Effect of route of delivery on heterologous protection against HCV induced by an adenovirus vector carrying HCV structural genes

BACKGROUND: An effective vaccine and new therapeutic methods for hepatitis C virus (HCV) are needed, and a potent HCV vaccine must induce robust and sustained cellular-mediated immunity (CMI). Research has indicated that adenoviral and vaccinia vectors may have the ability to elicit strong B and T cell immune responses to target antigens. RESULTS: A recombinant replication-defective adenovirus serotype 5 (rAd5) vector, rAd5-CE1E2, and a recombinant Tian Tan vaccinia vector, rTTV-CE1E2, were constructed to express the HCV CE1E2 gene (1-746 amino acid HCV 1b subtype). Mice were prime-immunised with rAd5-CE1E2 delivered via intramuscular injection (i.m.), intranasal injection (i.n.), or intradermal injection (i.d.) and boosted using a different combination of injection routes. CMI was evaluated via IFN-γ ELISPOT and ICS 2 weeks after immunisation, or 16 weeks after boost for long-term responses. The humoral response was analysed by ELISA. With the exception of priming by i.n. injection, a robust CMI response against multiple HCV antigens (core, E1, E2) was elicited and remained at a high level for a long period (16 weeks post-vaccination) in mice. However, i.n. priming elicited the highest anti-core antibody levels. Priming with i.d. rAd5-CE1E2 and boosting with i.d. rTTV-CE1E2 carried out simultaneously enhanced CMI and the humoral immune response, compared to the homologous rAd5-CE1E2 immune groups. All regimens demonstrated equivalent cross-protective potency in a heterologous surrogate challenge assay based on a recombinant HCV (JFH1, 2a) vaccinia virus. CONCLUSIONS: Our data suggest that a rAd5-CE1E2-based HCV vaccine would be capable of eliciting an effective immune response and cross-protection. These findings have important implications for the development of T cell-based HCV vaccine candidates.