There is an urgent need for an effective vaccine to protect against infection and/or disease due to hepatitis C virus (HCV). In the USA alone, the Centers for Disease Control and Prevention estimates there were 17,000 new cases in 2007 and there is a global prevalence of 170 million carriers worldwide.
Most acute HCV infections are either asymptomatic or mild and approximately 25% of acute HCV infections resolve spontaneously.[1
] Most individuals develop chronic infection, and 20% of these slowly progress to cirrhosis of the liver.[3
] Chronic HCV infection is the leading cause of liver transplantation in the US.[5
] Currently there is no vaccine to prevent chronic infection; therapeutic treatments are only partially effective and have significant side effects[6
]. While preventing acute infection would be ideal, a vaccine that prevents chronic infection is expected to prevent clinically significant sequelae including cirrhosis and hepatocellular carcinoma.[7
HCV, an enveloped virus belonging to the flaviviridae family, contains a single stranded plus-sense RNA genome with a single open reading frame encoding both structural and nonstructural proteins.[12
] At least six distinct genotypes and many subtypes of HCV exist[13
] and infected individuals have complex mixtures of related viruses circulating as a quasi-species.[17
] Although E1 is thought to be variable, the E2 surface glycoprotein contains a hypervariable region,[19
] and is under marked selective pressure to evolve into antigenic variants.[22
] Because glycoproteins E1 and E2 are expressed on the surface of the virion, the proteins are expected to elicit neutralizing antibodies. Therefore recombinant HCV E1and E2 glycoproteins were constitutively expressed from the same RNA in permanent Chinese hamster ovary cell lines and purified under native conditions for use as a candidate vaccine. The antigen sequence was derived from the HCV genotype 1a, a predominant genotype in the US [16
] and Canada, and was passaged in chimpanzees.
In chimpanzees, vaccination with the E1E2 produced superior immune responses compared to E2 administered alone. Vaccination of chimpanzees followed by intravenous HCV challenge demonstrated that an adjuvanted prototype vaccine containing E1E2 modified the natural course of infection and appeared to sterilize against acute infection following homologous virus challenge[25
] in animals which developed high antibody titers; whereas chimpanzees with low anti-E1E2 antibody titers became acutely infected but generally resolved their infections. Vaccination of chimpanzees did not sterilize against acute infection following experimental challenge with heterologous HCV genotype 1a strain but importantly the majority did not develop chronic infection unlike the unimmunized controls. Interestingly, protection against chronic infection did not correlate strongly with anti-E1E2 antibody titers induced by vaccination, suggesting that such protection may be mediated by a combination of anti-E1E2 antibodies and cellular immune responses to vaccine.[26
] It is also important to note that in small animals, this vaccine induced anti-E1E2 antibodies capable of cross-neutralizing HCV pseudoparticles (HCVpp) derived from diverse HCV genotypes. [29
The present study extended the testing of an adjuvanted HCV E1E2 envelope glycoproteins vaccine to humans. Based on dose escalation studies in chimpanzees, vaccine was administered in this study on Day 0, and Weeks 4, 24 and 48. A dose ranging study with 4 μg, 20 μg and 100 μg of HCV E1E2 adjuvanted with MF59C.1 was expected to yield a dose response curve for selecting an optimal dose and schedule for future studies.