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

• 批准号: 10195402
• 负责人: David Scott Wilson
• 金额: $ 20.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10195402
• 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; Cations; Cells; Clinical; Development; Endothelium; Epithelial; Flow Cytometry; Free Radicals; Goals; Half-Life; Immune; Immune Targeting; Immune response; Immunity; Immunize; In Vitro; Intramuscular; Intramuscular Injections; Irrigation; Label; Ligands; Liquid substance; Location; Lung; Lymph; Lymphoid Tissue; Mannose; Measures; Mediating; Mucosal Immune Responses; Mucous Membrane; Mucous body substance; Mus; Nasal Epithelium; Nasal cavity; Nose; Pathway interactions; 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-Lymphocyte; Testing; Thigh structure; Tight Junctions; Time; Tissues; Toll-like receptors; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccines; Viral; Viral Load result; Water; aluminum sulfate; base; combat; copolymer; design; di-block copolymer; efficacy evaluation; efficacy validation; fluorescence imaging; immunogenicity; lymph nodes; mannose receptor; monomer; mouse model; mucosal site; mucosal vaccine; neutralizing antibody; novel; pandemic disease; polymerization; pre-clinical; preclinical efficacy; protective efficacy; receptor binding; respiratory; respiratory virus; seasonal influenza; uptake; vaccine access; vaccine candidate; vaccine development

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。摘要/摘要 鉴于SARS-COV-2的进入部位是呼吸粘膜，SARS-COV-2的有效疫苗应 引发体液和呼吸粘膜免疫反应。虽然鼻内亚基疫苗将是 SARS-COV-2的理想平台，跨鼻粘膜运输以及缺乏安全有效的粘膜疫苗 佐剂阻止了临床可行的鼻内亚基疫苗的发展。我们建议开发鼻内 由SARS-COV-2蛋白组成的疫苗与免疫刺激性生物材料相结合，以克服 鼻粘膜的转运屏障，从而诱导保护性粘膜和全身免疫力。我们的平台是 由SARS-COV-2受体结合结构域（RBD）组成，该部分与水溶性聚合物共轭，称为 MPGAP是由结合鼻粘液，破坏内皮大腿连接和靶标的单体合成的 激活抗原呈递细胞（APC）。因此，当鼻内施用时，RBD- MPGAP结合物应（1） 粘附于鼻粘液，增加鼻上皮的居住时间，（2）拆卸紧密连接，最大化 细胞细胞运输到潜在的APC和鼻相关淋巴组织，（3）靶标共轭RBD并激活 APC，引起激活T和B细胞的APC衍生信号。通过克服鼻腔的生物障碍 内皮和针对免疫细胞的免疫刺激因子，RBD-MPGAP应诱导保护性粘膜 在没有脱靶效应的情况下，全身免疫力。 RBD-MPGAP结合物将被生成，表征，并且 它们结合鼻粘液，增强细胞细胞运输以及靶向和激活抗原呈递细胞的能力将是 在小鼠中测试。来自RBD-MPGAP免疫小鼠的血清和呼吸道液的中和抗体滴度将 可以通过体外SARS-COV-2中和测定法进行评估。最后，保护性和耐用性 在SARS-COV-2小鼠模型中，将研究由内纳斯RBD-MPGAP引起的粘膜和全身免疫力。 该项目的完成将验证鼻内SARS-COV-2亚基疫苗的临床前功效 一个可以打击许多其他呼吸道感染的平台，从季节性流感到下一个呼吸道病毒 大流行。