There has been some discussion as to what type of vaccine would be best for the Hep C virus.
Ideal would be a vaccine that would prevent initial infection (prophylactic vaccine), but a vaccine that
would prevent the infection from becoming chronic would be sufficient (therapeutic vaccine). The problem is
that the virus has so many strains and mutates so easily. An effective vaccine would have to work against at
least one genotype of the virus, preferably genotype 1, which is the most common. Other problems are developing
a vaccine that confers lasting protection and finding good models for testing
().
Types of possible vaccines:
Passive Immunization: One would think that having HCV antibodies would cure the disease and protect a person against re-infection, but it doesn’t work that way with the hepatitis C virus. Attempts at using this method on chimpanzees have seemingly failed. HCV hyperimmune globulin has worked, but doesn’t last and doesn’t protect against re-infection.
Aventis Pasteur (Lyons, FR) applied for a US patent for a vaccine of this sort in March 2003
(
Envelope Glycoprotein Vaccines: This is the most encouraging vaccine possibility at this time. The vaccine makes antibodies to parts of the virus’ outer coating,
called E1 and E2. This vaccine seems to be showing promise in chimpanzees (See III.4.2 InnoVac-C and III.4.3 XTL-002).
Epitope Based Vaccines: This type of computer-generated vaccine is designed to make the body produce a strong immune response (CD4+ and CD8+) using
T-cell epitopes. It is hoped that this technology won’t allow mutations to escape, and that it will cover several genotypes,
not just one. The disadvantages are that the technology requires large computer databases, and an effective vaccine would probably
have to include some protein from actual HCV
(). (See III.4.4 Epimmune Vaccine).
Naked DNA Vaccines: “Naked” DNA means DNA that isn’t associated with a
virus. Therapeutic DNA is introduced into a virus to deliver it to the
body. The “C” gene of the hepatitis C gene is often used in these
experiments, because it is similar in all the genotypes. Side effects of
a vaccine of this type may be a problem, and safety may be an issue,
although some researchers say there are no viral components to cause
unwanted immune responses, infections, or permanent changes in the cell's
genetic makeup. DNA vaccines for hepatitis C are still in pre-clinical
stages of development, and they show great potential, even for
therapeutic treatment.
(). (See III.4.5 Vical)
Chiron Corporation is involved in clinical studies with naked DNA vaccines.
Viral Vector Vaccines: These vaccines, like naked DNA vaccines, are designed to place foreign DNA into a cell to stimulate the immune system.
Viral vector vaccines have an advantage because they allow specific host cells to be targeted, so that the vector will not
enter the genetic material of the cell. Few vaccines like this have been tried, so little is known about how effective they are.
().
Recombinant viruses can be used to deliver DNA efficiently. Experiments in animals have induced protective immunity
to many viruses, and some are being tested for HCV vaccines. A favorite virus is the defective adenovirus because its natural
“habitat” is the liver. However, the recent tragedy of death in a gene therapy trial using adenovirus has severely dampened the
enthusiasm for the use of this viral vector in humans (
).
There has been recent good news about an adenovirus vector called BID
(BH3–interacting death domain death agonist). The vector is designed to
cause cells infected with HCV NS3/NS4A protease to commit suicide
(aptosis), stopping the progression of the disease. Studies done with
chimeric mice at the Ontario Cancer Institute, and reported in the May
issue of Nature Biotechnology, show the treatment to be effective, and
nontoxic to healthy neighboring cells. “A targeted therapeutic approach
using modified BID "may be useful as a prophylactic against accidental
virus exposure, in the early stages of hepatitis, during limited
infection of the liver, or for ex vivo therapy of hepatocytes,..It may
also reduce virus loads in chronically infected patients, and in
conjunction with interferon and ribavirin therapy, might eradicate HCV
from the infected host," say the researchers (Reuters Health 05/01/03).
Peptide Vaccines: The reason behind this approach is that certain T-cell epitopes on the HCV polyprotein may be needed for viral clearance.
Several CTL and T helper epitopes on the HCV polyprotein that may be important for the design of a peptide vaccine have been
identified. Because HVR1 contains a neutralizing epitope, it is an attractive target for peptide-based vaccines, but this region of the virus mutates rapidly (
).
Intercell AG is involved in a Phase II trial in non-responders, with a peptide-type vaccine consisting of 6 vaccinations
within 5 months. The serum used consists of poly-arginin and a mixture of 5 hepatitis-C-peptids. If the study is successful, licensing
will take place in 2007. The formula proved safe and effective in Phase I trials (See Cancer Research 2002 Mar 1;62(5):1477-80) (
).
Recombinant Protein Subunit Vaccines: The first attempt to develop an HCV vaccine was by generating a recombinant protein subunit vaccine.
Chiron used recombinant HCV E1 and E2 proteins in early vaccination studies. Results of experiments showed that the vaccine did
not protect any of the chimpanzees when challenged with the virus, but self-limited infection occurred more frequently than in
nonvaccinated animals. The results show that although no sterilizing immunity was achieved, chronic infection might be prevented.
