Porous silicon microparticle-based subunit vaccines for SARS-CoV-2

基于多孔硅微粒的 SARS-CoV-2 亚单位疫苗

• 批准号: 10678133
• 负责人: Tian Wang
• 金额: $ 61.31万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-10 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678133
• 关键词: 2019-nCoV; Adjuvant; Antigens; B-Lymphocytes; COVID-19; COVID-19 vaccine; Cells; Clinical; Clinical Trials; Coronavirus; Disease; Disease Outbreaks; Dose; Epithelial Cells; Epithelium; Epitopes; Exhibits; FDA Emergency Use Authorization; FOLH1 gene; Formulation; Future; Goals; Grant; Hamsters; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immunity; Immunization; Immunoglobulin A; Infection; Infection Control; Inflammation; Lung; Measures; Mediating; Mesocricetus auratus; Messenger RNA; Modeling; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Nasal Epithelium; Nose; Nucleocapsid; Population; Porosity; Prevention; Proteins; Public Health; RNA vaccine; Reporting; Role; Route; SARS-CoV-2 B.1.1.529; SARS-CoV-2 B.1.617.2; SARS-CoV-2 infection; SARS-CoV-2 transmission; SARS-CoV-2 variant; Sarbecovirus; Severe Acute Respiratory Syndrome; Severity of illness; Silicon; Subunit Vaccines; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Toxic effect; Vaccination; Vaccine Antigen; Vaccines; Variant; Viral Load result; Virus Diseases; Work; aged; airway epithelium; betacoronavirus; cell mediated immune response; combat; combinatorial; cross immunity; cross reactivity; dosage; efficacy evaluation; future outbreak; immunogenicity; in vivo; mucosal uptake; mucosal vaccination; novel vaccines; pandemic virus; parenteral administration; particle; prevent; protective efficacy; receptor binding; response; safety testing; success; transmission process; uptake; vaccine candidate; vaccine development; vaccine platform; vaccine-induced immunity; variants of concern; viral transmission

SUMMARY: The Coronavirus disease 2019 virus (COVID-19) pandemic has made a devastating impact on global public health and economy over the past three years. Despite the success in rapid progress of COVID-19 vaccine development, increasing rates of variants of concern (VOCs) with enhanced viral transmission and disease severity, and/or ability to escape vaccine-induced immunity have challenged the global vaccine efficiency efforts. Continuous work toward optimizing existing vaccine platforms and development of more effective novel vaccines is needed. Intranasal immunization can lead to the induction of antigen-specific immunity in both the mucosal and systemic immune compartments, and thus is effective in control of SARS-CoV-2 infection and disease. However, most SARS-CoV-2 vaccines granted for emergency use authorization or in clinical trials are limited to parenteral delivery as soluble antigens do not breach the nasal epithelial barrier but are transported by microfold cells. We recently reported that a modified porous silicon microparticle (mPSM) adjuvant to SARS-CoV-2 receptor-binding domain (RBD) vaccine triggered potent and durable systemic humoral and type 1 helper T cell- mediated immune responses following parenteral vaccination. mPSM also facilitated mucosal uptake of SARS-CoV-2 RBD antigens. Two doses of parenteral and intranasal combined vaccinations with mPSM-RBD elicited more potent lung resident T and B cells and mucosal IgA responses than parenteral vaccinations alone, which led to markedly diminished viral loads and inflammation in the lung following SARS- CoV-2 Delta variant challenge. Our results suggest that mPSM is an effective adjuvant for SARS-CoV-2 subunit vaccine in both systemic and mucosal vaccinations. We also found that combinatorial mRNA- S+Nucleocapsid (N) vaccination provided stronger protection against Delta and Omicron variants infection than the clinically approved S-expressing mRNA vaccine alone. Thus, to further optimize the immunogenicity of mPSM-adjuvanted subunit vaccine, we will modify the formulation of antigens. Here, we hypothesize that parenteral and intranasal vaccination with mPSM-based subunit vaccine triggers durable systemic and mucosal immune responses which provide cross protection against SARS-CoV-2 VOCs infection and transmission. We will initially optimize the immunogenicity and test the safety of m-PSM subunit vaccines in mice (Aim 1). Next, we will study the protective efficacy of parenteral and intranasal vaccination with m-PSM subunit vaccine against SARS-CoV-2 VOCs infection in young and aged mice and identify the immune correlates of host protection (Aim 2). Lastly, we will confirm the immunogenicity of m-PSM subunit vaccine in hamsters and evaluate its efficacy on prevention of SARS-CoV-2 VOCs transmission and enhanced control of infection (Aim 3). The result of this project will be an effective SARS-CoV-2 vaccine candidate that induces balanced systemic and mucosal immunity, provides long-lived cross-reactive host protection against SARS- CoV-2 VOCs, and prepares us for future coronavirus outbreaks.

概括： 2019 年冠状病毒病 (COVID-19) 大流行对全球公众造成了毁灭性影响 过去三年的健康和经济。尽管 COVID-19 疫苗取得了快速进展 随着病毒传播和疾病的增强，关注变体 (VOC) 的发生率不断增加 严重程度和/或逃避疫苗诱导免疫的能力对全球疫苗效率提出了挑战 努力。持续努力优化现有疫苗平台并开发更有效的新型疫苗 需要疫苗。鼻内免疫可以诱导抗原特异性免疫 粘膜和全身免疫区室，因此可有效控制 SARS-CoV-2 感染和 疾病。然而，大多数获得紧急使用授权或处于临床试验阶段的 SARS-CoV-2 疫苗都是 仅限于肠胃外递送，因为可溶性抗原不会突破鼻上皮屏障，而是被运输 由微折叠细胞。我们最近报道了一种改良的多孔硅微粒（mPSM）佐剂 SARS-CoV-2 受体结合域 (RBD) 疫苗引发有效且持久的全身体液和类型 1 肠外疫苗接种后辅助 T 细胞介导的免疫反应。 mPSM 还促进粘膜 SARS-CoV-2 RBD 抗原的摄取。两剂肠外和鼻内联合疫苗接种 mPSM-RBD 比肠胃外给药更能引起肺内 T 细胞和 B 细胞以及粘膜 IgA 反应 仅疫苗接种就导致 SARS 后病毒载量和肺部炎症显着减少 CoV-2 Delta 变体挑战。我们的结果表明 mPSM 是 SARS-CoV-2 的有效佐剂 亚单位疫苗可用于全身疫苗接种和粘膜疫苗接种。我们还发现组合 mRNA- S+核衣壳 (N) 疫苗接种可提供比 Delta 和 Omicron 变体感染更强的保护 临床批准的 S 表达 mRNA 疫苗单独使用。因此，为了进一步优化其免疫原性 mPSM佐剂亚单位疫苗，我们会修改抗原的配方。在这里，我们假设 使用基于 mPSM 的亚单位疫苗进行肠外和鼻内疫苗接种可引发持久的全身性和 粘膜免疫反应可提供针对 SARS-CoV-2 VOC 感染的交叉保护， 传播。我们将初步优化m-PSM亚单位疫苗的免疫原性并测试其安全性 小鼠（目标 1）。接下来，我们将研究 m-PSM 肠外和鼻内疫苗接种的保护效果 针对年轻和老年小鼠的 SARS-CoV-2 VOC 感染的亚单位疫苗并鉴定免疫 宿主保护的相关性（目标 2）。最后，我们将确认m-PSM亚单位疫苗的免疫原性 仓鼠并评估其预防 SARS-CoV-2 VOC 传播和加强控制的功效 感染（目标 3）。该项目的成果将是一种有效的 SARS-CoV-2 候选疫苗，可诱导 平衡的全身和粘膜免疫，提供针对 SARS 的长效交叉反应宿主保护 CoV-2 VOC，让我们为未来的冠状病毒爆发做好准备。