Regulation of germinal center responses by SARS-CoV-2 messenger RNA vaccines

NIH Pandemic-Era Grants

Pandemic Era Grants

2023

↗ Live URL (may be dead)

Document text

Principal Investigator: Michela  Locci
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2023
Award: $668,622
Funding agency: National Institute of Allergy and Infectious Diseases

SUMMARY
Messenger RNA (mRNA) vaccines represent a powerful vaccine approach for the induction of protective immune
responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since this vaccine platform
was approved for human use in 2020 for the first time, little is known about the durability and mechanisms of
induction of the immune responses elicited by SARS-CoV-2 mRNA vaccines. In mice, the generation of SARS-
CoV-2 neutralizing antibodies (nAbs) driven by mRNA vaccines is associated with the formation of robust
germinal centers (GCs). GCs are sophisticated processes during which antigen-specific B cells give rise to high-
affinity Ab-secreting cells and memory B cells. The GC reaction is tightly regulated by T follicular helper (Tfh)
cells, which are also efficiently generated during SARS-CoV-2 mRNA vaccination. In this grant proposal, we
seek to address the following 3 fundamental questions related to SARS-CoV-2 mRNA vaccines: 1) How durable
are the GC-derived B cell responses to SARS-CoV-2 mRNA vaccines in mice and humans?; 2) What types of
antigen presenting cells (APCs) promote Tfh cell differentiation in SARS-CoV-2 mRNA vaccination? And how
do these APCs sense these mRNA vaccines?; and 3) How do SARS-CoV-2 mRNA vaccines induce GC B cell
responses? Overall, the studies that we propose here will allow us to determine the longevity of GC-derived B
cell responses and to shed light on the mechanisms by which SARS-CoV-2 mRNA vaccines ensure a powerful
elicitation of Tfh and GC B cells. The knowledge acquired here will be important to inform future boosting
strategies for SARS-CoV-2 mRNA vaccination, as well as the rational design of next generation vaccines for
difficult-to-neutralize pathogens.

Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><Address><Affinity><Antibodies><Antibody Affinity><Antibody Response><Antibody titer measurement><Antibody-Producing Cells><Antibody-Secreting Cells><Antigen Presentation><Antigen-Presenting Cells><Antigenic Determinants><Antigens><Applications Grants><B blood cells><B cell><B cells><B-Cell Activation><B-Cells><B-Lymphocytes><B-cell><Binding Determinants><Blood Plasma Cell><Booster Immunization><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><COVID-19 infection><COVID-19 vaccine><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 vaccine><COVID19 virus><Cell Differentiation><Cell Differentiation process><Cell Shape><CoV-2><CoV2><Complex><Dendritic Cells><Encapsulated><Endowment><Ensure><Epitopes><Event><FDA EUA><FDA Emergency Use Authorization><Food and Drug Administration EUA><Food and Drug Administration Emergency Use Authorization><Fostering><Future><Generations><Germinal Center><Grant Proposals><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Human><Immune response><Immunoglobulin-Producing Cells><Immunoglobulin-Secreting Cells><Immunological response><Individual><Inducer Cells><Inducer T-Lymphocytes><Infection><Knowledge acquisition><Label><Length><Length of Life><Licensing><Longevity><Mediating><Membrane><Memory B Cell><Memory B-Lymphocyte><Messenger RNA><Mice><Mice Mammals><Modern Man><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Murine><Mus><Names><Nature><Nucleosides><Pathway interactions><Plasma Cells><Plasmacytes><Process><Proteins><RNA immunization><RNA vaccination><RNA vaccine><RNA-based vaccine><Race><Races><Reaction><Regulation><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV-2 vaccine><SARS-CoV2><SARS-CoV2 infection><SARS-CoV2 vaccine><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Secondary Immunization><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 CoV 2 vaccine><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 infection><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Speed><Structure of germinal center of lymph node><T4 Cells><T4 Lymphocytes><TLR protein><Technology><Testing><Time><Toll-Like Receptor Family Gene><Toll-like receptors><Vaccination><Vaccine Design><Vaccines><Veiled Cells><Wuhan coronavirus><accessory cell><activated B cells><antibody titering><antigen antibody affinity><booster vaccination><cell type><conformation><conformational><conformational state><conformationally><conformations><corona virus disease 2019 vaccine><coronavirus disease 2019 infection><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease-19 vaccine><coronavirus disease-19 virus><cytokine><deploy vaccines><develop a vaccine><develop vaccines><development of a vaccine><distribute vaccines><emergency use authorization><hCoV19><host response><immune system response><immunogen><immunoresponse><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><innovate><innovation><innovative><life span><lifespan><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA immunization><mRNA vaccination><mRNA vaccine><mRNA-based vaccine><membrane structure><mouse model><murine model><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nCoV2><name><named><naming><neutralizing antibody><new vaccines><next generation vaccines><novel vaccines><pandemic><pandemic disease><pathogen><pathway><plasmocyte><programs><racial><racial background><racial origin><rational design><response><secondary lymph organ><secondary lymphatic organ><secondary lymphoid organ><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine deployment><vaccine development><vaccine distribution><vaccine for novel coronavirus><vaccine platform><vaccine roll-out><vaccine rollout>