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.