Research Article: A recombinant bovine herpesvirus-4 vectored vaccine delivered via intranasal nebulization elicits viral neutralizing antibody titers in cattle

Date Published: April 19, 2019

Publisher: Public Library of Science

Author(s): Laura B. A. Williams, Lindsay M. Fry, David R. Herndon, Valentina Franceschi, David A. Schneider, Gaetano Donofrio, Donald P. Knowles, Paulo Lee Ho.


Recombinant herpesvirus vaccine vectors offer distinct advantages in next-generation vaccine development, primarily due to the ability to establish persistent infections to provide sustainable antigen responses in the host. Recombinant bovine herpesvirus-4 (BoHV-4) has been previously shown to elicit protective immunity in model laboratory animal species against a variety of pathogens. For the first time, we describe the induction of antigen-specific immune responses to two delivered antigens in the host species after intranasal nebulization of recombinant BoHV-4 expressing the chimeric peptide containing the bovine viral diarrhea virus (BVDV) glycoprotein E2 and the bovine herpesvirus 1 (BoHV-1) glycoprotein D (BoHV-4-A-CMV-IgK-gE2gD-TM). In this study, four cattle were immunized via intranasal nebulization with the recombinant BoHV-4 construct. Two of the cattle were previously infected with wild-type BoHV-4, and both developed detectable serologic responses to BVDV and BoHV-1. All four immunized cattle developed detectable viral neutralizing antibody responses to BVDV, and one steer developed a transient viral neutralizing response to BoHV-1. Approximately one year after immunization, immunosuppressive doses of the glucocorticoid dexamethasone were administered intravenously to all four cattle. Within two weeks of immunosuppression, all animals developed viral neutralizing antibody responses to BoHV-1, and all animals maintained BVDV viral neutralizing capacity. Overall, nebulization of BoHV-4-A-CMV-IgK-gE2gD-TM persistently infects cattle, is capable of eliciting antigen-specific immunity following immunization, including in the presence of pre-existing BoHV-4 immunity, and recrudescence of the virus boosts the immune response to BoHV-4-vectored antigens. These results indicate that BoHV-4 is a viable and attractive vaccine delivery platform for use in cattle.

Partial Text

Bovine herpesvirus-4 (BoHV-4) is within the rhadinovirus genus in the gammaherpesvirus subfamily of the Herpesviridae family [1]. As is typical of other gammaherpesviruses, BoHV-4 initially infects mucosal epithelial cells, and replicates and undergoes latency in monocytes and macrophages [2]. BoHV-4 has been isolated from a variety of tissues from healthy cattle [3, 4]. Although BoHV-4 has also been identified in diseased respiratory, enteric, and most often, reproductive tissues, causal associations with disease have not been definitively established, and experimental infection of cattle does not reliably result in overt clinical disease [5, 6].

The results of this study indicate that nebulization of BoHV-4-A-CMV-IgK-gE2gD-TM is capable of eliciting and maintaining BoHV-4-vectored antigen-specific immunity following immunization, including in the presence of pre-existing BoHV-4 immunity. Thus, BoHV-4 is a viable and attractive vaccine delivery platform for use in cattle. Livestock production demands have increased steadily for decades, and are projected to continue to trend upwards on a global scale [36, 37]. As production demands increase, efficient methods of disease prevention in bovine herd health management are necessary. The provision of long-term, or even lifelong, immunity with a single dose of vaccine would be an obvious advantage for many types of cattle operations, including large-scale production systems and small-holder agropastoralists. Additionally, the development of polyvalent recombinant vaccines to immunize against multiple pathogens using a single vaccination would similarly increase the level of efficiency for large-scale vaccination strategies. Given the ability of BoHV-4 to persistently infect cattle and the ability to accommodate large amounts of foreign genetic material, as evidenced by the inclusion of multiple antigens in this study, makes the development and use of BoHV-4 appealing as a vaccine vector for use in cattle.