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岁儿童的第二大死亡原因，超过 艾滋病，疟疾和麻疹结合在一起。我们的长期目标是开发针对腹泻的有效疫苗 细菌。这个工业伙伴关系项目的目的是结合专业知识和领导 学术疫苗研究和工业疫苗开发和制造业，以加速 Mecvax的开发，一种用于肠毒素大肠杆菌的多价交叉保护亚基疫苗 （ETEC）。 ETEC细菌是儿童腹泻的五个原因之一，也是最常见的原因 旅行者的腹泻。 ETEC被列为B类优先病原体（NIH）和抗生素的严重威胁 耐药性（CDC），每年导致超约2.2亿腹泻病例，导致发育迟缓和差 腹泻儿童的认知发展，由于残疾（YLD）损失了1,06.5，000年，6,894,000年 残疾调整的终身年份（Daly）和大约100,000人死亡（许多儿童<5岁）。 ETEC也是 年轻动物腹泻的主要原因，在全球造成巨大的经济损失。 目前，没有针对ETEC腹泻的许可疫苗。开发有效的疫苗 ETEC是谁，联合国儿童基金会和许多其他公共卫生机构的重中之重。通过应用创新 疫苗接种平台，我们已经构建了两个多价蛋白质，并开发了一种基于蛋白质的多价 ETEC疫苗候选者，Mecvax。 Mecvax是唯一诱导保护性的ETEC疫苗 针对ETEC毒素（LT和STA）和七种最重要的ETEC粘附素（CFA/I，CS1-）的抗体 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 表达粘合剂CFA/I或CS1 -CS6的菌株> 66％的ETEC临床病例，抗毒素的协同作用 Mecvax的抗粘合剂免疫可为ETEC儿童的腹泻和 旅行者的腹泻。麦克伐克斯被证明可以广泛预防ETEC临床腹泻和定殖 小肠的临时。这个面向里程碑的疫苗开发项目的核心目标是 优化Mecvax疫苗配方，分析开发和生产处理。理由是 该应用程序的完成将识别Mecvax最佳公式，优化上游和下游 加工和分析开发以及生产疫苗CGLP产品 - 加速至关重要 Mecvax开发。为了实现这些目标，我们将1）评估Mecvax的保护防止ETEC依从性 并以不同的抗原剂量，佐剂，缓冲液和搁架条件下的肠毒性，2）优化分析 测定，上游和下游处理，3）制造和测试Mecvax大型细胞库，4） 执行产品生产工程运行并提交Mecvax预先申请。 积极的影响是，有效的ETEC疫苗将挽救近100,000人的生命，并预防2亿次生命 每年腹泻临床病例，并减少长期营养和发育影响。