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Environmental assessment for licensing West Nile virus vaccine, live canarypox vector in Canada

For Public Release

April 30, 2004

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 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

West Nile Virus Vaccine, Live Canarypox Vector consists of the live attenuated canarypox vaccine virus (ALVAC) modified by the introduction of a gene sequence from the West Nile virus. This West Nile virus vaccine (RECOMBITEK Equine West Nile Virus, 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.

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 Equine West Nile Virus Vaccine for licensing in Canada:

  • West Nile Virus Vaccine, Live Canarypox Vector (RECOMBITEK Equine West Nile Virus), USDA Product Code 1991.R0, CFIA File 830VV/W2.0/R2.1

The Environmental Assessment was prepared by VBS as part of the overall assessment for licensing of the above vaccine in Canada, and was based on information provided by the manufacturer, as well as documents from other sources.

1.2 Background

West Nile Virus Vaccine, Live Canarypox Vector is manufactured by Merial Ltd., Athens, Georgia (US Veterinary Biologics Establishment License No. 298), and is currently licensed for sale in the US. This recombinant vaccine consists of live canarypox virus, modified by the insertion of genetic material from the West Nile virus. The vaccine is a stand-alone product. VBS has previously registered vaccines comprised of recombinant canarypox constructs containing portions of rabies virus or canine distemper virus for use in canines, felines and ferrets.

Health Canada's 2002 surveillance report for West Nile virus (WNV) identified 336 presumptive or confirmed cases of WNV in horses in Canada, ranging from Manitoba to Quebec. Their report in 2003 indicated that there were 445 presumptive or confirmed WNV-positive horses, from Nova Scotia to Alberta. Taken together, these data suggest an expanding geographic area in Canada where horses are at risk of WNV infection.

2. Purpose and need for proposed action

2.1 Significance

The label indication for RECOMBITEK Equine West Nile Virus Vaccine is for the vaccination of healthy horses as an aid in the prevention of viremia due to West Nile virus infection.

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 these 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 RECOMBITEK Equine West Nile Virus Vaccine 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

The proposed vaccine qualifies as a Category III Veterinary Biologic (live expression vectors that contain heterologous genes for immunizing antigens and/or other immune stimulants). The recombinant vaccine construct consists of a gene sequence from West Nile virus inserted into the ALVAC canarypox viral vector. ALVAC is a purified canarypox clone isolated from the attenuated viral strain, KANAPOX, licensed in France for use as a canarypox vaccine in canaries. Other ALVAC-based vaccines are currently USDA licensed and commercially-available, including a canarypox-vectored canine distemper vaccine (dogs, ferrets) and a canarypox-vectored rabies vaccines (cats). In addition, ALVAC provides the backbone for the feline leukemia virus vaccine, which is licensed and commercially available in Europe.

4.2 Source, Description and Function of Foreign Genetic Material

Gene sequences from West Nile virus were selected from those likely to stimulate protective immunity in horses, and the details of the actual sequences are on file at VBS.

4.3 Method of Accomplishing Genetic Modification

Standard coupled reverse-transcriptase polymerase chain reaction (RT-PCR) techniques were used to amplify WNV sequences from extracted viral ribonucleic acid (RNA). A donor plasmid was generated that contained the desired WNV sequences. This plasmid was subsequently used in in vitro recombination experiments, which led to the creation and isolation of this West Nile Virus Vaccine, Live Canarypox Vector.

4.4 Genetic and Phenotypic Stability of the Vaccine Organism

Canarypox has been shown to be host restricted and the only known permissive host for productive infection has been shown to be the canary bird. Because of this highly restricted host range, genetic stability of the vaccine in the target animal species (horses) in which canarypox virus replication would not occur, is not a concern for animal, human or environmental safety. Studies showed that the master seed virus (MSV) is genetically and phenotypically stable up to passage MSV+10, and is free of extraneous agents as per 9CFR § 113.300.

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-West Nile virus does not replicate in the equine 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

The canarypox virus strain used in the construct is an attenuated vaccine strain and does not replicate in non-avian cell lines. In vivo and in vitro studies conducted by Merial indicate that the biological properties (host range specificity and virulence properties) of ALVAC vaccine strains are similar to those of the parental canarypox virus vaccine strain (KANAPOX). In vivo, ALVAC does establish infection in canaries upon skin inoculation, but causes no disease or death since it is an attenuated strain. ALVAC inoculation into nude mice demonstrated no evidence of disseminated infection. Consistent with its inability to replicate in mammalian cells, ALVAC is not shed from vaccinated animals.

4.7 Comparison of the Modified Organisms to Parental Properties

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

4.8 Route of Administration/Transmission

Studies in target and non-target species other than canaries demonstrated that there was no indication of virus shed or spread to the sentinels or the control animals, as evidenced by the lack of virus recovery from the sentinel or control animals.

5. Human Safety

Previously, the regulatory group formerly known as the Bureau of Biologics and Radiopharmaceuticals, Health Protection Branch, Health Canada, was consulted for the "Environmental Assessment for Licensing Vaccine Combinations Containing Canine Distemper Vaccine, Live Canarypox Vector in Canada (1998)". After reviewing the human safety data supplied by Virogenetics Corporation, Troy, New York and Merial Inc., Athens, Georgia, for the use of 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), Health Canada concluded that they had no objection from the human safety aspect to the use of these vaccines in dogs. Similarly, Health Canada was consulted for the "Environmental Assessment for Licensing Vaccine Combinations Containing Rabies Glycoprotein Vaccine, Live Canarypox Vector in Canada (2000)" and had no objection from the human safety aspect to the use of these vaccines in cats.

Merial Ltd. has provided human safety data in support of the RECOMBITEK Equine West Nile Virus Vaccine, including data to support the safety of consuming meat from vaccinated horses. In addition, Merial Ltd. has shown that other human safety aspects associated with RECOMBITEK are similar to other canarypox-vectored products licensed in Canada for use in cats, dogs and ferrets.

5.1 Previous Safe Use

ALVAC-based recombinants have been safely tested in a number of 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). Canarypox-vectored vaccines have been used in human clinical trials of rabies, measles, Japanese encephalitis virus and cytomegalovirus vaccines and vaccines containing HIV envelope or other genes. These vaccines have been well tolerated, and no significant adverse events have been reported when canarypox-vectored vaccines are administered to HIV-infected adults.

The West Nile Virus Vaccine, Live Canarypox Vector has a 21 day withdrawal period to ensure the safety of humans consuming horse meat, even through the vaccine components are considered safe for human consumption. The active ingredient in the diluent is approved in Europe and North America as a human pharmaceutical ingredient in oral and topical medication, and has had a thorough toxicological evaluation. Other stabilizing agents in the vaccine are commonly used in food animal vaccines and are listed as GRAS (Generally Recognized As Safe).

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. Inadvertent injection of the vaccine into human subjects is expected to cause no serious adverse effects. Vaccinated animals do not shed the vaccine, so as a result human exposure is not expected to occur through animal excretions.

5.3 Possible Outcomes of Human Exposure

Canarypox virus is not a zoonotic agent, and is not expected to affect human health. Human volunteers who have been injected with ALVAC-based recombinant rabies vaccines reported some mild transient local reactions such as tenderness and discomfort, as well as a few systemic complaints such as mild headache and fatigue (Cadoz et al., 1992; Fries et al., 1996).

5.4 Pathogenicity of Parent Microorganisms in Humans

The parental stain of canarypox vaccine virus has not been tested for pathogenicity in man, but is not expected to be pathogenic in humans. Various recombinant canarypox vaccines have been tested in humans, as discussed in Section 5.1, and no serious adverse events were reported as a consequence of their use.

5.5 Effect of Gene Manipulation on Pathogenicity in Humans

The recombinant canarypox-West Nile virus vaccine is not expected to be any more pathogenic in humans than the recombinant canarypox rabies vaccine, which has been used safely in human clinical trials as per Section 5.3.

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. Ten canarypox-vectored distemper vaccines and six canarypox-vectored rabies vaccines are currently licensed by Merial, Ltd. for commercial use in dogs, cats and ferrets in the United States, Canada, Brazil and other countries. Risk analyses for these vaccines, on file with USDA-APHIS, concluded that the likelihood of an adverse event occurring was low to moderately low (Finding of No Significant Impact) and previous Environmental Assessments on these products in Canada have also concluded that these products satisfied the requirements of licensing Veterinary Biologics in Canada.

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. Two additional ALVAC constructs proposed as vaccines for equine disease were also shown to be safe for horses following intramuscular administrations.

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

The WNV vaccine was found to be safe in experimental studies in horses (intended target species), as well as in several non-target species. All the studies in target and non-target species indicate that the host range and tropism of the WNV vaccine were not altered from the parent ALVAC strain.

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

There was no evidence of virus replication when the vaccine was tested in in vivo studies or in in vitro studies in cell lines of different animal origin. Studies in target and non-target species other than canaries demonstrated that there was no indication of virus shed or spread to the sentinels or the control animals, as evidenced by the lack of virus recovery from the sentinel or control animals.

6.4 Reversion to Virulence Resulting from Back Passage in Animals

Studies showed that the master seed virus is genetically and phenotypically stable up to passage MSV+10, and is free of extraneous agents as per 9CFR § 113.300. Since the virus does not replicate in mammals, back passage attempts have not shown any reversion to virulence.

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

Studies injecting 10 and 100 times the expected minimum protective dose in horses did not demonstrate any adverse signs of disease in horses.

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-West Nile virus is not shed from vaccinated horses and, thus, no spread of the organism is expected.

6.7 Safety in Pregnant Animals and to Offspring Nursing Vaccinated Animals

Since the canarypox-West Nile virus vaccine 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. The vaccine does not carry a specific safety claim that it is safe for use in pregnant horses, and it is generally recommended to avoid causing stress by injecting horses with anything during pregnancy.

7. Affected Environment

7.1 Extent of Release into the Environment

There are no ecological concerns associated with the use of canarypox-vectored vaccines. For example, shed-spread studies with ALVAC- Distemper, ALVAC-Rabies, and two other ALVAC-based constructs in mammals have shown that the recombinant virus is not shed or spread. In addition, studies with this ALVAC-WNV vaccine demonstrated that the vaccine is not shed-spread in target and non-target mammals. Potential for occasional limited environmental release through accidental spills, unintended syringe aerosols or contamination of the skin and hair around the vaccination site does exist during routine use of this vaccine.

7.2 Persistence of the Vector in the Environment / Cumulative Impacts

Avipox viruses have been reported to be resistant to drying and can remain infectious in dried tissue of infected host species for extended periods of time; however, the injection of Canarypox-WNV Vaccine into horses should not release virus into the environment.

7.3 Extent of Exposure to Non-Target Species

The very limited host range of avipoxviruses reduces the risk of spread to non-target mammalian species. The risk of using this canarypox-vectored vaccine is not expected to be greater than that for the other licensed canarypox-vectored vaccines.

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

Avipoxviruses infecting their defined avian hosts can be mechanically transmitted, primarily by mosquitoes, but there is no evidence of replication in the insect vector or transmission to non-avian species [Tripathy, Deoki. Pox. In Diseases of Poultry (Ed. Calnek, B.W.) Iowa State University Press, Ames, Iowa, 1991, pp. 583-596]. In vivo, the attenuated canarypox vaccine virus (ALVAC) does establish infection in canaries upon skin inoculation, but causes no disease or death. Wild- type canarypox virus infections are 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, inflammatory or hypersensitivity reactions have been seen in animals vaccinated with other canarypox-recombinant vaccines. This risk is identified on the product label along with the recommendation that appropriate symptomatic treatment be given, which may include antihistamines, anti-inflammatory drugs, and/or epinephrine. The efficacy of the canarypox-West Nile virus vaccine in protecting horses against viremia has been demonstrated in vaccination-challenge experiments, and West Nile virus infection is a significant risk to horses in Canada.

8.2 Relative Safety Compared to Other Vaccines

The recombinant vaccine carries only a fragment of West Nile virus and therefore does not have the ability to cause West Nile virus infection, and does not require inactivation. The canarypox-vectored vaccines do not have the ability to cause localized or systemic vaccinia-type lesions in mammalian hosts. The lack of potential for reversion to virulence and absence of adjuvants typical of killed virus vaccines are also positive safety features inherent with canarypox-vectored vaccines. In order to be licensed or 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 is manufactured at Merial Ltd. in Athens, Georgia, which is a Veterinary Biologics Establishment licensed by the US Department of Agriculture. Individuals working with the vaccine in this production facility, as well as veterinarians and animal technicians could be exposed to the live recombinant organism. As was discussed in the Section above on human safety, such exposure is not considered to be a safety concern.

9.2 Handling Vaccinated or Exposed Animals

Exposure of groups such as horse 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/horse 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.
20000 Clark Graham Ave.
Baie d'Urfé, QC H9X 3R8

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, may be amended to allow importation of the following product from the manufacturer Merial Ltd., Athens, Georgia:

  • West Nile Virus Vaccine, Live Canarypox Vector (RECOMBITEK Equine West Nile Virus), USDA Product Code 1991.R0, CFIA File 830VV/W2.0/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