Rapid, simple manufacture and clinical evaluation of an oral plague vaccine

正如最近的疾病爆发所表明的那样，世界需要更快、更好地开发、制造、测试和分发疫苗。Prokarium是一家总部位于英国的疫苗开发公司，专注于口服疫苗，与大多数注射疫苗相比，它可以更快地从工作台转移到临床6-12个月，使用相同的制造工艺生产各种疫苗，将成本削减高达70%，并在非常简单的门诊条件下对其口服疫苗进行临床测试。在包括101名儿童在内的471名志愿者进行的10项1期和2期临床试验中，普罗卡利姆的输送菌株已经建立了良好的安全性记录。在这个项目中，Prokaurum将对其下一代疫苗平台“Vaxonella”进行临床试验，该平台商业化后，可以在高达40摄氏度的温度下分发至少12周，在紧急情况下可以自我管理，而不需要医务人员。这些是对抗严重疾病和潜在流行病所需的疫苗特性，例如由鼠疫耶尔森氏菌引起的鼠疫。从历史上看，鼠疫是几次流行病的罪魁祸首，包括中世纪晚期导致欧洲5000多万人死亡的黑死病。今天，鼠疫仍在夺去人们的生命，近年来，鼠疫流行的国家数量增加，导致世界卫生组织将其列为一种新出现的疾病。再加上未来出现具有抗药性的鼠疫杆菌菌株的风险，以及它作为气雾剂传播的生物恐怖主义武器的潜力，有必要开发一种有效的疫苗。理想的鼠疫疫苗必须设计用于低收入和中等收入国家，以免疫高危人群(如马达加斯加、刚果民主共和国等)。在季节性的基础上，当水库人口受到干扰时，迅速分发，以应对洪水或地震等重大干扰造成的疫情。Prokum的Vaxonella平台是基于活的沙门氏菌菌株，沙门氏菌被削弱，因此不会导致疾病。沙门氏菌是以胶囊或液体再悬浮的形式口服给儿童的，它们通过胃进入小肠，在那里它们积极地通过肠道衬里进入免疫系统的抗原呈递细胞。这个项目中使用的沙门氏菌已经被编程为在人体自身的免疫细胞内表达两种来自鼠疫杆菌的蛋白质抗原。这种有针对性的疫苗接种意味着所有免疫武器都被触发，包括第一道防线，即粘膜免疫。此外，由于消除了注射剂所需的昂贵纯化，制造成本降低了高达70%。普罗卡坎已经成功地在老鼠身上测试了一种鼠疫疫苗。现在，它将确认一种改进的疫苗可以保护小鼠免受鼠疫杆菌的攻击，然后快速制造液体悬浮液，然后在临床试验中在人类志愿者身上进行测试，在那里将测量安全性和免疫反应。这将为鼠疫疫苗的进一步开发提供信息，至关重要的是，它将成为下一代瓦克森氏菌平台的第一个概念证明，该平台可能改变疫苗的开发、制造和分销方式。

As recent disease outbreaks show, the world needs to be faster and better at developing, manufacturing, testing and distributing vaccines. Prokarium, a UK-based vaccine development company focusing on oral vaccines, can move from bench to clinic 6-12 months faster compared to most injectable vaccines, use the same manufacturing process to produce a wide range of vaccines, cut costs by up to 70% and clinically test its oral vaccines under very simple out-patient conditions. Prokarium’s delivery strain has established a strong safety record in 10 phase 1 and 2 clinical trials in 471 volunteers including 101 children. In this project Prokarium will clinically trial its next generation vaccine platform ‘Vaxonella’, which when commercialised can be distributed at temperatures of up to 40 C for at least 12 weeks and which in emergencies can be self-administered without the need for medical personnel. These are the vaccine characteristics needed to combat serious diseases and potential epidemics such as plague caused by the bacterium Yersinia pestis. Historically plague was responsible for several epidemics, including the Black Death, which killed over 50 million people in Europe in the late medieval period. Today plague still kills people and in recent years the number of countries where plague is endemic increased, resulting in the World Health Organization labelling it a re-emerging disease. Coupled with the risk of future antibiotic resistant strains of Y. pestis arising, and its potential as an aerosol-delivered bioterrorism weapon, there is a need to develop an effective vaccine. An ideal plague vaccine must be designed for use in low- and medium-income countries to immunise high risk populations (e.g. Madagascar, DRC, etc.) on a seasonal basis and to rapidly distribute in response to an outbreak caused by major disturbances such as floods or earthquakes when the reservoir populations are disturbed. Prokarium’s Vaxonella platform is based on live strains of Salmonella bacteria which are weakened so that they cannot cause disease. The Salmonella are taken orally as a capsule or liquid resuspension for children, they transit the stomach into the small intestine where they actively enter through the gut lining into the antigen-presenting cells of the immune system. The Salmonella to be used in this project have been programmed to express two protein antigens from Y. pestis from within the body’s own immune cells. This targeted vaccination means all arms of immunity are triggered including the first line of defence, namely mucosal immunity. Also, manufacturing is up to 70% cheaper because costly purification needed for injectables is eliminated. Prokarium has already successfully tested a plague vaccine in mice. Now it will confirm that an improved vaccine can protect mice against Y. pestis, then rapidly manufacture a liquid suspension, and then test it on human volunteers in a clinical trial, where the safety and immune response will be measured. This will provide information to support further development of the plague vaccine and crucially be the first proof of concept of the next generation Vaxonella platform that could transform the way vaccines are developed, manufactured and distributed.