Bursal Disease – Marek's Disease Vaccine, Serotype 3, Live Marek's Disease Vector – Environmental Assessment for Licensing in Canada

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For Public Release

January 23, 2012

Prepared and revised by:

Canadian Centre for Veterinary Biologics
Terrestrial Animal Health Division
Canadian Food Inspection Agency

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 Canadian Centre for Veterinary Biologics 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 and Spread Capabilities
    • 4.7 Comparison of the Modified Organisms to Parental Properties
    • 4.8 Route of Administration and 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
  • 7. Affected Environment
    • 7.1 Extent of Release into the Environment
    • 7.2 Persistence of the Vector in the Environment and 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

Bursal Disease – Marek's Disease Vaccine, Serotype 3, Live Marek's Disease Vector (Trade Name: Vectormune HVT-IBD) consists of a live turkey herpesvirus (also known as Marek's disease virus, serotype 3) modified to express an antigenic protein of infectious bursal disease virus. This vaccine is administered to healthy chicken embryos at 18 or 19 days of embryonation, or to healthy chicks at one day of age, as an aid in the prevention of Marek's disease and infectious bursal disease. The vaccine was evaluated by the Canadian Centre for Veterinary Biologics of the Canadian Food Inspection Agency for licensing in Canada. As part of the requirements for licensing this product in Canada, an Environmental Assessment was conducted, and a public document containing information on the molecular and biological characteristics of the live genetically modified organism, target animal and non-target animal safety, human safety, environmental considerations, and risk mitigating measures was prepared.

1. Introduction

1.1 Proposed Action

The Canadian Centre for Veterinary Biologics (CCVB) of the 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 the Health of Animals Regulations. Any veterinary biologic manufactured, sold or represented for use in Canada must comply with the requirements specified by the CFIA regarding the safety, purity, potency, and efficacy of the product. Biomune Company (Lenexa, Kansas, U.S.) has submitted the following vaccine for licensing in Canada:

  • Bursal Disease – Marek's Disease Vaccine, Serotype 3, Live Marek's Disease Vector. (Trade Name: Vectormune HVT-IBD), USDA Product Code 1A88.R0, CCVB File 800VV/B20.20/B10.

This Environmental Assessment was prepared by the CCVB as part of the overall assessment for licensing the above vaccine in Canada.

1.2 Background

Bursal Disease – Marek's Disease Vaccine, Serotype 3, Live Marek's Disease Vector is manufactured by Biomune Co. (U.S. Veterinary Biologics Establishment License No. 368), and is currently licensed for sale in the U.S. This avian vaccine consists of a live turkey herpesvirus (HVT) genetically modified to express an antigenic protein of infectious bursal disease (IBD). The vaccine is intended for use in healthy 18- or 19-day-old chicken embryos and healthy one-day-old chicks as an aid in the prevention of Marek's disease (MD) and IBD.

Marek's disease is a highly contagious, ubiquitous disease of chickens caused by a gallid herpesvirus-2 (Marek's disease virus, serotype 1). Chickens predominantly become infected with a MD virus during the first few weeks of life and carry the infection throughout their lives. Clinical MD generally afflicts birds after four to six weeks of age, causing paralysis, carcass condemnation at slaughter, and/or mortality. Internally, MD is characterized by lymphoid cell infiltration and proliferation forming tumours (lymphomas) in various organs, including the liver, kidneys, heart, gonads, and spleen, and/or lesions or enlargement of peripheral nerves. Bursal tumours are relatively rare, helping to differentiate MD from avian lymphoid leukosis. The serologically related, non-oncogenic HVT, also referred to as Marek's disease virus serotype 3, has been used effectively in vaccines against MD for more than 30 years. Vaccination with HVT does not prevent infection with MD viruses, but rather impedes the development of lymphoma.

Infectious bursal disease, commonly called Gumboro disease, is caused by the extremely stable and contagious IBD virus (IBDV), which targets and destroys the bursa of Fabricius, the organ where B lymphocytes are produced in chickens. Acute, or clinical, IBD typically occurs in birds aged three to six weeks and is characterized by a lack of coordination, watery diarrhea, and mortality. Non-acute or subclinical infection, common in birds less than three weeks of age, is associated with immunosuppression causing increased susceptibility to other diseases and decreased response to subsequent vaccination, and culminates into poor performance and/or death of birds. Because of the stability of IBDV in the environment, control by sanitation and isolation has had limited success in commercial poultry production. Consequently, the principal method of control is by vaccination. Current strategies typically involve vaccinating the laying hens to provide passive immunity to chicks, and/or vaccinating the chicks after maternal antibody titres have diminished. Alternatively, one-day-old chicks may be vaccinated with live attenuated strains of IBDV. However, it has been suggested that "mild" live IBDV vaccine strains might show decreased efficacy in the presence of maternal antibodies, and "intermediate" or "hot" live IBD vaccines might retain some pathogenicity (Coletti et al., 2001; Sahar et al., 2004).

2. Purpose and Need for Proposed Action

2.1 Significance

The labelling for Vectormune HVT-IBD indicates that the product is recommended for the in ovo vaccination of healthy 18- to 19-day-old embryonated chicken eggs, or for subcutaneous vaccination of healthy one-day-old chickens, as an aid in the prevention of bursal disease (due to standard and variant IBDV types) and Marek's disease.

2.2 Rationale

The CCVB evaluates veterinary biologic product submissions for licensure under the Health of Animals Act and the Health of Animals Regulations. The general criteria for licensing are as follows: a) the product must be pure, safe, potent and efficacious; b) vaccine components must be relevant to Canadian disease conditions; c) foreign products must be licensed in the country of origin; and d) the product must be produced and tested in accordance with generally accepted "good manufacturing practices." This U.S. origin vaccine meets these general criteria, and presents no unacceptable importation risk, and thus was evaluated for licensing by the CCVB.

3. Alternatives

The two alternative options being considered are: a) to issue a Permit to Import Veterinary Biologics to ASEA Inc. (Georgetown, Ontario) for the importation of Bursal Disease – Marek's Disease Vaccine, Serotype 3, Live Marek's Disease Vector, 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 parental HVT (FC-126 strain) is a double-stranded DNA, enveloped virus originally isolated from turkey's blood. This strain has been used as a vaccine against MD since the early 1970s (Purchase et al., 1971).

4.2 Source, Description and Function of Foreign Genetic Material

The foreign genetic material is an expression cassette consisting of 1) a chicken promoter; 2) double-stranded DNA encoding an antigenic protein of IBDV; and 3) viral polyadenylation signal sequences. Details of the source, description and function of the foreign genetic material are on file at the CCVB.

4.3 Method of Accomplishing Genetic Modification

Details of the methods used to create the recombinant virus are on file with the CCVB.

4.4 Genetic and Phenotypic Stability of the Vaccine Organism

The manufacturer examined the stability of the insert in the HVT genome after passage in the cell type used to propagate the virus during vaccine production. No gross genetic rearrangements were evident by Southern blot hybridization in the insertion site region of the recombinant virus following the maximum number of passages permitted during vaccine production. Sequencing of the insertion site region demonstrated the absence of minor mutations in the nucleotide sequence. Imunoprecipitation results confirmed the continued expression of the IBDV antigenic protein at its expected size after passage in the vaccine production cells, and a black plaque assay, using an antibody against the IBDV antigenic protein to stain plaques, showed that 100% of the high passage plaques expressed the IBDV antigenic protein. These data support the genetic and phenotypic stability of the recombinant virus in the vaccine production cells.

The manufacturer also examined the genetic and phenotypic stability of the recombinant vaccine virus following successive administration and reisolation events ("backpassages") in specific pathogen free (SPF) chickens. The banding patterns obtained by Southern blot hybridizations using probes for the IBDV portion and HVT sequences surrounding the insertion site were unaltered for the virus isolated from the fifth backpassage in chickens. The IBDV antigenic protein immunoprecipitated from chicken embryo fibroblast (CEF) cells infected with the fifth backpassage virus remained at the expected size. A black plaque assay demonstrated that all plaques in a CEF monolayer infected with the fifth backpassage virus expressed the IBDV antigenic protein. Taken together, these data indicate that the inserted sequences are stable in the recombinant vaccine organism.

4.5 Horizontal Gene Transfer and Potential for Recombination

Marek's disease viruses, including HVT, are known to latently infect lymphocytes (Holland et al., 1998). Latently infected cells often harbour multiple copies of the viral genome, which can be found episomally or integrated into host chromosomes (Hirai et al., 1981; Delecluse et al., 1993a; Delecluse et al., 1993b; Robinson et al., 2010). When integrated into the chicken genome, MD viruses appear to have a preference for the telomeric regions of chromosomes. Avian telomeric regions contain repeats of the sequence TTAGGG; this same sequence is present in the genomes of MD viruses, including HVT FC-126, which could facilitate homologous recombination (Kishi et al., 1988; Nanda et al., 2002; Robinson et al., 2010; refer to Genbank accession no. AF291866 for HVT FC-126 sequence).

Presumably, the recombinant HVT-IBD vaccine virus will behave in much the same way as parental HVT regarding the tendency of the virus to recombine with host DNA. The only unparalleled result of such a recombination event would be the introduction of the foreign expression cassette contained within the genetically modified virus. Within the expression cassette, the constitutive chicken promoter is the component most likely to have an effect on the host cell. One could envision that this cis-acting regulatory DNA element could alter the expression of host genes neighbouring the integration site. However, if the recombinant virus integrates into the telomeric regions at the ends of chromosomes, it would be some distance from the vast majority of chicken genes. There are numerous naturally occurring promoter sequences in the HVT genome, so the addition of the chicken promoter should not be expected to greatly increase the risk of aberrant host gene expression from loci neighbouring a site of viral integration compared to that associated with the integration of wild type HVT.

The presence of the chicken promoter in the recombinant virus could, however, encourage the integration of viral sequences into its homologous sequences in chicken chromosomal DNA. Such an event might disrupt gene expression in the affected cell. There was nothing in the manufacturer's safety studies to suggest that this conjectured recombination event is occurring and causing adverse health effects. It should be noted that other sequences homologous to the chicken genome are already present in HVT, including the aforementioned telomeric repeats and portions of the Gallus gallus anti-apoptotic NR-13 gene (Gene ID 395193; determined by NCBI BLAST searches).

Recombination occurring between the non-pathogenic HVT-IBD vaccine virus and related viruses within chicken cells to create a new virus that is pathogenic to chickens is another theoretical possibility. The parental HVT has been widely used as a component of bivalent vaccines with other live attenuated MD viruses, suggesting that if recombination does occur between these related viruses, such events are not regularly producing pathogenic virus. Since the Vectormune HVT-IBD vaccine virus consists of double-stranded DNA that presumably replicates in the nucleus like parental HVT, whereas wild type IBDV is double-stranded RNA replicating in the cytoplasm (Petek et al., 1973), it is unlikely that a live pathogenic IBDV would swap antigenic protein coding sequences with that contained in the vaccine virus.

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

Marek's disease viruses replicate exclusively in cells of avian origin (particularly chicken, turkey, duck, and quail) and attempts to infect mammalian cells have repeatedly failed (Sharma, 1998). In exposed birds, MD viruses initially infect and replicate within lymphocytes, where the virus remains cell associated. After about seven days, although lymphocytes continue to harbour the viral genome, the infection becomes latent and viral antigen expression wanes in lymphocytes. Productive infection, producing mature cell-free infectious virus, begins after about a week or more in feather follicle epithelium cells.

Since IBDV also targets chicken lymphocytes, the tissue tropism of the modified HVT virus would not be expected to change. Indeed, studies performed by the manufacturer indicate that the recombinant HVT-IBD vaccine virus retains tissue tropism for white blood cells isolated from the blood, spleen, thymus and bursa of vaccinated chickens.

As expected, based on the tissue tropism of parental HVT, the manufacturer was also able to detect recombinant HVT-IBD vaccine virus in the feather follicles of vaccinated birds. The amount of HVT-IBD virus in feather follicle samples peaked at two to four weeks post-vaccination, and became undetectable by five weeks in flight feathers and 13 weeks in contour feathers.

Parental HVT can be shed in feather dander, but it is not thought to readily spread horizontally between chickens (Cho, 1975). Data submitted by the manufacturer indicate that the genetic manipulations did not render the HVT-IBD vaccine virus capable of spreading from vaccinated chickens to in-contact chickens. However, parental HVT and other licensed HVT-vectored vaccines are known to be capable of spreading from vaccinated chickens to in-contact turkeys (Witter and Solomon, 1972; data on file with the CCVB). The recombinant HVT-IBD virus in the present vaccine is therefore presumed to likewise be transmissible to in-contact turkeys.

Marek's disease viruses, including the parental HVT, are not known to be transmitted vertically from an infected bird to its egg embryo (Paul et al., 1972).

4.7 Comparison of the Modified Organisms to Parental Properties

The recombinant HVT-IBD vaccine virus differs genetically from the parental HVT by the integration of the expression cassette described in section 4.2. The foreign DNA is inserted into what is thought to be a non-coding region of the HVT genome, and hence, presumably does not disrupt any endogenous genes. The genetically modified organism does not contain any selectable markers such as antibiotic resistance genes.

4.8 Route of Administration and Transmission

The Vectormune HVT-IBD vaccine is to be administered either in ovo to 18 or 19 days of embryonation eggs, or subcutaneously in the neck to one-day-old chicks.

5. Human Safety

5.1 Previous Safe Use

The parental HVT strain has been widely used in MD vaccines for over 35 years. The Vectormune HVT-IBD vaccine has been licensed for use in the U.S. since 2007. Presumably, during this time, humans have been exposed to the parental virus, and to a lesser extent, to the recombinant organism.

5.2 Probability of Human Exposure

Human exposure to the Vectormune HVT-IBD vaccine itself is likely to be limited to employees in the manufacturing facility, veterinarians, animal technicians, and poultry farm operators. However, since the parental HVT is known to persistently infect chickens, and literature suggests that it may replicate in these species for extended and possibly indefinite periods, as it is a herpesvirus vector that is capable of persistent infection (Calnek and Witter, 1991; Islam and Walkden-Brown, 2007), there is a chance that individuals working in abattoirs will also be exposed to the recombinant virus. Exposure to humans through the consumption of meat from vaccinated birds will be reduced by the fact that the HVT-IBD vaccine virus is mainly localized to lymphocytes associated with visceral organs and feather follicles, and not the tissues humans predominantly consume as meat. Moreover, even if trace amounts of the recombinant virus were present in chicken meat, studies have shown that the vast majority of ingested nucleic acid is efficiently degraded in the human digestive tract (Jonas et al., 2001).

5.3 Possible Outcomes of Human Exposure

Human exposure to the recombinant HVT-IBD vaccine virus is not expected to be a significant health concern. Researchers have repeatedly been unable to infect mammalian cells with MD viruses, including HVT and recombinant HVT-IBD vaccine viruses.

5.4 Pathogenicity of Parent Microorganisms in Humans

The parental HVT organism has not been associated with pathogenicity in humans.

5.5 Effect of Gene Manipulation on Pathogenicity in Humans

The genetic manipulation of the parental HVT has added foreign genetic material encoding an antigenic protein of IBDV. This addition is not expected to cause pathogenicity in humans, since the foreign component is merely one piece (protein) of IBDV, and the intact IBDV itself is only known to produce clinical disease in chickens. Furthermore, an IBDV strain has been safely administered to a few human volunteers as part of an immunotherapy experiment (Csatary et al., 1999). The polyadenylation signal component of the foreign expression cassette is also unlikely to invoke human toxicity, as constructs containing these DNA sequences have been safely administered to human volunteers in various clinical trials. Although published studies indicating the previous use of the chicken promoter in humans could not be found, this promoter, or a related hybrid promoter with cytomegalovirus promoter/enhancer sequences, has been used without complication in various animal models, as well as in numerous human cell lines, and is not expected to cause human pathogenicity.

Again, the inability of HVT-based viruses to replicate in mammalian hosts is expected to preclude any adverse effect of these viruses on humans.

5.6 Risk Associated with Widespread use of the Vaccine

No risks to human safety associated with the widespread use of the vaccine have been identified.

6. Animal Safety

6.1 Previous Safe Use

Field safety trials involving over 300,000 chickens were conducted by the manufacturer in the U.S. Significant adverse events attributable to vaccination or signs of MD or IBD were not reported. These data support the safety of the vaccine in its target population under the conditions of its intended use. Moreover, Bursal Disease – Marek's Disease Vaccine, Serotype 3, Live Marek's Disease Vector has been licensed for use in the U.S. since 2007.

The manufacturer also tested the safety of the vaccine in non-target species by inoculating turkeys (the natural host of the viral backbone), pheasants, quail, and pigeons with a 10X dose of the recombinant HVT-IBD vaccine virus. No clinical signs indicative of vaccine pathogenicity were observed during the five-week observation period, and no gross lesions were evident upon necropsy at the end of the study.

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

The manufacturer has demonstrated that, like parental HVT, the recombinant HVT-IBD vaccine virus can be recovered from leukocytes in the blood, and from buffy coat extractions (a method to isolate blood leukocytes including lymphocytes) taken from multiple organs, including the spleen, bursa of Fabricius, and thymus, as well as from feather follicles of vaccinated chickens.

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

Marek's disease viruses, including HVT, are shed in feather dander (sloughed skin and feather cells), and since the recombinant HVT-IBD vaccine virus can be found in feather follicles, it is assumed that the recombinant virus is likewise shed by this route. Similar to parental HVT, data presented by the manufacturer indicate that the HVT-IBD vaccine virus is not horizontally transmitted between chickens; however, it is anticipated that HVT-IBD might be capable of spreading from vaccinated chickens to in-contact turkeys, like the parental HVT virus (Witter and Solomon, 1972) and other HVT-vectored vaccines. The manufacturer has not fully characterised the duration of virus shedding, but it is presumed that the HVT-vectored virus, much like the parental virus, may be shed continuously or intermittently throughout the life of the infected bird (Witter and Solomon, 1971; Islam and Walkden-Brown, 2007).

6.4 Reversion to Virulence Resulting from Back Passage in Animals

The manufacturer performed a back passage study with five passages in chickens. No increase in morbidity or mortality was observed with in vivo passage, demonstrating that the recombinant virus does not acquire pathogenicity when passaged through multiple birds. These results were expected since the parental HVT is a stable, naturally occurring non-pathogenic virus strain.

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

The vaccine has been administered in ovo and subcutaneously to chickens at doses approximately tenfold the dose anticipated in the commercial vaccine, without any observed complications. No signs of pathogenicity were observed when turkeys, pheasants, quail and pigeons were administered a similar amount of the vaccine.

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

The HVT backbone is restricted in its host range to avian species, including turkeys, chickens, ducks, and quail.

7. Affected Environment

7.1 Extent of Release into the Environment

The vast majority of vaccinated chickens will be housed indoors in biosecure facilities, and thus will have little direct exposure to the environment. However, limited release of the vaccine organism may occur when poultry houses are cleaned out, or through the vented air. HVT-contaminated litter and air (dust) appear to be capable of infecting turkeys (Witter and Solomon, 1971).

7.2 Persistence of the Vector in the Environment and Cumulative Impacts

The manufacturer performed a study examining the environmental persistence of the recombinant HVT-IBD vaccine virus as a cell-associated virus (the form present in the vaccine), and found that it does not survive for more than six to eight hours at ambient temperatures in this form.

The environmental persistence of the recombinant HVT-IBD virus as mature virus (as shed from feather follicles) was not examined. Herpesviruses are typically inactivated by UV light from the sun (Lytle and Sagripanti, 2005). However, MD viruses in dried feathers and poultry dust have been reported to remain infectious for up to a year (Jurajda and Klimes, 1970; Schat, 1985).

7.3 Extent of Exposure to Non-Target Species

The extent of exposure to non-target species is expected to be curbed by the fact that vaccine administration predominantly occurs in housed domestic poultry without access to the outside. Nonetheless, wild turkeys are a growing population in Canada, increasing the likelihood that the hypothesized limited release of the vaccine virus from barns could inadvertently be transmitted to turkeys. Moreover, backyard and free-range chicken operations are also becoming more prevalent. Even though studies performed by the manufacturer indicate that the recombinant vaccine virus is non-pathogenic to turkeys, precautionary measures should be taken to reduce the potential for spread of the virus to turkey populations. For this reason, the manufacturer has agreed to add a special warning to the labelling of Vectormune HVT-IBD indicating that the product should not be administered to chickens with probable direct or indirect exposure to turkeys.

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

The parental HVT virus is not known to be pathogenic to any species.

8. Environmental Consequences

8.1 Risks and Benefits

One of the primary benefits of this genetically modified vaccine is that the vaccine appears to be effective at inducing immunity, even when administered to maternal antibody-positive chickens (manufacturer's data in licensing dossier). Overcoming maternal antibody immunity has been a challenge for many of the currently available IBD vaccines (van den Berg and Meulemans, 1991; Coletti et al., 2001). In addition, the recombinant HVT-IBD vaccine virus does not appear to cause the bursal lesions associated with some "hot" live IBD vaccines. It is also possible that the persistence of the recombinant HVT-IBD virus (due to the HVT backbone) in vaccinated chickens might enhance the vaccine's duration of immunity against IBD, and hence reduce the need for booster vaccinations (Tsukamoto et al., 2002). Finally, the HVT backbone has already been established as a safe and effective tool in the protection of chickens against MD.

The primary risk identified for Vectormune HVT-IBD relates to its potential to spread to turkey populations (and potentially other Galliformes) and, consequently, persist in the environment. It is important to note, however, that no pathogenicity in turkeys is expected for the recombinant HVT-IBD virus, even if it does spread to turkeys, as the parental HVT has been shown to do (Witter and Solomon, 1972). The Canadian labelling for Vectormune HVT-IBD also carries a precautionary statement that measures should be taken to avoid contact between vaccinated chickens and turkeys, which should further mitigate the proposed risk of spread to turkeys.

In summary, even though there is a hypothesized risk that turkeys might inadvertently become infected with the vaccine virus, since there is no evidence to indicate that such an occurrence would be detrimental to turkeys, the benefits of the vaccine in promoting chicken animal health are believed to outweigh the proposed risk of vaccine virus spread to turkeys at the present time.

8.2 Relative Safety Compared to other Vaccines

Currently, three other HVT-based recombinant vaccines have been licensed for use in Canada, including one that similarly expresses an antigenic protein of IBDV.

Some current vaccines against IBD contain live "hot" strains of IBDV, which, in order to help the vaccine overcome maternal antibodies, are not fully attenuated. Consequently, live "hot" IBDV strains often possess residual pathogenicity, causing bursal lesions and immunosuppression in vaccinated chickens (Mazariegos et al., 1990; Sahar et al., 2004), leaving some to question the relative safety of these traditional vaccines against IBD.

9. Mitigative Measures

9.1 Worker Safety

The vaccine will be manufactured at Biomune Co. (Kansas, U.S.), a veterinary biologics establishment licensed by the United States Department of Agriculture (USDA). Individuals working with the vaccine such as employees in the production facility, as well as veterinarians, animal technicians, and poultry operators, can be exposed to the live genetically modified organism. Since the recombinant HVT-IBD vaccine virus is based on a naturally non-pathogenic virus backbone that is unable to replicate in mammalian cells, human exposure is not anticipated to be a human health concern. The in ovo route of vaccine administration proposed for Vectormune HVT-IBD should help reduce the incidence of accidental vaccinator self-injection compared to live bird vaccination. Moreover, since the vaccine does not contain any adjuvant, the risk of clinical problems due to accidental self-injection of oil adjuvant is removed.

9.2 Handling Vaccinated or Exposed Animals

Since chicks reared in a biosecure facility are not often handled directly by humans, and poultry workers typically employ precautionary biosafety measures, exposure through handling vaccinated chicks is not expected to be great. However, poultry workers could become exposed to the vaccine virus through dust and air inside barns that might be contaminated with virus shed through feather dander. Again, the recombinant virus is not believed to be pathogenic to humans.

10. Monitoring

10.1 General

The vaccine licensing regulations in Canada require manufacturers to report all significant suspected adverse reactions to the CFIA within 15 days of receiving notice from an owner or a veterinarian. Veterinarians may also report suspected adverse reactions directly to the CFIA. If an adverse reaction complaint is received by the CCVB, the manufacturer is asked to investigate and prepare a report for the owner's veterinarian and the CFIA. If the problem is resolved to the satisfaction of the veterinarian or client, usually, no further action is requested by the CCVB. However, if the outcome of the investigation is unsatisfactory, the CCVB may initiate regulatory action, depending on the case, which may include further safety testing, temporary stoppage of product sales, 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, vaccinators, and producers should report any suspected adverse reactions to the CCVB as indicated above. Suspected adverse reactions should be reported, using Form CFIA/ACIA 2205 – Notification of Suspected Adverse Events to Veterinary Biologics.

11. Consultations and Contacts

Manufacturer

Biomune Co.
8906 Rosehill Road
Lenexa, Kansas USA 66215

Importer

ASEA Inc.
128 Rexway Drive
Georgetown, Ontario L7G 1R7

12. Conclusions and Actions

Based on our assessment of the available information, the CCVB has concluded that the importation and use of Bursal Disease – Marek's Disease Vaccine, Serotype 3, Live Marek's Disease Vector in Canada would not be expected to have any significant adverse effect on the environment, when manufactured and tested as described in the approved Outline of Production, and used according to label directions.

Following this assessment and the completion of the Canadian veterinary biologics licensing process, the Permit to Import Veterinary Biologics held by ASEA Inc. may be amended to allow the importation and distribution of the following product in Canada:

  • Bursal Disease – Marek's Disease Vaccine, Serotype 3, Live Marek's Disease Vector. (Trade Name: Vectormune HVT-IBD), USDA Product Code 1A88.R0, CCVB File 800VV/B20.20/B10.

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

13. References

Calnek, B.W., Witter, R.L. (1991). Marek's Disease. In Diseases of Poultry, edited by B.W. Calnek et al., Iowa State University Press, Iowa. pages 342-385.

Cho, B.R. (1975). Horizontal transmission of turkey herpesvirus to chickens IV. Maturation in the feather follicle epithelium. Avian Diseases. 19:136-141.

Coletti, M., Del Rossi, E., Franciosini, M.P., Passamonti, F., Tacconi, G. and Marini, C. (2001) Efficacy and safety of an infectious bursal disease virus intermediate vaccine in ovo. Avian Diseases 45(4): 1036-1043.

Csatary, L. K., Schnabel, R. and Bakács, T. (1999) Successful treatment of decompensated chronic viral hepatitis by bursal disease virus vaccine. Anticancer Research 19(1B): 629-633.

Delecluse, H.J. and Hammerschmidt, W. (1993b) Status of Marek's disease virus in established lymphoma cell lines: Herpesvirus integration is common. Journal of Virology 67: 82-92.

Delecluse, H.J., Schüller, S. and Hammerschmidt, W. (1993a) Latent Marek's disease virus can be activated from its chromosomally integrated state in herpesvirus-transformed lymphoma cells. EMBO Journal 12(8): 3277-3286.

Hirai, K., Ikuta, K., Kitamoto, N. and Kato, S. (1981) Latency of herpesvirus of turkey and Marek's disease virus genomes in a chicken T-lymphoblastoid cell line. The Journal of General Virology 53(1): 133-143.

Holland, M.S., Mackenzie, C.D., Bull, R.W. and Silva, R.F. (1998) Latent turkey herpesvirus infection in lymphoid, nervous, and feather tissues of chickens. Avian Diseases 42(2): 292-299.

Islam, A. and Walkden-Brown, S.W. (2007) Quantitative profiling of the shedding rate of the three Marek's disease virus (MDV) serotypes reveals that challenge with virulent MDV markedly increases shedding of vaccinal viruses. The Journal of General Virology 88(8): 2121-2128.

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