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

Authors: WILLIAMS, LAURA - Washington State University; Fry, Lindsay; Herndon, David; FRANCESCHI, VALENTINA - University Of Parma; Schneider, David; DONOFRIO, GAETANO - University Of Parma; KNOWLES, DONALD - Washington State University

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/5/2019
Publication Date: 4/19/2019
Citation: Williams, L.B., Fry, L.M., Herndon, D.R., Franceschi, V., Schneider, D.A., Donofrio, G., Knowles, D.P. 2019. A recombinant bovine herpesvirus-4 vectored vaccine delivered via intranasal nebulization elicits viral neutralizing antibody titers in cattle. PLoS One. 14(4):e0215605. https://doi.org/10.1371/journal.pone.0215605.
DOI: https://doi.org/10.1371/journal.pone.0215605

Interpretive Summary: East Coast Fever (ECF) is a tick-borne disease of African cattle caused by the parasite, Theileria parva. Over one million cattle die of ECF each year, resulting in greater than 300 million U.S. dollars in annual losses. The parasite is spread to cattle by ticks, and causes disease and death when parasite-infected cells invade organs and are attacked by responding white blood cells. Currently available mechanisms of prevention are expensive and difficult to administer in the field. Thus, development of a next-generation vaccine that induces broad immune protection, is economically sustainable, and is convenient to store and administer is paramount to the long-term control of this devastating disease. The goal of this work was to test bovine herpesvirus-4 (BoHV-4)-vectored vaccines as a means of immunizing cattle, so that this platform could eventually be used to vaccinate cattle against T. parva. We immunized cattle with BoHV-4 vaccine containing antigens to bovine viral diarrhea virus (BVDV) and bovine rhinotracheitis virus (BoHV-1), and assessed immune responses and degree of protection against BVDV and BoHV-1. We found that this vaccine induced protective immunity to both BVDV and BoHV-1. Thus, BoHV-4 is a promising mode of vaccination against other severe diseases in cattle, including T. parva.

Technical Abstract: Recombinant herpesvirus vaccine vectors offer distinct advantages in next-generation vaccine development, primarily due to the ability to undergo 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.