Nucleoside modified mRNA based HIV vaccine

 描述（由申请人提供）：在人体临床试验中，单一HIV疫苗RV 144表现出低水平和短期有效性。该疫苗使用痘病毒初免-蛋白加强方法，由于活病毒初免， 规模生产和安全。我们已经开发了一种新的方法来制备HIV疫苗的主要部分，该方法使用完全由生理组分组成的核苷修饰的mRNA，其生产简单且具有成本效益，不需要冷链，并且应该没有由于mRNA引起的不良事件。mRNA复合在脂质纳米颗粒（LNP）中，其制剂已进入siRNA的3期临床试验，没有由于脂质引起的不良事件，并通过皮内途径递送。为了补充这种引发免疫应答的新方法，我们还开发了一种新的免疫原，它是一种不需要CD 4结合就能感染细胞的HIV包膜（不依赖于CD 4）。这种包膜具有更开放的构象，并且我们已经证明，与其亲本相比，它诱导更高水平的Env特异性IgG、Tier-1和Tier-2中和以及V1/V2定向应答。在3个具体目标中，我们将从传播/创始者进化枝C病毒中开发新的CD 4非依赖性免疫原，将其与兔模型中已经产生的CD 4 i免疫原进行比较，并向下选择用于恒河猴中的研究。我们还将分析加强蛋白，比较gp 120单体与SOSIP三聚体，在兔子中用作猕猴的加强。然后，我们将比较单免疫原初免-加强与多基因疫苗接种。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IgG、1级和2级中和以及V1/V2定向应答。此外，我们已经证明核苷修饰的mRNA-LNP引发剂诱导非常高水平（总抗原特异性CD 4 + T细胞应答的一半）的抗原特异性T滤泡辅助（Tfh）细胞，其在高亲合力IgG和长期记忆的产生中是关键的，这两者都是开发有效HIV疫苗的关键要素。这项拨款将推动一种新的疫苗引发方法，并优化免疫原，用于在兔子和恒河猴中进行测试。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.