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WRCE Theme 3: Vaccine Development for Diseases Caused by Intracellular Bacteria

Theme Leader: James Samuel, PhD – The Texas A&M University System Health Science Center, College Station, TX

Expected Product: This thematic area will pursue the range of product development, from discovery to late-stage validation, as well as lead to major advances in understanding essential components of protection against these agents.

Description: Five major projects, one Career Development award, and one Developmental Project (that include the agents Brucella melitensis, Burkholderia mallei, B. pseudomallei, Francisella tularensis, Rickettsia prowazekii, R. typhi, and Coxiella burnetii) comprise this theme from groups with diverse and complementary expertise in bacteriology, pathogenesis, immunology, and vaccinology. A lead, late stage vaccine against Brucella, which has completed discovery and early validation stages, is ready for nonhuman primate testing and will provide other projects a clear pathway toward product advancement. Within the specific discovery platforms of the proposals are common issues, which will lead to important synergies between projects. One common principle is based on new studies that demonstrate a major role for antibody against surface-exposed bacterial structures in protective immunity against intracellular bacteria. Two major projects (involving Burkholderia and Coxiella) have as goals the expression of these protective, surface-exposed carbohydrates on heterologous structures, either as recombinant lipopolysaccharides or as N-linked glycoproteins. A second, synergizing approach to vaccine design is the evaluation of dominant T-cell antigens as subunit vaccines.

All projects in the theme will monitor correlates of protective immunity, expecting robust stimulation of major T-cell populations as critical for engendering strong and long-lived immunity. These proposals will utilize a wide range of adjuvants, immunization routes, and vectored antigen delivery using novel Salmonella platforms that will enhance the final comparisons of efficacy across all subunit projects. All the vaccines will target the protective immune responses against aerosol challenge. Among the strongest synergistic opportunities provided in the thematic collaboration is the ability to predict efficiently predict the subunit vaccine candidates that will be optimal human vaccines. Expertise in animal models for each agent is clearly available in each project, including mice, guinea pigs, and humanized mice for MHC-II recognition using HLA-DR to model antigen specificity by a human allele. These models will be complemented by the availability of mice that have human hematolymphoid systems by engraftment of CD34+ fetal liver cells into NOD/SCID-IL2Rγ null mice co-transplanted with fetal liver and thymus. Several projects testing subunit vaccine candidates (against Burkholderia, Francisella, Rickettsia and Coxiella) will utilize these animals in downstream validation studies prior to studies in nonhuman primates.