NEXT GENERATION VACCINES AGAINST GASTROINTESTINAL MUCOSAL PATHOGENS, USING HELICOBACTER PYLORI AS MODEL PATHOGEN

为了克服危及全球公共卫生的抗菌素耐药性（AMR），需要开发针对AMR病原体的下一代疫苗的新战略。然而，对于发生在粘膜部位，特别是胃肠道的细菌感染，开发有效的疫苗是具有挑战性的。在这种背景下，幽门螺杆菌被列为高度优先的AMR病原体和最常见的慢性细菌感染，影响世界上一半的人口，具有发展为胃癌的高风险。先前幽门螺杆菌疫苗开发方法的失败表明，需要诱导粘膜免疫来提供保护。因此，Vax2Muc将以直接的方式开发一种合理的预防幽门螺杆菌的先导候选物，并在I期临床试验中直接评估该候选物的安全性和免疫原性，作为Vax2Muc开发的新疫苗技术的概念证明。为了诱导由组织常驻记忆T细胞维持的长期保护性粘膜免疫反应，我们将使用我们之前鉴定的疫苗抗原，结合强效佐剂进行系统启动，并在创新的口腔粘膜膜中实施粘膜牵拉。Vax2Muc将进一步推进GMP生产，并研究和推进针对粘膜应用的新型疫苗技术和策略。我们将在临床前小鼠和猪模型中评估我们的主要候选方法和替代方法，以确定大多数胃肠道/ AMR感染仍然缺乏的免疫和保护的有意义的相关性。因此，Vax2Muc将提供(i)一种针对幽门螺杆菌作为PoC的预防性候选疫苗，（ii）丰富的知识和技术可转化为临床开发管道，广泛适用于各种GI/AMR粘膜病原体，从而显著造福具有挑战性的粘膜疫苗接种领域，最终减轻AMR/GI疾病的疾病负担。

To overcome antimicrobial resistance (AMR) compromising global public health, novel strategies to develop next generation vaccines against AMR pathogens are required. However, the development of effective vaccines is challenging for bacterial infections occurring at mucosal sites, in particular in the gastrointestinal (GI) tract. In this context, H. pylori is listed as high priority AMR pathogen and the most common chronic bacterial infection affecting half of the world’s population with a high risk to progress into gastric cancer. Previous failures in H. pylori vaccine development approaches suggest that induction of mucosal immunity is required for protection. Thus, Vax2Muc will develop a rational prophylactic lead candidate against H. pylori in a straight-forward manner and directly evaluate this candidate for safety and immunogenicity in a phase I clinical trial, serving as proof-of-concept for novel vaccine technologies developed in Vax2Muc. To induce long-term protective mucosal immune responses sustained by tissue resident memory T cells, we will apply our previously identified vaccine antigens, combined with potent adjuvants for a systemic prime, and implemented in an innovative oro-mucosal film for a mucosal pull. Vax2Muc will further advance GMP manufacturing, and investigate and progress novel vaccine technologies and strategies tailored for mucosal application. We will evaluate our lead candidate and alternative approaches in pre-clinical mouse and pig models to define meaningful correlates of immunity and protection, which are still lacking for most of GI/ AMR infections. Thus, Vax2Muc will deliver (i) a prophylactic vaccine candidate against H. pylori as PoC, and (ii) a wealth of knowledge and technologies that can be translated into the clinical development pipeline and are broadly applicable for various GI/AMR mucosal pathogens to significantly benefit the challenging field of mucosal vaccination and finally reduce disease burden from AMR/GI diseases.