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（bNAbs） 靶向HIV-1包膜（Env）尖峰。BG 505 SOSIP.664 gp 140可溶性计时器设计用于显示 这些构象表位被几种bNAb识别，但不被非中和抗体识别。SOSIP原型 目前正在两项临床试验中对疫苗进行评估。一种有效的信使RNA（mRNA）疫苗 表达BG 505 SOSIP.664将补充临床疫苗，并开辟异源性免疫途径。 免疫策略，以引起免疫反应的定义增加的广度和幅度。最近 在mRNA疫苗方面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，与一种新的脂质无机纳米颗粒（LION）载体一起递送，诱导了有效的结合， 中和抗体在小鼠和非人灵长类动物中。在建议的R61/R33应用中，我们会 研究和优化LION配方的属性，以设计BG 505 SOSIP.664的免疫力 表达repRNA疫苗（repRNA-SOSIP.664）。目标是确定一种先导疫苗和管理途径 其促进诱导高亲和力Env抗体所需的B细胞分化和成熟， 保护猕猴SHIV攻击模型。建议的工作将通过三路 HDT Bio的Amit Khandhar博士和西雅图儿童研究所的Noah Sather博士 （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（具体目的2）筛选候选疫苗在小鼠中的免疫原性 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攻击模型中的保护功效。R61阶段的里程碑是（里程碑 1)确定靶向淋巴结或保留在注射部位的制剂（里程碑2）， 用于鼻内递送repRNA的优化的LION制剂，（里程碑3）一种或多种repRNA/LION 诱导中和抗体大于或等于BG 505 SOSIP的免疫方案。664 蛋白/佐剂疫苗。我们将使用每个里程碑的明确定义的go/no-go指标来确定过渡 项目的R33阶段。R33阶段的里程碑是（里程碑1）一个或多个疫苗方案 与猕猴SHIV攻击模型中的对照相比， 通过一种或多种保护措施和（里程碑2）接种动物中的一种或多种免疫应答 与一个或多个保护措施相关联。

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.