Typhoid priority antigen identification and vaccine development

描述（由申请人提供）：微生物病原体产生可被感染宿主的适应性免疫反应识别的蛋白质。确定这些免疫靶点是合理设计新型疫苗和更好地诊断的先决条件，包括针对B类生物恐怖制剂沙门氏菌的诊断。本建议的具体目标是：目标1。利用已建立的高通量筛选技术，鉴定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。目标2。从同型转换抗体应答的靶标中鉴定并确认沙门氏菌特异性CD4 T细胞的抗原靶标。目标3。产生一种亚单位伤寒疫苗原型，在高度易感的小鼠株中具有免疫原性和保护性。我们的初步数据表明，微生物蛋白质组的高通量筛选是鉴定适应性免疫反应靶向微生物蛋白质的有效策略。我们的假设是，鉴定和生产沙门氏菌特异性反应的天然抗原目标，将有助于改进伤寒的诊断和亚单位疫苗的发展。伤寒每年导致60多万人死亡，是对美国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，但目前可获得的减毒活疫苗未获许可用于这些人群。目前迫切需要开发一种有效的亚单位疫苗，专门针对最脆弱的人群。我们的假设将使用新的高通量蛋白质组技术来鉴定沙门氏菌适应性免疫系统的蛋白靶点，并开发伤寒亚单位疫苗原型。公共卫生相关性：伤寒是一种传染病，每年在发展中国家造成60多万人死亡，在美国被认为是一种潜在的生物恐怖主义威胁。本研究旨在鉴定被感染小鼠和人的抗体和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，这一建议有可能发现在开发伤寒新疫苗和诊断方法中可能很重要的靶抗原。

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.