Clinical development of a new vaccine for rapid response against Plague: GMP

该项目旨在将在Innovate UK Stream 1项目期间开发的新型鼠疫疫苗（鼠疫耶尔森菌）进展到临床开发，包括在批准的设施中生产用于人类的疫苗和I期临床试验。该试验将确定新疫苗在健康成年志愿者中的安全性，并允许量化和表征其在人体中的免疫原性。我们的新型鼠疫疫苗使用了一种有效的疫苗输送技术，适用于低收入国家的疫情。鼠疫是一种高度传染性和致命性的传染病：自20世纪90年代以来，人类鼠疫病例在25个国家增加，现在鼠疫被列为重新出现的传染病，原因如下：1.在非洲、亚洲和美洲有大型水库，2.其在全世界的地方性导致零星感染和爆发（包括最近在21世纪世纪的流行），3.除非在症状出现后24小时内开始肺鼠疫的抗生素治疗，否则死亡率为100%。由于其极强的毒性和易于传播（通过气溶胶），其作为生物武器的潜在用途;抗药性菌株的出现针对鼠疫的疫苗开发工作主要是使用减毒活疫苗和亚单位蛋白。减毒活疫苗带来了重大的安全问题，对所达到的保护水平存在分歧。佐剂中的亚单位蛋白质在动物模型中已证明具有一定程度的保护作用，但免疫应答似乎仅限于抗体，而细胞应答与增加的功效相关。我们的新型疫苗是基于一种无害的复制能力低下的病毒，通常是上呼吸道感染的原因，但通过基因改造变得无害。该疫苗技术具有高度免疫原性，目前用于开发针对几种传染病如埃博拉病毒、疟疾、流感、HIV、TB和荚膜B群脑膜炎球菌的新疫苗。除了鼠疫等抗体反应外，它还适用于需要细胞免疫反应来保护的疾病。此外，它也适合低收入国家的疫情，因为它在单次注射后引起快速反应。对于最近的埃博拉疫情，所有在实地评估的疫苗都是基于病毒载体。我们已经创造了一种载体鼠疫疫苗，它表达了已知能引发保护性免疫反应的蛋白质。我们已经证明，单剂量疫苗诱导所需的免疫应答，其水平与两次注射高剂量佐剂化亚单位蛋白基疫苗诱导的应答相匹配。在该项目中，疫苗将按照良好生产规范（GMP条件）生产，并将在首次人体I期临床试验中进行测试。我们的团队在将针对细菌病原体的基于载体的疫苗进展到GMP生产和I期试验方面具有专业知识。我们将评估疫苗组合物在健康成人志愿者中的安全性，研究在人体中诱导的免疫应答，测量抗体诱导的保护水平，并确定用于成人的最佳剂量。如果成功，该项目将为在第二阶段开发中推进这种新的鼠疫疫苗提供强有力的案例。

This project aims to progress a novel vaccine against plague (Yersinia pestis), developed during a Innovate UK stream 1 project, to clinical development, including production of the vaccine in an approved facility for use in humans and a phase I clinical trial. The trial will determine the new vaccine’s safety in healthy adult volunteers, and also allow the quantification and characterization of its immunogenicity in humans. Our novel vaccine against plague uses a potent vaccine delivery technology suitable for outbreak situations in low-income countries. Plague is a highly contagious and virulent infectious disease: Since the 1990s, the number of human plague cases has increased in 25 countries, and plague is now classified as a re-emerging infectious disease for the following reasons: 1. there are large reservoirs in Africa, Asia and the Americas, 2. its endemicity throughout the world results in sporadic infections and outbreaks (including recent epidemic in the 21st century), 3. There is 100% mortality unless antibiotic treatment of pneumonic plague is commenced within 24 h after the onset of symptoms, 4. its potential use as a bioweapon due to its extreme virulence and ease of spread (through aerosol), and 5. the emergence of antibiotic-resistance strains. Vaccine development efforts against plague have been dominated by the use of live attenuated vaccines and sub-unit proteins. Live attenuated vaccines pose significant safety concerns and there is disagreement over the level of protection achieved. Sub-unit proteins in adjuvant have demonstrated a certain degree of protection in animal models, but the immune response seems limited to antibodies, while a cellular response correlates with increased efficacy. Our novel vaccine is based on a harmless replication-incompetent virus, usually responsible for upper respiratory tract infections, but rendered harmless by genetic modification. This vaccine technology is highly immunogenic, currently used for developing new vaccines against several infectious diseases such as Ebola, malaria, influenza, HIV, TB and capsular group B meningococcus. It is also suitable for diseases for which cellular immune responses are required for protection, in addition to antibody responses as is the case for plague. Moreover it is also suited to outbreak situation in low-income countries, as it induces rapid response after a single injection. For the recent Ebola outbreak, all vaccines evaluated in the field were based on viral vectors. We have created a vectored plague vaccine that expresses proteins known to elicit protective immune responses. We have demonstrated that a single dose vaccine induces the desired immune response, with levels matching the responses induced by two injections of a high-dose adjuvanted sub-unit protein-based vaccines. In this project, the vaccine will be produced to good manufacturing practice (GMP conditions), and will be tested in a first-in-man phase I clinical trial. Our group has expertise in progressing vectored based vaccines against bacterial pathogens to GMP production and phase I trial. We will assess the safety of the vaccine composition in healthy adult volunteers, investigate the immune responses induced in humans, measure the level of protection induced by the antibodies, and identify the optimal dose to be used in adults. If successful, this project will provide a strong case for progressing this new vaccine against plague in phase II development.