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.

研究综述 志贺氏菌在全球范围内引起痢疾的高负担。5岁以下儿童，尤其是幼儿 2-3生活在缺乏清洁水和卫生设施的贫困地区的20岁以上儿童受影响最大。重复 感染会导致终身健康受损和残疾。志贺氏菌也会在工业化的 国家（日托中心和医疗机构），并由于其多重耐药性而构成严重威胁。 没有批准的疫苗。大多数现有的候选人依赖于对志贺氏菌O抗原的免疫力， 志贺菌属有4个种和50多个血清型。志贺氏菌O-多糖 (OPS)缀合物（例如，SF 2a-TT 15和Flexyn 2a）是临床上最先进的。这些疫苗是有限的 他们使用无关的（非志贺氏菌）蛋白质作为载体。SF 2a-TT 15使用破伤风类毒素，其包括在 许多疫苗给予目标年龄的儿童，并已知抑制对其他疫苗的反应 件. Flexyn 2a使用rEPA作为载体，但在最近的挑战研究中具有适度的功效（未满足 研究终点）。早期的S。Sonnei OPS-rEPA在较大的儿童中有效，但在幼儿（目标年龄）中无效。 作为对RFA-AI-22-037的回应，马里兰州大学（UMB）与Vaxcyte合作，建议 利用志贺菌IpaB，a型， III分泌蛋白，在所有志贺氏菌属中高度保守，作为载体。IpaB异常 免疫原性，是一种已知的广泛保护性抗原;血清IgG（IgG 1）水平和IpaB抗体功能 在对照人类挑战研究中发现与疾病减少呈正相关。 这是我们第一次使用Vaxcyte的方法以高（工业）产量生产可溶性免疫反应性IpaB。 无细胞蛋白表达系统。IpaB与S缀合。flex 2a和S. Sonnei OPS使用Vaxcyte的网站- 特异性结合技术。S.在两种情况下用明矾肌内给予小鼠flex 2a OPS-IpaB 间隔28天，引发了强大的免疫应答，并提供了78%的抗S. flex 2a（同源） 对S. Sonnei（异源）致死性肺志贺氏菌攻毒。疫苗对S. flex 2a比S. flex 2a OPS-缀合至CRM 197（白喉类毒素突变体）。 该提案包括三个目标，以优化工艺开发，配方和放大生产 S. flex 2a-和S. Sonnei OPS-IpaB偶联物（目的1），在两种情况下评价免疫原性和疫苗效力 动物模型：小鼠（肺激发）和豚鼠（直肠结肠炎感染）（目的2），并确定免疫 通过被动转移实验和一系列体外实验， 功能测定（目的3）。预期二价志贺氏菌-OPS-IpaB疫苗具有良好的耐受性， 比现有疫苗更强的保护能力。 UMB和Vaxcyte拥有独特的互补专业知识。该项目的成功完成将为 疫苗进入cGMP生产并启动人体研究。