Nucleoside modified mRNA based HIV vaccine

 描述(申请人提供)：单一HIV疫苗在人体临床试验中显示出低水平和短期效果，RV144。本疫苗采用痘病毒素剂-蛋白质增强方法学，由于活病毒素剂的存在，给大 规模化生产和安全。我们已经开发出一种新的方法来处理艾滋病毒疫苗的主要部分，该方法使用完全由生理成分组成的核苷修饰的mRNA，生产起来简单且具有成本效益，不需要冷链，并且应该不会因该mRNA而发生不良事件。该信使核糖核酸被复合在脂质纳米粒(LNP)中，其制剂已经进入siRNA的第三阶段临床试验，没有因脂质而引起的不良反应，并通过皮内途径递送。为了补充这种启动免疫反应的新方法，我们还开发了一种新的免疫原，即HIV包膜，它不需要结合CD4来感染细胞(不依赖于CD4)。该包膜具有更开放的构象，我们已经证明，与其亲本相比，它能诱导更高水平的Env特异性IgG、Tier-1和2中和，以及V1/V2定向反应。在三个特定的目标中，我们将从传播/创始分支C病毒中开发一种新的CD4非依赖免疫原，将其与已生产的CD4i免疫原在兔模型中进行比较，并在猕猴身上进行下选研究。我们还将在兔体内分析Boost蛋白，将gp120单体与SOSIP三聚体进行比较，以用于猕猴的Boost。然后，我们将比较单一免疫原强化免疫和多基因疫苗接种。我们相信这种新的疫苗方法将是有效的，因为它将产生高水平的Env特异性免疫球蛋白、Tier-1和2中和以及V1/V2定向反应。此外，我们还证明，核苷修饰的mRNA-LNP能诱导非常高水平的抗原特异性T滤泡助手(TFH)细胞(占总抗原特异性CD4T细胞反应的一半)，这对产生高亲和力的免疫球蛋白和长期记忆都是至关重要的，而这两个因素都是开发有效的HIV疫苗的关键因素。这笔赠款将推动疫苗接种的新方法，并优化免疫原用于在兔子和猕猴身上进行试验的最佳和增强免疫原。产生的数据将能够将这种疫苗方法转移到临床试验开发中，只需进行少数额外的实验。

 DESCRIPTION (provided by applicant): A single HIV vaccine in human clinical trials demonstrated low level and short-term effectiveness, RV144. This vaccine used Pox virus prime - protein boost methodology, which because of the live virus prime, presents difficulties for large scale production and safety. We have developed a new approach to the prime portion of an HIV vaccine that uses nucleoside modified mRNA composed entirely of physiologic components that is simple and cost effective to produce, does not require a cold chain, and should have no adverse events due to the mRNA. The mRNA is complexed in a lipid nanoparticle (LNP) whose formulation has entered phase 3 clinical trials for siRNA with no adverse events due to the lipids and is delivered by the intradermal route. To complement this novel method of priming an immune response, we have also developed a new immunogen that is an HIV envelope that does not require CD4 binding to infect a cell (CD4 independent). This envelope has a more open conformation, and we have demonstrated that it induces higher levels of Env-specific IgG, Tier-1 and 2 neutralization, and V1/V2 directed responses compared to their parents. In 3 specific aims, we will developed a new CD4 independent immunogen from a transmitted/founder clade C virus, compare it to already produced CD4i immunogens in the rabbit model and downselect for study in Rhesus macaques. We will also analyze boost proteins, comparing gp120 monomers to SOSIP trimers, in rabbits for use as a boost in macaques. We will then compare single immunogen prime-boost to multi-genic vaccination. We believe this new vaccine approach will be effective, in that it will develop high levels of Env-specific IgG, Tier-1 and 2 neutralization, and V1/V2 directed responses. In addition, we have demonstrated that the nucleoside modified mRNA-LNP prime induces very high levels (half of the total antigen-specific CD4+ T cell response) of antigen-specific T follicular helper (Tfh) cell that are critical in both the generation of high avidity IgG and long term memory, both of which are critical elements in the development of an effective HIV vaccine. This grant will move a new approach to vaccine priming and optimize immunogens for the prime and boost for testing in rabbits and Rhesus macaques. The data generated will be capable of moving this vaccine approach to clinical trial development with a minority of additional experiments.