Abstract
Bovine viral diarrhea virus (BVDV) plays a key role in bovine respiratory disease complex, which can lead to pneumonia, diarrhea and death of calves. Current vaccines are not very effective due, in part, to immunosuppressive traits and failure to induce broad protection. There are diverse BVDV strains and thus, current vaccines contain representative genotype 1 and 2 viruses (BVDV-1 & 2) to broaden coverage. BVDV modified live virus (MLV) vaccines are superior to killed virus vaccines, but they are susceptible to neutralization and complement-mediated destruction triggered by passively acquired antibodies, thus limiting their efficacy. We generated three novel mosaic polypeptide chimeras, designated NproE2123; NS231; and NS232, which incorporate protective determinants that are highly conserved among BVDV-1a, 1b, and BVDV-2 genotypes. In addition, strain-specific protective antigens from disparate BVDV strains were included to broaden coverage. We confirmed that adenovirus constructs expressing these antigens were strongly recognized by monoclonal antibodies, polyclonal sera, and IFN-γ-secreting T cells generated against diverse BVDV strains. In a proof-of-concept efficacy study, the multi-antigen proto-type vaccine induced higher, but not significantly different, IFN-γ spot forming cells and T-cell proliferation compared to a commercial MLV vaccine. In regards to the humoral response, the prototype vaccine induced higher BVDV-1 specific neutralizing antibody titers, whereas the MLV vaccine induced higher BVDV-2 specific neutralizing antibody titers. Following BVDV type 2a (1373) challenge, calves immunized with the proto-type or the MLV vaccine had lower clinical scores compared to naïve controls. These results support the hypothesis that a broadly protective subunit vaccine can be generated using mosaic polypeptides that incorporate rationally selected and validated protective determinants from diverse BVDV strains. Furthermore, regarding biosafety of using a live vector in cattle, we showed that recombinant human adenovirus-5 was cleared within one week following intradermal inoculation.
Highlights
Bovine viral diarrhea virus (BVDV), an infectious pathogen that is prevalent in cattle herds globally, is a key agent responsible for causing Bovine Respiratory Disease Complex (BRDC) [1]
Immunocytometric analysis of human embryonic kidney (HEK)-293A cells transfected with the pAdNproE21-3, pAdNS2-31, or pAdNS2-32 constructs probed with anti-FLAG monoclonal antibodies (mAbs) confirmed that each construct expressed the encoded antigen (Fig 1B)
Immunocytometric analysis of HEK-293A cells infected with the AdNproE21-3, AdNS2-31, or AdNS2-32 recombinant adenoviruses probed with anti-FLAG mAb confirmed protein expression (Fig 1C)
Summary
Bovine viral diarrhea virus (BVDV), an infectious pathogen that is prevalent in cattle herds globally, is a key agent responsible for causing Bovine Respiratory Disease Complex (BRDC) [1]. The secondary infections are responsible for high rates of morbidity and mortality, and it is estimated that the U.S livestock industry loses >$1billion annually due to BRDC [4, 5]. This virus is classified as a member of the genus Pestivirus within the family Flaviviridae [6]. The prevalence of PI animals in selected herds in the United States is estimated at 1.7% of the cattle population, and these animals are considered to be the primary source of infection of susceptible animals [13]
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