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; 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年冠状病毒病毒（COVID-19）大流行对全球公众产生了毁灭性的影响 过去三年的健康和经济。尽管Covid-19疫苗的快速进展取得了成功 开发，随着病毒传播和疾病增强的关注变异率（VOC）的增长速率 严重性和/或逃脱疫苗诱导的免疫力的能力已挑战了全球疫苗效率 努力。持续努力优化现有的疫苗平台和开发更有效的小说 需要疫苗。鼻内免疫可以导致两者中抗原特异性免疫的诱导 粘膜和全身免疫室，因此有效控制SARS-COV-2感染和 疾病。但是，大多数用于紧急使用授权或临床试验中授予的SARS-COV-2疫苗是 仅限于肠胃外的肠胃外交付，因为可溶性抗原不会违反鼻上皮屏障，但被运输 通过微膜细胞。我们最近报道说，修饰的多孔硅微粒（MPSM）佐剂 SARS-COV-2受体结合结构域（RBD）疫苗触发了有效耐用的全身体液和类型 肠胃外疫苗接种后的1个辅助T细胞介导的免疫反应。 MPSM还促进了粘膜 摄取SARS-COV-2 RBD抗原。两剂肠胃外和鼻内的疫苗接种与 MPSM-RBD比肠胃外引起更多有效的肺居民T和B细胞以及粘膜IgA反应 仅疫苗接种，这导致SARS-肺部病毒载量明显减少和炎症 COV-2三角洲变体挑战。我们的结果表明，MPSM是SARS-COV-2的有效佐剂 全身和粘膜疫苗中的亚基疫苗。我们还发现组合mRNA- S+Nucleocapsid（N）疫苗接种提供了针对三角洲和Omicron变体感染的保护 仅临床批准的S表达S表达mRNA疫苗。因此，进一步优化了 MPSM辅助亚基疫苗，我们将修改抗原的配方。在这里，我们假设 基于MPSM的亚基疫苗接种肠胃外疫苗接种，触发耐用的全身性和 粘膜免疫反应可为SARS-COV-2 VOC感染提供交叉保护和 传播。我们最初将优化免疫原性并测试M-PSM亚基疫苗的安全性 小鼠（目标1）。接下来，我们将使用M-PSM研究肠胃外疫苗和鼻内疫苗的保护作用 针对年轻小鼠和老年小鼠的SARS-COV-2 VOC感染的亚基疫苗，并鉴定免疫 宿主保护的相关性（AIM 2）。最后，我们将确认M-PSM亚基疫苗的免疫原性 仓鼠并评估其在预防SARS-COV-2 VOC传输方面的功效和增强的控制 感染（目标3）。该项目的结果将是诱导的有效SARS-COV-2疫苗候选者 平衡的系统性和粘膜免疫，可为SARS提供长期寿命的交叉反应宿主保护 COV-2 VOC，并为我们准备未来的冠状病毒爆发。