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Interrogating human anti-staphylococcal antibody responses for S. aureus vaccine insights

探究人类抗葡萄球菌抗体反应以获得金黄色葡萄球菌疫苗见解

基本信息

批准号：
10826874
负责人：
Clarence Buddy Creech
金额：
$ 81.88万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10826874
关键词：
Accounting Active Immunization Address Age Animal Model Antibiotic Resistance Antibodies Antibody Response Antibody-mediated protection Antigen Targeting Antigens Bacterial Infections Biological Assay Biological Models Child Clinical Clinical assessments Coupled Development Disease Elderly Environment Exposure to Generations Genes Genus staphylococcus Goals Human Human Characteristics Immune Immune response Immunity Impairment In Vitro Infection Infrastructure Intervention Kinetics Life Membrane Proteins Memory Modeling Mus Passive Immunization Patients Prospective cohort Reporting Sampling Sepsis Series Serology Serum Shapes Staphylococcal Infections Staphylococcal Vaccines Staphylococcus aureus Staphylococcus aureus infection Surveys Vaccination Vaccines alpha Toxin clinically relevant cohort cytotoxicity experimental study exposed human population human pathogen humanized mouse imprint in vivo in vivo Model insight mouse model novel novel strategies predictive modeling prevent prototype rational design recruit response success vaccination strategy vaccine candidate vaccine development vaccine efficacy vaccine evaluation vaccine failure vaccine response

项目摘要

Abstract Staphylococcus aureus is a leading cause of infection worldwide and a major driver of antibiotic resistance. Although many experimental staphylococcal vaccines have been reported, all vaccines tested to date in human trials have failed for unclear reasons. Unlike mice, humans are exposed to S. aureus beginning early in life, leading to generation of antibodies to S. aureus antigens. In preliminary experiments, we have shown that select human anti-S. aureus antibodies are protective, but many are not. In mice exposed to S. aureus, vaccination against protective antigens leads to immunity against S. aureus whereas vaccination against non-protective antigens induced recall of non-protective immunity which further interferes with protective antibodies by direct competition. Based on these findings, we generated a model of how pre-existing antibodies shape vaccine responses and how this predicts novel ways to develop effective vaccines against S. aureus. To query the validity of our model, in Aim 1, we will recruit children and old adults with invasive S. aureus infections, survey the anti-S. aureus antibody profile and define functionally protective antibody responses to S. aureus antigens. In Aim 2, we will identify and characterize protective and non-protective anti-S. aureus antibodies from candidate samples acquired in Aim 1, and assess structural and functional features of the specific antibodies that confer protection or non-protection. In Aim 3, we will study these antibodies and their target in the context of naïve mice and mice previously exposed to S. aureus. We will evaluate mechanisms whereby non-protective memory shapes vaccine efficacy and test strategies that circumvent interference. Overall, using the novel model systems, we aim to develop a more predictive framework for explaining staphylococcal vaccine failures and developing novel strategies for effective vaccination against S. aureus.

摘要