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Environmental assessment for licensing vaccine combinations containing canine distemper vaccine, live canarypox vector in Canada

For Public Release

June 15, 1998

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

Canarypox-distemper live recombinant vaccine consists of the live canarypox virus modified by the introduction of two canine distemper virus genes coding for haemagglutinin (HA) and fusion protein (F). Four combination canine vaccines containing the canarypox-distemper vaccine component (RM Recombitek C4, RM Recombitek C4/CV, RM Recombitek C6 and RM Recombitek C6/CV manufactured by Merial Ltd., Athens, Georgia) were 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 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 canine vaccines containing a live canarypox vector-distemper component for licensing in Canada:

  1. Canine Distemper-Adenovirus Type 2-parainfluenza-parvorius vaccine, modified live virus, live canarypox vector, (RM Recombitek C4), USDA Product Code 13D1.R1, VBS File: 820VV/C40.5/R2.1

  2. Canine Distemper-Adenovirus Type 2-coronavirus-parainfluenza-parvorius vaccine, modified live virus, live canarypox vector, (RM Recombitek C4/CV), USDA Product Code 1591.R1, VBS File: 820VV/C42.5/R2.1

  3. Canine Distemper-Adenovirus Type 2-parainfluenza-parvorius, modified live virus, live canarypox vector, Leptospira bacterin (RM Recombitek C6), USDA Product Code 4639.R1, VBS File: 820V2X/C35.6/R2.1

  4. Canine Distemper-Adenovirus Type 2-coronavirus-parainfluenza-parvorius, modified live virus, live canarypox vector, Leptospira bacterin (RM Recombitek C6/CV), USDA Product Code 46J9.R1, VBS File: 820 V2X/CO.5/R2.1

The Environmental Assessment was prepared by VBS as part of the overall assessment for licensing the above vaccines in Canada. CFIA worked collaboratively with Health Canada in the assessment process, specifically on the evaluation of human safety aspect of the vaccine.

1.2 Background

The above combination vaccines containing the live recombinant canarypox-distemper component are manufactured by Merial Ltd., Athens, Georgia (US Veterinary Biologics Establishment License No. 298). They are currently licensed for sale in the US. The recombinant vaccine component in these vaccine combinations consists of live canarypox virus, modified by the introduction of genetic material coding for two glycoproteins - haemagglutinin (HA) and fusion protein (F) genes isolated from canine distemper virus.

2. Purpose and need for proposed action

2.1 Significance

The label indication for Recombitek C4 vaccine is for the vaccination of dogs against diseases caused by canine distemper virus, hepatitis virus, adenovirus type 2 and parainfluenza virus. Combination vaccines Recombitek C4/CV, Recombitek C6 and Recombitek C6/CV have additional claims for use against canine parvovirus, canine coronavirus, and Leptospira stains, L. canicola and L. icterohaemorrhagiae depending of the formulation.

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 alternatives available are: (a) to issue a Permit to Import Veterinary Biologics to Merial Canada Inc. for the importation of Recombitek C4, Recombitek C4/CV, Recombitek C6 and Recombitek C6/CV from the US, if all licensing requirements are satisfactory, or (b) not to issue a Permit to Import Veterinary Biologics for all products, 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

Canarypox virus
Canarypox virus is a double stranded deoxyribonucleic acid (DNA) virus belonging to the genus Avipoxvirus (family: Poxviridae, subfamily: Chordopoxviridae). Avipox viruses are known to produce productive infections only in avian species. The parent strain of canarypox virus used in the construction of the recombinant organism is an attenuated strain (Rentschler strain) of canarypox licensed as a vaccine in France.

Canine distemper virus
Canine distemper virus (CDV) is a single stranded ribonucleic acid (RNA) virus belonging to the genus Morbillivirus, family Paramyxovirus. The source of the haemagglutinin (HA) and fusion (F) protein genes for the recombinant organism was the Onderstepoort strain of canine distemper virus obtained from Cornell University, New York.

Vaccinia virus
Vaccinia virus, the prototypic of virus of the genus Orthopoxvirus, is a large double stranded DNA virus. In the construction of the recombinant organism, vaccinia virus H6 promoter was cloned upstream of HA and F genes to direct the transcription of recombinant proteins.

4.2 Source, Description and Function of Foreign Genetic Material

Haemagglutinin and fusion proteins from the genus Morbillivirus appear to be important in viral infectivity and act as immunogens for the generation of protective host responses. In the construction of the recombinant organism, genetic sequences for HA and F proteins were inserted into the genomic DNA of a plaque purified isolate of the parental canarypox strain designated as ALVAC.

4.3 Method of Accomplishing Genetic Modification

Details of the methods used in the construction of the recombinant organism are on file with VBS. The identify and the purity of the recombinant organism has been verified by in situ hybridization to screen for the absence of parental canarypox virus, and by indirect immunofluorescence to screen for the expression of HA and F proteins on the surface of ALVAC-CDV infected tissus culture cells, and in gels following immunoprecipitation. A Master Seed stock of the recombinant organism was establish by the manufacturer and tested for mammalian and avian extraneous agents, purity and safety according to the methods described in US Code of Federal Regulations (ie. 9CFR). Expression of the HA and F proteins was tested by indirect immunofluorescence using monoclonal antibodies specific for the proteins.

4.4 Genetic and Phenotypic Stability of the Vaccine Organism

Genetic and phenotypic stability of a recombinant construct is an important consideration in the evaluation of purity and safety of any genetically modified organism that is to be used as a vaccine. The recombinant ALVAC-distemper organism passaged to the maximum level allowed for production has been tested for the expression of HA and F proteins using a plaque immunoassay and found to be satisfactory.

4.5 Horizontal Gene Transfer and Potential for Recombination

Recombination as a result of molecular interaction between poxviruses within co-infected cells was reported (see Moss, 1992). It is also a property exhibited by many other viruses including coronaviruses. Since live recombinant canarypox - distemper vaccine is administered together with other modified live vaccine organisms such as canine adenovirus type 2, canine coronavirus, canine parainfluenza and canine parvovirus in the combination vaccines, the potential for horizontal gene transfer and recombination should be considered. Such a recombination event may result in canarypox - distemper organism or other modified live viruses acquiring genetic material from each other which in turn may lead to changes in the virulence of the affected virus. The virulence may decrease, remain unchanged or increase as a result of gene transfer. However, the likelihood of the occurrence of horizontal gene transfer and recombination between these viruses following vaccination is likely to be very low because of the following factors: (a) no significant sequence homologies have been documented between different vaccine virus components, (b) recombination is not observed between members of paramyxovirus family (member: canine parainfluenza virus), and (c) canine adenovirus and canine parvovirus undergo replication in the nucleus whereas poxviruses replicate in the cytoplasm (canarypox virus does not replicate in the canine host).

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

The natural host range of avipoxviruses is limited to avian species. Avipoxviruses occur worldwide and infect close to sixty avian species. Some members of the avipoxvirus family, particularly those infecting wild birds, exhibit a high degree of host specificity, while others appear to be less host specific. Canarypox virus is known to infect canaries, ducks, chickens, turkeys and pigeons (Tripathy and Cunningham, 1984) but the host range may not be limited to these species. In canaries, wild type canarypox virus causes local pox lesions and death. In pigeons, wild canarypox virus causes generalized infections and local lesions, while in chickens, turkeys and ducks it causes only localized lesions. Localized lesions of canarypox usually occur in the skin on comb and wattles and are characterized by distinct white/yellow nodules. In the generalized from of the disease, diphtheritic lesions occur in the mucous membranes of the mouth, oesophagus and trachea of birds with respiratory signs.

4.7 Comparison of the Modified Organisms to Parental Properties

The host range of the recombinant organism is expected to be same as the parental canarypox vaccine strain.

4.8 Route of Administration/Transmission

Avipoxviruses are transmitted mechanically from infected birds by aerosols, animal handlers, mosquitoes, Diptera spp. and mites. Poxviruses are typically capable of surviving for long periods in the environment, particularly in dried scabs (Tripathy and Reed, 1997).

5. Human Safety

As part of the safety assessment, the regulatory group formerly known as the Bureau of Biologicals and Radiopharmaceuticals, Health Protection Branch, Health Canada reviewed the human safety data supplied by Virogenetics Corporation, Troy, New York and Merial Inc., Georgia. Following the assessment, Health Canada indicated that they had no objection from the human safety aspect to the use of the above recombinant canarypox-distemper vector vaccines in dogs.

5.1 Previous Safe Use

Several ALVAC based recombinants have been used in phase I human clinical trials (Cadoz et al., 1992; Taylor et al., 1994; Plotkin et al., 1995; Paoletti et al., 1996). ALVAC-RG, which is a canarypox virus construct containing the rabies glycoprotein gene, has been administered safely to human volunteers in France (Cadoz et al., 1992) and the US (Fries et al., 1996). Also, a number of human clinical trials have been carried out using ALVAC based experimental recombinant vaccines to test the immunogenicity against human immunodeficiency virus (Pialoux et al., 1995; Fleury et al., 1996; Coeffier et al., 1997; Clements-Mann et al., 1998)

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

Canarypox virus is not a zoonotic agent and is not expected to affect human health. Upon intramuscular injection of human volunteers with an ALVAC based recombinant rabies vaccine, mild transient local reactions such as tenderness and discomfort as well as systemic complaints such as mild headache and fatigue have been observed (Cadoz et al., 1992; Fries et al., 1996).

5.4 Pathogenicity of Parent Microorganisms in Humans

The parental strain of canarypox virus has not been tested for pathogenicity in man. Several ALVAC recombinant constructs derived from the Rentschler strain of canarypox have been tested in man (see section 5.1).

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

The recombinant ALVAC-distemper organism has been administered to dogs in a large scale field safety trial involving 1875 dogs conducted in several US veterinary clinics. Experimental ALVAC based recombinants have been used in cats to test for immunity against feline leukaemia virus (Tartaglia et al., 1992, et al. 1993) and in ferrets for evaluating protection against canine distemper virus (Stephenson et al., 1997). A number of experimental ALVAC based vaccines against human immunodeficiency virus has been tested in primates - eg. chimpanzees (Girard et al., 1997), cynomolgus monkeys (Anderson et al., 1996) and rhesus macaques (Myagkikh et al., 1996). A number of human clinical trials have also been carried out using ALVAC based recombinants to test for immune responses against human immunodeficiency virus (Cadoz et al., 1992; Tartaglia et al., 1996; Clements-Mann et al., 1998).

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

Upon inoculation into dogs, the vaccine organism is not expected to replicate since avipoxviruses cannot productively replicate in mammalian cells. In an experiment conducted using the ALVAC-distemper recombinant, ten dogs were inoculated subcutaneously with a high dose of the vaccine, and virus isolation was attempted from conjunctival, nasal and faecal swabs as well as from blood and injection site biopsy samples. Virus isolation results were negative for all samples. In another experiment, intradermal injection of the vaccine organism into mice and serial sampling of the injection site by biopsy suggested that the ALVAC-distemper recombinant organism is non-replicative in the mammalian host. In the same experiment, replication was shown to occur in canaries inoculated in the skin as expected. Non target animal testing of the vaccine has included intracerebral and intraperitoneal inoculation of mice (9CFR § 133.33 - two groups of eight mice per test), subcutaneous inoculation of five ferrets (9CFR § 113.306 (b)(ii)), subcutaneous inoculation of 20 chickens (9CFR § 113.36), subcutaneous and intramuscular administration to three cats, and subcutaneous administration to 19 gray foxes (Rhone Merieux report title "Risk Analysis for a canarypox-vector distemper vaccine for dogs", 1996).

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

Since the canarypox-distemper recombinant organism is not detected in blood, conjunctival fluids, nasal secretions or faecal swabs following parenteral administration, shedding and spreading of the vaccine organism to contact target and non-target animals is not expected.

6.4 Reversion to Virulence Resulting from Back Passage in Animals

Back passage studies in dogs using the recombinant canarypox distemper organism has been attempted but because no virus could be isolated from animal tissues and secretions following inoculation, the study was limited to the initial passage. The virus does not replicate in the mammalian host (dogs, squirrel monkeys and mice) but it can replicate in avian species.

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

The host range of the recombinant organism is restricted to avian species. The recombinant organism is not shed from vaccinated dogs and therefore no spread of the vector is expected.

6.7 Safety in Pregnant Animals and to Offspring Nursing Vaccinated Animals

Since the canarypox virus vector does not replicate in and is not shed from 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

The vaccines containing the recombinant canarypox-distemper organism would only be used in veterinary clinics. The recombinant vaccine organism is not shed by the vaccinated animals. Potential for occasional environmental release through accidental spills, unintended syringe aerosols and contamination of the skin and hair around the vaccination site does exist during routine use of these vaccines in veterinary clinics.

7.2 Persistence of the Vector in the Environment / Cumulative Impacts

Poxviruses are capable of surviving for months or sometimes years under normal environmental conditions, especially if it is associated with dried scab material and protected from direct sunlight (Tripathy and Reed, 1997). Desiccated poxviruses are extremely resistant to environmental conditions. Specific survival characteristics of the recombinant organism in the environment is not known but is not expected to be different from other poxviruses.

7.3 Extent of Exposure to Non-Target Species

Exposure of the non-target species to the recombinant organism is likely to be very low since the vaccine administration occurs in a clinical setting and the vaccinates do not shed the virus. The potential for accidental and unintended release of the organism was discussed in section 7.1.

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

The avian restricted host range of the recombinant organism excludes non-avian species from the risk of productive infections. The host range of the ALVAC-distemper recombinant organism is expected to be the same as the Rentschler strain of canarypox virus used as the parental organism. The ALVAC-distemper recombinant organism shows the characteristics of an attenuated canarypox virus in that it causes skin infections in canaries upon skin inoculation but does not cause death. Wild canarypox virus is capable of causing death in canaries following skin inoculation (see Tripathy and Cunningham, 1984).

8. Environmental Consequences

8.1 Risks and Benefits

The efficacy of the ALVAC-distemper vaccine component in protecting dogs against canine distemper has been demonstrated in vaccination-challenge experiments (Pardo et al., 1997). For any vaccine, risks of vaccination can be attributed to potential adverse reactions. Occasional adverse reactions such as transient lethargy, mild fever, urticaria and facial swelling as well as rare cases of anaphylaxis resulting in collapse, dyspnea and cardiac arrest have been noted in dogs vaccinated with vaccine combinations containing the ALVAC-distemper recombinant organism.

8.2 Relative Safety Compared to Other Vaccines

The recombinant canarypox organism contains two canine distemper virus genes - F and HA - and the vaccinia virus H6 promoter. The recombinant construct does not have the ability to cause canine distemper or localized and systemic vaccinia-type lesions. Inability to cause clinical distemper following vaccination, adjuvant-free administration and lack of potential for reversion to virulence are positive safety features of canarypox-vectored vaccine. In order to be licensed in Canada, all veterinary vaccines must be shown to be pure, potent, safe and efficacious when used according to label recommendations.

9. Mitigative Measures

9.1 Worker Safety

The vaccine will be manufactured at Merial Inc. Athens, Georgia, USA, which is a veterinary biologics establishment licensed by the US Department of Agriculture. Individuals working with the vaccine either in the production facility or veterinarians and animal technicians working in veterinary clinics can be exposed to the live recombinant organism. Since avipoxviruses cannot cause productive infections in humans, such exposure is not considered to be a safety concern.

9.2 Handling Vaccinated or Exposed Animals

Unlike the worker group, exposure of groups such as dog owners to the live recombinant organism is likely to be very low since vaccinated animals do not shed the virus. 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/dog 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

Human health

Therapeutic Products Directorate
Health Canada
Tunney's Pasture
Ottawa, ON K1A 0L2

Importer

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

Manufacturer

Merial Ltd.
115 Transtech Drive
Athens, Georgia USA 30601-1649

12. Conclusions and actions

Following this assessment, the Permit to Import Veterinary Biologics held by Merial Canada Inc., Québec will be amended to allow the importation of the following products from the manufacturer Merial Ltd., Athens, Georgia:

  1. Canine Distemper-Adenovirus Type 2-parainfluenza-parvorius vaccine, modified live virus, live canarypox vector, (RM Recombitek C4), USDA Product Code 13D1.R1, VBS File: 820VV/C40.5/R2.1

  2. Canine Distemper-Adenovirus Type 2-coronavirus-parainfluenza-parvorius vaccine, modified live virus, live canarypox vector, (RM Recombitek C4/CV), USDA Product Code 1591.R1, VBS File: 820VV/C42.5/R2.1

  3. Canine Distemper-Adenovirus Type 2-parainfluenza-parvorius, modified live virus, live canarypox vector, Leptospira bacterin (RM Recombitek C6), USDA Product Code 4639.R1, VBS File: 820V2X/C35.6/R2.1

  4. Canine Distemper-Adenovirus Type 2-coronavirus-parainfluenza-parvorius, modified live virus, live canarypox vector, Leptospira bacterin (RM Recombitek C6/CV), USDA Product Code 46J9.R1, VBS File: 820V2X/CO.5/R2.1

All serials of these products must be released by the USDA prior to importation into Canada. All conditions described in the Permit to Import Veterinary Biologics must be followed in the importation and sale of this product.

13. References

Boursnell E.G. 1992. Avipoxvirus vectors. In Recombinant Poxviruses, edited by M.B. Binns and G.L. Smith, CRC Press, Florida. pp 269-283.

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.

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.

Moss B. 1992. Molecular biology of poxviruses. In Recombinant Poxviruses, edited by M.B. Binns and G.L. Smith, CRC Press, Florida. pp 45-80.

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

Pardo, MC., Bauman, J.E. and Mackowiak, M. 1997. Protection of dogs against canine distemper by vaccination with a canarypox virus recombinant expressing canine distemper virus fusion and haemagglutinin glycoproteins. Am J Vet Res 58: 833-836.

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 report titled "Risk analysis for a canarypox-vector distemper vaccine for dogs", 1996 (confidential business information removed).

Stephenson C.B., Welter J, Thaker S.R., Taylor J., Tartaglia J. and Paoletti, E. 1997. Canine distemper virus infection of ferrets as model for testing Morbillivirus vaccine strategies: NYVAC-and ALVAC based CDV recombinants protect against symptomatic infection. J. Virology 71: 1506-1513.

Taylor J., Weinberg R, Tartaglia J., Richardson C., Alkhatib G., Briedis D., Appel N., Norton E. and Paoletti E. 1992. Non-replicating viral vectors as potential vaccines: recombinant canarypox virus expressing measles virus fusion and haemagglutinin (HA) glycoproteins. Virology 187:321-328.

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.

Tripathy D.L. and Reed W.M. 1997. Pox. In Diseases of Poultry, 10th edition, edited by B.W. Calnek, H.J. Barnes, C.W. Beard, L.R. McDougald and Y.F. Saif. Iowa State University Press, Iowa. pp 643-659.


Prepared and revised by:

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