Research Project
3141422
A new vaccine for tuberculosis is required. Although the existing, live Mycobacterium bovis BCG vaccine protects children against tuberculosis in many countries, it causes side-effects, such as fatal disseminated disease in immunodeficient people (1). This is of particular concern in countries where the incidence of AIDS is increasing rapidly and of particular concern in countries where the incidence of AIDs is increasing rapidly and BCG is widely used. A safer vaccine than BCG is needed. This project aims to address the problem by inserting a M. tuberculosis antigen gene, which has been cloned, into attenuated vaccinia virus recombinants which lymphokine genes such as interleukin-2 (IL-2). IL-2- expressing vaccinia recombinants are dramatically less virulent for immunodeficient nude mice, whilst retaining immunogenicity. The vaccinia- M.tuberculosis antigen gene recombinants will be tested out in immunodeficient mice, and the mortality of the vaccinia recombinant treated mice will be compared with that of BCG treated mice. It is hoped that this direction of research will retain the very considerable advantages of live vaccines, such as BCG, whilst reducing the risk of dissemination in the increasing number of Immunodeficient individuals infected with the AIDS virus. An additional objective of this project is to identify which M. tuberculosis antigen (s) induce protection. This should greatly assist in answering the important question: why does BCG fail to protect is some countries (3), and why does it not influence the incidence of the disease (4). Vaccinia recombinants are good carriers for this experiment because vaccinia induces powerful cell-mediated immunity (5) and resistance to tuberculosis is also cell-mediated (6). Protective immunity will be assessed in the mouse. The applicant proposes that protection may require insertion of multiple M.tuberculosis antigen genes together with co- boosters of cell-mediated immunity such as IL-2, IL-4, interferon-y (IFN- y) and granulocyte monocyte colony stimulating factor (GMCSF), and so will insert these additional genes into vaccinia.
