Carbon Nanotube Enabled Delivery of mRNA for an HIV Vaccine Candidate

项目摘要 在开发安全有效的HIV-1疫苗方面进行了大量研究。 虽然尝试了许多策略，但没有一个成功建立。甚至 部分有效的疫苗可以减少感染艾滋病毒的人数， 减少了可以将病毒传染给他人的人数。通过大幅减少 新感染的人数，我们最终可以阻止大流行。迄今为止， 广泛中和抗体（bNAb）已被证明极难实现， 在新型三聚体的设计和修饰上做了大量的努力。与此同时，人们发现， 诱导的HIV特异性CD 8 + T细胞反应可以限制传播和建立 持续的病毒库。所有的证据都表明，没有一个单独的因素会决定 bNAb诱导HIV-1疫苗的最终成功，这可能需要结合 有效的前体B细胞引发，Env设计和呈递的优化，持续的 异源Env加强、基于T细胞的策略和新开发的递送系统，或 佐剂佐剂或递送系统可以刺激免疫系统的不同分支， 是亚单位疫苗的重要组成部分，特别是在免疫原性差的情况下， 糖蛋白递送系统还可以被设计为解决基于mRNA的细胞的不稳定性。 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，生物可降解性， 制造的短碳纳米管（CNTVac）平台。Env-三聚体和mRNA编码 肽将是用于递送的抗原，并且将靶向产生体液和细胞免疫应答。 应答将使用人源化小鼠模型和非人灵长类动物模型进行研究。 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，我们将建立潜在的GMP生产方法，并生成安全配置文件 根据FDA的要求。

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.