Immunogenicity and Cross-Reactivity of Human and Rhesus Adenoviral Vectors

Abstract

Preexisting adenovirus immunity in humans limits the use of adenoviruses vectors for gene therapy and vaccines. Therefore, in this thesis, a newer class of adenovirus (Ad) vectors belonging to the poorly understood species G of adenoviruses, rhesus adenoviruses (RhAds), are investigated for their viability as vaccine vectors and for their ability to evade preexisting human adenovirus (HuAd) immunity. Moreover, we investigate the extent of cross-reactive adenovirus immunity. RhAd vectors exhibited potent humoral and cellular immunogenicity as both priming and boosting vectors and induced favorable immunological phenotypes with high anamnestic capacity. Moreover, RhAds vectors were not hindered by preexisting human adenovirus immunity in the mouse model. In humans, we detected extensive CD4+, but limited CD8+ T cell cross-reactivity between RhAd and HuAd vectors, and cross-reactive CD8+ T cells were largely driven by single immunodominant epitopes in conserved regions. Minimal to no cross-reactive neutralizing antibodies were detected. These data suggest the potential utility of RhAd vectors for vaccines or gene therapy and define cross-reactive T cell epitopes between phylogenetically distinct adenoviruses that may be useful in future vector design.