DEVELOPMENT OF A LIPOSOMAL PNEUMOCOCCAL VACCINE FOR CLINICAL READINESS

项目总结 肺炎链球菌从携带者转变为疾病所引起的疾病导致 在美国，成人的死亡率约为3%-10%，老年患者的死亡率约为12%-25%。 此外，肺炎球菌病肆虐资源贫乏的国家，估计造成476,000人死亡。 每年死于肺炎球菌感染的人(约占以下儿童疫苗可预防死亡的32% 五岁)。最有效的疫苗，多糖蛋白结合物，需要一个复杂的过程 从肺炎球菌血清型收集多糖抗原，并将其连接到蛋白质佐剂。 Abcomi Biosciences公司已经开发出一种肺炎球菌疫苗，该疫苗使用脂质体包裹 多糖(LEPs)对70+血清型的链球菌表现出结合样的药效。 通过动物激发模型和吞噬细胞活性(OPA)检测肺炎。自从收到我们的前科 第一阶段SBIR奖，Abcomi Biosciences已经完成了所有拟议的里程碑，以解决人们的担忧 关于与LEPS疫苗配方相关的潜在负面副作用的风险。 这项工作的完成导致了第二代LEPS疫苗的开发。随函附上的 直接第二阶段SBIR提案概述了达到下一项主要目标所需的剩余临床前研究 里程碑，IND前与FDA的会议。这些研究的完成将有助于解决 FDA在疫苗制造和表征(即化学)方面的重要考虑 制造和控制(CMC)和疗效(即动物法则)。简而言之，这些研究将涉及 完成以下关键开发步骤：1)优化我们面向所有人的封装流程 肺炎球菌荚膜多糖(CPSS)，2)确定多糖量，3)评估 疫苗的稳定性，以及4)在小鼠和兔子身上的重复剂量毒理学研究。优化我们的 通过系统地改变我们的工艺条件，将实现多糖包埋过程 所有24种多糖，以确保每个抗原的有效和一致的包裹体。vt.在.的基础上 优化这一过程，然后我们将通过测定抗体来确定多糖的最佳剂量 效价和OPA检测性能，以确定每种多糖足够的剂量 免疫原性。然后，我们将通过评估蛋白质pH和温度来表征LEPS疫苗的稳定性 储存超过12个月时的稳定性以及脂质体的完整性。最后，我们将评估 该疫苗在小鼠和兔子身上进行了重复剂量的毒性研究。在整个过程中， 研究中，将采集血清以评估器官毒性并量化抗体效价。此外，尸检结果显示 将提取组织样本以可视化组织病理学。这项工作的圆满完成将 为我们的候选疫苗与FDA举行IND前会议做好准备，并确保平稳过渡到 临床试验。

PROJECT SUMMARY The illnesses caused by Streptococcus pneumoniae’s transition from carriage to disease result in a mortality rate between approximately 3-10% in adults and 12-25% in elderly patients in the United States. Furthermore, pneumococcal disease devastates resource-poor countries, causing an estimated 476,000 people to succumb to pneumococcal infection annually (~32% of vaccine-preventable deaths in children below age five). The most effective vaccines, polysaccharide protein conjugates, require a complicated process of collecting polysaccharide antigens from pneumococci serotypes and conjugating them to a protein adjuvant. Abcombi Biosciences has developed a pneumococcal vaccine using liposomal encapsulation of polysaccharides (LEPS), which has demonstrated conjugate-like efficacy against 70+ serotypes of S. pneumoniae via animal challenge models and opsonophagocytosis activity (OPA). Since receiving our prior Phase I SBIR award, Abcombi Biosciences has completed all proposed milestones to address concerns regarding the risk for potential negative side effects associated with the LEPS vaccine’s formulation. Completion of this work has led to the development of a second generation LEPS vaccine. The enclosed Direct Phase II SBIR proposal outlines the remaining preclinical studies necessary to reach our next major milestone, a pre-IND meeting with the FDA. The completion of these studies will serve to address important considerations of the FDA regarding vaccine manufacturing and characterization (i.e., chemistry manufacturing and controls, CMC) and efficacy (i.e., the animal rule). Briefly, these studies will involve the completion the following key developmental steps: 1) optimization of our encapsulation process for all pneumococcal capsular polysaccharides (CPSs), 2) finalization of polysaccharide dosage, 3) evaluation of vaccine stability, and 4) a repeated-dose toxicology study in mice and rabbits. Optimization of our polysaccharide encapsulation process will be achieved by systematically varying our process conditions across all 24 polysaccharides to ensure efficient and consistent encapsulation for each antigen. Upon optimizing this process, we will then identify the optimal dosage of polysaccharide by measuring antibody titers and OPA assay performance to determine the dosage of each polysaccharide required for sufficient immunogenicity. We will then characterize the LEPS vaccine stability by evaluating protein pH and thermal stability as well as the integrity of the liposomes when stored over 12 months. Lastly, we will evaluate the vaccine for toxicity in a repeated dose study in mice and rabbits. Throughout the duration of this study, serum will be collected to evaluate organ toxicity and quantify antibody titers. In addition, post-mortem tissue samples will be extracted to visualize histopathology. Successful completion of this work will prepare our vaccine candidate for a pre-IND meeting with the FDA and ensure a smooth transition into clinical trials.