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.

Start Date08 Nov 2022

Sponsor / Collaborator

BioNTech SE

[+1]

100 Clinical Results associated with SARS-CoV-2 ORF1Ab

100 Translational Medicine associated with SARS-CoV-2 ORF1Ab

0 Patents (Medical) associated with SARS-CoV-2 ORF1Ab

Literatures (Medical) associated with SARS-CoV-2 ORF1Ab

01 Oct 2024·Biochimie

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

Article

Author: 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.

01 May 2024·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

Author: 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.

25 May 2023·CellQ1 · BIOLOGY

The T-cell-directed vaccine BNT162b4 encoding conserved non-spike antigens protects animals from severe SARS-CoV-2 infection.

Q1 · BIOLOGY

Article

Author: Liu-Lupo, Yunpeng ; Poran, Asaf ; Rothenberg, Daniel A. ; Cadima Couto, Carla Iris ; Thanki, Kaushik ; Sahin, Ugur ; Harjanto, Dewi ; Meda, Shirisha ; Xie, Yushu Joy ; Fesser, Stephanie ; Vogel, Annette B. ; Tureci, Ozlem ; Walzer, Kerstin ; Arieta, Christina M. ; Srouji, John R. ; Lobo, Alexander ; Hein, Stephanie ; Marquart, Krisann ; Diao, Huitian ; Krumm, Stefanie A. ; Sciuto, Tracey E. ; Heinen, Andre P. ; Zuiani, Adam ; Addona, Theresa A. ; Koenitzer, Byron ; Ziegenhals, Thomas ; Gaynor, Richard B.

T cell responses play an important role in protection against beta-coronavirus infections, including SARS-CoV-2, where they associate with decreased COVID-19 disease severity and duration.To enhance T cell immunity across epitopes infrequently altered in SARS-CoV-2 variants, we designed BNT162b4, an mRNA vaccine component that is intended to be combined with BNT162b2, the spike-protein-encoding vaccine.BNT162b4 encodes variant-conserved, immunogenic segments of the SARS-CoV-2 nucleocapsid, membrane, and ORF1ab proteins, targeting diverse HLA alleles.BNT162b4 elicits polyfunctional CD4+ and CD8+ T cell responses to diverse epitopes in animal models, alone or when co-administered with BNT162b2 while preserving spike-specific immunity.Importantly, we demonstrate that BNT162b4 protects hamsters from severe disease and reduces viral titers following challenge with viral variants.These data suggest that a combination of BNT162b2 and BNT162b4 could reduce COVID-19 disease severity and duration caused by circulating or future variants.BNT162b4 is currently being clin. evaluated in combination with the BA.4/BA.5 Omicron-updated bivalent BNT162b2 (NCT05541861).

Analysis

Perform a panoramic analysis of this field.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

SARS-CoV-2 ORF1Ab

Basic Info

Related

Analysis