Document text
Principal Investigator: Norbert Pardi
Organization: UNIVERSITY OF CALIFORNIA-IRVINE
Fiscal Year: 2024
Award: $3,953,703
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract – Project 2: mRNA Vaccine Development against Bunyaviruses,
Paramyxoviruses and Picornaviruses
As the emergence of new pathogenic outbreaks in the future is not a matter of “if”, but of “when”, development
of prophylactic vaccines against viruses with high pandemic potential prior to actual outbreaks is a reasonable
strategy to contribute to global pandemic preparedness. The lipid nanoparticle (LNP)-formulated nucleoside-
modified mRNA platform is particularly suitable for vaccine development against viral pathogens because it can
efficiently generate T follicular helper cell responses associated with the induction of durable and broadly
protective antibody responses. Beside potency, this novel, synthetic vaccine platform has important advantages
over other vaccine types, including rapid, scalable production that does not require complicated infrastructure
(such as mammalian cell culture and protein purification systems). Additionally, the enormous flexibility of the
mRNA-LNP platform allows the co-formulation of several antigen-encoding mRNAs into a single vaccine regimen
to elicit more potent and/or broadly protective immune responses. The overall goal of Project 2 of this U19
Program is to develop potent mRNA-based vaccines against select members of Bunyaviruses, Paramyxoviruses
and Picornaviruses, capable of inducing protective immune responses and evaluate them in animal models.
In Aim 1.1, we will design and produce nucleoside-modified mRNA immunogens targeting select members of
Bunyaviruses, Paramyxoviruses and Picornaviruses. In Aim 1.2, we will collaborate with Project 1 (Felgner Lab)
on LNP-formulation of the mRNA immunogens using various lipids. In Aim 1.3, in vitro characterization
(confirmation of protein production from each mRNA) of mRNA-LNP vaccines will be performed using HEK293T
cells. Evaluation of the immunogenicity of Bunyavirus, Paramyxovirus and Picornavirus mRNA-LNP vaccines
will be performed in Aims 2.1, 2.2 and 2.3, respectively. In all 3 subaims, antibody responses (antigen-specific
IgG, virus neutralization) as well as T and B cell (T follicular helper cell, CD8+ T cell, germinal center B cell,
memory B cell and plasma cell) responses will be evaluated. The durability of antibody responses will also be
assessed. Based on the results of challenge experiments (performed by Projects 3-5), multivalent vaccines will
be generated and tested for immunogenicity and protective efficacy. If the multivalent formulations provide high
levels of protection in mice (tested by Projects 3-5), they will be evaluated in nonhuman primates by the
Translational Immunology Core.
The proposed work will yield “prototype” vaccines that can be tested in clinical trials and quickly be adjusted to
a pandemic pathogen and be produced and distributed at large scale. These deliverables have an immediate
translational potential and will significantly contribute to our pandemic preparedness against Bunyaviruses,
Paramyxoviruses and Picornaviruses with high pandemic potential.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><7S Gamma Globulin><Amino Acid Sequence><Animal Model><Animal Models and Related Studies><Animals><Antibody Response><Antigen Targeting><Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Blood Plasma Cell><Bunyavirales><Bunyavirus><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 virus><COVID-19 years><COVID19 virus><Cancers><Cell Body><Cell Culture Techniques><Cells><Clinical><Clinical Trials><CoV-2><CoV2><Collaborations><Communicable Diseases><Complex><Death Rate><Development><Disease Outbreaks><EBOV><Ebola><Ebola virus><Ebola-like Viruses><Encapsulated><Evaluation><Face><Family><Family Picornaviridae><Ferrets><Formulation><Future><Germinal Center><Goals><Grippe><H1N1><H1N1 Virus><HHV-2><HHV2><HSV-2><HSV2><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Herpes Simplex Virus 2><Herpes Simplex Virus Type 2><Herpesvirus 2 (alpha), Human><Herpesvirus progenitalis><Human><Human (alpha) herpes virus 2><Human Herpesvirus 2><Human herpes simplex virus type 2><IgG><Immune response><Immunoglobulin G><Immunological response><In Vitro><Inducer Cells><Inducer T-Lymphocytes><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza><Influenza A Virus, H1N1 Subtype><Influenza Virus><Infrastructure><Investments><Lead><Length><Lipids><MERS><MERS coronavirus disease><MERS-CoV disease><Malignant Neoplasms><Malignant Tumor><Mammalian Cell><Memory B Cell><Memory B-Lymphocyte><Messenger RNA><Mice><Mice Mammals><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome coronavirus disease><Modeling><Modern Man><Murine><Mus><Nucleosides><Orthobunyavirus><Outbreaks><Paramyxoviridae><Paramyxovirus><Pathogenicity><Pb element><Phase><Picornaviridae><Picornaviruses><Plasma Cells><Plasmacytes><Pre-Clinical Model><Preclinical Models><Preventative vaccine><Preventive vaccine><Primary Protein Structure><Process><Production><Prophylactic vaccine><Proteins><RNA vaccine><RNA-based vaccine><Regimen><Rodent><Rodentia><Rodents Mammals><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus><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 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Structure of germinal center of lymph node><Synthetic Vaccines><System><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Testing><Transmission><Vaccines><Virus><Work><Wuhan coronavirus><ZIKA><ZIKV><Zika Virus><cell culture><cell cultures><chikungunya><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><experience><experiment><experimental research><experimental study><experiments><faces><facial><flexibility><flexible><future outbreak><hCoV19><heavy metal Pb><heavy metal lead><herpes simplex ii><host response><human alphaherpesvirus 2><immune system response><immunogen><immunogenic><immunogenicity><immunoresponse><influenzavirus><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA vaccine><mRNA-based vaccine><malignancy><member><model of animal><mortality rate><mortality ratio><nCoV2><neoplasm/cancer><next outbreak><non-human primate><nonhuman primate><novel><outbreak in the future><pandemic><pandemic concern><pandemic disease><pandemic disease preparedness><pandemic pathogen><pandemic planning><pandemic potential><pandemic preparedness><pandemic readiness><pandemic risk><pandemic threat><pathogen><pathogenic virus><plasmocyte><pre-clinical><pre-clinical study><preclinical><preclinical study><programs><protective efficacy><protein purification><protein sequence><prototype><response><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome-CoV><thymus derived lymphocyte><translational immunology><translational opportunities><translational potential><transmission process><vaccine candidate><vaccine development><vaccine platform><viral epidemic><viral pathogen><virus pathogen><zikav>