Lyophilized mRNA-lipid nanoparticle vaccines with long-term stability and high antigenicity against SARS-CoV-2

Ai, Liangxia; Li, Yafei; Zhou, Li; Yao, Wenrong; Zhang, Hao; Hu, Zhengbing; Han, Jinyu; Wang, Weijie; Wu, Junmiao; Xu, Pan; Wang, Ruiyue; Li, Zhangyi; Li, Zhouwang; Wei, Chengliang; Liang, Jianqun; Chen, Haobo; Yang, Zhimiao; Guo, Ming; Huang, Zhixiang; Wang, Xin; Zhang, Zhen; Xiang, Wenjie; Sun, Dazheng; Xu, Lianqiang; Lu, Ligong; Lv, Bin; Peng, Peiqi; Zhang, Shangfeng; Ji, Xuhao; Luo, Huiyi; Nanping, Chen; Chen, Jianping; Lan, Ke; Hu, Yong

doi:10.1038/s41421-022-00517-9

Cited by 33 publications

(14 citation statements)

References 30 publications

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“…LNPs are known to be fragile and subject to aggregation and breakage when physically stressed, such as during buffer exchange, freeze–thaw cycles, or mechanical stirring. The LNPs in this study have a typical range of polydispersity with PDI below 0.2 (Table ) and comparable or below those reported in the literature for typical LNPs. − PDI is expected to be impacted by the presence of aggregates.…”

Section: Resultssupporting

confidence: 66%

Morphological Characterization of Self-Amplifying mRNA Lipid Nanoparticles

Thelen,

Leite,

Urban

et al. 2024

ACS Nano

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The mRNA technology has emerged as a rapid modality to develop vaccines during pandemic situations with the potential to protect against endemic diseases. The success of mRNA in producing an antigen is dependent on the ability to deliver mRNA to the cells using a vehicle, which typically consists of a lipid nanoparticle (LNP). Self-amplifying mRNA (SAM) is a synthetic mRNA platform that, besides encoding for the antigen of interest, includes the replication machinery for mRNA amplification in the cells. Thus, SAM can generate many antigen encoding mRNA copies and prolong expression of the antigen with lower doses than those required for conventional mRNA. This work describes the morphology of LNPs containing encapsulated SAM (SAM LNPs), with SAM being three to four times larger than conventional mRNA. We show evidence that SAM changes its conformational structure when encapsulated in LNPs, becoming more compact than the free SAM form. A characteristic "bleb" structure is observed in SAM LNPs, which consists of a lipid-rich core and an aqueous RNA-rich core, both surrounded by a DSPC-rich lipid shell. We used SANS and SAXS data to confirm that the prevalent morphology of the LNP consists of two-core compartments where components are heterogeneously distributed between the two cores and the shell. A capped cylinder core−shell model with two interior compartments was built to capture the overall morphology of the LNP. These findings provide evidence that bleb two-compartment structures can be a representative morphology in SAM LNPs and highlight the need for additional studies that elucidate the role of spherical and bleb morphologies, their mechanisms of formation, and the parameters that lead to a particular morphology for a rational design of LNPs for mRNA delivery.

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Section: Resultssupporting

confidence: 66%

Morphological Characterization of Self-Amplifying mRNA Lipid Nanoparticles

Thelen,

Leite,

Urban

et al. 2024

ACS Nano

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“…After that, the vaccine exhibited a significant decrease in mRNA integrity and particle size, as well as a decrease in immunogenicity and mRNA concentration [ 109 ]. Recently, a study reported that the physiochemical properties and bioactivities of lyophilized vaccines showed no change at 25 °C over 6 months, and the lyophilized SARS-CoV-2 mRNA vaccines could elicit potent humoral and cellular immunity whether in mice, rabbits, or rhesus macaques [ 110 ].…”

Section: Factors Affecting Mrna Vaccine Stabilitymentioning

confidence: 99%

Research Advances on the Stability of mRNA Vaccines

Cheng

Wang

Bai

et al. 2023

Viruses

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Compared to other vaccines, the inherent properties of messenger RNA (mRNA) vaccines and their interaction with lipid nanoparticles make them considerably unstable throughout their life cycles, impacting their effectiveness and global accessibility. It is imperative to improve mRNA vaccine stability and investigate the factors influencing stability. Since mRNA structure, excipients, lipid nanoparticle (LNP) delivery systems, and manufacturing processes are the primary factors affecting mRNA vaccine stability, optimizing mRNA structure and screening excipients can effectively improve mRNA vaccine stability. Moreover, improving manufacturing processes could also prepare thermally stable mRNA vaccines with safety and efficacy. Here, we review the regulatory guidance associated with mRNA vaccine stability, summarize key factors affecting mRNA vaccine stability, and propose a possible research path to improve mRNA vaccine stability.

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“…Besides, lyophilization of mRNA‐LNP platforms can retain the stability and high antigenicity of mRNA at 25 °C over six months, thus dramatically improving the accessibility of mRNA‐based therapeutics in remote areas. [ 233 ] Apart from LNP, Badieyan et al. used collagen matrix to deliver mRNA and this platform remained stable for at least six months at room temperature.…”

Section: Summary and Perspectivementioning

confidence: 99%

From structural design to delivery: mRNA therapeutics for cancer immunotherapy

Zhou,

Huang,

et al. 2023

Exploration

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AbstractmRNA therapeutics have emerged as powerful tools for cancer immunotherapy in accordance with their superiority in expressing all sequence‐known proteins in vivo. In particular, with a small dosage of delivered mRNA, antigen‐presenting cells (APCs) can synthesize mutant neo‐antigens and multi‐antigens and present epitopes to T lymphocytes to elicit antitumor effects. In addition, expressing receptors like chimeric antigen receptor (CAR), T‐cell receptor (TCR), CD134, and immune‐modulating factors including cytokines, interferons, and antibodies in specific cells can enhance immunological response against tumors. With the maturation of in vitro transcription (IVT) technology, large‐scale and pure mRNA encoding specific proteins can be synthesized quickly. However, the clinical translation of mRNA‐based anticancer strategies is restricted by delivering mRNA into target organs or cells and the inadequate endosomal escape efficiency of mRNA. Recently, there have been some advances in mRNA‐based cancer immunotherapy, which can be roughly classified as modifications of the mRNA structure and the development of delivery systems, especially the lipid nanoparticle platforms. In this review, the latest strategies for overcoming the limitations of mRNA‐based cancer immunotherapies and the recent advances in delivering mRNA into specific organs and cells are summarized. Challenges and opportunities for clinical applications of mRNA‐based cancer immunotherapy are also discussed.

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Lyophilized mRNA-lipid nanoparticle vaccines with long-term stability and high antigenicity against SARS-CoV-2

Cited by 33 publications

References 30 publications

Morphological Characterization of Self-Amplifying mRNA Lipid Nanoparticles

Morphological Characterization of Self-Amplifying mRNA Lipid Nanoparticles

Research Advances on the Stability of mRNA Vaccines

From structural design to delivery: mRNA therapeutics for cancer immunotherapy

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