Intrinsic Control Strategies for Herpesvirus-based Vaccine Vectors
type: CreativeWork
description: Herpesvirus-based vectors have been used in vaccine strategies to target zoonotic diseases such as Ebola and human monkeypox, through eliciting a highly immunogenic response. We are investigating strategies to attenuate the virus and control its ability to replicate and persist, while maintaining its ability to elicit protective immune responses. In this project we have investigated three distinct and innovative means to provide intrinsic control of herpesvirus-based vectors. The first strategy is based on deletion of a gene essential for viral latency to modify persistence in vivo. Studies by Thirion et al have shown that the bovine herpesvirus 4 (BoHV-4) ORF73 gene product is required for persistence through enabling episome tethering to mitotic chromosomes. The first aim of the project was to investigate the ability of a latency-defective BoHV-4 Δ ORF73 vector expressing heterologous antigens to induce immune responses. Four recombinant defective BoHV-4 Δ ORF73 vectors, each expressing different heterologous target antigens, were constructed. One of these constructs, which expressed a target antigen from Mycobacterium bovis, was tested in vivo. The results showed the attenuated version of BoHV-4 Δ ORF73 was able to induce an immune response against its heterologous antigen. The second attenuation strategy was based on modulation of viral replication fidelity through mutation of the viral DNA polymerase. Based on a substantial body of published work from other laboratories studying the impact of genome replication fidelity on RNA viruses, we hypothesized that the genetic reduction in the fidelity of human cytomegalovirus (HCMV) replication would introduce an unsustainable level of mutations during replication of the virus, and thereby eventually result in 'genomic catastrophe' and demise of the virus. The aim of this second part of the thesis was to characterize a HCMV that has been modified through deletion of an aspartic acid residue 413 of domain II of exonucle…
abstract: Herpesvirus-based vectors have been used in vaccine strategies to target zoonotic diseases such as Ebola and human monkeypox, through eliciting a highly immunogenic response. We are investigating strategies to attenuate the virus and control its ability to replicate and persist, while maintaining its ability to elicit protective immune responses. In this project we have investigated three distinct and innovative means to provide intrinsic control of herpesvirus-based vectors. The first strategy is based on deletion of a gene essential for viral latency to modify persistence in vivo. Studies by Thirion et al have shown that the bovine herpesvirus 4 (BoHV-4) ORF73 gene product is required for persistence through enabling episome tethering to mitotic chromosomes. The first aim of the project was to investigate the ability of a latency-defective BoHV-4 Δ ORF73 vector expressing heterologous antigens to induce immune responses. Four recombinant defective BoHV-4 Δ ORF73 vectors, each expressing different heterologous target antigens, were constructed. One of these constructs, which expressed a target antigen from Mycobacterium bovis, was tested in vivo. The results showed the attenuated version of BoHV-4 Δ ORF73 was able to induce an immune response against its heterologous antigen. The second attenuation strategy was based on modulation of viral replication fidelity through mutation of the viral DNA polymerase. Based on a substantial body of published work from other laboratories studying the impact of genome replication fidelity on RNA viruses, we hypothesized that the genetic reduction in the fidelity of human cytomegalovirus (HCMV) replication would introduce an unsustainable level of mutations during replication of the virus, and thereby eventually result in 'genomic catastrophe' and demise of the virus. The aim of this second part of the thesis was to characterize a HCMV that has been modified through deletion of an aspartic acid residue 413 of domain II of exonucle…
author: Alqirbi, Hujaz Ismail Abdulrazzaq
language: eng
keywords: Herpesviruses, Viral vectors, Vaccine, Intrinsic control strategies
date published: 2020-01-01T08:00:00Z
date modified: 2026-07-24T03:50:16Z
provider: University of Plymouth
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Plymouth