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

总结： 2019冠状病毒病（COVID-19）大流行对全球公众造成了毁灭性影响 在过去的三年里，健康和经济。尽管COVID-19疫苗的快速进展取得了成功， 发展，增加关注的变异（VOC）的比率，增强病毒传播和疾病 严重性和/或逃避疫苗诱导免疫的能力对全球疫苗效率提出了挑战， 努力不断努力优化现有疫苗平台，开发更有效的新型疫苗。 需要疫苗。鼻内免疫可导致在两个组织中诱导抗原特异性免疫， 粘膜和全身免疫区室，因此有效控制SARS-CoV-2感染， 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 由于可溶性抗原不破坏鼻上皮屏障 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）疫苗引发有效和持久的全身体液和型 1辅助性T细胞介导的免疫应答。mPSM还促进粘膜 SARS-CoV-2 RBD抗原的摄取。两剂胃肠外和鼻内联合疫苗接种， mPSM-RBD比肠外给药引起更强的肺驻留T和B细胞以及粘膜IgA应答 仅接种疫苗，就能显著降低SARS后肺部的病毒载量和炎症， CoV-2 Delta变体挑战。我们的结果表明mPSM是SARS-CoV-2的有效佐剂 亚单位疫苗在全身和粘膜接种中的应用。我们还发现组合mRNA- S+核衣壳（N）疫苗接种对Delta和Omicron变体感染的保护作用强于 临床批准的表达S的mRNA疫苗。因此，为了进一步优化免疫原性， mPSM佐剂亚单位疫苗，我们将修改抗原的配方。在这里，我们假设， 使用基于mPSM的亚单位疫苗的肠胃外和鼻内疫苗接种引发持久的全身和 粘膜免疫应答，提供针对SARS-CoV-2 VOC感染的交叉保护， 传输我们将初步优化m-PSM亚单位疫苗的免疫原性，并测试m-PSM亚单位疫苗在 小鼠（Aim 1）。接下来，我们将研究肠外和鼻内接种m-PSM的保护效力 SARS-CoV-2 VOCs亚单位疫苗对幼龄和老龄小鼠的感染及免疫原性鉴定 主机保护的相关因素（目标2）。最后，我们将证实m-PSM亚单位疫苗的免疫原性， 并评估其预防SARS-CoV-2 VOCs传播和加强控制 感染（目标3）。该项目的结果将是一种有效的SARS-CoV-2候选疫苗， 平衡的全身和粘膜免疫力，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.