? The focus of this application is to develop an adenovirus-based vaccine against rabies virus that can provide rapid immunity following a single administration in response to a bioterrorism attack. The vaccines to be evaluated are based on an E1-deleted simian adenoviral vector derived from a chimpanzee isolate. In animal models, E1-deleted human adenoviral recombinants of the serotype 5 (AdHu5) have shown high efficacy as vaccine carriers. Humans are infected by common serotypes of human adenovirus such as AdHu5 and a significant percentage has neutralizing antibodies to this serotypes, which impair the efficacy of AdHu5 based vaccines. To circumvent this problem, novel replication-defective adenoviral vaccine carriers based on El-deleted recombinants of chimpanzee-derived adenoviruses were developed. These viruses do not circulate in the human population and fail to carry neutralizing B cell epitopes that cross-react with the common serotypes of human adenoviruses. Lack of preexisting virus-neutralizing antibodies in the human population suggests that these novel adenoviral recombinants may provide improved vaccine carriers for use in humans. A simian adenoviral vector termed adenovirus C68 (AdC68) was generated as a molecular clone to express the glycoprotein of rabies virus. In mice, this vector induced after a single dose complete protection to rabies virus challenge. Preliminary data with similar vectors tested in non-human primates were equally promising. Additional pre-clinical studies are needed to further characterize and improve vector production and performance.
In aim 1, we are proposing to implement standardized methods for vector characterization. These will include methods to determine vector infectivity and stability and the effect of batch variability on immunogenicity. The vector's expression cassette or backbone will be modified to improve vector performance.
In aim 2, we are proposing mouse studies to determine the efficacy of the AdC68rab.gp vector in post-challenge vaccination experiments with and without concomitant application of rabies immunoglobulin (RIG).
In aim 3, we are proposing experiments in non-human primates to test the vaccine for efficacy in pre- and post-challenge vaccination experiments with and without concomitant application of RIG. ? ?
