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Principal Investigator: Norbert Pardi
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2023
Award: $613,686
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
Influenza virus is one of the most important human infectious diseases. The influenza mortality is estimated to
be approximately 650,000 per year worldwide, in addition, occasional global pandemics can infect up to 20-
40% of the world's population. Licensed influenza virus vaccines require annual reformulation and
readministration due to poor IgG longevity and lack of neutralization of related viruses. We have developed a
new vaccine approach against influenza virus that uses antigen-encoding nucleoside-modified mRNA
encapsulated in lipid nanoparticles (LNPs). This vaccine format composed entirely of physiologic components
that is simple and cost effective to produce and should induce no adverse events after administration.
Additionally, mRNA vaccine production is sequence-independent and does not require eggs, cell culture or
protein purification. We demonstrated that monovalent mRNA-LNP vaccines encoding full-length
hemagglutinin (HA) induced potent immune responses against the immunosubdominant HA stalk region, one
of the targets of universal influenza virus vaccines, which was associated with protection against homologous,
heterologous and heterosubtypic influenza viruses in mice. Furthermore, we showed that a single
immunization with nucleoside-modified mRNA-LNP vaccines induced durable protective HA stalk-specific
antibody responses. Finally, we demonstrated that nucleoside-modified mRNA-LNP immunization induced high
levels of antigen-specific T follicular helper (Tfh) cells that are critical for the generation of germinal centers,
immunoglobulin class switch, and long-term memory, which are vital elements in the development of an
effective influenza vaccine. In this grant, we aim to develop and evaluate new generation, broadly protective
influenza virus vaccines in mice and ferrets using nucleoside-modified mRNA-LNPs encoding hemagglutinin,
neuraminidase, nucleoprotein and the ectodomain of M2. Additionally, we aim to investigate the mechanisms
of action of mRNA-LNP influenza virus vaccines. We will have 3 specific aims: 1) Design and production of
mRNA immunogens for conserved regions of influenza virus. 2) Immunogenicity and protective efficacy of
nucleoside-modified mRNA-LNP influenza virus vaccines in mice and ferrets. 3) Investigation of the
mechanisms of action of nucleoside-modified mRNA-LNP influenza vaccines. This proposal will develop safe,
new generation influenza virus vaccines that are easy to manufacture and administer and can protect against
antigenically distant influenza viruses. The data generated will be capable of moving this vaccine approach to
clinical trial development.
Terms: <7S Gamma Globulin><Acylneuraminyl hydrolase><Adverse Experience><Adverse event><Affinity><Animals><Antibodies><Antibody Affinity><Antibody Response><Antigens><Aves><Avian><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Birds><Cancers><Cell Culture Techniques><Cell Mediated Immunology><Cell-Mediated Immunity><Cellular Assay><Cellular Immunity><Cessation of life><Class Switching><Class Switchings><Clinical Trials><Combination Vaccines><Combined Vaccines><Communicable Diseases><Data><Death><Dendritic Cells><Development><Disease Outbreaks><Distant><Elements><Encapsulated><FPLC><Ferrets><Ferritin><Formulation><Generations><Germinal Center><Grant><Grippe><Head><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hemagglutinin><Human><Humoral Immunities><IgG><Immune><Immune response><Immunes><Immunity><Immunization><Immunize><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunoglobulin G><Immunological response><In Vitro><Inducer Cells><Inducer T-Lymphocytes><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza><Influenza A><Influenza A virus><Influenza B><Influenza B Virus><Influenza Vaccines><Influenza Virus><Influenza Viruses Type A><Influenza Viruses Type B><Influenzavirus A><Injections><Investigation><Ion Channel><Ionic Channels><Isotype Switching><Isotype Switchings><KO mice><Knock-out Mice><Knockout Mice><Length><Length of Life><Licensing><Longevity><M mulatta><M. mulatta><Macaca mulatta><Malignant Neoplasms><Malignant Tumor><Membrane><Membrane Channels><Memory><Memory B Cell><Memory B-Lymphocyte><Messenger RNA><Mice><Mice Mammals><Modern Man><Morbidity><Morbidity - disease rate><Mouse Strains><Murine><Mus><N-Acylneuraminate Glycohydrolases><Neuraminidase><Nucleoproteins><Nucleosides><Null Mouse><Oligosaccharide Sialidase><Orthomyxovirus Type A><Orthomyxoviruses Type B><Outbreaks><Pathogenicity><Physiologic><Physiological><Population><Production><Publishing><RNA immunization><RNA vaccination><RNA vaccine><RNA-based vaccine><Reaction><Research><Rhesus Macaque><Rhesus Monkey><Seasons><Serology test><Sialidase><Site><Skin><Standard Model><Structure of germinal center of lymph node><TM Pharmacia Fast Protein Liquid Chromatography><Transfection><Type A Influenza><Vaccination><Vaccine Production><Vaccine Research><Vaccines><Veiled Cells><Viral><Viral Antigens><Virus><ZIKV><Zika Virus><antibody-based immunity><antigen antibody affinity><cell assay><cell culture><cell cultures><cost effective><design><designing><developmental><draining lymph node><egg><exo alpha sialidase><fast protein liquid chromatography><flu infection><flu vaccine><flu virus infection><flu virus vaccine><gene signatures><genetic signature><host response><immune system response><immunization strategy><immunogen><immunogenicity><immunoresponse><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><influenza virus vaccine><influenzavirus><life span><lifespan><lipid based nanoparticle><lipid nanoparticle><long term memory><longterm memory><mRNA><mRNA immunization><mRNA vaccination><mRNA vaccine><mRNA-based vaccine><malignancy><manufacture><membrane structure><mortality><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><neutralizing antibody><new vaccines><next generation vaccines><novel><novel vaccines><pandemic><pandemic concern><pandemic disease><pandemic potential><pandemic risk><pandemic threat><pressure><produce vaccines><programs><protective efficacy><protein purification><regional lymph node><serology assay><universal flu vaccine><universal influenza vaccine><universal influenza virus vaccine><universal vaccine against flu><universal vaccine against influenza><vaccination strategy><vaccination study><vaccination trial><vaccine against flu><vaccine against influenza><vaccine platform><vaccine study><vaccine trial><vaccine-related research><virus antigen><zikav>