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Environmental Assessment for Licensing Salmonella typhimurium Vaccine, Live Culture in Canada
(Poulvac ST)

For Public Release

December 27, 2006

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 Veterinary Biologics Section if you have any questions.


Table of Contents


Summary

Salmonella typhimurium Vaccine, Live Culture (Trade Name: Poulvac ST) manufactured by Fort Dodge Animal Health is an aroA gene deleted live Salmonella typhimurium vaccine. It is intended for mass administration to healthy chickens as an aid in the reduction of Salmonella enteritidis, Salmonella heidelberg and Salmonella typhimurium colonization of the internal organs, including the small intestines and caeca. The vaccine is recommended for use at 1 day of age as a spray, followed by administration in drinking water at 2 weeks of age. It was evaluated by the Veterinary Biologics Section, 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 this public document which contains information on the molecular and biological characteristics of this gene deleted vaccine, target animal and non-target animal safety, human safety, environmental considerations and risk mitigation measures was prepared.

1. Introduction

1.1 Proposed Action

The Veterinary Biologics Section (VBS), Terrestrial 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 with regard to safety, purity, efficacy and potency of the product. Fort Dodge Animal Health (FDAH) has submitted the following gene deleted live vaccine for licensure in Canada:

  • Salmonella typhimurium Vaccine, Live Culture (Trade Name: Poulvac ST), USDA Product Code 19C1.00, VBS File 800VB/S5.1/F3.2.

1.2 Background

Salmonella spp. are common pathogens of poultry, animals and humans. Various bacterins are licensed for use in Canada. Antibiotic treatment is also used.

2. Purpose and Need for Proposed Action

2.1 Significance

Salmonella spp. infect many animal species worldwide. Bacterins which are used to vaccinate poultry may provide limited protection as they do not always confer significant cell-mediated or mucosal immunity; the cost is greater since they have to be administered by injection. Antibiotics used as a preventive measure increase the cost of production and may result in increased antibiotic resistance of virulent Salmonella strains.

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) 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 vaccine meets the general criteria and therefore was evaluated for licensure by VBS.

3. Alternatives

The two alternative options being considered are: (a) to license the vaccine for sale in Canada if licensing requirements are met, or (b) to deny licensure if all licensing requirements are not met.

4. Molecular and Biological Characteristics of Parental and Vaccine Organisms

4.1 Parental Organism

The wild-type parent strain was an avian isolate of Salmonella typhimurium selected for its colonizing and invasive abilities across multiple species, its immunogenic capacity, antibiotic sensitivity pattern and growth in fermentation tanks.

4.2 Vaccine Organism

The vaccine organism was generated using bacteriophage to transduce the mutated aroA gene from Salmonella typhimurium LT2 strain to a wild type parent strain. An antibiotic sensitive, non-reverting aroA deletion mutant, thus auxotrophic for aromatic metabolites including tyrosine, tryptophan, phenylalanine, para-aminobenzoic acid and dihydrobenzoate, was selected. Additional details are on file at VBS. FDAH established a Master Seed Stock of this strain, for use as a vaccine for chickens. This stock has been tested for extraneous agents, purity and safety in accordance with recognized tests. This data has been reviewed and is on file at VBS.

5. Human Safety

The risk factors evaluated included: consumption of food products derived from vaccinated poultry; human exposure following environmental release of the vaccine strain due to accidental spills or shedding from vaccinated poultry; and, poultry workers' exposure to vaccine during and following administration to poultry.

5.1 Assessment by Health Canada

The risk factors evaluated included: consumption of food products derived from vaccinated poultry; human exposure following environmental release of the vaccine strain due to accidental spills or shedding from vaccinated poultry; and, poultry workers' exposure to vaccine during and following administration to poultry.

5.2 Previous Safe Use

This vaccine has been demonstrated to be safe in chickens. It has been widely used in Australia and the USA with over 50 million doses sold in the USA since licensing in 1991. No safety concerns have been reported.

5.3 Probability of Human Exposure

  1. Consumption of Food Products — Due to the aroA mutation, the vaccine strain requires para amino benzoic acid, a metabolite which is not found in vertebrate tissues; thus replication in vertebrates is limited. The virulence of this vaccine strain has not been studied in humans, but it is not expected to survive long enough in vaccinated birds to permit human exposure due to consumption of meat.
  2. Release into the environment due to accidental spills or shedding by vaccinated poultry represents a low risk to human health through indirect human exposure since the organism is incapable of survival in the environment.
  3. Administration of vaccine and work in proximity to vaccinated birds — The first dose is administered by spray application in a closed cabinet; the booster dose is administered in drinking water. Advice on precautionary measures is provided on the package insert. To limit the probability of worker exposure during vaccine administration, the package insert advises taking precautions such as wearing a mask and gloves. The package insert has cautionary statements regarding immunocompromised individuals.

5.4 Possible Outcomes of Human Exposure

The vaccine strain cannot survive in vertebrates. No adverse outcomes are anticipated since vaccines with aroA deletions have been safely administered to humans and to a wide range of animal species. In the unlikely event of infection, antibiotic treatment is an option.

5.5 Risk Associated with Widespread Use of the Vaccine

The widespread use of the vaccine is not expected to have any risks to public health and may mitigate the risks of getting infected with Salmonella spp. for people handling or consuming poultry meat.

6. Animal Safety

6.1 Target Animal

  • The manufacturer has submitted results of safety studies carried out in chickens.
  • A study demonstrated no reversion to virulence through five back passages in chickens.
  • The vaccine strain did not spread from vaccinates to contacts in the backpassage study.
  • Studies demonstrate that the vaccine is not shed beyond 21 days after vaccination.
  • In monitored field safety studies in the USA, a total of 67,700 chicks were vaccinated at one day and two weeks of age and an equal number were left unvaccinated. A comparison of mortality rates demonstrated vaccine safety under field conditions.
  • 50 million doses have been sold in the USA and no safety concerns have been reported.
  • In terms of relative safety, live vaccines may be considered safer than conventional vaccines (inactivated bacteria), since they do not contain oil adjuvants. Live attenuated vaccines may cause a risk of infection by mutants or may revert to virulence. In the case of this vaccine, the rate of reversion is lower than 10-18.

6.2 Non-Target Animal

  • The vaccine strain cannot survive in vertebrates.
  • Vaccines with aroA deletions have been safely administered to a wide range of animal species including mice, pigs, calves and sheep.

6.3 Potential of Spread from Vaccinates to Contact Target and Non-Target Animals

The vaccine strain is not shed beyond 3 weeks. The manufacturer has submitted study results demonstrating that the vaccine is not spread from vaccinated poultry to contacts.

6.4 Host Range and Spread of the Vaccine Organism

The parent strain infects many species and the mutant vaccine strain can theoretically do the same; however, the latter cannot persist in vertebrates due to its requirement for para-aminobenzoic acid (PABA).

7. Affected Environment

The manufacturer has submitted study results demonstrating that the vaccine is shed for up to three weeks, from vaccinated chickens. Accidental spills during vaccination may allow the vaccine strain to escape into the environment.

8. Environmental Consequences

8.1 Risks and Benefits

Since the gene deletion renders it auxotrophic, the vaccine strain cannot survive in vertebrates or in the environment. The risk to the environment is considered negligible.

8.2 Relative Safety Compared to Other Vaccines

The vaccine contains no additives, inactivating agents or adjuvants, and therefore presents no risks from these ingredients which are commonly found in conventional vaccines. Reversion to virulence is unlikely.

9. Mitigative Measures

Precautionary statements are on the package insert. No additional mitigative measures are considered necessary.

10. Monitoring

10.1 General

The vaccine licensing regulations in Canada require manufacturers to report all suspected significant 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. 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 or owner, no further action is usually requested by VBS. If the investigation is not satisfactory, VBS may initiate regulatory action, which may include further safety testing, temporarily stopping sales of the product, or product withdrawal from the market.

10.2 Animal

Veterinarians and owners should report any suspected adverse reactions to VBS. Suspected adverse reactions should be reported using the form Notification of Adverse Events to Veterinary Biologics (CFIA/ACIA 2205).

10.3 Human

No special monitoring of the human safety of the product will be carried out.

11. Consultations and Contacts

  1. The Bureau of Microbial Hazards, Health Canada was consulted regarding the sale of food products derived from vaccinated poultry for human consumption.
  2. The New Substances Assessment and Control Bureau, Health Canada was consulted regarding indirect human exposure since low numbers of the organism will likely be released into the environment due to accidental spills or shedding by vaccinated poultry.
  3. The manufacturer, Fort Dodge Animal Health, USA and the Canadian importer Wyeth Animal Health are the companies responsible for this product.

12. Conclusions and Actions

Following this assessment and the review of documentation submitted by the manufacturer, VBS has licensed the following vaccine for general distribution and sale and added it to the import permit issued to Wyeth Animal Health for importation of this vaccine manufactured by FDAH:

  • Salmonella typhimurium Vaccine, Live Culture (Trade Name: Poulvac ST), USDA Product Code 19C1.00, VBS File 800VB/S5.1/F3.2.

13. References

Hohmann, E.L., Oletta, C.A. & Miller, S.I. Evaluation of a PhoP/PhoQ-deleted, aroA-deleted live oral Salmonella typhi vaccine in human volunteers. Vaccine 14: 19-24 (1996).

Hosieth, S.K. & Stocker, B.A.D. Aromatic-dependent Salmonella typhimurium are non-virulent and effective as live vaccines. Nature 291: 238-239 (1981).

Kirkpatrick, B.D., McKenzie, R., O'Neill, J.P., Larsson, C.J., Bourgeois, A.L., Shimko, J., Bentley, M., Makin, J., Chatfield, S., Hindle, Z., Fidler, C., Robinson, B.E., Ventrone, C.H., Bansal, N., Carpenter, C.M., Kutzko, D., Hamlet, S., LaPointe, C. & Taylor, D.N. Evaluation of Salmonella enterica serovar Typhi (Ty2 aroC-ssaV-) M01ZH09, with a defined mutation in the Salmonella pathogenicity island 2, as a live, oral typhoid vaccine in human volunteers. Vaccine 24(2): 116-23 (2006).

Levine, M.M., Herrington, D., Morris, J.G., Murphy, J.R., Losonsky, G., Tall, B., Lindberg, A.A., Svenson, S., Baqar, S. & Edwards, M.F. Safety and infectivity immunogenicity and in vivo stability of two attenuated auxotrophic mutant strains of Salmonella typhi, 541Ty and 543Ty, as live oral vaccines in humans. The Journal of Clinical Investigation 79:888-902 (1987).

Lindberg, A.A. & Robertsson, J.A. Salmonella typhimurium infection in calves: cell-mediated and humoral immune reactions before and after challenge with live virulent bacteria in calves given live or inactivated vaccines. Infection and Immunity 41:751-757 (1983).

Lumsden, J.S., Wilkie, B.N. & Clarke, R.C. Resistance to faecal shedding of Salmonella in pigs and chickens vaccinated with an aromatic dependent mutant of Salmonella typhimurium. American Journal of Veterinary Research 52: 1784-1787 (1991).

Mukkur, T.K.S., McDowell, G.H., Stocker, B.A.D. & Lascelles, A.K. Protection in salmonellosis in mice and sheep by immunization with aromatic dependent Salmonella typhimurium. Journal of Medical Microbiology 24:11-19 (1987).

Robertsson, J.A., Lindberg, A.A., Hosieth, S. & Stocker, B.A.D. Salmonella typhimurium infection in calves: Protection and survival of virulent challenge bacteria after immunization with live or inactivated vaccines. Infection and Immunity 41:742-750 (1983).

Stocker, B.A. Auxotrophic Salmonella typhi as live vaccine. Vaccine 6:141-145 (1988).


Prepared and revised by:

Veterinary Biologics Section
Terrestrial Animal Health Division
Canadian Food Inspection Agency