Government of Canada
Symbol of the Government of Canada

Environmental assessment for licensing distemper vaccine, live canarypox vector for ferrets in Canada

For Public Release

September 4, 2002

The information in this environmental assessment was current at the time of its preparation. It is possible that the situation may have changed since that time. Please consult the VBS if you have any questions.


Table of Contents

  • Summary
  • 1. Introduction
    • 1.1 Proposed Action
    • 1.2 Background
  • 2. Purpose and need for proposed action
    • 2.1 Significance
    • 2.2 Rationale
  • 3. Alternatives
  • 4. Molecular and biological characteristics of parental and recombinant organisms
    • 4.1 Identification, Sources, and Strains of Parental Organisms
    • 4.2 Source, Description and Function of Foreign Genetic Material
    • 4.3 Method of Accomplishing Genetic Modification
    • 4.4 Genetic and Phenotypic Stability of the Vaccine Organism
    • 4.5 Horizontal Gene Transfer and Potential for Recombination
    • 4.6 Host Range/Specificity, Tissue Tropism and Shed/Spread Capabilities
    • 4.7 Comparison of the Modified Organisms to Parental Properties
    • 4.8 Route of Administration/Transmission
  • 5. Human Safety
    • 5.1 Previous Safe Use
    • 5.2 Probability of Human Exposure
    • 5.3 Possible Outcomes of Human Exposure
    • 5.4 Pathogenicity of Parent Microorganisms in Humans
    • 5.5 Effect of Gene Manipulation on Pathogenicity in Humans
    • 5.6 Risk Associated with Widespread Use of the Vaccine
  • 6. Animal Safety
    • 6.1 Previous Safe Use
    • 6.2 Fate of the Vaccine in Target and Non-Target Species
    • 6.3 Potential of Shed and/or Spread from Vaccinate to Contact Target and Non-Target Animals
    • 6.4 Reversion to Virulence Resulting from Back Passage in Animals
    • 6.5 Effect of Overdose in Target and Potential Non-Target Species
    • 6.6 The Extent of the Host Range and the Degree of Mobility of the Vector
    • 6.7 Safety in Pregnant Animals and to Offspring Nursing Vaccinated Animals
  • 7. Affected Environment
    • 7.1 Extent of Release into the Environment
    • 7.2 Persistence of the Vector in the Environment / Cumulative Impacts
    • 7.3 Extent of Exposure to Non-Target Species
    • 7.4 Behaviour of Parent Microorganisms and Vector in Non-Target Species
  • 8. Environmental Consequences
    • 8.1 Risks and Benefits
    • 8.2 Relative Safety Compared to Other Vaccines
  • 9. Mitigative Measures
    • 9.1 Worker Safety
    • 9.2 Handling Vaccinated or Exposed Animals
  • 10. Monitoring
    • 10.1 General
    • 10.2 Human
    • 10.3 Animal
  • 11. Consultation and Contacts
  • 12. Conclusions and Actions
  • 13. References

Summary

Distemper vaccine, live canarypox vector consists of the live canarypox virus modified by the introduction of two canine distemper virus genes encoding the fusion (F) and haemagglutinin (HA) glycoproteins. The canarypox-distemper vaccine (Purevax Ferret Distemper, manufactured by Merial Ltd., Athens, Georgia) was evaluated by the Veterinary Biologics Section (VBS), Canadian Food Inspection Agency (CFIA) for licensing in Canada. As part of the requirements for licensing this product in Canada, an ‘Environmental Assessment' was conducted and a public document which contains information on the molecular and biological characteristics of the live recombinant organism, target animal and non-target animal safety, human safety, environmental considerations and risk mitigation measures prepared. The product review process determined that the above product satisfied the requirements for licensing of a veterinary biologic in Canada.

1. Introduction

1.1 Proposed Action

Veterinary Biologics Section (VBS), Animal Health and Production Division, Canadian Food Inspection Agency (CFIA) is responsible for licensing veterinary biologics for use in Canada. The legal authority for the regulation of veterinary biologics in Canada is provided under the Health of Animals Act and Regulations. Any veterinary biologic manufactured, sold or represented for use in Canada must comply with the requirements specified by the CFIA regarding safety, purity, efficacy and potency of the product. Merial Canada Inc has submitted the following ferret vaccine for licensing in Canada:

  • Distemper Vaccine, Live Canarypox Vector (Purevax Ferret Distemper), USDA Product Code 1471.R0, CFIA File 850VV/M2.0/R2.1

The Environmental Assessment was prepared by VBS as part of the overall assessment for licensing the above vaccine in Canada.

1.2 Background

The above vaccine containing a live recombinant canarypox-distemper vaccine is manufactured by Merial Ltd., Athens, Georgia (US Veterinary Biologics Establishment License No. 298). This vaccine is currently licensed for sale in the US. The recombinant vaccine consists of live canarypox virus, modified by the insertion of genetic material coding for distemper fusion (F) and haemagglutinin (HA) glycoproteins. This is a stand-alone product. VBS has previously licensed this recombinant construct as a component of four canarypox-based combination vaccines for use in canines. Details of these canine products are on file at VBS under VBS file numbers 820VV/C40.5/R2.1, 820VV/C42.0/R2.1, 820V2X/C35.6/R2.1, and 820V2X/C0.5/R2.1. In addition further information is contained within the Environmental Assessment for Canarypox-Distemper Vaccine Component (1998). As the recombinant construct in this vaccine is identical to the recombinant construct found as a component in the canine products, where applicable, information and conclusions previously made for the canine products (see Environmental Assessment for Canarypox-Distemper Vaccine Component (1998)) will apply to the ferret vaccine product.

2. Purpose and need for proposed action

2.1 Significance

The label indication for Purevax Ferret Distemper is for the vaccination of healthy ferrets 8 weeks of age and older for the prevention of disease due to canine distemper.

2.2 Rationale

The VBS evaluates veterinary biologics submissions for licensing under the Health of Animals Act and Regulations. General criteria for licensing are (a) the product must be pure, safe, potent and efficacious, (b) the product must be licensed in the country of origin, (c) vaccine components must be relevant to Canadian disease conditions and (d) the product must be produced and tested in accordance with generally accepted “good manufacturing practices”. This US origin vaccine meets the general criteria and presented no unacceptable importation risk, and therefore was evaluated for licensing by VBS.

3. Alternatives

The two alternative options available are: (a) to issue a Permit to Import Veterinary Biologics to Merial Canada Inc. for the importation of Purevax Ferret Distemper from the US, if all licensing requirements are satisfactory, or (b) not to issue a Permit to Import Veterinary Biologics, if licensing requirements are not met.

4. Molecular and biological characteristics of parental and recombinant organisms

4.1 Identification, Sources, and Strains of Parental Organisms

Refer to section 4.1 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

4.2 Source, Description and Function of Foreign Genetic Material

Refer to section 4.2 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

4.3 Method of Accomplishing Genetic Modification

Refer to section 4.3 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

4.4 Genetic and Phenotypic Stability of the Vaccine Organism

Refer to section 4.4 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

4.5 Horizontal Gene Transfer and Potential for Recombination

Recombination as a result of molecular interaction between poxviruses within co-infected cells was reported by Moss (1992). As canarypox-distemper does not replicate in the ferret host and as it is not administered in combination with other modified live viruses the likelihood of recombination events is very low.

4.6 Host Range/Specificity, Tissue Tropism and Shed/Spread Capabilities

Refer to section 4.6 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

4.7 Comparison of the Modified Organisms to Parental Properties

Refer to section 4.7 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

4.8 Route of Administration/Transmission

Refer to section 4.8 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

5. Human Safety

A human safety assessment for the specific use of the canarypox-distemper vaccine in ferrets was not done. Previously, the regulatory group formerly known as the Bureau of Biologics and Radiopharmaceuticals, Health Protection Branch, Health Canada, reviewed the human safety data supplied by Virogenetics Corporation, Troy, New York and Merial Inc., Atlanta, Georgia, for the use of this canarypox-distemper vaccine in dogs (Refer to files 820VV/C40.5/R2.1, 820VV/C42.0/R2.1, 820V2X/C35.6/R2.1, and 820V2X/C0.5/R2.1). Following the assessment, Health Canada indicated that there was no objection from the human safety aspect to the use of the canarypox-distemper vaccine in dogs.

5.1 Previous Safe Use

Numerous canarypox-based recombinants have been used in phase I human clinical trials (Cadoz et al., 1992; Taylor et al., 1994; Pialoux et al.,1995; Plotkin et al., 1995; Fleury et al., 1996; Paoletti, 1996, Fries et al., 1996; Coeffier et al., 1997; Clements-Mann et al., 1998; Marshall et al., 1999 and others).

5.2 Probability of Human Exposure

Human exposure to the vaccine is likely to be limited to veterinarians, animal technicians, manufacturing staff and testing laboratory staff.

5.3 Possible Outcomes of Human Exposure

Refer to section 5.3 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

5.4 Pathogenicity of Parent Microorganisms in Humans

Refer to section 5.4 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

5.5 Effect of Gene Manipulation on Pathogenicity in Humans

Recombinant canarypox-distemper vaccine is not expected to be pathogenic in humans.

5.6 Risk Associated with Widespread Use of the Vaccine

The widespread use of the vaccine is not expected to have any public health significance.

6. Animal Safety

6.1 Previous Safe Use

Safety of the recombinant canarypox-distemper vaccine has been demonstrated in dogs (field safety trial involving 1875 dogs conducted in several US veterinary clinics) and in ferrets (field safety trial involving 1085 ferrets conducted in several US veterinary clinics). Experimental canarypox-based recombinants for a number of disease agents have been used in humans, cats, dogs, ferrets, canaries, chickens, primates (squirrel monkeys, cynomolgus monkeys, chimpanzees, macaques), and rodents. These data are on file at VBS.

6.2 Fate of the Vaccine in Target and Non-Target Species

Backpassage studies in dogs with this vaccine demonstrated a lack of reversion to virulence. The manufacturer was exempted from backpassage studies in ferrets. The vaccine does not replicate in mammalian animals. There are no reports of avipoxviruses causing productive infection in species other than the avian species. The vaccine is not shed after subcutaneous vaccination of mammals, therefore birds in the veterinary clinic should not be at risk. No local or systemic reactions were noted in ferrets vaccinated with more than 10X the release dose of canarypox distemper. Refer to section 6.2 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998) for further information.

6.3 Potential of Shed and/or Spread from Vaccinate to Contact Target and Non-Target Animals

Refer to section 6.3 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

6.4 Reversion to Virulence Resulting from Back Passage in Animals

Refer to section 6.4 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

6.5 Effect of Overdose in Target and Potential Non-Target Species

Overdose testing of the vaccine has been done in dogs and in ferrets. No adverse effects following vaccination were noted.

6.6 The Extent of the Host Range and the Degree of Mobility of the Vector

Canarypox virus is restricted in its host range to avian species. Recombinant canarypox-distemper is not shed from vaccinated ferrets and, thus, no spread of the organism is expected.

6.7 Safety in Pregnant Animals and to Offspring Nursing Vaccinated Animals

Since canarypox-distemper does not replicate and shed in mammalian hosts, the safety profile of the vaccine is not expected to be different for pregnant animals and offspring nursing vaccinated animals.

7. Affected Environment

7.1 Extent of Release into the Environment

Refer to section 7.1 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

7.2 Persistence of the Vector in the Environment / Cumulative Impacts

Refer to section 7.2 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

7.3 Extent of Exposure to Non-Target Species

Refer to section 7.3 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

7.4 Behaviour of Parent Microorganisms and Vector in Non-Target Species

Refer to section 7.4 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

8. Environmental Consequences

8.1 Risks and Benefits

For any vaccine, risks of vaccination can be attributed to potential adverse reactions. Occasional adverse reactions such as transient lethargy, inflammatory or hypersensitive types of reactions have been noted in ferrets vaccinated with canarypox-distemper. This risk is identified on the product label along with a recommended treatment regimen that may include antihistamines, anti-inflammatories, and/or epinephrine. The efficacy of the canarypox-distemper vaccine in protecting ferrets against distemper has been demonstrated in vaccination-challenge experiments.

8.2 Relative Safety Compared to Other Vaccines

Refer to section 8.2 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

9. Mitigative Measures

9.1 Worker Safety

Refer to section 9.1 of Environmental Assessment for Canarypox-Distemper Vaccine Component (June 15, 1998).

9.2 Handling Vaccinated or Exposed Animals

Exposure of groups such as ferret owners to the live recombinant organism is likely to be very low since vaccinated animals do not shed the virus and unintended contamination of hair and skin at the vaccination site is not considered to be of public health significance.

10. Monitoring

10.1 General

The vaccine licensing regulations in Canada require manufacturers to report all suspected adverse reactions to CFIA within 15 days of receiving notice from an owner or a veterinarian. Veterinarians may also report suspected adverse reactions directly to the CFIA. On VBS receipt of an adverse reaction complaint, the manufacturer is asked to investigate and prepare a report for the owner's veterinarian and CFIA. If the problem is resolved to the satisfaction of the veterinarian/client, no further action is usually requested by VBS. However, if the investigation is not satisfactory, VBS may initiate regulatory action depending on the case which may include further safety testing, temporary stop sale or product withdrawal from the market.

10.2 Human

No special monitoring of the human safety of the product will be carried out.

10.3 Animal

Veterinarians/ferret owners and manufacturers should report any suspected adverse reactions to VBS as indicated above. For reporting purposes, adverse reactions are divided into Type 1, 2, and 3 reactions. Type 1 reactions are defined as any systemic adverse reaction, anaphylactic or hypersensitivity requiring veterinary treatment including: persistent fever, recumbency, persistent lethargy, decrease in activity, muscle tremors, shivering, hypersalivation, dyspnea and other respiratory problems, cyanosis, diarrhea, vomiting, colic and other gastrointestinal problems, eye problems, abortions and other reproductive problems and neurological signs. Type 2 reactions are defined as death following vaccination. Type 3 reactions are defined as local persistent reactions such as edema, abscess, granuloma, fibrosis, alopecia, hyperpigmentation and excessive pain at the injection site. Suspected adverse reactions should be reported using the form Notification of Adverse Reactions to Veterinary Biologics (CFIA-ACIA 2205).

11. Consultation and Contacts

Importer

Merial Canada Inc.
500 boulevard Morgan
Baie d'Urfé, QC
H9X 3V1

Manufacturer

Merial Ltd.
115 Transtech Drive
Athens, Georgia USA 30601

12. Conclusions and Actions

The Permit to Import Veterinary Biologics held by Merial Canada Inc., Québec, was amended to allow importation of the following product from the manufacturer Merial Limited, Athens, Georgia:

  • Distemper Vaccine, Live Canarypox Vector (Purevax Ferret Distemper), USDA Product Code 1471.R0, CFIA File 850VV/M2.0/R2.1

13. References

Cadoz, M., A. Strady, B. Meignier, J. Taylor, J. Tartaglia, E. Paoletti, and S. Plotkin. 1992. Immunisation with canarypox virus expressing rabies glycoprotein. Lancet 339:1429-1432.

Clements-Mann, M.L., K. Weinhold, T.J. Matthews, B.S. Graham, G.J. Gorse, M.C. Keefer, M.J. McElrath, R.H. Hsieh, J. Mestecky, S. Zolla-Pazner, J. Mascola, D. Schwartz, R. Siliciano, L. Corey, P.F. Wright, R. Belshe, R. Dolin, S. Jackson, S. Xu, P. Fast, M.C. Walker, D. Stablein, J. L. Excler, J. Tartaglia, and E. Paoletti (1998). Immune responses to human immunodeficiency virus (HIV) type 1 induced by canarypox expressing HIV-1MN gp120, HIV-1SF2 recombinant gp120, or both vaccines in seronegative adults. NIAID AIDS Vaccine Evaluation Group. J. Infect. Dis. 177:1230-1246.

Coeffier, E., J.L. Excler, M.P. Kieny, B. Meignier, C. Moste, J. Tartaglia, G. Pialoux, D. Salmon-Ceron and C. Leclerc (1997). Restricted specificity of anti-V3 antibodies induced in humans by HIV candidate vaccines. AIDS Res Hum Retroviruses 17:1471-1485.

Environmental Assessment for Canarypox-Distemper Vaccine Component. Veterinary Biologics Section, Canadian Food Inspection Agency, June 15, 1998.

Fleury, B., G. Janvier, G. Pialoux, F. Buseyne, M.N. Robertson, J. Tartaglia, E. Paoletti, M.P. Kieny, J.L. Excler and Y. Riviere (1996). Memory cytotoxic T lymphocyte responses in human immunodeficiency virus type 1 (HIV-1)-negative volunteers immunized with a recombinant canarypox expressing gp 160 of HIV-1 and boosted with recombinant gp 160. J. Infect. Dis. 174:734-738.

Fries, L.F., J. Tartaglia, J. Taylor, E.K. Kauffman, B. Meignier, E. Paoletti, and S. Plotkin (1996). Human safety and immunogenicity of a canarypox-rabies glycoprotein recombinant vaccine: an alternative poxvirus vector system.

Marshall, J.L., M.J. Hawkins, K.Y. Tsang, E. Richmond, J.E. Pedicano, M.Z. Zhu, and J. Schlom (1999). Phase I study in cancer patients of a replication-defective avipox recombinant vaccine that expresses human carcinoembryonic antigen. J. Clin. Oncol. 17:332-337.

Paoletti, E. (1996). Application of pox virus vectors to vaccination: an update. Proc. Natl. Acad. Sci. USA 93:11349-11353.

Pialoux, G., J.L. Excler, Y. Reviere, G. Gonzales-Canali, V. Feuillie, P. Coulaud, J.C. Gluckman, T.J. Matthews, P. Meignier, M.P. Kieny, P. Gonnet, I. Diaz, C. Meric, E. Paoletti, J. Tartaglia, H. Solomon, and S. Plotkin, (1995). A prime-boost approach to HIV preventive vaccine using a recombinant canarypox virus expressing glycoprotein 160 (MN) followed by a recombinant glycoprotein (MN/LAI). The AGIS Group, and l'Agence Nationale de Recherche sur la Sida. AIDS Research and Human Retroviruses 11:373-381.

Plotkin, S.A., M. Cadoz, B. Meignier, C. Meric, O. Leroy, J.L. Excler, J. Tartaglia, E. Paoletti, E. Gonczol, and G. Chappuis. 1995. The safety and use of canarypox vectored vaccines. Dev. Biol. Stand. 84:165-170.

Rhone Merieux, Inc. (November 6, 1996). ‘Risk analysis for a canarypox-vector distemper vaccine for dogs'.

Taylor, J., J. Tartaglia, M. Riviere, C. Duret, B. Languet, G. Chappuis, and E. Paoletti. 1994. Applications of canarypox (ALVAC) vectors in human and veterinary vaccination. Dev. Biol. Stand. 82:131-135.

Tripathy, D.N. and C.H. Cunningham (1984) Avian pox. In Diseases of Poultry, 8th edition, edited by M.S. Hofstad, H.J. Barnes, B.W. Calnek, W.M. Reid, and H.W. Yoder Jr., Iowa State University Press, Iowa. pp 524-534.


Prepared and revised by:

Veterinary Biologics Section
Animal Health and Production Division
Canadian Food Inspection Agency