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.

总结 CD 8 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的细胞 主要组织相容性（MHC）I类分子（MHC-I）。CD 8 T细胞有助于清除许多 病毒感染感染消退后，扩增的“记忆”CD 8 T细胞（M CD 8 T细胞）群体 可能有助于更迅速地控制病毒的继发感染。疫苗可以模拟这个过程。 修饰的mRNA（mmRNA）包封在脂质纳米颗粒（mmRNA-LNP）中已经成为一种新的脂质纳米颗粒。 强大的疫苗平台mmRNA-LNP作为疫苗具有许多优点： 目标抗原。2)它们具有高度免疫原性。3)它们很容易制作。4)它们可以大量生产 迅速5)它们相对便宜。mmRNA-LNP疫苗的快速开发和批准， 抗击SARS-CoV-2证明了它们的潜力。虽然已知mmRNA-LNP诱导CD 8 T细胞应答， 关于其保护机制的大部分工作都集中在Abs上。mCD 8 T细胞由mmRNA- LNP可以潜在地补充Ab保护，或者可以为感染的病毒提供大部分保护。 对Ab介导的控制难治。mmRNA-LNP也可用于诱导CD 8 T细胞对抗癌症。 我们已经发表了由mmRNA-LNP诱导的mCD 8 T细胞应答保护小鼠免受高度免疫性疾病的侵袭。 致死性鼠痘，由正痘病毒（OPV）鼠痘病毒引起的小鼠全身性病毒性疾病 （ECTV）. ECTV是一般系统性病毒感染和可感染的OPV的杰出模型 人类，如根除天花病毒（天花病毒）和猴痘病毒（MPXV），最近 引发了一场大爆发在尚未发表的实验中，我们还发现，M CD 8 T细胞诱导的迷你- 仅编码SARS病毒的最小、高度保守的CD 8 T细胞表位VNFNFNGL的mmRNA疫苗- CoV-2刺突蛋白保护野生型小鼠免受小鼠适应的SARS致死性呼吸道感染- CoV-2株MA 30是SARS-CoV-2和其他严重呼吸道感染的杰出模型。这里我们 提出阐明mmRNA-LNP使用ECTV诱导保护性mCD 8 T细胞的机制 全身和MA 30 SARS-CoV-2呼吸道小鼠模型。我们的目标是：（1）具体目标。 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M CD 8 T细胞中的作用。 mRNA-LNP疫苗接种后的发育。