Live Attenuated Oral Typhoid-Shigellosis Vaccine

 说明(由申请人提供)：疫苗是在旅行者、军事人员和流行的发展中国家人群中预防传染病的一种合理和具有成本效益的手段。我们在这项建议中的目标是满足几个重要的疫苗需求：1)需要一个易于管理(无针头)和安全的口服疫苗载体平台，用于稳定表达和传递多种外来抗原，该平台在快速免疫方案后产生长期疗效，并且可以在不需要冷藏的情况下分发；2)缺乏用于预防志贺氏菌病的发病率和死亡率的许可疫苗；以及3)开发将同时预防多种病原体(即肠热病和志贺氏菌病的主要原因)的多价口服疫苗。为了应对这些挑战，我们利用现有口服减毒伤寒沙门氏菌活疫苗的广泛安全记录，将其作为我们的主要候选载体，开发出一种同时预防伤寒(具有对某些副伤寒的交叉保护)和志贺氏菌病的组合口服疫苗。此外，我们假设这种疫苗可以配制成安全、稳定、高度免疫原性的疫苗，并且可以很容易地口服。目前的建议旨在创造表达宋内氏志贺氏菌10型多糖(Ty21a-SS)和表达福氏2a志贺氏菌10型多糖(Ty21a-Sf2a)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Ty21a-SS和Ty21a-Sf2a，并从基因和生化角度对每个菌株进行充分的表征。Ty21a-SS、Ty21a-Sf2a、Ty21a-SS-GAD和Ty21a-Sf2a-GAD小鼠对伤寒沙门氏菌(TY2)、宋内氏沙门氏菌(53G)和福氏2a沙门氏菌(2457T)的免疫原性和保护效果将通过鼻腔给药和黏膜攻击的方式进行评估。在第二阶段，我们将对福氏志贺氏菌3a和6进行类似的工作，最终确定温度稳定的干燥产品为快速溶解晶片或片剂，进行所有临床前IND使能研究，最终确定临床方案，并提交IND。这一第一阶段项目将为第二阶段完成四价抗志贺氏菌病疫苗的建设奠定基础，该疫苗将在全球范围内预防85%以上的志贺氏菌病。

 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.