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pathogen-free birds at 1 day of age provided hemagglutinin-inhibiting antibodies that were maintained for the 8-week test period, which is the lifespan of a commercial broiler. Protective immunity was demonstrated against a combined intramuscular velogenic NDV challenge and a respiratory NDV challenge. Significantly, vaccination of commercial broiler chickens that retained a level of maternal immunity against both NDV and the vector resisted a subsequent challenge against both a lethal intramuscular NDV challenge, as well as a virulent fowlpox virus challenge. However, the NDV-specific immune response was at a reduced level. A fowlpox virus recombinant expressing NDV glycoproteins has received commercial licensure in the United States.

Avipox Virus Vectors in Nonavian Species

Members of the Avipox genus such as fowlpox and canarypox are distinguished by their host restriction for replication to avian species. It was discovered that inoculation of avipox-based recombinants into mammalian cells resulted in expression of the foreign gene and that inoculation into mammals resulted in the induction of protective immunity (6, 7). This surprising finding provided a significant safety profile to these vectors. Immunization could be affected in the absence of productive replication while eliminating the potential for dissemination of the vector within the vaccinate and, therefore, the spread of the vector to nonvaccinated contacts or to the general environment.

For reasons still not understood, it was demonstrated that a recombinant canarypox vector was a 100 times more efficient than a comparable fowlpox vector in inducing protective immunity and similar to a thymidine kinase-disrupted replication competent vaccinia virus vector (8).

Numerous examples have now been provided demonstrating the safety, immunogenicity, and protective efficacy of canary-pox-based recombinants in both experimental animal models and target species. A prime example has used canarypox-based recombinants expressing the rabies virus glycoprotein G. Rabies virus infection and immunization are issues for both veterinary and human medicine. A great deal of information is available in rabies virus immunization, experimental animals and target species are readily available for study, and the parameters of successful immunization are understood. The safety and immunogenicity of a canarypox-based rabies glycoprotein recombinant was demonstrated in a number of nonavian species (9). Protection of vaccinated experimental animals or target species cats and dogs was demonstrated.

To appreciate the duration of immunity that could be engendered by vaccination with a canarypox-based recombinant, naive beagles were vaccinated by a single subcutaneous dose of the vaccine followed by rabies challenge with rabies virus. All vaccinated dogs seroconverted with maximal titers at 1 month. At various times after vaccination, a subset of dogs was challenged. At 6 and 12 months postvaccination, all dogs vaccinated with a single dose of the vaccine resisted challenge that was lethal to all the control animals. At 24 months after vaccination, 11 of 12 vaccinated dogs survived challenge with similar protection observed at 36 months postvaccination (10). These studies demonstrated that a single vaccination was immunogenic and that a protective immune response was primed such that recall as long as 3 years later was protective against a rabies virus challenge in the target species.

Successful vaccination in the presence of rabies-specific maternal antibodies was demonstrated in the following experiment using beagles. A worst scenario situation was established wherein pregnant bitches with immunity to rabies were revaccinated 2 weeks before whelping to maximize the antirabies antibody titers transferred from the bitch to the offspring. At 2 weeks after birth, the pups were vaccinated with a single dose of a canarypox-based rabies vaccine recombinant. Serological responses were followed to monitor either the decay of maternal antibodies in the nonvaccinated control pups or the effect on antibody titers on the pups vaccinated in the presence of maternal antibodies. At 3 months, immunity was challenged by inoculation of live rabies virus in the temporal muscle. The maternal antibody titer in the unvaccinated pups decayed with the expected kinetics. Pups vaccinated with the recombinant virus showed a slight increase in rabies virus neutralizing titer at 2 weeks postvaccination that fell to undetectable levels at the time of challenge. In a vaccine dose-dependent fashion, pups immunized in the presence of maternal immunity survived the rabies virus challenge that was lethal to all the nonvaccinated pups (10). This study demonstrated that young animals could be successfully vaccinated in the presence of maternal immunity.

The concept of using a nonreplicating avipox virus vector, a canarypox-based rabies recombinant, has been evaluated for safety and immunogenicity in human clinical studies (11, 12). Rabies naive healthy adult volunteers were inoculated with increasing doses of the recombinant in a schedule including a boost at 1 and 6 months. For comparison, the standard inactivated human diploid cell rabies vaccine was used. All inoculations with the recombinant canarypox vaccine were well-tolerated with only mild and short-lived reactions at the inoculation site reported. In these two clinical trials, induction of antirabies immune responses were demonstrated, and it was demonstrated that canarypox recombinants could be used either by themselves or in a protocol wherein the priming vaccination with the vector could be followed by a booster with the inactivated rabies vaccine.

Although the immune responses to the experimental canarypox recombinant were comparable but not demonstrated to be superior to those obtained with the standard inactivated rabies vaccine, it perhaps is not surprising given the relative low doses of the recombinant vaccine used in these studies and the comparison with an optimized and highly immunogenic licensed vaccine.

Other examples demonstrating the utility of canarypox virus-based vectors for veterinary species have been provided. Canarypox virus recombinants expressing the measles virus fusion and hemagglutinin glycoproteins have been used to vaccinate dogs. Comparison of these recombinants with vaccinia virus vectors expressing the same genes were shown to provide similar levels of immune response and protection against a challenge with the related Morbilli virus, canine distemper (13).

Construction of specific canine distemper virus recombinants expressing the fusion and hemagglutinin have been evaluated in the highly susceptible ferret model and dog host and were demonstrated to provide protection against challenge (unpublished data).

Canarypox-based recombinants expressing the hemagglutinin from equine influenza virus were shown to be immunogenic when inoculated in horses and provided protection against a naturally occurring equine influenza virus infection (14).

Two canarypox virus-based recombinants were constructed, each expressing the entire gag gene and either the intact subgroup A envelope of feline leukemia virus (FeLV) or a modified version of the envelope from which the putative immunosuppressive region was deleted (15). These recombinants were evaluated for protective efficacy in kittens of 8–9 weeks of age. Two inoculations of the recombinants at 5 and 2 weeks before challenge failed to induce measurable FeLV neutralizing antibodies. Nevertheless, 50% of the cats receiving the mutated envelope recombinant and 100% of the cats receiving the intact envelope recombinant were protected against an oronasal challenge with the FeLV-A/Glasgow-1 isolate. Protection was assessed by evaluating p27 antigenimea, detecting FeLV antigen in blood smears, and the attempted recovery of infectious FeLV. This was the first description of



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