HCV Vaccine Development

At the 13th International Symposium on Viral Hepatitis and Liver Disease (ISVHLD), held May 20-24, 2009 in Washington, DC, experts were invited to present their views on various issues related to viral hepatitis. Dr. T.J. Liang of the Liver Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases (part of the National Institutes of Health) offered a summary of his views on the history and prospects for development of a vaccine to prevent hepatitis C virus (HCV) infection. Following are edited excerpts from his remarks.

The Current Status of HCV Vaccine Development

With the high global disease burden and public health impact of hepatitis C, development of an effective vaccine is of major importance. However, many challenging obstacles loom ahead of this goal. The hepatitis C virus (HCV), being an RNA virus, can mutate rapidly, thus contributing to the high sequence divergence of multiple viral isolates in the world.

The highest heterogeneity has been found in the hypervariable region of the envelope glycoprotein 2. HCV also causes persistent infection in a high percentage of immunocompetent hosts despite active immune response. Previous observations that convalescent humans and chimpanzees could be readily re-infected following re-exposure to HCV suggest a lack of induction of protective immunity even from natural infection. The lack of a robust tissue culture system for propagating HCV and testing neutralizing antibodies until recently further complicate the task of vaccine development.

Recent advances render a more optimistic assessment to the development of an HCV vaccine. The immunologic correlates associated with viral clearance and disease progression are being defined. Many recent studies demonstrate that a vigorous multispecific cellular immune response is important in the resolution of infection. Furthermore, spontaneous clearance of the virus can occur in up to 50% of acute infections.

Therefore, if we could understand the mechanisms of viral clearance, we should be able to recapitulate these immune responses by appropriately targeting the vaccine. Recent studies in humans and chimpanzees also demonstrated the existence of natural protective immunity after convalescence from a previous infection. But this protection is usually at the level of prevention to chronic infection rather than prevention of acute reinfection upon re-exposure. This definition of protection against chronic infection has become widely accepted in vaccine development against chronic viral infection, such as HIV, because chronic infection is the well-established cause of disease.

Several promising approaches have been pursued to develop an HCV vaccine. Many of these approaches parallel those used in vaccine research for other persistent infections like HIV, herpes simplex viruses and malaria. Novel vaccine candidates based on molecular technology such as recombinant proteins (E1 and/or E2 glycoprotein), poly peptides, virus-like particles, plasmid DNA and recombinant viral vectors including adenovirus, modified vaccinia Ankara, canary pox virus, and alphavirus are being explored.

Various novel adjuvants including toll-like receptor agonists have demonstrated enhanced immunogenicity when applied together with HCV immunogens. Finally, vaccination regimens like prime-boost strategy have shown promise. Induction of high-titer, long-lasting and cross-reactive anti-envelope antibodies and a vigorous, multispecific cellular immune response that includes both helper and cytotoxic T lymphocytes may be necessary for an effective vaccine.

The final vaccine product may require multiple components that target various aspects of protective immunity. Demonstrating the efficacy of an HCV vaccine in humans has become a significant challenge because access to groups at high risk of HCV infection is not simple. Transfusion-associated hepatitis C is no longer common in the developed countries like the U.S. because of donor screening.

Other high-risk groups have inherent problems, such as intravenous drug users and sex workers (poor compliance), persons with occupational and sexual exposure (low incidence of infection), and institutionalized people like prisoners (ethical concerns).

Although it is possible to conduct vaccine study in developing countries where the incidence and prevalence of HCV infection is still high, regional politics and lack of infrastructural support are major barriers.

As a final note, even if an effective HCV vaccine is available, it is debatable as to who should receive the vaccine. Whether it should be given to the high-risk groups only or adopted as a universal vaccine program like HBV vaccine needs to be determined.

TJ Liang. The Current Status of HCV Vaccine Development. 13th International Symposium on Viral Hepatitis and Liver Disease (ISVHLD). Washington, DC. May 20-24, 2009. Abstract SP-28.