Accelerated development of a safe and easily manufactured Q fever vaccine

Q热是由革兰氏阴性杆菌贝氏柯克斯体（Coxiellaburnetii）引起的一种重要的高度传染性疾病，在世界范围内影响牲畜和人类。人类的感染发生在暴露于少至1-10个细菌后，可导致急性和慢性疾病。感染可导致死亡，尤其是老年人或免疫功能低下者。牲畜，特别是绵羊和山羊，是人类感染的主要来源，感染可导致流产、死产和分娩虚弱的后代。羔羊和儿童的损失可能对欧洲和LMIC国家的农民生计造成毁灭性的经济损失，特别是在堕胎风暴期间，损失可能高达35%。疫苗被认为是目前控制Q热最有效的方法，基于灭活C. Burnetii生物体可商购用于反刍动物和人类。然而，这些疫苗的安全性是一个主要问题，考虑到在先前暴露于细菌的人类中接种后发生严重的局部和全身反应，并且反刍动物的接种与显著的产量损失相关。此外，这些疫苗的制造涉及生物体的培养，这具有成本和安全性问题。这些问题导致这些疫苗的使用有限。因此，迫切需要开发安全、有效和易于制造的疫苗来控制人和家畜的Q热。Burnettii蛋白质，其生产更安全，并且可以工程化以在接种后诱导更少的副作用。然而，目前的亚单位疫苗的发展受到严重阻碍，缺乏知识的适当的细菌蛋白质的目标。在这个项目中，我们将使用新的肽芯片技术来确定关键的C。本发明的目的是以高通量和详细的方式，通过来自接种了当前保护性但不安全的商业疫苗的绵羊和山羊的抗体识别贝氏体蛋白。将这些抗体应答与非保护性C.贝氏体疫苗，其基于细菌的不同（无毒）形式。通过比较来自保护性和非保护性疫苗的抗体应答，将鉴定保护性疫苗特异性靶向的细菌蛋白。然后将生成这些蛋白质的合成版本，并在绵羊攻击模型中测试基于这些蛋白质库的亚单位疫苗。这将提供初步的安全性和有效性数据，为未来的Q热疫苗开发计划提供信息。

Q fever is an important and highly contagious disease of worldwide importance affecting both livestock and humans caused by the intracellular Gram-negative bacterium, Coxiella burnetii. Infection of humans occurs following exposure to as few as 1-10 bacteria and can result in both acute and chronic forms of disease. Infections can result in death, especially in the elderly or immunocompromised. Livestock, in particular sheep and goats, are the major source of human infections where infection can cause abortion, stillbirth and delivery of weak offspring. The loss of lambs and kids can result in devastating economic losses to the livelihoods of farmers in Europe as well as LMIC countries, particularly during abortion storms where up to 35% losses can occur. Vaccines are currently considered the most effective way to control Q fever, and vaccines based on inactivated C. burnetii organisms are commercially available for use in both ruminants and humans. However, the safety of these vaccines is a major issue considering that severe local and systemic reactions occur post-vaccination in humans previously exposed to the bacteria and vaccination of ruminants is associated with significant production losses. Furthermore, manufacture of these vaccines involves culture of the organisms, which has both cost and safety issues. These issues have resulted in limited use of these vaccines. There is therefore an urgent need to develop safe, effective and easily manufactured vaccines to control Q fever in both humans and livestock species.To this end, attempts have been made to develop subunit vaccines targeting key C. burnettii proteins which would be safer to manufacture and could be engineered to induce fewer side effects following vaccination. However, current approaches to subunit vaccine development have been severely hampered by a lack of knowledge of the appropriate bacterial proteins to target.In this project, we will use novel peptide chip array technology to identify the key C. burnetii proteins recognised by antibodies from sheep and goats vaccinated with the current protective, but unsafe commercial vaccine in a high throughput and detailed manner. These antibody responses will be compared with those generated by a non-protective C. burnetii vaccine which is based on a different (non-virulent) form of the bacteria. By comparing antibody responses from protected and non-protective vaccines, bacterial proteins which are specifically targeted by the protective vaccine will be identified. Synthetic versions of these proteins will then be generated and subunit vaccines based on pools of these proteins will be tested in a sheep challenge model. This will provide preliminary safety and efficacy data to inform future Q fever vaccine development programmes.