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1.
Immunity ; 55(11): 1993-2005, 2022 Nov 08.
Article in English | MEDLINE | ID: covidwho-2105131

ABSTRACT

The lipid nanoparticle (LNP)-encapsulated, nucleoside-modified mRNA platform has been used to generate safe and effective vaccines in record time against COVID-19. Here, we review the current understanding of the manner whereby mRNA vaccines induce innate immune activation and how this contributes to protective immunity. We discuss innate immune sensing of mRNA vaccines at the cellular and intracellular levels and consider the contribution of both the mRNA and the LNP components to their immunogenicity. A key message that is emerging from recent observations is that the LNP carrier acts as a powerful adjuvant for this novel vaccine platform. In this context, we highlight important gaps in understanding and discuss how new insight into the mechanisms underlying the effectiveness of mRNA-LNP vaccines may enable tailoring mRNA and carrier molecules to develop vaccines with greater effectiveness and milder adverse events in the future.


Subject(s)
COVID-19 , Humans , COVID-19/prevention & control , Vaccines, Synthetic , RNA, Messenger/genetics , Immunity, Innate
2.
J Pharm Sci ; 2022 Nov 16.
Article in English | MEDLINE | ID: covidwho-2096155

ABSTRACT

The remarkable impact of mRNA vaccines on mitigating disease and improving public health has been amply demonstrated during the COVID-19 pandemic. Many new mRNA-based vaccine and therapeutic candidates are in development, yet the current reality of their stability limitations requires their frozen storage. Numerous challenges remain to improve formulated mRNA stability and enable refrigerator storage, and this review provides an update on developments to tackle this multi-faceted stability challenge. We describe the chemistry underlying mRNA degradation during storage and highlight how lipid nanoparticle (LNP) formulations are a double-edged sword: while LNPs protect mRNA against enzymatic degradation, interactions with and between LNP excipients introduce additional risks for mRNA degradation. We also discuss strategies to improve mRNA stability both as a drug substance (DS) and a drug product (DP) including the (1) design of the mRNA molecule (nucleotide selection, primary and secondary structures), (2) physical state of the mRNA-LNP complexes, (3) formulation composition and purity of the components, and (4) DS and DP manufacturing processes. Finally, we summarize analytical control strategies to monitor and assure the stability of mRNA-based candidates, and advocate for an integrated analytical and formulation development approach to further improve their storage, transport, and in-use stability profiles.

3.
Mol Ther Nucleic Acids ; 30: 226-240, 2022 Dec 13.
Article in English | MEDLINE | ID: covidwho-2042066

ABSTRACT

mRNA and lipid nanoparticles have emerged as powerful systems for the preparation of vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The emergence of novel variants or the necessity of cold chain logistics for approved mRNA vaccines undermines the investigation of next-generation systems that could preserve both potency and stability. However, the correlation between lipid nanoparticle composition and activity is not fully explored. Here, we screened a panel of ionizable lipids in vivo and identified lead lipid nanoparticles with a branched-tail lipid structure. Buffer optimization allowed the determination of lyophilization conditions, where lipid nanoparticle-encapsulated mRNA encoding SARS-CoV-2 spike protein could induce robust immunogenicity in mice after 1 month of storage at 5°C and 25°C. Intramuscularly injected lipid nanoparticles distributed in conventional dendritic cells in mouse lymph nodes induced balanced T helper (Th) 1/Th2 responses against SARS-CoV-2 spike protein. In nonhuman primates, two doses of 10 or 100 µg of mRNA induced higher spike-specific binding geometric mean titers than those from a panel of SARS-CoV-2-convalescent human sera. Immunized sera broadly inhibited the viral entry receptor angiotensin-converting enzyme 2 (ACE2) from binding to the spike protein in all six strains tested, including variants of concern. These results could provide useful information for designing next-generation mRNA vaccines.

4.
Polymer Reviews ; 2022.
Article in English | Scopus | ID: covidwho-1984894

ABSTRACT

Vaccine development is among the critical issues for ceasing the COVID-19 pandemic. This review discusses the current usage of biomaterials in vaccine development and provides brief descriptions of the vaccine types and their working mechanisms. New types of vaccine platforms (next-generation vaccines and DNA- or mRNA-based vaccines) are discussed in detail. The mRNA vaccine encoding the spike protein viral antigen can be produced in a cell-free system, suggesting that mRNA vaccines are safer than “classic vaccines” using live or inactivated virus. The mRNA vaccine efficacy is typically high at approximately 95%. However, most mRNA vaccines need to be maintained at −20 or −70 degrees for storage for long periods (half a year) and their transportation because of mRNA vaccine instability in general, although mRNA vaccines with unmodified and self-amplifying RNA (ARCT-154, Arcturus), which have a lyophilized form, have recently been reported to be kept at room temperature. mRNA vaccines are typically entrapped in lipid nanoparticles composed of ionizable lipids, polyethylene glycol (PEG)-lipids, phospholipids, and cholesterol. These components and their composition affect mRNA vaccine stability and efficacy and the size of the mRNA vaccine. The development of an improved mRNA vaccine entrapped in sophisticated biomaterials, such as novel lipid nanoparticles, using new types of biopolymers or lipids is necessary for high efficacy, safe transportation and long-term storage of the next generation of mRNA vaccines under mild conditions. © 2022 Taylor & Francis Group, LLC.

5.
Arhiv za Farmaciju ; 72(1):20-35, 2022.
Article in English | Scopus | ID: covidwho-1964483

ABSTRACT

In the light of the recommended application of the third dose, both public and professional community would benefit from a detailed report on the technological advances behind the developed messenger ribonucleic acid (mRNA) based COVID-19 vaccines. Although many vaccine developers are yet to reveal their precise formulations, it is apparent they are founded on nanotechnology platforms similar to the one successfully used for registered drug Onpattro™ (INN: patisiran). Optimal encapsulation of mRNA requires the presence of four lipids: an ionizable cationic lipid, a polyethylene-glycol (PEG)-lipid, a neutral phospholipid and cholesterol. Together with other excipients (mainly buffers, osmolytes and cryoprotectives), they enable the formation of lipid nanoparticles (LNPs) using rapid-mixing microfluidic or T-junction systems. However, some limitations of thermostability testing protocols, coupled with the companies’ more or less cautious approach to predicting vaccine stability, led to rigorous storage conditions:-15° to-25°C or even-60° to-80°C. Nevertheless, some inventors recently announced their mRNA-LNP based vaccine candidates to be stable at both 25° and 37°C for a week. Within the formulation design space, further optimization of the ionizable lipids should be expected, especially in the direction of increasing their branching and optimizing pKa values, ultimately leading to the second generation of mRNA-LNP COVID-19 vaccines. © 2022, Pharmaceutical Association of Serbia. All rights reserved.

6.
Adv Drug Deliv Rev ; 188: 114416, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1914095

ABSTRACT

Lipid nanoparticles (LNPs) play an important role in mRNA vaccines against COVID-19. In addition, many preclinical and clinical studies, including the siRNA-LNP product, Onpattro®, highlight that LNPs unlock the potential of nucleic acid-based therapies and vaccines. To understand what is key to the success of LNPs, we need to understand the role of the building blocks that constitute them. In this Review, we discuss what each lipid component adds to the LNP delivery platform in terms of size, structure, stability, apparent pKa, nucleic acid encapsulation efficiency, cellular uptake, and endosomal escape. To explore this, we present findings from the liposome field as well as from landmark and recent articles in the LNP literature. We also discuss challenges and strategies related to in vitro/in vivo studies of LNPs based on fluorescence readouts, immunogenicity/reactogenicity, and LNP delivery beyond the liver. How these fundamental challenges are pursued, including what lipid components are added and combined, will likely determine the scope of LNP-based gene therapies and vaccines for treating various diseases.


Subject(s)
COVID-19 , Nanoparticles , Nucleic Acids , Vaccines , COVID-19/prevention & control , COVID-19 Vaccines , Genetic Therapy , Humans , Lipids/chemistry , Liposomes , Nanoparticles/chemistry , RNA, Small Interfering/chemistry , RNA, Small Interfering/genetics
7.
Biomaterials ; 286: 121570, 2022 07.
Article in English | MEDLINE | ID: covidwho-1821147

ABSTRACT

The mRNA vaccine technology has promising applications to fight infectious diseases as demonstrated by the licensing of two mRNA-based vaccines, Comirnaty® (Pfizer/BioNtech) and Spikevax® (Moderna), in the context of the Covid-19 crisis. Safe and effective delivery systems are essential to the performance of these vaccines and lipid nanoparticles (LNPs) able to entrap, protect and deliver the mRNA in vivo are considered by many as the current "best in class". Nevertheless, current mRNA/LNP vaccine technology has still some limitations, one of them being thermostability, as evidenced by the ultracold distribution chain required for the licensed vaccines. We found that the thermostability of mRNA/LNP, could be improved by a novel imidazole modified lipid, DOG-IM4, in combination with standard helper lipids. DOG-IM4 comprises an ionizable head group consisting of imidazole, a dioleoyl lipid tail and a short flexible polyoxyethylene spacer between the head and tail. Here we describe the synthesis of DOG-IM4 and show that DOG-IM4 LNPs confer strong immunization properties to influenza HA mRNA in mice and macaques and a remarkable stability to the encapsulated mRNA when stored liquid in phosphate buffered saline at 4 °C. We speculate the increased stability to result from some specific attributes of the lipid's imidazole head group.


Subject(s)
COVID-19 , Nanoparticles , Animals , COVID-19/prevention & control , Imidazoles , Immunization , Lipids , Liposomes , Mice , Primates/genetics , RNA, Messenger/genetics , Vaccines, Synthetic , mRNA Vaccines
8.
Drug Metab Pharmacokinet ; 41: 100424, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1458828

ABSTRACT

Nucleic acid therapeutics are developing into precise medicines that can manipulate specific genes. However, the development of safe and effective delivery system for the target cells has remained a challenge. Lipid nanoparticles (LNPs) have provided a revolutionary delivery system that can ensure multiple clinical translation of RNA-based candidates. In 2018, Patisiran (Onpattro) was first approved as an LNP-based siRNA drug. In 2020, during the coronavirus disease 2019 (COVID-19) outbreak, LNPs have enabled the development of two SARS-CoV-2 mRNA vaccines, Tozinameran (Comirnaty or Pfizer-BioNTech COVID-19 vaccine) and Elasomeran (Spikevax or COVID-19 vaccine Moderna) for conditional approval. Here, we reviewed the state-of-the-art LNP technology employed in three approved drugs (one siRNA-based and two mRNA-based drugs) and discussed the differences in their mode of action, formulation design, and biodistribution.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Liposomes/immunology , RNA, Small Interfering/immunology , Vaccines, Synthetic/immunology , /immunology , Animals , Humans , Nanoparticles , Technology/methods
9.
Vaccines (Basel) ; 9(1)2021 Jan 19.
Article in English | MEDLINE | ID: covidwho-1389566

ABSTRACT

The recent success of mRNA vaccines in SARS-CoV-2 clinical trials is in part due to the development of lipid nanoparticle delivery systems that not only efficiently express the mRNA-encoded immunogen after intramuscular injection, but also play roles as adjuvants and in vaccine reactogenicity. We present an overview of mRNA delivery systems and then focus on the lipid nanoparticles used in the current SARS-CoV-2 vaccine clinical trials. The review concludes with an analysis of the determinants of the performance of lipid nanoparticles in mRNA vaccines.

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