Immunogenicity of RNA Replicons Encoding HIV Env Immunogens Designed for Self-Assembly into Nanoparticles
Immunogenicity of RNA Replicons Encoding HIV Env Immunogens Designed for Self-Assembly into Nanoparticles
复制标题
DOI：
10.1016/j.ymthe.2019.08.007
复制
发表时间：
2019-12-04
影响因子：
12.4
通讯作者：
Irvine, Darrell J.
中科院分区：
文献类型：
--
作者：
Melo, Mariane;Porter, Ely;Irvine, Darrell J.
RNA复制子是一种很有前途的疫苗平台技术。为了评估脂质纳米颗粒配制的复制子用于递送 HIV 免疫原的潜力，我们设计并测试了表达自组装蛋白纳米颗粒免疫原、糖蛋白 120 (gp120) 种系靶向工程外域 (eOD-GT8) 60 聚体的甲病毒复制子。 eOD-GT8 免疫原是一种种系靶向抗原，旨在引导能够进化为 VRC01 类广泛中和抗体的人类 B 细胞。复制子 RNA 被高效封装在基于 1,2-二油酰基-3-三甲基铵-丙烷 (DOTAP) 的脂质纳米粒子中，可在肌肉中有效递送，并且荧光素酶的表达在正常小鼠中持续类似于 30 天，与通过递送等效修饰 mRNA (modRNA) 获得的非常短暂和低水平的表达形成鲜明对比。与蛋白质免疫相比，eODGT8 60 聚体编码复制子在小鼠单次注射后可引发高滴度的 gp120 特异性抗体，并且抗原特异性生发中心 B 细胞的水平增加。对表达人推断种系 VRC01 重链 B 细胞受体（eOD 抗原的靶标）的转基因小鼠进行免疫，导致 B 细胞启动和与 VRC01 类抗体开发一致的体细胞超突变。总而言之，这些数据表明 Env 免疫原的复制子传递可能是 HIV 疫苗开发的一个有前途的途径。
RNA replicons are a promising platform technology for vaccines. To evaluate the potential of lipid nanoparticle-formulated replicons for delivery of HIV immunogens, we designed and tested an alphavirus replicon expressing a self-assembling protein nanoparticle immunogen, the glycoprotein 120 (gp120) germline-targeting engineered outer domain (eOD-GT8) 60-mer. The eOD-GT8 immunogen is a germline-targeting antigen designed to prime human B cells capable of evolving toward VRC01-class broadly neutralizing antibodies. Replicon RNA was encapsulated with high efficiency in 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-based lipid nanoparticles, which provided effective delivery in the muscle and expression of luciferase lasting similar to 30 days in normal mice, contrasting with very brief and low levels of expression obtained by delivery of equivalent modified mRNA (modRNA). eODGT8 60-mer-encoding replicons elicited high titers of gp120specific antibodies following a single injection in mice, and increased levels of antigen-specific germinal center B cells compared with protein immunization. Immunization of transgenic mice expressing human inferred-germline VRC01 heavy chain B cell receptors that are the targets of the eOD antigen led to priming of B cells and somatic hypermutation consistent with VRC01-class antibody development. Altogether, these data suggest replicon delivery of Env immunogens may be a promising avenue for HIV vaccine development.