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Methods to synthesize oligosaccharide-fusion protein conjugates and enhancement of their antigenicity

寡糖-融合蛋白缀合物的合成方法及其抗原性增强

基本信息

批准号：
10543444
负责人：
Steven Sucheck
金额：
$ 44.27万
依托单位：
UNIVERSITY OF TOLEDO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543444
关键词：
Address Adjuvant Animal Model Antibodies Antibody Response Antibody titer measurement Antigen Targeting Antigen-Presenting Cells Antigens Antimicrobial Resistance Bacteria Bacterial Antigens C-terminal CD8-Positive T-Lymphocytes CD8B1 gene Carbohydrates Cell Culture Techniques Cessation of life Chemistry Chimeric Proteins Collaborations Complex Cysteine Cytotoxic T-Lymphocytes Development Dose ESKAPE pathogens Economics Engineering Epitopes Escherichia coli Extracellular Domain Family Fc domain Glycoconjugates Goals Health Helper-Inducer T-Lymphocyte Human Hybrids IgG3 Immune response Immune system Immunization Immunology Inbred Mouse Lipids Lipopolysaccharides Liposomes Maps Mediating Medicine Membrane Proteins Methods Molecular Molecular Biology Mus Oligosaccharides OprF protein Organic Chemistry Pathogenesis Peptides Play Polymers Polysaccharides Production Proteins Pseudomonas aeruginosa Publishing Rhamnose Role Route Serotyping Site T-Lymphocyte Tertiary Protein Structure Tumor Antigens Vaccine Antigen Vaccines Viral Antigens Work chemical synthesis cost cytokine design experimental study humanized mouse immunogenicity improved in vivo investigator training member mouse model novel novel strategies pathogen receptor recruit response single molecule synthetic biology vaccine candidate vaccine immunogenicity

项目摘要

Project Summary Carbohydrates have been used in some of the world most effective glycoconjugate vaccines. However, traditional glycoconjuates produced by oligosaccharide isolation have failed to produce effective vaccines against the ESKAPE pathogen Pseudomonas aeruginosa. ESKAPE pathogens are pathogens that have acquired extensive antimicrobial resistance (AMR) and are becoming increasingly difficult and in some cases impossible to treat. There is an urgent need to identity new approaches for controlling AMR which is projected to cause up to 10 million deaths annually and cost 100 trillion dollars in cumulative economic damage by the year 2050. This application addresses AMR by using a powerful soluble polymer-based synthetic method to chemically synthesize serotype-independent oligosaccharide epitopes from the lipopolysaccharide (LPS) of P. aeruginosa bacteria. In addition, we develop robust methods to site-specifically conjugate these synthetic oligosaccharide domains with protective fusion protein domains prepared by synthetic biology-based methods. We develop methods to further site-specifically conjugate these glycoconjugates with lipid adjuvants to form well-defined single molecule lipoglycoproteins. These materials will be used to determine the beneficial role of both the oligosaccharide and the protein in provoking a protective immune response. In addition, the work will allow mapping of the protective oligosaccharide and protein epitopes. The antigens are designed to overcome known obstacles to development of a protective immune response against this bacterium and to provide protection against multiple bacterial strains. A second aspect of the proposal is the systematic study of the resulting conjugates in mice that will lead to new approaches to enhance vaccine immunogenicity in humans. The approach takes advantage of naturally occurring antibodies in humans that can participate in enhancing the recognition of the vaccine by the immune system. This proposal takes advantage of a collaboration between investigators trained in organic chemistry, immunology, and molecular mechanisms of pathogenesis.

项目总结