O-polysaccharide (OPS)-IpaB Conjugate Vaccine to Prevent Shigellosis

O-多糖 (OPS)-IpaB 结合疫苗预防志贺氏菌病

• 批准号: 10704815
• 负责人: Marcela F Pasetti
• 金额: $ 89.83万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704815
• 关键词: 3 year old; 5 year old; Adjuvant; Advanced Development; Affect; Age; Agonist; Animal Model; Antibiotic Resistance; Antibodies; Antigens; Antimicrobial Resistance; Biological Assay; Carrier Proteins; Cavia; Cells; Child; Childhood; Clinical; Clinical Trials; Combined Vaccines; Conjugate Vaccines; Cyclic GMP; Day center care; Developed Countries; Development; Developmental Disabilities; Diarrhea; Diphtheria Toxoid; Disease; Disease Outbreaks; Dysentery; Evaluation; Exotoxins; Fc Receptor; Formulation; Goals; Human; IgG1; Immune; Immune Sera; Immune response; Immunity; Immunize; Immunoglobulin G; Immunologics; Immunology; Immunosuppression; Impaired health; In Vitro; Individual; Industrialization; Infection; Institution; Intramuscular; Life Expectancy; Link; Lung; Maryland; Medical; Modeling; Multi-Drug Resistance; Mus; O Antigens; Oligosaccharides; Organism; Oryctolagus cuniculus; Pathogenicity; Pattern; Phagocytes; Polysaccharides; Poverty Areas; Preparation; Procedures; Process; Proctocolitis; Protein Secretion; Proteins; Pseudomonas aeruginosa; Pulmonary Challenge; Reporting; Research; Safety; Sanitation; Serotyping; Serum; Severities; Shigella; Shigella Infections; Shigella Vaccines; Shigella flexneri; Shigella sonnei; Site; System; TLR4 gene; Technology; Testing; Tetanus Toxoid; Time; Toddler; Toxicology; Type III Secretion System Pathway; Universities; Vaccine Production; Vaccines; Water; aluminum sulfate; antimicrobial; cognitive disability; cost; cross reacting material 197; disability; experimental study; immunogenic; immunogenicity; immunoreactivity; in vivo; infection risk; innovative technologies; manufacture; manufacturing scale-up; mutant; novel; preclinical development; prevent; process optimization; protective efficacy; protein expression; receptor binding; research clinical testing; resistant strain; response; scale up; unvaccinated; vaccine candidate; vaccine efficacy; vaccine strategy

RESEARCH SUMMARY Shigella causes a high burden of dysentery globally. Children younger than 5 years of age, particularly toddlers 2-3 years old, living in impoverished areas lacking clean water and sanitation are the most affected. Repeated infection results in lifelong health impairment and disability. Shigella also causes outbreaks in industrialized countries (daycare centers and medical institutions) and is a serious threat due to its multi-drug resistance. There is no approved vaccine. Most of the existing candidates rely on immunity to the Shigella O-antigen, which is serotype-specific (there are 4 species and >50 diarrheagenic Shigella serotypes). Shigella O-polysaccharide (OPS) conjugates (e.g., SF2a-TT15 and Flexyn2a) are the most clinically advanced. These vaccines are limited in their use of irrelevant (non-Shigella) proteins as carriers. SF2a-TT15 uses tetanus toxoid, which is included in many vaccines given to children of the target age and is known to suppress responses to other vaccine components. Flexyn2a uses rEPA as carrier but had modest efficacy in a recent challenge study (did not meet study endpoints). An earlier S. sonnei OPS-rEPA was effective in older children but not in toddlers (target age). In response to RFA-AI-22-037, the University of Maryland (UMB), in partnership with Vaxcyte, proposes to develop a bivalent (Shigella flexneri 2a and Shigella sonnei) OPS conjugate vaccine using Shigella IpaB, a Type III secretion protein that is highly conserved among all Shigella spp., as carrier. IpaB is exceptionally immunogenic and is a known broadly protective antigen; serum IgG (IgG1) levels and IpaB antibody function were found to be positively associated with reduced disease in controlled human challenge studies. For the first time, we have produced soluble, immunoreactive IpaB at a high (industrial) yield using Vaxcyte’s cell-free protein expression system. IpaB is conjugated to S. flex 2a and S. sonnei OPS using Vaxcyte’s site- specific conjugation technology. S. flex 2a OPS-IpaB given to mice intramuscularly with Alum on two occasions 28 days apart, elicited robust immune responses and afforded 78% protection against S. flex 2a (homologous) and 56% against S. sonnei (heterologous) lethal pulmonary Shigella challenge. Vaccine efficacy against S. flex 2a was higher as compared with S. flex 2a OPS-conjugated to CRM197 (a diphtheria toxoid mutant). This proposal consists of three aims to optimize process development, formulation, and scale-up production of S. flex 2a- and S. sonnei OPS-IpaB conjugates (Aim 1), evaluate the immunogenicity and vaccine efficacy in two animal models: mice (pulmonary challenge) and guinea pigs (rectocolitis infection) (Aim 2), and identify immune operatives associated with protective immunity through passive transfer experiments and a suite of in vitro functional assays (Aim 3). A bivalent Shigella-OPS-IpaB vaccine is expected to be well tolerated and to have enhanced protective capacity than existing vaccines. UMB and Vaxcyte have unique complementary expertise. Successful completion of this project will prepare the vaccine to enter cGMP manufacturing and initiate human studies.

研究摘要 志贺氏菌在全球造成了高度燃烧的痢疾。 5岁以下的儿童，尤其是幼儿 2-3岁，生活在缺乏清洁和卫生的贫困地区，受到影响最大。重复 感染会导致终身健康障碍和残疾。志贺氏菌还导致工业化爆发 国家（日托中心和医疗机构），由于其多药的抵抗而是严重的威胁。 没有批准的疫苗。大多数现有候选人都依赖于对志贺氏菌O-Antigen的免疫力， 是血清型特异性的（有4种，> 50种腹泻志贺氏菌血清型）。 Shigella O-Polysacchilide （OPS）共轭物（例如SF2A-TT15和Flexyn2a）是临床上最先进的。这些疫苗有限 在使用无关的（非辣椒菌）蛋白作为载体中。 SF2A-TT15使用Tetanius毒素，其中包括 许多疫苗给目标年龄的儿童，已知可以抑制对其他疫苗的反应 成分。 Flexyn2a使用REPA作为载体，但在最近的挑战研究中具有适度的效率（没有满足 研究终点）。较早的S. Sonnei Ops-Repa对年龄较大的儿童有效，但在幼儿（目标年龄）没有生效。 为了回应马里兰州大学（UMB）的RFA-AI-22-037，与Vaxcyte合作，提议 使用Shigella ipab（一种类型 III分泌蛋白在所有Shigella spp中都高度保守，作为载体。 IPAB异常 免疫原性，是已知的广泛保护的抗原；血清IgG（IgG1）水平和IPAB抗体功能 在受控人类挑战研究中，发现我们与疾病减少呈正相关。 我们第一次使用Vaxcyte的速度产生了高（工业）产量的固体免疫反应性IPAB 无细胞蛋白表达系统。 IPAB使用Vaxcyte的网站与S. flex 2a和S. Sonnei Ops进行了缀合 - 特定的共轭技术。 S. flex 2a Ops-Ips-IPAB两次给予小鼠肌内用明矾给予小鼠 相距28天，引起了强大的免疫反应，并为S. flex 2a（同源）提供了78％的保护 和56％的人对S. sonnei（异源）致命的肺志贺氏菌挑战。针对S. Flex的疫苗效率 与与CRM197（白喉毒素突变体）相结合的S. flex 2a OPS相比，2a更高。 该提案包括三个旨在优化过程开发，制定和扩大生产的旨在 S. flex 2a-和S. sonnei ops-ipab结合物（AIM 1），评估两种的免疫原性和疫苗效率 动物模型：小鼠（肺挑战）和豚鼠（直肠结肠炎感染）（AIM 2），并识别免疫 通过被动转移实验与保护性免疫相关的特工和一套体外 功能分析（AIM 3）。预计一种二价志贺氏菌 - ipab疫苗将具有良好的耐受性，并具有 与现有疫苗相比，受保护能力增强。 UMB和Vaxcyte具有独特的完整专业知识。成功完成该项目将准备 疫苗进入CGMP制造并启动人类研究。