Priming Cross-Protective Bovine Viral Diarrhea Virus-Specific Immunity Using Live-Vectored Mosaic Antigens

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.

Vaccines the tugboat for prevention-based animal production

“…Therefore vaccine formulations require either one or both genotypes depending upon the prevalence of BVDV in a particular continent or geographical strata. To address this aforementioned problem, a novel mosaic polypeptide chimeras having three protective determinants; of BVDV-1a, BVDV-1b and BVDV-2 genotypes using adenovirus vector construct (adBVDV prototype vaccine) was evaluated and found better immunogenic with heterologous protection (Lokhandwala et al, 2017).…”

Mosaic Bovine Viral Diarrhea Virus Antigens Elicit Cross-Protective Immunity in Calves

“…Apart from neutralizing antibodies, CD4 + T cells are critical for enhancing the BVDV-specific antibody response and for clearance of infected cells, whereas CD8 + T cells can be directly cytotoxic for BVDV-infected cells (23)(24)(25)(26). The BVDV E2 and NS2/3 are immunodominant antigens that drive majority of neutralizing antibody and T cell responses and hence, are frequently selected targets for BVDV subunit vaccine development (11,(27)(28)(29). Experimental BVDV subunit vaccines involving recombinant E2 glycoprotein can provide some protection in cattle by limiting pyrexia, weight loss, leucopenia and viremia (21,(29)(30)(31)(32).…”

“…The focus of vaccine development efforts has been chiefly on inducing neutralizing antibody response by E2 glycoprotein (21,30,33). Some of the latest reports have highlighted the importance of inclusion of NS2 and NS3 in vaccine for induction of protective BVDV-specific T cell responses (27)(28)(29). MHC DR-restricted T cell epitopes identified from the highly conserved regions of E2 and NS3 are suitable for inclusion in a subunit vaccine (26,34).…”

“…MHC DR-restricted T cell epitopes identified from the highly conserved regions of E2 and NS3 are suitable for inclusion in a subunit vaccine (26,34). Given the heterogeneity of protective antigens among diverse BVDV isolate, mosaic antigens designed based on consensus protein sequences from circulating strains and addition of unique epitopes from disparate strains is likely to result in a chimeric antigen capable of eliciting broad protection (27,35,36).…”

“…In a previous proof-of-concept study, we found that an adenovirus-vectored prototype vaccine conferred better protection than a commercial multivalent MLV vaccine upon challenge with a BVDV-2a strain (27). In the antigen validation study, three novel mosaic antigens, designated E2 123 , NS2-3 1 , and NS2-3 2 were designed for immunization of calves.…”