The goal of this project is to develop a novel anti-tuberculosis subunit vaccine constituted of new and unique M. tuberculosis antigens formulated either in novel adjuvants approved for human use or in vectored virus delivery systems to be used in prime boost strategies. The vaccine candidates are molecules identified in either bodily fluid of patients with tuberculosis or associated with MHC Class I molecules of adherent spleen cells of M. tuberculosis-infected mice. The M. tuberculosis proteins identified in human secretions are apparently the only antigens reported to date that are derived directly from tuberculosis patients from tuberculosis-endemic regions. This work is based on the central hypothesis that pathogen's antigens that are actively produced during disease are interesting target molecules for vaccine development. Therefore, a vaccine developed from these two groups of in vivo derived antigens represents an important new strategy for producing full protective immunity. The genes coding for most of these antigens have been cloned and the recombinant proteins have been produced and purified. In addition we have begun the production of virus vectored formulations designed to test them as vaccine candidates delivered in a DNA format. The next challenge in the clinical translation of these original findings into promising vaccine candidates is to complete our initial studies that demonstrated that some of the these novel antigens are readily recognized by PBMC from healthy PPD positive individuals and less so by PBMC of patients with tuberculosis and induce protective immunity. Successful completion of this project will result in the validation of an antigen formulation comprising one or more of these novel antigens that is suitable for clinical testing in a future project.
The specific Aims are:
Aim 1 : Construction and evaluation of virus vectored and other gene delivery systems containing the cloned genes coding for MHC class I associated M. tuberculosis peptides/proteins.
Aim 2 : Selection of adjuvant/antigen formulations and delivery systems that are safe for human use and that promote needed protective T cell responses.
Aim 3 : Pre-clinical validation of vaccine candidates in protection experiments in animal models of tuberculosis.
Tuberculosis remains a major infectious cause of morbidity and mortality worldwide. The incidence of the disease remains high and is increasing in many parts of the world due in part to its association with human immunodeficiency virus (HIV) infection. It is estimated that one third of the world's population is infected with the microbe that causes tuberculosis and up to 2.5 million deaths occur each year as a consequence of this disease. Effective treatment of tuberculosis is difficult because it requires several medications that must be used over extended periods of time and because more than 50 million people around the world already are infected with incurable drug-resistant M. tuberculosis, the causative agent of this disease. BCG, the only available vaccine, has been in use since the early 1920s and unfortunately has limited or no efficacy to prevent adult pulmonary tuberculosis the most common and contagious form of the disease. The present project proposes to develop and evaluate novel and unique vaccine candidates against M. tuberculosis for assessment in future clinical trials.
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