SBIR-STTR Award

This STTR grant proposal is for the development of a safe and efficacious Anthrax Toxin Vaccine. The present world-wide threat of the use of anthrax spores as a bioterrorist weapon in military theaters as well as on the general population has focused attention on the need for a more effective vaccine against anthrax. The recognition during the past few months that few members of the medical community have seen an anthrax infection in humans and therefore only a very few are equipped to diagnose and treat anthrax. The availablity of a safe and efficacious prophylactic vaccine would effectively neutralize this form of bioterrorist threat. Price, et al. (2001, Infect. Immun. 69, 4509-4515) have showne that a vaccine comprised of plasmid DNAs encoding detoxified protective antigen (PA) and lethal factor (LF) protects mice from an intravenous challenge using 5X the lethal dose of toxic protein. Based on this work and subsequent work (presented here) showing that a similar DNA vaccination protocol can protect rabbits from a more rigorous spore inhalation challenge, this grant proposes the pre-clincal work required to support testing of a DNA vaccine in human clinical trials. The work would advance an FDA approved plasmid DNA vector encoding the the PA or LF plasmids or a formulation combining the PA + LF plasmids through a series of experimental protocols to demonstrate the generation of a protective immunne response in both mice and rabbits. The thrust of this proposal is to determine the best plasmid to deliver these coding sequences, the best formulation for intramuscular delivery, and the best injection regime and dosage for achieving protection in a large mammal This work demonstrates the best use of STTR funding. It brings together Vical, the company which has advanced DNA vaccination technology over the past 12 years and holds the intellectural property required to make DNA vaccines commercial products, with Dr. Darrell Galloway, a professor at Ohio State University and a researcher who has advanced the use of DNA vaccines against anthrax. The proposal also presents how the combined efforts of an academic laboratory with the expertise, animal facilities, and reagents required for these pre-clinical experiments and a small biotechnology company expert in the development of DNA vaccines, can work together to quickly advance this novel vaccine technology into the clinic

Vical Inc. seeks SBIR Phase II funding to develop and produce a licensable prophylactic anthrax vaccine. This project will move on an accelerated but realistic timeline with plans for human clinical trials to begin in September 2003. Although many candidate vaccines are being studied for anthrax prevention or post-exposure prophylaxis, the Vical approach has a number of advantages. First, we are finishing the preclinical work needed, and will approach the FDA for a pre-IND meeting to be held in March 2003. Second, DNA vaccines studied to date have been very safe in humans. Third, these vaccines have the potential for long-term stability and storage. Fourth, we are achieving antibody titers that are consistent with the levels needed for protection. Fifth, our vaccine may induce greater T cell help and memory than planned recombinant protein vaccines. Sixth, the Vical vaccine will focus on two gene products (PA plus LF) rather than PA alone, which may induce broader protection. The vaccine development plan will follow a logical series of experiments in mice, rabbits, cynomologus monkeys, and humans. In Aim 1 we will determine the final vaccine formulation that will proceed to human trials. Present experiments funded by a Phase I STTR will provide the data for choosing a final 2 formulations and constructs from among our many candidate vaccines. Cynomologus immunogenicity studies will then be performed with these candidates to determine which combination induces the optimal antibody titers. Rabbit studies will also be performed to better define the length of protection induced by our vaccines. In Aim 2 we will move a final single formulation forward into human clinical trials. This will be accomplished by conducting the appropriate quality control, toxicology and safety studies of the GMP produced vaccine, and by filing the appropriate regulatory paperwork for an IND with the FDA. The human clinical phase I trial will be a dose-ranging, open-label safety study. In Aim 3 we will select a dose from our phase I studies needed to perform a sufficiently powered clinical trial to establish vaccine safety in humans. We will also conduct the necessary studies in non-human primates to demonstrate protection from an aerosolized B. anthracis challenge using the same vaccine studied in humans. We will also collect sufficient antibody through plasmapheresis of the human subjects during our clinical trials to be able to perform passive transfer experiments in the cynomologus monkeys. These final studies will better define the role of antibody in the expected immunity to challenge.

Thesaurus Terms:
Bacillus anthracis, active immunization, anthrax vaccine, bacterial toxin, drug screening /evaluation, vaccine development, vector vaccine anthrax, bioterrorism /chemical warfare, clinical trial phase I, gene delivery system, human therapy evaluation, lethal gene, nonhuman therapy evaluation, plasmid, spore Macaca fascicularis, clinical research, human subject, laboratory mouse, laboratory rabbit, patient oriented research