OAdV7, an ovine adenoviral vector as a novel vaccine vector for tumour immunotherapy

Abstract

Adenoviruses are a large family of non-enveloped DNA viruses with the ability to efficiently transduce human cells and activate the innate immune system, making them one of the most popular viral vectors for vaccine development. To date, the majority of the studies in the literature have focused upon human adenovirus serotype 5 (HAdV5) for the development of adenoviral vectors. However, the use of HAdV5 is limited due to its high prevalence in the general population. The pre-existing immunity to HAdV5 can ultimately lead to a reduction in transduction efficiency and immnunogenicity. Identification of adenoviral isolates of non-human origin facilitated development of alternative vectors to overcome pre-existing immunity in the human population. Ovine adenoviral isolate, OAdV287 (OAdV7), the prototype of the genus Atadenovirus, has been characterized as a gene delivery and vaccine vector. The study described in this project aims to address the utility of OAdV7 as a tumour vaccine, with in vitro experiments to characterize the ability of OAdV7 to transduce and activate human antigen presenting cells – monocyte-derived DCs (mono-DCs); and in vivo experiments to assess its in vivo immunogenicity. Transduction of human mono-DCs with OAdV7 showed successful transduction at high multiplicity of infection. Treatment of mono-DCs with OAdV7 led to DC maturation, evident by up-regulation of activation markers. Moreover, OAdV7 encoding a tumour antigen, the MART- 1-derived ELA peptide, successfully delivered antigen to DCs and melanoma cells to stimulate MART-1-specific CD8+ T cells. These data support the use of OAdV7 as a vaccine vector to deliver antigen to human antigen presenting cells and induce their activation. In mice, immunization with OAdV7 encoding the model antigen Ovalbumin rapidly induced a potent cytotoxic T cell responses. Splenocytes isolated from immunized mice responded to antigen restimulation in vitro by proliferation and production of IFN. Importantly, immunization with OAdV7-OVA prevented and retarded tumor growth in both prophylactic and therapeutic tumor trials.This is the first study that reports the ability of OAdV7 to be used as a tumour vaccine and warrants further studies that characterize the utility of this vector for immunotherapy.