A biodegradable nano-microparticle prime-boost vaccine strategy

可生物降解的纳米微粒初免-加强疫苗策略

• 批准号: 9042930
• 负责人: Rhoel David Ramos Dinglasan
• 金额: $ 9.79万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042930
• 关键词: Adjuvant; Africa South of the Sahara; African; Agonist; Animal Model; Anopheles gambiae; Antibodies; Antibody Response; Antigen Targeting; Antigens; Back; Beds; Blocking Antibodies; CD4 Positive T Lymphocytes; Child; Communicable Diseases; Consensus; Country; Culicidae; Dendritic Cells; Development; Disease; Dose; Drug resistance; Encapsulated; Engineering; Enhancing Antibodies; Exhibits; Formulation; Funding; Glycolic-Lactic Acid Polyester; Goals; Health; Helper-Inducer T-Lymphocyte; Human; Hybrids; Immune response; Immune system; Immunization; Individual; Ligands; Malaria; Malaria Vaccines; Methods; Midgut; Modeling; Mus; Ovalbumin; Parasites; Plasmodium falciparum; Polystyrenes; Preparation; Research Infrastructure; Research Personnel; Rodent; Rodent Model; Sheep; Surface; System; T-Cell Activation; Technology; Toll-like receptors; United States National Institutes of Health; Vaccinated; Vaccination; Vaccine Antigen; Vaccines; Virus-like particle; Work; base; density; ethylene glycol; follow-up; global health; improved; killings; lymph nodes; malaria transmission-blocking vaccine; mathematical model; mouse model; nano; nanoparticle; next generation; prevent; targeted delivery; tool; trafficking; transmission process; transmission-blocking vaccine; uptake; vaccine delivery; vaccine development; vaccine efficacy; vector mosquito

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.

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、协同的方法，用于在单一制剂中将疫苗抗原以多模式呈现给人类免疫系统。我们的建议利用（1）病毒样纳米粒子实现强启动免疫反应的能力，（2）可生物降解微粒作为缓释“天然”增强平台的效率，以及（3）共同传递免疫刺激激动剂整合为单一平台，用于开发下一代阻断疟疾传播的疫苗（TBV）。 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耐药性和易感性寄生虫从一个人传播到另一个人。然而，TBV 缺乏自然加强作用，因为目标抗原本身只存在于蚊子体内，而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的单一免疫方法至少一年以上，但最好更长。为了规避这些 TBV 以及一般疫苗开发问题，我们建议设计一种“混合模式”纳米/微米颗粒递送系统，该系统利用淋巴结 (LN) 的不同属性，靶向可生物降解纳米颗粒，以有效呈递 TBV 抗原 AnAPN1 ，树突状细胞（DC）和可生物降解的微粒持续释放AnAPN1抗原以允许持续加强，从而在接种疫苗的个体中诱导优异的免疫反应。对于我们在啮齿动物模型中的初步研究，我们将开发尺寸控制的可生物降解的 LN 靶向纳米颗粒，用于将 AnAPN1 抗原有效递送和呈递给 LN 驻留 DC，然后对 AnAPN1 特异性免疫反应进行功能表征。然后，我们将设计 DC 激活纳米粒子，以增强对共同递送的 AnAPN1 抗原的抗体反应，然后表征纳米粒子递送的佐剂对功能性 AnAPN1 特异性免疫反应的影响。最后，我们将使用靶向 DC 的可生物降解纳米粒子和释放 AnAPN1 的微粒构建单剂量疫苗，并在大型动物模型中评估 AnAPN1 特异性抗体的耐久性和传播阻断功效。