Mechanisms of protective memory CD8 T-cell induction by mRNA-LNP vaccines

mRNA-LNP 疫苗诱导保护性记忆 CD8 T 细胞的机制

• 批准号: 10753981
• 负责人: Luis J Sigal
• 金额: $ 72.27万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753981
• 关键词: 2019-nCoV; ACE2; Affect; Antigen Presentation; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Binding; Bone Marrow; CD8-Positive T-Lymphocytes; Cell surface; Cells; Complement; Cross Presentation; Cytokine Signaling; Cytoprotection; Data; Dendritic Cells; Development; Disease Outbreaks; Encapsulated; Family; Feedback; Generations; Goals; Hematopoietic; Histocompatibility; Human; IFNAR1 gene; Immune response; Immunity; Immunize; In Vitro; Infection; Infectious Ectromelia; Inflammatory; Interferon Type I; Interferon Type II; Interferon-beta; Interferons; Interleukin-6; Langerhans cell; Lung; Macrophage; Malignant Neoplasms; Mediating; Memory; Messenger RNA; Modeling; Monkeypox virus; Mouse Pox Virus; Mus; Orthopoxvirus; Peptides; Play; Population; Process; Production; Publishing; RNA; RNA vaccine; Refractory; Respiratory Tract Infections; Role; SARS-CoV-2 spike protein; Source; Systemic infection; T cell differentiation; T cell response; T-Cell Development; T-Lymphocyte; T-Lymphocyte Epitopes; TNF gene; Tissues; Transgenic Mice; Vaccinated; Vaccination; Vaccines; Variola major virus; Viral; Virus; Virus Diseases; Wild Type Mouse; Work; combat; cytokine; draining lymph node; experimental study; immunogenic; immunoregulation; improved; in vivo; interest; lipid nanoparticle; monocyte; mouse model; rational design; receptor; recruit; respiratory; secondary infection; transcriptome; vaccine platform

Summary CD8 T-cells recognize and kill virus-infected cells displaying at the cell surface short viral peptides bound to major histocompatibility (MHC) class I molecules (MHC-I). CD8 T-cells contribute to the clearance of many viral infections. After an infection subsides, an expanded population of “memory” CD8 T-cells (M CD8 T-cells) may contribute to more rapidly controlling a secondary infection with the virus. Vaccines can mimic this process. Modified mRNA (mmRNA) encapsulated in lipid nanoparticles (mmRNA-LNP) have emerged as a powerful vaccine platform. mmRNA-LNPs have many advantages as vaccines: 1) They can be focused on the antigen of interest. 2) They are highly immunogenic. 3) they are easy to make. 4) They can be mass-produced rapidly. 5) They are relatively inexpensive. The swift development and approval of the mmRNA-LNP vaccines to combat SARS-CoV-2 attest to their potential. While it is known that mmRNA-LNPs induce CD8 T-cell responses, most of the work on their protection mechanisms has focused on Abs. The mCD8 T-cells induced by mmRNA- LNP can potentially complement Ab protection or may provide most of the protection for viruses that are refractory to Ab-mediated control. mmRNA-LNPs could also be used to induce CD8 T-cells against cancer. We have published that the mCD8 T-cell responses induced by mmRNA-LNPs protect mice from highly lethal mousepox, a systemic viral disease of the mouse caused by the Orthopoxvirus (OPV) ectromelia virus (ECTV). ECTV is an outstanding model for systemic viral infections in general and for OPVs that can infect humans, such as the eradicated variola virus (virus of smallpox) and for monkeypox virus (MPXV), which recently caused a major outbreak. In still unpublished experiments, we also found that M CD8 T-cells induced by a mini- mmRNA vaccine encoding for only the minimal, highly conserved CD8 T-cell epitope VNFNFNGL of the SARS- CoV-2 Spike protein protects wild-type mice from lethal respiratory infection with the mouse-adapted SARS- CoV-2 strain MA30, an outstanding model for SARS-CoV-2 and other grave respiratory infections. Here we propose elucidating the mechanisms whereby mmRNA-LNPs induce protective mCD8 T-cells using the ECTV systemic and the MA30 SARS-CoV-2 respiratory mouse models. Our Specific Aims are to: A) Specific Aim 1. Investigate the Mechanisms of MHC-I antigen presentation after mmRNA-LNP vaccination. B) Specific Aim 2. Investigate the roles of Type I interferon (IFN-I) and other proinflammatory cytokines in protective M CD8 T-cell development after mRNA-LNP vaccination.

概括 CD8 T 细胞识别并杀死在细胞表面展示结合的短病毒肽的病毒感染细胞 主要组织相容性 (MHC) I 类分子 (MHC-I) CD8 T 细胞有助于清除许多物质。 病毒感染消退后，“记忆”CD8 T 细胞（M CD8 T 细胞）数量会增加。 疫苗可能有助于更快地控制病毒的继发感染。 封装在脂质纳米粒子 (mmRNA-LNP) 中的修饰 mRNA (mmRNA) 已成为一种 mmRNA-LNP 作为疫苗具有许多优势：1）它们可以专注于 2）它们具有高度免疫原性 3）它们易于制造 4）它们可以大规模生产。 5) mRNA-LNP 疫苗的开发和批准相对便宜。 对抗 SARS-CoV-2 证明了它们的潜力，虽然众所周知，mmRNA-LNP 会诱导 CD8 T 细胞反应， 关于其保护机制的大部分工作都集中在 mmRNA- 诱导的 mCD8 T 细胞上。 LNP 可以潜在地补充 Ab 保护，或者可以为以下病毒提供大部分保护： 对 Ab 介导的控制无效的 mmRNA-LNP 也可用于诱导 CD8 T 细胞对抗癌症。 我们已经发表了由 mmRNA-LNP 诱导的 mCD8 T 细胞反应可以保护小鼠免受高度 致命性鼠痘，一种由正痘病毒 (OPV) 鼠痘病毒引起的小鼠全身性病毒性疾病 (ECTV) 是一般系统性病毒感染和可感染的 OPV 的杰出模型。 人类，例如根除的天花病毒（天花病毒）和猴痘病毒（MPXV），最近 在尚未发表的实验中，我们还发现 M CD8 T 细胞是由微型病毒诱导的。 mmRNA 疫苗仅编码 SARS 的最小、高度保守的 CD8 T 细胞表位 VNFNFNGL SARS-CoV-2刺突蛋白可保护野生型小鼠免受致命性呼吸道感染 CoV-2 菌株 MA30，SARS-CoV-2 和其他严重呼吸道感染的杰出模型。 建议利用 ECTV 阐明 mmRNA-LNPs 诱导保护性 mCD8 T 细胞的机制 系统性和 MA30 SARS-CoV-2 呼吸系统小鼠模型 我们的具体目标是： A) 具体目标 1。 研究 mmRNA-LNP 疫苗接种后 MHC-I 抗原呈递的机制 B) 具体目标 2。 研究 I 型干扰素 (IFN-I) 和其他促炎细胞因子在保护性 M CD8 T 细胞中的作用 mRNA-LNP 疫苗接种后的发育。