Alpha-defensin 5 differentially modulates adenovirus vaccine vectors from different serotypes in vivo.

Adenoviral vectors have shown significant promise as vaccine delivery vectors due to their ability to elicit both innate and adaptive immune responses. α-defensins are effector molecules of the innate immune response and have been shown to modulate natural infection with adenoviruses, but the majority of α-defensin-adenovirus interactions studied to date have only been analyzed in vitro. In this study, we evaluated the role of α-defensin 5 (HD5) in modulating adenovirus vaccine immunogenicity using various serotype adenovirus vectors in mice. We screened a panel of human adenoviruses including Ad5 (species C), Ad26 (species D), Ad35 (species B), Ad48 (species D) and a chimeric Ad5HVR48 for HD5 sensitivity. HD5 inhibited transgene expression from Ad5 and Ad35 but augmented transgene expression from Ad26, Ad48, and Ad5HVR48. HD5 similarly suppressed antigen-specific IgG and CD8+ T cell responses elicited by Ad5 vectors in mice, but augmented IgG and CD8+ T cell responses and innate cytokine responses elicited by Ad26 vectors in mice. Moreover, HD5 suppressed the protective efficacy of Ad5 vectors but enhanced the protective efficacy of Ad26 vectors expressing SIINFEKL against a surrogate Listeria-OVA challenge in mice. These data demonstrate that HD5 differentially modulates adenovirus vaccine delivery vectors in a species-specific manner in vivo. Author summary: Previous studies have shown that human α-defensin 5 (HD5) modulates adenovirus gene expression in vitro. Species D and F adenoviruses are generally augmented in the presence of HD5, while most other adenoviruses are inhibited. However, data regarding Ad-HD5 interactions in vivo are limited. We therefore sought to elucidate the capacity of HD5 to modulate Ad vectors from various serotypes in vivo. We immunized mice with Ad5 or Ad26 vectors together with HD5. We observed that HD5 augmented Ad26-elicited innate, cellular, and humoral immune responses but suppressed Ad5 immunogenicity. This study demonstrates that HD5 regulates Ad vector immunogenicity in vivo and suggests potential therapeutic applications of HD5. [ABSTRACT FROM AUTHOR]