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: 9241953
• 负责人: Rhoel David Ramos Dinglasan
• 金额: $ 30.67万
• 依托单位: UNIVERSITY OF FLORIDA
• 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 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241953
• 关键词: Adjuvant; Africa South of the Sahara; African; Agonist; Animal Model; Anopheles gambiae; Antibodies; Antibody Response; Antibody titer measurement; 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; Exhibits; Formulation; Funding; Glycolic-Lactic Acid Polyester; Goals; Helper-Inducer T-Lymphocyte; Human; Hybrids; Immune response; Immune system; Immunization; Immunize; Immunologics; 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; 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; public health relevance; 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颗粒技术可能会提供安全的协同方法，用于单个配方中对人免疫系统的疫苗抗原的多模式呈现。我们的提案线束（1）类似病毒样纳米颗粒获得强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“自然”增强平台的效率，（3）（3）将免疫抗速托的能力促进了下一代杀伤型杀伤力的能力。 TBV被认为是消除和消除疟疾的全球努力中的关键工具之一，因为它们的作用是阻止抗药性和易感寄生虫从一个人到另一个人的蚊子传播。但是，TBV缺乏自然的增强，因为目标抗原本身仅存在于蚊子内，而最近实施的数学模型表明，理想的疫苗发育目标是一种能够为至少一年以上的高滴度抗体引起高滴度抗体的单一免疫方法。 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抗原允许继续增强，因此在接种的个体中引起了优势免疫反应。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，以有效递送和呈现ANAPN1抗原向LN居民DCS，然后进行ANAPN1特异性免疫反应的功能表征。然后，我们将设计DC激活纳米颗粒，以增强对共释放的ANAPN1抗原的抗体反应，然后表征纳米颗粒递送的辅助剂对功能ANAPN1特异性免疫反应的影响。最后，我们将构建一种单剂量疫苗，具有DC靶向生物降解的纳米颗粒和释放ANAPN1的微粒，并评估大型动物模型中ANAPN1特异性抗体的耐用性和传输阻滞功效。