Novel Adenovirus-Based Vaccines Induce Broad and Sustained T Cell Responses to HCV in Man

Abstract

Currently no vaccine exists for hepatitis C virus (HCV), a major pathogen thought to infect 170 million people globally. Many studies suggest that host T cell responses are critical for spontaneous resolution of disease, and preclinical studies have indicated a requirement for T cells in protection against challenge. We aimed to elicit HCV-specific T cells with the potential for protection using a recombinant adenoviral vector strategy in a Phase I study of healthy human volunteers. Two adenoviral vectors expressing NS proteins from HCV genotype 1B were constructed based on rare serotypes (Human Adenovirus 6 (Ad6) and Chimpanzee Adenovirus 3 (ChAd3)). Both vectors primed T cell responses against HCV proteins; these T cell responses targeted multiple proteins and were capable of recognizing heterologous strains (genotypes 1A and 3A). HCV-specific T cells consisted of both CD4+ and CD8+ T cells subsets, secreted IL-2, IFNγ, and TNFα, and could be sustained for at least a year after boosting with the heterologous adenoviral vector. Studies using MHC peptide tetramers revealed long-lived central and effector memory pools that retained polyfunctionality and proliferative capacity. These data indicate that an adenoviral vector strategy can induce sustained T cell responses of a magnitude and quality associated with protective immunity, and open the way for studies of prophylactic and therapeutic vaccines for HCV.

A PartialE3Deletion in Replication-Defective Adenoviral Vectors Allows for Stable Expression of Potentially Toxic Transgene Products

“…Clinical experiences with Ad vectors have shown them to be well tolerated at doses needed to induce transgene product-specific immune responses. 7,9,24 We developed AdC vectors to circumvent preexisting neutralizing antibodies, which are commonly found in humans to human Ad serotypes. 38,39 Ad-neutralizing antibodies reduce uptake of the corresponding Ad vectors and hence their ability to induce transgene product-specific immune responses.…”

An update on hepatitis C virus

“…These trials demonstrated that the vaccines induced robust and functional CD4 + and CD8 + T-cell responses to multiple antigenic sites, and that these responses were sustained for up to one year. 21,23 Phase-II studies are currently underway in the USA.…”

Ebola vaccines in clinical trial: The promising candidates

“…The incidences and severity of local and systemic adverse reactions were similar to those observed in previous studies of other adenovirus vectored vaccines. 23,36 Beside, another phaseI, dose-escalation, open-label study was conducted to assess the safety and immunogenicity of a single dose of the ChAd3-EBO-Z at 3 different dosages 1 £ 10 10 , 2.5 £ 10 10 and 5 £ 10 10 vp, with 20 participants per group, respectively 33 (ClinicalTrials.gov NCT02240875) ( Table 1). The highest dosage of the experimental vaccines in this trial only a quarter of that in the previous trial.…”