Typhoid priority antigen identification and vaccine development

描述（由申请方提供）：微生物病原体产生的蛋白质可被感染宿主的适应性免疫应答识别。这些免疫靶点的鉴定是合理设计新型疫苗和更好诊断的先决条件，包括针对B类生物恐怖剂沙门氏菌的疫苗和诊断。本提案的具体目标是：目标1。使用已建立的高通量筛选技术，以确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.从同种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：制备在高度易感小鼠品系中具有免疫原性和保护性的原型亚单位伤寒疫苗。我们的初步数据表明，微生物蛋白质组的高通量筛选是一种有效的策略，用于识别适应性免疫反应所靶向的微生物蛋白质。我们的假设是，沙门氏菌特异性反应的天然抗原靶标的鉴定和生产将允许开发改进的诊断和伤寒的亚单位疫苗，伤寒是一种每年导致60多万人死亡的疾病，是对美国的重大生物恐怖主义威胁。老年人和非常年轻的人最有可能患伤寒，但目前可用的减毒活疫苗尚未获准在这些人群中使用。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口。我们的假设将使用新的高通量蛋白质组技术进行测试，以确定适应性免疫系统的沙门氏菌蛋白质靶点，并开发伤寒亚单位疫苗的原型。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，在美国被认为是潜在的生物恐怖主义威胁。该提案旨在确定被感染小鼠和人类的抗体和T细胞识别的主要抗原靶标，并利用这些信息产生新的亚单位疫苗。因此，这一提议有可能发现可能在开发新型疫苗和伤寒诊断中重要的靶抗原。

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.