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Environmental assessment for licensing vaccine combinations containing modified live, type 2 bovine viral diarrhea virus (strain 296) in Canada

For Public Release

March 8, 2000

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

Three combination cattle vaccines (StarvacT 3 Plus, StarvacT 4 Plus, and StarvacT 9 Plus), manufactured by Diamond Animal Health, Inc., Des Moines, Iowa, were submitted to the Veterinary Biologics Section (VBS), Canadian Food Inspection Agency (CFIA) for licensing in Canada. One of the components in each of these vaccines is a modified live, cytopathic, type 2 bovine viral diarrhea virus (BVDV) (strain 296), which has not been previously licensed or released for use in Canada. Therefore, as part of the requirements for licensing of cattle vaccines containing this component in Canada, an 'Environmental Assessment' was conducted and this public document was prepared, which contains information on the molecular and biological characteristics of the organism, target animal and non-target animal safety, human safety, and environmental considerations.

The modified live, type 2 BVDV (strain 296) has been demonstrated to be efficacious in accordance with current standard requirements for BVDV vaccines in the United States and Canada. It has also been demonstrated to be attenuated and stable, and is not expected to cause clinical signs of disease indicative of virulent type 2 BVDV in target or non-target species. Over 3,462,000 doses of vaccine, containing the modified live, type 2 BVDV (strain 296) component, have been distributed in the United States during the past year with no substantiated cases of vaccine induced disease or death.

Based on the environmental assessment, it was concluded that release of a modified live, cytopathic, type 2 BVDV (strain 296) vaccine for distribution and sale in Canada did not present a greater risk to the health of cattle and other non-target animals, to human health, or to the environment, than other currently licensed, modified live, type 1 BVDV vaccines. Given that vaccines containing the modified live, type 2 BVDV (strain 296) component satisfactorily meet all requirements for licensing veterinary biologic products in Canada and importers comply with all conditions regarding the importation, distribution, and sale of these vaccines, CFIA-VBS may issue or amend import permits to allow importation of products containing the BVDV type 2 (strain 296) component from the manufacturer, Diamond Animal Health, Inc., Des Moines, Iowa.

1. Introduction

1.1 Proposed Action

This Environmental Assessment was prepared to determine if the release of cattle vaccines in Canada, containing a cytopathic, modified live, type 2 bovine viral diarrhea virus (BVDV) (strain 296), presented a greater risk to the health of cattle and other non-target animals, to human health, or to the environment, than the currently licensed, modified live, type 1 BVDV vaccines. It is based, in part, on the information provided by the manufacturer (1).

1.2 Background

The Veterinary Biologics Section (VBS), Animal Health and Production Division (AHPD), Canadian Food Inspection Agency (CFIA) is responsible for licensing veterinary biologic products for use in Canada. The legal authority for the regulation of these products in Canada is provided under the Health of Animals Act and Regulations (section 120. to 135.1). Any veterinary biological product manufactured, sold or represented for use in Canada must comply with the requirements specified by the CFIA-VBS, regarding safety, purity, efficacy, and potency of the product.

Diamond Animal Health, Inc., Des Moines, Iowa, through Biostar Inc., Saskatoon, Saskatchewan, submitted documents and data in support of licensing three combination cattle vaccines in Canada, which contain a modified live, type 2 BVDV (strain 296) component. A modified live, type 2 BVDV vaccine has not been previously licensed or released for use in Canada. The three products identified below have been licensed for sale in the United States since August 1998 under the trade names "TitaniumT 5" (StarvacT 4 Plus), "TitaniumT 4" (StarvacT 3 Plus), and "TitaniumT 5L5" (StarvacT 9 Plus):

Bovine Rhinotracheitis-Virus Diarrhea-Parainfluenza3-Respiratory Syncytial Virus Vaccine, Modified Live Virus (StarvacT 4 Plus) (USDA Product Code 1181.20) (CFIA File No. 810VV/B35.31/D5).

Bovine Rhinotracheitis-Virus Diarrhea-Parainfluenza3 Vaccine, Modified Live Virus (StarvacT 3 Plus) (USDA Product Code 1171.20) (CFIA File No. 810VV/B30.31/D5).

Bovine Rhinotracheitis-Virus Diarrhea-Parainfluenza3-Respiratory Syncytial Virus Vaccine, Modified Live Virus-Leptospira Canicola-Grippotyphosa-Hardjo-Icterohaemorrhagiae-Pomona Bacterin (StarvacT 9 Plus) (USDA Product Code 4461.20) (CFIA File No. 810V2X/B60.30/D5).

2. Purpose and need for proposed action

2.1 Significance

BVDV is a worldwide economically important viral pathogen of cattle. Two distinct genotypes of BVDV, type 1 and type 2, are now recognized (2). Viral virulence does not appear to be linked to genotype. All diseases classically associated with type 1 BVDV are induced by type 2 BVDV (2). Type 2 BVDVs are similar to type 1 BVDVs in their ability to induce persistent infection, mucosal disease, and chronic BVD; however, virulent type 2 BVDVs predominate as the cause of hemorrhagic syndrome and peracute BVD (2, 3, 4, 5) . They have been associated with severe thrombocytopenia and hemorrhagic lesions in cattle in several outbreaks in Canada and North America, and cases have been reported in Europe (5, 6, 7, 8, 9, 10, 11, 12, 13, 14).

2.2 Rationale

It has been hypothesized in the scientific literature that the antigenic differences between type 1 and type 2 BVDVs may permit virus of one genotype to escape neutralization by antibody induced by virus of the other genotype, i.e. type 2 BVDVs have been isolated from cattle herds vaccinated with inactivated type 1 BVDV (2, 10, 15). Pellerin et al. found that cross-reacting virus neutralizing antibodies produced using type 1 viruses were high against homologous virus, but low against type 2 viruses (8). Referring to protection conferred by vaccines, Bolin states that "antibody induced by vaccine virus was 100 times more effective for neutralization of vaccine virus than for neutralization of BVDV that escaped vaccination" (i.e. more virulent BVDV strains) (16). It has been stated in the scientific literature that some protection may be obtained through proper use of conventional (i.e. type 1) vaccines although complete protection from disease was not apparent (10, 17). Thus, vaccines are required that induce antibody against both types of BVDV (10).

Duration of protection studies are not currently available for either inactivated or modified live BVDV vaccines. Anecdotal field information suggests that the duration of protection provided by the inactivated BVDV vaccines is limited, possibly lasting less than six months (2). It has been suggested in the scientific literature that the protection provided by modified live BVDV vaccines may be of longer duration than that provided by inactivated vaccines (2).

3. Alternatives

The two possible courses of actions considered by this environmental assessment are:

3.1 Amendment

Given that vaccines containing the modified live, type 2 BVDV (strain 296) component satisfactorily meet all requirements for licensing veterinary biologic products in Canada and importers comply with all conditions regarding the importation, distribution, and sale of these vaccines, CFIA-VBS may issue or amend import permits to allow importation of products containing the BVDV type 2 (strain 296) component from the manufacturer, Diamond Animal Health, Inc., Des Moines, Iowa (U.S.).

3.2 Maintain Status Quo

Vaccines containing inactivated and modified live, type 1 BVDVs of various strains are currently licensed in Canada. Three combination cattle vaccines have been recently licensed, which include an inactivated BVDV type 2 component. Data are also on-file at CFIA-VBS demonstrating that type 1 BVDV vaccines cross-protect against BVDV type 2 infection in vaccination-challenge clinical trials. Duration of protection studies are not currently available for either inactivated or modified live BVDV vaccines.

4. Molecular and biological characteristics of parental and recombinant organisms

4.1 Identification, Source, and Strain of Parental Organism

BVDV is a small enveloped, positive-stranded ribonucleic acid (RNA) virus belonging to the genus Pestivirus within the Flaviviridae family. The parent organism of the vaccine isolate, identified as cytopathic, type 2 BVDV (strain 296), was isolated from the spleen of a calf diagnosed with mucosal disease in 1994 in Manden, North Dakota.

4.2 Method of Attenuation

Following passaging of the organism on primary bovine cells, the biologically selected, type 2 BVDV (strain 296) was subject to an attenuation regimen by multiple continuous passage through alternating host cells and non-host cells to produce a Master Seed Virus. Details of the methods used in the attenuation process are on-file with CFIA-VBS (18).

4.3 Genetic Stability

The genotype of the biologically selected BVDV (strain 296) was determined to be type 2 by analysis of the 5 untranslated region of the viral genome (4). Following attenuation, the genotype of the resultant Master Seed Virus was confirmed by an indirect fluorescence antibody assay with type 2 BVD specific monoclonal antibody. This same monoclonal antibody is used to differentiate the type 2 from the type 1 BVDV in the combination vaccines.

4.4 Phenotypic Stability

The cytopathic biotype of the biologically selected, type 2 BVDV (strain 296) isolate was confirmed: a) by passage in bovine cells, b) following further expansion of the virus in different bovine cells, and c) following attenuation in alternating host and non-host cell cultures to produce the Master Seed Virus.

4.5 Comparison of the Modified Organism to Parental Properties

Both the biologically selected BVDV (strain 296) and the Master Seed Virus are cytopathic organisms having a type 2 genotype.

4.6 Route of Administration

The vaccine is intended for use by the intramuscular or subcutaneous injection.

5. Human Safety

BVDV virus has been present in North America since the mid to late 1940's. There have been no reports of clinical illness in humans associated with BVDV. However, Giangaspero et al. have reported serological evidence for pestivirus infection in man, noting a seropositive result in 15.3% of subjects in a survey of 1,272 individuals in Europe and Zambia (19). Virus isolation was also conducted on 212 individuals (buffy coat samples) with one person being positive. This virus was characterized as a pestivirus based upon reactivity with an anti-BVDV serum. No clinical symptoms were associated with these results. It was suggested that contact with persistently infected cattle was a possible source of the virus.

6. Animal Safety

6.1 Previous Safe Use

In a field safety trial taking place in the United States, serials of a vaccine containing the modified live, type 2 BVDV (strain 296) component were given to 746 cattle in combination with modified live infectious bovine rhinotracheitis virus (IBR), BVDV type 1, parainfluenza 3 virus (PI-3), bovine respiratory syncytial virus (BRSV), and a Leptospira bacterin made up five serovars (20). The vaccine was administered by two routes of injection (390 cattle intramuscularly and 356 cattle subcutaneously), while 150 cattle where given a placebo vaccine (75 animals by each route). No local or systemic adverse reactions were observed in any animal over a 14 day post-vaccination observation period.

Products containing the same modified live, type 2 BVDV (strain 296) in combination with the following modified live viruses: IBR, BVDV type 1, PI-3, and BRSV, have been licensed by the United States Department of Agriculture-Center For Veterinary Biologics (USDA-CVB) for use in the United States since July 30, 1998 ("TitaniumT 5" and "TitaniumT 5L5").

In a letter dated July 14, 1999 (on-file with CFIA-VBS), the manufacturer stated that at least 3,462,000 doses of vaccine have been sold with no reports of adverse reactions at the injection site. Similarly, they indicated that no cases of vaccine-induced disease or death of cattle directly related to use of the vaccines have been substantiated.

6.2 Reversion to Virulence Resulting From Back Passage in Animals

The modified live, type 2 BVDV (strain 296) was demonstrated to be attenuated by back passaging the Master Seed Virus in young calves (18). A 16-fold higher dose than the serial release titre of the modified live, type 2 BVDV (strain 296) was instilled via the intra-nasal route in each of 10 calves. Virus was re-isolated from nasal secretions from four animals. Nasal secretions were pooled for instillation in a second group of five animals. Due to the low amount of virus secreted from the first group, only low amounts of virus were used to infect the second group. Shedding of vaccine virus by the second group of calves was sporadic and did not persist beyond day 8 post intra-nasal instillation. No signs of disease indicative of virulent type 2 BVDV were evident in any of the animals. Animals in group one seroconverted, while those in group two did not.

6.3 Potential for Shed and/or Spread of Vaccine Virus From Vaccinated to Contact Target and Non-target Animals

The manufacturer's studies indicate that, when the modified live, type 2 BVDV (strain 296) vaccine was administered according to label directions (intramuscularly or subcutaneously), no transmission of BVDV from vaccinated to non-vaccinated cattle was apparent, as evidenced by the absence of clinical signs of disease and the lack of serum neutralization titres in 10 control calves on day 29 post-vaccination (21, 22 ). Overdose intra-nasal administration of the modified live, type 2 BVDV (strain 296) vaccine (see section 6.2), a non-approved route of administration, indicated that, there is a limited potential for transmission of modified live, type 2 BVDV (strain 296) vaccine from vaccinated to non-vaccinated cattle. Clinical signs of disease indicative of virulent type 2 BVDV should not be evident in vaccinated cattle.

Studies of the transmission of this modified live, type 2 BVDV (strain 296), in other domestic species and captive or free-living ruminants, were not carried out by the manufacturer.

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

The effect of an overdose was examined in target (see (b) below) and non-target species (see (a) below) using four pre-licensing serials of two combination vaccines, which included the modified live, type 2 BVDV (StarvacT 4 Plus - three serials; StarvacT 3 Plus - one serial).

(a) Mouse Safety Test: For each serial, final container samples of completed vaccine were tested for safety by inoculating young adult mice both intracerebrally and intraperitoneally with vaccine prepared for use as recommended on the label. No unfavourable reactions were observed. The satisfactory test results are on-file with CFIA-VBS.

(b) Calf Safety Test: For each serial, each of two calves were injected with the equivalent of 10 doses of final container samples of completed vaccine, administered in the manner recommended on the label and observed for 21 days. No unfavourable reactions were observed. The satisfactory test results are on-file with CFIA-VBS.

6.5 Host Range/Specificity

Persistently infected cattle are the main source of BVD virus transmission in the environment (23). However, acutely infected cattle may also transmit the virus. BVDV has been isolated from many other captive and free-living ruminants, and transmission between small ruminants and cattle (in both directions), has been demonstrated (23). BVDV has also been isolated from swine (23). Infection of pigs with a virulent type 2 isolate of BVDV known to cause severe disease in calves, led to serum neutralizing antibody titres in pigs, but did not result in clinically apparent disease (24).

6.6 Safety in Pregnant Animals and Offspring Nursing Vaccinated Animals

Modified live BVDV vaccines are potentially fetopathogenic and should not be used in pregnant cows. This vaccine is not recommended for use in pregnant cattle or in calves nursing pregnant cows.

7. Affected Environment

7.1 Extent of Release into the Environment

The vaccine will be used by cattle producers and veterinarians on Canadian ranches, feedlots, dairies and in veterinary clinics, to vaccinate healthy cattle as an aid in prevention of disease caused by virulent type 2 BVDV. In general, BVD viruses can be isolated from nasal discharge, saliva, semen, faeces, urine, tears, and milk, each of which allows for wide dissemination of the virus. Potential for occasional environmental release through accidental spills, unintended syringe aerosols, and contamination of the skin and hair around the vaccination site also exists during routine use of this vaccine on farms and in veterinary clinics.

7.2 Persistence of the Organism in the Environment

Pestiviruses are inactivated by temperature, detergents and lipid solvents, but are relatively resistant to pH as they survive over a broad range of values (25). In meat products, a related pestivirus, hog cholera virus may survive for weeks or months (25). Virus is excreted in all secretions, although faeces appear to be a poor source of virus, even in situations where there is severe damage to the gut (26). Transmission of the virus between immunocompetent animals is unlikely to occur to any significant extent (27), and spread from benign infections in animals kept under grazing conditions has not been recognized (27).

A related flavivirus, St. Louis encephalitis virus, has been shown to be stable in aerosol suspension for six hours (23-80% humidity) (28). Similarly, rubella (a togavirus) virus can remain infectious for several days at 4 °C. in the presence of protein (29).

7.3 Extent of Exposure to Non-target Species

Vaccinated cattle may be housed or pastured in veterinary clinics, ranches, feedlots or dairies, with other domestic species (sheep, goats, pigs, horses, etc.), and/or captive or free-living ruminants. As with other modified live BVDV vaccines, use of this vaccine virus may result in limited shedding of the virus by vaccinated cattle with the potential for transmission to non-vaccinated cattle, other domestic species, or other captive or free-living ruminants (sections 6.2 and 6.3). Pestiviruses have been isolated from several species of wild ruminants and serological evidence indicates that a variety of wild species in North America have previously been exposed to BVDV in the absence of vaccination (30). BVDV (both type 1 and 2) appear to occur in wild animal species, depending on the range and water sources shared with domestic livestock (30). Exposure of other domestic species, such as swine, to virulent type 2 BVDV have not caused clinical signs of disease (24).

8. Environmental Consequences

8.1 Risks and Benefits

BVD vaccines are required that induce antibody against both BVD viral genotypes. The efficacy of the modified live, type 2 BVDV vaccine has been demonstrated by the manufacturer in two laboratory studies according to the current standards for BVDV vaccines described in the United States and Canada (21, 22). In the absence of duration of protection studies, there is only anecdotal evidence that modified live BVDV vaccines will provide protection for a longer duration of time than inactivated BVDV vaccines.

For any vaccine, there are risks of adverse reactions. However, no local or systemic adverse reactions were observed in any animal during a field safety study (20). As well, the manufacturer stated in a letter dated July 14, 1999, that 3,462,000 doses of vaccine containing the modified live, type 2 BVDV vaccine have been sold with no substantiated cases of vaccine induced disease or death.

As with other modified live BVDV vaccines, there is a low risk of shed and spread of the vaccine virus to non-vaccinated cattle, other domestic species, or other captive or free-living ruminants. Type 2 BVDVs have been indigenous to Canada since the early 1980's (10, 13). In North America, the serological data indicate that a wide variety of wild animal species are seropositive to BVDV in the absence of vaccination (30). Host animal safety of the vaccine virus has been established with the provision that pregnant cattle and calves nursing pregnant cows not be vaccinated. Exposure of other domestic species, such as swine, to virulent type 2 BVDV did not cause clinical signs of disease.

As with other modified live BVDV vaccines, there is the risk of potentially fatal consequences if persistently infected animals are inoculated with a modified live BVDV vaccine causing mucosal disease (31, 32, 33).

8.2 Relative Safety Compared to Other Vaccines

In order to be licensed in Canada, all veterinary vaccines must be shown to be pure, potent, safe, and efficacious, when used according to the label recommendations. As discussed above, based on the data on-file with CFIA-VBS, it was concluded that the modified live, cytopathic, type 2 BVDV (strain 296) vaccine did not present a greater risk to the health of cattle and other non-target animals, to human health, or to the environment, than other currently licensing modified live type 1 BVDV vaccines. As with other modified live BVDV vaccines, this vaccine has the potential to be fetopathogenic; however, inactivated BVDV vaccines do not share this risk.

9. Mitigative Measures

The use of the vaccine will be in accordance with the package insert supplied with the vaccine and with the label instructions. The personnel involved in the vaccination procedure should be provided proper instructions on the handling of live virus vaccines. It is recommended on the label to "Burn the containers and all unused contents." following use of the vaccine.

The manufacturer has indicated on both the container labels and in a package insert, that these vaccines are not recommended for use in pregnant cattle or in calves nursing pregnant cows.

The applicant will be required to stop the use of the vaccine should adverse reactions attributable to the vaccine be observed. In the event of serious adverse effects, the CFIA-VBS will consult the manufacturer and other experts, and the applicant will be advised accordingly.

10. Monitoring

10.1 Human

No special monitoring of human safety will be carried out.

10.2 Animal

The Health of Animals Regulations Section 135.1 states that "Every holder of a license or permit issued under this Part shall report to the Minister in writing, any information concerning or any evidence of a significant deficiency in safety, potency, or efficacy of a veterinary biologic within 15 days from the date on which such information or evidence is known to him or is generally known to the industry, whichever is earlier." Veterinarians and animal owners may also report suspected adverse reactions directly to CFIA-VBS. Suspected adverse reactions should be reported using the form Notification of Adverse Reactions to Veterinary Biologics - CFIA/ACIA 2205, as described in the Guidelines for Reporting Suspected Adverse Reactions to Veterinary Biologics (34).

When CFIA-VBS receives a suspected adverse reaction complaint, the importers/manufacturers are asked to investigate and prepare a report for the owner's veterinarian and CFIA-VBS. If the problem is resolved to the satisfaction of the veterinarian/animal owner, no further action is usually required by CFIA-VBS. However, if the investigation is not satisfactory, CFIA-VBS may initiate regulatory action, which may include further safety testing, temporary stop sale, or product withdrawal from the market. Depending on the nature of the complaint, the manufacturer may be required to submit samples of the product to CFIA laboratories for testing or conduct additional safety studies. If the adverse reaction rate is excessive for a particular serial or vaccine, the manufacturer may be ordered to temporarily stop sale of an affected serial, or withdraw the vaccine from the market. When a product must be withdrawn from the market or a specific serial must be recalled, the manufacturer must provide written notice to veterinarians and other purchasers. This notification is done through a letter, which must be approved by CFIA-VBS. For reporting purposes in Canada, adverse reactions are divided into Type 1, 2 and 3 reactions. In view of the above regulations, the following categories of suspected adverse reactions should be reported to CFIA-VBS:

Type 1 reactions are defined as any systemic adverse reaction, anaphylactic or hypersensitivity, requiring veterinary treatment including: persistent fever (lasting more than 48 hours), recumbency, persisting lethargy, decrease in activity, muscle tremors, shivering, hyper salivation, dyspnea and other respiratory problems, cyanosis, diarrhea, vomiting, colic and other gastrointestinal problems, eye problems, significant persistent drop in production, abortions and other reproductive problems, 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, hyper pigmentation) and/or excessive pain at injection site reported by a veterinarian or owner.

Manufacturers are obligated to maintain records of all suspected adverse reactions, and all cases involving Type 1, 2 and 3 reactions must be investigated and reported to CFIA-VBS. Isolated cases of mild, transient local injection site reactions that resolve without treatment must be investigated by the manufacturer, but need not be reported to CFIA-VBS.

11. Consultation and Contacts

First Importer

Biostar Inc.
343-111 Research Drive
Saskatoon, Saskatchewan
S7N 3R2 Canada

Manufacturer

Diamond Animal Health, Inc.
2538 South East, 43rd Street
Des Moines, Iowa
50317 USA

12. Conclusions and Actions

Since the early 1980's, type 2 BVDVs have been indigenous to Canada and virulent strains have been associated with severe thrombocytopenia and haemorrhagic lesions in cattle in several disease outbreaks. They have been demonstrated in the scientific literature to be similar to type 1 BVDVs in their ability to induce persistent infection, mucosal disease, and chronic BVD. Thus, BVDV vaccines are required that induce antibody against both viral genotypes.

The modified live, type 2 BVDV (strain 296) has been demonstrated to be efficacious in accordance with current standard requirements for BVDV vaccines in the United States and Canada.

It has also been demonstrated to be attenuated and stable, and is not expected to cause clinical signs of disease indicative of virulent type 2 BVDV in target or non-target species. Over 3,462,000 doses of vaccine, containing the modified live, type 2 BVDV (strain 296) component, have been distributed in the United States during the past year with no substantiated cases of vaccine induced disease or death.

As with other modified live BVDV vaccines, use of this vaccine virus may result in limited shedding of the virus by vaccinated cattle with subsequent transmission to non-vaccinated cattle, other domestic species, or other captive or free-living ruminants. Serological evidence indicates that a variety of wild species in North America have previously been exposed to BVDV in the absence of vaccination. Exposure of other domestic species, such as swine, to virulent type 2 BVDV have not caused clinical signs of disease. There have been no reports of clinical illness in humans associated with BVDV. As with other modified live BVDV vaccines, this modified live virus has the potential to be fetopathogenic and is not recommended for use in pregnant cows or calves nursing pregnant cows. Also, as with other modified live BVDV vaccines, there is the risk from the potentially fatal consequences of inoculating persistently infected animals with a modified live BVDV vaccine causing mucosal disease.

Based on the above information, it was concluded that release of a modified live, cytopathic, type 2 BVDV (strain 296) vaccine for distribution and sale in Canada did not present a greater risk to the health of cattle and other non-target animals, to human health, or to the environment, than other currently licensed modified live type 1 BVDV vaccines. Given that vaccines containing the modified live, type 2 BVDV (strain 296) component satisfactorily meet all requirements for licensing veterinary biologic products in Canada and importers comply with all conditions regarding the importation, distribution, and sale of these vaccines, CFIA-VBS may issue or amend import permits to allow importation of products containing the BVDV type 2 component from the manufacturer, Diamond Animal Health, Inc., Des Moines, Iowa.

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  20. Confidential Business Information - Diamond Animal Health, Inc. Final report on field safety evaluation of a modified live attenuated bovine virus diarrhea virus type 2 (strain 296) in combination with modified live, attenuated infectious bovine rhinotracheitis virus, bovine virus diarrhea virus type1, bovine respiratory syncytial virus, bovine parainfluenza 3 and a five Leptospira serovar bacterin in cattle. June 16, 1998.

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Prepared and revised by:

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