Development of O Antigen-based Vaccines Against Q Fever

描述（由申请人提供）：伯氏克希菌是一种专性细胞内革兰氏阴性细菌，可引起人类急性Q热和慢性感染。它是一种未被充分研究的B类选择剂，可以通过气溶胶传播，因此创造一种安全有效的疫苗来预防Q热仍然是一个重要的公共卫生和国家生物安全目标。该项目的长期目标是开发新的方法，以发现安全、有效的疫苗，防止气溶胶传播的细胞内细菌病原体。本应用程序的目的是鉴定伯纳氏梭菌I期脂多糖（PI-LPS）的表位，该表位可以保护肺部免受雾化伯纳氏梭菌感染，这是实现这一目标的重要一步。为了实现这一目标，我们将验证伯氏梭菌PI-LPS的O抗原是赋予Q热保护性免疫的关键抗原的中心假设。本研究的目的是为了证明PI-LPS O抗原保护性表位的肽模拟物可以赋予对伯氏杆菌感染的保护性免疫。本提案有两个具体目的：目的1：确定PI-LPS的O抗原是否为关键保护抗原。我们将确定针对伯纳蒂胞杆菌PI-LPS O抗原的抗体是否具有保护作用，并鉴定单克隆抗体（mab）对伯纳蒂胞杆菌感染具有保护作用。我们还将确定从PI-LPS中纯化的O抗原是否能对伯纳蒂胞杆菌感染提供保护。目的2：鉴定肽模拟物，可以赋予保护免疫对伯氏杆菌感染。我们将鉴定能对伯纳氏菌感染产生保护性免疫的肽模拟物，并确定O抗原保护性表位的肽模拟物是否能引起对伯纳氏菌感染的保护性免疫。我们还将确定化学合成的肽模拟物，在佐剂和合适的递送系统的背景下，是否可以提供对伯纳蒂胞杆菌感染的保护。作为本研究的结果，我们期望证明O抗原保护性表位的肽模拟物可以引起对伯氏杆菌感染的保护性免疫。这将对人类健康产生重大的积极影响，因为它将为Q热疫苗的设计提供信息，并反过来导致开发新的策略来干扰其他危险的细胞内细菌病原体的气溶胶传播。

DESCRIPTION (provided by applicant): Coxiella burnetii is an obligate intracellular gram-negative bacterium that causes acute Q fever and chronic infections in humans. It is an understudied category B select agent and can be transmitted via aerosol, thus creation of a safe and effective vaccine to prevent Q fever remains an important public health and national biosecurity goal. The long-term goal of this program is to develop new approaches to discover safe, effective vaccines against aerosol-transmitted intracellular bacterial pathogens. The objective of this application, which is an essential step towards this goal, is to identify the epitopes on C. burnetii phase I lipopolysaccharide (PI-LPS) that can confer protection against pulmonary infection with aerosolized C. burnetii. To achieve this objective, we will test the central hypothesis that O antigen of C. burnetii PI-LPS is the key antigen to confer protective immunity against Q fever. The purpose of this proposal is to prove the concept that peptide mimics of protective epitopes on O antigen of PI-LPS can confer protective immunity against C. burnetii infection. The proposal has two specific aims: Aim 1: to determine if O antigen of PI-LPS is the key protective antigen. We will determine if Ab against O antigen of C. burnetii PI-LPS is protective and identify the monoclonal antibodies (mAbs) that can provide protection against C. burnetii infection. We will also determine if purified O antigen from PI-LPS can confer protection against C. burnetii infection. Aim 2: to identify the peptide mimics that can confer protective immunity against C. burnetii infection. We will identify the peptide mimics that can confer protective immunity against C. burnetii infection and determine if peptide mimics of protective epitopes of O antigen can elicit protective immunity against C. burnetii infection. We will also determine if chemically synthesized peptide mimics, in the context of an adjuvant and a suitable delivery system, can provide protection against C. burnetii infection. As an outcome of this research, we expect to prove the concept that peptide mimics of protective epitopes of O antigen can elicit protective immunity against C. burnetii infection. This would have significant positive effects on human health, because it would provide information for vaccine design against Q fever, and in turn lead to development of new strategies to interfere with aerosol transmission of other dangerous intracellular bacterial pathogens.