Engineering the Immune Response of a Self-replicating and Adjuvanting RNA HIV-1Vaccine

项目概要/摘要 HIV-1 疫苗开发的一个关键要求是诱导广泛中和抗体 (bNAb) 靶向 HIV-1 包膜 (Env) 尖峰。 BG505 SOSIP.664 gp140 可溶定时器设计用于显示 构象表位可被多种 bNAb 识别，但不能被非中和抗体识别。原型SOSIP 目前正在两项临床试验中评估疫苗。一种有效的信使 RNA (mRNA) 疫苗 表达 BG505 SOSIP.664 将补充临床疫苗并开辟异源疫苗之路 引发免疫反应的免疫策略，其定义是增加广度和强度。最近 mRNA 疫苗的成就是纳米颗粒递送技术进步的结果。我们最近 报道了编码 SARS-CoV 刺突 (S) 蛋白的复制 RNA (repRNA) 疫苗的免疫原性 2；这种疫苗采用新型脂质无机纳米颗粒 (LION) 载体传递，可诱导有效的结合并 小鼠和非人灵长类动物体内的中和抗体。在拟议的 R61/R33 应用中，我们将 研究并优化 LION 配方的属性，以设计 BG505 SOSIP.664 的免疫力 表达repRNA疫苗(repRNA-SOSIP.664)。目标是确定主要疫苗和给药途径 促进 B 细胞分化和成熟，这是诱导高亲和力 Env 抗体所需的 猕猴 SHIV 挑战模型中的保护。拟议的工作将以三向方式进行 HDT Bio 的 Amit Khandhar 博士与西雅图儿童研究所的 Noah Sather 博士合作 (SCRI) 和华盛顿大学 (UW) 的 Deborah Fuller 教授。 R61 阶段的拟议活动将 包括（具体目标 1）优化用于肌内（IM）、皮内（ID）和 鼻内 (IN) 递送和（具体目标 2）筛选候选疫苗在小鼠和 兔子模型。在 R33 阶段，我们将推进（具体目标 3）一种或多种先导候选疫苗 评估猕猴 SHIV 攻击模型的保护效果。 R61 阶段的里程碑是（里程碑 1) 确定针对淋巴结或保留在注射部位的制剂，（里程碑 2）开发一种 用于鼻内递送repRNA的优化LION配方，（里程碑3）一种或多种repRNA/LION 诱导中和抗体大于或等于 BG505 SOSIP.664 的免疫方案 蛋白质/佐剂疫苗。使用每个里程碑明确定义的通过/不通过指标，我们将确定过渡 到项目的R33阶段。 R33阶段的里程碑是（里程碑1）一个或多个疫苗团 经测量，与猕猴 SHIV 攻击模型中的对照相比，提供了统计上显着的保护 通过一项或多项保护措施以及（里程碑 2）接种疫苗的动物中的一项或多项免疫反应 与一项或多项保护措施相关。

Project Summary/Abstract A key requirement for HIV-1 vaccine development is the induction of broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope (Env) spike. The BG505 SOSIP.664 gp140 soluble timer is engineered to display conformational epitopes recognized by several bNAbs but not non-neutralizing antibodies. The prototype SOSIP vaccine is currently being evaluated in two clinical trials. An effective messenger RNA (mRNA) vaccine expressing BG505 SOSIP.664 will complement the clinical vaccine and open a path to heterologous immunization strategies to elicit immune responses defined by increased breadth and magnitude. Recent achievements in mRNA vaccines is a result of advancements in nanoparticle delivery technologies. We recently reported immunogenicity of a replicating RNA (repRNA) vaccine encoding the spike (S) protein of SARS-CoV- 2; this vaccine, delivered with a novel Lipid Inorganic Nanoparticle (LION) carrier, induced potent binding and neutralizing antibodies in both mice and non-human primates. In the proposed R61/R33 application, we will investigate and optimize attributes of the LION formulation to engineer the immunity of a BG505 SOSIP.664 expressing repRNA vaccine (repRNA-SOSIP.664). The goal is to identify a lead vaccine and administration route that promotes B cell differentiation and maturation needed for induction of high affinity Env antibodies that confer protection in a macaque SHIV challenge model. The proposed work will be performed with a three-way collaboration between Dr. Amit Khandhar at HDT Bio, Dr. Noah Sather at Seattle Children’s Research Institute (SCRI) and Prof. Deborah Fuller at the University of Washington (UW). Proposed activities in the R61 phase will include (specific aim 1) optimizing the repRNA/LION platform for intramuscular (IM), intradermal (ID) and intranasal (IN) delivery and (specific aim 2) screening immunogenicity of vaccine candidates in mouse and rabbit models. In the R33 phase, we will advance (specific aim 3) one or more lead vaccine candidates to evaluate protective efficacy in a macaque SHIV challenge model. Milestones in the R61 phase are (milestone 1) identification of formulations that target lymph nodes or remain at injection site, (milestone 2) develop an optimized LION formulation for intranasal delivery of repRNA, (milestone 3) one or more repRNA/LION immunization regimens that induce neutralizing antibodies greater than or equal to the BG505 SOSIP.664 protein/adjuvant vaccine. Using clearly defined go/no-go metrics for each milestone we will determine transition to the R33 phase of the project. Milestones in the R33 phase are (milestone 1) one or more vaccine regiment affords statistically significant protection compared to controls in a macaque SHIV challenge model as measured by one or more protection measures and (milestone 2) one or more immune responses in vaccinated animals correlate with one or more protection measure.