Mycobacterium tuberculosis and other mycobacterial pathogens have reemerged as public health threats. There is an increasing incidence of drug resistant mycobacterial strains and the rate of infection of immunocompromised individuals and health care workers has escalated. Conventional vaccination methods have shown mixed results, leaving an urgent need for a safe and more effective vaccine. Human T lymphocytes specifically recognize mycobacterial lipids presented by CD1 cell surface proteins. To develop a prophylactic or therapeutic tuberculosis vaccine, we are investigating whether M. tuberculosis lipids, as presented by CD1 proteins, constitute an effective vaccine in guinea pigs, the most appropriate tuberculosis small animal model. We have cloned and expressed guinea pig CD1 and beta2-microglobulin genes and produced anti-CD1 monoclonal antibodies. We have obtained positive results from in vitro immune response analyses and from guinea pig vaccine trials involving mycobacterial lipid vaccination and aerosol challenge with virulent M. tuberculosis. We will formulate these lipid antigens to optimize their immunogenicity in in vitro assays as well as their potency as subunit vaccines protecting guinea pigs. Another objective is to chemically characterize these lipids and develop synthetic or semi-synthetic chemical means for larger scale production. This will ultimately enable clinical trials to evaluate their ability to protect humans from tuberculosis.
Tuberculosis has re-emerged a public health threat. Existing TB vaccines are inadequate, ineffective and/or unsafe in certain individuals. There is therefore a critical need and a significant market for an effective tuberculosis vaccine. This proposal describes how we intend to capitalize on recent research discoveries to guide identification and development of a lipid vaccine for tuberculosis.
