Development of a novel vaccine to protect against Q fever epidemics

该项目的目的是研制一种新型疫苗，用于预防由伯纳氏杆菌引起的Q热。我们建议使用一种强有力的疫苗递送技术，这种技术非常适合低收入国家的疫情情况，而且从未尝试过这种疾病。Q热具有高度传染性，通常通过受感染的牲畜传染给人类。这是一个全球性的健康问题，被英国政府、疾病预防控制中心和世界卫生组织列为潜在的爆发病原体，原因如下：它会引起一系列疾病，从急性感染到可能致命的慢性感染，对怀孕尤其危险。2. 暴发期间可能需要广泛和昂贵地使用抗生素：虽然感染可能是自我限制的，但抗菌药物治疗在缩短病程和严重程度方面是有效的，但急性疾病需要治疗14天。3. 慢性Q热很难治疗，经常复发，引起严重的症状，即使治疗也可能致命。4. 症状无特异性，因此Q热难以诊断（没有可靠的诊断测试）。5. Q热在世界范围内分布，尤其影响低收入国家。报告的病例数可能被低估了。在美国，约3%的健康成年人和10-20%从事高风险职业的人受到过辐射。最近在荷兰（2007年至2010年）发生了一场大规模流行病，导致数人死亡和长期疾病。6. 这种细菌对干燥和高温具有不同寻常的抵抗力，它可以存活数年，极低的感染剂量（低至单个细菌）足以引起感染。因此，它也是一种潜在的生物武器。在澳大利亚获得许可的灭活全细胞疫苗会产生严重的不良反应，需要在接种前进行筛查，因此不适合广泛使用，特别是在低收入国家和疫情暴发时。基于佐剂中的蛋白质的传统疫苗的保护功效非常有限，可能是由于这种配方在诱导与Q热感染解决相关的细胞免疫反应方面存在弱点。在这种情况下，我们提出的解决方案是使用病毒载体作为疫苗递送平台。这项技术是基于无害的、不能复制的病毒，目前已开发用于对抗许多传染病（埃博拉病毒、疟疾、艾滋病毒……），但尚未对Q热进行研究。该技术非常适用于需要细胞免疫反应和抗体反应来保护的情况，因为它可以在非常高的水平上诱导细胞免疫反应和抗体反应。这项技术适用于低收入国家的疫情：为最近的埃博拉疫情开发的所有疫苗都是基于病毒载体。重要的是，这项技术完全适合于Q热疫苗抗原选择的挑战：虽然保护性免疫反应的重点目前还在争论中，但载体技术允许在很短的时间内，直接在配方中进行多种抗原靶点和组合的配方和测试，从而可以进入临床。我们将使用已知的Q热蛋白引发免疫反应，并将其配制成临床相关的病毒疫苗载体。我们将研究新疫苗诱导的免疫反应和保护水平，并确定最有效的候选疫苗。如果成功，该项目将为在人身上测试这种新的Q热疫苗提供有力的理由。

The aim of this project is to create an innovative vaccine against Q fever, caused by the bacterium Coxiella burnetii. We propose to use a potent vaccine delivery technology, highly suited to outbreak situations in low-income countries, and never tried for this disease. Q fever is highly contagious, often transmitted to humans by infected livestock. It is a global health concern, classified a potential outbreak pathogens by the UK government, the CDC and WHO for several reasons: 1. It causes a range of disease from acute to potentially fatal chronic infection, and is particularly dangerous in pregnancy. 2. Extensive and costly antibiotic use may be required during outbreaks: while infections may be self-limited, antimicrobial therapy is effective in shortening illness duration and severity, but acute illness requires 14 days treatment. 3. Chronic Q fever is very difficult to treat, results in frequent relapses, causes severe symptoms and can be fatal despite treatment. 4. The symptoms are non-specific and thus Q fever is difficult to diagnose (there is no reliable diagnostic test). 5. Q fever has a worldwide distribution, particularly affecting low-income countries. The number of reported cases is likely an underestimation. In the US, around 3% of healthy adults, 10-20% of persons in high-risk occupations have been exposed. A large epidemic occurred recently in the Netherlands (2007 to 2010) that led to several deaths and long-term illnesses. 6. The bacterium is unusually resistant to drying and to heat, it can survive for years, and extremely low infectious doses (down to a single bacterium) are sufficient to cause infection. It is therefore also a potential bioweapon. The inactivated whole cell vaccine licenced in Australia induces severe adverse effects, requires pre-vaccination screening and thus is not suitable for extensive use, particularly in low-income countries and for outbreaks. The protective efficacy of conventional vaccines based on proteins in adjuvant is very limited, likely due to the weakness of this formulation in inducing the cellular immune responses that have been linked to resolution of Q fever infection. In this context, our proposed solution is to use viral vectors as a vaccine delivery platform. This technology is based on harmless replication-incompetent viruses, currently developed against numerous infectious diseases (Ebola, malaria, HIV…), but not yet investigated for Q fever. This technology is highly suitable when cellular immune responses are required for protection in addition to antibody responses, as it can induce both at remarkably high levels. This technology is suited to outbreaks in low-income countries: all vaccines developed for the recent Ebola outbreak were based on viral vectors. Importantly, this technology is perfectly suited to the challenge of antigen selection for Q fever vaccines: while the focus of the protective immune response is currently debated, the vectored technology allows the formulation and testing of multiple antigen targets and combinations, in a very short time frame, directly in the formulation that can progress to clinic. We will use Q fever proteins known to elicit immune responses and formulate them into our clinically relevant viral vaccine vectors. We will investigate the immune responses and levels of protection induced by the novel vaccines, and identify the most potent candidate. If successful, this project will provide a strong case for testing of this new Q fever vaccine in people.