Pulmonary tuberculosis remains an important public health problem despite extensive use of BCG vaccine to control its further spread. The incidence of tuberculosis in the United States is once again on the increase, particularly in homeless, alcoholic and AIDS patients. BCG vaccination is recommended for individuals at high risk (family members of tuberculosis patients, health care personnel, HIV infected individuals) despite concern regarding its effectiveness under some circumstances. Because of poor protection in a number of field trials, calls have been made for the development of new vaccines taking advantage of recent advances in molecular biology. We still know surprisingly little about the protective antigens of the tubercle bacillus or how they induce a protective cell-mediated immunity in the infected host. We also need to know which antigens (or epitopes) induce a strong memory immune T-cell response which will protect the vaccinated host against subsequent reinfection months or years later. Live mycobacteria secrete a number of protein antigens which are associated with the induction of T-cell immunity in appropriately vaccinated mice. The dynamics of this T-cell response (Tdth, Tcmi, Tmemory) will be followed in mice infected with BCG and restimulated with proteins present in culture filtrate concentrates. Monoclonal antibodies directed against selected, protective protein antigens will be used to screen various recombinant DNA vaccines bearing the putative protective genes of M. tuberculosis. Positive recombinants will be tested in vaccinated mice for protection against a fully virulent tuberculous challenge. The proposal is divided into 3 specific aims.
Aim 1. To compare the relative immunogenicity of M. tuberculosis with M.bovis (BCG) culture filtrate stress proteins.
Aim 2. To determine the ability of stress proteins to stimulate memory T-cell immunity.
Aim 3. To screen recombinant DNA vaccines for those protective BCG stress proteins. Hopefully this data will eventually lead to the development of more protective antituberculous vaccines for human use.
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