A team of scientists from the University of
North Carolina at Chapel Hill and Vanderbilt University have pinpointed the
region on dengue virus that is neutralized in people who overcome infection
with the deadly pathogen.
The
results challenge the current state of dengue vaccine research, which is based
on studies in mice and targets a different region of the virus.
"In
the past researchers have relied on mouse studies to understand how the immune
system kills dengue virus and assumed that the mouse studies would apply to
people as well," said senior study author Aravinda M. de Silva, PhD.
associate professor of microbiology and immunology at the UNC School of
Medicine.
"Our
study for the first time shows what region the immune system of humans target
when they are fighting off the virus. The region on the virus targeted by the
human immune system is quite different from the region targeted by mice."
The new
research, which will appear online during the week of April 11-14, 2012 in the
Proceedings of the National Academy of Sciences, was performed using blood
cells from local travelers infected with dengue virus.
The
global incidence of dengue has grown dramatically in recent decades, putting
about half of the world's population at risk. Creation of a vaccine is
complicated by the fact that there are four distinct, but closely related forms
of the virus that cause dengue. Once people have recovered from infection with
one form of the virus, they have lifelong immunity against that form.
But if
they become infected with one of the other three forms of the virus, they
increase their chances of developing the severe bleeding and sometimes fatal
dengue hemorrhagic fever and dengue shock syndrome. The leading theory to
explain why some people develop dengue hemorrhagic fever is that under some
conditions the human immune response can actually enhance the virus and disease
during a second infection.
"This
is a huge issue for vaccine development," said lead study author Ruklanthi
de Alwis, a graduate student in de Silva's lab. "We have to figure out a
way to develop dengue vaccines that induce the good response that protects
against infection, at the same time avoiding the bad response that enhances
disease."
de
Alwis looked at a particular subset of the immune response -- specialized
molecules called antibodies.
UNC
investigators identified 7 local individuals who had contracted dengue during
travel to an endemic region and sent blood cells from these individuals to Vanderbilt
School of Medicine. Drs. Scott Smith and James Crowe at Vanderbilt were able to
isolate dengue antibodies from these cells for further study at UNC. The team
found that instead of binding to small fragments of the virus -- like mouse
antibodies do -- human antibodies that neutralized the virus bound to a complex
structure that was only present on a completely assembled dengue virus.
"Though
this is the first time this phenomenon has been shown with dengue, just last
year there were a number of studies showing that antibodies recognize similar
complex epitopes in both HIV and West Nile Virus," said de Alwis.
"New vaccines as well as those already in the pipeline will need to be
assessed to see if they bind just a small fragment or the whole virus, which
may determine whether or not they work in humans."
The
research was funded by the National Institute of Allergy and Infectious
Diseases, the Southeastern Regional Center for Biodefense and Emerging
Infections and a Pediatric Dengue Vaccine Initiative Targeted Research Grant.
Study
co-authors from UNC were Nicholas P. Olivarez; William B. Messer; Jeremy P.
Huynh; M. P. B. Wahala; and Ralph S. Baric.
ScienceDaily
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