Sepsis Vaccine Proves Protective in Preliminary Studies
A group of researchers from The Scripps Research Institute
(TSRI) have designed a vaccine that might be used to protect
against the pernicious consequences of severe sepsis, an acute
and often deadly disease that is estimated to strike 700,000
Americans a year and millions more worldwide.
Though the new vaccine has not yet been applied to clinical
trials in humans, it has worked well in preclinical studies,
the results of which the team reports in the latest issue
of the journal Angewandte Chemie.
"The vaccine provided outstanding protection," says author
Kim Janda, who holds the Ely R. Callaway, Jr. Chair in Chemistry
at TSRI.
A Rapid and Deadly Disease
Sepsis, also known as septic shock and systemic inflammatory
response syndrome, is characterized by shock to one's organs
following poisoning with endotoxins—chemical components
of certain bacteria. The endotoxin molecules themselves are
not particularly harmful, but the way that the immune system
reacts to them is.
When bacteria like the deadly N. meningitidis invade the
body, they trigger the immune system to stage a biochemical
defense. One of the ways that the body initially responds
to such an infection is to recruit white blood cells, like
macrophages, which engulf the pathogens and destroy them.
The macrophages also fight the pathogens by producing chemicals
at the site of an infection that induce inflammation.
However, there is a limit to how much inflammation a body
can take. If the infection is widespread, the systemic endotoxin
levels can be so high that the macrophages respond by producing
a lethal amount of inflammatory chemicals. One of these chemicals
is called tumor necrosis factor alpha (TNF-a).
The prognosis for sepsis is dire. It can affect many parts
of the body, from the bones to the brain, and death due to
septic shock can occur in a matter of hours. According to
the National Institutes of Health, two percent of all hospital
admissions suffer from sepsis, and its typical case-fatality
rate is around 30 percent. According to the Centers for Disease
Control and Prevention, sepsis is one of the ten leading causes
of both infant and adult mortality in the United States, and,
in 1999, directly caused more than 30,000 deaths.
A New Approach
The best current treatment is to administer broad-spectrum
antibiotics to try to quell the infection after the fact,
but this is often too little too late and scientists have
sought a better approach for years.
Since many patients who fall victim to sepsis acquire bacterial
infections in the hospital, after undergoing major surgeries
for instance, one approach would be to try to "prophylactically"
protect a patient before he/she undergoes surgery.
Many scientists have sought to achieve such protection through
passive immunization—by infusing antibodies into the
patient to target the endotoxins. Many of the compounds that
have been tested to date have proven to have limited effect,
though, for reasons that are not entirely clear.
The TSRI team's approach is fundamentally different. They
sought to use active immunization to protect patients against
sepsis. Active immunization, used in measles, smallpox and
polio vaccines, involves exposing patients to a substance
that resembles the pathogen that one is immunizing against.
If the vaccine works, the body responds with an effective
immune response both to the vaccine and to the pathogens that
are later encountered. In this case, the TSRI team designed
a synthetic "glycoconjugate" that mimics one of the most common
bacterial endotoxins, called "lipid A."
Post-vaccination, they observed a nearly 95 percent reduction
in the inflammatory chemical TNF-a, which indicated that the
vaccine successfully controlled the body's response to infection.
Significantly, the vaccine seems to raise a broad antibody
response, possibly inducing the formation of antibodies that
have some enzymatic ability and can "hydrolyze" or chop up
the lipid A. Researchers designed the vaccine to raise such
"catalytic" antibodies by making a portion of it resemble
a form of lipid A. This two-pronged approach may be the reason
why the vaccine proved particularly protective.
"Now that we have evidence that [the vaccine] provides good
protection in a mouse model, we really want to go on to a
clinical working model," says Associate Professor Paul Wentworth,
Jr, who is a corresponding author on the paper.
The researchers are also now looking to formulate their
synthetic glycoconjugate into a slow-release form that can
be administered well in advance of major surgery, for instance,
in the hope of someday providing outstanding protection to
hospital patients.
The article, "Active Immunization with a Glycolipid Transition
State Analog Protects against Endotoxic Shock," is authored
by Lyn H. Jones, Laurence J. Altobell III, Mary T. MacDonald,
Nicholas A. Boyle, Paul Wentworth, Jr., Richard A. Lerner,
and Kim D. Janda and appears in the November 18, 2002 issue
of the journal Angewandte Chemie.
This work was supported by The National Institutes of Health
and The Skaggs Institute for Chemical Biology, and also funded
through a Merck Science Initiative Research Fellowship.
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