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Investigation of Synthetic DNA-based Viral Particles for Spatially Controlled Antigen Presentation

基于 DNA 的合成病毒颗粒空间控制抗原呈递的研究

基本信息

批准号：
10460559
负责人：
Mark Bathe
金额：
$ 38.78万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-02 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10460559
关键词：
3-Dimensional Acquired Immunodeficiency Syndrome Adjuvant Affinity Agonist Animal Model Antibody Affinity Antibody Formation Antigen Presentation Antigen-Presenting Cells Antigens Artificial nanoparticles B-Cell Activation B-Cell Antigen Receptor B-Cell Receptor Binding B-Lymphocytes Benchmarking Biodistribution Biological Assay Biomedical Engineering Calcium Signaling Cell model Cells Cellular Immunity Characteristics Communicable Diseases Confocal Microscopy Cues DNA Development Dimensions Engineering Ensure Evaluation Event HIV HIV Envelope Protein gp120 HIV Infections HIV vaccine HIV-1 Health Hepatitis B Vaccines Heterogeneity Human Human Papilloma Virus Vaccine Humoral Immunities Image Immobilization Immune Immune response Immunologic Adjuvants Immunology In Vitro Infection Investigation Ligands Memory Modeling Modification Nanotechnology Peripheral Receptor Activation Receptor Signaling Resolution Role Scaffolding Protein Signal Pathway Signal Transduction Stimulus Structure Subunit Vaccines Surface T-Lymphocyte Technology Testing Toll-like receptors Vaccination Vaccine Design Vaccines Variant Viral Virus-like particle adaptive immune response base cellular imaging clinical development clinically relevant crosslink density design env Gene Products experience flexibility fluorescence imaging human model immune activation in vivo in vivo evaluation link protein lymph nodes mouse model nanocluster nanometer nanoparticle nanoparticulate nanoscale neutralizing antibody pandemic disease particle pathogen preclinical development preservation prevent response scaffold synthetic construct tool translational potential vaccine development vaccine formulation

项目摘要

PROJECT SUMMARY 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, and may be especially important for difficult-to-neutralize pathogens such as HIV. 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, and most notably enhances 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. However, to date it remains unclear what are the ideal characteristics of nanoparticle antigen display. In this project, we use the unique technology of scaffolded DNA origami to engineer nanoparticles on the 10–100 nanometer scale that offer the ability to investigate the impact of scaffold size, antigen copy number up to more than 100, antigen-BCR affinity, as well as the nanoscale spatial organization and dimensionality of antigen presentation on BCR activation. Specifically, we test the relative importance of these parameters on B-cell activation, which are of central importance to the development of a successful subunit vaccines, using the germline targeting engineered outer domain of HIV-1 gp120, termed eOD-GT8, and its variants with different affinities, as a testbed. In vitro evaluation of early B-cell signaling and pathway activation will be characterized, and contrasted with the benchmark strongly activating 60-mer control organized on a protein scaffold. Single-cell fluorescence imaging is used to investigate the detailed mechanism of BCR-binding and B-cell activation based on the optimal immunogen presentation found. These constructs are then used to test the impact of these optimal HIV DNA-NP constructs on T-cell and B-cell response in vivo using mouse models. Taken together, our results will offer the elucidation of the optimal immunogen presentation parameters for effective immune cell response in the development of more effective subunit vaccines, with major translational potential for HIV and other infectious diseases.

项目总结