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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