Trimer Production and Immunogenicity Testing

三聚体生产和免疫原性测试

• 批准号: 7661038
• 负责人: WILLIAM C OLSON
• 金额: $ 97.59万
• 依托单位: PROGENICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661038
• 关键词: Address; Adjuvant; Agreement; Animals; Antibodies; Antigen Presentation; Antigens; Area; Biological Assay; CD4 Antigens; Cell surface; Cells; Cleaved cell; Collaborations; Complement; Complex; Crystallography; Data; Dendritic Cells; Disulfides; Doctor of Philosophy; Elements; Endotoxins; Fab Immunoglobulins; FarGo; Foundations; Funding; Generations; Genetic; Genetic Determinism; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; HIV-1; HIV-1 vaccine; Hemorrhage; Human; Immune response; Immune system; Immunogenetics; Immunology; Immunosuppressive Agents; In Vitro; Institutes; Instruction; Letters; Lymphoid Cell; Malignant Neoplasms; Methods; Molecular; Mus; National Institute of Allergy and Infectious Disease; Nucleic Acids; Oryctolagus cuniculus; Population; Post-Translational Protein Processing; Preventive; Procedures; Production; Property; Proteins; Reagent; Research Design; Resolution; Resources; Role; Source; Specificity; Structure; System; Technical Expertise; Technology; Testing; Texas; Universities; Vaccine Antigen; Vaccine Design; Vaccines; Variant; Viral; Virion; animal resource; base; cytokine; design; env Gene Products; experience; immunogenic; immunogenicity; improved; in vivo; innovation; interest; meetings; monomer; multidisciplinary; neutralizing antibody; nonhuman primate; novel; pathogen; programs; response; success; trimer core; vaccine delivery; vaccine evaluation

This HIVRAD program builds upon our recent successes in generating stable, proteolytically mature gp140 trimers (SOSIP gp140s) that mimic virion-associated envelope (Env) in topology and antigenicity. The overall goals of this HIVRAD program are reflected in three major milestones: 1) determine the structure of cleaved Env trimers at <4A resolution, 2) demonstrate methods to overcome HIV-1 Env's immunosuppressive properties, and 3) identify a SOSIP trimer vaccine that elicits heterologous neutralization of diverse HIV-1 isolates. These goals are reliant on the preparative production of novel SOSIP trimers in highly purified, homogeneous form. SOSIP trimers are exceptionally complex biomolecules whose production requires a high level of technical expertise, and Core B lends this expertise to the HIVRAD in order to support the goals of Project 1 (HIV-1 Env Vaccine Design, Dr. Moore) and Project 2 (HIV-1 Env Trimer Crystallography, Dr. Wilson). The overall role of Core B is expressed in terms of four Specific Aims: 1) Produce and characterize Env proteins for crystallography studies; 2) Produce and characterize Env proteins for immunogenicity studies; 3) Evaluate the immunogenicity of Env proteins in small animals, 4) Evaluate Env proteins for effects on human dendritic cells and antigen presentation in vitro. In addition to producing SOSIP trimers, Core B provides a central resource for additional high-quality materials (e.g., gp120 monomers, control antigen, CD4-based proteins, antibody Fabs) that are required by Project 1 and Project 2. Core B also possesses significant experience in vaccine testing and thus will be responsible for performing small-animal immunogenicity studies in collaboration with Project 1. Lastly, Core B will collaborate with external groups to explore and understand the interactions of HIV-1 Env with human dendritic cells in vitro. In addition, Core B will serve as a central point of contact and will manage consortial/contractual agreements with several leading academic and corporate collaborators who lend specialized expertise in the areas of vaccine delivery (Aldevron, Fargo, ND), NAb analyses (Monogram Biosciences, South San Francisco, CA), NAb specificity analyses (Dr. James Binley, Torrey Pines Institute for Molecular Studies, San Diego, CA), in vitro immunogenicity studies (VaxDesign, Orlando, FL), and exploratory immunogenetics (Dr. Sunil Ahuja, University of Texas). In fulfilling these roles, Core B represents an integral element of this innovative, multidisciplinary HIVRAD program. RELEVANCE (See instructions): Nearly 1% of the world's population is infected with HIV, and a preventive vaccine is urgently needed. Most efficacious vaccines elicit antibodies that can neutralize the pathogen, but current-generation HIV vaccines are not effective in this regard. Obstacles include our limited understanding of the structure and immunology of HIV-1 envelope trimers. This HIVRAD represents an innovative approach to addressing these challenges in order to provide a fundamental advance in our ability to elicit HIV-neutralizing antibodies with a vaccine.

这一hiv / aids项目建立在我们最近在生产稳定的、蛋白水解成熟的产品方面的成功基础上