Effects of cellular receptors on the vaccine efficacies of adenovirus vector-based vaccines following intramuscular and intranasal administration

Adenovirus (Ad) vectors are a promising next-generation vaccine modality currently under development. An Ad particle is composed of three major capsid proteins—fiber, penton base, and hexon—that play critical roles in cellular entry. However, the extents to which the receptor-mediated cellular entry pathways influence the efficacy of Ad vector-based vaccines are not well understood. In this study, we examined the effects of the cellular uptake pathway on the vaccine efficacy of Ad vectors by using the β-galactosidase (β-gal)-expressing, capsid-modified Ad vectors that utilize the different cellular entry routes. Following intramuscular vaccination, all capsid-modified Ad vectors induced serum anti-β-gal antibody levels comparable to those induced by the conventional Ad vector. In contrast, after intranasal vaccination, the Ad vectors with mutations in the penton base or hexon elicited anti-β-gal antibody titers in the serum, bronchoalveolar lavage fluid (BALF), and nasal wash at levels comparable with the conventional Ad vector. On the other hand, the coxsackievirus-adenovirus receptor (CAR)-binding-ablated Ad vector exhibited a significant reduction in the anti-β-gal IgG titers in the serum and BALF, and anti-β-gal IgA titers in the BALF and nasal wash. These findings highlight that CAR-mediated transduction is crucial for efficient vaccination with an Ad vector after intranasal administration.