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

设计自我复制和佐剂 RNA HIV-1 疫苗的免疫反应

• 批准号: 10390431
• 负责人: Amit Praful Khandhar
• 金额: $ 104.65万
• 依托单位: HDT BIO CORPORATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-09 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390431
• 关键词: Achievement; Adjuvant; Affinity; Animals; Antibodies; Antibody Response; Antibody titer measurement; Antigens; B cell differentiation; B-Lymphocytes; Benchmarking; Binding; Biodistribution; COVID-19 vaccine; Cations; Cell Maturation; Child; Clinical; Clinical Trials; Collaborations; Complement; Complex; Drops; Emulsions; Engineering; Epitopes; Formulation; Future; Goals; HIV; HIV-1; HIV-1 vaccine; Histology; Immune; Immune response; Immunity; Immunization; Immunize; Injections; Intramuscular; Lead; Lipids; Macaca; Measures; Messenger RNA; Modeling; Molecular Conformation; Mucous Membrane; Mus; Normal tissue morphology; Nucleic Acid Vaccines; Oryctolagus cuniculus; Pathway interactions; Phase; Phase I Clinical Trials; Proteins; RNA; RNA vaccine; Regimen; Reporting; Research Institute; Route; SARS-CoV-2 spike protein; Serum; Site; Squalene; Technology; Testing; TimeLine; Universities; Vaccinated; Vaccination; Vaccines; Viral; Viral Load result; Virus; Washington; Work; base; design; efficacy evaluation; immunoengineering; immunogenicity; lymph nodes; nanoparticle; nanoparticle delivery; neutralizing antibody; nonhuman primate; novel; preclinical development; protective efficacy; protein expression; prototype; response; screening; simian human immunodeficiency virus; trafficking; vaccination strategy; vaccine candidate; vaccine delivery; vaccine development; vaccine formulation; vaccine immunogenicity

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.

项目摘要/摘要 HIV-1疫苗开发的关键要求是诱导广泛中和抗体（BNAB） 针对HIV-1信封（ENV）尖峰。 BG505 SOSIP.664 GP140实体计时器已设计用于显示 构象表位由几个BNAB识别而非非中和抗体识别。原型SOSIP 目前正在两项临床试验中评估疫苗。有效的信使RNA（mRNA）疫苗 表达BG505 SOSIP.664将完成临床疫苗并打开异源途径 免疫策略，以增加宽度和幅度的增加而定义的免疫反应。最近的 mRNA疫苗的成就是纳米颗粒输送技术进步的结果。我们最近 据报道，复制RNA（RERNNA）疫苗的免疫原性编码SARS-COV的尖峰蛋白 2;这种疫苗用新型脂质无机纳米颗粒（狮子）载体传递，诱导了有效的结合和 小鼠和非人类隐私的中和抗体中和抗体。在拟议的R61/R33应用程序中，我们将 调查和优化狮子公式的属性，以设计BG505 SOSIP的免疫力664 表达reprna疫苗（Reprna-Sosip.664）。目标是确定铅疫苗和管理路线 这促进了诱导高亲和力ENV抗体所需的B细胞分化和成熟 在猕猴的Shiv挑战模型中进行保护。拟议的工作将通过三路进行 HDT Bio的Amit Khandhar博士之间的合作，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（特定目标1）优化肌内（IM），皮内（ID）和 鼻内（IN）递送和（特定目标2）筛查小鼠疫苗候选物的免疫原性和 兔子模型。在R33阶段，我们将促进（特定目标3）一台或多个铅疫苗候选者 在猕猴Shiv挑战模型中评估受保护的有效性。 R61阶段的里程碑是（里程碑） 1）鉴定靶向淋巴结或留在注射部位的公式，（里程碑2）发展 优化的狮子递送递送的狮子公式，（里程碑3）一个或多个reprna/狮子 免疫方案诱导大于或等于BG505 SOSIP的中和抗体。664 蛋白质/辅助疫苗。对于每个里程碑，使用明确定义的go/no-go指标，我们将确定过渡 到该项目的R33阶段。 R33期的里程碑是（里程碑1）一个或多个疫苗团 与猕猴Shiv挑战模型中的对照相比，具有统计学上显着的保护 通过一项或多项保护措施和（里程碑2）在接种动物中进行一次或多个免疫复杂 与一种或多种保护措施相关。