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

病毒样颗粒（vlp）是一种灵活的递送平台，提供了同时向免疫系统呈递多种抗原的潜力。乙型肝炎核心抗原在相对低成本的酵母表达系统中自我组装形成高度稳定的免疫原性VLPs。病毒蛋白可以适应在从VLPs表面突出的刺突上显示外来抗原。该技术规避了对高成本、高密封生产设施、冷运输和储存的需求。我们的目标是利用VLP技术作为生产平台，生产一种具有成本效益的第二代Q热疫苗。在最初的概念验证研究中，Mologic-Dstl-Iceni Diagnostics联盟已经成功地生产并测试了假马氏伯克氏菌候选疫苗，该疫苗基于酵母生产的VLPs，呈现肽或多糖抗原。这些候选药物在类鼻疽小鼠模型中有效，表明该技术已准备好用于抗菌疫苗的生产。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热的病原体伯纳蒂克希菌，该病原体被世界卫生组织和联合国列为关注的病原体。Q热在全世界都有，在低收入国家发病率很高。此次VLP平台竞标将利用伯纳氏杆菌抗原性方面的专业知识开发针对Q热的疫苗。有研究表明，伯氏C. burnetii脂多糖（LPS）具有抗攻击的保护作用，是一种重要的保护性抗原。LPS本身是一种与t细胞无关的抗原；结合到蛋白质载体上可以改善抗体同型的发展，关键是刺激B细胞记忆。因此，为了提高疫苗的效力和培养对克氏菌的免疫记忆，我们建议将天然伯氏炭疽杆菌LPS或其合成片段偶联到VLP载体上。同时，我们将在vlp上表达先前鉴定的伯纳蒂氏菌蛋白表面抗原，为与LPS-VLP偶联物混合生产多抗原疫苗提供材料。本研究生产的新型VLP疫苗将在我们建立的伯纳蒂胞杆菌气溶胶感染小鼠模型中进行测试；免疫反应将被确定并与疫苗效力相关。几种VLP疫苗已经获准用于人类，这表明了一条既定的上市途径。在没有高水平控制的情况下生产的机会将导致廉价疫苗的生产，从而可以将生产转移到低收入国家。这将有助于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。

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.