Development of a novel vaccine to protect against Q fever epidemics: late stage preclinical formulation and progression to clinical trial

一种预防Q热流行的新型疫苗的开发：后期临床前配方和临床试验的进展。该项目旨在通过确定保护所需的最小配方，将在批准的GMP生产设施中生产GMP前起始材料，将在Innovate UK stream 1项目期间开发的针对Q热（伯纳氏杆菌）的新型疫苗推进到临床开发。我们的新型Q热疫苗使用了一种适用于低收入国家疫情的有效疫苗递送技术。Q热是一种高度传染性的细菌性疾病，目前被英国政府、疾病预防控制中心和世界卫生组织视为全球健康问题和潜在的爆发病原体，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。2. 暴发期间可能需要广泛和昂贵的抗生素使用。3. 慢性Q热很难治疗。4. 症状无特异性，因此Q热难以诊断。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。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，特别是对预先接触的个体（一种称为致敏的现象），因此需要进行疫苗接种前筛查，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，部分原因是这种配方在诱导与Q热感染解决相关的细胞免疫反应方面存在弱点。我们的新疫苗是基于明智地使用高度免疫原性复制无能的病毒载体，能够诱导所需的t细胞反应，而没有全细胞疫苗的副作用。病毒疫苗技术目前用于开发针对埃博拉、疟疾、流感、艾滋病毒、结核病、荚膜B群脑膜炎球菌和鼠疫等几种传染病的新疫苗。它特别适用于需要细胞免疫反应来保护的疾病，比如Q热。我们已经创建了载体Q热候选疫苗，并证明单剂量注射三种或五种成分可诱导强烈的t细胞免疫反应。在小鼠模型中，三种抗原的组合能够减少Q热感染。在这个后续项目中，我们将确定负责减少感染的最小保护性抗原组成，设计和生产适合人类使用的临床相关载体。然后生产pre-GMP（良好生产规范）起始材料，为GMP生产和I期试验做好准备。我们集团在将针对细菌病原体的载体疫苗推进到GMP生产和I期试验方面具有专业知识。

Development of a novel vaccine to protect against Q fever epidemics: late stage preclinical formulation and progression to clinical trial. This project aims to progress a novel vaccine against Q fever (Coxiella burnetii), developed during an Innovate UK stream 1 project, to clinical development, by identifying the minimal formulation required for protection, and includes production of the pre-GMP starting material in an approved GMP production facility. Our novel vaccine against Q fever uses a potent vaccine delivery technology suitable for outbreak situations in low-income countries. Q fever is a highly contagious bacterial disease, currently regarded as a global health concern and 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. 2. Extensive and costly antibiotic use may be required during outbreaks. 3. Chronic Q fever is very difficult to treat. 4. The symptoms are non-specific and thus Q fever is difficult to diagnose. 5. Q fever has a worldwide distribution, particularly affecting low-income countries. The number of reported cases is likely an underestimation. 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 licensed in Australia induces severe adverse effects, particularly in pre-exposed individuals (a phenomenon known as sensitization), and thus requires pre-vaccination screening, 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, in part due to the weakness of this formulation in inducing the cellular immune responses that have been linked to resolution of Q fever infection. Our novel vaccine is based on the judicious use of a highly immunogenic replication-incompetent viral vector, able to induce the desired T-cell responses without the side effects of the whole cell vaccine. The viral vaccine technology is currently used for developing new vaccines against several infectious diseases such as Ebola, malaria, influenza, HIV, TB, capsular group B meningococcus and plague. It is particularly suitable for diseases for which cellular immune responses are required for protection, as is the case for Q fever. We have created vectored Q fever vaccine candidates, and demonstrated that a single dose injection of three or five components induces strong T-cell immune responses. A combination of three antigens was able to reduce Q fever infection in a mouse model. In this follow on project, we will identify the minimal protective antigen composition responsible for the reduction of infection, design and produce the clinically relevant vector suitable for human use. The pre-GMP (good manufacturing practice) starting material will then be produced, ready for GMP production and phase I trial. Our group has expertise in progressing vectored based vaccines against bacterial pathogens to GMP production and phase I trial.