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技术可以提供安全的协同方法，用于在单一制剂中将疫苗抗原多模式呈递给人类免疫系统。我们的建议利用（1）病毒样纳米颗粒实现强启动免疫应答的能力，（2）可生物降解的微粒作为缓释“天然”增强平台的效率，以及（3）将免疫刺激激动剂共递送到单一平台中用于开发下一代疟疾传播阻断疫苗（TBV）的能力。TBV被认为是全球努力消除和根除疟疾的关键工具之一，因为它们的作用是阻止蚊子将抗药性和易感性寄生虫从一个个体传播到另一个个体。然而，由于靶抗原本身仅存在于蚊子体内，因此TBV缺乏天然加强，并且最近的实施数学模型表明，理想的疫苗开发目标是能够引发高滴度抗体至少一年以上，但优选更长时间的单一免疫方法。为了规避这些TBV以及一般的疫苗开发问题，我们提出设计一种“混合模式”纳米/微粒递送系统，其利用淋巴结（LN）靶向的生物可降解纳米颗粒的不同属性将TBV抗原AnAPN 1有效呈递给树突状细胞（DC），并利用生物可降解微粒持续释放AnAPN 1抗原以允许持续加强，因此在接种个体中诱导上级免疫应答。对于我们在啮齿动物模型中的初步研究，我们将开发尺寸可控的可生物降解的LN靶向纳米颗粒，用于将AnAPN 1抗原有效递送和呈递给LN驻留的DC，然后对AnAPN 1特异性免疫应答进行功能表征。然后，我们将工程化DC活化纳米颗粒以增强对共递送的AnAPN 1抗原的抗体应答，随后表征纳米颗粒递送的佐剂对功能性AnAPN 1特异性免疫应答的影响。最后，我们将构建具有DC靶向生物可降解纳米颗粒和AnAPN 1释放微粒的单剂量疫苗，并在大型动物模型中评估AnAPN 1特异性抗体的持久性和传播阻断功效。

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.