August 15, 2002
New Approach to Malaria Vaccine Effective in Mice
A new vaccine against the main toxin produced by malaria parasites
can alleviate some of the most dangerous effects of the disease in
mice. If such a vaccine can be fashioned for use in humans, it may
provide much needed protection against a disease that kills two million
people worldwide each year.
Malaria affects some five to ten percent of the world’s
population. New drugs to combat malaria are in great demand because the
parasites that spread the disease are rapidly becoming resistant to the
standard anti-malarial drugs, chloroquine and mefloquine. Although
vaccines have been suggested as an alternative to drug therapy for
malaria, none has proven effective at countering the disease. One of
the keys to developing a successful vaccine lies in finding just the
right molecule that can stimulate an immune response against the
invading pathogen.
“We are aiming for a cheap, synthetic molecule that can be conjugated to a carrier protein that is approved for use in humans.”
Louis Schofield
Now, researchers led by Louis Schofield, a Howard Hughes Medical
Institute international research scholar at the Walter and Eliza Hall
Institute of Medical Research in Melbourne, Australia, have identified
a toxin, glycosylphosphatidylinositol (GPI), that contributes to the
virulence of malaria in mice, and quite likely in humans. The
scientists published their work on GPI in the August 15, 2002, issue of
the journal Nature.
“In 1886, it was proposed by Camillo Golgi that malaria
produces a toxin that appears to be associated with the intense
periodic fevers caused by the infection,” said Schofield.
“In 1993, we published findings on the properties of GPI, showing
that it was a toxin that produces a potent inflammatory response both
in cell culture and in mice. That work proposed GPI to be the toxin
that Golgi hypothesized more than one hundred years earlier. Our work
also led us to believe that GPI constituted an excellent target for a
vaccine.”
GPI is a glycolipid, a molecule consisting of sugar and fat that is
a component of cell membranes. Schofield and his colleagues found that
a glycan chain, which is a core component of GPI, was necessary for the
molecule to function as a toxin. They reasoned that this glycan would
be a good candidate for use in a vaccine.
Schofield’s collaborators Peter H. Seeberger and Michael C.
Hewitt in the department of chemistry at the Massachusetts Institute of
Technology synthesized a pure form of the GPI glycan molecule.
“Seeberger’s elegant synthesis provided for the first time a
means to address the problem,” said Schofield.
To create a compound that would stimulate an immune response,
Schofield and his colleagues coupled the synthetic glycan to large
carrier molecules that trigger recognition by the immune system. In
initial tests, the researchers found that the anti-GPI vaccine provoked
an antibody response in mice. Their results suggested that the GPI from
the malaria parasite was sufficiently different from the mouse’s
own GPI molecules to be recognized as foreign.
The researchers also tested the effects of antibodies from mice
immunized with the GPI vaccine on cultured immune cells called
macrophages. They discovered that anti-GPI-antibody-treated macrophages
showed greatly reduced immune reactions to extracts of the malaria
parasite. These experiments demonstrated that GPI itself is a malarial
toxin capable of producing inflammation.
In studying the effectiveness of the anti-GPI vaccine, the
researchers found that the vaccine alleviated three complications of
the disease: blood acidosis, pulmonary edema, and cerebral syndrome, in
which the parasite causes clogging of the cerebral arteries.
“These findings not only show the efficacy of the anti-GPI
vaccine in the best available animal model of the disease, but also
that GPI is central to the initiation of all these effects, which there
was little reason to believe would be causally connected,” said
Schofield.
According to Schofield, the findings provide additional evidence
that GPI is a good candidate for use in a vaccine. “We found
effects across a wide enough range of processes that I’m very
confident that GPI contributes to disease in humans,” he said.
“However, we still have to be cautious about predicting that we
can produce a vaccine against GPI in humans.”
Over the next few years, Schofield and his colleagues will create a
variety of anti-GPI vaccines and test them in other animal models of
malaria. “This paper represents only a proof of principle,”
Schofield said. “It does not represent an optimized regime on any
level, either in terms of synthesis of the GPI molecule or in the
carrier protein.”
Schofield emphasized that since GPI is an essential molecule in all
malaria parasites, a successful anti-GPI vaccine for use in humans
could prove permanently effective. “We are aiming for a cheap,
synthetic molecule that can be conjugated to a carrier protein that is
approved for use in humans,” he said. “And this vaccine can
be given to children to produce antibodies very specific for the
parasite GPI and that don’t cross-react with human GPI.”
The clinical impact of such a vaccine could be major, said
Schofield, affording children protection during the first years of life
by giving them time to develop acquired immunity to the parasite.
“Ninety percent of malaria fatalities are in young children, and
the long-term hope is that such a vaccine could become a part of
standard childhood immunization,” he said.
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