Live Attenuated Oral Typhoid-Shigellosis Vaccine

口服伤寒志贺氏减毒活疫苗

• 批准号: 8903927
• 负责人: B. KIM LEE SIM
• 金额: $ 30.74万
• 依托单位: PROTEIN POTENTIAL, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903927
• 关键词: Acids; Address; Antibiotic Resistance; Antibodies; Antigens; Attenuated; Chromosomal Insertion; Chromosomes; Clinical Protocols; Communicable Diseases; Cysteine; Developing Countries; Development; Disease; Dose; Foundations; Generations; Genes; Genetic; Glutamate Decarboxylase; Goals; Immunization; Investigational New Drug Application; Lead; Licensing; Life; Methods; Military Personnel; Morbidity - disease rate; Mus; Needles; Nose; O Antigens; Oral; Paratyphoid Fever; Phase; Phase I Clinical Trials; Phenotype; Polysaccharides; Population; Prevention; Production; Refrigeration; Regimen; Resistance; Safety; Salmonella typhi; Sequence Analysis; Serotyping; Shigella; Shigella Infections; Shigella flexneri; Shigella sonnei; Tablets; Temperature; Tryptophan; Ty21a typhoid vaccine; Typhoid Fever; Vaccines; Valine; Work; cost effective; design; genome sequencing; immunogenic; immunogenicity; indexing; intraperitoneal; meetings; mortality; oral vaccine; pre-clinical; protective efficacy; public health relevance; vaccine candidate; vector

 DESCRIPTION (provided by applicant): Vaccines are a rational and cost-effective means for protecting against infectious diseases in travelers, military personnel, and in endemic developing country populations. Our goal in this proposal is to address several significant vaccine needs: 1) the need for an easy-to-administer (needle-free) and safe oral vaccine vector platform for stable expression and delivery of multiple foreign antigens, that generates long term efficacy following a rapid immunization regimen and which can be distributed without the need for refrigeration; 2) the lack of a licensed vaccine for prevention of morbidity and mortality due o shigellosis; and 3) development of a multivalent oral vaccine that will simultaneously protect against multiple disease agents (i.e. enteric fever plus the major causes of shigellosis). To address these challenges, we exploit the extensive safety record of the existing live, oral, attenuated Salmonella Typhi Ty21a typhoid vaccine by utilizing it as our lead candidate vector to develop a combination oral vaccine that will simultaneously protect against both typhoid fever (with cross-protection against some paratyphoid fevers) and shigellosis. Further, we hypothesize that this vaccine can be formulated to be safe, stable, and highly immunogenic and can be easily administered orally. The current proposal is aimed at creating multivalent vaccine strains Ty21a expressing S. sonnei form 1 O polysaccharide (Ty21a-Ss) and Ty21a-expressing S. flexneri 2a form 1 O polysaccharide (Ty21a-Sf2a). We will also create acid resistant Ty21a-Ss and Ty21a-Sf2a by adding Shigella glutamate decarboxylase (GAD) genes into vaccine candidates and fully characterize each strain genetically and biochemically. Immunogenicity and protective efficacy against S. Typhi (Ty2), S. sonnei (53G) and S. flexneri 2a (2457T) in mice of Ty21a-Ss, Ty21a-Sf2a, Ty21a-Ss-GAD and Ty21a-Sf2a-GAD will be assessed by immunization via intranasal installation of doses followed by mucosal challenge. In Phase II, we will conduct similar work for S. flexneri 3a and 6, finalize a temperature-stable dried product as rapidly dissolvable wafers or tablets, conduct all pre-clinical IND enabling studies, finalize a clinical protocol, and submit an IND. This Phase I project will provide the foundation for the Phase II to complete construction of a quadrivalent anti-shigellosis vaccine that will protect against more than 85% of shigellosis worldwide.

 描述（由申请人提供）：疫苗是预防旅行者、军事人员和流行性发展中国家人群感染传染病的合理且具有成本效益的手段。我们在本提案中的目标是解决几个重要的疫苗需求：1）需要一种易于管理（无针）且安全的口服疫苗载体平台，用于稳定表达和递送多种外源抗原，在快速免疫方案后产生长期疗效，并且无需疫苗即可分发冷藏；2) 缺乏用于预防志贺氏菌病引起的发病和死亡的疫苗；以及 3) 开发可同时预防多种疾病的多价口服疫苗（即肠热病和志贺氏菌病的主要原因）。为了应对这些挑战，我们利用现有活口服减毒伤寒沙门氏菌 Ty21a 伤寒疫苗的安全记录，将其作为我们的主要候选载体来开发一种组合口服疫苗，该疫苗可广泛用于将同时预防伤寒（对某些副伤寒有交叉保护）和志贺氏菌病。此外，我们追求这种疫苗可以安全、稳定、具有高免疫原性，并且可以轻松口服。旨在创建表达宋内沙门氏菌 1 O 型多糖 (Ty21a-Ss) 和表达 Ty21a 福氏沙门氏菌 2a 型的多价疫苗株 Ty21a我们还将通过将志贺氏菌谷氨酸脱羧酶（GAD）基因添加到候选疫苗中来创建耐酸的Ty21a-Ss和Ty21a-Sf2a，并全面表征每种菌株对志贺氏菌的免疫原性和保护功效。伤寒 (Ty2)、宋内沙门氏菌 (53G) 和弗氏沙门氏菌 2a (2457T) 在 Ty21a-Ss、Ty21a-Sf2a、Ty21a-Ss-GAD 和 Ty21a-Sf2a-GAD 小鼠中，将通过鼻内安装剂量进行免疫评估，然后进行粘膜攻击。在第二阶段，我们将进行类似的工作。 S. flexneri 3a 和 6，最终形成温度稳定的干燥产品，作为可快速溶解的威化饼或片剂，进行所有临床前 IND 授权研究，最终确定临床方案，并提交 IND。 该 I 期项目将为 II 期项目奠定基础，以完成四价抗志贺氏病疫苗的构建，该疫苗将预防超过 85 种疾病。全球志贺氏菌病的百分比。