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Principal Investigator: Darrell J Irvine
Organization: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Fiscal Year: 2021
Award: $500,599
Funding agency: National Institute of Biomedical Imaging and Bioengineering
PI: Irvine, Darrell J.
Project Summary/Abstract:
Strategies to promote the magnitude and quality of T cell and antibody responses following immunization have
broad relevance for the development of new prophylactic and therapeutic vaccines for the treatment of cancer
and infectious diseases. Recent studies, including work from our own laboratories, have demonstrated that the
kinetic pattern of antigen and adjuvant exposure to lymphoid tissues has a substantial impact on the immune
response to vaccination. However, active control over the temporal pattern of antigen/inflammatory cue
delivery to lymph nodes is lacking in all current vaccine approaches. Here we propose an approach applying
methods from synthetic biology to create nucleic acid-based vaccines where vaccine antigen/adjuvant
expression dynamics can be controlled by (i) exogenous regulation by orally-available FDA-approved small
molecule drugs or (ii) intrinsically programmed in genetic circuits carried by the RNA. Based on the promising
features of RNA-based vaccines, in preliminary studies we established a lipid nanoparticle-delivered self-
replicating alphavirus replicon RNA as the platform for these regulated vaccines. We will systematically study
the impact of vaccine antigen and adjuvant kinetics on the immune response to vaccination, create pre-
programmed vaccine kinetic patterns, and test the capacity of regulated replicons to enable single-shot
vaccines with prime and boost controlled by an orally-available small molecule drug. Our specific aims are (1)
To optimize small molecule-regulated expression of antigen and molecular adjuvants from RNA replicons, (2)
To use the regulated replicon platform to define optimal kinetics of antigen and adjuvant expression during
vaccination, (3) To design RNA-based replicon genetic circuits with pre-programmed temporal patterns, and
(4) To determine factors limiting replicon expression lifetimes in vivo, and engineer strategies to prolong
expression toward the goal of small molecule-regulated prime-boost regimens. These studies will lead to
fundamental discoveries in basic immunology, provide a framework for rationally designing immunization
regimens, and create technologies to practically implement them.
Terms: <Adjuvant><Alpha Virus><Alphavirus><Antibody Response><Antigens><Cancer Treatment><Cell Mediated Immunology><Cell-Mediated Immunity><Cellular Immunity><Communicable Diseases><Cues><Development><Dose><Doxycycline><Drugs><Edodekin Alfa><Engineering><Exposure to><FDA approved><Gene Transcription><Genetic><Genetic Transcription><Goals><Group A Arboviruses><Humoral Immunities><IL-12><IL-15><IL12><IL15><IL15 Protein><Immune memory><Immune response><Immunization><Immunologic Factors><Immunologic Memory><Immunologic Sensitization><Immunologic Stimulation><Immunological Factors><Immunological Memory><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunology><Immunomodulation><Immunostimulation><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory><Injections><Interleukin-12><Interleukin-15><Interleukin-15 Precursor><Kinetics><Laboratories><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic Tissue><Lymphatic cell><Lymphatic nodes><Lymphocyte><Lymphocytic><Lymphoid Tissue><MGC9721><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Medication><Methods><Molecular><NKSF><Natural Killer Cell Stimulatory Factor><Non-Polyadenylated RNA><Nucleic Acid Vaccines><Oral><Output><Pattern><Pharmaceutic Preparations><Pharmaceutical Preparations><Preventative vaccine><Preventive vaccine><Prophylactic vaccine><RNA><RNA Expression><RNA Gene Products><RNA vaccine><RNA-based vaccine><Regimen><Regulation><Replication Unit><Replicon><Ribonucleic Acid><System><T-Cells><T-Lymphocyte><Technology><Testing><Transcription><Vaccination><Vaccine Adjuvant><Vaccine Antigen><Vaccines><Vibramycin><Work><active control><alpha-6-Deoxyoxytetracycline><anamnestic reaction><anti-cancer therapy><antibody-based immunity><anticancer therapy><assess effectiveness><base><cancer therapy><cancer-directed therapy><clinically translatable><cytokine><design><designing><determine effectiveness><developmental><drug/agent><effectiveness assessment><effectiveness evaluation><evaluate effectiveness><host response><immune modulation><immune regulation><immune system response><immunogen><immunogenicity><immunologic reactivity control><immunologic substance><immunological substance><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vivo><lipid nanoparticle><lymph cell><lymph gland><lymph nodes><lymphnodes><mRNA vaccine><mRNA-based vaccine><nano particle delivery><nanoparticle delivered><nanoparticle delivery><nucleic acid-based vaccine><pill><programs><replicon vaccine><secondary immune response><small molecule><synthetic biology><therapeutic vaccine><thymus derived lymphocyte><treatment vaccines><vaccine for the treatment><vaccine for treatment><vaccine-induced immunity><vaccine-induced protection>