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Environmental assessment for licensing vaccine combinations containing rabies glycoprotein vaccine, live canarypox vector

For Public Release

March 28, 2000

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-rabies live recombinant vaccine consists of live canarypox virus modified by the introduction of two copies of rabies glycoprotein genes. The canarypox-rabies vaccine (Purevax Feline Rabies) along with four combination feline vaccines containing the canarypox-rabies vaccine component (Purevax Feline 4/Rabies + Leucat, Purevax Feline 3/Rabies + Leucat, Purevax Feline 4/Rabies, Purevax Feline 3/Rabies, 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 these products 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.

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 feline vaccines containing a live canarypox vector-rabies component for licensing in Canada:

  1. Rabies Vaccine, Live Canarypox Vector (Purevax Feline Rabies), USDA Product Code 1901.R1, CFIA File 840VV/R5.0/R2.1
  2. Feline Leukemia-Rhinotracheitis-Calici-Panleukopenia-Chlamydia Psittaci-Rabies Vaccine, Modified Live Virus and Killed Virus and Chlamydia, Canarypox Vector (Purevax Feline 4/Rabies + Leucat), USDA Product Code 16A9.R0, CFIA File 840V4X/F25.1/R2.1
  3. Feline Leukemia-Rhinotracheitis-Calici-Panleukopenia-Rabies Vaccine, Modified Live Virus and Killed Virus, Canarypox Vector (Purevax Feline 3/Rabies + Leucat), USDA Product Code 16S9.R0, CFIA File 840VV/F1.6/R2.1
  4. Feline Rhinotracheitis-Calici-Panleukopenia-Chlamydia Psittaci-Rabies Vaccine, Modified Live Virus and Chlamydia, Canarypox Vector (Purevax Feline 4/Rabies), USDA Product Code 1619.R1, CFIA File 840V4X/F11.0/R2.1
  5. Feline Rhinotracheitis-Calici-Panleukopenia-Rabies Vaccine, Modified Live Virus, Canarypox Vector (Purevax Feline 3/Rabies), USDA Product Code 16T9.R0, CFIA File 840VV/F21.0/R2.1 CFIA

The Environmental Assessment was prepared by VBS as part of the overall assessment for licensing the above vaccines in Canada. CFIA consulted with Health Canada for the human safety aspect of these vaccines.

1.2 Background

The above five vaccines containing a live recombinant canarypox-rabies component are manufactured by Merial Ltd., Athens, Georgia (United States (US) Veterinary Biologics Establishment License No. 298). They are currently licensed for sale in the US. The recombinant vaccine component in these vaccines consists of live canarypox virus, modified by the insertion of genetic material coding for rabies glycoprotein. VBS has previously licensing four canarypox-based combination vaccines, consisting of live canarypox virus modified by the insertion of two canine distemper virus genes (haemagglutinin and fusion protein), for use in canines. Details of these canine products are on file at VBS. In addition further information is contained within the Environmental Assessment for Canarypox-Distemper Vaccine Component (1998).

2. Purpose and need for proposed action

2.1 Significance

The label indication for Purevax Feline Rabies is for the vaccination of healthy cats against rabies. Combination vaccines Purevax Feline 4/Rabies + Leucat, Purevax Feline 3/Rabies + Leucat, Purevax Feline 4/Rabies, and Purevax Feline 3/Rabies have additional claims for use against feline leukemia virus, feline rhinotracheitis, calici virus, panleukopenia virus and Chlamydia psittaci, depending on 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”. These five US origin vaccines met the general criteria and presented no unacceptable importation risk, and therefore were 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 Feline Rabies, Purevax Feline 4/Rabies + Leucat, Purevax Feline 3/Rabies + Leucat, Purevax Feline 4/Rabies, Purevax Feline 3/Rabies from US, if all licensing requirements are satisfactory, or (b) not to issue a Permit to Import Veterinary Biologics for the above 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

  1. Canarypox Virus: Canarypox virus is a large, enveloped double stranded deoxyribonucleic acid (DNA) virus belonging to the Genus Avipoxvirus (Family: Poxviridae, Subfamily: Chordopoxviridae). Avipox viruses cause productive infections exclusively in avian species. The parent strain of the canarypox virus is known as the Rentschler strain. It was attenuated by 200 serial passages on chick embryo fibroblasts to yield the KANAPOX strain, a vaccine strain that has been licensed in France since 1982. The KANAPOX strain was subjected to four successive plaque purifications yielding the attenuated canarypox vaccine virus (ALVAC) strain of canarypox, used in the construction of this recombinant organism.
  2. Rabies Virus: Rabies virus is a single stranded negative ribonucleic acid (RNA) virus belonging to the Genus Lyssavirus (Family: Rhabdoviridae). Rabies affects all warm-blooded animals including cats and humans. The source of the glycoprotein gene was the ERA strain of rabies. The rabies glycoprotein induces virus neutralizing antibodies.
  3. Vaccinia Virus: Vaccinia virus is a double stranded DNA virus belonging to the Genus Orthopoxvirus. It has been very well characterized and serves as the prototypic recombinant viral vector. In the construction of the recombinant canarypox virus, the vaccinia virus H6 promoter was cloned upstream of the rabies glycoprotein gene to direct transcription of the recombinant protein.

4.2 Source, Description and Function of Foreign Genetic Material

The rabies virus glycoprotein stimulates the production of virus neutralizing antibodies. Virus neutralizing antibodies are correlated with protection against rabies, a neurotropic virus causing a fatal disease of warm blooded animals. In the construction of the recombinant canarypox, the genetic sequence for the rabies glycoprotein was inserted into the genomic DNA of a plaque purified isolate of the parent canarypox strain designated as ALVAC; the recombinant canarypox-rabies virus is known as ALVAC-RG, vCP65, or CP65.

4.3 Method of Accomplishing Genetic Modification

Details of the methods used in the construction of ALVAC-RG are on file with VBS. The identity and the purity of the ALVAC-RG has been verified using in situ plaque hybridization and restriction analysis of the viral DNA to screen for the absence of parental canarypox virus. Rabies glycoprotein expression was confirmed by immunoprecipitation of glycoprotein from infected cellular extracts, and by indirect immunofluorescence of surface expression on cells infected with the recombinant canarypox-rabies; in both instances, a rabies specific monoclonal antibody was used during detection. The manufacturer established a Master Seed stock of the recombinant organism; this was tested for mammalian and avian extraneous agents, purity and safety according to tests described in Chapter 9 of the US Code of Federal Regulations (9CFR). This data has been reviewed and is on file at VBS.

4.4 Genetic and Phenotypic Stability of the Vaccine Organism

No gross genetic or phenotypic alterations were detected after 20 passages of ALVAC-RG in cell culture.

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). Canarypox-rabies will be combined with modified live viruses feline rhinotracheitis virus, calici virus, and panleukopenia, and, as such, one should consider potential gene transfer and recombination between these viruses. Such a recombination may result in novel modified live viruses which 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. The likelihood of horizontal gene transfer and recombination is likely to be very low as: (a) no significant sequence homologies have been documented between different vaccine virus components, (b) canarypox virus does not replicate in the feline host, (c) feline panleukopenia (family Parvoviridae) and feline rhinotracheitis (family Herpesviridae) replicate in the nucleus whereas poxviruses such as canarypox replicate in the cytoplasm.

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

Avipoxviruses are restricted in their host range (ie. potential to replicate) to 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 form 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 ALVAC and the recombinant organism ALVAC-RG is expected to be the same as the parental canarypox vaccine strain. However, ALVAC has the attributes of an avirulent canarypox virus causing infection and skin lesions in canaries upon skin inoculation but no disease nor death.

4.8 Route of Administration/Transmission

Avian poxviruses such as canarypox are transmitted mechanically from infected birds by aerosols, animal handlers, mosquitoes, 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 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. Following the assessment, Health Canada indicated that there is no objection from the human safety aspect to the use of the above canarypox vector vaccines in cats.

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, 1996, Fries et al., 1996; Marshall et al., 1999). ALVAC-RG has been administered safely to human volunteers (Cadoz et al., 1992; Fries et al., 1996). Phase I trials with ALVAC based experimental recombinant vaccines against human immunodeficiency virus have also been reported (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

Several ALVAC recombinant constructs derived from the Rentschler strain of canarypox have been tested in humans; see section 5.1.

5.5 Effect of Gene Manipulation on Pathogenicity in Humans

Recombinant canarypox-rabies vaccine was not pathogenic in humans; see section 5.1.

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 virus has been demonstrated experimentally in humans, cats, dogs, canaries, chickens, primates (squirrel monkeys, cynomolgus monkeys, chimpanzees, macaques), and rodents. These data are on file at VBS. The manufacturer has also provided laboratory and field safety data for over 1700 cats.

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

Backpassage studies in cats have demonstrated that ALVAC-RG is unlikely to revert to virulence. The vaccine does not replicate in the targeted feline 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. In a reversion to virulence, study ten rabies seronegative kittens were vaccinated subcutaneously with CP65A at a dose corresponding to 32 times the release dose. No virus shedding was detected from conjunctival, nasal and fecal swabs taken on days 0, 3, 5, 7, and 10. Positive biopsy samples were detected in four out of 10 cats; an in vivo passage of the biopsy material did not reveal any evidence of a virulent effect of the virus. In another experiment, intradermal injection of the vaccine organism to mice and serial sampling of the injection site showed that the virus did not replicate. Safety studies were also provided for squirrel monkeys, cynomolgus monkeys, dogs, canaries, and chickens; these reports are on file at VBS.

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

Since the canarypox-rabies recombinant virus is not detected in blood, nasal, conjunctival and nasal fluids, or fecal 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

A backpassage study in 10 cats was done. Positive biopsy samples were detected in four cats; these samples were further passaged in vivo for two more passages in kittens without any evidence of a virulent effect of the virus.

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

Overdose testing (100 times the recommended dose) was done in specific pathogen-free (SPF) kittens and puppies. The animals remained clinically healthy following vaccination.

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-rabies is not shed from vaccinated cats and, thus, no spread of the organism is expected.

6.7 Safety in Pregnant Animals and to Offspring Nursing Vaccinated Animals

Since canarypox rabies 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

The vaccines containing recombinant canarypox-rabies 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 extended periods of time under normal environmental conditions, especially in association with dried scab material and protected from direct sunlight (Tripathy and Reed, 1997). Desiccated poxviruses are extremely resistant to environmental conditions. The survival characteristics of the recombinant canarypox-rabies are not predicted to be different from the parent poxvirus.

7.3 Extent of Exposure to Non-Target Species

Extent of exposure to non-target species is expected to be low since the vaccine administration occurs in a clinical setting and the vaccinates do not shed the virus.

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

Recombinant canarypox-rabies is restricted in its host range to avian species and will not develop a productive infection in non-avian species. In avian species, the canarypox-rabies resembles an attenuated canarypox virus by causing skin infections in canaries upon skin inoculation but does not cause death. Wild type canarypox virus is capable of causing death in canaries following skin inoculation (Tripathy and Cunningham, 1984).

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, mild fever, and inflammatory or hypersensitive types of reactions have been noted in cats vaccinated with vaccine combinations containing ALVAC-RG. This risk is identified on the product label along with a recommended treatment regimen that may include antihistamines, anti-inflammatories, and/or epinephrine. The benefit of the vaccine is its ability to protect cats against rabies as demonstrated in vaccination-challenge studies on file in VBS. Rabies is a public health concern leading to death in untreated infected individuals. Inability to cause rabies following vaccination and adjuvant-free administration are additional benefits of ALVAC-RG.

8.2 Relative Safety Compared to Other Vaccines

The recombinant canarypox ALVAC-RG contains rabies glycoprotein genes and the vaccinia virus H6 promoter. ALVAC-RG does not have the ability to cause rabies virus or localized and systemic vaccinia-type lesions. Inability to cause rabies following vaccination, adjuvant-free administration and lack of potential for reversion to virulence are positive safety features of ALVAC-RG.

9. Mitigative Measures

9.1 Worker Safety

The vaccine will be manufactured at Merial Inc., Athens, Georgia, 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

Exposure of groups such as cat 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/cat 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

Health Canada
Therapeutic Products Directorate
Bureau of Biologics and Radiopharmaceuticals
Vaccines Division
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

12. Conclusions and Actions

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

  1. Rabies Vaccine, Live Canarypox Vector (Purevax Feline Rabies), USDA Product Code 1901.R1, CFIA File 840VV/R5.0/R2.1
  2. Feline Leukemia-Rhinotracheitis-Calici-Panleukopenia-Chlamydia Psittaci-Rabies Vaccine, Modified Live Virus and Killed Virus and Chlamydia, Canarypox Vector (Purevax Feline 4/Rabies + Leucat), USDA Product Code 16A9.R0, CFIA File 840V4X/F25.1/R2.1
  3. Feline Leukemia-Rhinotracheitis-Calici-Panleukopenia-Rabies Vaccine, Modified Live Virus and Killed Virus, Canarypox Vector (Purevax Feline 3/Rabies + Leucat), USDA Product Code 16S9.R0, CFIA File 840VV/F1.6/R2.1
  4. Feline Rhinotracheitis-Calici-Panleukopenia-Chlamydia Psittaci-Rabies Vaccine, Modified Live Virus and Chlamydia, Canarypox Vector (Purevax Feline 4/Rabies), USDA Product Code 1619.R1, CFIA File 840V4X/F11.0/R2.1
  5. Feline Rhinotracheitis-Calici-Panleukopenia-Rabies Vaccine, Modified Live Virus, Canarypox Vector (Purevax Feline 3/Rabies), USDA Product Code 16T9.R0, CFIA File 840VV/F21.0/R2.1 CFIA

13. References

Anilionis et al. (1981). Structure of the glycoprotein gene in rabies virus. Nature 294:275-278.

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.

Cox et al. (1977). Rabies virus glycoprotein. II. Biological and serological characterization. Infection and Immunity 16:754-759.

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.

Kieny et al. (1984). Expression of rabies virus glycoprotein from a recombinant vaccinia. Nature 312:163-166.

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. 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 rabies vaccine (CP65A) for cats. Research Report: rec RAB 96/073.

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