Clinical Protection of Goats against CpHV-1 Induced Genital Disease with a BoHV-4-Based Vector Expressing CpHV-1 gD

Abstract

Caprine herpesvirus type 1 (CpHV-1) is an alphaherpesvirus causing genital disease leading to abortion in adult pregnant goats and a systemic disease with high morbility and mortality in kids. Further, Caprine herpesvirus 1 infection represents a valuable large animal model for human herpesvirus induced genital disease, exploitable for pathogenic studies, new vaccines and antiviral molecules testing. Here, the bovine herpesvirus 4 (BoHV-4) based vector derived from an apathogenic isolate of BoHV-4 and expressing the immunodominant CpHV-1 glycoprotein D (BoHV-4-A-gDcpgD106ΔTK) was constructed and its ability to protect goats against CpHV-1 induced genital disease evaluated. The subcutaneous route of recombinant BoHV-4 administration was first tested in vivo/ex vivo by in vivo image analysis and in vitro by goat skin primary cultures preparation and transduction. Next, an exploratory immunization and safety study in goats was performed with two recombinant BoHV4, BoHV-4-A-gDcpgD106ΔTK or BoHV-4-CMV-IgK-gE2gD-TM. In both cases no clinical signs were evident but a good titer of serum neutralizing antibodies was produced in all inoculated animals. When a challenge experiment was performed in a new group of animals using a highly pathogenic dose of CpHV-1, all the vaccinated goats with BoHV-4-A-gDcpgD106ΔTK were protected toward CpHV-1 induced genital disease respect to the unvaccinated control which showed typical vaginal lesions with a high grade of clinical score as well as a long lasting viral shedding. In summary, the data acquired in the present study validate BoHV-4-based vector as a safe and effective viral vector for goat vaccination against CpHV-1 induced genital disease and pave the way for further applications.

BoHV-4-based vector delivering Ebola virus surface glycoprotein

“…4b, c). As previously described for BoHV-4-based vaccine vector inoculation in goats [15], in the present study, a single inoculation of BoHV-4-syEBOVgD106ΔTK was able to elicit a humoral immune response 2 weeks post inoculation. Moreover, the antibody titer did not decrease when evaluated 6 months later (data not shown), showing long lasting immunization.

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“…Due to the lack of a direct correlation between BoHV-4 infection and specific lesions or pathology, BoHV-4 is not considered a primary pathogen and its genome was cloned as bacterial artificial chromosome (BAC), in order to be exploited as a gene delivery vector for immunization purposes and oncolysis. BoHV-4-based vector delivering antigens have been employed to immunize mice [9], rats [11], rabbits [12], sheep [13], swine [14], cows (paper in preparation) and goats [15] without any associated clinical signs or pathology.…”

“…Although goats are not susceptible to EBOV infection, BoHV-4-syEBOVgD106ΔTK immunization was performed in adults goats as they have previously been shown to be an appropriate large animal model for BoHV-4-based vector immunization [15]. Further, goats could be exploited as a source of antibodies production for antibody-based therapeutic in post-exposure treatment of EBOV disease.…”

“…The sub-cutaneous route of BoHV-4-based vector administration was shown to facilitate antigen production and vector replication takes place only at the site of inoculation [15], without spreading to the rest of the animal body. No BoHV-4-syEBOVgD106ΔTK viremia was detected in inoculated animals, although all BoHV-4-syEBOVgD106ΔTK inoculated animals were successfully immunized and high titers of EBOV GP antibodies were detected.…”

“…Bovine herpesvirus 4 (BoHV-4)-is a relatively new viral vector derived from bovine gammaherpesvirus . Recombinant BoHV-4s cloned as bacterial artificial chromosome (BAC), delivering ORFs coding for immune-dominant antigens from different pathogens, were shown to successfully elicit a functional immune-response in mice [9, 10], rats [11], rabbits [12], sheep [13], swine [14] and goats [15]. In the present paper, a BoHV-4-based vector platform was generated exploiting a synthetic gene approach; a recombinant BoHV-4 delivering EBOV GP ORF expression cassette was constructed and goats were successfully immunized.…”