Viral Cancers: Previous page | 1,2,3,4

Hepatitis C

Viral Cancers Introduction Epstein-Barr virus Hepatitis C Human papillomavirus

The majority of the worldwide hepatitis burden, with subsequent chronic hepatitis, cirrhosis and liver cancer is due to hepatitis virus B (HBV), which kills 4000 to 5000 Americans each year, and about 1.2 million people worldwide. Approximately 350 million people have chronic hepatitis B infection, with endemic areas primarily in Africa and Asia. Fortunately, the global burden of hepatitis B should eventually decrease as affordable recombinant subunit vaccines based on the surface antigen of the virus (HBsAg) and effective control strategies are deployed to control the disease on a global basis. Infants in developing countries begin their HBV immunization at birth; this has resulted in dramatic reductions in virus transmission in high-risk populations, and in decrease in incidence of liver cancer, as seen in China (Province of Taiwan).

Other viral hepatitis, initially regrouped under the designation “Non A-non B” hepatitis and against which there is still no vaccine, include hepatitis C and hepatitis E. The search for a possible “non A-E” virus which would be responsible for the 4% acute cases of hepatitis of undiagnosed origin led to the successive identification of the HGV/GBV-C, TTV and SEN-V viruses, none of which appear to be the right candidate.

Disease Burden

Hepatitis C has been compared to a “viral time bomb”. WHO estimates that about 180 million people, some 3% of the world's population, are infected with hepatitis C virus (HCV), 130 million of whom are chronic HCV carriers at risk of developing liver cirrhosis and/or liver cancer. It is estimated that three to four million persons are newly infected each year, 70% of whom will develop chronic hepatitis. HCV is responsible for 50–76% of all liver cancer cases, and two thirds of all liver transplants in the developed world.

Disease prevalence is low (< 1%) in Australia, Canada and northern Europe, about 1% in countries of medium endemicity such as the USA and most of Europe, and high (>2%) in many countries in Africa, Latin America and Central and South-Eastern Asia. In these countries, prevalence figures between 5% and 10% are frequently reported. The extremely high seroprevalence of HCV in the Nile delta of Egypt was found to increase with age from 19% in those 10–19 years of age to about 60% in 30 year-old persons, and is thought to be the major cause of the high prevalence of liver cirrhosis in the country.

Current estimates in the USA are that 3.9 million Americans are chronically infected with HCV, with prevalence rates as high as 8–10% in African Americans. Haemodialysis patients, haemophiliacs, drug addicts and people transfused with blood before 1990 are particularly affected by the disease. Injectable drug use remains the main route of transmission, accounting for nearly 90% of new HCV infections. Sexual transmission is thought to be relatively unfrequent.

Mother-to-child HCV transmission has been widely documented. The risk of perinatal infection ranges from 3–15% in different populations. Transmission is believed to occur in utero, as a consequence of a high viral load in the mother. However, correlates of transmission remain to be defined and targeted studies are needed to provide adequate counseling to HCV-infected pregnant women and to identify possible preventive measures.

HCV infection is asymptomatic or paucisymptomatic in 90% of cases. In contrast with viral hepatitis A or B, jaundice is relatively rare, and fulminant hepatitis forms are rarely observed. In 50–80% of adult cases, the immune system is nevertheless unable to eliminate the virus and the disease becomes chronic, with persistent asthenia and vascularitis, porphyria cutanea, glomerulonephritis and others. The patients usually show elevated transaminase levels and mixed cryoglobulinemia. Chronic hepatitis C disease is the first cause of liver transplantation in developed countries. Furthermore, about 20–50% of chronically infected persons will eventually develop cirrhosis or cancer of the liver. Incidence rates of hepatocellular carcinoma among patients with HCV-related cirrhosis is highest in Japan. It has been estimated that only about 50% of HCV-infected persons are diagnosed in most developed countries and that two-thirds of them need to undergo antiviral treatment.

Virology

HCV belongs to the genus Hepacivirus in the family Flaviviridae. There are 6 HCV genotypes and more than 100 subtypes. In addition, HCV, very much like HIV, is characterized by the continuous emergence of virus variants, thus making a moving target for vaccine design. Like other flaviviruses, HCV is an enveloped virus with an icosahedral capsid that contains a 9.6 kb-long, single-stranded, positive sense genomic RNA. The virus does not grow in cell culture; this made its initial identification in 1989 a molecular biology tour de force and does not facilitate the selection of attenuation mutants or the titration of neutralizing antibodies. Its envelope contains two glycoproteins, E1 and E2, which form heterodimers at the surface of the virion. The genomic RNA is translated into a viral polyprotein which is cleaved by cellular proteases to generate the capsid protein (C), the two glycoproteins E1 and E2, a small protein the role of which is unclear (p7), viral proteases NS2 and NS3 and nonstructural proteins NS4A and 4B and NS5A and 5B, which are required for viral RNA replication. The putative HCV receptor has recently being identified as protein CD81.

Vaccine Development

The development of an HCV vaccine is an obvious necessity as an overall 50% of treated patients do not experience significant long-term benefits from the current pegylated interferon and ribavirin-based combination therapy. Such a development, however, meets with many obstacles. Chimpanzees remain the only animal model for HCV infection, but they are an endangered species and difficult to work with because of high costs and other restrictions. Even though HCV infection generates antibodies, none of these seem capable of resolving the infection. One reason might be that the virus does not appear to circulate as free virions but is always found in association with lipoprotein particles or immune complexes.

Recovery from acute hepatitis is typically associated with broad and early class II-CD4+ responses and class I-CD8+ responses to HCV. A vaccine, to be successful, will presumably need to elicit strong CTL and T helper cell responses. It also will have to face high variability of the virus favouring immune evasion.

No vaccine is yet available. Several vaccine approaches, essentially therapeutic, are currently in development.

• Native heterodimer complexes comprising both envelope glycoproteins E1 and E2 have been produced in CHO cells and used as a subunit vaccine added with the MF59 adjuvant (Chiron). The vaccine elicited high titre antibodies and CD4+ T-cell responses and provided nonsterile protection against challenge in 50% of the vaccinated chimpanzees. Phase I trials of this vaccine are in progress.
• A vaccine candidate based on recombinant E1 in alum, developed by Innogenetics in Europe, has reached Phase II trials in non-responders to interferon treatment. Results showed that it is well tolerated and seems to slow down the progression of liver fibrosis, but no changes in plasma HCV loads were detected, despite decreased antigen levels in the liver and strong antibody and cellular responses to E1. An additional Phase II randomized study should be completed in 2005.
• VLPs (HCV-LPs) were produced in insect cells using a recombinant baculovirus expressing the cDNA of the HCV structural proteins C, E1 and E2. This approach is attractive because particulate structures are more immunogenic than soluble proteins. HCV-LPs resemble the putative HCV virions and induce strong HCV-specific immune responses in mice and baboons, including antibodies to HCV structural proteins and IFN-γ CD4+ and CD8+ T-cell responses. The immunogenicity of the HCV-LPs was only marginally enhanced by the addition of CpG oligonucleotides or the ASO1 formulation as adjuvants.
• An immunostimulatory complex formulation (ISCOMATRIX) with the HCV core antigen has been studied by CSL in Phase II trials in Australia, in collaboration with Chiron.
• HLA-A2-restricted core epitope peptides formulated with influenza virosomes as carriers are being developed by Berna/Pevion in Switzerland for both therapeutic and prophylactic vaccine strategies. This formulation is in preclinical studies. To improve the induction of T-cell immunity, the aminoacid sequence of the peptides was modified so as to increase their affinity for the HLA molecule (epitope enhancement)
• Several other vaccine projects are at an early preclinical stage, including HCVACC and Innogenetics in Europe and GenPhar, Epimmune, and Merix in the USA.
• Two Chinese teams also are making significant progress in HCV vaccine research: Fudan University and the National Taiwan University, Taipei, China (Province of Taiwan).
• Finally, an MVA-based live recombinant vaccine expressing three NS protein genes should reach the clinics by the end of 2005 (BioMérieux, France).

Viral Cancers: 1,2,3,4 | Next page