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Principal Investigator: Yizhou Dong
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2023
Award: $778,064
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
A vaccine is a promising approach for stopping the spread of HIV infections. Although vaccine regimens in clinical
trials show various levels of protection against HIV, there is no effective vaccine available for a large population
yet. Preclinical and clinical data demonstrate the importance of both adjuvants and antigens for an effective HIV
vaccine. Particularly, stimulation of toll-like receptors (TLRs) or stimulator of interferon genes (STING) boosts
the immune response of the HIV antigens in multiple animal models. Meanwhile, HIV immunogens are a critical
factor for both humoral immunity and cell-mediated immunity such as broadly neutralizing antibodies (bnAbs)
and cytotoxic T cells. Despite these important advances, significant challenges remain in immunogen design,
immunogen delivery, and adjuvant choice. To overcome these challenges, we propose to integrate adjuvant
derived nanoparticles and engineered mRNA for HIV vaccine discovery. In preliminary studies, we developed
adjuvant derived nanoparticles (ANPs) using TLR or STING agonists, which showed great potential for efficient
mRNA delivery as a vaccine platform. Moreover, we constructed glycosylated HIV immunogens that trigger
mannose-binding lectin (MBL)-mediated innate immune recognition, leading to enhanced antibody responses.
Additionally, we systematically investigated the untranslated regions (UTRs) of mRNAs in order to enhance
protein production. Through a comprehensive analysis of endogenous gene expression and de novo design of
UTRs, we identified the optimal combination of 5’ and 3’ UTR for mRNA engineering. Based on these results
and findings, the goal of this proposed project is to develop adjuvant derived nanoparticles as functional
nanomaterials capable of efficiently delivering HIV immunogens in vivo, consequently generating strong and
durable humoral and cell-mediated immunity against HIV. The following specific aims will be carried out to
accomplish our goal: 1) Synthesis and characterization of adjuvant derived nanoparticles (ANPs); 2) Engineering
of mRNA transcripts encoding various HIV immunogens with high translation efficiency; and 3) Determination of
immunogenicity and safety profiles of ANPs-mRNA in mouse and non-human primate models. Encouraged by
results from our preliminary studies, we expect the newly designed nanomaterials from this proposal to establish
a vaccine candidate, which can facilitate clinical translation and a new avenue for HIV vaccine discovery.
Knowledge gained from this study can also be extended to other types of vaccines for emerging pathogens.
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Immunity><Cellular model><Charge><Chemicals><Clinical><Clinical Data><Clinical Research><Clinical Study><Clinical Trials><CoV-2><CoV2><Country><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Data><Dendritic Cells><Development><Engineering><Envelope Protein><Epidemic><Epitopes><Europe><Exhibits><Formulation><Future><Gene Expression><Goals><HIV><HIV Antigens><HIV Infections><HIV vaccine><HIV-Associated Antigens><HIV/AIDS Vaccines><HTLV-III Antigens><HTLV-III Infections><HTLV-III-LAV Antigens><HTLV-III-LAV Infections><Healthcare><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Antigens><Human T-Lymphotropic Virus Type III Infections><Humoral Immunities><Immune><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immune response><Immunes><Immunological response><Investigators><Knowledge><LAV Antigens><LAV-HTLV-III><Lead><Lymphadenopathy-Associated Antigens><Lymphadenopathy-Associated Virus><Macaca><Macaque><Mannan-Binding Lectin><Mannan-Binding Protein><Mannose Binding Lectin><Mannose-Binding Protein><Mannose-Specific Lectin><Mediating><Messenger RNA><Metabolic Glycosylation><Mice><Mice Mammals><Modeling><Modern Man><Moderna COVID-19 vaccine><Moderna coronavirus disease 2019 vaccine><Murine><Mus><Nanotechnology><Non-Polyadenylated RNA><Organ><Pathway interactions><Pattern><Pb element><Persons><Pfizer-BioNTech COVID-19 vaccine><Pfizer-BioNTech coronavirus disease 2019 vaccine><Polymerase><Population><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Process><Production><Property><Protein Modification><Proteins><Public Health><RNA><RNA Gene Products><RNA immunization><RNA vaccination><RNA vaccine><RNA-based vaccine><Recombinants><Regimen><Reporting><Research Personnel><Researchers><Resistance><Retroviral Antigen gag Protein><Ribonucleic Acid><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 vaccine><SARS-CoV2><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><SIV><Safety><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 vaccine><Severe acute respiratory syndrome related corona virus 2><Simian Immunodeficiency Viruses><South Africa><Stimulator of Interferon Genes><Structural Protein><Surface><T cell response><T-Cell Epitopes><T-Cells><T-Lymphocyte><T-Lymphocyte Epitopes><T8 Cells><T8 Lymphocytes><TLR protein><TLR7><TLR7 gene><Technology><Thailand><Toll-Like Receptor 7><Toll-Like Receptor Family Gene><Toll-like receptors><Transcript><Translations><UTRs><Untranslated Regions><Vaccinated><Vaccination><Vaccine Design><Vaccines><Veiled Cells><Viral><Viral Antigens><Viral Diseases><Viral gag Proteins><Virus Diseases><Virus-HIV><Wuhan coronavirus><access to vaccination><access to vaccines><adaptive immunity><antibody-based immunity><antibody-mediated immunity><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><care burden><clinical translation><clinically translatable><corona virus disease 2019 vaccine><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease-19 vaccine><coronavirus disease-19 virus><cyclic GMP-AMP synthase/STING><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><discover vaccines><emerging pathogen><env Antigens><env Gene Products><env Polyproteins><env Protein><experience><gag Antigens><gag Gene Products><gag Polyproteins><gag Protein><glycosylation><group specific antigen><hCoV19><health care><health goals><heavy metal Pb><heavy metal lead><high level production><high scale production><high volume manufacturing><high volume production><host response><human immunodeficiency virus vaccine><immune system response><immunogen><immunogenicity><immunomodulatory biologics><immunoresponse><in vivo><infection rate><killer T cell><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA delivery><mRNA immunization><mRNA vaccination><mRNA vaccine><mRNA-1273><mRNA-based vaccine><mRNA1273><model of animal><mouse model><murine model><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nCoV2><nano materials><nano particle><nano tech><nano 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