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Principal Investigator: Parisa Yousefpour
Organization: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Fiscal Year: 2024
Award: $40,682
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Infectious diseases such as HIV, malaria, tuberculosis, and seasonal influenza epidemics and emergence of
new pandemics remain major global health problems highlighting the need for innovative approaches in vaccine
design. The precise kinetics of antigen exposure relative to inflammatory cues is known to play a critical role in
shaping a coordinated cellular and humoral immunity and thereby enhancing the vaccine immunogenicity and
efficacy. Current vaccination strategies, however, do not include mechanisms for the temporal control of antigen
and adjuvant exposure to lymphoid tissues. Here, we propose incorporating synthetic biology approaches
to create nucleic acid-based vaccines where the kinetics of vaccine (antigen and adjuvant) exposure can
be controlled using orally-available FDA-approved small molecule drugs. This strategy is enabled using
self-replicating RNAs termed replicons that encode antigens and cytokine molecular adjuvants and encompass
regulatory mechanisms governed by the FDA-approved small molecule drug, trimethoprim (TMP). This strategy
allows the delivery of replicons encoding antigens and cytokines in vivo with a single bolus injection and then
controlling the amplitude and duration of antigen and cytokine expression by oral administration of TMP. Using
the RNA replicon platform provides several advantages: (i) it allows antigens and cytokines to be produced in
their native conformation; (ii) it self-replicates and therefore persists inside the cells longer than mRNA and
sustains a steady supply of “fresh” antigen and adjuvant; (iii) unlike DNA therapeutics, it does not harbor the risk
of genome integration and also does not require delivery to the nucleus for transgene expression. An HIV
envelope immunogen, known as the engineered outer domain (eOD-GT8), will be used as the model antigen,
and interleukine-2 and interleukine-12 will be used as the cytokine molecular adjuvants.
The Specific Aims of this project are: (1) Generate small molecule-responsive RNA replicon vaccines enabling
control over the dynamics of antigen and adjuvant expression. (2) Identify optimal temporal patterns of antigen
and adjuvant exposure maximizing the protective immunity elicited by replicon vaccines. Results from this project
will establish a vaccine platform that allows modulating and promoting the magnitude and quality of T cell and
antibody responses following immunization by taking a drug available as an oral pill, as a simple and clinically-
translatable strategy to enhance vaccine-induced immunity. In addition, elucidating the optimal cytokine and
antigen exposure patterns that confer protection will provide critical information and insights for use in conceiving
better vaccine design strategies.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adjuvant><Antibodies><Antibody Response><Antigen Presentation><Antigens><Bolus><Bolus Infusion><Cell Body><Cell Mediated Immunology><Cell Nucleus><Cell-Mediated Immunity><Cells><Cellular Immunity><Class I Genes><Co-Stimulator><Communicable Diseases><Complex><Costimulator><Cues><Cytoplasm><DNA><DNA-Dependent RNA Polymerases><DNA-Directed RNA Polymerase><DNA-based therapeutics><Deoxyribonucleic Acid><Development><Dose><Drugs><Edodekin Alfa><Engineering><Epidermal Thymocyte Activating Factor><Exposure to><FDA approved><Flu epidemic><Gene Action Regulation><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Genes><Genome><Genomics><HIV><HIV envelope><HIV envelope protein><HIV-1><HIV-I><HIV1><Health><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Humoral Immunities><IL-12><IL-2><IL12><IL2 Protein><Immune memory><Immune response><Immunity><Immunization><Immunologic Memory><Immunological Memory><Immunological response><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory><Injections><Interleukin 2><Interleukin 2 Precursor><Interleukin II><Interleukin-12><Interleukin-2><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Kinetics><LAV-HTLV-III><Laboratories><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphadenopathy-Associated Virus><Lymphatic Tissue><Lymphatic cell><Lymphatic nodes><Lymphocyte><Lymphocyte Mitogenic Factor><Lymphocytic><Lymphoid Tissue><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MHC Class I><MHC Class I Genes><MTB infection><Malaria><Mediating><Medication><Messenger RNA><Methods><Mitogenic Factor><Modeling><Molecular><Molecular Configuration><Molecular Conformation><Molecular Stereochemistry><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><NKSF><Natural Killer Cell Stimulatory Factor><Non-Polyadenylated RNA><Nucleic Acid Vaccines><Nucleic Acids><Nucleus><Oral><Oral Administration><Oral Drug Administration><Outcome><Paludism><Patient Compliance><Pattern><Pharmaceutical Preparations><Plasmodium Infections><Play><Production><Proloprim><Proteins><RNA><RNA Gene Products><RNA Polymerases><RNA replication><RNA vaccine><RNA-based vaccine><Replication Unit><Replicon><Reporter><Ribonucleic Acid><Risk><Role><Schedule><Seasons><Shapes><Subunit Vaccines><T cell growth factor><T cell response><T-Cell Growth Factor><T-Cell Stimulating Factor><T-Cells><T-Lymphocyte><TB infection><Therapeutic><Thymocyte Stimulating Factor><Trimethoprim><Trimpex><Tuberculosis><Vaccination><Vaccination acquired immunity><Vaccination induced immunity><Vaccine Design><Vaccines><Virus-HIV><Work><anamnestic reaction><antibody-based immunity><clinical translation><clinically translatable><conformation><conformational><conformational state><conformationally><conformations><constitutive expression><constitutive gene expression><cytokine><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><disseminated TB><disseminated tuberculosis><drug/agent><emergent pandemic><emerging epidemic><emerging pandemic><engineered immune system><global health><host response><immune engineering><immune response to vaccination><immune response to vaccines><immune system response><immunization strategy><immunoengineering><immunogen><immunoresponse><in vivo><infection due to Mycobacterium tuberculosis><influenza epidemic><innovate><innovation><innovative><insight><interest><intraoral drug delivery><lymph cell><lymph gland><lymph nodes><lymphnodes><mRNA><mRNA vaccine><mRNA-based vaccine><new epidemic><new pandemic><novel><novel epidemic><novel pandemic><nucleic acid-based vaccine><pandemic concern><pandemic potential><pandemic risk><pandemic threat><patient adherence><patient cooperation><pill><replicon vaccine><response><seasonal flu><seasonal influenza><secondary immune response><small molecule><social role><synthetic biology><therapeutic DNA><thymus derived lymphocyte><tool><transgene expression><translatable strategy><translation to humans><tuberculosis infection><tuberculous spondyloarthropathy><vaccination strategy><vaccine acquired immunity><vaccine associated immune response><vaccine associated immunity><vaccine development><vaccine efficacy><vaccine immune response><vaccine immunogenicity><vaccine induced immune response><vaccine platform><vaccine strategy><vaccine-induced immunity><vaccine-induced protection>