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，我们率先将其称为PRINT？（非润湿模板中的颗粒复制），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提供了对颗粒尺寸、形状和化学组成的完全控制，并能够系统地定制抗原与颗粒的接近度、抗原密度以及颗粒尺寸和形状，以筛选和鉴定最佳颗粒参数，从而引发增强的免疫应答。向下选择的颗粒参数将提供设计规则来制造流感和登革热颗粒多价疫苗，以研究对每种抗原产生完整和稳健的中和抗体应答的能力。此外，我们计划中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调节免疫应答的问题。将在人源化小鼠模型中评价这些颗粒疫苗，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。我们将联合收割机从每个项目中学习，以扩大最有前途的多价颗粒疫苗的规模，并将其推进到流感和登革热的大型动物攻毒研究中。由于对流感和登革热多价疫苗的迫切医疗需求以及我们颗粒成型技术的cGMP合规性，这些制剂可以进入人体试验的产品开发阶段。

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.