Vaccination With Recombinant Adenoviruses Expressing the Bluetongue Virus Subunits VP7 and VP2 Provides Protection Against Heterologous Virus Challenge

Abstract

Bluetongue virus (BTV) is the causative agent of a disease that affects domestic and wild ruminants and leads to critical economic losses. BTV is an arbovirus from the Reoviridae family that is typically transmitted by the bite of infected Culicoides midges. BTV possesses multiple serotypes (up to 28 have been described), and immunity to one serotype offers little cross-protection to other serotypes. The design of vaccines that provide protection across multiple serotypes is therefore highly desirable to control this disease. We previously reported that a recombinant replication-defective human adenovirus serotype 5 (Ad5) that expresses the VP7 inner core protein of BTV serotype 8 (Ad5VP7-8) induced T-cell responses and provided protection. In the present work, we evaluated as BTV vaccine the combination of Ad5VP7-8 with another recombinant Ad5 that expresses the outer core protein VP2 from BTV-1 (Ad5VP2-1). The combination of Ad5VP2-1 and Ad5VP7-8 protected against homologous BTV challenge (BTV-1 and BTV-8) and partially against heterologous BTV-4 in a murine model. Cross-reactive anti-BTV immunoglobulin G (IgG) were detected in immunized animals, but no significant titers of neutralizing antibodies were elicited. The Ad5VP7-8 immunization induced T-cell responses that recognized all three serotypes tested in this study and primed cytotoxic T lymphocytes specific for VP7. This study further confirms that targeting antigenic determinant shared by several BTV serotypes using cellular immunity could help develop multiserotype BTV vaccines.

The Interplay between Bluetongue Virus Infections and Adaptive Immunity

“…Jeggo et al also showed that T cell adoptive transfer from BTV-recovered sheep protected from BTV challenge in monozygotic twins [ 41 ]. Cellular immunity in absence of neutralizing antibodies typically only provides partial protection [ 41 , 43 ], but it is cross-reactive between serotypes [ 44 , 45 , 46 , 47 , 48 , 49 ]. Indeed, vaccination based on BTV antigenic determinants that are conserved between serotypes (such as VP7 or NS1) have shown promising results in eliciting at least partial cross-serotype protection in animal models [ 44 , 46 ].…”

Increased Clinical Signs and Mortality in IFNAR(−/−) Mice Immunised with the Bluetongue Virus Outer-Capsid Proteins VP2 or VP5, after Challenge with an Attenuated Heterologous Serotype

“…However, they also indicate that it is important to consider the possibility of ADE responses when designing vaccination campaigns using serotypespecific inactivated or subunit vaccines. To prevent problems that could be caused by ADE, vaccines should include components that induce a more widely cross-serotype protective immune response, for example the more highly conserved BTV non-structural proteins NS1 and NS2, or structural protein VP7, which induce cross-reactive and protective T-cell mediated responses [2,55].…”

Vaccination as a Strategy to Prevent Bluetongue Virus Vertical Transmission

“…Several platforms have been employed to induce immunity to BTV in the natural host. These include, among others, poxviruses [128][129][130], adenoviruses [130][131][132], Rift Valley fever virus (RVFV) [133,134], or herpesviruses [135,136]. These recombinant constructs were able to induce immunity to BTV in murine models and/or in the natural host, and protection was also demonstrated in some studies in the natural host [129][130][131]133,134].…”

“…They are non-pathogenic as they are often based on replication-defective viruses. They can offer protection over multiple BTV serotypes with the same formulation [128,132]. Recombinant vector vaccines based on attenuated vaccine strains, such as RVFV, can even induce bivalent protection in ruminants against RVFV and BTV [133].…”