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

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Luis J Sigal
Organization: THOMAS JEFFERSON UNIVERSITY
Fiscal Year: 2024
Award: $708,737
Funding agency: National Institute of Allergy and Infectious Diseases

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 In still unpublished experiments, we also found that M CD8 T-cells induced by a mini-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.

Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><Affect><Airway infections><Antigen Presentation><Antigen-Presenting Cells><Antigens><B blood cells><B cell><B cell differentiation factor><B cell stimulating factor 2><B cells><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><B-Cells><B-Lymphocytes><B-cell><BCDF><BSF-2><BSF2><Binding><Blood monocyte><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19 S protein><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19 virus><Cachectin><Cancers><Cell Body><Cell Protection><Cell surface><Cells><CoV-2><CoV2><Complement><Complement Proteins><Cross Presentation><Cytokine Signal Transduction><Cytokine Signaling><Cytoprotection><Data><Dendritic Cells><Development><Disease Outbreaks><ECTV><Ectromelia virus><Encapsulated><Endogenous Interferon Beta><Family><Feedback><Fibroblast Interferon><Generations><Goals><HPGF><Hematopoietic><Hepatocyte-Stimulating Factor><Histocompatibility><Human><Hybridoma Growth Factor><IFN><IFN-Beta><IFN-Gamma><IFN-beta 2><IFN-g><IFN-β><IFN-γ><IFNAR><IFNAR1><IFNAR1 gene><IFNB2><IFNG><IFNb><IFNγ><IL-6><IL6 Protein><Immune Interferon><Immune response><Immunity><Immunize><Immunological response><Immunomodulation><In Vitro><Infection><Infectious Ectromelia><Inflammatory><Interferon Gamma><Interferon Type I><Interferon Type II><Interferon-beta><Interferon-β><Interferons><Interleukin-6><Langerhans cell><Lung><Lung Respiratory System><MGI-2><Macrophage><Macrophage-Derived TNF><Malignant Neoplasms><Malignant Tumor><Marrow monocyte><Mediating><Memory><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Monkey Pox Virus><Monkeypox virus><Monkeypoxvirus><Monocyte-Derived TNF><Mouse Pox><Mouse Pox Virus><Mousepox><Mousepox virus><Murine><Mus><Myeloid Differentiation-Inducing Protein><Mφ><Natural Interferon Beta><Natural human interferon beta><Non-Polyadenylated RNA><Orthopox virus><Orthopoxvirus><Outbreaks><P variolae><P. variolae><P.variolae><Peptides><Plasmacytoma Growth Factor><Play><Population><Poxvirus muris><Poxvirus variolae><Process><Production><Publishing><RNA><RNA Gene Products><RNA vaccine><RNA-based vaccine><Receptor Protein><Refractory><Respiratory Infections><Respiratory Tract Infections><Ribonucleic Acid><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Smallpox virus><Source><Systemic infection><T cell differentiation><T cell response><T-Cell Development><T-Cell Epitopes><T-Cell Ontogeny><T-Cells><T-Lymphocyte><T-Lymphocyte Development><T-Lymphocyte Epitopes><T8 Cells><T8 Lymphocytes><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Tissue Compatibility><Tissues><Transgenic Mice><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Vaccinated><Vaccination><Vaccines><Variola major virus><Variola virus><Veiled Cells><Viral><Viral Diseases><Virus><Virus Diseases><Wild Type Mouse><Work><Wuhan coronavirus><accessory cell><angiotensin converting enzyme 2><angiotensin converting enzyme II><combat><complementation><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytokine><cytoprotective><developmental><draining lymph node><experiment><experimental research><experimental study><experiments><global gene expression><global transcription profile><hCoV19><hemopoietic><host response><immune modulation><immune regulation><immune system response><immunogen><immunogenic><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><in vivo><interest><interferon beta 2><lFN-Gamma><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA vaccine><mRNA-based vaccine><malignancy><monocyte><mouse model><mpox virus><mpxv><murine model><nCoV2><neoplasm/cancer><pulmonary><rational design><receptor><recruit><regional lymph node><respiratory><secondary infection><small pox virus><social role><spike proteins on SARS-CoV-2><thymus derived lymphocyte><transcriptome><vaccine platform><viral infection><virus infection><virus-induced disease><wildtype mouse>