Engineering Monodisperse Particulate Vaccines to Tailor Immunological Responses

该项目专注于开发一种独特的符合GMP的颗粒成型技术，我们首创的称为Print�(非湿润模板中的颗粒复制)，作为针对流感和登革热病毒的颗粒多价疫苗的输送平台。Print提供对颗粒大小、形状和化学成分的完全控制，并使系统地调整抗原与颗粒的接近程度、抗原密度以及颗粒大小和形状，以筛选和识别最佳颗粒参数，以引起增强的免疫反应。向下选择的颗粒参数将为制造流感和登革热颗粒多价疫苗提供设计规则，以调查对每个抗原产生完整和强大的中和抗体反应的能力。此外，我们计划内的其他项目将利用这些多价颗粒疫苗来解决使用新型佐剂来调节免疫反应的问题。这些颗粒疫苗将在人源化的小鼠模型中进行评估，以确定如何预防同型或所有4种登革热病毒血清型的感染。我们将结合每个项目的经验教训，扩大最有希望的多价颗粒疫苗，并将这些疫苗推进到针对流感和登革热的大型动物挑战研究中。由于对流感和登革热多价疫苗的迫切医疗需求，以及我们的颗粒成型技术符合cGMP的性质，这些配方可以推进到产品开发中，用于人体试验。

This project is focused on the development of a unique GMP-compliant particle molding technology that we have pioneered called PRINT� (Particle Replication in non-wetting templates) as a delivery platform for particulate multivalent vaccines targeting influenza and Dengue viruses. PRINT provides complete control over particle size, shape and chemical composition, and enables the systematic tailoring of antigen proximity to the particle, antigen density and particle size and shape to screen and identify the optimal particle parameters to elicit enhanced immunological responses. The down-selected particle parameters will provide design rules to manufacture influenza and dengue particulate multivalent vaccines to investigate the ability to generate a complete and robust neutralizing antibody response to each antigen. Also, additional Projects within our Program will utilize these multivalent particulate vaccines to address the use of novel adjuvants to modulate the immune response. These particulate vaccines will be evaluated in a humanized mouse model to determine how to prevent infection of homotypic or all 4 dengue virus serotypes. We will combine the learning from each Project to scale-up the most promising multivalent particulate vaccines and advance these to large animal challenge studies for both influenza and dengue. Due to the immediate medical need for multivalent vaccines for influenza and dengue and the cGMP-compliant nature of our particle molding technology, the formulations can be advanced into product development for human trials.