Typhoid priority antigen identification and vaccine development

描述(申请人提供)：微生物病原体产生的蛋白质可以被感染宿主的适应性免疫反应识别。识别这些免疫靶点是合理设计新疫苗和更好诊断的先决条件，包括针对B类生物恐怖主义制剂沙门氏菌的疫苗。这项建议的具体目的是：目的1.使用已建立的高通量筛选技术来识别沙门氏菌感染诱导的抗体识别的沙门氏菌蛋白质组的共同方面。目的2.从同种类型转换抗体反应的靶点中确定沙门氏菌特异性CD4T细胞的抗原靶点。目的3.研制一种对高度敏感的小鼠具有免疫原性和保护性的亚单位伤寒疫苗原型。我们的初步数据表明，高通量筛选微生物蛋白质组是识别适应性免疫反应靶标微生物蛋白质的有效策略。我们的假设是，识别和生产沙门氏菌特异性反应的天然抗原靶，将有助于开发改进的诊断方法和伤寒亚单位疫苗。伤寒每年导致60多万人死亡，是美国面临的重大生物恐怖主义威胁。老年人和幼儿患伤寒的风险最大，但目前可用的减毒活疫苗尚未获得在这些人群中使用的许可。迫切需要开发一种可专门针对最脆弱人口的有效亚单位疫苗。我们的假设将通过新的高通量蛋白质组技术进行验证，以确定适应性免疫系统的沙门氏菌蛋白靶标，并开发伤寒亚单位疫苗的原型。与公共卫生相关：伤寒是一种传染病，在发展中国家每年导致60多万人死亡，在美国已被视为潜在的生物恐怖威胁。这项提议旨在识别受感染的小鼠和人类的抗体和T细胞识别的主要抗原靶点，并利用这些信息产生一种新的亚单位疫苗。因此，这一提议有可能发现目标抗原，这些抗原可能对伤寒新疫苗和诊断的开发很重要。

DESCRIPTION (provided by applicant): Microbial pathogens produce proteins that can be recognized by the adaptive immune response in an infected host. Identification of these immune targets is a prerequisite for the rational design of novel vaccines and better diagnostics, including those directed against the category B bioterrorism agent Salmonella. The specific aims of this proposal are: Aim 1. Use an established high throughput screening technology to identify common aspects of the Salmonella proteome recognized by antibodies induced by Salmonella infection. Aim 2. Identify and confirm antigenic targets of Salmonella-specific CD4 T cells from among the targets of isotype-switched antibody responses. Aim 3. To generate a prototype sub-unit typhoid vaccine that is immunogenic and protective in highly susceptible mouse strains. Our preliminary data demonstrate that high throughput screening of microbial proteomes is an effective strategy for the identification of microbial proteins targeted by the adaptive immune response. Our hypothesis is that identification and production of natural antigenic targets of Salmonella-specific responses will allow the development of improved diagnostics and a sub-unit vaccine for typhoid fever, a disease that kills over 600,000 people per year and is a significant bioterrorism threat to the US. The elderly and very young are most at risk from typhoid, yet currently available live attenuated vaccines are not licensed for use in these populations. There is an urgent need to develop an effective sub-unit vaccine that could be specifically targeted to the most vulnerable demographics. Our hypothesis will be tested using novel high-throughput proteome technology to identify Salmonella protein targets of the adaptive immune system and develop a prototype sub-unit vaccine for typhoid. PUBLIC HEALTH RELEVANCE: Typhoid is an infectious disease that kills over 600,000 people per year in developing countries and has been recognized as a potential bioterrorist threat in the US. This proposal aims to identify the major antigenic targets recognized by antibodies and T cells from infected mice and humans, and use this information to generate a novel sub-unit vaccine. This proposal therefore has the potential to uncover target antigens that may be important in the development of novel vaccines and diagnostics for typhoid fever.