Immunogenicity to B and T cell vaccines in non-human primates (NHPs)

B 细胞和 T 细胞疫苗在非人灵长类动物 (NHP) 中的免疫原性

• 批准号: 10205551
• 负责人: BALI PULENDRAN
• 金额: $ 51.16万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10205551
• 关键词: Adjuvant; Affinity; Agonist; Antibodies; Antibody Response; Antibody titer measurement; Antigens; Antiviral Agents; Antiviral Response; B-Lymphocytes; Blood; Bone Marrow; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Collaborations; Environment; Epitopes; Evaluation; Gene Expression Profiling; Genes; Genotype; Glycoproteins; Goals; Hepatitis C Vaccine; Hepatitis C virus; Hepatocyte; Home; Human; Immune response; Immunity; Immunization; Immunize; Infection; Learning; Ligands; Lipid A; Liposomes; Liver; Molecular; Mosaicism; Mucous Membrane; Mus; Myeloid Cells; Phase I Clinical Trials; Plasma Cells; QS21; Saponins; Shapes; Somatic Mutation; Specificity; T cell response; T memory cell; T-Lymphocyte; TLR4 gene; TLR7 gene; Testing; Tissues; Vaccination; Vaccine Design; Vaccines; Variant; Viral; Viral Vaccines; Viral Vector; Walkers; Work; adaptive immune response; aluminum sulfate; antigen-specific T cells; biological systems; design; immunogenicity; neutralizing antibody; nonhuman primate; novel; response; scaffold; vaccination strategy; vaccine development

ABSTRACT - PROJECT 3 The goal of Project 3 is to assess in nonhuman primates (NHPs), immunization strategies aimed at inducing HCV-specific bnAbs and TRMs in the liver. In particular, we will assess the magnitude and durability of bnAb responses induced by immunization with HCV E1/E2 antigens administered with adjuvants; and T cell responses induced by sequential immunization with heterologous viral vectors expressing HCV NS3-NS5b mosaic antigens. Our recent work has demonstrated the adjuvant capacity of TLR7/8 ligand 3M-052 to potently stimulate robust and durable nAb responses as well as remarkably long-lived plasma cells (LLPCs) in bone marrow, similar to responses observed with live viral vaccines. Therefore, in Aim 1 we will evaluate the capacity of 3M-052/alum to stimulate a high magnitude and durability of HCV E1/E2 specific bnAb responses. As a comparator, we will use a novel adjuvant, composed of a liposome, a TLR4 agonist (monophosphoryl lipid A, MPL) and the saponin called QS-21, (Lipo/ QS-21/ MPL), which was recently shown to induce a superior HCV glycoprotein-specific T cell response in mice. Aim 1: To determine the capacity of 3M-052/alum and Lipo/QS-21/MPL to adjuvant antigen- specific immune responses to HCV E1/E2. In this aim, we will test the hypothesis that immunization with HCV E1/E2 with adjuvant results in robust and sustained nAb responses in NHPs. In the case of T cells, our recent results demonstrate that vaccination induced CD8+ TRMs and nAb responses can synergize to provide enhanced protection against viral acquisition to mucosal infectioN. Using single cell transcriptional profiling we demonstrated that reactivation of TRMs in mucosal tissues stimulates anti-viral restriction factors in mucosal myeloid cells, thereby creating a restrictive local environment for viral entry. We hypothesize that an HCV vaccine that induces antigen-specific liver TRMs and nAbs will confer superior protection against HCV, through a similar mechanism involving local innate antiviral responses in myeloid cells and hepatocytes in the liver. Aim 2: To characterize the innate and adaptive immune responses induced by sequential immunization with heterologous viral vectors expressing HCV NS3-NS5b mosaic antigens, followed by immunization with E1/E2 and NS3-5 antigens plus adjuvant. We will immunize NHPs sequentially with Ad48 and MVA expressing Mosaic NS3-5, (to induce NS3-5 specific CD8+ T cells), followed by immunization with soluble HCV E1/E2 antigens (to induce nAbs), and soluble NS3-5 antigens (to boost the CD8+ T cell response primed by viral vectors), administered with an adjuvant. We will analyze the innate and adaptive response in three sub-aims.

摘要 - 项目3 项目3的目的是评估非人类灵长类动物（NHP），旨在的免疫策略 在肝脏中诱导HCV特异性BNAB和TRM。特别是，我们将评估大小和 用佐剂施用的HCV E1/E2抗原免疫引起的BNAB反应的耐用性； 以及通过表达HCV的异源病毒载体顺序免疫引起的T细胞反应 NS3-NS5B镶嵌抗原。我们最近的工作证明了TLR7/8配体3M-052的辅助能力 能够刺激健壮和耐用的NAB响应以及非常长的浆细胞 （LLPC）在骨髓中，类似于用活病毒疫苗观察到的反应。因此，在目标1中，我们将 评估3M-052/明矾的容量，以刺激HCV E1/E2特异性的高幅度和耐用性 BNAB响应。作为比较器，我们将使用由脂质体组成的新型佐剂，TLR4激动剂 （单磷酸脂质A，MPL）和皂苷称为QS-21，（Lipo/ QS-21/ MPL），最近显示 诱导小鼠中的HCV上HCV糖蛋白特异性T细胞反应。 目标1：确定3M-052/明矾和Lipo/QS-21/MPL的能力对辅助抗原 - 对HCV E1/E2的特异性免疫反应。在此目标中，我们将检验以下假设 带有辅助的HCV E1/E2导致NHP中的稳健和持续的NAB响应。 对于T细胞，我们最近的结果表明，疫苗接种诱导CD8+ TRM和 NAB反应可以协同作用，以增强防止粘膜感染的病毒性获取的保护。 使用单细胞转录分析，我们证明了粘膜组织中TRM的重新激活 刺激粘膜髓样细胞中的抗病毒限制因子，从而创造了限制性的局部环境 用于病毒。我们假设一种HCV疫苗可诱导抗原特异性肝脏TRM和 NABS将通过涉及当地先天的类似机制赋予对HCV的优越保护 髓样细胞和肝细胞的抗病毒反应。 目标2：表征由顺序诱导的先天和适应性免疫反应 用表达HCV NS3-NS5B马赛克抗原的异源病毒载体免疫，然后 用E1/E2和NS3-5抗原和佐剂进行免疫。我们将使用 AD48和MVA表达马赛克NS3-5（诱导NS3-5特异性CD8+ T细胞），然后进行免疫 使用可溶性HCV E1/E2抗原（诱导Nabs）和可溶性NS3-5抗原（以增强CD8+ T细胞 由病毒载体启动的响应），由佐剂给药。我们将分析先天和自适应 在三个子手中的响应。