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: 10603311
• 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/10603311
• 关键词: ADME Study; Address; Adjuvant; Affinity; Antibodies; Antigenic Variation; Antigens; B-Lymphocytes; Binding; Biotechnology; CD8-Positive T-Lymphocytes; CD8B1 gene; Carbon Nanotubes; 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; Masks; Mediating; Messenger RNA; Methodology; Methods; Modeling; Modification; Molecular Conformation; Peptides; Persons; Phase; Physiological; Polysaccharides; Process; Production; RNA vaccine; Radiolabeled; Recombinants; Research; Retroviridae; Safety; 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; Yang; analytical method; arm; base; 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; manufacturing process; meetings; mouse model; nanovaccine; neutralizing antibody; nonhuman primate; novel; pandemic disease; 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.

项目摘要 为HIV-1开发了安全有效的疫苗，已经进行了重大研究。 尽管已经尝试了许多策略。没有成功建立。甚至 部分有效的疫苗可能会减少感染艾滋病毒的人数，进一步 减少可以将病毒传递给他人的人数。通过大大减少 新感染的数量，我们最终可以阻止大流行。迄今为止，启发 事实证明，广泛中和的抗体（BNAB）非常困难，这带来了 在新颖的三聚体设计和修改方面做了很多努力。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 持续的病毒库。所有证据表明，任何个人因素都不会决定 诱导BNAB的HIV-1疫苗的最终成功，这可能需要组合 有效的前体B细胞启动，Env设计和演示的优化，持续 异源Env Boosting，一种基于T细胞的策略以及新开发的交付系统或 佐剂。佐剂或输送系统可以刺激免疫系统的不同臂 是亚基疫苗的重要成分，特别是在免疫原性差的情况下 糖蛋白。交付系统也可以设计用于解决基于mRNA的不稳定 疫苗。因此，该计划的目的是克服HIV-1疫苗接种的挑战 并使用生物相容性，可生物降解，容易提供安全有效的疫苗 制造的短碳纳米管（CNTVAC）平台。 env-trimer和mRNA编码 肽将是用于递送的抗原，并将靶向体液和细胞的产生 回答。人源化的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，我们将建立潜在GMP生产的方法论并生成安全概况 根据FDA要求。