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A muco-penetrating biomaterial-based subunit vaccine for programming protective immune responses to SARS-CoV-2

一种基于粘膜穿透生物材料的亚单位疫苗，用于编程针对 SARS-CoV-2 的保护性免疫反应

基本信息

批准号：
10612436
负责人：
David Scott Wilson
金额：
$ 24.56万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2021-07-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612436
关键词：
2019-nCoV Address Adjuvant Animals Antibodies Antibody titer measurement Antigen Targeting Antigen-Presenting Cells Antigens Avidity B-Lymphocytes Binding Biocompatible Materials Biological Biological Assay COVID-19 vaccine Cells Clinical Development Education Endosomes Endothelium Epithelium Flow Cytometry Free Radicals Goals Half-Life Immune Immune Targeting Immune response Immunity Immunize In Vitro Intramuscular Intramuscular Injections Intranasal Administration Irrigation Label Ligands Liquid substance Location Lung Lymph Lymphoid Tissue Mannose Measures Mediating Mucosal Immune Responses Mucosal Immune System Mucous Membrane Mucous body substance Mus Nasal Epithelium Nasal cavity Nose Pathway interactions Penetration Peptides Polymers Protein Subunits Proteins Residencies Respiratory Mucosa Respiratory Tract Infections SARS-CoV-2 spike protein Safety Serum Signal Transduction Site Spleen Structural Protein Structure of mucous membrane of nose Subunit Vaccines T cell response T-Cell Activation T-Lymphocyte Testing Thigh structure Tight Junctions Time Tissues Toll-like receptors Vaccinated Vaccination Vaccine Adjuvant Vaccines Viral Viral Load result Water aluminum sulfate combat copolymer design di-block copolymer efficacy evaluation efficacy validation fluorescence imaging immunogenicity lymph nodes mannose receptor manufacture monomer mouse model mucosal vaccine neutralizing antibody novel polymerization pre-clinical preclinical efficacy protective efficacy receptor binding respiratory respiratory virus seasonal influenza uptake vaccine access vaccine candidate vaccine development vaccine platform viral pandemic

项目摘要

1. ABSTRACT/SUMMARY Given that the site of entry of SARS-CoV-2 is the respiratory mucosa, an effective vaccine for SARS-CoV-2 should initiate both humoral and respiratory mucosal immune responses. Although an intranasal subunit vaccine would be an ideal platform for SARS-CoV-2, transport across the nasal mucosa and a lack of safe and effective mucosal vaccine adjuvants thwart the development of a clinically-viable intranasal subunit vaccine. We propose to develop an intranasal vaccine composed of SARS-CoV-2 proteins conjugated to an immunostimulatory biomaterial that overcomes the transport barriers of the nasal mucosa and thus induces protective mucosal and systemic immunity. Our platform is composed of SARS-CoV-2 receptor-binding domain portion (RBD) conjugated to water-soluble polymers, termed MPGAP, that are synthesized from monomers that bind nasal mucus, disrupt endothelial thigh junctions, and target and activate antigen presenting cells (APCs). Thus, when administered intranasally, RBD- MPGAP conjugates should (1) adhere to nasal mucus, increasing residency time at the nasal epithelium, (2) dismantle tight junctions, maximizing paracellular transport to underlying APCs and nasal associated lymphoid tissue, (3) target conjugated RBD to and activate APCs, eliciting APC-derived signals that activate T and B cells. By overcoming the biological barriers of the nasal endothelium and targeting immunostimulatory factors to immune cells, RBD- MPGAP should induce protective mucosal and systemic immunity in the absence of off-target effects. RBD-MPGAP conjugates will be produced, characterized, and their ability to bind nasal mucus, enhance paracellular transport, and target and activate antigen presenting cells will be tested in mice. The neutralizing antibody titer of serum and respiratory fluids from RBD-MPGAP-immunized mice will be assessed via an in-vitro SARS-CoV-2 neutralization assay. Finally, the protective efficacy and durability of the mucosal and systemic immunity elicited by internasal RBD-MPGAP will be investigated in a SARS-CoV-2 mouse model. Completion of this project will validate the preclinical efficacy of an intranasal SARS-CoV-2 subunit vaccine and deliver a platform that could combat numerous other respiratory infections, from seasonal influenza to the next respiratory viral pandemic.

1. 抽象/总结