A cross protective multivalent vaccine for Shigella and ETEC

针对志贺氏菌和 ETEC 的交叉保护性多价疫苗

• 批准号: 10633470
• 负责人: DAVID A SACK
• 金额: $ 79.85万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-06 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10633470
• 关键词: Adhesions; Adult; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Antibodies; Antibody Response; Antibody titer measurement; Antibody-mediated protection; Antigens; Antimicrobial Resistance; Bacterial Adhesins; Biological Assay; Blocking Antibodies; Cessation of life; Child; Child Health; Childhood; Chimeric Proteins; Clinical; Combined Vaccines; Developing Countries; Development; Development Plans; Diarrhea; Disease; Enterotoxins; Enzyme-Linked Immunosorbent Assay; Epitopes; Escherichia coli; Escherichia coli Adhesins; Escherichia coli EHEC; Escherichia coli Proteins; Escherichia coli Vaccines; Evaluation; Family suidae; Goals; Heterogeneity; Human; Illinois; Immune response; Immunity; Immunization; Immunize; Immunologics; Infant; Infection; Injectable; International; Intestines; Invaded; Laboratories; Licensing; Lung; Measures; Modeling; Mus; Oryctolagus cuniculus; Outcome; Population; Preparation; Production; Proteins; Pulmonary Challenge; Records; Research Personnel; Sanitation; Schedule; Serotyping; Serum; Shiga Toxin; Shigella; Shigella Infections; Shigella Vaccines; Shigella boydii; Structure; Technology; Testing; Time; Toxicology; Toxin; Toxoids; Traveler' s diarrhea; United States National Institutes of Health; Universities; Vaccine Antigen; Vaccine Research; Vaccines; Virulence; Water; age group; antibody test; colonization factor antigens; cytotoxicity; diarrheal disease; enteric infection; enterotoxigenic Escherichia coli; experience; global health; immunogenic; immunogenicity; improved; infection rate; innovation; invention; low and middle-income countries; novel; oral vaccine; porcine model; pre-clinical; preclinical efficacy; prevent; product development; response; testing services; vaccination schedule; vaccine candidate; vaccine development; vaccine evaluation; vaccinology

Project Summary: Even though Shigella and enterotoxigenic Escherichia coli (ETEC) are the two most important bacterial causes of moderate-to-severe diarrhea in children in developing countries and in international travelers, there are currently no licensed vaccines for these infections. The goal of this application is the development of an injectable combination vaccine to protect from these two bacterial enteric infections. To accomplish this, we developed an ETEC vaccine candidate (MecVax) using the epitope- and structure- based vaccinology platform, MEFA (Multi-Epitope Fusion Antigen) which results in a polyvalent fusion protein with multiple epitopes on a single protein. MecVax includes two proteins, one to stimulate immunity to the colonization factor antigens (CFAs) of ETEC and another to stimulate immunity to the two enterotoxins. The first has epitopes for the seven most common CFAs while the second has epitopes for the heat-labile enterotoxin (LT) and the heat stable enterotoxin (STa). Animals immunized with MecVax develop functional antibodies to the CFAs and the two toxins and are protected when challenged with ETEC. Developing a safe and immunogenic antigen for STa is innovative since this small protein (19AA) is not naturally immunogenic. To extend protection to shigellosis, we developed a MEFA for Shigella which includes epitopes for the different virulence proteins that are common among all strains of Shigella and invasive E. coli. To further extend protection, the Shigella MEFA also includes epitopes for shiga toxins (including shiga toxin producing E coli - STEC). Because this vaccine is based on the virulence proteins which are common to all strains, this MEFA is expected to protect against all Shigella species and serotypes and not be limited by serotype as are the other vaccines which are based solely on the LPS antigen. There is no single animal model which can effectively evaluate the protective immune responses to the MEFA vaccines; thus, we use a combination of assays to determine the immune responses to the MEFA vaccines. Antibody responses in mice quantitate the responses to the specific epitopes in MEFA fusion while we use functional antibody assays to determine if the antibodies block adhesion (for ETEC), invasion (for Shigella) and neutralize toxins (for LT, STa and Shiga toxins). We then determine protection in animal models using a rabbit colonization model (both ETEC and Shigella) and protection against disease in a pig model (for ETEC) and a mouse lethal pulmonary challenge model (for Shigella). Using a combination of these assays and animal models, we will build the preclinical evidence for the combined ETEC-Shigella combination vaccine. The central hypothesis is that unlike current oral vaccine candidates, an injectable Shigella-ETEC MEFA vaccine will stimulate higher serum antibody titers and protect when the subject is most vulnerable and that natural exposure will boost local intestinal immunity. An effective Shigella-ETEC vaccine will prevent hundreds of millions diarrhea clinical cases and save > 200,000 lives annually.

项目概述：尽管志贺氏菌和产肠毒素大肠杆菌（ETEC）是两种最常见的细菌， 发展中国家和国际上儿童中度至重度腹泻的重要细菌原因 旅行者，目前还没有针对这些感染的许可疫苗。此应用程序的目标是 开发可注射的组合疫苗以保护免受这两种细菌肠道感染。 为了实现这一目标，我们开发了一种ETEC候选疫苗（MecVax），使用表位和结构- 基于疫苗学平台的MEFA（多表位融合抗原），其产生多价融合蛋白 一个蛋白质上有多个抗原决定基MecVax包括两种蛋白质，一种是刺激免疫， ETEC的定植因子抗原（CFA）和另一种刺激对两种肠毒素的免疫力。第一 第一个具有七种最常见CFA的表位，而第二个具有不耐热肠毒素的表位 (LT)和热稳定肠毒素（STa）。用MecVax免疫的动物产生功能性抗体， CFAs和两种毒素，并在ETEC挑战时受到保护。开发一种安全且具有免疫原性的 STa的抗原是创新性的，因为这种小蛋白质（19 AA）不是天然免疫原性的。 为了扩大对志贺氏菌病的保护，我们开发了一种针对志贺氏菌的MEFA， 这些毒力蛋白在志贺菌和侵袭性大肠杆菌的所有菌株中是共同的。杆菌进一步延长 保护，志贺菌MEFA还包括志贺毒素的表位（包括产志贺毒素的大肠杆菌- STEC）。因为这种疫苗是基于所有菌株共有的毒力蛋白，所以这种MEFA是 预期保护所有志贺氏菌属和血清型，而不像其他志贺氏菌属和血清型那样受血清型限制。 仅基于LPS抗原的疫苗。 没有单一的动物模型可以有效地评估对MEFA的保护性免疫应答 因此，我们使用一系列试验来确定对MEFA疫苗的免疫应答。 小鼠中的抗体应答定量了对MEFA融合中的特异性表位的应答，而我们使用 功能性抗体测定，以确定抗体是否阻断粘附（对于ETEC）、侵袭（对于志贺氏菌）和 中和毒素（LT、STa和滋贺毒素）。然后，我们使用兔子在动物模型中确定保护作用， 定植模型（ETEC和志贺氏菌）和猪模型（ETEC）和 小鼠致死性肺攻击模型（志贺氏菌）。使用这些测定和动物模型的组合， 我们将为ETEC-志贺氏菌联合疫苗建立临床前证据。 中心假设是，与目前的口服候选疫苗不同， 疫苗将刺激更高的血清抗体滴度，并在受试者最脆弱时提供保护， 自然接触可提高局部肠道免疫力。一种有效的志贺氏ETEC疫苗将预防数百 治疗数百万例腹泻临床病例，每年挽救20多万人的生命。