Building a Better Vaccine for Hep
by John C. Martin
Article Date: 07-20-05

When thinking of vaccines, most people are familiar with the prophylactic
kind—those used to prevent infections, such as the measles vaccine or the flu
shot. However, there are also therapeutic vaccines available that are designed
for patients who have already acquired chronic infections, such as HIV or
hepatitis.

Therapeutic Vaccines: Disappointing Results
These therapeutic vaccines target the immune system, enhancing its ability to
combat the cause of a certain infection, such as a virus. Medical experts are
also working on a number of vaccines designed to treat several different types
of cancer.1-3

As of now, there are relatively few therapeutic vaccines in widespread use
today, explained E. John Wherry, PhD, an immunologist at The Wistar Institute in
Philadelphia, who headed an animal study to test the effectiveness of such a
vaccine.

In addition, with the exception of the rabies or HBV postexposure vaccines, the
effectiveness of many experimental therapeutic vaccines have fallen short of
expectations in recent years, experts say.4,5 After these vaccines are given,
the immune response against the organisms that cause infection isn't as powerful
in many cases as what scientists had hoped.

One therapeutic vaccine, however, has demonstrated its efficacy. The hepatitis B
vaccine, designed for postexposure prophylaxis, includes the use of either
hepatitis B immune globulin (HBIG), hepatitis B vaccine, or a combination of the
two. Effectiveness of this vaccine ranges from 70% to 95%, depending on the type
of exposure a patient encounters.6

“As with the rabies vaccine, post exposure vaccination is usually given very
shortly after exposure at a time when the immune system still has a chance to
respond effectively to the primary infection,” Wherry explained, in an interview
with Priority Healthcare. The vaccine, like other therapeutic vaccines, is
designed “to boost or redirect an ongoing, but ineffective immune response to
chronic infection,” he said.

But other therapeutic vaccines don’t seem to have the same punch.

Why Do Therapeutic Vaccines Fizzle Out?
In their study,7 Wherry and his fellow scientists at The Wistar Institute and
Emory University in Atlanta delve into the possible reasons why the immune
response in these cases seems to be so lackluster.

"In this study, we wanted to look at why therapeutic vaccines are generally less
effective than prophylactic vaccines," Wherry said.

For their research, Wherry and his colleagues tested the effectiveness of a
therapeutic vaccine in a group of rodents infected with lymphocytic
choriomeningitis (LCMV), a type of viral meningitis.

The vaccine was designed to boost the production of T-cells—a type of white
blood cell—in the animals that would target the virus. However, the vaccine
wasn’t as successful in some animals. "What we found was that the T-cells in the
chronically infected mice responded poorly to the vaccine," Wherry explained.

Two Reasons for Poor T-Cell Response
Mice with lower viral loads at the time they were vaccinated responded better
than those with higher viral loads, Wherry and his team learned. The numbers of
T-cells in chronically infected mice were also lower than in mice that already
developed immunity to LCMV, "suggesting that poor T-cell expansion may be an
important reason for suboptimal responses to therapeutic vaccination," the
scientists wrote.

It appears that the T-cells can’t expand in cases of high viral load because the
immune system is simply overwhelmed, Wherry theorized. In other cases, such as
with HIV and HCV infection, while there may be a high level of anti-viral
T-cells in the bloodstream, they don’t function properly because of mutations in
the viruses. As a result, T-cells don’t recognize the viruses, and consequently
ignore them.

While it was confirmed that such a therapeutic vaccine was not as effective as
what Wherry and his cohorts had hoped, the findings, nevertheless, give other
scientists a basis to possibly develop an improved vaccine to target viruses
such as hepatitis. If, somehow, the viral load could be lowered before the
vaccine was administered, its efficacy might be improved, Wherry speculates.

Different Strategy Planned
The next step for the research will be to combine therapeutic vaccines with
other treatment approaches that either lower viral load or augment the function
of T cells, particularly their ability to expand in number. Possible scenarios
include the administration of anti-viral medication prior to the delivery of a
therapeutic vaccine. Patients might also be given therapy with cytokines,
special immune-regulating proteins that could boost the proliferation or
survival of T-cells.

“It appears that lowering viral load prior to therapeutic vaccination appears
beneficial,” Wherry said. “However, many more studies are needed.” Much interest
in this concept has surfaced in the HIV field in recent years, he added.

What’s Next?
Wherry and his colleagues are continuing their work to better understand the
process that leads to this type of poor immune response after a therapeutic
vaccine is used during chronic infection. He is also planning to compare the
immune response using different types of therapeutic vaccine approaches.

Specifically, the researchers want to better understand the differences between
functional memory T-cells that fight off certain infections after recalling the
same previous infection and dysfunctional T-cells that exist in chronic
infection. By studying the activity of genes, Wherry and his colleagues have
been able to understand the underlying mechanisms behind dysfunctional T-cells,
which could “provide interesting targets for immunotherapy,” he said.

Another question is whether dysfunctional T-cells can be stimulated to become
functional again in chronically infected people.

While Wherry's interest lies mostly in chronic infection, he says findings like
these would also be beneficial for researchers studying the effectiveness of
therapeutic vaccines in cancer. He says the same deficiencies in immune response
have also been noted in cancer research.

Wherry’s study was published in the Journal of Virology.

1. Vonka V. Promise of immunotherapy of the chronic myeloid leukaemia
[Translated from Czech]. Cas Lek Cesk 2005;144(3):172-6.
2. Wu Q, Xia D, Carlsen S, Xiang J. Adenovirus-mediated transgene-engineered
dendritic cell vaccine of cancer. Curr Gene Ther 2005 Apr;5(2):237-47.
3. Reinartz S, Wagner U. Current approaches in ovarian cancer vaccines. Minerva
Ginecol 2004 Dec;56(6):515-27.
4. Velders MP, Schreiber H, Kast WM. Active immunization against cancer cells:
impediments and advances. Semin Oncol 1998;25(6):697-706.






Sandra Tara Balduf (Ane)

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