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

项目摘要/摘要 开发HIV-1疫苗的一个关键要求是诱导广谱中和抗体(BNAbs)。 瞄准HIV-1包膜(Env)尖峰。BG505 SOSIP.664 gp140可溶定时器设计用于显示 可被几种bNAbs识别但不能被非中和抗体识别的构象表位。SOSIP原型机 疫苗目前正在两项临床试验中进行评估。一种有效的信使RNA(MRNA)疫苗 表达BG505 SOSIP.664将补充临床疫苗，并开辟一条通往异源疫苗的道路 免疫策略，以激发由增加的广度和幅度定义的免疫反应。近期 信使核糖核酸疫苗的成就是纳米颗粒递送技术进步的结果。我们最近 SARS冠状病毒S蛋白(S)复制核糖核酸疫苗的免疫原性研究 2.该疫苗以新型脂质无机纳米颗粒(LION)载体递送，可诱导强有力的结合和 老鼠和非人类灵长类动物中的中和抗体。在建议的R61/R33应用程序中，我们将 研究和优化狮子配方的属性，以工程BG505 SOSIP.664的免疫力 表达的epRNA疫苗(epRNA-SOSIP.664)。目标是确定一种主要的疫苗和给药途径 促进B细胞分化和成熟，是诱导高亲和力Env抗体所需的 猕猴Shiv挑战模型中的保护。拟议的工作将以三方方式进行 HDT Bio的Amit Khandhar博士和西雅图儿童研究所的Noah Sather博士之间的合作 (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)优化用于肌肉内(IM)、皮内(ID)和 鼻腔给药和(特异靶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)一个或多个主要候选疫苗以 在猕猴Shiv挑战模型中评估保护效果。R61阶段的里程碑是(里程碑 1)确定靶向淋巴结或留在注射部位的配方，(里程碑2)开发 鼻腔给药的优化Lion配方，(里程碑3)一个或多个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。对于每个里程碑，我们将使用明确定义的通过/不进行指标来确定过渡 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 与猕猴SHIV挑战模型中的对照组相比，提供了统计上显著的保护 通过一项或多项保护措施和(里程碑2)接种动物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.