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Environmental Assessment for Canadian Licensing of Equine Influenza Vaccine, Live Canarypox Vector

For Public Release

January 30, 2008

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/Ttransmission
  • 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. Consultations and Contacts
  • 12. Conclusions and Actions
  • 13. References

Summary

Equine Influenza Vaccine, Live Canarypox Vector consists of two live attenuated canarypox vaccine viruses (ALVAC) each modified by the introduction of a gene sequence from an equine influenza virus; one carries a gene from a H3N8 strain of European lineage and the other carries one from a H3N8 strain of North American lineage. This equine influenza vaccine (RECOMBITEK Equine Influenza 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. The product review process determined that the above product satisfactorily met the requirements for licensing veterinary biologics in Canada.

1. Introduction

1.1 Proposed Action

Veterinary Biologics Section (VBS), Animal Health 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 influenza vaccine for licensing in Canada:

  • Equine Influenza Vaccine, Live Canarypox Vector (Trade Name: RECOMBITEK Equine Influenza Virus), CFIA File 830VV/E11.1/R2.1, USDA Product Code 1501.R0.

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

1.2 Background

The above vaccine containing two live, recombinant canarypox-equine influenza viruses 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 viruses, each modified by the insertion of genetic material from an equine influenza virus. This is a stand-alone product. VBS has previously licensed recombinant canarypox constructs, with: an insert from West Nile virus for use in equines; an insert from rabies virus for use in felines; and an insert from canine distemper virus for use in canines and ferrets.

2. Purpose and Need for Proposed Action

2.1 Significance

The label indication for RECOMBITEK Equine Influenza Virus is for the vaccination of healthy horses as an aid in the prevention of disease caused by equine influenza viruses, type A2.

2.2 Rationale

The VBS evaluates veterinary biologics submissions for licensure under the Health of Animals Act and Regulations. General criteria for licensure are: (a) the product must be pure, safe, potent and efficacious; (b) the product must be licensed in the country of origin; (c) the 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 presents no unacceptable importation risk, and therefore was evaluated for licensure 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 the vaccine, RECOMBITEK Equine Influenza Virus, 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 two vaccine constructs are canarypox-vectored recombinants, each containing haemagglutinin coding sequences from an equine influenza virus (EIV) H3N8 strain, inserted into the ALVAC recipient. ALVAC is derived from an attenuated, licensed vaccine strain of canarypox (KANAPOX). It is also the recipient organism in several vaccines licensed in the US and Canada including the following canarypox-vectored (vCP) vaccines: West Nile virus vaccine (equines), canine distemper vaccine (dogs, ferrets) and rabies vaccine (cats). Additionally, ALVAC is the recipient in a European and US licensed vCP, feline leukemia virus (FeLV) vaccine (cats).

4.2 Source, Description and Function of Foreign Genetic Material

The haemagglutinin coding sequence from EIV, either Kentucky/94 or Newmarket/2/93, was inserted into ALVAC recipients. Details of the actual sequences are on file at VBS. The same insertion locus is used in the construction of other licensed vCP vaccines. There are no known regulatory elements in the flanking sequences of the insertion site that could moderate the inserted donor DNA. The promoter used in each recombinant was derived from the attenuated Copenhagen strain of vaccinia virus. The same promoter is used in the other licensed vCP vaccines.

4.3 Method of Accomplishing Genetic Modification

Standard reverse-transcriptase polymerase chain reaction (RT-PCR) techniques were used to amplify haemagglutinin sequences from extracted EIV RNA, from both Kentucky/94 and Newmarket/2/93. Donor plasmids were generated containing one or the other haemagglutinin sequence. These final plasmids were used for separate in-vitro recombination experiments which led to the isolation of the two canarypox-vectored constructs which compose the Equine Influenza 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, virus replication will not occur in the target animal species (horses), hence genetic stability of the vaccine is not a concern for animal, human or environmental safety. Studies showed that the Master Seed Virus is genetically and phenotypically stable up to passage MSV+9, 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). Canarypox-Equine Influenza Virus does not replicate in the equine host. In vivo recombination between this recombinant vCP virus and an EIV is unlikely because of their different natures (DNA virus - RNA virus) and different replication sites (cytoplasm - nucleus). Recombination between the two vaccinated recombinants would not alter tissue tropism or virulence. There is a remote, theoretical possibility of recombination taking place between a wild-type canarypox virus and the vaccine virus in canaries; however, since the recombinant virus is not administered to canaries, and it is not shed by horses, it is very unlikely to spread to canaries, which severely restricts this possibility. In addition, in such a recombination case, the wild-type strain would become predominant.

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 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. ALVAC inoculation into nude mice demonstrated no evidence of disseminated infection.

4.7 Comparison of the Modified Organisms to Parental Properties

The host range of the recombinant organism is expected to be the same as the parental canarypox vaccine strain. Donor sequences do not enhance the virulence or the ability to survive in target or non-target species.

4.8 Route of Administration/Transmission

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

5. Human Safety

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., 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 was consulted on the human safety aspect of vCP vaccine usage when VBS was preparing the “Environmental Assessment for Licensing Vaccine Combinations Containing Canine Distemper Vaccine, Live Canarypox Vector in Canada (1998)” and had no objection to the use of these vaccines. Similarly, Health Canada was consulted on the human safety aspect when VBS was preparing the “Environmental Assessment for Licensing Vaccine Combinations Containing Rabies Glycoprotein Vaccine, Live Canarypox Vector in Canada (2000)” and had no objection to the use of these vaccines. Merial Ltd. has provided additional human safety data for the RECOMBITEK Equine West Nile virus vaccine, including data to support the safety of consumption of meat from vaccinated horses. There are no human safety concerns unique or specific to RECOMBITEK Equine Influenza Virus vaccine.

5.1 Previous Safe Use

ALVAC-based recombinants have been safely tested in a number of phase I and phase II 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; Triozzi et al., 2005; Karnasuta et al., 2005; Thongcharoen et al., 2007; Cleghorn et al., 2007; 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 genes, or genes encoding IL-12. Not all these vaccines were efficacious; however, they were well-tolerated and there have been no significant adverse events when canarypox-vectored vaccines were administered to HIV-infected adults.

This vaccine has a 21-day withdrawal period to ensure the safety of humans consuming horse meat, and 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). Similar vCP vaccines are approved for use in vaccines for food animals.

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 strain 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

Recombinant canarypox-Equine Influenza 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. vCP distemper vaccines and vCP 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 satisfactorily meet the requirements of licensing Veterinary Biologics in Canada.

6. Animal Ssafety

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: newborn humans (McFarland et al., 2006); ponies (Minke et al., 2006); cats (Jourdier et al., 2003); dogs and cats (Karaca et al., 2005); ferrets, canaries, chickens, and primates (squirrel monkeys, cynomolgus monkeys, chimpanzees, rhesus macaques) (Pal et al., 2006); and rodents. These data are on file at VBS. Other ALVAC constructs used as vaccines for equine diseases were also shown to be safe for horses.

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

The EIV vaccine was found to be safe in experimental studies in horses (intended target species), including foals and pregnant mares, at different stages of gestation; as well, it was found to be safe in several avian non-target species, including canaries (permissive host), chickens, and ducks; and in mammalian non-target species such as guinea pigs, mice and pigs. All the studies in target and non-target species indicate that the host range and tropism of the EIV 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 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 of other vCP vaccines is genetically and phenotypically stable up to passage MSV+10. Since the virus does not replicate in mammals or in mammalian cell lines, and the EIV genes have been inserted into the same locus as the other vCP vaccines, this vaccine was exempted from the requirement for back passage studies to demonstrate non- reversion to virulence.

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

In studies in which they were injected with 10 times the expected Minimum Protective Dose (MPD), horses did not demonstrate any signs of disease.

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

Canarypox virus’ host range is restricted to avian species. The recombinant canarypox-equine influenza viruses do not multiply in, and are not shed by, vaccinated horses; thus no spread of the organisms is expected.

6.7 Safety in Pregnant Animals and to Offspring Nursing Vaccinated Animals

Since canarypox-Equine Influenza 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. In several studies using pregnant mares at different stages of gestation, the vaccine proved safe with no abortive or teratogenic effects.

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, ALVAC-WNV and two other ALVAC-based constructs in mammals have shown that the recombinant virus is not shed or spread. In addition, studies with this EIV 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

Avipoxviruses have been reported to be resistant to drying and can remain infectious in dried tissue of infected host species for extended periods of time, but the injection of 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 expected not 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, Pages 583-596]. In vivo, the canarypox vaccine virus (ALVAC) does establish infection in canaries upon skin inoculation, but causes no disease or death. Wild- type canarypox virus infections are more virulent, 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 and 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. Equine influenza virus infection is a significant risk to horses in Canada, and the efficacy of the canarypox-equine influenza virus vaccine in protecting horses against viremia has been demonstrated in vaccination-challenge experiments.

8.2 Relative Safety Compared to other Vaccines

The recombinant vaccines do not have the ability to cause equine influenza virus infection and do 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 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 and veterinarians and animal technicians can 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 events should be reported using the form Notification of Adverse Events to Veterinary Biologics (CFIA/ACIA 2205).

11. Consultations and Contacts

Importer

Merial Canada Inc.
20000 Clark-Graham
Baie D'Urfé, Quebec H9X 4B6

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

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

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.

Cleghorn, F., Pape, J.W., Schecheter, M., Bartholomew, C., Sanchez, J., Jack, N., Metch, B.J., Hansen, M., Allen, M., Cao, H., Montefiori, D.C., Tomaras G.D., Gurunathan, S., Eastman, D.J., do Lago R.F., Jean, S., Lama, J.R., Lawrence, D.N., Wright, P.F., 026 Protocol Team and the NIAID HIV Vaccine Trials Network. 2007. Lessons from a multisite international trial in the Caribbean and South America of an HIV-1 Canarypox vaccine (ALVAC-HIV vCP1452) with or without boosting with MN rgp 120. J. Acquir Immune Deficient Syndrome 2007 October 1: 46(2): 222-30.

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 gp 120, HIV-1SF2 recombinant gp 120, 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.

Jourdier, T.M., Moste, C., Bonnet, M.C., Delisle, F., Tafani, J.P., Devauchelle, P., Tartaglia, J., Moingeon, P., 2003. Local immunotherapy of spontaneous feline fibrosarcomas using recombinant poxviruses expressing interleukin 2 (IL2). Gene Ther. 2003 December: 10(26): 2126-32.

Karaca, K., Bowen, R., Austgen, L.E., Teehee, M., Siger, L., Grosenbaugh, D., Loosemore, L., Audonnet, J.C., Nordgren, R., Minke, J.M., 2005. Recombinant canarypox vectored West Nile virus (WNV) vaccine protects dogs and cats against a mosquito WNV challenge. Vaccine 2005 May 31:23(29): 3808-13.

Karnasuta, C., Paris, R.M., Cox, J.H., Nitayaphan, S., Pitisuttithum, P., Thongcharoen, P., Brown, A.E., Gurunathan, S., Tartaglia, J., Heyward, W.L., McNeil, J.G., Birx, D.L., de Souza, M.S.; Thai AIDS Vaccine Evaluation Group, Thailand. 2005. Antibody-dependent cell-mediated cytotoxic responses in participants enrolled in a phase I/II ALVAC-HIV/AIDSVAX B/E prime-boost HIV-1 vaccine trial in Thailand. Vaccine 2005 March 31; 23(19): 2522-9.

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.

MacFarland, E.J., Johnson, D.C., Muresan, P., Fenton, T., Tomaras. G.D., Mcnamara, J., Read, J.S., Douglas, S.D., Deville, J., Gurwith, M., Gurunathan, S., Lambert, J.S., 2006 HIV-1 vaccine induced immune responses in newborns of HIV-1 infected mothers. AIDS 2006 July 13; 20(11):1481-9.

Minke, J.M., Fischer, L., Baudu, P., Guigal, P.M., Sindle, T., Mumford, J.A., Audonnet, J.C., 2006. Use of DNA and recombinant canarypox viral (ALVAC) vectors for equine herpes virus vaccination. Vet Immunol Immunopathol 2006 May 15; 111(1-2): 47-57.

Pal, R., Venzon, D., Santra, S., Kalyanaraman, V.S., Montefiori, D.C., Hocker, L., Hudacik, L., Rose, N., Nacsa, J., Edghill-Smith, Y., Moniuszko, M., Hel, Z., Belyakov, I.M., Berzofsky, J.A., Parks, R.W., Markham, P.D., Letvin, N.L., Tartaglia, J., Franchini, G., 2006 Systemic immunization with an ALVAC-HIV-1/protein boost vaccine strategy protects rhesus macaques from CD4+ T-cell loss and reduces both systemic and mucosal simian-human immunodeficiency virus SHIVKU2 RNA levels. J. Virol 2006 April; 80(8):3732-42.

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.

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Prepared and revised by:

Veterinary Biologics Section
Terrestrial Animal Health Division
Canadian Food Inspection Agency