Next generation vaccines for bovine respiratory disease (BRD) complex utilizing virus vaccine vectors to target both bacterial and viral pathogens.

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Bovine respiratory disease (BRD) is a complex condition influenced by a combination of environmental stressors, host immune responses, and multiple pathogens. It is most prevalent in young cattle that are housed in close quarters and was called shipping fever due to its association with animal movements. The economic consequences of BRD are significant worldwide, for example, one feed lot study showing more than one in six cattle being affected by BRD and over 2% mortality, with a reduction in net return of 50% in affected cattle. BRD is initiated in susceptible cattle by respiratory virus infections, with bovine herpesvirus 1 (BoHV-1), bovine respiratory syncytial virus (BRSV) and parainfluenza virus 3 (PI3) being among the most prevalent. Secondary infections with bacterial pathogens, in particular Mannheimia haemolytica and Pasteurella multocida, follow leading to clinical disease.Moredun Research Institute (MRI) and Ceva Sante Animale (Ceva) have active programs developing new vaccines for the pathogens that cause BRD. At Moredun, we have developed vaccine vectors to deliver antigen payloads from the virus pathogens using four of our vaccine vector platforms. Concurrently, Ceva has identified antigens from the same viral pathogens as well as 2 bacterial pathogens as potential vaccine payloads for a multivalent recombinant protein vaccine. These are presently being tested at Moredun, specifically by the contract research organization (CRO), Moredun Scientific, Ltd. In this proposal, we have selected (from the Ceva antigens) one protein from bacteria and one protein from a virus to test in all of the vector formats. These will both be cloned into each of the vectors under study, specifically, replication defective human adenovirus 5 (Ad5), Maedi visna virus (MV), Alcelaphine herpesvirus 1 (AlHV-1), and Orf virus. All vaccine vectors made expressing the targeted antigens (A from a virus and B from a bacterium, from the Ceva antigens) will be tested in vitro as a pre-screen before conducting animal trials. If, as expected, all express the protein payload in vitro, they will be tested in cattle. We will assay for serum antibody responses, mucosal antibody responses, and the comparative levels of CD4 T helper cell responses. Results will provide data to determine if one or more of these vectors out-perform the others in the delivery of the selected antigens. Further, we will demonstrate whether these vectors induce stronger and more protracted immune responses than the recombinant proteins in adjuvant as well as presently available commercial vaccines. If any of the vectored vaccines are superior performers, this will advance the development of more effective BRD vaccines. These vector systems allow for delivery of multiple proteins in a single payload, providing multivalent vaccines. They also allow rapid change of the payload if new, antigenically divergent strains of either bacteria or virus pathogens are identified. Additionally, these vectors do not require adjuvants for delivery, removing that expense and reducing injection reactions often seen with strong adjuvants.