Animal Models and Relevance/Predictivity: how to better leverage the knowledge of

the veterinarian field

“Les Pensières”Fondation Mérieux Conference Centre

Veyrier-du-Lac - France

October 10-12, 2011 Steering Committee:

• Dominique Buzoni-Gatel

•Thierry Decelle

•Catherine Dutel

•Patrick Hardy

•Xavier Montagutelli

•Jacques Louis

Scientific Report : Valentina Picot

Welcome Letter

October 10, 2011

Dear Participant,

It is our pleasure to welcome you to the symposium entitled:

‘Animal Models and Relevance/Predictivity: how to better leverage

the knowledge of the veterinarian field’

in Fondation Mérieux’s Conference Center “Les Pensières.” We hope you will enjoy this meeting, which brings together some of the world’s foremost experts.

The format of the discussion is intended to generate discussion and interaction among participants and to foster the dissemination of new information on this topic. The conference will provide an opportunity for specialists to exchange their knowledge and experience through collaboration with researchers from around the world.

Over the next three days, the team at Les Pensières will be on hand to help you with any questions you may have and to make your stay and conference as comfortable and valuable as possible.

Benoît Miribel Director General Fondation Mérieux

For more information: www.fondation-merieux.org

Background and rationale

Theyear2011isthe250thanniversaryofthefirstveterinaryschoolinLyon.ClaudeBourgelatwasitsfirstdirectorandtheinventoroftheconceptofcomparativebio-pathologyaswrittendownintheDeclaration of the Veterinary School of Lyon, 1761. Ars Veterinaria, historically focused on livestock and more empiric, was opposed to the science of human medicine. Nowadays, however, the development of the concept «one world, one health» reconciled both Ars and Science.Biomedical research, as an experimental science, has been relying on animal models. Some people claim that these animal-based models are not relevant and not ethical. However, by working on comparative anatomy and physiology, major progress in medicine has occurred. Infectious agents, which ignore species boundaries, can be equally studied in animals and in humans. The deciphering of the human genome and those of several animal and vegetal species provide a tremendous development of biological science. But as any models, predictivity does not mean direct transposition of results. Nonetheless, similarities between species are relevant enough to permit translational research, from the cells and tissues to animals, then to humans. Despite the efforts and the successes to reduce the use of animals in research, it is not possible to avoid completely using animals to improve human health. Whole organisms are still necessary to explore physiology and pathology, toevaluatetheinteractionsbetweenorgansandfunctions,andtoassesstheefficacyandsafetyofnovel drugs and vaccines. The combination of several models is done to increase the predictivity of modelsandtheconfidenceinthescientificoutcomes.Inthiscontext,basicandappliedbiomedicalresearchbenefitstobothhumansandanimals.Considering the global sanitary situation, emergence of new infectious diseases is accelerating. The last sanitary crises came from animals: AIDS in the 80s, BSE in the 90s, and SRAS in the 2000s. Pandemicfluisstillaconstantconcernforworldwidehealthorganizations.One of these challenges is the spread of infectious diseases that emerge (or re-emerge) from the interfaces between animals and humans and the ecosystems in which they live. The OIE, WHO and FAO have prepared a consensus document on global measures needed to coordinate medical and veterinary health policies more effectively, taking into account new requirements to prevent and controlzoonoses:«AStrategicFrameworkforReducingRisksofInfectiousDiseasesattheAnimal–Human–EcosystemsInterface»,14October2008.Attheanimal–humanhealthinterface,ecosystemscontributetothedevelopmentofoutbreaksandthe dissemination of infectious agents. Development of arboviroses is one of the consequences where both animals and human beings are concomitantly affected. The objective of the workshop is to review the importance of the animals in the basic and applied research, the interactions between veterinary medicine and human medicine, the susceptibility to common infectious diseases as illustrated by the concept of «one world, one health». The first daywill bededicated to animalmodels and their relevanceand to get anoverviewoftranslational research. The second day will focus on common infections to animals and human beings and the leverage and complementarities between veterinary and human medicine.

Scientific Programme

Monday 10 october 2011

17.30 - 18.30 Registration

18.30-18.40 Welcome Address Fondation Mérieux

18.40-19.20

Keynote lecture:Infectious disease research in livestock: models, targets and beyond

Christian MENGE

19.30 Welcome dinner

Session 1 Societal issues08.30-09.40 ChairedbyThierryDecelle

Tuesday 11 october 2011

08.30 - 08.50 The “One Health One World” concept and strategy Thierry PINEAU

08.50 - 09.05 Discussion

09.05 - 09.25 Responsibility in the use of animals in biomedical research Katheryn CHAPMAN

09.25-09.40 Discussion

Session 2 Recent technological advances in the study of animal models of human diseases09.40-11.50 ChairedbyXavierMontagutelli

09.40-10.00 The mouse clinics, improving phenotyping Yann HERAULT

10.00 - 10.15 Discussion

10.15-10.45 Coffee break

Scientific Programme

10.45-11.05 Humanized mouse models to study human diseases Jim DI SANTO

11.05 - 11.20 Discussion

11.20 - 11.35 Advances in in vivo small animal imaging Alain LEPAPE

11.35 - 11.50 Discussion

Session 3 Animal models for translationl biomedical research11.50 - 16.05 Chaired by Patrick Hardy

11.50 - 12.10 Pigs models of cystic fibrosis David K. MEYERHOLz

12.10 - 12.25 Discussion

12.30-14.00 Lunch

14.00-14.20 The use of animal models in the development of vaccines Volker GERDTS

14.20-14.35 Discussion

14.35-14.55 Animal models for Parkinson disease: Brain repair Philippe NAVEILHAN

14.55-15.10 Discussion

15.10 - 15.30Animal models of inherited retinal degeneration to test novel therapeutic approaches

Jacques MALLET

15.30-15.45 Discussion

15.45-16.10 Coffee break

Scientific Programme

Wednesday 12 october 2011

16.10 - 16.30 Animal models for type I diabetes Malin FLODSTROM-TULLBERG

16.30 - 16.50 Discussion

16.50 - 17.10 Animal models in influenza vaccines testing Carla HERBERTS

17.10 - 17.30 Discussion

17.30 - 17.50Animal Models in Preclinical Evaluation of Sanofi Pasteur Flavivirus Vaccines

Jean LANG

17.50 - 18.10 Discussion

19.00 Dinner

08.30 - 08.50 Animal models for multiple sclerosis Randolph NOELLE

08.50 - 09.05 Discussion

09.05 - 09.25 The use of genetic reference population in metabolic diseases Philippe CETTOUR-ROSE

09.25-09.40 Discussion

09.40-10.00 Transgenic pigs as models for translational biomedical research Eckhard WOLF

10.00 - 10.15 Discussion

10.15-10.45 Coffee break

Session 4 Physiopathology of spontaneous animal diseases08.30-10.45 ChairedbyAlainLepape&ThierryPineau

Session 4 Physiopathology of spontaneous animal diseases16.10-17.30 ChairedbyAlainLepape&ThierryPineau

Scientific Programme Session 5 Animal models of infectious diseases

10.45-17.30 ChairedbyDominiqueBuzoni-Gatel&Pierre-AndréCazenave

10.45-11.05The influence of host-microflora interactions in pathological processes

Nadine CERF-BENSUSSAN

11.05 - 11.20 Discussion

11.20-11.40 The cotton rat model of respiratory viral infections Jorge C. BLANCO

11.40-11.55 Discussion

11.55 - 12.15

Using wild mice to takle genetic control of resistance to infectious diseases (West-Nile, Rift Valley Fever, Plague)

XavierMONTAGUTELLI

12.15 - 12.30 Discussion

12.30-14.00 Lunch

14.00-14.20 Animal models for Borreliosis Reinhard STRAUBINGER

14.20-14.35 Discussion

14.35-14.55 An aerosol model of tuberculosis in rats for testing new drugs Radha K. SHANDIL

14.55-15.10 Discussion

15.10 - 15.30

Primates models of SIV infection: different susceptibility of green monkeys and rhesus macaques to develop AIDS after SIV infection

Michaela MüLLER-TRUTWIN

15.30-15.45 Discussion

15.45-16.05 Coffee break

Scientific Programme

16.05 - 16.25 Animal models for understanding immunity to Malaria Jane LANGHORNE

16.25-16.40 Discussion

16.40-17.00

Animal models for the analysis of immune responses to Leishmaniases, relevance to human diseases

David SACKS

17.00 - 17.15 Discussion

17.15 - 17.30 Concluding remark and end of the meeting

Keynote lecture

Infectious disease research in livestock - Models, targets and beyond

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Infectious disease research in livestock - Models, targets, and beyond

Christian MENGEFriedrich-Loeffler-Institut - Federal Research Institute for AnimalHealth - Institute of Molecular Pathogenesis - Germany

The advantage of performing infection research in the target species when using livestock is a hallmark of veterinary research. Moreover, large animal models offer the distinctive opportunity to obtain results with high biological relevance in translational medicine and as comparative models in biomedical research. Models: As compared to rodents a considerably longer life-span of livestock supports investigations on chronic infections in close-to-natural pathogen-host settings. The possibility of monitoring intra-individual kinetics minimises the biological variability of data sets. Parallel assessments of multiple parameters reduce the number of animals needed. Non-invasive methods limit the animals´ stress and improve the quality of data sets. Diagnostic procedures conveyed from human medicine ease translation of results. Current protocols togeneticallymanipulatelivestockmakemodifiedanimalsreadilyaccessible to cutting edge research. Beside technical advantages genetic, morphological and functional commonalities increase the biological relevance of large animal models. Aetiology and pathogenesis of naturally occurring infections are similar in humans and livestock, e. g. bovine tuberculosis, norovirus-induced enteric diseases in calves, mycoplasma and chlamydia infections of the bovine lung. Prion diseases of ruminants mimic the pathophysiology of human neurodegenerative disorders, herpes¬virus infections, e. g. in swine, allow for studying factors that determine immunogenicity and latency. Targets: Infection research deploying large animals provided the basis for counteracting and preventing numerous infectious diseases in livestock e. g. by implementing vaccination strategies. Eradication campaigns eventually succeeded in the eradication of animalepidemicsasachievedforAujeszky’sDiseaseandBovineTuberculosis in some countries and for Rinderpest even on a global scale.Theappearanceofnewandtheemergenceofoldzoonoticdiseases urgently demands unveiling complex pathogen-host interactions in the natural host, i. e. the reservoir species. Formerly termed “comparative medicine” by Virchow, the contemporary “OneHealth”conceptisofmutualbenefitforveterinaryandhumanmedicineinordertojointlycombatemergingzoonoticdiseases.

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Beyond: Beyond efforts to protect humans from emerging zoonosesbyidentifyingtheinfectionsourceintheanimalpopulation, being able to predict the development and appearance ofzoonoticagentswouldprovidenovelopportunitiestoveterinary and human public health. Understanding the evolution of microorganisms - that may not even be pathogenic in their initial host - to become human pathogens will help to early implement effective countermeasures in the course of developing pandemics. Studying the mechanisms by which microorganisms adopt to commensal-like lifestyles in their reservoir hosts is of outmostimportance.Hostswitchingofinfluenzavirusesandestablishment of persistent intestinal infections in ruminants by enterohemorrhagic E. coli are current examples. Relevantlivestockmodels–withthespeciesinvestigatedbeingselectedaccordingtotheparticularrequirementsofthescientificquestions to be solved - embedded into the communication and collaboration between several disciplines from human and veterinary medicine possess the utmost potential to fuel progress according to the “One Health” concept.

Session 1

Societal issues

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‘One World - One Medecine - One health’: a strategy behind the concept ?

Thierry PINEAUINRA - France

While global change and the evolution of human societies (urbanization,humanpresence/settlementinallkindsofecosystems)favor the emergence (re-emergence) and spreading of infection diseases (epidemic diseases, vector-borne diseases) it became obvious for all international agencies (WHO, OIE, FAO) that future health threats and public health stakes are located at the Animal-Human-Ecosysems interface. Thus, in terms of research needs, the ‘One World, One medicine, One health’ approach has emerge as a common sense concept. But is it fully clear for all stake holders what this implies in terms of goals, priorities, administrative and financialsupportforresearch,educationandtraining?Behindthisintellectually challenging and promising concept lie a tremendous number of challenges which should be addressed collectively at a global scale. This presentation will be an attempt to identify true opportunities and priorities for the near future, while focussing on animal models. It aims at promoting the necessary cross-talks betweenmedicalandveterinary researchwhen facingconflictinginterests to feed the planet, to adapt to deep social evolutions, to preserve by various means the public health.

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Responsibility in the use of animals in biomedical research

Kathryn CHAPMANNationalCentrefortheReplacement,RefinementandReductionofAnimals in Research - UK

All scientists using animals in research have a responsibility to think abouttheirreplacement,refinementandreduction.Butwhatdoesthatactuallymeaninpractice?AttheNationalCentreforthe3Rsinthe UK, we use the 3Rs as a framework to stimulate innovation, to connectscientistsfromdifferentfieldsandsectorsandtoimprovescience. This presentation will use case studies to demonstrate thebenefitofthe3Rsbeingplacedattheheartofthebioscienceagenda. These case studies will range from cross-company initiatives in the pharmaceutical and chemical industries to reduce and replace toxicity studies through to international programmes to connectscientistsfromacademiaandindustryinspecificbusinessdriven problems that involve the use of animals in research. Many animal models have limitations in terms of their predictivity and translation to man and science is driving us to think more about the 3Rs. Taking responsibility for the use of animals in research does not hinder research or create bureaucracy but should be embraced to benefit basic research, drug development, safety testing andultimately, animals.

Session 2

Recent technological advances in the study of animal models of human diseases

Session 2

Recent technological advances in the study of animal models of human diseases

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The mouse clinics, improving phenotyping

Yann HERAULTInstitut de Génétique et de Biologie Moléculaire et Cellulaire France

Avec une génétique qui a débuté au début du 20eme siècle par l’établissement des premières lignées consanguines, et qui s’est renforcée par la manipulation des cellules embryonnaires souches et le ciblage génique dans les années 1990, (Prix Nobel en 2007), la souris s’est imposée, incontournable dorénavant dans le processus de recherche de la biologique contemporaine. Avec des centres entièrement dédiés à cet organisme modèle, elle permet d’aborder au moins 3 enjeux principaux de la génomique fonctionnelle 1) Améliorer notre connaissance du génome : la fonction des gènes dans les processus intégrés (développement, fonctions physiologiques, vieillissement …) et les fonctions des régions non-codantes,conservéeset/outranscrites;2)Identifieretcomprendrelesvariationsdugénomeàl’originedesmaladies;3)Proposerdenouvelles perspectives pour la société en recherche fondamentale, translationnelle, préclinique pour l’ innovation et le développement de thérapies, de médicaments.L’ICS a été créée en 2002 par le Professeur Pierre Chambon dans le but de proposer un outil haut débit et performant pour la génération et l’étude fonctionnelle, le phénotypage, de ces sourisgénétiquementmodifiées.Aufildesannéeslesprincipalesmissions de l’ICS, comme infrastructure de service, sont devenues: 1) D’être une plateforme de services pour la recherche combinant la capacité de générer, sur une grande échelle, des mutations cibléeschezlasourisavecl’analysephénotypiquecomplèteàhautdébit de la souris dans le but de faciliter la création, l’analyse et l’utilisationdumodèlede lasouris ;2)D’entreteniruneexpertisepertinente à la fois dans la recherche interne et les programmes de développement pour appuyer les activités de l’ICS dans le domaine de la mutagenèse, transgénèse, le phénotypage, la bioinformatique et l’analyse des données ; 3) D’être un centrede référence dans le domaine de la génomique fonctionnelle de lasourisetdelarecherchetranslationnelle;4)Depromouvoirlameilleureformationàlafoiseninterneetpourlesutilisateursafindegarantirlaprocédurelaplusefficacedanslerespectdel’éthiqueet du bien-être des animaux.

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L’ICS est ainsi capable de gérer et réaliser chacune des étapes clés d’un projet allant de la génération de souris génétiquement modifiées, leur maintien et amplification en animalerie, leurphénotypage et leur distribution. Elle peut également conduire des études précliniques pour la validation de cibles thérapeutiques, les tests de molécules et la détermination de leurs effets principales, secondairesoul’interférenceavecd’autresfonctions;desétapes-clé de la démarche pharmaceutique.

Depuis son ouverture l’ICS a contribué à la région de plus de 1000 modèles souris et plus de 500 projets de phénotypage pour les secteurs académiques ou privés. Depuis cette année elle a rejoint l’initiative PHENOMIN, lauréat des infrastructures nationales en Santé et Biologie dans le cadre des investissements d’avenir en 2011. Avec ces deux partenaires, l’ICS entre dans une nouvelle perspective et va renforcer son positionnement en Phenogénomique chez la souris. Elle contribuera notamment àl’initiative internationale du consortium de Phénotypage (IMPC, http://www.mousephenotype.org/) afin de créer la premièreencyclopédiedelafonctiondesgèneschezunmammifère.

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Humanized mouse models to study human diseases

James DI SANTOInstitut Pasteur - France

We have developed new immune deficient recipient mousestrains that can be reconstituted with a Human Immune System (HIS), Human Hepatocytes (HuHEP) or both (HIS/HuHEP). Thehumanizedmousemodelsprovideapreclinicaltechnologyplatformto study human disease-causing pathogens and to create novel therapeutics to combat them. Our improvments include human cytokine supplementation and transgenic MHC expression to boost T cell and dendritic cell development, andmodulation of SIRPa/CD47interactionsthatreducehostinnaterejectionmechanismsofengraftedhumancells.ThesemodifiedHISmicehaveenhancedantibody responses following vaccination, and substantially improved T cell homeostasis, and can be used to develop novel, potentially therapeutic, antigen-specific human mAbs as well asscreen new adjuvants and DC targeting strategies. These improved HIS mice offer new tools to investigate innate and adaptive immune responses to HIV infection in vivo. Improved HuHEP mouse models have been developed to study hepatitis B (HBV) and C viruses (HCV) pathogenesis and for preclinical assessment of antiviral intervention strategies. Finally, a recipient mouse strain permissive for engraftment of both human immune system and liver (HIS/HuHEP) has been developed and shown to be susceptible to HBV infection. These novel HuHEP-based models will provide a new means to understand the pathophysiology of hepatotropic diseases (including those caused by malaria parasites) and to develop new therapeutic and vaccine strategies to combat these devastating global health problems.

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Advances in in vivo animal imaging

Alain LEPAPECenterforSmallAnimalImaging-CIPA-TAAM-UPS44-CNRSTranslational Imaging - Inserm U618 - IFR 135 - France

The ability of medical imaging modalities to provide in vivo anatomical, functional and molecular explorations is of great value for studies on infection, inflammation and cancer, thanks to noninvasivity and absence of impact on processes to investigate. Medicalimagingsystemsaresuitableformediumsizeanimalsandadult rats but not for small rodents due to limitations in sensivity and resolution. Evidence of strong homology between human and mouse genomes resulted in boosting transgenic mice models while technological ruptures allowed improvements in modalities derived from medical imaging (CT, SPECT, PET, Ultra-Sounds and MRI) and drived development of Bioluminescence and Near Infra Red Fluorescence (NIRF). Scintigraphy and PET, thanks to sensitivity and quantitation, offers the most reliable strategy to document early exposure and dissemination of micro-organisms, to study biodistributionsand toexplore specificbiomarkers.CT isusuallycombined to molecular imaging to precise anatomical location . Bioluminescence, a gene expression imaging based on non invasive detection of photons is of great value for direct exploration of infection in small animal models and can be operated as an advanced resource for mechanistic studies thanks to transgenic mice expressing light under the control of specific promotors.NIRF, with a variety of fusion proteins, molecular probes for biomarkersandenzymesactivity,isoperationalfor2Dimaginginrodents but quantitation requires 3D with still further technological improvements. At the end, we will present how imaging in medium andsmallanimalssetsupasanethicalandefficientstrategy forresearch in infectiology, the development of vaccines and viral gene vectorization.

Session 3

Animal models for translationl biomedical research

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Pig models of cystic fibrosis

David K. MEYERHOLzDepartment of Pathology - University of Iowa - USA

Cysticfibrosis(CF)isalife-shorteningdiseasecausedbymutationsinthecysticfibrosistransmembraneconductanceregulator(CFTR)gene.TheCFTR-/-mousewasfirst reportednearly twentyyearsago. While it displayed an intestinal phenotype soon after birth, the CF mouse lacked the multiorgan lesions as seen in humans. Development of another animal model was important for study of CF disease. The pig model was chosen because of its anatomic and physiologic similarities to humans, reproductive characteristics and thedevelopmentoftransgenicpigs.CFpigs(withhomozygousnullandΔF508mutations)weregeneratedusingsomaticcellnucleartransfer technology. At birth, CF pigs had multiorgan disease similar to CF described in infants. Importantly, within weeks to months after birth, CF pigs developed lung disease similar to that associated with CF. Studies on the CF pig model have been useful to: 1) validate that mutatedCFTRissufficienttocausedisease;2)answerpersistentquestions regarding CF pathogenesis; and 3) identify previouslyunrecognizedclinical featuresofhumandisease. Currenteffortsinclude the development of biomarkers for disease progression and assessment of novel therapeutics to treat the disease.

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The use of animal models in the development of vaccines

Volker GERDTSVaccine and Infectious Disease Organization - University ofSaskatchewan - Canada

Vaccines have saved more lives than any other medical intervention in history. Over 100 vaccines are now commercially available for the prevention of some of the most common infectious diseases of humans and animals. Many of these vaccines were developed empirically using live-attenuated or heat-killed pathogens and toxins. Modern vaccine development, however, requires the use of well definedanimalmodelsand immunological readouts todeterminevaccine efficacy in relevant animalmodels.Here,wewill reviewthecharacteristicsofwell-definedanimalmodelsandhighlighttheadvantages and disadvantages of using small and large animal species for vaccine research.

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Animal models for Parkinson disease: brain repair

Philippe NAVEILHANINSERMU643/ITUN-France

Because of their prevalence and resulting handicaps, neurodege-nerativedisorders(Alzheimer,Parkinson,Huntington,amyotrophiclateral sclerosis, etc..) constitute one of the main public health pro-blem for the next decades in occidental countries. Among them, Parkinson disease (PD) is the second most common neurodegene-rative disease with three major symptoms: akinesia, stiffness of the muscles and resting tremor. These motor impairments are due to a progressive loss of nigral dopaminergic neuron that leads to drama-tic lack of dopamine in the striatum. In several cases, administra-tionofL-Dopaordeepbrainstimulationcompensateefficientlyforthisdeficitbuttheirbeneficialeffectsdecreaseovertimeandthesesymptomatictreatmentsdonotcurenonmotordeficits.So,severallaboratories are currently working on long-term or curative thera-pies for PD. In this aim, animal models mimicking PD attempts, and in particular, the progressive degeneration of dopaminergic neurons in the substantia nigra, would be highly valuable. The pre-sentation will focus on the different chemical and genetic models for PD, pointing out their advantages and limits compared to the human disease.

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A pig model of inherited retinal degeneration to test novel therapeutic approaches

Jacques MALLETCNRS/ICM-HôpitalPitié-Salpêtrière-NewVectys-France

In the era of modern biomedical research, new diagnostic, therapeutic and preventive techniques are continuously being developed. However, preclinical and clinical research testing proves time-consuming and expensive.

However, preclinical and clinical research testing are time-consumingandexpensive.Globalefficiencyremainsrelativelylow:in average above 90% of new medical compounds entering Phase I clinical trials fail to make it to market. Each failure represents considerable wasted time and resources.

There is a clear need to obtain high quality data relevant to humans as early as possible in the development and trial process. Clearly, better animal models of human diseases are required. Ideally, these shouldbegenetically-defined,sothattheunderlyingmechanismsare understood.

Onemajor cause forR&Dattrition is the lack of predictability ofcurrent disease models. Typically, rodent models are often unable to fairly mimic the human pathology and experimentation on non-human primates is mainly limited to wild type animals, excluding preclinical studies in diseased animals. In addition, experimentation on primates is time and money consuming, and creates increasingly ethical concerns.

Therefore,itisgenerallyrecognizedthatlargeanimalssuchaspigsand sheep are the most relevant species for biomedical research. Pigs are widely used in biomedical research to develop a variety of experimental surgical procedures, organ transplantation, imaging techniques and to model some human diseases conditions.

Hereditary retinal dystrophies are a broad and growing group of hereditary disorders affecting the retina. Mutations in the GUCY2D gene, which encodes a retina-specific guanylate cyclase, havebeen shown to cause autosomal dominantly inherited cone degeneration and cone–rod degeneration. The importance ofthese affections prompted us to develop a pig model for cone degeneration, using a lentiviral vector encoding the human double mutantGUCY2DE837D/R838ScDNA,placedunderthecontrolofthe pig arrestin-3 promoter (Arr3).

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This endeavor was performed through a collaboration involving the CNRS/ICMlaboratory,theRoslinInstitute,UniversityofEdinburgh,the Jules-Gonin Eye Hospital, University of Lausanne and the biotech company NewVectys, located at the Pitié-Salpêtrière Hospital. The resulting model has been patented.

The ratio of transgenic pigs born after lentiviral-directed transgenesis was close to 50%. Investigations included electroretinography (ERG), optical coherence tomography (OCT), histological analyses, and behavioral tests performed at various ages. Transgenic animals display a variety of functional phenotypes consistent with the fact that each animal is a different founder. Cone function, morphology and behavior are altered in several GUCY3Dmut transgenic animals. Clearly, the pig model of a cone degeneration disease we have developed is a key tool to decipher the pathophysiological mechanisms underlying retinal dystrophies, and will open novel pharmacological, cellular and gene therapy avenues.

Session 4

Physiopathology of spontaneous animal diseases

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Animal models for type 1 diabetes

Malin FLODSTRÖM-TULLBERGKarolinska Institute - Sweden

Type 1 diabetes is a chronic metabolic disease that results from the destruction of the insulin-producing pancreatic beta cell. Animal models have been of great importance for the generation of our current views on disease pathogenesis. Such models have also been valuable in the development and pre-clinical testing of new preventative or curative therapies. This lecture will give a brief overview of the most commonly used experimental models for type 1 diabetes and give a few examples on how they are currently being used in order to increase our knowledge on the etiopathogenesis of the disease.

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Animal models in influenza testing

Carla HERBERTSSection on Pharmacology, Toxicology and Biotechnology Medicine Evaluation Board - The Netherlands

Influenza virus infection and complications associated with fludisease are a leading cause of morbidity and mortality worldwide. Despite the availability of effective influenza vaccines, furtherdevelopment of vaccines is still needed. Currently, the most used animal species to study the host response influenza virusvaccinationand/orinfectionaremiceandferrets,howeveravarietyof other species have been used these include guinea pigs, cats, pigs, and monkeys. Thechoiceofananimalmodelforinfluenzavaccinetestingdependson the characteristics of the animal model and the purpose of the study. For example for immunogenicity testing mice are often used becauseoftheirsize,theknowledgeoftheirimmunesystemandthewide availability of reagents. However for challenge studies ferrets arethegoldenstandardastheyareanaturalhostforinfluenzaanddisplay symptoms similar to humans.Alltheanimalmodelsusedininfluenzavaccinetestinghavetheirspecificadvantagesanddisadvantages.Theseshouldbekept inmind in the design and during the interpretation of the results of non-clinicalinfluenzavaccinestudies.

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Animal models for multiple sclerosis

Randolph NOELLEKings College - UK

Murine models of multiple sclerosishave proven extremely valuable for the identification of therapeutics to treat human autoimmunedisease. Experimental autoimmune encephalomyelitis (EAE) is the murine autoimmune disease that has been extensively used to model human multiple sclerosis. A variety of EAE models will be discussed with regard to their utility in the testing of novel therapeutics. Over the pastdecade this model has been used extensively to evaluate the therapeutic efficacyof awide varietyof both the small molecules and proteins based therapeutics. The successes and failures of testing novel drugs in this model will be discussed

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The use of genetic reference population in metabolic diseases

PénélopeANDREUX*,EvanWILLIAMS*,CharlesTHOMAS,Phi-lippeCETTOUR-ROSE**,XavierWAROT,RobertW.WILLIAMS§,JohanAUWERX*

*LaboratoryofIntegrativeandSystemsPhysiology,SchoolofLifeSciences,EPFL,Lausanne,Switzerland**PhenotypingUnit,Cen-ter of PhenoGenomics, School of Life Sciences, EPFL, Lausanne, Switzerland§ Department of Anatomy and Neurobiology, University of Ten-nessee, Memphis, USA

Chronic multifactorial diseases involving the metabolic system, such as type 2 diabetes and obesity, result from the combined action of many genes and environmental factors, such as diet or exercise. The involvement of mitochondria in these diseases are widely accepted but the complex networks underlying mitochondrial disturbances are poorly understood.In order to define these networks, we use a mouse geneticreference population allowing control of both genetic and environmentalconditions.Inourstudy,weuseapanelof47BXDrecombinant inbredmouse lines, descended fromC57BL/6JandDBA2/J strains, to identify quantitative trait loci (QTL) and genenetworks that modulate mitochondrial homeostasis. Importantly, our initial bioinformatic sequence analysis showed that more than 10% of nuclear genes encoding mitochondrial proteins are significantly different between the twoparental strains, indicatingthat heterogeneity in their mitochondrial function can be expected.Mitochondrial activity in the different BXD strains is assessedby a clinical phenotyping focused on metabolic activity. This characterization includes exercise endurance and adaptivethermogenesis by means of resistance to a cold stress and diet-induced obesity. To evaluate dietary influence, we perform thestudies in mice fed either a chow diet (CD) or a high-fat diet (HFD).Among 28 strains fully phenotyped until now, the body weight increaseduringthedietrangedfrom16%to45%intheCDgroupsversus 45% to 110% in the HFD groups. Similarly, we foundsignificantdifferences in thebodyweight lossafter twoweeksofvoluntary exercise, with a variation range of -1 to 12% in the CD groups versus 1 to 23% in the HFD groups. These results reinforce the heterogeneity in the VO2 max, the cold resistance and the glucose tolerance that could be observed between strains and groups. The broad data set generated with this method will enable QTLmappingstrategiesthroughtheGeneNetworkresource(www.genenetwork.org).

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After completion of the in vivo phenotyping, we will perform detailed mitochondrial analysis in vitro, including gene expression analysis, proteomics,enzymaticassaysandmetabolitemeasurement.We envision that the outcome of this work will provide novel insights into mitochondrial metabolism with the identification of signalingpathways and network regulations. These results will initiate new strategies for diagnosis, prevention and therapy complex diseases associated with aging, such as obesity, type 2 diabetes, sarcopenia, and neurodegeneration.

Session 5

Animal models of infectious diseases

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Transgenic pig models for translational biomedical research

Eckhard WOLFChair for Molecular Animal Breeding and Biotechnology - Gene Center and Department of Veterinary Sciences - Ludwig-Maximi-lians - Universität München - Germany

The translation of novel discoveries from basic research to clinical application is a long, often inefficient and thus costly process.Accordingly,theprocessofdrugdevelopmentrequiresoptimizationboth for economic and for ethical reasons, in order to provide patients with appropriate treatments in a reasonable time frame. Consequently, “Translational Medicine” became a top priority in national and international roadmaps of human health research. Appropriateanimalmodelsfortheevaluationofefficacyandsafetyof new drugs or therapeutic concepts are critical for the success of translational research. In this context rodent models are most widely used due to the possibility of genetic and environmental standardization, a broad spectrum of strains tailored for specificscientific questions, and their acceptance by the regulatoryauthorities. However, findings in rodent models do not alwaysreflecttheclinicalsituation.Thus,animalmodelsmimickinghumananatomy and physiology more closely are urgently required. In this respect the pig is an excellent candidate. As monogastric omnivores pigs share many anatomical and physiological characteristics with humans. The excellent reproductive performance of the pig is idealforamodelorganism.Thefirstpigwholegenomesequenceand many other genomic resources will be available in the near future.Importantly,efficientandprecisetechniquesforthegeneticmodificationofpigshavebeenestablished,facilitatingthegenerationof tailored disease models. This talk provides an overview of the currenttechniquesforgeneticmodificationofpigsandtheirpotentialas models for diabetes research and regenerative medicine.

Session 5

Animal models of infectious diseases

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The influence of host-microflora interactions in immune pathological processes

Nadine CERF-BENSUSSAN INSERM U989, Université Paris Descartes - France

The intestine is an open ecological system that is colonizedimmediately after birth by a microbial population, which reaches an impressive density of 1012 bacteria per gram of luminal content in the distal gut. Growing experimental evidence underscores the profound influence of the microbiota on host physiology in andbeyond the gut and its possible contribution to diseases. The notion is emerging that hosts and their gut microbiota have evolved mutualistic interactions and form superorganisms in which energy and metabolites are exchanged while homeostasis is maintained by the immune system Gnotobiotic animal models provide a powerful to dissect the rules that govern the interactions between hosts and their microbiota and the trade-off established during their long coevolution to maintain mutualistic relationships. Taking advantage of experiments performed in gnotobiotic mice, we willdiscusshowthemicrobiotainfluencesthepost-natalmaturationof the host immune system and elicits innate and adaptive immune mechanisms that cooperate to protect the host, maintain intestinal andperipheral homeostasisandbuildanefficientbarrieragainstinvasive pathogens. We will discuss how the characteristics of the microbiota and of the hosts may affect the balance between pro-inflammatoryandregulatoryimmuneresponsesandprevent,oronthecontrary,promotetherisktodevelopinflammatorydiseases.

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The cotton rat model of respiratory viral diseases

Jorge C. BLANCOSigmovir Biosystems Inc. - USA

The first use of the cotton rat in biomedical research occurredin 1937 when Dr. Charles Amstrong of the National Institute of Health tested several live-trapped animals in an effort to identify a small animal model for polio vaccine development. Amongst all the species tested, only the cotton rat developed polio paralytic disease. Over the ensuing decades the cotton rat has been shown to be a preferred model for Respiratory Syncytial Virus (RSV) infection and pathogenesis, and a reliable model for an impressive list of human respiratorypathogens including influenza (AandBserotypes),adenoviruses (severalserotypes),parainfluenzavirus(type 3), measles, human metapneumovirus, and Mycobacterium tuberculosis. The most significant contribution of the cotton rat to biomedicalresearch has been the development of anti-RSV antibodies for prophylactic use in high-risk infants. Pre-clinical studies in the cotton rat lead directly to clinical studies that resulted in the licensure of two formulations by the FDA: RespiGam®, a polyclonal antibodyderivedfromplasmadonors;andSynagis®,ahumanizedmonoclonal antibody that is now administered to approximately a quarter-million infants annually, and has reduced hospitalizationamong targeted populations by up to 80%. Thus the cotton rat continues to be the “gold standard” model for RSV. During the last ten years the model has established its presence further, by predicting failure of antibody therapy against RSV, establishing parameters for predicting RSV vaccine enhanceddisease,introducingmodelsofefficacyofvaccinationinthe presence of maternal antibodies, and modeling pathogenesis of RSV in elderly and immunossupressed animals. In parallel, rapid advancesinthecottonratmodelofinfluenzahasbeenperformedin the last decade. Cotton rats are susceptible to non-adapted strainsofhuman,avian,andswine influenza. That isdue to thepresenceofα2-3andα2-6sialicacidreceptors intherespiratorytract of cotton rats. Thus, this is a model of increasing interest for testing the efficacy of new vaccine and therapeutics againstcirculatingstrainsofinfluenzawithoutadaptation.

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Using wild mice to takle genetic control of resistance to infectious diseases (West-Nile, Rift Valley Fever, Plague)

XavierMONTAGUTELLIInstitut Pasteur - France

The outcome of most infectious diseases is influenced by thegenetic composition of the host. Mice often provide valuable models to study human infectious diseases. We have adopted several genetic approaches to identify genetic mechanisms of resistance to three life-threatening human pathogens : West-Nile virus, Rift Valley fever virus and Yersinia pestis, the plague agent. We take advantage of the vast genetic polymorphism between laboratory strains and a collection of wild-derived inbred strains of different mouse species and subspecies, which translates into variable degrees of susceptibility to these pathogens. A combination of classical two-generation crosses, congenic strains, and gene expression analysis is used to identify key players in the host-pathogen interactions Candidate genes can be validated through functional studies and investigated in human or animal populations through association studies.

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Animal Models for Borreliosis

Reinhard STRAUBINGERInstitute for Infectious Diseases and zoonoses, Faculty of Veterinary Medicine - LMU Munich - Germany

Borrelia infections can affect humans and animals in two ways. On the one hand, spirochetes of the Borrelia burgdorferi sensu lato group can cause a complex illness, best known as Lyme borreliosis. A disease, which after an initial harmless bite of a hard-shell ixodid tick may become more severe over weeks and months and may last foryears.Theaffectedindividualsproduceinflammatorylesionsinvarious tissues, especially in the skin, in large joints or eventually intheperipheraland/orcentralnervoussystem.Rashes,recurringarthritis, meningitis or paralysis due to neuritis are the consequences of the infection. Besides humans, dogs and horses are the two most prominent companion animal species, which are susceptible to the infection and produce clinical signs that are comparable with pathological changes seen in humans.On the other hand, relapsing fever spirochetes such as Borrelia recurrentis, B. duttoni, B. hispanica, B. persica are transmitted by lice or soft ticks (e.g. Ornithodorus spp.). Within days after the tick bite these microorganisms propagate in the blood of the new host. Due to the large numbers of spirochetes in the blood stream, patients suffer from episodes with high fever, headaches, nausea, joint aches and eventually bleeding. Mortality rate is generally low, but can be up to 30 %, sometimes 70 % of the infected population. Also cats, dogs and other animals succumb to the infection.Both, Lyme borreliosis and relapsing fever, have in common that after the infection the immune system of the host rigorously interacts with specificantigensoftheinvadingbacteria.Pathologicinflammatoryas well as protective humoral responses can be induced and investigated in animals. Studies in the appropriate animal models help first of all to understand the underlying pathomechanisms,whichleadtoclinicalsigns;theyalsohelptoexplorethearsenalofprotectivetools,thatareavailableduringthecourseoftheinfection;and they advance our knowledge needed to develop diagnostic toolsinordertorecognizetheseinfectionsearlyandreliably.

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Animal models of tuberculosis for testing new drugs

Radha K. SHANDILAstrazeneca - India

Tuberculosis is a difficult to treat disease that kills ~1.8 millionpeople annually. Animal models of tuberculosis play a critical role in understanding complex mycobacterial pathobiology and development of newer interventional therapies. A standard, WHO recommended combination regimen of four drugs takes six months tocurepatients.Ithasbeenhypothesizedthatthelongerdurationoftreatment required for eradication of disease is due to the presence of physiologically distinct bacillary populations or emergence of phenotypically drug tolerant and slowly replicating populations in the human lung. Thus, there is an urgent need to develop new drugs that can selectively target replicating and non-replicating bacillary populations in the patients. Such drugs will have potential tosterilizeandshortendurationoftuberculosistherapy.We developed a high dose aerosol infection model in mice that mimics acute (replicating bacilli) and chronic (non-replicating bacilli) stages of infection. Treatment with various classes of antitubercular drugs like Rifampicin, Isoniazid, Ethambutol andPyrazinamideandfewfluoroquinolonesrevealedthattheinfectionmodel allows differentiation of ineffective, bacteriostatic and bactericidal agents and that bactericidal activity of anti TB drugs is dictated by physiological state of the bacilli in vivo. The acute mouse infection model may facilitate differentiation of anti TB compounds withpotentialEBAor/andsterilizingpotential.Relevanceofmiceinfection model with the human disease and drug discovery process will be presented.

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Primate models of SIV infection : different susceptibility of African green monkeys and rhesus macaques to develop AIDS after SIV infection

Michaela MüLLER-TRUTWINInstitut Pasteur - Unité de Régulation des Infections Rétrovirales France

The molecular mechanism leading to AIDS in HIV-infected individuals is not yet elucidated. It is considered that chronic bystander immune activation(IA)isthemajordrivingforceofCD4+Tcelldepletion.Current antiviral treatments of HIV-positive patients are highly efficient,butfailtoabolishresidualchronicIA.ThisresidualIAcanlead to HIV-associated premature ageing of the immune system and slow progression towards AIDS. The level of IA already at the very early stage of HIV-1 infection is predictive of the rate of progression towards AIDS. It is therefore important to understand which factors are involved in the regulation of the IA level immediately after HIV infection. Non human primate models (NHP) allow to study the early interactions between virus and host in lymphoid tissues. Two types of NHP models are available: (i) macaques (MAC) infected by SIV progressing with various rates to AIDS, and (ii) the natural hosts of SIV. The latter correspond to African non human primates. SIV infection in African NHP, such as African green monkeys (AGM) and sooty mangabeys (SM), is non-pathogenic despite high viral replication levels. The most striking difference between non-pathogenicSIVandpathogenicHIV-1/SIVmacinfectionsisthelackofchronicIA.WehaveshownthatAGMshoweverduringthefirsttwoweeksofSIVinfection,firstshowarobustinnateandadaptiveimmune response, that is however rapidly down-regulated before the end of the acute phase of infection. We will discuss here the majorsimilaritiesanddifferencesintheinflammatoryanddendriticcell response during the early phase of non-pathogenic versus pathogenicSIVinfections,andtherelevanceofthefindingsforHIV-1 infection in humans.

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Plasmodium chabaudi ; a relevant model for human malaria

Jean LANGHORNEPhillip SPENCE, Ana Paula ROSARIO, Deirdre CUNNIGHAM

Division of Parasitology - MRC National Institute for Medical Research - UK

Plasmodium chabaudi infection in mice is considered to be a good model for investigating immune responses and immunoregulation during malaria, particularly in blood-stage infections. In most mouse strains it is a non-lethal infection, with an acute high parasitaemia that is rapidly resolved to low levels, followed by a long (2-3 month) low-level chronic infection. Mice are immune to re-infection with the same strain of P. chabaudi, thus providing a good system for studying mechanisms of protective immunity. Plasmodium chabaudi also exists as several independently generated laboratory isolates and clones, and these can be used to investigate homologous and heterologous immunity as would be seen in human infections. Furthermore the parasite undergoes antigen variation and expresses proteins encoded by multigene families (eg CIR) on the surface of infected red blood cells. CIR proteins are analogous the VIR variant antigens of the human parasite P. vivax, and are similar to RIFINS of P. falciparum and therefore this model can be used to determine the role of relevant variant antigens in protective immunity. We have shown that the protective immune response to P. chabaudi blood-stagesisdependentonCD4Tcellsandantibody.TheinitialTH1CD4TcellresponseischaracterisedbytheproductionofIFNγ,andthiscontributestothepathologyoftheinfection;anemia,hypoglycemia,weightlossandliverdamage.Thisinflammatoryresponseisrapidlydown-regulatedbyIL-10.TH1CD4TcellsthemselvesaretheoneofthemainsourcesoftheIL-10,andthesedouble-producingIFNγ/IL-10 cells are responsible for controlling acute stage pathology. More recently we have extended the relevance of P. chabaudi as an experimental model with the development of mosquito -transmitted infections and successful transfection of the parasite. This has enabled us to follow the parasite and the host response from the bite of the infected mosquito through to the blood-stage infection.

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Animal models for the analysis of immune responses to Leishmaniases, relevance to human disease

David SACKSLaboratory of Parasitic Diseases - National Institutes of Allergy and Infectious Diseases - National Institutes of Health - USA

Numerous experimental, non-living vaccines have been developed that protect against Leishmania infection in mouse models, but despite an extensive series of clinical trials involving a killed vaccine, an effective human vaccine still does not exist. At issue may be the relevance of the mouse models to human disease. Only rarely have anti-Leishmania vaccines been properly evaluated under experimental conditions employing natural vector-transmission by infected sand fly bite. We observed that while C57Bl/6mice vaccinated with autoclaved L. major antigen (ALM)+CpGoligodeoxynucleotides or recombinant protein vaccines were protected against needle inoculation of parasites, these mice were notprotectedagainstinfectedsandflychallenge.Onlymicewithahealed infection with L. major were well protected against infected sandflychallengethatwascorrelatedwiththerapidrecruitmentofmultifunctionalcytokineproducingCD4+Tcellstothechallengebitesitewithin24hours.Sandfly,butnotneedle,challenge,resultedin themaintenanceofamassive, localizedneutrophilic responseat the inoculation site, and removal of neutrophils following vector transmissionledtoincreasedparasite-specificimmuneresponsesand promoted the efficacy of the non-living vaccines. Theseobservationsbegintoidentifythecriticalfactorsinfluencingvaccineefficacy following natural transmission of Leishmania, and arguethat mouse models are suitable experimental models to predict vaccineefficacy inhumansprovidedmorestringentconditions toevaluate protection are employed.

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Poster

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Can accurate preclinical mouse models be developed for efficacy, safety and toxicology assessment of pharmaceuticals and NCEs?

Alexandre FRAICHARDGenOway - France

Over the past decade, the range of biotechnology products and NCE either on the market or in the latest stages of development has increased (recombinantpeptidesandproteins,modifiedproteins,monoclonal antibodies and related products…). One of the biggest challenges in their preclinical assessment is to overcome the speciespecificitybarrierforcompoundefficacyandsafetyinvivoassessment. A more rational approach of mouse model (the main animal model used by biopharmaceutical scientists) designed for in vivoevaluationofdrugefficacyandsafetyhasbecomeanunavoidable step in toxicological studies. The use of sophisticated models such as kinase-dead or humanized models to addressproof-of-concept and safety is becoming a standard within the biopharmaceutical industry; however the performances of thesemodels is highly dependent on the model design per se.

Forexamplethegenerationofahumanizedmodeldoesnotconsistin only substituting the mouse gene by the human counterpart. Indeed, althoughmost of these products are highly specific andor selective, their targets often modulate cellular response in a pleiotropic manner. Consequently, the model should express the human target gene instead of the mouse endogenous one, but the genetic manipulation should preserve the physiological expression of the target gene, its regulation, the expression of different isoforms when relevant, the interactions with key molecules such as signaling molecules, co-receptors in order to trigger the proper cell activation at the proper magnitude upon engagement of the humanizedtarget.Humanizedmodelareoftenusedforcompoundefficacy studies; they could also be designed to provide tolerantmodelstorecombinantpeptides/proteins/derivativesorIgFcfromhuman origin enabling repeated injection of the biologics and long term assessment of their toxicology and immunogenicity in vivo.

Similarly, the use of functional KO models (model expressing the protein of interest devoid of a given phosphorylation site or catalytic site) or point mutant models is becoming the gold standard for the validationofkinases,enzymesandreceptorsastargets..

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The generation of inducible point mutation models enables the time specific inactivation of a target gene therefore providing a bettermodel mimicking the effect of a drug. As an example, the generation of kinase-dead models using an inducible point mutation approach enables investigating the consequences of time and tissues restricted kinases inactivation while overcoming the general limits of KO and conditional KO models (compensatory mechanisms, complex phenotypes…). Same as the humanized model, thedesign is crucial, as the overall homeostasis of the model must be preserved to provide an accurate preclinical model.

Thepresentationwillprovide(1)acriticaloverviewofthescientificstrategies used today in genetically modified mouse modeldevelopment and (2) some success stories in preclinical studies.

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Speakers and chairs

Speakers and chairs BLANCO Jorge C. USA Sigmovir Biosystems Inc. jblanco@virionsystems.com

CAzENAVE Pierre - André France Institut Pasteur pierre-andre.cazenave@pasteur.fr

BUzONI-GATEL Dominique France INRA Dominique.Buzoni@tours.inra.fr

CERF-BENSUSSAN Nadine France Inserm Nadine.cerf-bensussan@inserm.fr

CETTOUR-ROSE Philippe Switzerland Phenotyping Unit Center Of Phenogenomics School of Life Sciences Ecole Polytechnique Fédérale De Lausanne philippe.cettour-rose@epfl.ch

CHAPMAN Katheryn UK RefinementAndReductionOfAnimalsInRe search (nc3rs) kathryn.chapman@nc3rs.org.uk

DECELLE Thierry France SanofiPasteur thierry.decelle@sanofipasteur.com

DI SANTO Jim France Institut Pasteur james.di-santo@pasteur.fr

FLODSTROM TULLBERG Malin Sweden Karolinska Institutet Malin.Flodstrom-Tullberg@ki.se

GERDTS Volker CanadaVaccineAndInfectiousDiseaseOrganizationInternational Vaccine Centrevolker.gerdts@usask.ca;lisa.mess@usask.ca HARDY PatrickFranceMerialPatrick.HARDY@Merial.com

HERBERTS Carla The NetherlandsCollege Ter Beoordeling Van Geneesmiddelenca.herberts@cbg-meb.nl

HERAULT Yann FranceIGBMCherault@igbmc.fr

LE PAPE Alain FranceUniversité de Toursalain.lepape@univ-tours.fr

MALLET JacquesNewVectysJacques.mallet@newvectys.com

MENGE ChristianGermanyFriedrich-loeffler-institutBundesforschungsinstitut Für Tiergesundheitchristian.menge@fli.bund.de

MEYERHOLz David USA University of IOWAdavid-meyerholz@uiowa.edu

MONTAGUTELLIXavierFranceInstitut Pasteurxavier.montagutelli@pasteur.fr

Speakers and chairs MULLER TRUTWIN Michaela FRANCE Institut Pasteur michaela.muller-trutwin@pasteur.fr

NAVEILHAN Philippe FRANCE Université de Nantes Philippe.Naveilhan@univ-nantes.fr

NOELLE Randolph UK Kings College Randolph.J.Noelle@Dartmouth.Edu

PINEAU Thierry France thierry.pineau@toulouse.inra.fr

SACKS David USA Intracellular Parasite Biology Section Laboratory Of Parasitic DSACKS@niaid.nih.gov

SHANDIL Radha India Astra zeneca radha.shandil@astrazeneca.com

STRAUBINGER Reinhard Institute for Infectious Diseases and zoonoses Faculty of Veterinary Medicine - LMU Munich Germany R.Straubinger@lmu.de

WOLF Eckhard Germany Universityf of Munich ewolf@lmb.uni-muenchen.de

Participants

Participants

ANCERIz Nadia SwitzerlandNovimunnanceriz@vovimune.com

BARBAN Véronique FranceSanofiPasteurveronique.barban@sanofipasteur.com

BONBLED PhilippeFranceVet 2011p.bonbled@vet2011.org

BUATOIS Vanessa SwitzerlandNovimunvbuatois@novimune.com

BURDIN NicolasFranceSanofiPasteurnicolas.burdin@sanofipasteur.com

CHATEL LaurenceSwitzerlandNovimunlchatel@novimune.com

CHAUVEAU Fabien FranceCreatis Lab chauveau@creatis.insa-lyon.fr

CONS Laura SwitzerlandNovimunlcons@novimune.com

CORBISIER MagalieFrance Phatophymagalie.corbisier@phatophy.com

CURTIN Francois SwitzerlandGeneurofrancois.curtin@geneuro.com

DAUBEUF Bruno SwitzerlandNovimunbdaubeuf@novimune.com

DE GRAVE Dany France SanofiPasteurdanydegrave@sanofipasteur.com

FRAICHARD Alexandre FranceGenOwayfraichard@genoway.com

GIRERD-CHAMBAz Yves FranceSanofiPasteuryves.girerd-chambaz@sanofipasteur.com

GOETSCH LilianeFrance Institut De Recherche Pierre Fabreliliane.goetsch@pierre-fabre.com

GRANDMONTAGNE Claude FranceVet 2011c.grandmontagne@vet2011.org

GUY BrunoFranceSanofiPasteurbruno.guy@sanofipasteur.com

HATTERER Eric SwitzerlandNovimunehatterer@novimune.com

Participants

HERRENSuzanneSwitzerlandNovimunsherren@novimune.com

LANG Jean FranceSanofiPasteurjean.lang@sanofipasteur.com

LIPENS CarlaSwitzerlandNovimunclippens@novimune.com

MAC DONALD Rhona UK MoredumScientificrmacdonald@moredun-scientific.com

MANTEL Nathalie FranceSanofiPasteurnathalie.mantel@sanofipasteur.com

MEURENS François FranceInra De Toursmeurens@tours.inra.fr

MOINE Valery Suisse Novimunvmoine@novimune.com

RIOU Patrice FranceSanofiPasteurpatrice.riou@sanofipasteur.com

WEIGL Josef GermanyBavarian Nordic Gmbhweigl@pediatrics.uni-kiel.de

This meeting was made possible through unrestricted educational grants from Sanofi Pasteur.