Antigen Presentation and Pulmonary Immunity to Plague

描述(由申请人提供)： 该项目的总体目标是开发一种新的黏膜疫苗，以产生快速有效的肺免疫，以对抗雾化鼠疫杆菌。这些研究将集中在一种由脂质体-抗原-核酸复合体(LANAC)组成的新型疫苗递送系统。我们的初步研究表明，LANAC疫苗可以诱导对肽和蛋白质抗原的显著和长期的T细胞反应，在大多数情况下，其效率超过病毒载体疫苗或树突状细胞疫苗。此外，初步数据还表明，LANAC疫苗可诱导明显的肺内免疫和体液免疫，并在粘膜接种后有效。激发强大细胞免疫的能力对于控制受感染巨噬细胞内的耶尔森氏菌可能特别有用。因此，本研究的目的是确定脂质体-核酸复合体增强抗原提呈的免疫学机制，并确定用耶尔森氏菌蛋白或多肽抗原制成的粘膜LANAC疫苗是否能诱导保护性免疫，以抵御耶尔森氏菌的气溶胶攻击。本项目的具体目的是：(1)确定脂质体和核酸如何相互作用以增强抗原提呈；(2)确定LANAC的关键抗原提呈细胞靶点以及免疫的粘膜途径如何影响抗原提呈；(3)确定重组耶尔森菌F1或V抗原的粘膜或肠外接种是否能诱导对气溶胶攻击的保护性免疫；(4)确定耶尔森菌分泌的小肽是否能诱导保护性CTL反应。这些研究与本RFA规定的目标相关，因为它们将产生关于一种用于鼠疫和其他A-C类制剂免疫的新型疫苗佐剂的重要机制信息。此外，该项目还将对LANAC疫苗方法以及对吸入性耶尔森菌快速肺部免疫的能力提供关键的原则验证，特别是在粘膜免疫之后。

DESCRIPTION (provided by applicant): The overall goal of this project is to develop a novel mucosal vaccine for generating rapid and effective pulmonary immunity against aerosolized Yersinia pestis. These studies will focus on a novel vaccine delivery system that consists of liposome-antigen-nucleic acid complexes (LANAC). Our preliminary studies indicate that LANAC vaccines can elicit marked and long-lived T cell responses against both peptide and protein antigens, with an efficiency that in most cases exceeds that elicited by viral-vectored or dendritic cell vaccines. Moreover, preliminary data also indicate that LANAC vaccines can elicit marked intrapulmonary immunity and humoral immunity and are effective after mucosal administration. The ability to elicit strong cellular immunity may be particularly useful for control of Yersinia within infected macrophages. Therefore, the objectives of this proposal are to define the immunological mechanisms by which liposome-nucleic acid complexes enhance antigen presentation and to determine whether mucosal LANAC vaccines formulated with either Yersinia protein or peptide antigens can elicit protective immunity against aerosol challenge with Yersinia. The specific aims of this project are to (1) determine how liposomes and nucleic acids interact to enhance antigen presentation; (2) identify critical antigen-presenting cell targets for LANAC and how mucosal routes of immunization affect antigen presentation; (3) determine whether mucosal or parenteral vaccination with recombinant Yersinia F1 or V antigens can elicit protective immunity to aerosol challenge; (4) determine whether small secreted peptides from Yersinia can elicit protective CTL responses. These studies have relevance to the stated objectives of this RFA because they will yield important mechanistic information on a novel vaccine adjuvant for use in immunization against plague and other Category A-C agents. In addition, this project will provide critical proof-of-principal validation of the LANAC vaccine approach and the ability to elicit rapid pulmonary immunity against inhaled Yersinia, particularly after mucosal immunization.