Risk Analysis for Veterinary Biologics: Case Studies

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United States Department of Agriculture Animal and Plant Health Inspection Service Risk Analysis for Veterinary Biologics: Case Studies Richard E. HILL, Jr.

1 United States Department of Agriculture Animal and Plant Health Inspection Service Risk Analysis for Veterinary Biologics: Case Studies Richard E. HILL, Jr., Patricia FOLEY Center for Veterinary Biologics Veterinary Services Animal and Plant Health Inspection Service United States Department of Agriculture Ames, Iowa USA Center for Veterinary Biologics

2 Topics Risk Analysis for Biotechnologyderived Biologics (brief summary) Case Studies Vectored vaccines (review of risk decisions and mitigations) Transgenic Plant-derived Vaccines (additional considerations and example) Emerging Issues and Unique Biologics

3 Risk Review of Biotech-derived Applications Data: Summary Information Format (SIF) The biologics firm provides the requested information using the pertinent SIF, reviewed by USDA Risk Assessment (RA) outline Completed by the firm, evaluated by USDA Risk analysis by USDA of proposed field safety trials Environmental assessment (EA) of any potential effects On animal safety, public health, or the environment

4 Biotech Risk Assessment Objective of Studies: ID Hazards Examine genotypic and phenotypic stability in target host animals (reversion to virulence?) Evaluate changes in tissue tropism Assess shed/spread capabilities Assess host range specificity Consider recombination potential and consequences Identify effect of overdosing Assess survivability in environment Expected risk: Risk Rating = [(L) x (D)] x [(C) x (D)]

Formal Risk Review of Biotechnology-Derived Products USDA conducts Master Seed & prelicense serial testing The firm provides to USDA Confidential business information-deleted SIF/RA For live

5 Formal Risk Review of Biotechnology-Derived Products USDA conducts Master Seed & prelicense serial testing The firm provides to USDA Confidential business information-deleted SIF/RA For live vaccines: Federal Register Notice of pending trials CBI-deleted SIF/RA & EA available to the public Public comment period Finding of No Significant Impact (FONSI) Approval of field trials if no issues arise Licensure If the field trials showed the product to be safe and all other requirements are met

6 Request to Ship + Test an Experimental Biologic 9 CFR Analysis of pre-license data & information Hazard Identification & Release Assessment Risk Characterization Low: Acceptable Risk Approve Request Medium: Unacceptable Risk Satisfactory Mitigation High: Unacceptable Risk Deny Request Yes: Approve Request No: Deny Request

Environmental Considerations Deliberate release of any organism containing recombinant DNA into the environment is subject to review and approval by appropriate Federal agencies.

7 Environmental Considerations Deliberate release of any organism containing recombinant DNA into the environment is subject to review and approval by appropriate Federal agencies. Under normal husbandry and laboratory practices, injected veterinary biologicals are not considered to be released into the environment if testing shows the agents are not shed.

8 Overview Each biotech product is evaluated individually to determine the appropriate requirements to establish purity, safety, potency, and efficacy. Replication proficient products must undergo an environmental risk assessment. Killed or inactivated (non-replication competent) biotechnology products must undergo an abbreviated risk assessment.

9 Case Studies Vaccinia-vectored oral baited rabies vaccine (V-RG) for wildlife Canarypox-vectored vaccines Transgenic plant-derived vaccines

rabies vaccine (ORV) FY2007: 11,361,002 ORV baits in 17 states

10 Rabies U. S. Risks and Costs Risks < 1960, mostly domestic animals Now: > 90% of animal cases in wildlife (carnivores, bats) Livestock: most often cattle & horses Costs > $300 million/year in US for oral rabies vaccine (ORV) FY2007: 11,361,002 ORV baits in 17 states Need new ORVs, baits & biomarkers Current ORV effective in raccoon, coyote, gray fox Need vaccines for use in skunk, bat, mongoose

11 Rabies Domestic Animals

12 Rabies Wild Animals

Rabies Virus Licensed Global Vaccines ORV - attenuated strains (various SAD vaccine viruses, ERA G 333) red foxes, raccoons ORV - freeze-dried or encapsulated SAG2 dogs, red foxes, raccoons Cell

13 Rabies Virus Licensed Global Vaccines ORV - attenuated strains (various SAD vaccine viruses, ERA G 333) red foxes, raccoons ORV - freeze-dried or encapsulated SAG2 dogs, red foxes, raccoons Cell culture or nerve-tissue KV for use in dogs, cats, ferrets, horses, cattle, or sheep Live poxvirus vectored vaccines, per WHO, 2004: > 75 million doses of V-RG red foxes (Belgium, France, Israel, Luxemburg, Ukraine); raccoons (Republic of Korea); coyotes, raccoons, grey foxes (Canada, US), domestic dogs (Sri Lanka)

V-RG Oral Rabies Vaccine Case Study 1983: Vaccinia-vectored vaccine developed containing Rabies glycoprotein G unique, baited, oral use in wildlife Extensive studies in containment, then in the field

14 V-RG Oral Rabies Vaccine Case Study 1983: Vaccinia-vectored vaccine developed containing Rabies glycoprotein G unique, baited, oral use in wildlife Extensive studies in containment, then in the field (Belgium, France): contact with baits in a wide variety of species Safe in rabbits, various spp. mice + voles, woodchucks, squirrels, badgers, fox, raccoon, skunk, coyote, wild boar, gulls, hawks, owls, buzzards, kestrels, crows, magpies, jays Risk review for environmental release in the US: NEPA: recombinant, air- + land-based bait drops Public health: zoonotic concerns Review by subject matter experts, public meetings

15 V-RG Oral Rabies Vaccine Raccoons 1 st North American test: August 20,1990, the Wistar Institute initiated a field trial on Parramore Island, Virginia 1991: field trials in Pennsylvania : field trials in New Jersey April 20, 1995, Conditional license for use in raccoons Today: 16 states use V-RG to control raccoon rabies, 1 state uses for gray fox + coyote rabies Example: Ohio with 59 positive raccoons in 1997, but no positive cases in 2000, only 1 in 2001

V-RG Oral Rabies Vaccine Coyote and Fox 1994 Efficacy studies in coyotes & foxes prior to field trials with experimental vaccine 1995 Experimental field use in Texas Annual use of experimental

16 V-RG Oral Rabies Vaccine Coyote and Fox 1994 Efficacy studies in coyotes & foxes prior to field trials with experimental vaccine 1995 Experimental field use in Texas Annual use of experimental vaccine in Texas, with manufacturer submitting reports of the testing results May 16, 2002, USDA accepted data supporting a label claim for use in coyotes Currently, fully licensed for use in raccoons, coyotes; conditionally licensed for use in gray foxes.

17 Request to Ship + Test an Experimental Biologic 9 CFR Analysis of pre-license data & information Hazard Identification & Release Assessment Risk Characterization Low: Acceptable Risk Approve Request Medium: Unacceptable Risk Satisfactory Mitigation High: Unacceptable Risk Deny Request Yes: Approve Request No: Deny Request

18 Rabies Wild Animals

19 *

Canarypox Vectored Vaccines Case Study The backbone strain ALVAC is derived from an attenuated vaccine strain KANAPOX Tested in humans and animals: NIH Risk Group 1 (lowest) Host range is restricted:

20 Canarypox Vectored Vaccines Case Study The backbone strain ALVAC is derived from an attenuated vaccine strain KANAPOX Tested in humans and animals: NIH Risk Group 1 (lowest) Host range is restricted: no replication in mammalian cells, but protein is expressed for an immune response Many back passage and shed-spread studies, tests in target and non-target species, incl. 4 spp. of mosquitoes Vaccines are for canine distemper (1 st ), feline rabies, several strains of equine flu, West Nile virus, feline leukemia Field trials in at least 3 different geographical areas for each of these prelicense vaccines

21 Request to Ship + Test an Experimental Biologic 9 CFR Analysis of pre-license data & information Hazard Identification & Release Assessment Risk Characterization Low: Acceptable Risk Approve Request Medium: Unacceptable Risk Satisfactory Mitigation High: Unacceptable Risk Deny Request Yes: Approve Request No: Deny Request

22 Category I: Non-replicating Recombinant Antigen(s) Subunit or Killed Vaccines examples: Feline Leukemia, Porcine Circovirus Diagnostic Kits examples: Antibody Test Kits for EIA, IBD, AI, PRRS Viruses Antibody Test Kits for Anaplasma, Babesia Equi, B. Caballi DNA Vaccines - examples: West Nile virus, Canine Melanoma

23 Category II: Live Gene-Deleted Salmonella Typhimurium Vaccine Poultry Escherichia Coli Vaccine Poultry Salmonella Dublin Vaccine Bovines Pseudorabies Vaccine Swine

24 Category III Licensed Live Vectored Vaccines ~15 live vectored vaccines: some are made by several companies +/or are in combination vaccines Antigens in fowl pox vector: from avian influenza H5, Newcastle disease virus, infectious laryngotracheitis virus Antigens in turkey herpesvirus vector: from Marek s disease virus, Newcastle disease virus, infectious bursal disease, infectious laryngotracheitis virus Rabies glycoprotein in vaccinia virus vector Marek s disease virus: herpes-chimera Antigens in canarypox vector: from canine distemper, rabies, equine influenza, West Nile, feline leukemia virus

problematic; post-translational modifications occur Compartmentalization within the cell (e.g.

25 Transgenic Plants as Bioreactors Potential for high levels of accumulated recombinant proteins: faster, less cost, easier Expression by transient vectors, or stable transgenes (through nuclear or chloroplast transformation) Glycosylation differences apparently not problematic; post-translational modifications occur Compartmentalization within the cell (e.g. chloroplast) Natural storage stability in certain organs (e.g. seeds) No contamination from animal byproducts Ease of delivery: possibly oral, with no cold chain requirement for refrigeration

26 Types of Plant-Based Biologics Vaccines Feed-based for oral mucosal immunization Whole plant or partial plant Purified protein Parenteral subunit or feed additive Plantibodies Diagnostic kit components Antigens, plantibodies

Safety Considerations Environmental effects Non-target animals Pollen drift: spatial & temporal Food crops Wild/weedy relatives Confinement, persistence,

27 Safety Considerations Environmental effects Non-target animals Pollen drift: spatial & temporal Food crops Wild/weedy relatives Confinement, persistence, dormancy Accidental release to food/feed facility Viable/nonviable material Health risk: toxin, allergen, immunotolerance? Loss of public confidence in segregation

Guidance Documents USDA/FDA, 9/12/02 Guidance for Industry Drugs, biologics, and medical devices derived from bioengineered plants for use in humans and animals USDA/APHIS, 7/9/08 Guidance APHIS

28 Guidance Documents USDA/FDA, 9/12/02 Guidance for Industry Drugs, biologics, and medical devices derived from bioengineered plants for use in humans and animals USDA/APHIS, 7/9/08 Guidance APHIS Permits for Field Testing or Movement of Organisms Intended for Pharmaceutical or Industrial Use USDA/APHIS, 10/9/08 Proposed Rule Importation, Interstate Movement, and Release Into the Environment of Certain Genetically Engineered Organisms

29 Requirements for Oral Vaccines Outline must state pesticide, herbicide use Serial: mixed as a batch or representative sampling to demonstrate homogeneity Purity: within accepted levels for mycotoxins, pesticides, herbicides, soil-borne contaminants, naturally occurring plant toxins, etc. Target Animal Safety: overdose/tolerance study but not reversion-to-virulence; reproductive safety; response in young/old Environmental safety: use, manufacture, disposal Potency & stability: identify & measure the protective Ag or Ab in bulk or finished product

30 Transgenic Plant Cell Line Producing a Subunit Vaccine 1 st plant cell-derived vaccine: Newcastle Disease Vaccine, Subunit, licensed in 2006, modified tobacco cell line Testing=9CFR, Parts (conventional regs), plus: Genetic and phenotypic ID of the Master Cell Line Transformation event and passage history Testing for host plant cell-specific pathogens and unwanted secondary metabolites Genetic, phenotypic stability at X and X + _ (highest pass used in production) Methods other than karyology

31 Transgenic Plant-Derived Proteins for Animal Vaccines* Rabbit hemorrhagic disease virus VP60 in potato (injection) Foot-and-mouth disease virus VP1 in Arabidopsis (injection) VP1 in alfalfa (injection, oral) Transmissible gastroenteritis virus S protein in Arabidopsis (injection) S protein in tobacco (injection) S protein in maize (oral) *Daniell et al., Trends in Plant Science 6: , 2001

32 Additional Transgenic Plant-Derived Animal Vaccines Infectious bursal disease virus VP2: in Arabidopsis (oral) Enterotoxigenic E. coli binding inhibitor: from tobacco (oral) Canine parvovirus VP2: from recombinant plant virus, also tobacco chloroplasts (injection) Classical swine fever virus E2: tobacco chloroplasts (injctn.) Foot and mouth disease virus VP1 epitope: in Arabidopsis, alfalfa, and potato (injection, oral) Bovine rotavirus epitope ebrv4: in alfalfa (injection, oral) Bovine viral diarrhea virus E2: in alfalfa (injection, oral) Newcastle disease virus: from tobacco plants

33 Unique Vaccines/Emerging Issues Nanovaccines the (distant) future???

34 Unique Vaccines/Emerging Issues Foreign animal diseases: [example: Foot-and-Mouth Disease Vaccine, Live Adenovirus Vector (pending field trials, testing on US mainland)] Compendium of Veterinary Vaccines for Transboundary Diseases: Innovations: [example: modified live vaccines for use in pregnant animals (e.g. Bovine virus diarrhea {BVD} virus, special testing requirements)] Public perception of risk (Biotechnology) Domestic/wildlife interface One Health approach (zoonotic agents) Regulatory flexibility and product innovation

35 Questions or comments?

Anja Holm Danish Medicines Agency. Genetic vaccines Oslo, 2008

Anja Holm Danish Medicines Agency Genetic vaccines Oslo, 2008 Legal basis for authorisation Special double environmental assessment Authorised GMO products Anja Holm - GMO vaccines - Oslo 2008 2 Regulation