Ovine herpesvirus 2 glycoprotein B complementation restores infectivity of a bovine herpesvirus 4 gB-null mutant

Authors: MORE', DANIELA - Washington State University; Baker, Katherine; SHRINGI, SMRITI - Washington State University; Bastos, Reginaldo; O'TOOLE, DONAL - University Of Wyoming; DONOFRIO, GAETANO - University Of Parma; Cunha, Cristina

Submitted to: Pathogens
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/26/2024
Publication Date: 3/1/2024
Citation: More', D.D., Baker, K.N., Shringi, S., Bastos, R.G., O'Toole, D., Donofrio, G., Cunha, C.W. 2024. Ovine herpesvirus 2 glycoprotein B complementation restores infectivity of a bovine herpesvirus 4 gB-null mutant. Pathogens. 13(3):219. https://doi.org/10.3390/pathogens13030219.
DOI: https://doi.org/10.3390/pathogens13030219

Interpretive Summary: Ovine herpesvirus 2 (OvHV-2) and bovine herpesvirus 4 (BoHV-4) are related viruses that use their respective glycoprotein B (gB) as part of the mechanisms to invade host cells. While OvHV-2 is the causative agent of sheep-associated malignant catarrhal fever (SA-MCF), a fatal disease of ungulates, BoHV-4 can infect a variety of ruminants with limited pathogenicity. In this study, we replaced the BoHV-4 gB by the OvHV-2 version of the gene with the goal of producing a chimeric virus, named BoHV-4 /OvHV-2-gB. We demonstrated that the chimeric virus was viable and able to infect cells in culture. This result prompted us to evaluate BoHV-4/OvHV-2-gB as a vaccine against SA-MCF in rabbits, a very well-established animal model for the disease. Data showed that BoHV-4 /OvHV-2-gB-vaccinated rabbits developed robust humoral response against OvHV-2-gB, including neutralizing antibodies. Upon challenge with wild type OvHV-2, we observed that only 28.5% of vaccinated animals were protected. This study is part of a continuous effort of our research team to develop a vaccine to SA-MCF. Although the immune responses induced by the vaccine candidate tested here are encouraging, vaccine efficacy was low, indicating more efficient strategies to express OvHV-2 proteins is necessary to develop an effective vaccine to control SA-MCF.

Technical Abstract: Ovine herpesvirus 2 (OvHV-2) and bovine herpesvirus 4 (BoHV-4) are gamma herpesviruses that belong to the genera Macavirus and Rhadinovirus, respectively. As with all herpesviruses, both OvHV-2 and BoHV-4 express glycoprotein B (gB), which plays an essential role in the infection of host cells. In that context, it has been demonstrated that a BoHV-4 gB-null mutant is unable to infect host cells. In this study, we used homologous recombination to insert OvHV-2 ORF 8, encoding gB, into the BoHV-4 gB-null mutant genome, creating a chimeric BoHV-4 virus carrying and expressing OvHV-2 gB (BoHV-4'gB/OvHV-2-gB) that was infectious and able to replicate in vitro. We then evaluated BoHV-4'gB/OvHV-2-gB as a potential vaccine candidate for sheep-associated malignant catarrhal fever (SA-MCF), a fatal disease of ungulates caused by OvHV-2. Using rabbits as a laboratory model for MCF, we assessed the safety, immunogenicity, and efficacy of BoHV-4'gB/OvHV-2-gB in an immunization/challenge trial. The results showed that while BoHV-4'gB/OvHV-2-gB was safe and induced OvHV-2 gB-specific humoral immune responses, immunization conferred only 28.5% protection upon challenge with OvHV-2. Therefore, future studies should focus on alternative strategies to express OvHV-2 proteins to develop an effective vaccine against SA-MCF.