SBIR-STTR Award

Edible vaccines have received much attention since, in theory, they represent a source of vaccine that would stimulate mucosal immune responses, be cost-effective to produce, be safe to administer, and be stable to ship throughout the world. Studies proposed in this collaborative STTR effort will develop an oral vaccine against a non-toxic form of Staphylococcus enterotoxin B (SEB) by expressing this immunogen in transgenic soybeans. Completion of such studies will be significant since SEB has been identified as a potential agent of bioterrorism, and since no vaccine is presently available. Furthermore, once transgenic soybeans expressing a non-toxic form of enterotoxin B have been produced, these stably transfected plant lines will forever be a renewable source of this edible vaccine. A demonstration of the feasibility and efficacy of expressing an edible human vaccine against a non-toxic, mutant form of SEB in soybeans will be accomplished by performing the following specific aims. Specific aim #1: Expression of an immunogen, mutant SEB, in transgenic soybeans. The purpose of this aim is to characterize expression of a mutant form of SEB in soy milk formulations for use in an oral vaccine. Specific aim #2: To determine the efficacy of soybean-derived SEB as a mucosal immunogen following oral administration. In specific aim #2, we will address whether expression of SEB in transgenic soybean plants can elicit high levels of immunity following oral immunization of mice. Results from these studies will determine the magnitude of the B and T lymphocyte responses following administration of this edible vaccine. In addition, the ability of this edible vaccine formulation to protect against an SEB toxin challenge in a mouse model will be tested. Taken together, these studies will represent a significant, practical advance for the use of edible vaccines that are expressed in transgenic soybeans. In addition, the availability of this renewable resource will provide a product for future Phase II studies.

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Staphylococcus aureus is a significant human pathogen which can produce a variety of toxins, including the exotoxin, staphylococcal enterotoxin B (SEB). SEB is highly toxic in small doses, and the compact structure of this protein makes it resistant to heat and denaturation. The combination of toxity and stability caused this toxin to be selected for weaponization in the 1960s as a biowarfare agent for aerosol dispersal. In fact, it has been suggested that SEB is one of the "two most important toxin threats on the battlefield or in bioterrorism." Unfortunately, no effective vaccine exists that provides protection against this category of B agent of bioterrorism. In previous Phase I studies, we demonstrated our ability to express a non-toxic form of SEB at high levels in transgenic soybeans. Oral immunizations using soy milk formulations made from transgenic seeds expressing mutant SEB could elicit protective immunity in mice challenged with lethal doses of native toxin. In the present Phase II studies, we will demonstrate the efficacy of the immunization with our soybean-derived vaccine using a highly relevant piglet model of SEB toxicity. Since SEB is also a superantigen for pigs, the toxicity induced in these animals following exposure to the native toxin provides a valuable model for assessing the efficacy of vaccination. In collaboration with Drs. Stahl and Odle at NC State University, we will use this model to define dosing and safety of our soybean-derived vaccine using several immunization strategies. Immune piglets will then be challenged with natie SEB to demonstrate the ability to protect animals form exposure to this toxin. Due to the relevance of the model, results from these studies will be translational to developing a human vaccine. Due to the novel nature of our platofrm technology for expressing immunogens in transgenic soybeans, there are no clear standards for GMP production of soy meal containing a vaccine. Therefore, we propose initial studies to begin to establish the procedures which will be required to produce uniform lots o vaccine that will be safe for procesing to final formulations. In the end, the completion of these Phase II studies will provide necessary information to fulfill some of the requirements set by the FDA for developing vaccines against agents of bioterrorism.

Public Health Relevance:
Staphylococcal enterotoxin B (SEB) is highly toxic in small doses, and the compact structure of this protein makes it resistant to heat and denaturation. The combination of toxicity and stability caused this toxin to be selected for weaponization in the 1960s as a biowarfare agent for aerosol dispersal. Unfortunately, no effective vaccine exists that provides protection against this category B agent of bioterrorism. In the present PHASE II studies, we will demonstrate the efficacy of immunization with our soybean-derived vaccine using a highly relevant piglet model for SEB toxicity. The completion of these Phase II studies will provide necessary information to fulfill some of the requirements set by the FDA for developing vaccines against agents of bioterrorism