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Principal Investigator: SHAOYI JIANG
Organization: CORNELL UNIVERSITY
Fiscal Year: 2024
Award: $657,623
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
The immunogenicity of nanomaterials is directly related to their performance and toxicity. However, there is still
a lack of systematic studies of how nanomaterials interact with the immune system. In this work, we will focus
on the immunogenicity of lipid nanoparticles (LNPs). Various studies have raised concerns about the adverse
event of LNPs from PEG lipids, ionizable lipids, and even helper phospholipids, such as anti-polyethylene glycol
(PEG) antibodies found in BioNTech/Pfizer and Moderna COVID vaccines. During our recent studies of LNP-
based mRNA cancer vaccines, the side effects, including ulcerative dermatitis, were also found on vaccinated
mice after subcutaneous administrations. Most studies of LNPs via screening or design today have mainly
focused on LNP efficacy while few on LNP immunogenicity. Very limited human data on very limited formulations
in the context of COVID-19 vaccines following intramuscular administration have very limited scope in
immunogenicity such as accessing the overall outcome of immunogenicity only. The investigations have not
extensively delved into the underlying causes of the widely reported adverse effects associated with LNP-based
mRNA vaccines, the specific immunological pathways of immunogenicity, and the underlying relationship
between immunogenicity and components of LNPs. Currently, the mechanism of how LNPs induce adverse
events is yet to be fully understood. Here we will formulate three libraries of LNPs covering widely used lipids
and vary chemical properties of each component. We will perform immunological assays on primary murine cells
to evaluate cytokine secretion and profile inducible gene expression. Similar tests will be performed in human
peripheral blood mononuclear cells (hPBMCs). Toll-like receptor (TLR) and NOD-like receptor (NLR)-dependent
immune response will be evaluated by reporter assays and validated in deficient mouse primary cells.
Furthermore, the immunogenicity of LNPs will be profiled in the setting of intramuscular injections by assessing
local inflammatory responses at the injection sites, and intravenous injections by evaluating the systemic
response including accelerated blood clearance effects. Through these studies, we will identify key components
that are responsible for LNP immunogenicity, understand how the chemistry of each LNP component alters the
level of immune activation, and discover any synergistic effects on the immunogenicity among the components.
The success of this work will advance current LNP technologies and provide clinical benefits for applications
from vaccines to therapeutics.
Terms: <2019-nCoV vaccine><Acceleration><Adverse Experience><Adverse effects><Adverse event><Amines><Antibodies><Antineoplastic Vaccine><Assay><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bioassay><Biological Assay><Blood><Blood Reticuloendothelial System><Bone Marrow><Bone Marrow Reticuloendothelial System><COVID-19 vaccine><Cancer Vaccines><Cell Body><Cell Maturation><Cells><Charge><Chemistry><Clinical><Collaborations><Dendritic Cells><Dermatitis><Drug Kinetics><Ensure><Evaluation><Formulation><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Genetic Medicine><Germinal Center><Guidelines><Hepatotoxic effect><Hepatotoxicity><Human><Hydration><Hydration status><Immune><Immune Cell Activation><Immune infiltrates><Immune response><Immune system><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunology><Immunology procedure><In Vitro><In vivo analysis><Individual><Inflammatory Response><Injections><Intramuscular><Intramuscular Injections><Investigation><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Length of Life><Libraries><Lipids><Liver Toxicity><Longevity><Macrogols><Macrophage><Maps><Measures><Mediating><Medicine><Messenger RNA><Mice><Mice Mammals><Microbiology><Modern Man><Moderna COVID-19 vaccine><Moderna coronavirus disease 2019 vaccine><Mononuclear><Murine><Mus><Mφ><Neoplasm Vaccines><Null Mouse><Outcome><PBMC><Pathway interactions><Performance><Peripheral><Peripheral Blood Mononuclear Cell><Pharmacokinetics><Phenotype><Phosphates><Phosphatides><Phospholipids><Polyethylene Glycols><Polyethylene Oxide><Polyethyleneoxide><Polymers><Polyoxyethylenes><Population><Proteins><Proteomics><RNA Seq><RNA sequencing><RNA vaccine><RNA-based vaccine><RNAseq><Receptor Activation><Receptor Protein><Reporter><Reporting><SARS-CoV-2 vaccine><SARS-coronavirus-2 vaccine><Safety><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 vaccine><Site><Spikevax><Structure><Structure of germinal center of lymph node><TLR protein><Technology><Testing><Therapeutic><Toll-Like Receptor Family Gene><Toll-like receptors><Toxic effect><Toxic effect on liver cells><Toxicities><Transcript Expression Analyses><Transcript Expression Analysis><Transfection><Tumor Vaccines><Vaccinated><Vaccines><Veiled Cells><Veterinary Medicine><Wild Type Mouse><Work><amine><analyze gene expression><anti-tumor vaccine><chemical property><clinical relevance><clinical translation><clinically relevant><clinically translatable><college><collegiate><coronavirus disease 2019 vaccine><coronavirus disease-19 vaccine><cytokine><design><designing><gene expression analysis><gene expression assay><hepatic toxicity><hepatoxicity><host response><human data><immune activation><immune cell infiltrate><immune system response><immunogenicity><immunologic assay><immunologic assay/test><immunoresponse><in vivo evaluation><in vivo testing><inducible expression><inducible gene expression><inorganic phosphate><intramuscular drug administration><intravenous injection><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA vaccine><mRNA-1273><mRNA-based vaccine><mRNA1273><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nanocarrier><nanomaterials><nanovessel><pathway><polymer><polymeric><professor><receptor><response><screening><screenings><side effect><subcutaneous><subdermal><success><systemic toxicity><tertiary amine><transcriptional profiling><transcriptome sequencing><transcriptomic sequencing><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine candidates against SARS-CoV-2><vaccine for cancer><vaccine for novel coronavirus><vaccines preventing COVID><vaccines to prevent COVID><wildtype mouse>