An Exploratory Phase I, Randomized, Observer-blind, Active-controlled, Dose-escalation Trial Evaluating the Safety, Tolerability, and Immunogenicity of an Investigational RNA-based SARS-CoV-2 Vaccine in COVID-19 Vaccine Experienced Healthy Adults

This is an exploratory Phase I, randomized, observer-blind, active-controlled, dose-escalation trial to evaluate four dose levels (DLs) of BNT162b4 given in combination with BNT162b2 Bivalent (original/Omicron BA.4/BA.5) to select a safe and tolerable dose and to evaluate BNT162b4 + BNT162b2 Bivalent (original/Omicron BA.4/BA.5) when given as Dose 1 and Dose 2 (booster) in Cohorts 1 and 2 and BNT162b4 + BNT162b2 Monovalent (OMI XBB.1.5) when given as Dose 2 (booster) in Cohorts 3a, 3b, 4a, and 4b, and 30 μg BNT162b4 when given alone as Dose 1 and Dose 2 in Cohort 5.
The trial will use a staggered dosing process schema, i.e., enrollment into the next higher dose level is done sequentially and subject to safety data from the previous dose levels, with sentinel participants in Cohorts 1, 2, 3a, and 4a. Cohort 3b investigating the same dose level as cohort 3a but in participants aged >55 years will be opened after safety data for participants aged 18-55 years in Cohort 3a has been reviewed. Enrollment into Cohorts 4a and 4b will be opened after safety data for Cohort 3a and 3b has been reviewed. Cohort 5 participants will not be randomized and will receive two doses of BNT162b4 alone after which a safety review will be performed after all participants have received Dose 2 in this cohort.
BNT162b4 plus BNT162b2 Bivalent (original/Omicron BA.4/BA.5)/Monovalent (OMI XBB.1.5) will be co-administered (as a single injection).
BNT162b4 alone will be administered as a single injection.

开始日期2022-11-08

申办/合作机构

BioNTech SE

[+1]

100 项与 SARS-CoV-2 ORF1Ab 相关的临床结果

登录后查看更多信息

100 项与 SARS-CoV-2 ORF1Ab 相关的转化医学

登录后查看更多信息

0 项与 SARS-CoV-2 ORF1Ab 相关的专利（医药）

登录后查看更多信息

项与 SARS-CoV-2 ORF1Ab 相关的文献（医药）

2024-10-01·Biochimie

Myelin basic protein antagonizes the SARS-CoV-2 protein ORF3a-induced autophagy inhibition

Article

作者: Saratov, George A ; Belogurov, Alexey A ; Kudriaeva, Anna A

Inhibition of autophagy is one of the hallmarks of the SARS-CoV-2 infection. Recently it was reported that SARS-CoV-2 protein ORF3a inhibits fusion of autophagosomes with lysosomes via interaction with VPS39 thus preventing binding of homotypic fusion and protein sorting (HOPS) complex to RAB7 GTPase. Here we report that myelin basic protein (MBP), a major structural component of the myelin sheath, binds ORF3a and is colocalized with it in mammalian cells. Co-expression of MBP with ORF3a restores autophagy in mammalian cells, inhibited by viral protein. Our data suggest that basic charge of MBP drives suppression of ORF3a-induced autophagy inhibition as its deaminated variants lost ability to bind ORF3a and counteract autophagy blockade. These results together with our recent findings, indicating that MBP interacts with structural components of the vesicle transport machinery-synaptosomal-associated protein 23 (SNAP23), vesicle-associated membrane protein 3 (VAMP3) and Sec1/Munc18-1 family members, may suggest protective role of the MBP in terms of the maintaining of protein traffic and autophagosome-lysosome fusion machinery in oligodendrocytes during SARS-CoV-2 infection. Finally, our data may indicate that deimination of MBP observed in the patients with multiple sclerosis (MS) may contribute to the previously reported worser outcomes of COVID-19 and increase of post-COVID-19 neurologic symptoms in patients with MS.

2024-05-01·International Journal of Biological Macromolecules

ORF3a of SARS-CoV-2 modulates PI3K/AKT signaling in human lung epithelial cells via hsa-miR-155-5p

Article

作者: Ahmad, Faiyaz ; Keshri, Vishal ; Singh, Sunit K

SARS-CoV-2 infection results in cytokine burst, leading to proinflammatory responses in lungs of COVID-19 patients. SARS-CoV-2 ORF3a triggers the generation of proinflammatory cytokines. However, the underlying mechanism of dysregulation of proinflammatory responses is not well understood. We studied the role of microRNA in the generation of proinflammatory responses as a bystander effect of SARS-CoV-2 ORF3a in human lung epithelial cells. We observed upregulation of hsa-miR-155-5p in SARS-CoV-2 ORF3a transfected human lung epithelial cells, which led to the reduced expression of SHIP1. This resulted in phosphorylation of AKT and NF-κB, which further led to the increased expression of the proinflammatory cytokines IL-6 and TNF-α. Additionally, overexpression and knockdown studies of hsa-miR-155-5p were performed to confirm the role of hsa-miR-155-5p in the regulation of the SHIP1. We demonstrated that hsa-miR-155-5p modulates the proinflammatory response by activating the PI3K/AKT pathway through the inhibition of SHIP1 in SARS-CoV-2 ORF3a transfected human lung epithelial cells.

2022-11-02·Autophagy1区 · 生物学

SARS-CoV-2 ORF3a induces RETREG1/FAM134B-dependent reticulophagy and triggers sequential ER stress and inflammatory responses during SARS-CoV-2 infection

1区 · 生物学

Article

作者: Wang, Pei-Hui ; Sun, Qinqin ; Li, Xiaojuan ; Pan, Ting ; Kuang, Ersheng ; Zhang, Xiaolin ; Yang, Ziwei ; Long, Xubing

SARS-CoV-2 infections have resulted in a very large number of severe cases of COVID-19 and deaths worldwide. However, knowledge of SARS-CoV-2 infection, pathogenesis and therapy remains limited, emphasizing the urgent need for fundamental studies and drug development. Studies have shown that induction of macroautophagy/autophagy and hijacking of the autophagic machinery are essential for the infection and replication of SARS-CoV-2; however, the mechanism of this manipulation and the function of autophagy during SARS-CoV-2 infection remain unclear. In the present study, we identified ORF3a as an inducer of autophagy (in particular reticulophagy) and revealed that ORF3a localizes to the ER and induces RETREG1/FAM134B-related reticulophagy through the HMGB1-BECN1 (beclin 1) pathway. As a consequence, ORF3a induces ER stress and inflammatory responses through reticulophagy and then sensitizes cells to the acquisition of an ER stress-related early apoptotic phenotype and facilitates SARS-CoV-2 infection, suggesting that SARS-CoV-2 ORF3a hijacks reticulophagy and then disrupts ER homeostasis to induce ER stress and inflammatory responses during SARS-CoV-2 infection. These findings reveal the sequential induction of reticulophagy, ER stress and acute inflammatory responses during SARS-CoV-2 infection and imply the therapeutic potential of reticulophagy and ER stress-related drugs for COVID-19.Abbreviations: CQ: chloroquine; DEGs: differentially expressed genes; ER: endoplasmic reticulum; GSEA: gene set enrichment analysis; HMGB1: high mobility group box 1; HMOX1: heme oxygenase 1; MERS-CoV: Middle East respiratory syndrome coronavirus; RETREG1/FAM134B: reticulophagy regulator 1; RTN4: reticulon 4; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TN: tunicamycin.

项与 SARS-CoV-2 ORF1Ab 相关的新闻（医药）

2023-10-17

·生物谷

郑春福教授在JMV发表新冠病毒阻断自噬流促进病毒复制和致病的文章

近日郑春福教授和合作者历在Journal of Medical Virology发表研究论文“SARS-CoV-2 ORF7a blocked autophagy flux by inte 近日郑春福教授和合作者历在Journal of Medical Virology发表研究论文“SARS-CoV-2 ORF7a blocked autophagy flux by intervening in the fusion between autophagosome and lysosome to promote viral infection and pathogenesis” (SARS-CoV-2 ORF7a通过干预自噬体和溶酶体之间的融合来阻断自噬流，从而促进病毒感染和致病)。值得一提的是，最后一轮的审稿者（应该是新的审稿者）对我们的工作给予高度的评价。 2019 年冠状病毒病 (COVID-19) 对全球公共卫生构成重大威胁。尽管许多研究已经阐明了SARS-CoV-2（严重急性呼吸综合征冠状病毒-2）感染过程，但病毒入侵和免疫逃避的潜在机制仍不清楚。本研究重点关注 SARS-CoV-2 ORF7a（开放阅读框-7a），它是感染和发病机制中必不可少的开放阅读框（ORF）之一。首先，通过分析其理化特性，SARS-CoV-2 ORF7a是一种不稳定的疏水性跨膜蛋白。然后，对ORF7a跨膜域三维晶体结构模型进行了预测和验证。 SARS-CoV-2 ORF7a 定位于内质网，通过与 p62 相互作用参与自噬-溶酶体途径。此外，本研究还阐明了ORF7a拦截自噬流、促进双膜囊泡形成、逃避宿主自噬-溶酶体降解和抗病毒先天免疫的潜在分子机制。这项研究表明 ORF7a 可能是一个治疗靶点，而Glecaprevir可能是通过靶向 ORF7a 来对抗 SARS-CoV-2 的潜在药物。全面了解 ORF7a 的功能可能有助于开发 COVID-19 的新疗法和临床药物。图 1. SARS-CoV-2 ORF7a 的序列和功能分析。(a) SARS-CoV-2完整基因序列示意图；(b) 不同物种中SARS-CoV-2系列的系统发育树；(c) SARS-CoV-2 ORF7a 的极性分析。图 2. SARS-CoV-2 ORF7a跨膜结构域三维晶体结构模型的分析、预测和验证。 (a) ORF7a的跨膜结构分析；(b) SARS-CoV-2 ORF7a 的三维结构；(c) SARS-CoV-2 ORF7a 的二维结构；(d) ORF7a的三维跨膜结构；(e) 拉马钱德兰地图；(f) 验证 ORF7a 模型的 3D 评估图。图 3. SARS-CoV-2 ORF7a 通过与 p62 相互作用干扰 ER 中的自噬-溶酶体途径。图 4. SARS-CoV-2 ORF7a 通过阻断自噬体和溶酶体之间的融合来阻止自噬流。图 5. Glecaprevir 是一种靶向 ORF7a 抗 SARS-CoV-2 感染和发病的潜在药物。(a) SARS-CoV-2 ORF7a 的两个口袋结构；(b) Glecaprevir与ORF7a口袋A的模拟组合。图 6. Glecaprevir抑制SARS-CoV-2 GFP/ΔN trVLP 的感染。图 7. ORF7a阻断自噬流、逃逸宿主自噬溶酶体降解的模式图