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Environmental Assessment for Licensing Salmonella typhimurium Vaccine, Live Culture in Canada
(AviPro® Megan® Vac 1)

For Public Release

November 10, 2008

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. If you have any questions, please consult the Veterinary Biologics Section, Terrestrial Animal Health Division.


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/Ttransmission
  • 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/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

The Salmonella typhimurium Vaccine, Live Culture (AviPro® Megan® Vac 1) consists of a live Salmonella typhimurium bacterial strain that has been attenuated by the deletion of its cya and crp genes, thereby incapacitating the synthesis of adenylate cyclase and the cAMP receptor protein, respectively. The vaccine is recommended as an aid in the reduction of Salmonella typhimurium, Salmonella enteritidis and Salmonella heidelberg colonization of the internal organs of young growing chickens, and as an aid in the reduction of Salmonella enteritidis colonization of the crop and digestive tract including the ceca. It is to be administered to chicks at one day of age by spray, with a booster dose to be given at 14 days of age in the drinking water. The vaccine was evaluated by the Veterinary Biologics Section 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

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 regarding the safety, purity, potency, and efficacy of the product. Lohmann Animal Health International (Winslow, ME, USA) has submitted the following vaccine for licensing in Canada:

  • Salmonella typhimurium Vaccine, Live Culture (Trade Name: AviPro® Megan® Vac 1), USDA Product Code 19C1.01, CFIA File Number 800VB/S5.0/M1.

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

1.2 Background

Salmonella typhimurium Vaccine, Live Culture is manufactured by Lohmann Animal Health International (US Veterinary Biologics Establishment License No 196) and is currently licensed for sale in the US. This avian vaccine is intended for administration to chicks at one day of age and again at 14 days of age, as an aid in the reduction of Salmonella typhimurium, Salmonella enteritidis and Salmonella heidelberg colonization of the internal organs of young growing chickens, and as an aid in the reduction of Salmonella enteritidis colonization of the crop and digestive tract including the ceca.

Human cases of bacterial foodborne illness worldwide are often attributed to the group of facultative intracellular pathogens known as Salmonella spp. (Zhang-Barber et al., 1999). Salmonellosis in humans may range from subclinical to fatal, depending on the serovar and the individual, but is so prevalent that it is considered to be a disease of major importance from a public health perspective (White et al., 2001). Human Salmonella infections usually involve non-host-adapted "paratyphoid" or "non-typhoid" serotypes, which are of particular concern due to their zoonotic nature and thus their ability to infect a variety of animals, including birds, mammals, reptiles and even insects (Davison, 2005). It is estimated that there are nearly 2500 paratyphoid serotypes in existence (Trevejo et al., 2003).

Domestic animals, especially those raised for food production, are believed to be a significant reservoir for this disease in humans (Khakhria, et al., 1997). For example, Salmonella infections are commonly present in commercial poultry flocks, whose products intended for human consumption may become contaminated at various points in the food production chain. Over the past two decades in Canada, some of the serotypes that have been commonly both implicated in cases of foodborne illness and found in poultry flocks include Salmonella typhimurium, Salmonella enteritidis and Salmonella heidelberg, (Foley et al., 2007; Zhang et al., 2005; Guerin et al., 2004; Khakhria R et al., 1997; Poppe et al., 1991a; Poppe et al., 1991b).

Paratyphoid salmonellosis may be transmitted to poultry directly from flockmates, zoonotically via rodents, or from contaminated environments or feed (Davison, 2005). In very young birds, paratyphoid Salmonella infections may result in a low degree of mortality and morbidity, including non-specific signs such as diarrhea, dehydration, depression, and failure to thrive. Clinical signs of disease are not commonly seen in adult birds, as infected individuals often remain asymptomatic carriers, which may serve as ongoing sources of infection. Possible methods attempting to control paratyphoid Salmonella in poultry flocks range from stringent hygiene and management to the use of prophylactic antibiotics, probiotics (competitive exclusion principle) and vaccines (Zhang-Barber et al., 1999).

Salmonella typhimurium Vaccine, Live Culture consists of a live culture of a Salmonella typhimurium bacterial strain that has been attenuated by deletion of its cya and crp genes, which encode adenylate cyclase and the cyclic adenosine monophosphate (cAMP) receptor protein, respectively. Adenylate cyclase is an enzyme that catalyzes the synthesis of cAMP from adenosine triphosphate. The cAMP receptor, which is activated by the binding of cAMP, modulates the transcription of numerous genes (and operons). Mutation of the cya and crp genes renders Salmonella typhimurium impaired in its ability to breakdown non-glucose sources of carbon, deficient in the transport of carbohydrates, peptides and amino acids and unable to produce flagella. Consequently, the Δcya Δcrp double mutants grow more slowly and have a diminished capacity to invade and infect internal organs (e.g. spleen, liver), leaving them effectively avirulent (Curtiss and Kelly, 1987; Hassan and Curtiss, 1994a; Hassan and Curtiss, 1994b; Hassan and Curtiss 1996; Zhang et al., 1999).

2. Purpose and Need for Proposed Action

2.1 Significance

The label indication for AviPro® Megan® Vac 1 is for administration to chicks at one day of age by spray as an aid in the reduction of Salmonella typhimurium, Salmonella enteritidis and Salmonella heidelberg colonization of the internal organs of young growing chickens, and as an aid in the reduction of Salmonella enteritidis colonization of the crop and digestive tract including the ceca. A booster dose is recommended at 14 days of age via the drinking water.

2.2 Rationale

VBS evaluates veterinary biologic product submissions for licensure under the Health of Animals Act and Regulations. The general criteria for licensing includes the following: a) the product must be pure, potent, safe 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 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 being considered are: a) to issue a Permit to Import Veterinary Biologics to Asea Inc. for the importation of Salmonella typhimurium Vaccine, Live Bacteria 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 Salmonella enteritica serovar typhimurium (S. typhimurium) organism was originally isolated from a moribund horse during a Salmonella surveillance study in New York state. It was subsequently administered to a one-day-old leghorn chicken and then reisolated five days later from the deep tissues of the chicken. The wild-type strain is designated χ3761 Salmonella typhimurium UK-1. χ3761 was reported to have an LD50 value of 3x103 colony forming units (CFU) for one-day-old chicks (Hassan and Curtiss, 1994b).

4.2 Source, Description and Function of Foreign Genetic Material

No foreign genes were added to the Salmonella typhimurium organism, but rather chromosomal DNA was deleted.

4.3 Method of Accomplishing Genetic Modification

No foreign genes were added to the Salmonella typhimurium organism, but rather chromosomal DNA was deleted.

4.4 Genetic and Phenotypic Stability of the Vaccine Organism

The stability of the master seed organism was tested at the "x" and "x+5" passage level. Culturing of the master seed organism to the highest level permitted in production did not restore its capacity to grow on minimal agar containing maltose, melibiose, xylose, sorbitol, lactose, sucrose, or rhamnose as sole carbon source, indicating that the vaccine organism did not revert to its wild type parental phenotype. Since the genetic defects in the vaccine organism are deletion mutations, it is highly unlikely (compared to a system of inactivation dependent on the modification of only a few nucleotides) that random spontaneous mutations will be able to restore the parental genotype. Although in vitro, the phenotype of a loss of function cya mutation can be masked by providing cells with supplemental cAMP, the amount of cAMP produced by mammalian cells is not believed to be sufficient to offset the cya deficiency (Curtiss and Kelly 1987). Moreover, double mutation of the vaccine organism ensures that restoration of the function of one of the modified genes will not be sufficient to enable reversion to the parental phenotype.

4.5 Horizontal Gene Transfer and Potential for Recombination

As a source of DNA, the vaccine strain poses no increased hazard compared to the parental Salmonella typhimurium, because it contains no new genes.

Salmonella typhimurium bacteria can acquire genes through horizontal gene transfer (HGT). In fact, one group has hypothesized that almost one quarter of the entire Salmonella enterica serovar typhimurium genome may have been introduced by lateral (horizontal) gene transfer (Porwollik and McClelland, 2003). The vaccine organism contains loss of function deletions in two genes, cya and crp. The cya and crp loci exist approximately 11 minutes apart (equivalent to about 550 kilobases [kb]) on the Salmonella typhimurium chromosome (Curtiss and Kelly, 1987). It is feasible that a HGT event could occur to restore the function of one of these two genes. However, due to their chromosomal location, it is quite unlikely that the introduced DNA would be large enough to encompass both of these genes. For example, the fragment of DNA packed into a phage head is only about 44 kb in length. Thus, the genes are too far apart to be carried on a single DNA fragment carried in a transducing particle. Since HGT is already a rare event, it would be highly unlikely that two of these rare events would occur in the same cell to restore both genes.

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

Salmonella typhimurium are known to infect a variety of hosts including chicken, horses, cattle, pigs, dogs, cats, and humans. Generally, wild type Salmonella typhimurium is introduced into an animal via the oral route. The bacteria colonize the intestinal tract and can attach to and proliferate within gut-associated lymphoid tissue (GALT). In some cases, the Salmonella typhimurium traverse the GALT to disseminate to and invade deep tissues such as the spleen, mesenteric lymph nodes, liver, kidneys, lungs and reproductive tissues. Studies performed by the manufacturer suggest that the vaccine organism retains this tissue tropism, although it might have a diminished capacity to colonize the internal organs. Birds administered the vaccine organism were observed to shed the bacteria for up to 13 weeks post-inoculation. The vaccine organism also appears capable of spreading to in-contact control birds.

4.7 Comparison of the Modified Organisms to Parental Properties

No differences were observed in the lipopolysaccharide (LPS) profile of the vaccine organism compared to the parental Salmonella typhimurium strain, and both bacteria express the O-antigen. The modified vaccine organism retains the naturally occurring ~91 kb plasmid present in the parental bacterium. Both bacteria can ferment glucose and mannose; however, in contrast to wild type Salmonella typhimurium, the vaccine organism is unable to utilize maltose, mannitol, sorbitol, sucrose, melibiose, rhamnose or xylose as the sole carbon source, due to the loss of function mutations in cya and crp. The growth rate of the mutant strain on Luria-Bertani broth is slightly reduced compared to the parental organism (Zhang et al., 1998). Whereas the parental Salmonella typhimurium strain is virulent to young chicks (LD50 value of 3x103 CFU), the Δcya Δcrp Salmonella typhimurium strain has lost the ability to cause disease, and has an LD50 value estimated to be greater than 4x109 CFU in one-day-old chicks (Hassan and Curtiss, 1994b).

4.8 Route of Administration/Transmission

Salmonella typhimurium Vaccine, Live Culture is recommended to be administered to chicks at one day of age by spray. A booster dose is recommended at 14 days of age to be delivered via the drinking water.

5. Human Safety

5.1 Previous Safe Use

The vaccine strain has not been directly administered to humans.

5.2 Probability of Human Exposure

Human exposure is likely to be limited to employees in the manufacturing facility, veterinarians, animal technicians, and poultry farm operators. A withdrawal period of 21 days is indicated for this product, which will help reduce the likelihood of humans being exposed to the vaccine organism through processing or consuming meat from the vaccinated chicken. The manufacturer provided data indicating that no vaccine organisms (nor wild type Salmonella typhimurium or other indigenous Salmonella species) were recovered from broiler carcass rinses of vaccinated birds from the field study. Additionally, even if low levels of contamination of poultry meat were to occur, food exposure to the vaccine strain in cooked meats in unlikely because the vaccine is readily inactivated at 56°C. These conclusions were corroborated by a report prepared by the Bureau of Microbial Hazards at Health Canada, which states that the use of this vaccine represents a low risk to the health of Canadians in regard to exposure via meat of broiler chickens (Couture et al., 2008). Health Canada has not evaluated the human health risks with respect to use of the vaccine in layers, in other species, or via different routes of administration (Couture et al., 2008).

5.3 Possible Outcomes of Human Exposure

Human exposure is not expected to be of significant health concern. The manufacturer has indicated that no serious adverse events have been reported involving employees who handle the production of the vaccine or those who handle vaccinated chickens.

5.4 Pathogenicity of Parent Microorganisms in Humans

As previously described, the parent microorganism, Salmonella typhimurium, has a broad host range, and strains exist which are capable of producing illness in humans (Foley et al., 2007; Trevejo et al., 2003). These strains account for a large percentage of food-borne illness in humans observed worldwide, and certainly in North America (Foley et al., 2007; Khakhria et al., 1997). In humans, non-typhoidal Salmonellosis, such as that caused by Salmonella typhimurium, usually manifests as a self-limiting gastroenteritis which rarely requires antibiotic treatment (Trevejo et al., 2007). Less frequently, severe complications such as septicaemia, pneumonia, meningitis, and death may occur, especially in paediatric, geriatric and immunocompromised populations (Trevejo et al., 2007). The parental wild-type Salmonella typhimurium strain UK-1 χ3761, used to create the non-pathogenic double-mutant vaccine strain, has not itself been evaluated in humans.

5.5 Effect of Gene Manipulation on Pathogenicity in Humans

Deletion of the cya and crp genes reduces the potential for pathogenicity in humans, because of the dysregulation of cAMP-mediated signal transduction and crp-regulated gene expression.

5.6 Risk Associated with Widespread use of the Vaccine

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

6. Animal Safety

6.1 Previous Safe Use

The safety of the modified live Salmonella typhimurium vaccine was evaluated under normal large-scale poultry production conditions at three geographically distinct farms in the USA. Approximately 57,500 chicks were vaccinated with two doses of the product, using one of the three pre-licensing serials being evaluated. Administration of the vaccine did not adversely affect livability, weight or carcass condemnation rates at slaughter, when compared to non-vaccinated chickens reared in paired houses on the same farm, or to historical data. In addition, necropsy of birds from the safety studies performed by the manufacturer did not reveal lesions or gross evidence of disease of internal organs. The vaccine has been licensed for sale in the USA since 1998.

The master seed organism has also been administered to young cats, rats, mice, pigeons, ducks, quail, and turkeys, and was not observed to cause clinical signs of disease or mortality in these non-target animal species.

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

The vaccine organism could be cultured from the duodenum, ilium, large intestine, spleen, liver, lung, heart, kidney, reproductive tissue, and cecal contents of vaccinated birds 14 days post-inoculation, suggesting the genetic modifications do not alter the natural dissemination of Salmonella typhimurium.

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

Similar to wild type Salmonella typhimurium, the vaccine organism is shed from inoculated chickens. 100% of the birds that were administered the parental organism continued to shed the bacteria, whereas 77% of birds administered a dose of the vaccine cleared the organism by the eighth week, thus suggesting a diminished capacity of the Δcya Δcrp Salmonella typhimurium to establish a persistent carrier state. The modified Salmonella typhimurium also retains the potential to spread, as it was cultured 14-day post exposure from a subset of control birds housed in contact with chicks receiving the vaccine.

6.4 Reversion to Virulence Resulting from Back Passage in Animals

A reversion to virulence study was undertaken by the manufacturer. Seven days following oral administration of the vaccine to the first group of chicks, the spleens of vaccinates were collected and homogenized, and the tissue suspension administered orally to another group of chicks. The number of colony-forming units of Δcya Δcrp Salmonella typhimurium in the spleen homogenate was measured after each passage. No vaccine organisms were recovered from the spleens of the third passage group. The material recovered from the last back passage was subjected to Southern blot analysis (probes corresponding to cya and crp gene sequences) alongside DNA from the master seed (x) and production seed (x+5). The matching banding patterns demonstrated that successive passage through target animals did not induce gross genetic changes in the DNA surrounding the deletions. Clinical signs indicative of the vaccine organism reverting to virulence were not observed.

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

The vaccine organism has been administered to chickens at approximately five times the specified minimum dose (CFU) at release without complication (Hassan and Curtiss, 1994; Hassan and Curtiss, 1995; Zhang et al., 1998). An overdose of the vaccine organism was also administered to outbred American deer mice, which can sometimes exist within chicken barns, and are known to be carriers of Salmonella spp. Mice administered two doses of the vaccine three days apart remained healthy throughout the 14-day observation period. The inoculated mice did not appear to shed the attenuated bacteria in their faeces, and the modified Salmonella typhimurium was not found to spread to untreated in-contact mice.

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

The full host range of the attenuated vaccine organism has not been verified but is expected to be the same as the parental S. typhimurium strain.

7. Affected Environment

7.1 Extent of Release into the Environment

The vaccine organism could be recovered up to 17 weeks post-inoculation from swabs taken from the inner surfaces of isolators housing vaccinated birds; however, the modified bacteria was recovered only periodically during this time frame. The wild type organism, conversely, was cultured almost invariably during the first 17 weeks of the 20-week monitoring period from isolators housing birds inoculated with the parental Salmonella typhimurium strain. These data support the expectation that the extent of release of the vaccine organism should be less than that of wild type Salmonella typhimurium.

7.2 Persistence of the Vector in the Environment/Cumulative Impacts

The Δcya Δcrp Salmonella typhimurium reportedly grows slower than the wild type parental organism, and has lost the ability to metabolize alternative carbohydrate sources. These defects and others induced by the gene deletions should hinder the persistence of the vaccine organism in the environment. The parental Salmonella typhimurium was described by the manufacturer as being sensitive to the antibiotics amikacin, ampicillin, carbenicillin, cefoxitin, cephalotin, chloramphenicol, gentamicin, tetracycline, tobramycin, trimethoprim sulfate, kanamycin, neomycin and streptomycin. The Δcya Δcrp Salmonella typhimurium should retain sensitivity to these same antibiotics.

7.3 Extent of Exposure to Non-Target Species

The extent of exposure to non-target species is expected to be low, because vaccine administration predominantly occurs in housed domestic poultry. Non-target species might become exposed if contaminated chicken litter is spread on neighbouring fields. However, as confirmed by the environmental monitoring performed by the manufacturer, viable Δcya Δcrp Salmonella typhimurium do not appear to be as contaminating as wild type Salmonella typhimurium. While mice can sometimes be present in chicken barns, the manufacturer has demonstrated that the vaccine organism does not harm this non-target animal. The Δcya Δcrp Salmonella typhimurium strain was also shown to be avirulent and safe when administered to rats, cats, ducks, quail and turkeys.

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

As previously described, the host range of the parent microorganism Salmonella typhimurium is very broad, and the organism may infect a plethora of animal species including mammals, reptiles, birds, and insects (Davison, 2005). Salmonella typhimurium is capable of not only causing acute clinical illness in animals (the parental wild type strain UK-1 χ3761 was isolated from a moribund horse) but it can also result in subclinical infection of individuals, which leads to a carrier state and provides a predictable means of transmission to other animals. As such, Salmonella typhimurium has been isolated from humans, domestic animals, and wild animals throughout the world and is considered an organism which is widely distributed in the environment. This is most likely because of the ability of the organism to persist in reservoirs of ubiquitous carrier animals, such as rodents and wild birds, from which it can be excreted frequently and persistently into the environment (Davison, 2005).

8. Environmental Consequences

8.1 Risks and Benefits

For any vaccine, the 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 chickens has been demonstrated. The benefit of the vaccine is its ability to preclude the colonization and visceral invasion of chickens with wild type pathogenic Salmonella typhimurium, Salmonella enteritidis and Salmonella heidelberg (Hassan and Curtiss, 1994b; Hassan and Curtiss, 1996; Holt et al., 2003). Salmonella typhimurium, Salmonella enteritidis and Salmonella heidelberg are three of the most prevalent serovars found colonizing poultry, and are commonly implicated in human food poisoning (salmonellosis).

8.2 Relative Safety Compared to other Vaccines

Two other live Salmonella typhimurium vaccines are already licensed in Canada. Live Salmonella vaccines appear to be superior to inactivated formulations, possibly due to the ability of the live organism to invade, and hence deliver antigens to, the gut-associated lymphatic tissue, which can enhance the adaptive immune response. The incorporation of loss of function deletions into two separate genes located some distance apart on the bacterial chromosome serve to attenuate the Salmonella typhimurium organism and ensure the safety of this live vaccine.

9. Mitigative Measures

9.1 Worker Safety

The vaccine will be manufactured at Lohmann Animal Health International (Maine, USA), a veterinary biologics establishment licensed by the US Department of Agriculture. Individuals working with the vaccine, such as employees in the production facility, veterinarians, animal technicians or poultry operators could be exposed to the live genetically modified organism. The vaccine Salmonella typhimurium organism is attenuated by the deletion of two genes with indispensable functions, hence it is not expected to cause human pathogenicity.

9.2 Handling Vaccinated or Exposed Animals

Since the vaccine is recommended to be administered by coarse spray, there is potential for exposure through handling vaccinated chicks. The directions for use of the vaccine advise operators to wear a mask and gloves when handling the vaccine, and recommend that they avoid breathing aerosolized vaccine, which should help reduce exposure.

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. 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 the CFIA. If the problem is resolved to the satisfaction of the veterinarian or 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, temporarily stopping the sale of the product 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, anaphylaxis or hypersensitivity requiring veterinary treatment, including the following: 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, as well as eye problems, abortions and other reproductive problems and neurological signs. Type 2 reactions are defined as death, or an increase in mortality rate, 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 Events to Veterinary Biologics (CFIA/ACIA 2205).

11. Consultations and Contacts

Manufacturer:

Lohmann Animal Health International
375 China Road, postal office box 255
Winslow, Maine 04901, USA

Health Canada:

Bureau of Microbial Hazards
Health Canada
Sir Frederick Banting Building, 4th Floor West
Tunney's Pasture
Ottawa, Ontario, K1A 0L2

12. Conclusions and Actions

Based on our assessment of the available information, VBS has concluded that the importation and use of Salmonella typhimurium Vaccine, Live Culture (Trade Name: AviPro® Megan® Vac 1), USDA Product Code 19C1.01, VBS File Number 800VB/S5.0/M1 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 of Asea Inc. may be amended to allow the importation and distribution of the following product in Canada:

  • Salmonella typhimurium Vaccine, Live Culture (Trade Name: AviPro® Megan® Vac 1), USDA Product Code 19C1.01, CFIA File Number 800VB/S5.0/M1.

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

Bureau of Microbial Hazards (2008) Salmonella typhimurium Vaccine, Live Culture, USDA Product Code 19C1.01. Internal Correspondence/Memorandum.

Curtiss R 3rd and Kelly SM. Salmonella typhimurium deletion mutants lacking adenylate cyclase and cyclic AMP receptor protein are avirulent and immunogenic. Infection and Immunity 1987; 55(12): 3035-43.

Davison S (2005) Newcastle Disease. In The Merck Veterinary Manual, 9th edition, edited by C.M. Kahn, S. Line, S.E. Aiello, Merck & Co., Inc., New Jersey. Downloaded Oct 15, 2008.

Foley SL, Lynne AM, Nayak R (2007) Salmonella challenges: Prevalence in swine and poultry and potential pathogenicity of such isolates.

Guerin MT, Martin W, Darlington GA, and Rajic A. A temporal study of Salmonella serovars in animals in Alberta between 1990 and 2001. Canadian journal of veterinary research 2004; 69: 88-99.

Hassan JO and Curtiss R 3rd. Virulent Salmonella typhimurium-induced lymphocyte depletion and immunosuppression in chickens. Infection and Immunity 1994a; 62(5): 2027-2036.

Hassan JO and Curtiss R 3rd. Development and evaluation of an experimental vaccination program using a live avirulent Salmonella typhimurium strain to protect immunized chickens against challenge with homologous and heterologous Salmonella serotypes. Infection and Immunity 1994b; 62(12): 5519-27.

Hassan JO and Curtiss R 3rd. Effect of vaccination of hens with an avirulent strain of Salmonella typhimurium on immunity of progeny challenged with wild type Salmonella strains. Infection and Immunity 1996; 64(3): 938-944.

Hassan JO and Curtiss R 3rd. Efficacy of a live avirulent Salmonella typhimurium vaccine in preventing colonization and invasion of laying hens by Salmonella typhimurium and Salmonella enteritidis. Avian Diseases 1997; 41(4): 783-791.

Holt PS, Gast, RK and Kelly-Aehle, S. Use of a live attenuated Salmonella typhimurium vaccine to protect hens against Salmonella enteritidis infection while undergoing molt. Avian Diseases 2003; 47: 656-661.

Khakhria R, Woodward D, Johnson WM, and Poppe C. Salmonella isolated from humans , animals and other sources in Canada, 1983 - 1992. Epidemiology and infection 1997; 119: 15-23.

McReynolds, JL, Moore, RW, McElroy, AP, Hargis, BM and Caldwell, DJ. Evaluation of a competitive exclusion culture and Megan Vac1 on Salmonella typhimurium colonization in neonatal broiler chickens. Journal of applied poultry research 2007; 16: 456-463.

Poppe C, Irwin RJ, Messier S, Finley GG, and Oggel J. The prevalence of Salmonella spp. among Canadian registered commercial chicken broiler flocks. Epidemiology and infection 1991a; 107: 201-211.

Poppe C, Irwin RJ, Forsberg CM, Clarke RC, Oggel J. The prevalence of Salmonella spp. among Canadian registered commercial chicken layer flocks. Epidemiology and infection 1991b; 106: 259- 270.

Porwollik S and McClelland M. Lateral gene transfer in Salmonella. Microbes and infection 2003; 5(11):9 77-89.

Trevejo RT, Courtney JG, Starr M, and Vugia DJ. Epidemiology of Salmonellosis in California, 1990-1999: Morbidity, Mortality, and Hospitalization Costs. American journal of epidemiology 2003; 17: 2538-2545.

White DG, Zhao S, Sudler R, Ayers S, Friedman S, Chen S, McDermott P, McDermott S, Wagner DD, and Meng J. The isolation of antibiotic-resistant Salmonella from retail ground meats. The New England journal of medicine 2001; 345(16): 1147-1154.

Zhang, X, Kelly, SM, Bollen, W and Curtiss, R 3rd. Protection and immune responses induced by attenuated Salmonella typhimurium UK-1 strains. Microbial pathogenesis 1999; 26(3): 121-130.

Zhang X, McEwan B, Mann E, and Martin W. Detection of clusters of Salmonella in animals in Ontario from 1991-2001. The Canadian veterinary journal 2005; 46: 517-523.

Zhang-Barber L, Turner AK, and Barrow PA Vaccination for control of Salmonella in poultry. Vaccine 1999; 17: 2538-2545.


Prepared and revised by:

Veterinary Biologics Section
Terrestrial Animal Health Division
Canadian Food Inspection Agency