Development of the Next Generation of Conjugate Vaccines

下一代结合疫苗的开发

• 批准号: 9750619
• 负责人: Luc Teyton
• 金额: $ 84.64万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-25 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750619
• 关键词: Address; Adjuvant; Adult; Affinity; Age; Animals; Anniversary; Anti-Bacterial Agents; Antibiotic Resistance; Antibodies; Antibody Affinity; Antibody Formation; Antibody Specificity; Antibody titer measurement; Antifungal Agents; Antigens; B-Lymphocytes; Bacteria; Binding; Biological Models; CD4 Positive T Lymphocytes; Carbohydrates; Carrier Proteins; Cell Maturation; Cells; Communities; Conjugate Vaccines; Coupled; Coupling; Dendritic Cells; Dependence; Development; Disease; Disease Resistance; Elderly; Environment; Eukaryota; Family; Generations; Glycolipids; Glycopeptides; Goals; Haemophilus Influenzae B Vaccine; Haemophilus influenzae; Histocompatibility Antigens Class II; Human; Immune response; Immune system; Immunocompromised Host; Immunoglobulin G; Immunologics; Immunology; Incidence; Individual; Influenza B Virus; Knowledge; Light; Mammals; Memory B-Lymphocyte; Molecular; Mus; Neisseria; Normal Cell; Oligosaccharides; Opsonin; Organism; Pathogenicity; Peptides; Pneumococcal Infections; Pneumococcal vaccine; Polysaccharides; Population; Process; Production; Prokaryotic Cells; Proteins; Publishing; Recombinants; Safety; Series; Serotyping; Severity of illness; Somatic Mutation; Specificity; Streptococcus pneumoniae; Structure; Surface; System; T cell response; T-Lymphocyte; Testing; Therapeutic Agents; Time; Vaccination; Vaccine Design; Vaccines; Water; X-Ray Crystallography; base; capsule; design; enhancing factor; flexibility; fungus; human disease; immunogenic; improved; in vivo; lymph nodes; microbial; mimicry; molecular recognition; nanomolar; neutralizing antibody; next generation; novel diagnostics; novel strategies; novel vaccines; particle; pathogenic bacteria; preclinical study; programs; resistant strain; response; success; sugar; tool

Project Summary Conjugate vaccines of the first generation have been effective at reducing incidence and severity of diseases caused by Haemophilus influenza B, Streptococcus pneumoniae, and Neisseria meningitides bacteria in individuals with fit immune systems. Their success in immunocompromised patients and elders, two fast growing populations, has been very limited. In addition, the approach used for their development and production is inappropriate to respond to rapidly emerging new pathogenic strains. The next generation of these glycan-targeting vaccines must introduce radically different concepts to produce vaccines against emerging bacterial and fungal diseases for which the glycan capsule is an ideal target for neutralizing antibodies. The fast selection of antibiotic-resistant strains makes this need even more urgent. We embarked on this task using Streptococcus pneumoniae (Sp) as a model system, with the working hypothesis that the limiting factor of current conjugate anti-glycan vaccines was the low quality of T cell help. We recently published examples of a new approach using two prototypical glycans from Sp. Anti-glycan antibodies with an accumulation of somatic mutations, exquisite specificity and low-nanomolar affinities were generated. Apo- and glycan bound structures revealed a unique mode of glycan binding. The production of these antibodies was totally dependent on CD4 T cell help and the presence of an NKT cell adjuvant, and protected animals against microbial challenge. These results suggest that we have developed a modular system capable of harnessing the anti-glycan response. To advance to pre-clinical studies, and understand the immunology of glycan recognition we will carry out three specific aims to expand our approach to develop vaccines based on the concept of synthetic microbial mimics. Aim 1: Optimization of the antigen and display platform. Mono- to tetrasaccharide motifs can define the 13 serotypes that prevail in human diseases and are included in licensed conjugate vaccines. We will attach minimal antigenic structures of all 13 serotypes to our immunogenic platform in ways designed to enhance T cell recognition and dependency. Antibody specificity will be examined on glycan micro-arrays. The immunological rules of B and T cell glycan recognition will be defined. Aim 2: Molecular recognition of glycans by high affinity antibodies and T cells. We will explore the structural rules of glycan recognition by B and T cells using x-ray crystallography. These studies will inform the design of optimal antigenic oligosaccharides. Aim 3: Increasing safety and potency in vivo. We hypothesize that some of the same factors that enhance the quality of anti-protein immune response will also apply to peptide-displayed glycans, particularly improved efficiency of delivery to the lymph node and capture of the vaccine by dendritic cells. This will be tested with the attachment of known opsonins to the particle to develop the concept of microbial mimicry. Finally, each optimized platform will be tested in bacterial challenge in mice.

项目总结