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

An adenoviral HCV vaccine induces antiviral T cell responses in human volunteers. Hepatitis Hide and Seek Like venture capitalists and Wall Street bankers, patients receiving results of their blood work don’t like surprises, and more than money is at stake. Because infections caused by the hepatitis C virus (HCV) frequently are asymptomatic, patients might not know they’ve been infected: Symptoms don’t usually appear until irreversible liver scarring has occurred, which may cause cirrhosis, liver failure, or cancer. Even if infection is caught early, current therapies to combat this stealth virus have serious side effects, and there is no vaccine to prevent or treat HCV infection. Now, Barnes et al. demonstrate that vaccines developed with adenoviral vectors can induce broad and sustained immune responses to HCV in humans. Adenoviral vectors have shown promise in vaccine trials in animal models; however, preexisting immunity to common serotypes in humans has limited their use. In a phase 1 clinical trial, Barnes et al. vaccinated healthy subjects with two rare serotype adenoviral vectors that expressed an HCV protein. Both the human and the chimp adenoviral vaccinations elicited HCV-specific immune responses in the recipients that responded to multiple HCV antigens, were sustained for at least a year with boost, and elicited memory responses. And the researchers got a surprise they liked: Vaccination primed T cells to respond to multiple HCV strains at a level consistent with protective immunity. Further trials will be needed to confirm protective or therapeutic roles in HCV-infected individuals. 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 1 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 cell subsets; secreted interleukin-2, interferon-γ, and tumor necrosis factor–α; and could be sustained for at least a year after boosting with the heterologous adenoviral vector. Studies using major histocompatibility complex 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.