ReviewThe challenge of developing a vaccine against hepatitis C virus
Introduction
Hepatitis C virus (HCV) is a single stranded positive-sense RNA virus belonging to the Flaviviridae family [1]. Members of this family are small enveloped viruses that have been classified into three different genera: Pestivirus, which contains animal pathogens such as bovine viral diarrhea virus and hog cholera virus; Flavirirus, which contains mostly arthropod-transmitted human pathogens such as dengue fever and yellow fever viruses; and Hepacivirus, whose only member is HCV [1]. The recently discovered GB virus-B (GBV-B), which causes hepatitis in experimentally infected tamarins, will probably be classified with HCV [2], [3].
HCV is an important human pathogen, but the scope of its impact on human health has only recently been truly appreciated. The prevalence of HCV infection in the general population varies depending on the geographical area and ranges from less than 1% in Northern Europe to as high as 20% in some developing countries such as Egypt. It has been estimated that approximately 170 million people are chronically infected with HCV worldwide [4]. However, despite effective screening of blood and blood products, and use of sterile techniques, acute HCV is still a problem in industrialized countries. For example, around 40 000 new HCV infections occur each year in the US [5] and the majority of individuals with acute infection become persistently infected [6]. The source of these infections is principally the illicit use of parenteral drugs. Exposure to contaminated blood, especially via contaminated needles, syringes and surgical instruments, also accounts for the spread of HCV in developing countries. Chronic HCV infection is an important cause of liver cirrhosis and hepatocellular carcinoma in the Western World and Japan and, furthermore, represents the most frequent indication for liver transplantation in developed countries.
Treatment of chronic HCV infection has improved considerably during the last few years: the combination of interferon and the nucleoside analogue ribavirin achieves a sustained virological response in approximately 40% of patients with chronic hepatitis C [7], [8], [9]. It is possible that during the next few years, new antiviral agents such as inhibitors of the viral protease, helicase or polymerase will further improve the response rate of the current therapeutic agents. However, antiviral therapy is not affordable in most developing countries, where the prevalence of HCV is generally the highest. Thus, given the huge reservoir of HCV worldwide, the development of an effective vaccine will be the only way to control disease associated with HCV infection.
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The prospect of success for the development of HCV vaccines
Prophylactic vaccines against some other members of the Flaviviridae family already exist or are under development [1]. For example, a live-attenuated vaccine against yellow fever virus is available and has proven to be highly effective. Efforts have been made since the 1940s to produce dengue vaccines. Immunity acquired from natural infection is specific for each dengue serotype and infection of an individual with three different serotypes has been reported. For this reason, tetravalent
Approaches to HCV vaccine development
The classical approaches to vaccine development, live attenuated or whole inactivated virus, are not feasible for HCV because there is no cell culture system to produce viral particles. In addition, a live attenuated approach is not realistic because of the high tendency of the virus to persist in the host. Even recombinant viruses, such as those with deletions of the 3′ untranslated region or HVR1, which appear to cause attenuated acute disease in chimpanzees, readily persist in the host [31],
Summary
It is apparent that the development of an HCV vaccine poses a great challenge to the scientific community. Some difficulties are inherent to the virus, such as its high genetic heterogeneity and the ability to establish persistent infections, perhaps by escaping the host immune responses. Other limitations are technical, such as the lack of a cell culture system or a small animal model for HCV. Several studies have demonstrated that neutralizing antibodies to HCV exist, but that they appear to
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