New Opportunities Projects
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Development and Evaluation of Human Brucellosis Vaccines
Collaborating Institution: Texas A&M University (TAMU), College of Veterinary Medicine, College Station, TX Principal Investigator: L. Garry Adams, D.V.M., Ph.D., D.A.C.V.P. Co-Investigators: Collaborator: David N. McMurray, Ph.D. – TAMUS HSC, College Station, TX Collaborators
- Core Labs: Expected Product: Development of a live, attenuated Brucella melitensis vaccine. Description: Brucella melitensis (Category B) is an intracellular bacterial pathogen that subverts or avoids both innate and acquired immunity both to cause a debilitating acute and to establish a chronic disease in man and animals alike. While moderately advanced diagnostics and vaccines exist for domestic livestock, antiquated diagnostics and no vaccines are licensed for human brucellosis. Currently available vaccine strains are virulent in humans, which along with their lack of genetic definition, makes them unsuitable for human use. The short-term aim of the proposed studies is to classify mutations in these genes according to their effect on survival in the mouse model (i.e., short vs. long-term survival). The long-range goal of our research program is to expand the fundamental knowledge base for improved disease prevention through safer, more effective vaccines for human brucellosis. Identification of specific virulence genes will be used to derive attenuated candidate strains for use as live vaccines. The ultimate goal of the proposed experiments is to perform the same experiments using Macaca mulatta non-human primates based on the predictive capabilities of the mouse model, and to estimate the safety and efficacy of these strains for human use further. Our first specific aim is to identify B. melitensis genes necessary for survival and virulence using the TraSH system for generating and screening mutants. Mariner transposon mutagenesis will be used to generate a bank of mutants that will be screened using the mouse model of infection to identify mutants that exhibit reduced survival and chronic persistence in mice. Screening for survivability and persistence will enhance identification of genes that are important for persistence in humans. Our second specific aim is to determine the safety and protection induced by B. melitensis vaccine candidates in the mouse model. Protection will be evaluated in this model to identify the optimal vaccine candidates for subsequent testing in non-human primates based on resistance to colonization of vaccinated animals to aerosol challenge with virulent B. melitensis. Our third and last specific aim is to evaluate safety, protection and host gene expression in response to candidate live B. melitensis vaccines in nonhuman primates. The Macaca mulatta aerosol model for acute and chronic infection will be used to characterize pulmonary colonization, systemic dissemination, and induced pathology. Protection will be evaluated based on resistance to pulmonary colonization, magnitude and burden of dissemination, and persistence of wild-type bacteria after aerosol challenge with wild-type B. melitensis 16M. Because of the threat posed by Brucella as a weapon, unavailability of vaccines for human use, and antibiotic therapies that may be unreliable, development of vaccines against human brucellosis is clearly the optimal approach for long-range protection of the public.
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