Engineered lipid vesicles as potent vaccine vectors for HIV

工程脂质囊泡作为有效的艾滋病毒疫苗载体

• 批准号: 8231268
• 负责人: Darrell J Irvine
• 金额: $ 32.07万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231268
• 关键词: AIDS Vaccines; Adjuvant; Agonist; Antigens; Avidity; Biological Preservation; CD8B1 gene; Cells; Cellular Immunity; Coated vesicle; Complex; Data; Deposition; Dose; Drug Formulations; Effector Cell; Encapsulated; Engineering; Epitopes; Face; Gagging; Generations; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Injection of therapeutic agent; Interferons; Licensing; Life; Light; Lipids; Luciferases; Macaca; Malaria; Memory; Modeling; Mucosal Immunity; Mucous Membrane; Mus; Nature; Needles; Population; Process; Proteins; Reagent; Recombinants; Reporting; Research; Safety; Secondary Immunization; Shapes; Signal Transduction; Site; Skin; Staging; Structure; System; T cell response; T-Lymphocyte; Testing; Transgenic Organisms; Vaccination; Vaccines; Vesicle; Viral Vector; aluminum sulfate; aqueous; base; cell motility; clinically relevant; crosslink; dosage; env Gene Products; functional status; gag Gene Products; human DNA; nanoparticle; novel; novel vaccines; particle; plasmid DNA; public health relevance; reproductive; response; trafficking; vaccine candidate; vaccine delivery; vector; vector vaccine

DESCRIPTION (provided by applicant): Successful vaccination against HIV will likely require the generation of coordinated humoral and cellular immunity. Among current strategies, protein vaccines fail to stimulate cellular responses, while plasmid DNA or live recombinant vectors capable of promoting cellular and humoral responses together face other issues, such as potency in humans (DNA), or challenges of vector-specific immunity and/or safety (live vectors). We propose here a new class of lipid-based vesicles for protein vaccine delivery, composed of multilamellar lipid vesicles stabilized by the introduction of crosslinks connecting the bilayers of the structure. These novel materials are synthesized and encapsulate protein antigens in a mild all-aqueous process, favoring the preservation of epitopes on complex antigens. In preliminary studies, we show that these novel vaccine carriers can be repeatedly administered for homologous boosting: Following a prime and 2 booster immunizations with a model antigen, these particles massively expand antigen-specific CD8+ T-cells, to the best of our knowledge substantially stronger than any previously reported protein vaccine. These T-cells were functional in terms of their capacity to produce IFN-?, and formed a substantial memory population a month after the second boost. In other preliminary studies, we found that this same system drives potent humoral responses against a candidate malaria antigen. Based on these promising initial results, we propose here to test the promise of this new vaccine delivery approach in the context of HIV vaccination, aiming to determine whether potent, durable T-cell and humoral responses can be elicited against HIV gag and env antigens. In addition, we will explore whether particular aspects of this vaccine system (e.g., the deposition of particles at the injection site) can be exploited to direct the localization of memory cells to key mucosal tissue sites that could promote protection against HIV infection. Our specific aims are: (1) How do the humoral and cellular responses to gag and env antigens evolve as a function of antigen dose and boosting with ICMV particle vaccination? (2) Are alternative clinically-relevant TLR agonist/danger signals capable of eliciting stronger immune responses than MPLA when delivered by ICMV vectors? (3) How do particles retained at the injection site influence memory/effector cell trafficking following ICMV particle immunization, compared to traditional protein immunization? (4) Can microneedle delivery be used to allow repeated needle-free particle boosting to be performed, without the need for refrigerated vaccines? Identification of ICMV formulations that can raise immune responses against HIV immunogens comparable to those shown in our preliminary data for OVA or malaria antigens will set the stage for subsequent testing in macaque protection models (either using ICMV vaccination alone or in tandem with other strong HIV vaccine candidates.

描述(由申请人提供)：成功接种艾滋病毒疫苗可能需要产生协调的体液和细胞免疫。在目前的策略中，蛋白质疫苗未能刺激细胞反应，而能够同时促进细胞和体液反应的质粒DNA或活重组载体面临其他问题，如对人类的效力(DNA)，或对载体特异性免疫和/或安全性的挑战(活载体)。在这里，我们提出了一类新的基于脂类的囊泡，用于蛋白质疫苗的递送，由多层脂泡组成，通过引入连接双层结构的交联剂来稳定。这些新型材料是在温和的全水过程中合成并包裹蛋白质抗原的，有利于复杂抗原上表位的保存。在初步研究中，我们表明这些新型疫苗载体可以重复注射用于同源增强：在用模型抗原进行一次初始免疫和两次加强免疫后，这些颗粒大规模地扩增抗原特异性CD8+T细胞，据我们所知，这些细胞比之前报道的任何蛋白质疫苗都要强得多。这些T细胞在产生干扰素-β的能力方面是有功能的，并在第二次增强后一个月形成了大量的记忆群体。在其他初步研究中，我们发现，同样的系统可以驱动针对候选疟疾抗原的强大体液反应。基于这些有希望的初步结果，我们建议在HIV疫苗接种的背景下测试这种新的疫苗交付方法的前景，旨在确定是否可以针对HIV Gag和env抗原引发强大的、持久的T细胞和体液反应。此外，我们将探索这种疫苗系统的特定方面(例如，注射部位的颗粒沉积)是否可以被用来将记忆细胞定位到关键的粘膜组织部位，从而促进对艾滋病毒感染的保护。我们的具体目标是：(1)对Gag和env抗原的体液和细胞反应是如何随ICMV颗粒疫苗的抗原剂量和增强而演变的？(2)由ICMV载体传递的替代临床相关TLR激动剂/危险信号能够引起比Mpla更强的免疫反应吗？(3)与传统的蛋白质免疫相比，保留在注射部位的颗粒如何影响ICMV颗粒免疫后的记忆/效应细胞运输？(4)微针传递是否可以在不需要冷藏疫苗的情况下进行重复的无针颗粒增强？识别能够提高对艾滋病毒免疫原的免疫应答的ICMV配方，与我们的OVA或疟疾抗原初步数据中显示的免疫应答相当，将为随后在猕猴保护模型中进行测试(单独使用ICMV疫苗或与其他强大的艾滋病毒候选疫苗联合使用)奠定基础。