Improved Q Fever Vaccine (DSTL, PHE, ICENI DX & Mologic)

改良 Q 热疫苗（DSTL、PHE、ICENI DX

• 批准号: 972218
• 金额: $ 66.62万
• 依托单位: MOLOGIC LTD.
• 依托单位国家: 英国
• 项目类别: Small Business Research Initiative
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=972218
• 关键词: Improved; Fever; Vaccine; DSTL; PHE

Virus-like particles (VLPs) are a flexible delivery platform that provides potential for presenting multiple antigens to the immune system concurrently. Hepatitis B core antigen self assembles to form highly stable, immunogenic VLPs in a relatively low cost yeast expression system. The viral protein can be adapted to display foreign antigens on spikes that protrude from the surface of the VLPs. This technology circumvents the need for high cost, high containment production facilities, cold transportation and storage. Our goal is to produce a cost effective, second generation Q fever vaccine, using VLP technology as a production platform. In initial proof of concept studies, the Mologic-Dstl-Iceni Diagnostics consortium has successfully produced and tested Burkholderia pseudomallei vaccine candidates based on yeast-produced VLPs presenting either peptide or polysaccharide antigens. These candidates were efficacious in a mouse model of Melioidosis, demonstrating the readiness of this technology for roll out for antibacterial vaccine production. In the current proposal, we will consolidate and extend our work on this platform, applying it to Coxiella burnetii, the causative agent of Q Fever, which is listed as an agent of concern by the WHO and UN. Q fever is found worldwide and there is high prevalence in low income countries. This VLP platform bid will draw on expertise in Coxiella burnetii antigenicity to develop a vaccine against Q fever. It has been shown that C. burnetii lipopolysaccharide (LPS) provides protection against challenge, indicating that it is a key protective antigen. LPS itself is a T-cell independent antigen; conjugation to a protein carrier can improve antibody isotype development and crucially stimulate B cell memory. Therefore, to increase vaccine efficacy and develop immune memory to Coxiella, we propose conjugating native C. burnetii LPS, or synthetic fragments thereof, to VLP carriers. In parallel, we will express previously identified C. burnetii protein surface antigens on VLPs, providing material for potential blending with LPS-VLP conjugates to produce multi-antigen vaccines. The novel VLP vaccines produced in this study will be tested in our established mouse model of C. burnetii aerosol infection; immune responses will be determined and related to the vaccine efficacy. Several VLP vaccines have already been licensed for human use, demonstrating an established path to market. The opportunity to manufacture without high level containment will result in inexpensive vaccines where manufacture can be transferred to low income settings. This will serve to pave the way for future development of low-cost vaccines for other globally significant pathogens.

病毒样颗粒（VLP）是一种灵活的递送平台，其提供同时向免疫系统呈递多种抗原的潜力。B型肝炎核心抗原在相对低成本的酵母表达系统中自组装形成高度稳定的免疫原性VLP。病毒蛋白可适于在从VLP表面突出的刺突上展示外源抗原。该技术避免了对高成本、高密封性生产设施、冷运输和储存的需要。我们的目标是利用VLP技术作为生产平台，生产具有成本效益的第二代Q热疫苗。在初步的概念验证研究中，Mologic-Dstl-Iceni Diagnostics联盟已经成功地生产和测试了基于酵母产生的VLP的类鼻疽伯克霍尔德菌候选疫苗，该VLP呈递肽或多糖抗原。这些候选物在类鼻疽的小鼠模型中是有效的，证明了该技术用于抗菌疫苗生产的准备就绪。在目前的提案中，我们将巩固和扩展我们在这个平台上的工作，将其应用于Q热的病原体贝氏柯克斯体，这是世界卫生组织和联合国列为关注的病原体。Q热在世界范围内都有发现，在低收入国家的发病率很高。这个VLP平台投标将利用贝氏柯克斯体抗原性的专业知识来开发针对Q热的疫苗。结果表明，C.贝氏菌脂多糖（LPS）提供针对攻击的保护，表明它是关键的保护性抗原。LPS本身是T细胞非依赖性抗原;与蛋白质载体缀合可以改善抗体同种型发育并关键地刺激B细胞记忆。因此，为了提高疫苗效力和发展对柯克斯体的免疫记忆，我们提出缀合天然C。贝氏菌LPS或其合成片段与VLP载体的结合。与此同时，我们将表达先前确定的C。本发明提供了用于在VLP上制备贝氏体蛋白表面抗原的方法，其提供了用于与LPS-VLP缀合物潜在共混以产生多抗原疫苗的材料。本研究中产生的新型VLP疫苗将在我们建立的C.贝氏气雾剂感染;将确定免疫应答并将其与疫苗效力相关。几种VLP疫苗已经被许可用于人类使用，证明了一条成熟的上市途径。在没有高水平控制的情况下生产疫苗的机会将导致廉价的疫苗，其中生产可以转移到低收入环境。这将为今后开发针对其他全球重要病原体的低成本疫苗铺平道路。