Development of MecVax, a Cross Protective Subunit Vaccine for ETEC

开发 ETEC 交叉保护亚单位疫苗 MecVax

• 批准号: 10704838
• 负责人: WEIPING ZHANG
• 金额: $ 117.07万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 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/10704838
• 关键词: Acceleration; Acquired Immunodeficiency Syndrome; Adherence; Adjuvant; Animal Model; Animals; Antibiotic Resistance; Antibiotics; Antibodies; Antibody Response; Antigens; Bacteria; Bacterial Adhesins; Biological Assay; Biological Sciences; Biomass; Buffers; Category B pathogen; Cause of Death; Cells; Cessation of life; Child; Clinical; Clinical Research; Collaborations; Cyclic GMP; Dehydration; Developing Countries; Development; Diarrhea; Dose; Economics; Engineering; Enterotoxins; Epitopes; Escherichia coli Adhesins; Escherichia coli Infections; Escherichia coli Vaccines; Excision; Family suidae; Formulation; Goals; Heterogeneity; Homeostasis; Illinois; Immunity; Immunologic Tests; Immunologics; Industrialization; Institution; International; Knowledge; Laboratories; Leadership; Licensing; Life; Liquid substance; Malaria; Measles; Mediating; Modeling; Nutritional; Oryctolagus cuniculus; Outcome; Plasmids; Play; Preparation; Process; Production; Proteins; Protocols documentation; Public Health; Qualifying; Records; Reference Standards; Role; Running; Safety; Shigella Vaccines; Side; Small Intestines; Structure; Subunit Vaccines; Testing; Toxicology; Toxin; Traveler' s diarrhea; UNICEF; United States National Institutes of Health; Universities; Vaccine Research; Vaccines; Virulence; Work; aged; analytical method; antitoxin; cell bank; cognitive development; disability; disability-adjusted life years; enterotoxigenic Escherichia coli; experience; gut colonization; immunogenic; industry partner; innovation; juvenile animal; manufacture; manufacturing test; novel; pre-Investigational New Drug meeting; pre-clinical; preclinical study; prevent; product development; protein expression; protein purification; receptor; synergism; vaccine candidate; vaccine development; vaccine formulation; vaccinology

Project Summary Diarrhea is the second leading cause of death in children aged <5 years in developing countries, more than AIDS, malaria, and measles combined. Our long-term goal is to develop effective vaccines against diarrheal bacteria. The objective of this industrial partnership project is to combine expertise and leadership from academic vaccine research and industrial vaccine development and manufacturing to accelerate the development of MecVax, a multivalent cross-protective subunit vaccine for enterotoxigenic Escherichia coli (ETEC). ETEC bacteria are one of the top five causes of children's diarrhea and the most common cause of travelers' diarrhea. ETEC is listed as a category B priority pathogen (NIH) and a serious threat of antibiotic resistance (CDC), and causes >220 million diarrhea clinical cases annually, resulting in stunting and poor cognitive development in diarrheal children, 1,065,000 years lost due to disability (YLD), 6,894,000 years to disability-adjusted life-years (DALY), and about 100,000 deaths (many are children < 5 years). ETEC is also a primary cause of diarrhea in young animals and causes significant economic losses worldwide. Currently, there are no licensed vaccines against ETEC diarrhea. The development of effective vaccines for ETEC is a top priority for WHO, UNICEF, and many other public health institutions. By applying an innovative vaccinology platform, we have constructed two polyvalent proteins and developed a protein-based multivalent ETEC vaccine candidate, MecVax. MecVax is the only ETEC vaccine candidate that induces protective antibodies against both ETEC toxins (LT and STa) and the seven most important ETEC adhesins (CFA/I, CS1 - CS6). Since ETEC bacteria producing LT and/or STa toxin are associated with all ETEC diarrhea cases and strains expressing adhesin CFA/I or CS1 - CS6 cause > 66% of ETEC clinical cases, the synergy of antitoxin and anti-adhesin immunity from MecVax provides truly broad protection against ETEC children's diarrhea and travelers' diarrhea. MecVax is demonstrated to broadly protect against ETEC clinical diarrhea and colonization of small intestines preclinically. The central goal of this milestone-oriented vaccine development project is to optimize MecVax vaccine formulation, analytical development, and production processing. The rationale is that the completion of this application will identify MecVax optimal formulation, optimize upstream and downstream processing and analytical development, and manufacture vaccine cGLP products, - essential to accelerate MecVax development. To achieve these goals, we will 1) evaluate MecVax protection against ETEC adherence and enterotoxicity at different antigen doses, adjuvants, buffers, and shelving conditions, 2) optimize analytical assays and upstream and downstream processing, 3) manufacture and test MecVax master cell banks, and 4) perform product production engineering runs and submit MecVax pre-IND application. The positive impact is that an effective ETEC vaccine will save nearly 100,000 lives and prevent >200 million diarrheal clinical cases each year, and reduce long-term negative nutritional and developmental impacts.

项目概要 腹泻是发展中国家 5 岁以下儿童的第二大死因，超过 艾滋病、疟疾和麻疹的总和。我们的长期目标是开发有效的腹泻疫苗 细菌。该工业合作伙伴项目的目标是结合来自各行业的专业知识和领导力 学术疫苗研究和工业疫苗开发制造加速 开发 MecVax，一种针对产肠毒素大肠杆菌的多价交叉保护亚单位疫苗 （ETEC）。 ETEC 细菌是儿童腹泻的五大原因之一，也是儿童腹泻的最常见原因。 旅行者腹泻。 ETEC被列为B类优先病原体（NIH），对抗生素构成严重威胁 耐药性（CDC），每年导致超过 2.2 亿腹泻临床病例，导致发育迟缓和贫困 腹泻儿童的认知发展，因残疾而损失 1,065,000 年（YLD），6,894,000 年 伤残调整生命年 (DALY)，以及约 100,000 人死亡（其中许多是 5 岁以下的儿童）。 ETEC 也是 是幼年动物腹泻的主要原因，并在全世界造成重大经济损失。 目前，还没有针对 ETEC 腹泻的许可疫苗。开发有效疫苗 ETEC 是世界卫生组织、联合国儿童基金会和许多其他公共卫生机构的首要任务。通过应用创新 疫苗学平台，我们构建了两种多价蛋白，并开发了基于蛋白质的多价蛋白 ETEC 候选疫苗 MecVax。 MecVax 是唯一能够诱导保护性的 ETEC 候选疫苗 针对 ETEC 毒素（LT 和 STa）和七种最重要的 ETEC 粘附素（CFA/I、CS1 - CS6）。由于产生 LT 和/或 STa 毒素的 ETEC 细菌与所有 ETEC 腹泻病例有关，并且 表达粘附素 CFA/I 或 CS1 - CS6 的菌株导致 > 66% 的 ETEC 临床病例，抗毒素的协同作用 MecVax 的抗粘附素免疫提供了真正广泛的保护，针对 ETEC 儿童腹泻和 旅行者腹泻。 MecVax 被证明可以广泛预防 ETEC 临床腹泻和定植 小肠的临床前研究。这个具有里程碑意义的疫苗开发项目的中心目标是 优化 MecVax 疫苗配方、分析开发和生产加工。理由是 此应用程序的完成将确定 MecVax 最佳配方，优化上游和下游 加工和分析开发以及疫苗 cGLP 产品的生产，对于加速至关重要 MecVax 开发。为了实现这些目标，我们将 1) 评估 MecVax 对 ETEC 依从性的保护 和不同抗原剂量、佐剂、缓冲液和搁置条件下的肠毒性，2) 优化分析 分析和上游和下游处理，3) 制造和测试 MecVax 主细胞库，以及 4) 执行产品生产工程运行并提交 MecVax 预 IND 申请。 积极影响是，有效的 ETEC 疫苗将挽救近 10 万人的生命并预防超过 2 亿人的死亡 每年减少腹泻临床病例，并减少对营养和发育的长期负面影响。