Optimization of vaccine responses with an E1, E2b, E3 deleted Ad5 vector circumvents pre-existing anti-vector immunity

Recombinant serotype 5 adenovirus (Ad5) vectors lacking E1 expression induce robust immune responses against encoded transgenes in preclinical models, but have muted responses in human trials due to wide spread pre-existing anti-adenovirus immunity. Attempts to circumvent Ad5 specific immunity by using alternative serotypes or modifying capsid components have not yielded profound clinical improvement. To address this issue, we explored a novel alternative strategy, specifically reducing the expression of structural Ad5 genes by creating E1 and E2b deleted recombinant Ad5 vectors. Our data demonstrate that [E1−, E2b−]vectors retaining the Ad5 serotype are potent immunogens in pre-clinical models despite the presence of significant Ad5 specific immunity, in contrast to [E1−] vectors. These preclinical studies with E1 and E2b deleted recombinant Ad5 vectors suggest that anti-Ad immunity will no longer be a limiting factor and that clinical trials to evaluate their performance are warranted.