Preview

PDF, English Download (15MB) | Terms of use

Abstract

The Epstein-Barr virus (EBV) is a γ-herpesvirus that establishes lifelong infection in the majority of the human population. Whilst EBV infection is asymptomatic in most cases, the global disease burden of EBV is substantial. EBV is the primary cause of infectious mononucleosis and approximately 200,000 cases of EBV-associated malignancies are annually diagnosed. EBV has multifaceted life cycle that comprises lytic replication and latency, with the establishment of latency enabling lifelong EBV carriage. The majority of EBV vaccine candidates have previously focused on the major glycoprotein gp350. However, the interrogation of a gp350 vaccine in a phase II clinical trial showed that it was unable to prevent EBV infection. Our laboratory has recently developed a vaccine candidate in the form of defective EBV particles. These defective particles lack viral DNA, are non-infectious and are composed of several dozen EBV lytic proteins. In the present work, the antigenic spectrum of defective EBV particles was enlarged to include immunodominant latent proteins. The introduction of latent proteins into the defective particles enabled the stimulation of several lytic protein- and latent protein-specific CD4+ T cells. Polyclonal T cells specific for the modified particles were shown to be far superior to gp350-specific T cells at controlling EBV-infected B cells ex vivo. Furthermore, the modified particles afforded significant protection against EBV-infection in humanised mice. This suggests that EBV vaccines can be enhanced through the inclusion of additional antigens. By incorporating the most immunodominant EBV antigens into defective particles, it would prime the immune system against EBV antigens that are expressed at all stages of viral infection and in all EBV-associated malignancies. Such a multipronged approach is likely increase the possibility of achieving sterile immunity after prophylactic vaccination.