Safety and immunogenicity of an optimized self-replicating RNA platform for low dose or single dose vaccine applications: a randomized, open label Phase I study in healthy volunteers

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 7, 2025

Self-replicating RNA (srRNA) technology, in comparison to mRNA vaccines, has shown dose-sparing by approximately 10-fold and more durable immune responses. However, no improvements are observed the adverse events profile. Here, we develop an srRNA vaccine platform with optimized non-coding regions demonstrate immunogenicity safety preclinical clinical development. Optimized vaccines generate protective immunity (according WHO defined thresholds) at doses up 1,000,000-fold lower than female mouse models of influenza rabies. Clinically, RBI-4000, vector encoding rabies glycoprotein, was evaluated a Phase I study (NCT06048770). RBI-4000 able elicit de novo majority healthy participants when administered dose 0.1, 1, or 10 microgram (71%, 94%, 100%, respectively) prime-boost schedule. Similarly, observe above benchmark protection following single administration most both 1 doses. There serious reported across all cohorts. These data establish high therapeutic index vectors, demonstrating feasibility low approaches for applications. Here authors report self-replicating approach that generates much mice. In using glycoprotein as antigen, they show robust responses 0.1 µg, favorable

Language: Английский

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Rational formulation and industrial manufacturing of lipid-based complex injectables: Landmarks and trends

Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 373, P. 617 - 639

Published: July 31, 2024

Language: Английский

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Transformative Approaches in SARS-CoV-2 Management: Vaccines, Therapeutics and Future Direction

Virology, Journal Year: 2025, Volume and Issue: 604, P. 110394 - 110394

Published: Jan. 11, 2025

Language: Английский

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Differential clearance rate of proteins encoded on a self-amplifying mRNA COVID-19 vaccine in muscle and lymph nodes

Biochemistry and Biophysics Reports, Journal Year: 2025, Volume and Issue: 42, P. 101999 - 101999

Published: April 5, 2025

Language: Английский

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A Novel Self‐Amplifying mRNA with Decreased Cytotoxicity and Enhanced Protein Expression by Macrodomain Mutations

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 23, 2024

Abstract The efficacy and safety of self‐amplifying mRNA (saRNA) have been demonstrated in COVID‐19 vaccine applications. Unlike conventional non‐replicating (nrmRNA), saRNA offers a key advantage: its self‐replication mechanism fosters efficient expression the encoded protein, leading to substantial dose savings during administration. Consequently, there is growing interest further optimizing efficiency saRNA. In this study, vitro adaptive passaging conducted under exogenous interferon pressure, which revealed several mutations nonstructural protein (NSP). Notably, two stable mutations, Q48P I113F, situated NSP3 macrodomain (MD), attenuated mono adenosine diphosphate ribose (MAR) hydrolysis activity exhibited decreased replication but increased payload compared wild‐type (wt saRNA). Transcriptome sequencing analysis unveils diminished activation double‐stranded RNA (dsRNA) sensor and, consequently, significantly reduced innate immune response wt Furthermore, mutant less translation inhibition cell apoptosis than saRNA, culminating higher both vivo. These findings underscore potential reducing replication‐dependent dsRNA‐induced responses through genetic modification as valuable strategy for enhancing efficiency, mitigating cytotoxicity.

Language: Английский

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Extracellular vesicles versus lipid nanoparticles for the delivery of nucleic acids

Advanced Drug Delivery Reviews, Journal Year: 2024, Volume and Issue: unknown, P. 115461 - 115461

Published: Oct. 1, 2024

Language: Английский

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Synthetic mRNAs Containing Minimalistic Untranslated Regions Are Highly Functional In Vitro and In Vivo

Cells, Journal Year: 2024, Volume and Issue: 13(15), P. 1242 - 1242

Published: July 24, 2024

Synthetic mRNA produced by in vitro transcription (ivt mRNA) is the active pharmaceutical ingredient of approved anti-COVID-19 vaccines and many drugs under development. Such synthetic typically contains several hundred bases non-coding “untranslated” regions (UTRs) that are involved stabilization translation mRNA. However, UTRs often complex structures, which may complicate entire production process. To eliminate this obstacle, we managed to reduce total amount nucleotides only four bases. In way, generate minimal ivt (“minRNA”), less than usual optimized mRNAs contained, for example, vaccines. We have compared efficacy minRNA common augmented (with globin genes or those included licensed vaccines) vivo could demonstrate equivalent functionalities. Our design will facilitate further development implementation mRNA-based therapies.

Language: Английский

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AI-Driven Resilience Strategies for Enhancing Healthcare Supply Chain Resilience: A Systematic Literature Review (Preprint)

Published: Jan. 22, 2025

The COVID-19 pandemic has exposed the vulnerabilities of global supply chains (SC), particularly within healthcare sector, underscoring need for advanced methods to enhance SC resilience and sustainability. Pandemics, such as Influenza, pose considerable risks chain (HSC) performance, demanding robust analytical tools optimize system efficiency under uncertain conditions. In this paper, we map current literature synthesize insights on role leadership in driving Artificial Intelligence (AI)-driven approaches enhancing HSC organizations. This systematic review aims HSC-resilience (HSCR) apply a novel network range directional measure model evaluate sustainability response pandemic. followed PRISMA guidelines, encompassing multiple databases, including Business Source Premier, CINAHL, ACM Digital Library, MEDLINE, PsycINFO, Web Science, PubMed, ScienceDirect. targeted articles published from 2016 2024, focusing empirical studies. A predetermined search strategy used keywords resilience, artificial intelligence, healthcare, related terms. analysis involved an inductive, thematic approach qualitatively evidence. screening data extraction processes were independently carried out by two reviewers, with Cohen's kappa assess interrater agreement. Data synthesis was accomplished through narrative approach. comprehensive case study demonstrates practical application model, revealing its capability diverse findings highlight how decision-making unit varies changing circumstances, showcasing model’s robustness evaluating performance during disruptions. final number studies included 39. These clinical units quantitative qualitative decision support models 16/39 (41%) 25/39 (59%), respectively. earliest article 2018; most recent 2022. is one first compare AI conventional human real-time gathering AI-driven strategies strengthen HSC. While proves effective assessing sustainability, key limitation lies implementation methodologies Future research should focus real-world deployment these face potential

Language: Английский

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mRNA Vaccines: Design Principles, Mechanisms, and Manufacturing—Insights From COVID‐19 as a Model for Combating Infectious Diseases

Biotechnology Journal, Journal Year: 2025, Volume and Issue: 20(2)

Published: Feb. 1, 2025

The full approval of two SARS-CoV-2 mRNA vaccines, Comirnaty and Spikevax, has greatly accelerated the development numerous vaccine candidates targeting infectious diseases cancer. vaccines provide a rapid, safe, versatile manufacturing process while eliciting strong humoral cellular immune responses, making them particularly beneficial for addressing emerging pandemics. Recent advancements in modified nucleotides lipid nanoparticle delivery systems have further emphasized potential this platform. Despite these transformative opportunities, significant improvements are needed to enhance efficacy, stability, immunogenicity. This review outlines fundamentals design, process, administration strategies, along with various optimization approaches. It also offers comprehensive overview developed since onset COVID-19 pandemic, challenges posed by variants, current strategies address variants. Finally, we discuss broad-spectrum combined examine future prospects

Language: Английский

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Broad-spectrum immune suppression encoded in self-amplifying RNA enables non-cytotoxic, non-immunostimulatory, externally controllable transgene expression

Published: April 3, 2025

Self-amplifying RNA (saRNA) has the potential to provide durable, non-integrative transgene expression for transient gene therapy. However, its auto-replicative nature mimics viral infection, triggering innate immune responses that shutdown cap-dependent translation, degrade cellular mRNA, induce cell death, and release cytokines. In non-immunotherapy applications, this activation is undesirable as it limits expression, depletes transfected cells, induces inflammation, undermining therapeutic outcomes. Moreover, use of exogenous suppressants mitigate these effects often increases treatment complexity risk unintended systemic side effects. To address challenges, we developed a strategy encode broad-spectrum suppression directly within saRNA. This approach leverages cap-independent translation bypass saRNA-triggered shutdown, enabling multiple inhibitors targeting diverse double-stranded RNA-sensing inflammatory signaling pathways. mouse primary fibroblast-like synoviocytes—a type relevant joint diseases—this eliminates need external inhibitors, reduces cytotoxicity antiviral cytokine secretion, enables sustained can be controlled with small-molecule antiviral. These findings support development saRNA therapeutics offer non-integrative, externally controllable without persistent or reliance on suppressants.

Language: Английский

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