Preclinical evaluation of psoralen inactivation as a platform for developing a killed, whole cell vaccine for Enterotoxigenic E. coli (ETEC)

补骨脂素灭活作为开发产肠毒素大肠杆菌 (ETEC) 灭活全细胞疫苗的平台的临床前评估

• 批准号: 10042258
• 负责人: Marlena Moors Westcott
• 金额: $ 7.75万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10042258
• 关键词: Acute Diarrhea; Address; Adult; Adverse effects; Antibiotic Resistance; Antibodies; Antibody Response; Antigen Presentation; Antigens; Area; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Bacterial Vaccines; Biological Assay; Campylobacter jejuni; Cells; Cessation of life; Chemicals; Child; Chronic; Collaborations; Complement; Data; Defect; Dengue Vaccine; Development; Disease; Engineering; Enteral; Enterobacteriaceae; Epitopes; Escherichia coli Vaccines; Etiology; Formalin; Gastrointestinal Diseases; Genome; Goals; Healthcare; Hospitals; Immune Targeting; Immune response; Immune system; Immunity; Immunologics; In Vitro; Individual; Infection; Infection prevention; Knowledge; Link; Measures; Medical Research; Membrane Proteins; Methods; Military Personnel; Modeling; Morbidity - disease rate; Mus; Nucleic Acids; Organism; Patient Care; Pharmaceutical Preparations; Prevention; Protein Conformation; Proteins; Pseudomonas aeruginosa; Psoralens; Public Health; Pyrimidine; Safety; Serum; Shigella; Shigella flexneri; Shigella sonnei; Surface; Syndrome; Testing; Time; Ultraviolet A radiation; Ultraviolet Rays; Vaccination; Vaccines; Virulence; Vulnerable Populations; Whole Cell Vaccine; Work; acute infection; clinical translation; comparative; crosslink; diarrheal disease; enterotoxigenic Escherichia coli; experience; experimental study; gastrointestinal; genetic manipulation; immune function; immunogenic; immunogenicity; improved; in vitro Assay; in vivo; irradiation; mortality; mouse model; novel strategies; pathogen; pathogenic bacteria; pre-clinical; preclinical evaluation; preclinical study; preservation; prevent; protein crosslink; resistant strain

Westcott.Project Summary/Abstract Enterotoxigenic E. coli (ETEC), Shigella flexneri and Campylobacter jejuni are the predominant bacterial causes of morbidity and mortality from gastrointestinal (GI) disease in the developing world. Episodes of acute diarrhea caused by these agents have been linked to developmental defects and chronic GI syndromes. Vaccines that are safe for use in young children as well as adult travelers and deployed military are needed to prevent infection and post-infection sequellae caused by these organisms. Formalin inactivation is the current standard for generating killed, whole cell bacterial vaccines. This approach does not require genetic manipulations or extensive knowledge of antigens that induce protective immune responses. However, formalin crosslinks proteins, which has the potential to destroy antigenic epitopes that induce protective immune responses in the context of live bacterial infection. We propose to test the feasibility of an alternative inactivation method to generate safe, whole cell vaccines for enteric bacteria. Psoralen is a photoactivatable drug that reversibly intercalates into nucleic acids. Following irradiation with long wavelength UV light (P+UVA), covalent inter-strand crosslinks form at pyrimidine residues, preventing genome replication. Since P+UVA inactivates bacteria by crosslinking nucleic acids rather than proteins, we hypothesize that protein antigens will be preserved in a native form, generating vaccines with superior immunogenicity. We have successfully inactivated ETEC using P+UVA. With this proposal we will extend the ETEC work by comparing P+UVA to formalin-inactivated ETEC with respect to antigen preservation and immunogenicity using established in vitro assays and murine models. A direct comparative analysis of the 2 inactivation methods is needed to assess the value and feasibility of the P+UVA approach as an agile platform for enteric bacterial vaccines, and more generally for vaccines to prevent antibiotic-resistant bacterial infections that impact patient care in hospital settings. . 1

项目成果

The Immunogenicity and Properties of a Whole-Cell ETEC Vaccine Inactivated with Psoralen and UVA Light in Comparison to Formalin.

• DOI: 10.3390/microorganisms11082040
• 发表时间: 2023-08-09
• 期刊: Microorganisms
• 影响因子: 4.5