This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall objective is to perform preclinical studies that are needed to successfully express and test HIV and malaria antigens in an attenuated Mycobacterium tuberculosis (MTB) vector. We ultimately aim to develop a trivalent vaccine for HIV, tuberculosis and malaria in an attenuated MTB. Specific objectives include: (1) Test attenuated strains of MTB for virulence in mice and macaques and test for their ability to protect macaques against challenge with virulent MTB (project 1); (2) Test attenuated MTB-MSP-119 and MSP-142 malaria agents, and test the attenuated MTB-MSP19 and MSP-142vectors for their ability to protect against Plasmodium knowlesi challenge in rhesus macaques (project 2) as proof of principal; (3) Test BCG and attenuated MTB as a vector for expression of HIV antigens of African HIV isolates that induce broadly reactive MHC Class I restricted CTL in mice and rhesus macaques (project 3); 4) Test BCG and attenuated MTB as a vector for expression of HIV envelope constructs that induce broadly reactive neutralizing antibodies to African HIV primate isolates (project 4). Taken together these studies will perform the research needed to determine the feasibility of attenuated MTB expressing HIV and malaria genes as a vaccine for AIDS, Tuberculosis and malaria. During the reporting period we have inoculated 24 cynomolgous macaques dividied into four groups of six. Six animals/group were inoculated intradermally with: MTB H37Rv RD1 panCD n=6 MTB H37Rv LysA panCD n=6 BCG-Danish n=6 Mock inoculated with Saline n=6 Animals were followed for 6.5 months and assessed for clinical and radiographic changes as well as immunologic responses. Alll animals were then challenged with 1000cfu of Mycobacterium tuberculosis Erdman s strain. The challenge was administered via bronchoscope into the caudal lung lobe. Animals were followed for six months during which time extensive immunological, radiographic and bacteriologic studies were performed. Two animals in groups one and four developed severe disease and had to be euthanized prior to the end of the study. One animal from each of the other two groups had to be euthanized. Data analysis is ongoing.
Showing the most recent 10 out of 352 publications
