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.

项目摘要 腹泻是发展中国家5岁以下儿童死亡的第二大原因， 艾滋病，疟疾，和麻疹。我们的长期目标是开发有效的疫苗来对抗霍乱 细菌该工业伙伴关系项目的目标是将联合收割机的专门知识和领导能力结合起来， 学术疫苗研究和工业疫苗开发和制造，以加快 大肠杆菌多价交叉保护性亚单位疫苗MecVax的研制 （ETEC）。ETEC细菌是儿童腹泻的五大原因之一，也是最常见的原因。 旅行者腹泻ETEC被列为B类优先病原体（NIH），是抗生素的严重威胁 耐药性（CDC），每年导致> 2.2亿例腹泻临床病例，导致发育迟缓和贫困。 残疾儿童的认知发展，1，065，000年因残疾而损失（YLD），6，894，000年 残疾调整生命年（DALY），约100，000例死亡（许多是5岁以下儿童）。ETEC也是一个 这是幼畜腹泻的主要原因，并在全世界造成重大经济损失。 目前，没有针对ETEC腹泻的许可疫苗。有效疫苗的研制 ETEC是世卫组织、联合国儿童基金会和许多其他公共卫生机构的首要任务。通过应用创新的 在疫苗学平台上，我们构建了两种多价蛋白，并开发了一种基于蛋白的多价疫苗。 ETEC候选疫苗，MecVax。MecVax是唯一一种能够诱导保护性ETEC的候选疫苗。 针对ETEC毒素（LT和STa）和七种最重要的ETEC粘附素（CFA/I，CS 1- CS6）。由于产生LT和/或STa毒素的ETEC细菌与所有ETEC腹泻病例相关， 表达粘附素CFA/I或CS 1- CS6的菌株导致> 66%的ETEC临床病例，抗毒素的协同作用 MecVax的抗粘附素免疫力提供了真正广泛的保护，防止ETEC儿童腹泻， 旅行者腹泻MecVax被证明可广泛预防ETEC临床腹泻和定植 临床前的小肠这个里程碑式的疫苗开发项目的中心目标是 优化MecVax疫苗配方、分析开发和生产工艺。基本原理是 该应用程序完成将确定MecVax最佳配方，优化上游和下游 加工和分析开发，以及生产疫苗cGLP产品，-对于加速 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 在不同抗原剂量、佐剂、缓冲液和搁置条件下的肠毒性，2）优化分析 检测和上游及下游处理，3）生产和检测MecVax主细胞库，以及4） 执行产品生产工程运行并提交MecVax pre-IND申请。 积极的影响是，有效的ETEC疫苗将挽救近10万人的生命，预防> 2亿人死亡。 每年减少临床病例，减少长期负面的营养和发育影响。