Vaccine Development Against Bacterial Pathogens Based on iron Acquisition Proteins

基于铁获取蛋白的针对细菌病原体的疫苗开发

• 批准号: 10615718
• 负责人: Mariette Barbier
• 金额: $ 49.18万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615718
• 关键词: Acellular Vaccines; Acute; Acute Pneumonia; Address; Adjuvant; Antibodies; Antigens; B-Lymphocytes; Bacteria; Bacterial Adhesins; Bioinformatics; Bordetella pertussis; Carrier Proteins; Communicable Diseases; DNA Sequence Alteration; Data; Detergents; Diphtheria Toxoid; Disease; Environment; Evolution; Formulation; Genes; Goals; Growth; Health; Heme; Human; Immune response; Immunization; Infection; Iron; Life; Memory; Memory B-Lymphocyte; Methodology; Methods; Micronutrients; Mission; Modification; Mus; Mutate; Outcome Study; Pathogenesis; Peptides; Pertussis; Pertussis Vaccine; Pneumonia; Production; Property; Proteins; Pseudomonas aeruginosa; Public Health; Research; Research Personnel; Respiratory Tract Infections; Siderophores; Structure of germinal center of lymph node; Supplementation; Surface; System; T memory cell; T-Lymphocyte; Testing; Tetanus Toxoid; Toxin; United States National Institutes of Health; Vaccination; Vaccine Antigen; Vaccines; Virulence; Virulence Factors; clinically significant; design; extracellular; immunogenic; immunogenicity; improved; innovation; novel; pathogen; pathogenic bacteria; pertactin; pressure; prevent; protein purification; receptor; respiratory pathogen; response; siderophore receptors; transcriptome; transcriptome sequencing; vaccine development; vaccine efficacy; vaccinology

Project Summary Bacteria constantly adapt to their environment and selective pressure through genetic mutations. They also mutate in response to vaccine selective pressure, leading to the rise of vaccine-escape strains and loss of vaccine efficacy. To avoid this, we propose that using proteins essential for bacterial growth and virulence is more advantageous to develop vaccine antigens with decreased propensity to lead to vaccine-escape strains. To identify these proteins, we developed a novel dual-RNA sequencing methodology and characterized bacterial transcriptomes during infection to identify proteins important for bacterial growth, virulence, and survival. We showed that genes encoding proteins involved in iron and heme acquisition in Bordetella pertussis are the most highly up-regulated genes during murine respiratory infection. These proteins are required for growth and virulence, surface-exposed, and highly conserved. In previous studies, we showed that proteins involved in iron acquisition provide protection against the respiratory pathogen Pseudomonas aeruginosa in mice. The overall hypothesis of this proposal is that proteins involved in bacterial iron acquisition are ideal antigens for inclusion in acellular vaccines against a wide spectrum of bacterial pathogens. This hypothesis is based on our preliminary data and on the evidence that iron is an essential micronutrient required for growth and pathogenesis. This hypothesis will be tested on B. pertussis, the causative agent of whooping cough, a disease on the rise and re-emerging as a major public health concern in the US and around the world. The rise of vaccine-escape strains is one of the main contributing factors to the loss of protection provided by currently available acellular pertussis vaccines (aP). We propose that the high expression levels of the surface exposed iron-acquisition proteins, together with their requirement for growth and virulence, will lead to an increase in overall vaccine protection, and a reduced propensity to generate vaccine-escape strains. The objective of this application is to evaluate the protection conferred by B. pertussis iron-acquisition proteins to improve the efficacy of aPs and slow vaccine-driven strain evolution. We will generate antigens from B. pertussis iron and heme acquisition receptors as peptides or using innovative detergent-free protein purification methods. We will test them as vaccine antigens against B. pertussis alone, or in combination with aP to determine their antigenicity and efficacy for protection against B. pertussis respiratory infections in mice. At the completion of this project, we expect to have formulated a new acellular pertussis vaccine that provides protection against pertussis while slowing vaccine-driven strain evolution, and established an additional proof of concept for the use of iron-acquisition proteins as vaccine antigens against bacterial pathogens.

项目摘要 细菌通过基因突变不断适应环境和选择压力。他们 也会在疫苗选择压力下发生突变，导致疫苗逃逸菌株的增加和 疫苗效力为了避免这种情况，我们建议使用细菌生长和毒力所必需的蛋白质， 更有利的是开发具有降低的导致疫苗逃逸菌株的倾向的疫苗抗原。 为了鉴定这些蛋白质，我们开发了一种新的双RNA测序方法， 在感染过程中的细菌转录组，以鉴定对细菌生长，毒力和 生存我们发现编码蛋白质的基因参与百日咳杆菌铁和血红素的获取 是小鼠呼吸道感染过程中上调最高的基因。这些蛋白质是 生长和毒性，表面暴露，高度保守。在以前的研究中，我们发现蛋白质 参与铁的获得提供保护，防止呼吸道病原体铜绿假单胞菌， 小鼠这一提议的总体假设是，参与细菌铁获取的蛋白质是理想的 用于包含在针对广谱细菌病原体的无细胞疫苗中的抗原。这种假设是 根据我们的初步数据和铁是生长所需的基本微量营养素的证据， 和发病机制。将在B上检验此假设。百日咳，百日咳的病原体， 这种疾病正在上升，并重新成为美国和世界各地的主要公共卫生问题。崛起 疫苗逃逸菌株的增加是目前疫苗提供的保护丧失的主要因素之一。 无细胞百日咳疫苗（aP）。我们认为，高表达水平的表面暴露 铁获取蛋白，连同它们对生长和毒力的需求，将导致 总体疫苗保护和产生疫苗逃逸菌株的倾向降低。 本申请的目的是评估由B赋予的保护。百日咳铁获得 蛋白质，以提高aPs的效力和减缓疫苗驱动的菌株进化。我们将从 B。百日咳铁和血红素获取受体作为肽或使用创新的无去污剂蛋白 纯化方法我们将测试它们作为抗B的疫苗抗原。单独使用百日咳，或与 aP以确定它们的抗原性和针对B的保护效力。小鼠百日咳呼吸道感染。 在这个项目完成后，我们预计已经制定了一个新的无细胞百日咳疫苗， 预防百日咳，同时减缓疫苗驱动的菌株进化，并建立了一个额外的证据 铁获取蛋白作为针对细菌病原体的疫苗抗原的用途的概念。

项目成果

Protocol for aerosolization challenge of mice with Bordetella pertussis.

• DOI: 10.1016/j.xpro.2022.101979
• 发表时间: 2023-03-17
• 期刊: STAR PROTOCOLS
• 作者: Bitzer, Graham;Weaver, Kelly;Barbier, Mariette;Damron, F. Heath
• 通讯作者: Damron, F. Heath

Bordetella pertussis whole cell immunization protects against Pseudomonas aeruginosa infections.

百日咳全细胞免疫可预防铜绿假单胞菌感染。

• DOI: 10.1038/s41541-022-00562-1
• 发表时间: 2022-11-10
• 期刊: NPJ VACCINES
• 影响因子: 9.2
• 作者: Blackwood, Catherine B.;Mateu-Borras, Margalida;Sen-Kilic, Emel;Pyles, Gage M.;Miller, Sarah Jo;Weaver, Kelly L.;Witt, William T.;Huckaby, Annalisa B.;Kang, Jason;Chandler, Courtney E.;Ernst, Robert K.;Damron, F. Heath;Barbier, Mariette
• 通讯作者: Barbier, Mariette