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Environmental assessment for licensing of Lawsonia intracellularis vaccine, avirulent live culture, in Canada

For Public Release

January 31, 2002

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

The Lawsonia intracellularis Vaccine, Enterisol Ileitis, consists of an avirulent live culture of Lawsonia intracellularis that is stored at or below -70°C, and is diluted in water prior to oral administration to swine. This vaccine 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 organism, target animal and non-target animal safety, human safety, environmental considerations and risk mitigation measures was 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. Boehringer Ingelheim (Canada) Ltd. has submitted the following veterinary biologic for licensing in Canada:

  • Lawsonia intracellularis Vaccine, Avirulent Live Culture (Trade Name: Enterisol Ileitis), CFIA File 880VB/L1.0/B8.2

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

1.2 Background

Lawsonia intracellularis Vaccine, Avirulent Live Culture is manufactured by Boehringer Ingelheim Vetmedica, Inc., St. Joseph, MO (US Veterinary Biologics Establishment License No. 124), and is currently licensed in the US. The vaccine is a purified and avirulent culture of Lawsonia intracellularis, which is thawed and diluted in water prior to oral use in swine. The vaccine strain has not been genetically modified.

Lawsonia intracellularis Vaccine, Avirulent Live Culture is intended as an aid in the prevention of gross and microscopic intestinal lesions due to Lawsonia intracellularis, the causative agent of Proliferative Enteropathy (PE). PE is an intestinal disease observed in a variety of unrelated animal and avian species, which is caused by an obligate intracellular bacterium, Lawsonia intracellularis. Staff at the Faculty of Medicine, St-Hyacinthe, Québec have reported PE in white-tailed deer (Drolet et al., 1996) and in foals (Lavoie et al., 2000) due to Lawsonia intracellularis, but infection in these species was not associated with contact with swine. The organism is widespread in swine world-wide, and up to 30% of swine in infected herds may have lesions.

Lawsonia intracellularis is classified in the delta division of the Proteobacteria, and is taxonomically distinct from other intracellular pathogens. Although strains of Lawsonia intracellularis appear to be closely related, this may be because the molecular methods used to demonstrate relatedness are relatively undefined with this highly fastidious organism. The proliferative intestinal lesions can be reproduced with pure cultures of the virulent organism in pigs, hamsters and mice, and the intestinal flora appears to influence the development of disease. Germ-free pigs do not appear to be susceptible to Lawsonia intracellularis infection or disease (reviewed by Smith and Lawson, 2001).

2. Purpose and need for proposed action

2.1 Significance

The label indication for Enterisol Ileitis is as an aid in the prevention of gross and microscopic intestinal lesions due to Lawsonia intracellularis in healthy swine, 3 weeks of age or older. The vaccine is thawed and diluted in water and is administered orally.

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) vaccine components must be relevant to Canadian disease conditions and (c) 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 Boehringer Ingelheim (Canada) Ltd., if all licensing requirements are satisfactory, or (b) not to issue a Permit to Import Veterinary Biologics for the above product, 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 Lawsonia intracellularis vaccine strain is derived from a biologically distinct intracellular pathogen, which was originally isolated from a clinical case of the disease in swine in the US.

4.2 Source, Description and Function of Foreign Genetic Material

The organism contains no foreign genetic material.

4.3 Method of Accomplishing Genetic Modification

The organism did not undergo any known genetic modification, but was purified and selected for avirulence in swine.

4.4 Genetic and Phenotypic Stability of the Vaccine Organism

The vaccine master strain was propagated through a series of passages in vitro. The purified and selected avirulent organism was then re-administered to susceptible swine in backpassage studies as recommended in the US Veterinary Services Memorandum No. 800.201, and no reversion to virulence occurred.

4.5 Horizontal Gene Transfer and Potential for Recombination

As the vaccine strain has not been genetically modified, there is no known potential for gene transfer or recombination resulting from genetic manipulation. Evaluation of several isolates of Lawsonia intracellularis demonstrated the absence of plasmid deoxyribonucleic acid (DNA), which further reduces any likelihood of horizontal gene transfer.

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

The avirulent vaccine strain of Lawsonia intracellularis is not known to be pathogenic to any species of mammal. Serials are tested for safety in both guinea pigs and swine prior to release. The vaccine strain has a similar tropism for the intestinal tract as the parent strain, and low numbers may be shed by vaccinated swine. The organism is an obligate intracellular pathogen, which does not survive on inanimate objects, and survives for less than 48 hours in laboratory conditions in cell free media at room temperature.

4.7 Comparison of the Modified Organisms to Parental Properties

Not applicable as the organism is not genetically modified.

4.8 Route of Administration/Transmission

Lawsonia intracellularis is diluted in water, and is administered orally to swine.

5. Human Safety

5.1 Previous Safe Use

The virulent organism is ubiquitous in domestic swine, but human infection has never been reported. The genus is on the current Health Canada list of organisms that are not considered to be human pathogens, and which do not require an import permit from the Office of Laboratory Security, Health Canada. The avirulent vaccine strain is tested for safety in guinea pigs and in the target species (swine), which supports the safety of the vaccine in other mammals, including humans.

5.2 Probability of Human Exposure

Human exposure to the vaccine is likely to be limited to producers, veterinarians, animal technicians, manufacturing staff and testing laboratory staff. In large-scale vaccinations of swine, accidental minor contact with diluted vaccine could occur.

5.3 Possible Outcomes of Human Exposure

Since exposure to the virulent organism does not seem to be harmful to humans, exposure to the avirulent vaccine is even less likely to result in any adverse reactions.

5.4 Pathogenicity of Parent Microorganisms in Humans

Virulent Lawsonia intracellularis and the avirulent vaccine strain are not pathogenic to humans according to current knowledge.

5.5 Effect of Gene Manipulation on Pathogenicity in Humans

Not applicable as the organism was not genetically modified.

5.6 Risk Associated with Widespread Use of the Vaccine

The widespread use of the vaccine is not expected to have any public health significance.

6. Animal Safety

6.1 Previous Safe Use

The master seed of the vaccine strain did not cause any pathogenicity in back passage studies, safety studies and/or efficacy studies conducted in pre-licensing laboratory and/or field trials.

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

The host range of the vaccine is expected to be limited to swine, and shed/spread to other species from vaccinated pigs is improbable. Virulent Lawsonia intracellularis has been isolated from horses and deer in Canada, but there is no indication of contact with pigs as sources of the infection in these species. There may be relative host specificity for swine with the virulent strains of Lawsonia intracellularis isolated from swine, and the vaccine strain is likely to have the same host range.

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

Seroconversion is occasionally observed in sentinel pigs co-housed with vaccinated swine, but Lawsonia intracellularis was not detectable in their intestinal tract or feces, suggesting a very low grade infection that is unlikely to spread any further. Normal swine husbandry practice would be to keep swine of similar ages and weights in a pen, and to vaccinate the entire group.

6.4 Reversion to Virulence Resulting from Back Passage in Animals

The vaccine master strain was propagated through a series of back passages in vivo in Lawsonia intracellularis-susceptible negative swine. The recovered organism after the second passage had no demonstration of virulence, pathogenicity, or changes in biochemical characteristics. No Lawsonia intracellularis organisms were recovered between passages 3 and 6. A repeat of the second passage with gut homogenate taken from Lawsonia intracellularis-positive pigs of the first passage confirmed the loss of the organism in host to host passage.

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

The vaccine organism is safe when delivered at two logs higher than the vaccine dose in the target species.

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

The vaccine is not known to be pathogenic to any known species.

6.7 Safety in Pregnant Animals and to Offspring Nursing Vaccinated Animals

The vaccine is intended for use in swine three weeks of age and older, and is not intended for use in pregnant swine or breeding age boars, as indicated on the vaccine label.

7. Affected Environment

7.1 Extent of Release into the Environment

Lawsonia intracellularis Vaccine, Avirulent Live Culture would only be used in swine, and commercial swine are normally housed in a biosecure environment. Since the vaccine is specified for use at least 21 days prior to slaughter, and the levels that are shed are both low as well as sporadic, it is unlikely that any live microorganism would be excreted in the feces of vaccinated swine to colonize non-target species in the environment. The potential for occasional environmental release through accidental spills is considered low since the organism is fastidious and is unlikely to survive outside of the host species for more than 48 hours.

7.2 Persistence of the Vector in the Environment / Cumulative Impacts

The risk of dispersal in the environment is low. The non-pathogenicity of the vaccine strain and lack of horizontal transmission in vivo indicate a low risk of spreading to other non-target species. There are no known or predicted adverse ecological effects of the vaccine strain to the environment.

7.3 Extent of Exposure to Non-Target Species

Extent of exposure to non-target species is expected to be low since the vaccine administration occurs in housed domestic swine.

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

The vaccine is not known to be pathogenic.

8. Environmental Consequences

8.1 Risks and Benefits

For any vaccine, risks of vaccination can be attributed to potential adverse reactions. In numerous laboratory and field studies no apparent risk has been posed by the vaccine strain, and the safety of this vaccine in swine has been demonstrated.

8.2 Relative Safety Compared to Other Vaccines

No other vaccines are available that have any efficacy claims for Lawsonia intracellularis infection in any species of animal.

9. Mitigative Measures

9.1 Worker Safety

The vaccine strain is not pathogenic to humans.

9.2 Handling Vaccinated or Exposed Animals

No additional precautions are recommended.

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. If an adverse reaction complaint is received by VBS, 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, vaccinators and producers 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

Manufacturer

Boehringer Ingelheim Vetmedica, Inc.
2621 North Belt Highway
St. Joseph, MO, USA 64506-2002

Canadian Distributor

Boehringer Ingelheim (Canada) Ltd.
5180 South Service Road
Burlington, Ontario, Canada

12. Conclusions and Actions

Following this assessment, and the completion of the Canadian veterinary biologics licensing process, the Permit to Import Veterinary Biologics of Boehringer Ingelheim (Canada) Ltd. will be amended to allow the importation and distribution of the following product in Canada:

  • Lawsonia intracellularis Vaccine, Avirulent Live Culture, (Trade Name: Enterisol Ileitis), CFIA File 880VB/L1.0/B8.2

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

Drolet R, Larochelle D, Gebhart CJ. 1996. Proliferative enteritis associated with Lawsonia intracellularis (ileal symbiont intracellularis) in white-tailed deer. J Vet Diagn Invest 8:250-253.

Lavoie JP, Drolet R, Parsons D, Leguillette R, Sauvageau R, Shapiro J, Houle L, Halle G, Gebhart CJ. 2000. Equine proliferative enteropathy: a cause of weight loss, colic, diarrhea and hypoproteinaemia in foals on three breeding farms in Canada. Equine Vet J 32:418-425.

Smith DGE, Lawson GHK. 2001. Lawsonia intracellularis: getting inside the pathogenesis of proliferative enteropathy. Vet Microbiol 82:331-345.


Prepared and revised by:

Veterinary Biologics Section
Animal Health and Production Division
Canadian Food Inspection Agency