Document text
Principal Investigator: Mark Bathe
Organization: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
Fiscal Year: 2021
Award: $370,098
Funding agency: National Institute of Biomedical Imaging and Bioengineering
PROJECT SUMMARY/ABSTRACT
COVID-19 has emerged from SARS-CoV-2 within the course of several months to spread worldwide as a deadly
pandemic, with the number of deaths approaching one-half million worldwide. While over one hundred vaccines
are currently in development, and several already in human clinical trials, most of these early candidates consist
of messenger RNA or DNA formulations used to transiently express SARS-CoV-2 subunit proteins, which may
not elicit sufficiently neutralizing, long-term antibody response. Strategies to enhance antigenicity, antibody
affinity maturation, and memory induction in response to subunit vaccines are of broad relevance for the design
of effective vaccines against infectious diseases such as COVID-19, and may be particularly important to
neutralize the SARS-CoV-2 pathogen. One approach to enhance the efficacy of subunit vaccines is to formulate
antigens in a multivalent, nanoparticulate form, which promotes several aspects of humoral immunity, most
notably crosslinking of B cell receptors (BCRs). This approach has been exploited both in licensed vaccines
(e.g., the HPV and HBV vaccines), and in a great variety of vaccines in preclinical and clinical development. In
this project, we use the unique technology of scaffolded DNA origami to engineer virus-like nanoparticles on the
10–100 nanometer scale that offer the ability to conjugate controlled copy numbers of SARS-CoV-2 antigens at
controlled inter-antigen spacings. We test the relative importance of copy number, spacing, and virus-like
nanoparticle size on B cell activation in vitro. Optimal constructs identified using B cell activation assays in vitro
will subsequently be used to characterize T-cell and B-cell response in vivo using mouse models. Successful
vaccine constructs identified from in vivo studies will be shared with commercial partners to facilitate follow-on
toxicity, safety, and efficacy studies in higher animal models including non-human primates. Our results will offer
a novel subunit vaccine formulation that may be generalized to other SARS-CoV variants including SARS-CoV-
1 through heterovalent protein antigen presentation, as a generalized vaccine platform to avoid future
coronavirus-induced pandemics.
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Immunity><CellLine><Cells><Cellular Immunity><Cessation of life><Chemotactic Cytokines><Clinical Trials><CoV-2><CoV2><Collaborations><Communicable Diseases><Coronaviridae><Coronavirus><DNA><Death><Deoxyribonucleic Acid><Development><Dimensions><Disease><Disease Outbreaks><Disorder><Engineering><Epitopes><Formulation><Functional RNA><Future><Generations><Glycoproteins><Grippe><HBV Vaccine><HIV><HPV Vaccine><Hepatitis B Vaccines><Hepatitis B virus vaccine><Homologous Chemotactic Cytokines><Hu-mABs><Human><Human Immunodeficiency Viruses><Human Papilloma Virus Vaccine><Human papillomavirus Vaccine><Humoral Immunities><Immune><Immune signaling><Immunes><Immunization><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunology><Immunostimulation><In Vitro><Inbred BALB C Mice><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza><Injections><Intercrines><Investigation><LAV-HTLV-III><Laboratories><Libraries><Life><Lymphadenopathy-Associated Virus><Macaca><Macaque><Malaria><Memory><Messenger RNA><Modern Man><Modification><Molecular Interaction><Nanotechnology><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nucleotides><Outbreaks><Paludism><Pathway interactions><Plasmodium Infections><Protein Binding Domain><Protein Binding Motif><Protein Fragment><Protein Subunits><Protein-Protein Interaction Domain><Proteins><Publishing><Receptor Signaling><Reporter><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV-2><SARS-CoV-2 antibody><SARS-CoV-2 antigen><SARS-CoV-2 infected patient><SARS-CoV-2 outbreak><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 vaccine><SARS-CoV2><SARS-CoV2 antibody><SARS-CoV2 antigen><SARS-CoV2 outbreak><SARS-CoV2 vaccine><SARS-Related Coronavirus><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><SIS cytokines><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 Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 outbreak><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Signal Pathway><Stimulator of Interferon Genes><Strains Cell Lines><Structure><Subunit Vaccines><T-Cells><T-Lymphocyte><Technology><Testing><Toxic effect><Toxicities><Translating><Untranslated RNA><Vaccine Production><Vaccines><Variant><Variation><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Virus-HIV><Virus-like particle><Wuhan coronavirus><activated B cells><antibody against COVID-19><antibody against SARS-CoV-2><antibody against SARS-CoV2><antibody against coronavirus disease 2019><antibody against severe acute respiratory syndrome coronavirus 2><antibody biosynthesis><antibody to COVID-19><antibody to SARS-CoV-2><antibody to SARS-CoV2><antibody to coronavirus disease 2019><antibody to severe acute respiratory syndrome coronavirus 2><antibody-based immunity><antigen antibody affinity><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><chemoattractant cytokine><chemokine><clinical development><corona virus><corona virus disease 2019><corona 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testing><scaffold><scaffolding><screening><severe acute respiratory syndrome coronavirus 2 antibody><severe acute respiratory syndrome coronavirus 2 antigen><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome-CoV><thymus derived lymphocyte><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine candidate><vaccine development><vaccine efficacy><vaccine evaluation><vaccine for novel coronavirus><vaccine formulation><vaccine screening><vaccine testing><virus protein><virus-like nanoparticles><viruslike particle>