Integration of adjuvant derived nanoparticles and engineered mRNA for HIV vaccine discovery

佐剂衍生纳米粒子与工程 mRNA 的整合用于 HIV 疫苗的发现

• 批准号: 10618542
• 负责人: Yizhou Dong
• 金额: $ 77.81万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-09 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618542
• 关键词: 2019-nCoV; 3' Untranslated Regions; Adjuvant; Affect; Agonist; Animal Model; Animals; Antibodies; Antibody Response; Antibody-mediated protection; Antigens; B-Lymphocytes; Biological Assay; Biological Response Modifiers; CD8-Positive T-Lymphocytes; COVID-19 vaccine; Cell model; Cells; Cellular Immunity; Charge; Chemicals; Clinical; Clinical Data; Clinical Research; Clinical Trials; Country; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Engineering; Epidemic; Epitopes; Europe; Exhibits; Formulation; Future; Gene Expression; Goals; HIV; HIV Antigens; HIV Infections; HIV vaccine; Healthcare; Human; Humoral Immunities; Immune; Immune response; Knowledge; Lead; Macaca; Mannose Binding Lectin; Mediating; Messenger RNA; Modeling; Moderna COVID-19 vaccine; Mus; Nanotechnology; Organ; Pathway interactions; Pattern; Persons; Pfizer-BioNTech COVID-19 vaccine; Polymerase; Population; Post-Translational Protein Processing; Process; Production; Property; Proteins; Public Health; RNA; RNA vaccination; RNA vaccine; Recombinants; Regimen; Reporting; Research Personnel; Resistance; SIV; Safety; South Africa; Stimulator of Interferon Genes; Structural Protein; Surface; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; TLR7 gene; Technology; Thailand; Toll-like receptors; Transcript; Translations; Untranslated Regions; Vaccinated; Vaccination; Vaccine Design; Vaccines; Viral; Viral Antigens; Virus Diseases; adaptive immunity; care burden; clinical translation; design; emerging pathogen; env Gene Products; experience; gag Gene Products; glycosylation; health goals; high volume manufacturing; immunogenicity; in vivo; infection rate; lipid nanoparticle; mRNA delivery; mouse model; nanomaterials; nanoparticle; neutralizing antibody; nonhuman primate; particle; pre-clinical; preclinical study; side effect; technology platform; vaccine access; vaccine candidate; vaccine development; vaccine discovery; vaccine platform

PROJECT SUMMARY A vaccine is a promising approach for stopping the spread of HIV infections. Although vaccine regimens in clinical trials show various levels of protection against HIV, there is no effective vaccine available for a large population yet. Preclinical and clinical data demonstrate the importance of both adjuvants and antigens for an effective HIV vaccine. Particularly, stimulation of toll-like receptors (TLRs) or stimulator of interferon genes (STING) boosts the immune response of the HIV antigens in multiple animal models. Meanwhile, HIV immunogens are a critical factor for both humoral immunity and cell-mediated immunity such as broadly neutralizing antibodies (bnAbs) and cytotoxic T cells. Despite these important advances, significant challenges remain in immunogen design, immunogen delivery, and adjuvant choice. To overcome these challenges, we propose to integrate adjuvant derived nanoparticles and engineered mRNA for HIV vaccine discovery. In preliminary studies, we developed adjuvant derived nanoparticles (ANPs) using TLR or STING agonists, which showed great potential for efficient mRNA delivery as a vaccine platform. Moreover, we constructed glycosylated HIV immunogens that trigger mannose-binding lectin (MBL)-mediated innate immune recognition, leading to enhanced antibody responses. Additionally, we systematically investigated the untranslated regions (UTRs) of mRNAs in order to enhance protein production. Through a comprehensive analysis of endogenous gene expression and de novo design of UTRs, we identified the optimal combination of 5’ and 3’ UTR for mRNA engineering. Based on these results and findings, the goal of this proposed project is to develop adjuvant derived nanoparticles as functional nanomaterials capable of efficiently delivering HIV immunogens in vivo, consequently generating strong and durable humoral and cell-mediated immunity against HIV. The following specific aims will be carried out to accomplish our goal: 1) Synthesis and characterization of adjuvant derived nanoparticles (ANPs); 2) Engineering of mRNA transcripts encoding various HIV immunogens with high translation efficiency; and 3) Determination of immunogenicity and safety profiles of ANPs-mRNA in mouse and non-human primate models. Encouraged by results from our preliminary studies, we expect the newly designed nanomaterials from this proposal to establish a vaccine candidate, which can facilitate clinical translation and a new avenue for HIV vaccine discovery. Knowledge gained from this study can also be extended to other types of vaccines for emerging pathogens.

项目概要 尽管临床上有疫苗治疗方案，但疫苗是阻止艾滋病毒感染传播的一种有前途的方法。 试验显示对艾滋病毒的保护程度不同，目前尚无适用于大量人群的有效疫苗 然而，临床前和临床数据证明了佐剂和抗原对于有效治疗艾滋病毒的重要性。 特别是，Toll 样受体 (TLR) 或干扰素基因刺激物 (STING) 的刺激可增强疫苗的效果。 同时，HIV 免疫原是多种动物模型中 HIV 抗原的免疫反应的关键。 体液免疫和细胞介导免疫的因素，例如广泛中和抗体 (bnAb) 尽管有这些重要进展，但免疫原设计仍然存在重大挑战， 为了克服这些挑战，我们建议整合佐剂。 在初步研究中，我们开发了用于 HIV 疫苗发现的纳米粒子和工程 mRNA。 使用 TLR 或 STING 激动剂的佐剂衍生纳米颗粒（ANP），显示出高效的巨大潜力 此外，我们构建了可触发的糖基化 HIV 免疫原。 甘露糖结合凝集素（MBL）介导的先天免疫识别，导致抗体反应增强。 此外，我们系统地研究了 mRNA 的非翻译区 (UTR)，以增强 通过内源基因表达的综合分析和从头设计。 根据这些结果，我们确定了 mRNA 工程的 5' 和 3' UTR 的最佳组合。 和研究结果，该拟议项目的目标是开发佐剂衍生的纳米颗粒作为功能性 纳米材料能够在体内有效地传递艾滋病毒免疫原，从而产生强而有力的免疫原 针对艾滋病毒的持久体液和细胞介导的免疫将实现以下具体目标。 实现我们的目标：1）佐剂衍生纳米颗粒（ANP）的合成和表征2）工程； 具有高翻译效率的各种编码HIV免疫原的mRNA转录本；以及3) 的测定； ANPs-mRNA 在小鼠和非人类灵长类动物模型中的免疫原性和安全性。 根据我们的初步研究结果，我们预计该提案中新设计的纳米材料能够建立 一种候选疫苗，可以促进临床转化并为艾滋病毒疫苗的发现提供新途径。 从这项研究中获得的知识也可以扩展到针对新出现病原体的其他类型的疫苗。