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

摘要： 冠状病毒病2019年病毒(新冠肺炎)大流行对全球公众造成毁灭性影响 过去三年的健康和经济状况。尽管新冠肺炎疫苗取得了快速进展 随着病毒传播和疾病的增强，关注变种(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挑战了全球疫苗的效率 努力。为优化现有疫苗平台和开发更有效的新疫苗而不断努力 疫苗是需要的。鼻腔免疫可诱导小鼠和小鼠的抗原特异性免疫 粘膜和系统免疫隔间，从而有效地控制SARS-CoV-2感染和 疾病。然而，大多数获得紧急使用授权或临床试验的SARS-CoV-2疫苗是 仅限于非肠道给药，因为可溶性抗原不会突破鼻腔上皮屏障，而是通过 通过微折叠细胞。我们最近报道了一种修饰的多孔硅微粒(MPSM)佐剂 SARS-CoV-2受体结合域(RBD)疫苗引发高效持久的系统性体液和型别 1静脉注射后辅助性T细胞介导的免疫反应。MPSM还促进了粘膜 SARS-CoV-2 RBD抗原摄取。两剂肠外和鼻腔联合疫苗接种 MPSM-RBD可诱导更强的肺T、B细胞和粘膜免疫球蛋白A反应 单独接种疫苗，导致SARS后肺部的病毒载量和炎症显著减少- COV-2三角洲变种挑战赛。我们的结果表明mPSM是一种有效的SARS-CoV-2佐剂。 全身疫苗和粘膜疫苗中的亚单位疫苗。我们还发现，组合的mRNA- S+核衣壳(N)疫苗对Delta和Omicron变种感染的保护作用强于 临床批准的单独表达S基因的疫苗。因此，为了进一步优化疫苗的免疫原性 MPSM佐剂亚单位疫苗后，我们将修改抗原的配方。在这里，我们假设 以mPSM为基础的亚单位疫苗的肠外和鼻腔接种可触发持久的全身和 针对SARS-CoV-2 VOCs感染提供交叉保护的粘膜免疫反应和 变速箱。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的肠外和鼻腔接种的保护效果。 青年和老年小鼠感染SARS-CoV-2 VOCs亚基疫苗及其免疫学鉴定 寄主保护的相关性(目标2)。最后，我们将确认m-PSM亚单位疫苗的免疫原性 并评价其预防SARS-CoV-2 VOCs传播和加强控制SARS-CoV-2 VOCs的效果 感染(目标3)。该项目的结果将是一种有效的SARS-CoV-2疫苗候选疫苗，可诱导 平衡的系统和粘膜免疫，提供针对SARS的长期交叉反应宿主保护- CoV-2 VOCs，并为我们未来的冠状病毒爆发做好准备。

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.