Carbon Nanotube Enabled Delivery of mRNA for an HIV Vaccine Candidate

碳纳米管能够递送 HIV 候选疫苗的 mRNA

• 批准号: 10700118
• 负责人: Yang Xu
• 金额: $ 29.68万
• 依托单位: LUNA LABS USA, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-07 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10700118
• 关键词: ADME Study; Address; Adjuvant; Affinity; Antibodies; Antigenic Variation; Antigens; B-Lymphocytes; Binding; Biotechnology; CD8-Positive T-Lymphocytes; CD8B1 gene; Carbon Nanotubes; Certification; Chemistry; Clinical; Clinical Research; Collaborations; Development; Ensure; Epitopes; Formulation; Generations; Glycoproteins; Goals; HIV; HIV resistance; HIV vaccine; HIV-1; HIV-1 vaccine; Immune response; Immune system; In Vitro; Individual; Infection; Injectable; Injections; Intramuscular; Macaca mulatta; Mediating; Messenger RNA; Methodology; Methods; Modeling; Modification; Molecular Conformation; Peptides; Persons; Phase; Physiological; Polysaccharides; Process; Production; RNA vaccine; Radiolabeled; Recombinants; Research; Retroviridae; Safety; Specific qualifier value; Structure; Subunit Vaccines; Surface; Synthetic Antigens; System; T cell response; T-Lymphocyte; Technology; Testing; Time; Toxic effect; Translations; Universities; Vaccination; Vaccines; Validation; Viral reservoir; Virus; Work; analytical method; arm; biomaterial compatibility; clinical translation; cost; cost effective; design; efficacy study; gang; gene transfer vector; humanized mouse; immunogenic; immunogenicity; in vivo; lipid nanoparticle; mRNA Instability; mRNA delivery; manufacture; manufacturing process; manufacturing scale-up; mouse model; nanovaccine; neutralizing antibody; nonhuman primate; novel; pandemic disease; pre-Investigational New Drug meeting; preclinical study; predicting response; preservation; programs; response; scale up; success; transmission process; vaccine candidate; vaccine delivery; vaccine development; vaccine discovery; vaccine formulation; vaccine platform

Project Summary Significant research has gone into the development of a safe and effective vaccine for HIV-1. Although many strategies have been attempted; none has been successfully established. Even a partially effective vaccine could decrease the number of people who are infected with HIV, further reducing the number of people who can pass the virus on to others. By substantially reducing the number of new infections, we could eventually stop the pandemic. To date, the elicitation of broadly neutralizing antibodies (bNAbs) has proven extremely difficult to achieve which brought a lot of effort on the novel trimer design and modification. At the same time, it was found that induced HIV- specific CD8+ T cell responses could limit both the transmission and establishment of persistent viral reservoirs. All the evidence suggest that no individual factor will determine the ultimate success of a bNAb-inducing HIV-1 vaccine, which will likely require a combination of efficient precursor B cell priming, optimization of Env design and presentation, sustained heterologous Env boosting, a T cell-based strategy, and newly developed delivery systems or adjuvants. Adjuvants or delivery systems can stimulate different arms of the immune system and are vital components of subunit vaccines, especially in the case of poorly immunogenic envelope glycoprotein. Deliver systems can also be designed to address instability of mRNA-based vaccines. The goal of this program is therefore to overcome challenges with HIV-1 vaccination and deliver a safe and effective vaccine using a biocompatible, biodegradable, easily manufactured short carbon nanotube (CNTVac) platform. Env-trimer and mRNA encoding peptide will be antigens for delivery and will target generation of both humoral and cellular responses. A humanized mouse model and a non-human primate model will be used for immunogenicity and efficacy studies. As the novel non-viral gene transfer vector for HIV-1 vaccine delivery, we will establish methodology for potential GMP production and generate safety profiles under FDA requirements.

项目概要 安全有效的 HIV-1 疫苗的开发已进行了大量研究。 尽管已经尝试了很多策略；没有一个已成功建立。甚至一个 部分有效的疫苗可以进一步减少感染艾滋病毒的人数 减少可以将病毒传染给他人的人数。通过大幅减少 新增感染人数，我们最终可以阻止大流行。迄今为止，已引出 事实证明，广泛中和抗体（bNAb）极其难以实现，这导致 在新颖的三聚体设计和修饰上付出了大量的努力。同时，发现 诱导的 HIV 特异性 CD8+ T 细胞反应可能会限制传播和建立 持久性病毒储存库。所有证据表明，没有任何个人因素可以决定 bNAb 诱导的 HIV-1 疫苗的最终成功可能需要结合 有效的前体 B 细胞启动、Env 设计和呈现的优化、持续 异源 Env 增强、基于 T 细胞的策略以及新开发的递送系统或 佐剂。佐剂或输送系统可以刺激免疫系统的不同部分， 是亚单位疫苗的重要组成部分，特别是在免疫原性较差的包膜的情况下 糖蛋白。递送系统还可以设计用于解决基于 mRNA 的不稳定性问题。 疫苗。因此，该计划的目标是克服 HIV-1 疫苗接种的挑战 并使用生物相容性、可生物降解、易于 制造短碳纳米管（CNTVac）平台。 Env-三聚体和mRNA编码 肽将作为用于递送的抗原并且将靶向产生体液和细胞 回应。人源化小鼠模型和非人类灵长类动物模型将用于 免疫原性和功效研究。作为HIV-1疫苗的新型非病毒基因转移载体 交付后，我们将建立潜在 GMP 生产的方法并生成安全概况 根据 FDA 的要求。