Simple idea to dramatically improve dengue
vaccinations
HOUSTON, March 29, 2006 -- An innovative new study explains, for
the first time, the failure of previous attempts to vaccinate
against the four known Dengue viruses, and it suggests a very
simple solution injecting the four vaccines simultaneously at
different locations on the body.
A mosquito-born disease, Dengue kills tens of thousands of people
per year and sickens 100 million more. Known as "bone-break
disease," Dengue is characterized by excruciating pain and was "the
most important mosquito-borne viral disease affecting humans" in
2005 according to the U.S. Centers for Disease Control.
The study, from bioengineers and physicists at Rice University,
appears in the March 24 issue of the journal Vaccine. The study
suggests that the multi-site vaccination strategy, termed polytopic
vaccination, may be effective against other diseases as well,
including HIV and cancer.
Dengue infection occurs from one of four closely related viruses.
Previous exposure to one of the four either by prior infection or
by vaccination makes people significantly more likely to develop
a potentially lethal hemorrhagic infection if they are later
infected by one of the other three viruses.
"This is a classic case of something called 'original antigenic
sin,' which happens when our immune system becomes overly reliant
upon memory when recognizing diseases similar to those that it has
seen before," said lead researcher Michael Deem, the John W. Cox
Professor in Biochemical and Genetic Engineering and professor of
physics and astronomy. "With diseases like HIV, influenza and
Dengue, our acquired immune system's tendency to
go-with-what-it-knows can leave us more vulnerable to infection
from a mutant strain or a related virus. The immune system may
respond less favorably in these cases than if it had never been
exposed to the disease in the first place."
Original antigenic sin, or immunodominance, arises out of the
procedure the immune system uses to target infection. This starts
when the immune system identifies infected cells and brings pieces
of them into the lymph node for targeting. Within a few days of
infection, the immune system completes a massive scan of the 100
million available T-cells in its arsenal. Through a complex
trial-and-error process, it identifies three to five T-cells that
best recognize and attack the components of the sickened cells.
Once the cells are selected, they are produced by the millions and
sent out to clear the infection. After the infection is gone,
thousands of these pre-programmed T-cells remain in the body, lying
in wait should the disease return.
In recent years, public health officials have documented the
disturbing co-existence of two or more Dengue viruses in Brazil,
Cuba, Thailand, and other tropical and subtropical countries.
Because sequential infection by multiple Dengue viruses can lead to
increased likelihood of deadly infections, public health officials
have attempted to counter the threat of co-existent versions of
Dengue by developing a vaccine against all four versions
simultaneously. Doctors found that patients who got a
four-component vaccine wound up only being protected against one or
two versions at most, due to immunodominance.
Intrigued by these results, Deem and graduate student Hao Zhou
developed a precise computer model of the immune system's
biochemical scanning process to see if they could recreate the
effect and find out what caused it. Their program conducts
statistical calculations about the likelihood of specific
interactions at the atomic level. They conducted trillions of
calculations and gradually built up a bigger picture of what occurs
in Dengue immunodominance.
"When faced with more than one version of the virus, the immune
system may respond preferentially against the version for which it
has T-cells with the strongest affinity, which is immunodominance,"
Deem said.
He said polytopic vaccination giving different vaccines
simultaneously at different locations on the body could help
overcome immunodominance by taking advantage of the relative
isolation of lymph nodes throughout the body. Each person has
hundreds of lymph nodes. Deem believes vaccinations at four
different sites, served by four different lymph nodes, could allow
the body to simultaneously develop immune responses against all
four versions of Dengue.
"The literature about immunodominance is new and growing," Deem
said. "Ours is the first model that can predict immunodominance,
and when we compare our results with experimental data from Dengue
vaccination trials, they match quite closely. There may be other
factors at work, but we appear to be explaining a significant
portion of the effect that occurs in Dengue immunodominance."
Immunodominance is also a problem for researchers working on
vaccines for both the AIDS virus and cancer, each of which mutate
quickly and occur in multiple strains.
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I think this is probably one of the worst suggestions to combat
dengue. No doubt, humans do have lots of lymph nodes, but injecting
the vaccine at different lymph nodes simultaneously may not help,
as explained by the article. Immunodominance might just occur.