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Environmental Assessment for Licensing Salmonella typhimurium Vaccine, Live Culture in Canada

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


Salmonella typhimurium Vaccine, Live Culture (Trade Name: Salmune) manufactured by Biomune Co. is a live, mutant Salmonella typhimurium vaccine produced by chemical mutagenesis. It is intended for mass administration to healthy chickens, as an aid in the reduction of Salmonella typhimurium colonization of the internal organs, including the small intestines and caeca, The vaccine is recommended for use in broiler chicks as a spray or in drinking water, at day of hatch and at day 7. 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 characteristics of this mutant 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. Biomune Co. (U.S. Veterinary Biologics Establishment License No 368) has submitted the following mutant live vaccine for licensure in Canada:

  • Salmonella typhimurium Vaccine, Live Culture (Trade Name: Salmune), USDA Product Code 19C1.02, VBS File 800VB/S5.2/B10.

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 of Salmonella typhimurium invades the intestinal epithelium, spreads to gut-associated lymphoid tissue and disseminates via the blood to the spleen, kidney, lungs, reproductive organs and liver of susceptible chickens.

4.2 Vaccine Organism

The vaccine organism was produced using chemical mutagenesis. It retains the ability to colonize and invade the tissues of day-old and older chickens, however, it is cleared by 28 days post vaccination. Unlike the parent strain, it is inhibited by erythromycin. The Master Seed Stock of this strain 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

As part of the safety assessment, Health Canada reviewed the risks to human safety. The Bureau of Microbial Hazards determined that this vaccine presents a low risk to the health of Canadians via exposure due to spills or through shedding of the microorganism by vaccinated poultry. Workers handling either the vaccine preparation or the vaccinated birds and their litter did not shed the vaccine organisms. In addition, since the vaccine strain is eliminated before the vaccinated broilers go to market, exposure through meat products for human consumption derived from broilers immunized with this vaccine is unlikely. The Bureau has determined that the exposure level of the Canadian population to the vaccine will be minimal.

5.2 Previous Safe Use

This vaccine has been demonstrated to be safe in chickens, turkeys, calves, pigs and mice. Four billion (4,000,000,000) doses have been used in Germany since 1995. It has been used in the USA since the year 2000. No safety concerns have been reported.

5.3 Probability of Human Exposure

  1. Consumption of Food Products — The vaccine strain is not expected to survive long enough in vaccinated birds to result in human exposure due to the 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. After 4 weeks, it could not be recovered from isolation units housing vaccinated chicks.
  3. Administration of vaccine and work in proximity to vaccinated birds — 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

No adverse outcomes are anticipated based on usage in other countries over more than a decade. Human exposure will be limited to persons administering the vaccine or handling vaccinated chickens. The vaccine poses no threat to humans when handled according to label instructions. The master seed is avirulent and is not expected to adversely affect humans.

5.5 Risk Associated with Widespread Use of the Vaccine

The widespread use of the vaccine is not expected to be a risk to public health. For people handling or consuming poultry meat, it may mitigate the risks of getting infected with Salmonella spp.

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 during 5 serial back passages in chickens.
  • Studies demonstrate that the vaccine is not shed beyond 21 days after vaccination.
  • In more than a decade of use, no safety concerns have been reported.
  • In terms of relative safety, live vaccines may be considered safer than conventional bacterins, 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, reversion to virulence was not observed in the backpassage study.

6.2 Non-Target Animal

  • No adverse reactions have been reported in turkeys, calves, pigs and mice.
  • In mice, the vaccine strain is 100,000 fold less virulent than the wild type parent strain.

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 may be spread to contacts, from poultry vaccinated with greater than 1 x 107 CFU.

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 does not persist in tissues beyond 28 days and is not shed beyond 21 days.

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 may occur during vaccination.

8. Environmental Consequences

8.1 Risks and Benefits

Since the mutant strain has a longer generation time, faster extinction in bedding and faeces, and reduced survival 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. There is no evidence of reversion to virulence.

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, Biomune Co., USA and the Canadian importers, Nuvac I.T., Clearbrook Grain & Milling Co. and Lloyd J. Weber Consulting Services 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 permits issued to Nuvac I.T., Clearbrook Grain & Milling Co. and Lloyd J. Weber Consulting Services, for importation of this vaccine manufactured by Biomune Co.:

  • Salmonella typhimurium Vaccine, Live Culture (Trade Name: Salmune), USDA Product Code 19C1.02, VBS File 800VB/S5.2/B10.

13. References

Angulo, F.J. & Swerdlow, D.L. Salmonella enteritidis infections in the United States. Journal of the American Veterinary Medical Association 213(12): 1729-1731 (1998).

Linde, K., Beer, J. & Bondarenko, V. Stable Salmonella live vaccine strains with two or more attenuating mutations and any desired level of attenuation. Vaccine 8:178-282 (1990).

Linde, K., Hahn, I. & Vielitz, E. Development of Live Salmonella Vaccines Optimally Attenuated for Chickens. Lohmann Information No 20, pages 23-31 (1997).

Prepared and revised by:

Veterinary Biologics Section
Terrestrial Animal Health Division
Canadian Food Inspection Agency