March 22, 2001
MEDIA CONTACT : Kate O'Rourke
For years, efforts to develop improved vaccines for asthma and allergies have been thwarted because the vaccines themselves often cause the very symptoms a person is trying to avoid. Now, at the 57th Annual American Academy of Allergy, Asthma, and Immunology's meeting this week, researchers at Johns Hopkins announce that a novel method of modifying an allergen, such as ragweed, by attaching a synthetic piece of DNA to it, is showing promise in initial clinical trials. The finding may lead to a more effective vaccine for treating allergic diseases such as hay-fever or asthma.
"This initial study shows that the vaccine can produce IgG antibody — this is a signal that it provides immunity in humans," says Peter S. Creticos, M.D., an associate professor of medicine at Johns Hopkins. "And the vaccine had few side effects." The vaccine was developed and produced by Dynavax Technologies Corporation in collaboration with Johns Hopkins and the University of California at San Diego.
The Hopkins phase I safety trial was conducted in 20 volunteers with ragweed allergy. In the study, individuals were randomly assigned to get a placebo or the vaccine injections, called AIC, in doses similar to those used in current allergy shot programs. The study team then measured levels of allergy-specific antibody production (IgG), an antibody formed by the body in fending off allergy to foreign proteins. Hopkins researchers have previously shown that production of IgG antibody is a clear predictor for likely clinical success with allergy shots.
"This study showed that AIC resulted in the production of an IgG antibody response similar to what one sees in conventional allergy shot therapy," says Creticos. "And none of the individuals experienced any serious adverse reactions." A few patients experienced mild reactions, such as itchy eyes, a flushing type sensation, or nasal congestion, but none of these required treatment with anything other than a simple antihistamine.
Furthermore, the vaccine did not cause a significant boost in IgE, antibodies produced by the immune system that cause allergic reactions. "This is particularly critical since conventional allergy shot therapy initially stimulates IgE, making the patient more allergic during the initial course of immunization," says Creticos.
People experience allergic reactions when their immune systems overreact to a foreign protein such as ragweed pollen, cat dander or dust particles. The allergen typically induces certain immune cells, including a specific type of "helper" T cell (Th2), to produce a variety of inflammatory biochemicals — notably histamine and leukotrienes — which are primarily responsible for the allergy sufferers' miseries.
To prevent these allergic reactions, doctors traditionally have injected patients with vaccines containing the "culprit" allergens. Beginning at a very small initial dose, these injections are increased as tolerated to a "maintenance" level in an effort to increase immunity and get the body to produce less Th2 than it would if it encountered the allergen "naturally." Allergy shots are to the body like handicapped fights in which the immune system learns how to defend itself and becomes a better fighter when the real agent attacks. Some of these vaccines, however, contain antigen so strong that, even in smaller doses, they cause an allergic reaction that can be severe and even life threatening.
To create their more tolerable vaccine, the researchers discovered how to mask the reactive sites on the allergen molecule by attaching a specific, short sequence of synthetic DNA. The "piggyback" sequence induces the body to produce protective molecules from a different family of helper T cells (Th1), which inhibit the Th2 cells responsible for the allergic inflammatory reaction.
"A therapeutic vaccine that maintains immunogenicity, or efficacy, while at the same time improving safety, would be a major advance in allergy shot therapy," states Creticos. "These results confirm previous clinical and preclinical data suggesting that AIC may represent an improved allergy vaccine therapy."
Creticos and his colleagues next plan to evaluate the efficacy of AIC in a classical clinical trial during the upcoming ragweed season. Future studies will also explore the frequency of injections and the actual number of doses of AIC needed to provide protection against ragweed-induced allergic respiratory disease.
The study was sponsored by Dynavax Technologies Corporation. Creticos is a scientific consultant to the company. Lawrence Lichtenstein, M.D., Ph.D., a Hopkins professor of clinical immunology and co-investigator of the study, serves on Dynavax's Scientific Advisory Board and owns Dynavax stock, which is subject to certain restrictions under Johns Hopkins policy. The terms of this arrangement are being managed by the university in accordance with its conflict-of-interest policies.
Other authors of the study include Antonella Cianferoni, John Schroeder, Jean Kim, John Schmidt, Lawrence Lichtenstein, and Steve Georas from Johns Hopkins. The research was funded by grants from the National Institutes of Health. For more information about asthma and allergy research at Johns Hopkins, visit http://www.hopkins_allergy.org.
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