Development of O Antigen-based Vaccines Against Q Fever

描述(申请人提供)：伯氏柯克斯体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。它是一种研究不足的B类选择剂，可以通过气雾剂传播，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。该计划的长期目标是开发新的方法，以发现安全、有效的疫苗来对抗气雾剂传播的细胞内细菌病原体。这项应用是实现这一目标的关键一步，其目的是确定伯氏弧菌I相脂多糖(PI-LPS)的表位，以保护其免受伯氏弧菌雾化感染的肺部感染。为了达到这一目的，我们将检验中心假设，即伯氏梭菌PI-LPS的O抗原是对Q热产生保护性免疫的关键抗原。本研究的目的是证明PI-LPSO抗原保护性表位的模拟多肽对伯氏弧菌感染具有保护性免疫作用。该提案有两个具体目的：目的1：确定PI-LPS的O抗原是否是关键保护性抗原。我们将确定抗伯氏弧菌PI-LPSO抗原的抗体是否具有保护性，并鉴定能够提供保护作用的单抗。我们还将确定从PI-内毒素中提纯的O抗原是否对伯氏梭菌感染具有保护作用。目的2：鉴定对伯氏梭菌感染具有保护性免疫作用的多肽模拟物。我们将鉴定能够对伯氏弧菌感染产生保护性免疫的多肽模拟物，并确定O抗原保护性表位的多肽模拟物是否能够诱导对伯氏弧菌感染的保护性免疫。我们还将确定化学合成的多肽模拟物，在佐剂和合适的递送系统的背景下，是否可以提供对伯氏梭菌感染的保护。作为这项研究的结果，我们希望证明O抗原保护性表位的多肽模拟可以诱导对伯氏弧菌感染的保护性免疫的概念。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。 公共卫生相关性：伯氏柯克斯体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。它是一种研究不足的B类选择剂，可以通过气雾剂传播，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。本研究的重点在于了解PI-LPS的伯氏弧菌O抗原在诱导对伯氏弧菌感染的保护性免疫中的作用，这将为伯氏弧菌O抗原疫苗对Q热的保护性免疫提供新的证据。

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. PUBLIC HEALTH RELEVANCE: 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. This proposal focuses on understanding the role of C. burnetii O antigen of PI-LPS in conferring protective immunity against C. burnetii infection, which will provide novel evidence to prove the concept that C. burnetii O antigen-based vaccines can confer protective immunity against Q fever.