Van Kampen Viral Vectored Vaccines

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Presented by Dr. Kent Van Kampen at the Alliance for Contraception in Cats & Dogs’ 4th International Symposium on Non-Surgical Contraceptive Methods of Pet Population Control, April 8-10, 2010, in Dallas, Texas, U.S.

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Slide 1: 

Immunocontraceptive Program Using Vaccines to Modify Sexual Behavior or Interfere with Fertility April 2010

Vaxin-Auburn Program : 

Vaxin-Auburn Program Broad technology platform Application of viral/bacterial vectors Oral, injected or inhaled For prevention of infectious disease To alter physiological function Unique, simple approach Program focus Injectable immunocontraceptive for domestic animals Oral immunocontraceptive for feral or wild animals

Goals : 

Goals Single dose vaccine – by injection for companion animals and other routes for feral and wild animals No significant adverse effects Inhibition of estrus and pregnancy Prolonged duration of immunity Cost effective

Adenovirus Vectors : 

Adenovirus Vectors Human adenovirus strain 5 CMV promoter, genetic insert for encoding desired protein Preclinical data – viral distribution, toxicity, safety, immunogenicity & protection for flu and anthrax vaccines Clinical data – Seasonal and pandemic influenza in man and avian influenza in chickens

Vaxin Technology : 

Vaxin Technology Clone Antigen gene Pathogen Genome Adenovirus Vaccine Multi-faceted Immune Response Non-medical personnel can administer Antigenic Gene Fast, efficient, non-egg based manufacturing Antigenic Gene Step 1: Modify virus for Antigenic Gene Step 2: Manufacture in bulk Step 3: Administer nasally Step 4: Body produces immune response

No Interference from Adenovirus Neutralizing Abs : 

No Interference from Adenovirus Neutralizing Abs Vaxin vaccines allow for repeat administration (Intranasally administered seasonal influenza vaccine; Van Kampen KR et al. Vaccine 23: 1029, 2005)

Immunization of Ferrets by Intranasal Administration : 

Immunization of Ferrets by Intranasal Administration Ferrets were immunized against A/Vietnam/1203/04 (H5N1) by intranasal administration

Ferrets Protected after Challenge with A/Vietnam/1203/04 (H5N1) : 

Ferrets Protected after Challenge with A/Vietnam/1203/04 (H5N1) Immunized i.n. on Days 0, 28 Challenged i.n. with 10 FLD50 (102 EID50) on Day 56 HA1+2 = vaccine encoding essentially full length HA w/o polybasic motif HA1 = vaccine encoding soluble HA Control = no treatment

Mice Protected Against A/Vietnam/1203/04 (H5N1) Challenge : 

Mice Protected Against A/Vietnam/1203/04 (H5N1) Challenge Immunized i.n. on Day 0 Challenged i.n., with 10 MLD50 (104.4 EID50) on Day 63 HA1+2 = vaccine encoding full length HA w/o polybasic motif HA1 = vaccine encoding soluble HA Control = no treatment

Other Vectored Vaccines : 

Other Vectored Vaccines Anthrax Avian Influenza Alzheimer’s Disease

Duration of Immunity – AdhPA10^7 ifu in 10 ul (IN) : 

Duration of Immunity – AdhPA10^7 ifu in 10 ul (IN) Group 1 Group 2 Group 3 Group 4 AdhPA Combination AVA Vector Control Comparison of Elisa Antibody Titers

Potential Benefits of Immunocontraception : 

Potential Benefits of Immunocontraception Reduced burden on Animal Shelters Prevent or interfere with transmission of infectious diseases Protect the environment Prevent loss of life and property Airplanes Automobiles Passengers Minimal impact on non-intended species

Raboral® V-RG The Vaccine Container : 

Raboral® V-RG The Vaccine Container Vaccine is enclosed in plastic sachet (like a ketchup packet) Tough, but penetrated by biting action Vaccine released into mouth Any residual vaccine becomes inactive in a short period of time following exposure to the surrounding environment

Vaxin-Auburn Program Objective : 

Vaxin-Auburn Program Objective Modification of Sexual Behavior and/or Fertility

GnRH : 

GnRH Small molecule – produced in the brain Not a good antigen Takes tricks to immunize Stops fertility and behavior Before puberty permanent Improvac® CSL of Melbourne, Pfizer An Health Available for boar taint in Australia Approved by USDA for dog prostatic enlargement

The Pathway : 

The Pathway

Proof of Principle in Male Cats Vaccinated with GnRH : 

Proof of Principle in Male Cats Vaccinated with GnRH Desired Results – Immunological Neutering – Testes from normal male cat (right) and from GnRH treated male cat (left)

Proof of Principle in Female Cats Vaccinated with GnRH : 

Proof of Principle in Female Cats Vaccinated with GnRH Desired Results – Immunological Neutering – Reproductive tract from normal female cat (left) and from an GnRH treated female cat (right)

Broad Potential for Recombinant Vectored Approach : 

Broad Potential for Recombinant Vectored Approach Vectors Replication competent (rc) Replication defective (rd) Genetic inserts GnRH multimers Others Delivery Oral – bacteria or viral vectors Intranasal – viral vector Topical – bacterial or viral vectors Injected – viral vector Combinations of vector, insert and route of delivery allow for species specific tailored solutions

Results in Targeted Animals Cats : 

Results in Targeted Animals Cats Response to Adenovirus Vector

Anti-tetC Antibodies inrdAd Vaccinated Cats via IM route : 

Anti-tetC Antibodies inrdAd Vaccinated Cats via IM route IM = intramuscular Two vaccinated cats (4004, 6A2D) and two non-vaccinated cats (OF3B, 1317)

Anti-tetC Antibodies inrdAd Vaccinated Cats via IN route : 

Anti-tetC Antibodies inrdAd Vaccinated Cats via IN route IN = intranasal Three vaccinated cats (1B2D, 29, 2C4F) and one non-vaccinated cat (520D)

Anti-tetC Antibodies in rdAd Vaccinated Cats via SQ route : 

Anti-tetC Antibodies in rdAd Vaccinated Cats via SQ route SQ = subcutaneous Three vaccinated cats (1C6F, 184D, 423F) and one non-vaccinated cat (1460)

Vaxin – Auburn Specific Program Results : 

Vaxin – Auburn Specific Program Results

Desirable Features of rdVectored Vaccines : 

Desirable Features of rdVectored Vaccines Safe – Non-replicating vectors do not shed or spread Effective – Limited number of doses required Invasive administration for pet animals Intramuscular or subcutaneous Non-invasive administration for feral or wild animals Oral, intranasal, topical Degradable by vaccinate Enzymatically degraded by host’s cells Easily manufactured

Anti-GnRH Antibodies in rdAd Vaccinated Cats : 

Anti-GnRH Antibodies in rdAd Vaccinated Cats Three cats vaccinated IM with 109 vp AdLTKGnRH vaccine on day 0 and boosted on day 180. Antibody levels were determined at baseline, 120 days and 35 days post-boost (day 215).

Testosterone Levels in rdAd Vaccinated Cats : 

Testosterone Levels in rdAd Vaccinated Cats Serum testosterone levels in three cats vaccinated IM with 109vp AdLTKGnRH vaccine at day 0 and boosted at180 days. Testosterone levels determined on day 0, day 36, and day 255. Results indicate significant reduction after initial vaccination (likely sterilizing immunity, however testosterone levels rise to pre-baseline levels even post-boost.

Issues : 

Issues Intellectual Property – rights belonging to multiple groups Multiple licensing agreements – royalty bearing licenses Pathway to licensure for manufacturing and distribution

Licensing Process : 

Licensing Process FDA controlled – not USDA Investigational New Animal Drug (INAD) Recombinant guidelines for vaccines Toxicity and safety data in target species Preclinical and clinical proof of efficacy Determination of duration of immunity Facility license to manufacture

Conclusions : 

Conclusions GnRH shown to induce sterilizing immunity in cats Recombinant vaccine will induce antibodies against GnRH in cats Antibodies against GnRH alter hormone balance necessary for sexual behavior and reproduction Recombinant vectors offer multiple routes of administration for potential population control in feral wild animals Vaccines can be manufactured economically

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