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.

项目摘要 在开发一种安全有效的艾滋病毒-1疫苗方面进行了重大研究。 虽然已经尝试了许多战略，但没有一项成功地建立起来。即使是一个 部分有效的疫苗可能会进一步减少感染艾滋病毒的人数 减少可能将病毒传染给其他人的人数。通过大幅降低 随着新感染人数的增加，我们最终可以阻止这场大流行。到目前为止， 广谱中和抗体(BNAbs)已被证明极难实现，这带来了 对新颖的三聚体进行了大量的设计和修改。同时发现， 诱导的HIV特异性CD8+T细胞反应可能会限制HIV的传播和建立 持久的病毒库。所有的证据都表明，没有任何个人因素会决定 诱导bNAb的HIV-1疫苗的最终成功可能需要以下几个方面的结合 高效前体B细胞启动，优化环境设计和呈现，持续 异源环境增强，一种基于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手臂，并 是亚单位疫苗的重要组成部分，特别是在免疫原性较差的情况下 糖蛋白。递送系统也可以被设计成解决基于mRNA的不稳定性 疫苗。因此，该方案的目标是克服艾滋病毒-1疫苗接种方面的挑战 并提供安全有效的疫苗，使用一种生物兼容、可生物降解的、容易的 制造的短碳纳米管(CNTVac)平台。Env-Trimer与mRNA编码 多肽将是递送的抗原，并将针对体液和细胞的生成 回应。人性化的小鼠模型和非人类的灵长类动物模型将用于 免疫原性和疗效研究。作为HIV-1疫苗的新型非病毒基因转移载体 交付时，我们将为潜在的GMP生产建立方法，并生成安全概况 根据FDA的要求。