Материал: Bovine Viral Diarrhea Virus Diagnosis, Management, and Control

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INTRODUCTION

Bovine viral diarrhea virus (BVDV) infects cattle of different age groups, from fetuses infected during pregnancy through adult cattle. The virus is prevalent in cattle populations worldwide and is responsible for considerable economic losses—e.g., reduction in feed conversion efficiency for meat and milk production, sick cattle, fatal diseases, and costs associated with treatment and prevention including vaccination.

Control programs for BVDV focus on three areas:

•Identification and removal of persistently infected (PI) cattle believed to be the major reservoirs of infection

•Biosecurity measures including prevention of BVDV exposure to herds believed to be BVDVfree through testing of new additions

•Vaccination of postnatal calves to protect them against disease after maternal antibody protection is lost and of heifers/cows to prevent fetal infections causing fetal losses and PI calves.

Vaccination to prevent fetal infections is likely the most important measures to control the occurrence of PI calves.

Since the 1960s, considerable research has been devoted to BVDV vaccines with numerous published studies. Two previous reviews offer extensive coverage, and readers are referred to them for discussion of earlier studies (van Oirschot et al., 1999; Bolin, 1995). In many BVDV vaccine studies, sheep have been used as a model because of their susceptibility to BVDV. The review by van Oirschot et al. (1999) covers numerous BVDV vaccine trials using sheep. This chapter focuses on BVDV vaccines in cattle, especially the efficacy of the vaccines and their impact on BVDV diversity.

Effective vaccines against infectious agents must

account for both antigenic and genetic diversity. There are two BVDV biotypes, cytopathic (cp) and noncytopathic (ncp) based on the presence or absence of visible cytopathic effects in infected cell cultures (Baker, 1995). There are two genotypes of BVDV (BVDV 1 and BVDV 2) based on genomic nucleotide differences, which are detectable by genomic sequence comparisons (Pellerin et al., 1984; Ridpath et al., 1984). Regions of the genome used in detecting genomic differences include the 5’ untranslated region (5’ UTR), NS (nonstructural protein) region, and E2 (envelope glycoprotein (gp53) region (Collett, 1996). The BVDV 1 genotype can be further separated into subgenotypes BVDV 1a and BVDV 1b (Ridpath and Bolin, 1998). Antigenic differences among these genotypes and subgenotypes are detected by differential virus neutralization tests (Fulton et al., 2003a; Jones et al., 2001).

Antigenic diversity in BVDV is a reflection of sequence diversity in the regions of the genome coding for the envelope protein E2, a glycoprotein (gp 53) E1, and Erns (ribonuclease) protein (Collett, 1996; Potgeiter, 1995). The differences in the 5’ UTR are reflected in the E2 region (Pellerin et al., 1994; Van Rijn et al. 1997). Bruschke et al. (1999) reported that the E2 immunogens of BVDV 1a and BVDV 1b may not provide immunity to a heterologous challenge. However, natural infections and the use of killed or modified live virus (MLV) vaccines does induce antibodies to several strains of BVDV including BVDV 1a, BVDV 1b, and BVDV 2 (Fulton et al., 1995; Cortese et al., 1998a; Jones et al., 2001; Fulton et al., 1997; Fulton and Burge, 2000; Fulton et al., 2000a; Fulton et al., 2002a; Grooms and Coe, 2002; Fulton et al., 2003a). However, vaccines containing BVDV 1a were found to induce higher antibody titers to the homologous BVDV 1a strains than to the heterologous BVDV 1b and

BVDV 2 strains. Although BVDV genotype is important in antigenic diversity, this does not appear to be true of biotypes. Studies have shown no differences in antibody titers when comparing cp and ncp strains of BVDV (Fulton et al., 1997; Fulton and Burge, 2000).

The impact of BVDV diversity on clinical forms of the disease is evident when examining BVDV isolates from cases submitted by veterinarians to the diagnostic laboratories (Fulton et al., 2000b). Of the 105 BVDV positive samples (Fulton et al., 2000b), 26 were BVDV 1 cp strains (24.8%), 38 were BVDV 1 ncp strains (36.2%), 10 were BVDV 2 cp strains (9.5%), and 31 were BVDV 2 ncp strains (29.5%). The ncp biotype was isolated more frequently (65.7%) than the cp biotypes (34.3%), and BVDV 1 genotype was more frequently isolated (61%) than BVDV 2 genotype (39.0%). Cattle with respiratory disease had more ncp biotypes than cp and more BVDV 1 genotypes than BVDV 2. In cases of fibrinous pneumonia, more BVDV 1 were isolated than BVDV 2 and of the 41 BVDV 1 isolates, 68.3% were BVDV 1b strains and 31.7% were BVDV 1a (Fulton et al., 2003a). In two studies of over 300 cattle commingled and observed for approximately 5 weeks, BVDV 1b was the most prevalent isolate (Fulton et al., 2002a). The results of these studies indicate that diverse BVDV strains (BVDV 1b, BVDV 1a, and BVDV 2) are found in various BVDV-associated diseases in the cattle population. BVDV 1a, BVDV 1b, and BVDV 2 were isolated from tissues of cattle receiving BVDV 1a vaccines weeks to months prior (Fulton et al., 2000b; Van Campen et al., 2000; and Fulton et al., 2003a). These BVDV strains may have been present due to two possible scenarios: the BVDV vaccinal strains did not induce protective immunity to these diverse strains, these BVDV strains may be PI strains.

VACCINES

Over 160 BVDV vaccines are listed in the Compendium of Veterinary Products (2003). These USDA licensed vaccines are based either on BVDV alone or BVDV in combination with bovine herpesvirus-1 (BHV-1), parainfluenza virus type 3 (PI-3), bovine respiratory syncytial virus (BRSV), Leptospira spp.,

Campylobacter spp., Haemophilus somnus, Mannheimia haemolytica and/or Pasteurella multocida immunogens. These vaccines meet the requirements for safety, purity, potency, and efficacy by the USDA’s Center for Veterinary Biologics (CVB) Code of Federal Regulations Sections 113.311 (“Live virus vaccines,” “Bovine virus diarrhea vac-

cine”) and 113.215 (“Killed virus vaccines;” “Bovine viral diarrhea vaccine, killed virus”). This information is available at the USDA APHIS CVB website (www. Aphis.usda.gov/vs/cvb/index.htm).

The requirements for efficacy of the killed or MLV vaccines include protection against clinical illness after challenge with virulent BVDV. For MLV vaccines, the challenge occurs at 14–28 days postvaccination with an observation period of 14 days. For killed vaccines, the challenge occurs 14 days or more after the last dose of the vaccine is given. There is no requirement for the use of a specific BVDV subtype as a challenge in either of these efficacy requirements. In September 2002, the USDA APHIS Center for Biologics Notice No. 02-19 published “Vaccine Claims for Protection of the Fetus Against Bovine Viral Diarrhea Virus.” Three categories for label claims were identified: “Aids in the prevention of abortion,” “Aids in prevention of persistently infected calves,” or “Aids in the prevention of fetal infection” or “Aids in the prevention of fetal infection including persistently infected calves.” A product label claim must be supported by research data filed by the vaccine manufacturing company during the licensing process.

BVDV vaccines have been available for use in cattle for over 40 years in the U.S. These vaccines, either MLV or killed, have been an integral part of bovine vaccination programs for beef breeding herd, stocker-feeder cattle for pasture forage or feedlots, dairy cattle, and veal operations. The merits of killed versus MLV vaccines have been debated over time. There are three important issues that have directed attention on the appropriate use of BVDV vaccines. First, in 1993 ncp BVDV strains with enhanced virulence were isolated in Canada from cases of severe acute BVD disease in cattle (Carman et al., 1998). Analysis of the isolates indicated that they were BVDV 2 strains. Cattle not properly vaccinated according to manufacturer’s instructions died with severe acute disease and hence efforts were made to increase the usage of BVDV vaccines. Also, the recognition of antigenic differences between BVDV 1 and BVDV 2 indicated the need for protection of cattle against BVDV 2 either by BVDV 1 vaccine or by developing BVDV 2-specific vaccines. The second issue is the recognition that PI cattle, because they shed virus throughout their lifetime, are likely reservoirs of infection for susceptible cattle. This focused attention on the need to control fetal BVDV infections by vaccination prior to exposure. Prior to this, fetal protection studies were not a part of efficacy requirements. The third issue is that the ability