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: 10409762
• 负责人: BALI PULENDRAN
• 金额: $ 42.16万
• 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/10409762
• 关键词: Adjuvant; Affinity; Agonist; Antibodies; Antibody Response; Antibody titer measurement; Antigens; 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的目标是评估非人灵长类动物（NHP）的免疫策略， 在肝脏中诱导HCV特异性bnAb和TRM。特别是，我们将评估规模和 通过与佐剂一起施用的HCV E1/E2抗原免疫诱导的bnAb应答的持久性; 用表达HCV的异源病毒载体序贯免疫诱导的T细胞应答 NS 3-NS 5 b嵌合抗原。我们最近的工作证明了TLR 7/8配体3 M-052的佐剂能力 有效地刺激强大和持久的nAb反应以及非常长寿的浆细胞 （LLPC），类似于用活病毒疫苗观察到的反应。因此，在目标1中， 评价3 M-052/明矾刺激HCV E1/E2特异性高强度和持久性的能力 bnAb应答。作为比较，我们将使用一种新的佐剂，由脂质体，TLR 4激动剂， （单磷酰脂质A，MPL）和称为QS-21的皂苷（Lipo/ QS-21/ MPL），其最近显示 以在小鼠中诱导更好的上级HCV糖蛋白特异性T细胞应答。 目的1：确定3 M-052/alum和Lipo/QS-21/MPL对佐剂抗原的能力。 针对HCV E1/E2的特异性免疫应答。在这一目标中，我们将测试免疫接种的假设， HCV E1/E2与佐剂在NHP中产生稳健和持续的nAb应答。 在T细胞的情况下，我们最近的研究结果表明，疫苗接种诱导的CD 8 + TRM和CD 8 + T细胞减少。 nAb应答可以协同作用以提供增强的保护以对抗病毒获得粘膜感染。 使用单细胞转录谱，我们证明了粘膜组织中TRM的再激活 刺激粘膜髓样细胞中的抗病毒限制因子，从而产生限制性局部环境 病毒进入。我们假设，诱导抗原特异性肝脏TRM的HCV疫苗， nAbs将通过类似的机制，包括局部先天免疫，赋予抗HCV的上级保护作用。 在肝脏中的骨髓细胞和肝细胞中的抗病毒应答。 目的2：研究序贯免疫诱导的先天性和适应性免疫应答， 用表达HCV NS 3-NS 5 b嵌合抗原的异源病毒载体免疫，然后 用E1/E2和NS 3 -5抗原加佐剂免疫。我们将免疫NHP依次与 表达嵌合NS 3 -5的Ad 48和MVA（以诱导NS 3 -5特异性CD 8 + T细胞），随后免疫 用可溶性HCV E1/E2抗原（以诱导nAb）和可溶性NS 3 -5抗原（以加强CD 8 + T细胞 由病毒载体引发的应答），与佐剂一起施用。我们将分析先天的和适应性的 在三个子目标中。