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: 8424296
• 负责人: Darrell J Irvine
• 金额: $ 30.08万
• 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/8424296
• 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HIV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，蛋白质疫苗不能刺激细胞应答，而能够促进细胞和体液应答的质粒DNA或活重组载体一起面临其他问题，例如在人体中的效力（DNA），或载体特异性免疫和/或安全性的挑战（活载体）。我们在这里提出了一类新的脂质为基础的囊泡蛋白质疫苗的交付，由多层脂质囊泡稳定的结构的双层连接的交联引入。这些新材料是在温和的全水性过程中合成和封装蛋白质抗原，有利于保护复杂抗原上的表位。在初步研究中，我们表明这些新型疫苗载体可以重复施用用于同源加强：在用模型抗原进行初次免疫和2次加强免疫后，这些颗粒大量扩增抗原特异性CD 8 + T细胞，据我们所知，比任何先前报道的蛋白质疫苗都要强。这些T细胞在产生IFN-β的能力方面具有功能，并在第二次增强后一个月形成了大量的记忆人口。在其他的初步研究中，我们发现同样的系统驱动针对候选疟疾抗原的有效体液反应。基于这些有希望的初步结果，我们建议在这里测试这种新的疫苗递送方法在HIV疫苗接种的背景下的承诺，旨在确定是否可以针对HIV gag和env抗原引起有效，持久的T细胞和体液应答。此外，我们将探讨这种疫苗系统的特定方面（例如，颗粒在注射部位的沉积）可用于将记忆细胞定位于关键的粘膜组织部位，这可促进对HIV感染的保护。我们的具体目标是：（1）对gag和env抗原的体液和细胞应答如何演变为抗原剂量和ICMV颗粒疫苗接种的加强的函数？(2)当通过ICMV载体递送时，替代的临床相关TLR激动剂/危险信号是否能够引起比MPLA更强的免疫应答？(3)与传统的蛋白质免疫相比，ICMV颗粒免疫后保留在注射部位的颗粒如何影响记忆/效应细胞运输？(4)微针递送是否可以用于重复进行无针颗粒增强，而不需要冷藏疫苗？鉴定ICMV制剂，其可以提高对HIV免疫原的免疫应答，与我们对OVA或疟疾抗原的初步数据中显示的免疫应答相当，这将为随后在猕猴保护模型中的测试奠定基础（单独使用ICMV疫苗接种或与其他强HIV候选疫苗联合使用）。