JEAN-CHRISTOPHE AUDONNET

Transcription

1 JEAN-CHRISTOPHE AUDONNET

2 Recombinant Veterinary Vaccines Overview of Progress in the past 30 years and Future Trends Jean-Christophe AUDONNET DVM, Ph.D. Merial R&D

3 OUTLINE OF THE TALK ORIGIN AND HISTORY OF RECOMBINANT VACCINES RABORAL AND LIVE VECTORED VACCINES 03 CANARYPOXVIRUS VECTOR (NON REPLICATIVE VECTOR CONCEPT) 04 APPLICATIONS OF ALVAC-BASED RECOMBINANT VACCINES 05 CURRENT LANDSCAPE AND EMERGING / FUTURE TRENDS 06 CONCLUSION

4 Jenner, smallpox (vaccinia) 1796 Louis Pasteur, rabies Two giant leaps for vaccination at 1 century interval 1885 Veterinary vaccines Chicken cholera, anthrax, erysipelas, sheep pox,

5 One century later, another giant leap?

6 More than 30 years of vectored vaccines development

7

8 RABORAL 1990 Oral vaccination : baits Safer for environment Safer for wild animals Efficacious in fox, raccoon, coyote Thermostable due to pox resistance vaccinia vector

9 LIVE VECTOR VACCINE 3 STEPS 1. Clone the protective gene 2. Insert the protective gene into the genome of the vector (virus: poxvirus, herpesvirus) 3. Produce the vector = vaccine influenza HA gene Virus HA protein virus vector vaccine

10 CANARYPOX VECTOR - ALVAC Vaccinal strain against canarypox Avipox host specificity Non replicative in mammals Virogenetics, Troy, NY

11 Opening a new vaccinology concept «non replicative vaccine vectors»

12 CANARYPOX VECTOR - ALVAC replicative non replicative Early Phase Late Phase

13 CANARYPOX VECTOR FOR CATS Rabies Feline leukemia Advantages No adjuvant Cell immunity Fibrosarcoma

14 CANARYPOX VECTOR FOR DOGS AND FERRETS RECOMBITEK Distemper Advantages Safety Efficacy in puppies with MDA 14

15 WILDLIFE ENDANGERED SPECIES RECOMBITEK rcdv

16 CANARYPOX VECTOR FOR HORSES PROTEQ FLU TM Equine influenza Advantages Rapid onset (1 shot) Long duration of immunity DIVA eradication (Australia) RECOMBITEK WNV West Nile Virus Advantages Rapid onset (1 shot) Protection against disease Protection against viremia

17 CANARYPOX VECTOR FOR EMERGENCY VACCINES Experimental protection against Bluetongue Virus African HorseSickness Virus Nipah and Hendra Viruses Japanese Encephalitis Virus Swine, Canine, Feline influenza

18 ALVAC-BTV, ALVAC-Nipah, ALVAC-AHSV

19 CURRENT LANDSCAPE FOR VECTORED VACCINE TECHNOLOGIES Replicating vectors Viruses Poxviruses Adenoviruses Herpesviruses Flaviviruses Bacteria Mycobacteria (BCG) Salmonella Non replicating vectors Viruses Poxviruses - Avipoxviruses Adenoviruses (E1 del) Herpesviruses (gd del) DNA vaccines Plasmids Linear expression cassettes DNA vectors Replicons RNA vectors Replicons (alphavirus) Technologies having at least one example of registered vaccine (human or veterinary)

20 THE NEW TECHNOLOGY VACCINE LANDSCAPE (2016) Protective immunogens The Bug Virus Bacterium Classical inactivated Classical fractionated Classical modified live New Tech Rec subunit New Tech VLPs New Tech * Vectored Vacc. New Tech DNA Vacc. * Different categories of vectored vaccines

21 DNA VACCINE TECHNOLOGY (1991) Protective gene sequence Immunization with purified plasmid (injection) Plasmid construction Bacterial transformation (E. coli) Bacterial fermentation Plasmid purification (downstream process)

22 DNA VACCINE TECHNOLOGY (1991) DNA vaccines Registered products only in animal health today Fish (salmon): IHNV DNA vaccine Horse: West Nile Virus vaccine Dog: Canine Melanoma DNA vaccine (Merial) Oncept : the first therapeutic cancer DNA vaccine

23 THE WAY FORWARD FOR RECOMBINANT VACCINES NEW TRENDS FOR BACTERIAL VECTORS New ways are available today for attenuating bacteria and to generate live vaccines or live bacterial vectors of especially high interest in animal health (poultry, swine, cattle) Salmonella, E. coli Pasteurella, Haemophilus, Actinobacillus, Streptococcus Mannheimia, Salmonella, Streptococcus availability of CRISPR-Cas9 technologies is enabling a very fast turnaround time for rationale-based attenuations CRISPR-Cas9 based technologies allow also access to new bacterial targets

24 THE WAY FORWARD FOR RECOMBINANT VACCINES NEW TRENDS FOR BACTERIAL VECTORS Bacterial vectors for expressing biologicals (e.g. cytokines) Avian Beta Defensin (yeast) PoEGF (Lactococcus lactis)

25 THE WAY FORWARD FOR RECOMBINANT VACCINES NEW TRENDS FOR BACTERIAL VECTORS Bacterial vectors for expressing: Vaccine antigens Avian Influenza H5N1 Neutralizing antibodies Clostridium difficile toxin

26 THE WAY FORWARD FOR RECOMBINANT VACCINES VLP-based and Nanoparticle-based vaccines (1) Auto-assembly of particles with key capsid proteins Empty viral particle (enveloped or non enveloped) Cheap manufacturing in yeast, insect cells, baculovirus, E. coli. PCV2 FCV PPV FIV BTV Several commercial vaccines already available: Human vaccines Human Papilloma Virus, Hepatitis B, Hepatitis C, Rotavirus Veterinary Vaccines: PCV2

27 THE WAY FORWARD FOR RECOMBINANT VACCINES VLP-based and Nanoparticle-based vaccines (2) Intense research activity for VLP- and biological nanoparticle-based vaccines Scaffold concept (multimeric protein on which antigens can be attached and displayed to the immune system) Advantages: cheap, new routes of administration (oral, mucosal, in ovo?), well-defined products, high versatility for combinations, no adjuvant or reduced need for adjuvant Disadvantages: not live

28 THE NEW TECHNOLOGY VACCINE LANDSCAPE (2016) Protective immunogens The Bug Virus Bacterium Classical inactivated Classical fractionated Classical modified live New Tech Rec subunit New Tech VLPs New Tech * Vectored Vacc. New Tech DNA Vacc. * Different categories of vectored vaccines Human vaccines

29 THE NEW TECHNOLOGY VACCINE LANDSCAPE (2016) Protective immunogens The Bug Virus Bacterium Classical inactivated Classical fractionated Classical modified live New Tech Rec subunit New Tech VLPs New Tech * Vectored Vacc. New Tech DNA Vacc. Veterinary vaccines * Different categories of vectored vaccines

30 THE NEW TECHNOLOGY VACCINE LANDSCAPE (2016) Protective immunogens The Bug Virus Bacterium Classical inactivated Classical fractionated Classical modified live New Tech Rec subunit New Tech VLPs New Tech * Vectored Vacc. New Tech DNA Vacc. * Different categories of vectored vaccines Merial vaccines

31 ADVANTAGES OF LIVE VECTORED VACCINES AND RECOMBINANT VACCINES Safety = safety of the vector / safety of recombinant VLPs Live attenuated (no reversion to virulence) No need for adjuvant Efficacy Broad immunity (cellular and humoral) Rapid onset after one administration Interference with maternal antibodies: vector dependent Bivalent vaccine if the vector is a vaccine

32 CONCLUSIONS Based on the advantages they are bringing, vectored vaccines had a fast development in the past 30 years : in Animal Health (poultry, pets, horses, swine) more recently in Human Health (dengue vaccine) Exciting technology developments (CRISPR, synthetic biology), are generating a wave of new ideas / approaches for improved vaccines One issue is still the identification of the right «protective genes» for generating the «golden bullet vaccine» However, research is again accelerating with the access to new tools (genomics, vaccinomics, structural vaccinology), and the next giant leap will certainly occur way before

33 ACKNOWLEDGEMENTS Merial R&D management Merial S.A.S. Lyon Merial Inc. Athens Sanofi Pasteur R&D Toronto Michel Bublot Jules Minke Kemal Karaca Teshome Mebatsion Frank Milward Bob Nordgren Sheena Loosmore Mark Parrington Jiansheng Yao Virogenetics Inc. colleagues ( ) Numerous external collaborators