Abstract
Bovine Viral Diarrhea Virus (BVDV) is an important pathogen that plays a significant role in initiating Bovine Respiratory Disease Complex (BRDC) in cattle. The disease causes multi-billion dollar losses globally due to high calf mortality and increased morbidity leading to heavy use of antibiotics. Current commercial vaccines provide limited cross-protection with several drawbacks such as safety, immunosuppression, potential reversion to virulence, and induction of neonatal pancytopenia. This study evaluates two prototype vaccines containing multiple rationally designed recombinant mosaic BVDV antigens for their potential to confer cross-protection against diverse BVDV strains. Genes encoding three novel mosaic antigens, designated E2123, NS2-31, and NS2-32, were designed in silico and expressed in mammalian cells for the formulation of a prototype protein-based vaccine. The mosaic antigens contain highly conserved protective epitopes from BVDV-1a, -1b, and -2, and included unique neutralizing epitopes from disparate strains to broaden coverage. We tested immunogenicity and protective efficacy of Expi293TM-expressed mosaic antigens (293F-E2123, 293F-NS2-31, and 293F-NS2-32), and baculovirus-expressed E2123 (Bac-E2123) mosaic antigen in calves. The Expi293TM-expressed antigen cocktail induced robust BVDV-specific cross-reactive IFN-γ responses, broadly neutralizing antibodies, and following challenge with a BVDV-1b strain, the calves had significantly (p < 0.05) reduced viremia and clinical BVD disease compared to the calves vaccinated with a commercial killed vaccine. The Bac-E2123 antigen was not as effective as the Expi293TM-expressed antigen cocktail, but it protected calves from BVD disease better than the commercial killed vaccine. The findings support feasibility for development of a broadly protective subunit BVDV vaccine for safe and effective management of BRD.
Highlights
Bovine Viral Diarrhea Virus (BVDV) is a single-stranded RNA virus from the genus Pestivirus in the family Flaviviridae with a 12.5 kb genome that encodes Npro; capsid; the Erns, E1, and E2 glycoproteins; NS2-3; NS4A-B; and NS5A-B proteins [1, 2]
Antigen-specific IFN-g responses were detected in calves immunized with the 293F-expressed antigen cocktail (E2123, Mosaic nonstructural 2-3 antigen from BVDV-1 (NS2-31), and Mosaic nonstructural antigen from BVDV-2 (NS2-32)) and in the calves immunized with the baculovirus-expressed E2123antigen (Figure 2A)
The Bac-Mosaic antigen containing E2 glycoprotein from BVDV-1a (E2123)-immunized calves had a significantly higher (p < 0.05) post-prime E2123-specific IFN-g response compared to the calves immunized with the 293Fexpressed antigen cocktail and the calves immunized with the Vira ShieldTM 6 commercial vaccine (Figure 2A)
Summary
Bovine Viral Diarrhea Virus (BVDV) is a single-stranded RNA virus from the genus Pestivirus in the family Flaviviridae with a 12.5 kb genome that encodes Npro; capsid; the Erns, E1, and E2 glycoproteins; NS2-3; NS4A-B; and NS5A-B proteins [1, 2]. The BVDV is grouped into antigenically distinct genotypes 1 and 2, and cytopathic (CP) and non-cytopathic (NCP) biotypes based on the effect of virus on infected cell cultures [3]. Both genotypes are further divided into various sub-genotypes and in the United States BVDV-1b is the predominant sub-genotype [4]. The BVDV is one of the major players in causing Bovine Respiratory Disease Complex (BRDC) in cattle worldwide. BVDV infection can be acute or persistent with a range of clinical symptoms such as fever, diarrhea, pneumonia, immunosuppression, congenital malformation, and abortion [5, 6]. Infected (PI) cattle are chronic virus shedders and if not diagnosed and culled, they are the main source of BVDV within a herd [7]
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