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.















"The vaccine provided outstanding protection."

——Kim Janda