A biodegradable nano-microparticle prime-boost vaccine strategy

描述(由申请人提供)：可生物降解的纳米和微粒子技术可以提供安全、协同的方法，以单一配方将疫苗抗原以多种模式呈现给人类免疫系统。我们的建议利用(1)类似病毒的纳米颗粒实现强大的启动免疫反应的能力，(2)可生物降解的微粒作为缓慢释放的“天然”增强平台的效率，以及(3)将免疫刺激激动剂共同输送到单一平台中以开发下一代疟疾传播阻断疫苗(TBV)的能力。TBV被认为是消除和根除疟疾的全球努力的关键工具之一，因为它们的功能是阻止蚊子将抗药性和易感寄生虫从一个人传播到另一个人。然而，由于目标抗原本身只存在于蚊子体内，TBV缺乏自然增强作用，最近用于实施的数学模型表明，理想的疫苗开发目标是能够在至少一年以上，但最好是更长时间内产生高滴度抗体的单一免疫方法。为了规避这些TBV以及一般疫苗开发方面的担忧，我们建议设计一种“混合模式”纳米/微粒递送系统，该系统利用不同属性的淋巴(LN)靶向生物可降解纳米粒，将TBV抗原AnAPN1有效地呈现给树突状细胞(DC)和可生物降解微粒，以持续释放AnAPN1抗原，从而在接种疫苗的个体中诱导更好的免疫反应。在啮齿动物模型的初步研究中，我们将开发尺寸可控的可生物降解的LN靶向纳米颗粒，以有效地将AnAPN1抗原递送到LN驻留的DC，随后将对AnAPN1特异性免疫反应进行功能表征。然后，我们将设计DC激活纳米颗粒来增强对共同传递的AnAPN1抗原的抗体反应，然后表征纳米颗粒传递的佐剂对功能性AnAPN1特异性免疫反应的影响。最后，我们将构建一种以DC为靶向的可生物降解纳米颗粒和AnAPN1释放微粒的单剂疫苗，并在大型动物模型中评估AnAPN1特异性抗体的持久性和传播阻断效果。

DESCRIPTION (provided by applicant): Biodegradable nano- and microparticle technologies may offer safe, synergistic approaches for the multi-mode presentation of a vaccine antigen to the human immune system in a single formulation. Our proposal harnesses (1) the ability of virus-like nanoparticles to achieve a strong priming immune response, (2) the efficiency of biodegradable microparticles as slow-release "natural" boosting platforms, and (3) the capability of co-delivery of immunostimulatory agonists into a single platform for the development of the next generation of malaria transmission-blocking vaccines (TBVs). TBVs are considered one of the critical tools in the global effort to eliminate and eradicate malaria, since they function to block mosquito transmission of both drug- resistant and susceptible parasites from one individual to another. However, TBVs suffer from the lack of natural boosting, as the target antigens themselves are only present inside the mosquito, and the recent mathematical models for implementation suggest that the ideal vaccine development goal is a single immunization approach that is capable of eliciting high titer antibodies for over at least one year, but preferably more. To circumvent these TBV as well as general vaccine development concerns, we propose to engineer a "mixed mode" nano-/microparticle delivery system that leverages different attributes of lymph node (LN)- targeting biodegradable nanoparticles for effective presentation of the TBV antigen, AnAPN1, to dendritic cells (DC) and biodegradable microparticles for sustained release of AnAPN1 antigen to permit continued boosting, therefore inducing a superior immune response in the vaccinated individual. For our initial studies in a rodent model, we will develop size-controlled biodegradable LN-targeting nanoparticles for effective delivery and presentation of the AnAPN1 antigen to LN-resident DCs, followed by functional characterization of the AnAPN1-specific immune response. We will then engineer DC-activating nanoparticles to potentiate the antibody response to co-delivered AnAPN1 antigen followed by characterization of the effect of nanoparticle- delivered adjuvant on the functional AnAPN1-specific immune response. Lastly, we will construct a single-dose vaccine with DC-targeting biodegradable nanoparticles and AnAPN1-releasing microparticles and assess the durability and transmission-blocking efficacy of AnAPN1-specific antibodies in a large animal model.