Chemokine and antigen-carrying nanoparticle co-delivery for an oral HIV vaccine

用于口服 HIV 疫苗的趋化因子和携带抗原的纳米颗粒共同递送

• 批准号: 7497471
• 负责人: Darrell J Irvine
• 金额: $ 19.28万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-18 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497471
• 关键词: Alginates; Antibody Formation; Antigens; Area; Biodistribution; CCL20 gene; Cells; Chemotactic Factors; Data; Dendritic Cells; Dendritic cell activation; Deposition; Diffuse; Drug Delivery Systems; Drug Formulations; Encapsulated; End Point; Fluorescence; Gastrointestinal tract structure; Generations; Gut associated lymphoid tissue; HIV; HIV Antigens; HIV Envelope Protein gp120; HIV vaccine; Hydrogels; Immune response; Immunity; Immunization; In Vitro; Kinetics; Ligands; Liquid substance; Localized; Lymphoid Tissue; M cell; Measures; Microspheres; Mucosal Immunity; Mucous Membrane; Needles; Oligonucleotides; Oral; Particle Size; Phagocytosis; Proteins; Recombinants; Reporting; Research Design; Research Personnel; Route; Signal Transduction; Simulate; Small Intestines; Stomach; Structure of aggregated lymphoid follicle of small intestine; System; Testing; Time; Toll-like receptors; Vaccination; Vaccines; Virus; base; chemokine; concept; cytokine; design; extracellular; fighting; gastrointestinal; in vivo; interest; killings; migration; mucosal site; nanoparticle; oral HIV vaccine; oral immunity; oral vaccine; particle; programs; prophylactic; response; size; trafficking; transcytosis; uptake

DESCRIPTION (provided by applicant): In order to provide prophylactic protection against HIV, a successful vaccine will need to elicit mucosal immunity, in order to fight the virus at the mucosal sites that are major points of entry. Among the potential routes for vaccines to promote mucosal immunity, oral delivery is of great interest as a simple, needle-free mode of administration, but is made challenging by the need to protect vaccines during transit through the gastrointestinal tract and achieve sufficient uptake of the vaccine by the mucosal tissue. We have recently developed a polymeric vaccine system comprised of chemokines and antigen-loaded nanoparticles co-delivered within alginate hydrogel microsphere carriers. Alginate microspheres are candidate materials for oral drug delivery due to their stability at low pH, and alginate particles have previously been reported to promote mucosal immunity via oral vaccination. Thus, we propose that the alginate microsphere carriers we have developed can (1) protect antigen/co-delivered chemokine (or cytokine) during transit through the gastrointestinal (Gl) tract and (2) promote uptake by the gut-associated lymphoid tissues (GALT). Microparticles are known to be transcytosed by M cells overlying Peyer's patches, and extracellular deposition of alginate carriers in the GALT would allow for local generation of dendritic cell (DC)-attracting chemokine gradients that would draw DCs to these microdepots of antigen-loaded nanoparticles. We propose here to perform initial tests of this concept for the generation of oral vaccines that could prime mucosal immunity to HIV. The specific aims are: Aim 1: We will characterize the ability of alginate microsphere carriers prepared by different means to protect antigen delivery nanoparticles and co-delivered chemokines from simulated gastric fluid in vitro and to be taken up by gut mucosa in vivo, and characterize GALT uptake of alginate carriers as a function of particle size. Aim 2: Using optimal carrier sizes and compositions defined from the studies in Aim 1, we will measure immune responses triggered by nanoparticles delivering gp120 antigen and CpG alone or with co-delivery of the chemokine CCL20, and analyze antigen dissemination and dendritic cell trafficking in response to these vaccine particles. The studies described will enable the rationale design of microsphere carriers that can promote strong mucosal and systemic immune responses to recombinant HIV antigens, as a step toward a prophylactic HIV vaccine.

描述（由申请人提供）：为了提供针对艾滋病毒的预防性保护，成功的疫苗需要引起粘膜免疫，以便在主要入境点的粘膜部位对抗病毒。在促进粘膜免疫的潜在途径中，口服输送是一种简单的，无针的给药方式，但由于需要在通过胃肠道过渡过程中保护疫苗并实现粘膜组织对疫苗的充分摄取而受到挑战。我们最近开发了一种聚合物疫苗系统，该系统由趋化因子和抗原负载的纳米颗粒组成，并在藻酸盐水凝胶微球载体中共同传递。藻酸盐微球是由于其在低pH值时的稳定性而是口服药物输送的候选材料，并且先前据报道藻酸盐颗粒通过口服疫苗接种促进粘膜免疫。因此，我们提出，我们开发的藻酸盐微球载体可以（1）在通过胃肠道（GL）小区域的转运过程中保护抗原/共同递送的趋化趋化因子（或细胞因子），并（2）促进与肠肠肠相关的淋巴机（GALT）促进吸收。已知微粒通过覆盖Peyer斑块的M细胞进行了转基因，并且在GALT中藻酸盐载体的细胞外沉积将允许局部产生树突状细胞（DC）吸收趋化因子梯度，这些趋化因子梯度会将DC吸引到这些抗原负载的纳米植物的这些微植物上。我们在这里建议对这种概念进行初步测试，以生成可以给粘膜免疫促进艾滋病毒的口服疫苗。具体目的是：目标1：我们将以不同方法制备的藻酸盐微球载体的能力来保护抗原递送纳米颗粒和在体外的合并趋化趋化因子免受模拟的胃液的影响，并在体内被肠粘膜吸收，并在体内吸收并表征颗粒尺寸的藻酸盐载体的吸收。 AIM 2：使用AIM 1中的研究定义的最佳载体大小和组合物，我们将测量由单独提供GP120抗原和CPG或与趋化因子CCL20的共递送的纳米颗粒触发的免疫反应，并分析抗原传播和抗抗原细胞对这些疫苗的响应。描述的研究将使微球载体的理由设计能够促进对重组HIV抗原的强粘膜和全身免疫反应，这是迈向预防性HIV疫苗的一步。

项目成果

Robust IgG responses to nanograms of antigen using a biomimetic lipid-coated particle vaccine.

• DOI: 10.1016/j.jconrel.2011.07.029
• 发表时间: 2012-02-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Bershteyn A;Hanson MC;Crespo MP;Moon JJ;Li AV;Suh H;Irvine DJ
• 通讯作者: Irvine DJ