5N1), in the natural environment; 2/ to generate scientific knowledge about the survival of avian influenza viruses, in experimental settings; 3/ to provide figures about the effect of various food processing methods (drying, salting, using acidic compounds etc .....) on influenza virus survival; and 4/ to elaborate models about the survival of avian influenza virus, mainly on A(H5N1), in natural environments to demonstrate their perpetuation in nature both in biological and environmental reservoirs. Once gathered, and fully analyzed, it is envisaged that the data corpus will provide researchers, risk managers and policy makers with an invaluable source for the prevention and control of avian influenza A(H5N1) at times of epizootics, and endemic but sustained viral circulation and at times of post crisis management..
b) Human health research projects
The ultimate objective of the EUROFLU project is to fill the knowledge gaps concerning the molecular factors and mechanisms of highly pathogenic avian influenza virus (HPAIV) transmission and pathogenesis. This objective will be reached through integration of interdisciplinary experimental research approaches and bioinformatics analyses. The project has three major aspects. One is to identify, characterize and validate HPAIV-factors that are involved in the recognition and targeting of the virus to the cellular host receptor. Since the latter varies between humans and different animals, it determines which species the virus attacks. The second objective is to reveal viral and cellular factors and mechanisms that regulate virus replication within the infected cell and can therefore determine cell tropism (the way the virus enters only certain kinds of cells and not others) and – again – host specificity. Focus will be on virus/host-interactions including viral factors from different HPAIV (H5 and H7, and H5/H7-reassortants). A third aspect is the use of mouse and chicken models for in vivo analysis of HPAIV infections of mammals and birds to monitor HPAIV-transmission and pathogenicity within organisms. Overall, the project covers many of the major aspects relating to the pathogenicity of avian influenza virus, and the process of flu infection, which in the medium term may lead to new treatments.
This project aims to identify and study the essential viral and host factors that determine the outcome of an influenza infection – so, unlike vaccine projects, which try to get a solution from the virus side, FLUINNATE approaches the problem from the host side. Influenza A virus (FLUAV) enters the human respiratory tract and must replicate in the face of multiple innate immune defence mechanisms to establish infection in vivo. Successful viruses must adapt and evolve the capacity of circumventing the body's antiviral interferon (IFN) response. The project will test the hypothesis that the speed and efficiency by which a given virus circumvents these early host responses determine its host range and the severity of the disease it causes. Virus-induced inflammatory mediators (like IFN) exert powerful effects against FLUAV in the lung. However, they may also worsen the patient's symptoms. The researchers will analyze viral factors governing the innate antiviral cytokine response and determine the impact of these factors on virus growth, cell survival and pathogenicity. Human, avian and pig FLUAV will be used in animal models and in cell culture systems, such as human airway lining cells. The present studies should generate important information that will help to better understand the processes involved in the emergence of lethal influenza viruses and to develop efficient control measures against these devastating pathogens.
Currently circulating H5N1 avian influenza viruses could cause a devastating pandemic if they became transmissible between humans. It is therefore crucial to understand the mechanisms whereby influenza virus adapts from avian to human hosts. Several recent studies have highlighted the importance for transmissibility of mutations in the proteins of the viral replicative machinery. This project will undertake a comprehensive study of the molecular structure and function of the influenza virus polymerase with the aim of understanding how it adapts during inter-species transmission. The researchers will focus on determination of the atomic structure of two important viral proteins: polymerase and the trimeric complex. Through advanced functional genomics, studies in animals and bioinformatic methods they will identify mutations that are particular important for transmission between different species. This will help to elaborate new molecular tools for influenza research and to design strategies for screening novel anti-influenza drugs targeting polymerase. The overall goal of the project is to provide new knowledge that will allow to better monitor and combat the emergence of pandemic influenza strains.
The novel adjuvant IC31TM stimulates both strong T cell and B cell responses and has a broad mechanism of action as well as an excellent safety profile. Pre-clinical animal studies with inter-pandemic (seasonal) influenza vaccines revealed that IC31TM induces long lasting cellular immune responses characterized by high levels of IFN-producing T cells and increased haemagglutination inhibition antibodies – a hallmark of the body's defence against the virus. At the same time, a more than 10-fold reduction in vaccine (antigen) dose could be achieved. This is important, since vaccine production capacity would be an important bottleneck in a potential epidemic. The consortium plans to perform thorough pre-clinical testing in order to prepare for clinical studies (Phase 1 and human challenge studies) with a whole inactivated virus vaccine based on a pandemic influenza virus strain (H5N1) produced in cell culture and adjuvanted with IC31TM. In contrast to the currently most widely used procedure of influenza virus production in eggs, the main benefits of cell culture production are in immediate and more reliable availability, constant quality of substrate and reduced risk of contamination. Successful clinical studies would provide safety data for the use of the novel adjuvant IC31TM and proof-of-concept for improved immunogenicity and dose sparing. In contrast to the common adjuvant Aluminium hydroxide, the combination of whole virus and IC31TM is expected to provide broader immunity due to the induction of T cell responses against conserved epitopes.
This project aims to characterize genetically engineered H5N1 vaccine candidates that are – through the deletion of a certain protein (NS1) at the same time unable to replicate and also exert a self-adjuvant effect: The genetically engineered virus more strongly stimulates the production of certain substances that help increase the body's immune response. While traditional vaccines need to be produced in chicken eggs, the vaccine candidates of this consortium will be produced in cell culture – an easier and faster way to get large quantities of vaccine. Given intra-nasally, it is expected to provide both systemic immunity and local immunity at the site of virus entry (on the mucosa of the respiratory tract). After pre-clinical assessment in ferrets and macaques (including the development of novel sensitive immunological assays), human phase I and IIa clinical trials as well as a human challenge study with attenuated H5N1 virus will be conducted.
The overall aim of PANFLUVAC is to construct vaccine delivery systems for intranasal and injectable vaccines. New H5N1 vaccines are to be based on well-established virosome technology - proven its worth for vaccines against seasonal influenza – as well as whole virus vaccines. This will permit direct comparison of these promising approaches. An intranasal vaccine would offer a very convenient and low-tech way of delivery, and whole virus vaccines promise to activate more broadly the different "branches" of the human immune system. Vaccine potency will be enhanced by a novel adjuvant - an agent that enhances the body's immune reaction to the vaccine - called ISCOMs. PANFLUVAC aims to generate the first intranasal H5N1 vaccine within the first 12 months of the project. The PANFLUVAC project is also designed to facilitate rapid modification of the vaccine in the face of virus drift. Within the preclinical evaluation, the new vaccines will be tested for the degree of cross protection they offer against different influenza virus variants. Overall, PANFLUVAC offers a generic vaccine development system to provide safe and efficacious vaccines against influenza.
antiviral interferon response = a general defence mechanism of the body (involving the secretion of a several substances, among them interferons) against all kinds of viruses
cell tropism = the specificity of the virus for certain kinds of target cells which it infects (the influenza virus for example infects the cells lining the airways and lungs, but will not infect muscle cells).
ecology = pattern of relations between organisms and their environment
epidemiology = all factors controlling the presence or absence of a disease
host susceptibility = the receptiveness of the human or animal host for the disease (in this case for example the fact that humans can only be infected with certain but not with other viruses).
In vivo = in live animals or humans (as opposed to in vitro = in the test tube, in cell culture)
pathogenesis = the mechanism by which certain factors cause disease
polymerase = a virus protein that is essential for its replication
self-adjuvant = an adjuvant is a substance that is added to a vaccine in order to increase the body's immune response to this vaccine. This will usually allow achieving efficient protection from the disease with a lower amount of vaccine. In this special case, the genetically engineered vaccine virus has properties that by themselves (without the addition of an extra adjuvant) increase the body's immune response.
Virosome = virosomes represent reconstituted empty influenza virus envelopes that cannot replicate but contain the important antigens HA (haemagglutinin) and NA (neuraminidase) that elicit the immune response and can therefore serve as an efficient vaccine.