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Principal Investigator: DANIEL G ANDERSON
Organization: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Fiscal Year: 2023
Award: $785,418
Funding agency: National Institute of Allergy and Infectious Diseases
Many HIV vaccine candidates have failed clinical trials, as they were unable to elicit a potent and durable response to
HIV viral challenge. Broadly neutralizing antibodies (bnAbs) have been identified in a number of HIV+ individuals with
well-controlled viral levels, and these bnAbs target epitopes that contain residues that are relatively conserved across viral
strains. It is thought bnAbs may have efficacy against various strains of HIV pathogen. It is therefore widely believed that
systems which induce a potent immune response that includes the generation of broadly neutralising antibodies (bnAbs) in
humans could be effective HIV vaccines, and help to mitigate the wide genetic diversity in envelope proteins and
relatively high mutation rate of HIV.
However, developing a vaccine which can elicit the production of these bnAbs in vivo has proven to be extremely
challenging. This is likely due to the complex affinity maturation process that is required to produce bnAbs. Immunization
protocols typically administer a single dose of antigen (prime dose), which is sometimes followed by a “boost” dose
delivered several weeks later. In a traditional bolus immunization, the half-life of the antigen present in lymph nodes is
generally shorter than the time scale over which germinal centres start producing higher affinity IgG antibodies relative to
the initial IgM response (~18 hrs). In contrast, natural infections expose the immune system to escalating antigen and
inflammation over days to weeks, resulting in the formation of a germinal centre with dynamic antigen presentation. This
germinal centre niche also supports activation of antigen presenting cells, T follicular helper cells, and appropriate
cytokine signalling to generate bnAbs. It is likely that to develop effective bnAbs, sophisticated vaccination techniques
which can more closely mimic natural infections and natural bnAb formation may be required.
We believe that to develop a successful HIV vaccine, researchers must aim to engineer more sophisticated and biomimetic
vaccines. Bioengineered vaccines should therefore consider three key parameters in parallel; 1) delivery of an
appropriately selected antigen, with 2) favourable kinetics of antigen expression, and 3) control of the immune response in
the germinal centre. We believe lymph node targeted delivery of computationally designed mRNA antigens inside
immunostimulatory lipid nanoparticles (mRNA LNPs) administered with computationally optimized immunization
protocols will address these three aspects in a unique way. Additionally,Translate Bio will provide expertise in
manufacturing considerations for mRNA therapeutics. As modifications to mRNA structure may impact the mRNA
antigen translation, stability, and immunogenicity, the input of our translational partner (Translate Bio) will allow us to
develop vaccines with a potential avenue for commercial development. This R61/R33 proposal combines our expertise in
computational antigen design, HIV immunology, combinatorial chemistry, and the commercialisation of mRNA
therapeutics to develop a new class of HIV mRNA vaccine candidates.
Terms: <19S Gamma Globulin><7S Gamma Globulin><AIDS Virus><Ab response><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adjuvant><Affinity><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Formation><Antibody Production><Antibody titer measurement><Antigen Presentation><Antigen Targeting><Antigen-Presenting Cells><Antigenic Determinants><Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Belief><Binding Determinants><Biological Mimetics><Biomedical Engineering><Biomimetics><Bolus><Bolus Infusion><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chemicals><Clinic><Clinical Trials><Clonal Expansion><Collaborations><Complex><Computer Models><Computerized Models><Cytokine Signal Transduction><Cytokine Signaling><Developing Countries><Developing Nations><Development><Dose><Engineering><Envelope Protein><Epitopes><Evaluation><Formulation><Future><Gene Transcription><Generations><Genetic Alteration><Genetic Change><Genetic Diversity><Genetic Transcription><Genetic Variation><Genetic defect><Germinal Center><HIV><HIV Antigens><HIV vaccine><HIV-1><HIV-Associated Antigens><HIV-I><HIV/AIDS Vaccines><HIV1><HLA-A><HLA-A gene><HLAA><HTLV-III Antigens><HTLV-III-LAV Antigens><Half-Life><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Antigens><Human immunodeficiency virus 1><IgG><IgM><Immune><Immune Cell Activation><Immune response><Immune system><Immunes><Immunity><Immunization><Immunoglobulin G><Immunoglobulin M><Immunologic Stimulation><Immunologic Tests><Immunological Stimulation><Immunological Tests><Immunological response><Immunology><Immunostimulation><Individual><Inducer Cells><Inducer T-Lymphocytes><Infection><Inflammation><Intracellular Communication and Signaling><Investigators><KI mice><Kinetics><Knock-in Mouse><LAV Antigens><LAV-HTLV-III><LYT3><Laboratories><Less-Developed Countries><Less-Developed Nations><Lipids><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphadenopathy-Associated Antigens><Lymphadenopathy-Associated Virus><Lymphatic nodes><Machine Learning><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Messenger RNA><Methods><Mice><Mice Mammals><Modeling><Modern Man><Modification><Molecular Dynamics Simulation><Murine><Mus><Mutation><Pathway interactions><Pattern><Process><Production><Property><Protocol><Protocols documentation><RNA Expression><RNA immunization><RNA vaccination><RNA vaccine><RNA-based vaccine><Research Personnel><Researchers><Scheme><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Structure of germinal center of lymph node><Surface Proteins><System><T cell response><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Tail><Techniques><Testing><Therapeutic><Third-World Countries><Third-World Nations><Time><Toxic effect><Toxicities><Transcription><Transgenic Mice><Translating><Translations><Under-Developed Countries><Under-Developed Nations><Vaccination><Vaccines><Variant><Variation><Viral><Virus-HIV><accessory cell><adoptive B cell therapy><adoptive B cell transfer><antibody biosynthesis><antibody titering><bio-engineered><bio-engineers><bioengineering><biological engineering><biological signal transduction><cell behavior><cellular behavior><clinical development><clinical translation><clinically translatable><combinatorial><combinatorial chemistry><computational modeling><computational models><computer based models><computerized modeling><cross reactivity><design><designing><develop a vaccine><develop vaccines><developing country><developing nation><development of a vaccine><developmental><efficacy validation><env Antigens><env Gene Products><env Polyproteins><env Protein><evaluate vaccines><genome mutation><host response><human immunodeficiency virus vaccine><humanized mice><humanized mouse><immune activation><immune system response><immunogen><immunogenicity><immunoglobulin biosynthesis><immunoresponse><improved><in vivo><knockin mice><lipid based nanoparticle><lipid nanoparticle><lymph gland><lymph nodes><lymphnodes><mRNA><mRNA delivery><mRNA immunization><mRNA vaccination><mRNA vaccine><mRNA-based vaccine><machine based learning><manufacture><model of animal><model-based simulation><models and simulation><molecular dynamics><mouse model><murine model><nano formulation><nano particle delivery><nano vaccine><nanoformulation><nanoparticle delivered><nanoparticle delivery><nanotherapeutic><nanovaccine><neutralizing antibody><next generation><novel><pandemic><pandemic disease><pathogen><pathway><response><site targeted delivery><targeted delivery><thymus derived lymphocyte><translation><vaccination protocol><vaccine candidate><vaccine development><vaccine efficacy><vaccine evaluation><vaccine protocol><vaccine screening><vaccine testing><validate efficacy>