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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目摘要：即使志贺氏菌和肠毒素大肠杆菌（ETEC）是最大的两个发展中国家和国际儿童中等重度腹泻的重要细菌原因旅行者，目前没有用于这些感染的许可疫苗。此应用程序的目的是开发可注射的组合疫苗，以防止这两种细菌肠道感染。为此，我们使用表位和结构 - 基于疫苗的平台MEFA（多质融合抗原）产生多价融合蛋白单个蛋白质上有多个表位。 Mecvax包括两种蛋白质，一种是刺激对 ETEC的定植因子抗原（CFA），另一种刺激对两种肠毒素的免疫力。第一个具有七个最常见的CFA的表位，而第二个具有热量肠毒素的表位（LT）和热稳定肠毒素（STA）。用Mecvax免疫的动物发展了功能抗体 CFA和两种毒素在用ETEC挑战时受到保护。开发安全且免疫原性 STA的抗原具有创新性，因为这种小蛋白质（19AA）不是自然的免疫原性。为了将保护扩展到志氏症，我们开发了一个用于志贺氏菌的MEFA，其中包括不同的表位在志贺氏菌和侵入性大肠杆菌的所有菌株中常见的毒力蛋白。进一步扩展保护，Shigella Mefa还包括志贺毒素的表位（包括产生e Coli的shiga毒素 - STEC）。因为该疫苗基于所有菌株共有的毒力蛋白，所以该MEFA是预计可以预防所有志贺氏菌和血清型，而不是被血清型限制仅基于LPS抗原的疫苗。没有单一的动物模型可以有效地评估对MEFA的保护性免疫反应疫苗;因此，我们使用各种测定的组合来确定对MEFA疫苗的免疫反应。小鼠中的抗体反应在使用时量化了MEFA融合中对特定表位的反应功能性抗体测定以确定抗体是否阻断粘附（用于ETEC），侵袭（用于志贺氏菌）和中和毒素（对于LT，Sta和Shiga毒素）。然后，我们使用兔子确定动物模型的保护猪模型（ETEC）和A 小鼠致命的肺挑战模型（用于志贺氏菌）。结合这些测定法和动物模型，我们将为ETEC-Shigella组合疫苗组合建立临床前证据。中心假设是与当前的口服疫苗候选者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保护自然暴露将增强局部肠道免疫。有效的Shigella-Etec疫苗将防止数百种数以百万计的腹泻临床病例，每年挽救> 200,000个生命。