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Vaccines
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The Development of mRNA Vaccines
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The Development of mRNA Vaccines

A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "Nucleic Acid (DNA and mRNA) Vaccines".

Deadline for manuscript submissions: 30 September 2026 | Viewed by 16139

Special Issue Editors

Dr. Minghui Yang

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Guest Editor
Advanced Research Institute of Multidisciplinary Sciences, Beijing Institute of Technology, Beijing, China
Interests: infectious disease; mRNA vaccine; coronavirus; immunology; adjuvant
Special Issues, Collections and Topics in MDPI journals
Dr. Yuming Li

E-Mail Website
Guest Editor
School of Public Health and Health Management, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
Interests: vaccine; virus–host interactions; antiviral immunity; coronavirus; enterovirus
Dr. Bo Hu

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Guest Editor
School of Life Science, Beijing Institute of Technology, Beijing, China
Interests: nucleic acid therapeutics; lipid nanoparticle; targeting delivery; cancer; immunoregulation; vaccines

Special Issue Information

Dear Colleagues,

mRNA vaccines have emerged as a transformative platform in modern medicine, demonstrating remarkable success in combating infectious diseases, such as COVID-19 and RSV. This Special Issue aims to explore the latest advancements in mRNA vaccine research, encompassing a wide range of applications, from infectious disease prevention to tumor immunity. Topics of interest include innovative mRNA delivery systems that enhance stability and efficiency, novel vaccine designs targeting emerging pathogens and cancer antigens, and the development of next-generation adjuvants to optimize immune responses. Additionally, we welcome studies addressing manufacturing scalability, regulatory challenges, and strategies to broaden mRNA vaccine accessibility. By showcasing cutting-edge research, this Special Issue seeks to advance the field and inspire new approaches to address global health challenges.

Dr. Minghui Yang
Dr. Yuming Li
Dr. Bo Hu
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Vaccines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • nanoparticle delivery system
  • mRNA vaccines
  • infectious disease
  • tumor immunity
  • adjuvant

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Published Papers (7 papers)

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Research

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19 pages, 1725 KB  
Article
Establishment and Validation of a Cell-Based Relative Potency Method for Respiratory Syncytial Virus mRNA Vaccine Drug Substance
by Shifeng Zheng, Xiaoqin Zhang, Wenhua Li and Hui Zhao
Vaccines 2026, 14(5), 401; https://doi.org/10.3390/vaccines14050401 - 29 Apr 2026
Viewed by 331
Abstract
Background: An accurate, sensitive, and robust potency assay is essential for the quality control of mRNA drug substances, which are characterized by complex manufacturing processes, intricate molecular structures, and high susceptibility to degradation. Currently, mRNA vaccine manufacturers use a variety of biological potency [...] Read more.
Background: An accurate, sensitive, and robust potency assay is essential for the quality control of mRNA drug substances, which are characterized by complex manufacturing processes, intricate molecular structures, and high susceptibility to degradation. Currently, mRNA vaccine manufacturers use a variety of biological potency assays, often without systematic method development or rigorous evaluation. As a result, these assays may lack sufficient accuracy and robustness, making it difficult to reliably distinguish mRNA drug substance samples with different potency levels. Therefore, there is a need for a standardized, robust, and reliable potency assay for the evaluation of mRNA drug substance samples across a range of potencies. Methods: In this study, we developed a cell-based relative potency assay for a respiratory syncytial virus (RSV) mRNA drug substance encoding an engineered prefusion (PreF) form of the RSV type A (RSV-A) F protein, a recognized target for RSV vaccine development. The RSV mRNA drug substance was complexed with transfection reagents and introduced into cells in vitro to enable expression of the RSV-A PreF protein, which was then quantified using a double-antibody sandwich ELISA. Results: Systematic optimization showed that cell line, cell density, transfection reagent, mRNA-to-transfection reagent ratios, and transfection duration all influenced assay performance. Under optimized conditions, the assay demonstrated acceptable accuracy and precision, with relative bias values ranging from −25% to 13% across the potency range of 44~156%, measured-to-expected ratios within 0.8~1.2, and relative standard deviations of 18% and 16% for intra- and inter-assay precision, respectively. Furthermore, the optimized potency assay effectively distinguished mRNA drug substance samples with varying potency levels. Conclusions: This study provides a useful functional complement to physicochemical characterization and supports quality control and batch-to-batch consistency of RSV mRNA drug substances. In addition, the development strategy may also serve as a useful reference for the establishment of in vitro potency assays for other mRNA drug substances. Full article
(This article belongs to the Special Issue The Development of mRNA Vaccines)
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18 pages, 6559 KB  
Article
Nucleoside Modifications and Poly(A) Tail Length Greatly Influence Protein Expression from In Vitro-Transcribed mRNA in a Salmonid Cell Line
by Thea Fossum Krog, Ida Soo Haukland and Gyri Teien Haugland
Vaccines 2026, 14(5), 367; https://doi.org/10.3390/vaccines14050367 - 22 Apr 2026
Viewed by 930
Abstract
Background/Objectives: It is challenging to develop efficient vaccines against intracellular pathogens such as viruses, and since viral infections are one of the main challenges for farmed salmon, a novel vaccine strategy is needed. mRNA vaccines are optimized and approved for humans, but for [...] Read more.
Background/Objectives: It is challenging to develop efficient vaccines against intracellular pathogens such as viruses, and since viral infections are one of the main challenges for farmed salmon, a novel vaccine strategy is needed. mRNA vaccines are optimized and approved for humans, but for fish, the mRNA technology is new, and optimization is required to ensure efficient protein expression. We made an mRNA tailored to salmon and studied the effect of modified nucleosides and the length of the poly(A) tail on protein expression from in vitro-transcribed mRNA in CHSE-214 cells, using enhanced green fluorescent protein (EGFP) as a reporter. Methods: Different lengths of the poly(A) tail were tested, and various modified nucleotides were incorporated in the mRNA during in vitro transcription, including pseudouridine (Ψ), N1-methylpseudouridine (m1Ψ), N6-methyladenosine (m6A), 5-methyluridine (m5U), and 5-methylcytidine (m5C). Protein expression was observed in fluorescence microscopy and quantified using flow cytometry. Results: mRNA containing Ψ resulted in the strongest EGFP expression 1–3 days post-transfection (dpt), while EGFP expression from m5C mRNA was high throughout the experiment (<10 dpt). m5U-containing mRNA had low EGFP expression until 6 dpt, but reached the level of m5C mRNA at 10 dpt. The m5U mRNA, however, expressed EGFP at much higher intensity than all the other mRNAs at all time points. Poly(A) tails with lengths of 40, 100, and >100 were tested, and the one with >100 adenines showed the highest expression. The effects of phosphatase treatment and purification of the mRNA were also investigated. Furthermore, EGFP expression was observed in yolk-sac salmon larvae following micro-injection. Conclusions: Our study provides an important basis for the development of efficient mRNA-based vaccines in the future. Full article
(This article belongs to the Special Issue The Development of mRNA Vaccines)
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19 pages, 3119 KB  
Article
Structural Design of T-Cell Epitope-Based mRNA Vaccine Constructs Determines the Quality of T-Cell Immunity and Protective Efficacy Against SARS-CoV-2 in Mice
by Vladimir A. Gushchin, Andrei E. Siniavin, Andrei A. Pochtovyi, Alina S. Dzharullaeva, Dmitriy N. Shcherbinin, Anastasia S. Ungur, Amir I. Tukhvatulin, Inna V. Shuliakova, Denis A. Kleymenov, Elena P. Mazunina, Evgeniia N. Bykonia, Sofia R. Kozlova, Evgeny V. Usachev, Ilya D. Zorkov, Daria M. Grousova, Anna A. Iliukhina, Alexander L. Gintsburg and Denis Y. Logunov
Vaccines 2026, 14(3), 281; https://doi.org/10.3390/vaccines14030281 - 23 Mar 2026
Viewed by 1111
Abstract
Background/Objectives: Epitope-based mRNA vaccines represent a promising strategy for eliciting protective T-cell immunity against SARS-CoV-2 and as well as for non-infectious mRNA-based vaccines. However, how the structural architecture of vaccine constructs (including epitope arrangement, linker composition, signal peptide presence, and the combination of [...] Read more.
Background/Objectives: Epitope-based mRNA vaccines represent a promising strategy for eliciting protective T-cell immunity against SARS-CoV-2 and as well as for non-infectious mRNA-based vaccines. However, how the structural architecture of vaccine constructs (including epitope arrangement, linker composition, signal peptide presence, and the combination of MHC class I and II epitopes) shapes the quality of T-cell responses remains poorly understood. Methods: Ten tandem minigene mRNA constructs (Cons1–10) encoding different combinations of MHC class I and class II epitopes from SARS-CoV-2 proteins (S, N, M, ORF3a) were designed, encapsulated in lipid nanoparticles, and administered to C57BL/6 mice. Immunogenicity was assessed by cytokine profiling (IFN-γ, IL-2, IL-4, IL-10) and T-cell proliferation assays. Protective efficacy was evaluated in K18-hACE2 transgenic mice challenged with SARS-CoV-2. Results: Constructs lacking a signal peptide and enriched in MHC class I-restricted epitopes induced robust Th1 responses and strong CD8+ T-cell proliferation, achieving up to 66% survival following lethal challenge. In contrast, constructs associated with elevated IL-10 and IL-4 production conferred limited protection (11–33%), consistent with functional skewing towards regulatory or Th2-associated immune profiles. Conclusions: These findings establish a direct link between construct design parameters and T-cell polarization quality, and provide a rational framework for next-generation epitope-based mRNA vaccine development. Full article
(This article belongs to the Special Issue The Development of mRNA Vaccines)
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16 pages, 1921 KB  
Article
A Bivalent mRNA Vaccine Efficiently Prevents Gammaherpesvirus Latent Infection
by Yannan Yin, Jinkai Zang, Huichun Shi, Zhuang Wang, Linlin Kuang, Shuxia Wang, Haikun Wang, Ning Li, Xiaozhen Liang and Zhong Huang
Vaccines 2025, 13(8), 830; https://doi.org/10.3390/vaccines13080830 - 4 Aug 2025
Cited by 1 | Viewed by 1651
Abstract
Background: It is still challenging to develop effective vaccines against tumorigenic human gammaherpesviruses such as Epstein–Barr virus (EBV). A major obstacle is the lack of a small animal model that reproduces the natural infection course of human gammaherpesviruses to allow for proper [...] Read more.
Background: It is still challenging to develop effective vaccines against tumorigenic human gammaherpesviruses such as Epstein–Barr virus (EBV). A major obstacle is the lack of a small animal model that reproduces the natural infection course of human gammaherpesviruses to allow for proper assessment of vaccine efficacy. Murine gammaherpesvirus 68 (MHV68) is a natural pathogen of wild rodents and laboratory mice and therefore can be used as a surrogate for human gammaherpesviruses to evaluate vaccination strategies. Methods: In this study, two mRNA vaccine candidates were generated, one encoding a fusion protein of the MHV68 gH with the gL (gHgL-mRNA) and the other expressing the MHV68 gB protein (gB-mRNA). The immunogenicity and protective efficacy of the mRNA vaccine candidates were evaluated in a mouse model of MHV68 infection. Results: The gHgL-mRNA but not the gB-mRNA candidate vaccine was able to induce neutralizing antibodies in mice, whereas both vaccines could elicit antigen-specific T-cell responses. Following MHV68 intranasal inoculation, complete blocking of the establishment of viral latency was observed in some mice immunized with individual gHgL-mRNA or gB-mRNA vaccines. Notably, co-immunization with the two mRNA vaccines appeared to be more effective than individual vaccines, achieving sterile immunity in 50% of the vaccinated mice. Conclusions: This study demonstrates that immunization with mRNA platform-based subunit vaccines is indeed capable of preventing MHV68 latent infection, thus validating a safe and efficacious vaccination strategy that may be applicable to human gammaherpesviruses. Full article
(This article belongs to the Special Issue The Development of mRNA Vaccines)
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21 pages, 3801 KB  
Article
Immunogenicity, Efficacy and Twelve-Month Storage Stability Studies of a Lyophilized Rabies mRNA Vaccine
by Chen Chen, Dandan Ling, Kai Ji, Liang Tang, Xiaojing Zhang, Xishan Lu, Xuemei Leng, Changyao Tan, Hongchao Wu, Wenqiang Pang, Quanren He, Jerry Zhang, Peng Gao, Xiaotao Wang, Linhui Wang and Bo Ying
Vaccines 2025, 13(7), 743; https://doi.org/10.3390/vaccines13070743 - 10 Jul 2025
Viewed by 4748
Abstract
Background: Many new mRNA-based vaccine candidates in liquid mRNA-LNP formulations are under development; however, their stability limitations necessitate frozen storage, posing a significant challenge for long-term storage and transportation. Methods: In this study, an mRNA-LNP rabies vaccine, ABO1005, was prepared, freeze-dried and stored [...] Read more.
Background: Many new mRNA-based vaccine candidates in liquid mRNA-LNP formulations are under development; however, their stability limitations necessitate frozen storage, posing a significant challenge for long-term storage and transportation. Methods: In this study, an mRNA-LNP rabies vaccine, ABO1005, was prepared, freeze-dried and stored at 2–8 °C for 12-month storage stability evaluation. The immunogenicity, vaccine potency (the NIH method), and protective efficacy of ABO1005 were assessed in mice or dogs and compared to a commercialized inactivated vaccine. Results: Research conducted in mice indicated that the lyophilized vaccine exhibited comparable immunogenicity to its liquid form counterpart. Furthermore, the vaccine candidate elicited a robust humoral response lasting at least 175 days, and the specific antibody titers were not affected by the pre-administration of hyperimmune serum. In comparison to the commercialized inactivated vaccine (HDCV or PVRV), ABO1005 elicited significantly higher levels of humoral and cellular immunity. Vaccine potency testing (NIH) revealed that the potency of ABO1005 at 15 μg/dose was 8.85 IU/dose, which is substantially higher than the standard required for the lot release of rabies vaccines for current human use. In a post-exposure prophylaxis (PEP) study in Beagle dogs, the lyophilized vaccine provided 100% protection for dogs following a two-dose regimen (D0-D7), whereas commercially approved inactivated vaccine offered 83% protection. After storage at 2–8 °C for 12 months, no notable changes were observed in the particle size, encapsulation efficiency, and integrity of mRNA or in the immunogenicity of the lyophilized vaccine. Conclusions: This study successfully developed a formulation and process of freeze-drying for a rabies mRNA vaccine, paving the way for future lyophilized mRNA vaccine development. Full article
(This article belongs to the Special Issue The Development of mRNA Vaccines)
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23 pages, 4903 KB  
Article
Highly Effective mRNA-LNP Vaccine Against Respiratory Syncytial Virus (RSV) in Multiple Models
by Huarong Bai, Xueliang Yu, Yue Gao, Qin Li, Baigang Wen and Rongkuan Hu
Vaccines 2025, 13(6), 625; https://doi.org/10.3390/vaccines13060625 - 10 Jun 2025
Cited by 6 | Viewed by 4321
Abstract
Background: The transmembrane fusion (F) protein of RSV plays important roles in RSV pathogenesis as it mediates the fusion between the virus and the target cell membrane. During the fusion process, the F protein transits from a metastable state (prefusion, preF) to a [...] Read more.
Background: The transmembrane fusion (F) protein of RSV plays important roles in RSV pathogenesis as it mediates the fusion between the virus and the target cell membrane. During the fusion process, the F protein transits from a metastable state (prefusion, preF) to a stable state (postfusion, postF) after the merging of the virus and cell membranes. The majority of highly neutralizing antibodies induced by natural infection or immunization target the preF form, which makes it the preferred antigen for vaccine development. Methods: Here, we designed an effective RSV mRNA vaccine, STR-V003, consisting of mRNA encoding preF protein in lipid nanoparticles (LNPs). The immunogenicity, protection efficacy and toxicity were measured in multiple animal models. Results: STR-V003 demonstrated robust immunogenicity in both mice and cotton rats, inducing high levels of neutralizing antibodies and RSV preF-specific IgG antibodies and significantly reducing the RSV viral loads in the lung and nose tissue of challenged animals. In addition, STR-V003 did not show significant enhancement of lung pathology without causing vaccine-enhanced disease (VED). The repeated dose general toxicology studies and local tolerance studies of STR-V003 were evaluated in rats and non-human primate (NHP). Conclusions: STR-V003 demonstrates a favorable safety profile and induces robust protective immunity against RSV. Full article
(This article belongs to the Special Issue The Development of mRNA Vaccines)
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Review

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14 pages, 257 KB  
Review
Unpacking the mRNA Supply Chain: Challenges and Opportunities for Global Health
by Ariane de Jesus Lopes de Abreu, Cheleka A. M. Mpande, Yang Song, Martin W. Nicholson, Claudia Nannei and Martin Friede
Vaccines 2026, 14(4), 324; https://doi.org/10.3390/vaccines14040324 - 6 Apr 2026
Viewed by 1736
Abstract
The COVID-19 pandemic highlighted both the transformative potential of mRNA vaccines and the structural challenges associated with their supply chains. Unlike traditional vaccine platforms, mRNA vaccines depend on highly specialized raw materials, including plasmid DNA (pDNA), nucleotides, enzymes, and lipid nanoparticles (LNP), that [...] Read more.
The COVID-19 pandemic highlighted both the transformative potential of mRNA vaccines and the structural challenges associated with their supply chains. Unlike traditional vaccine platforms, mRNA vaccines depend on highly specialized raw materials, including plasmid DNA (pDNA), nucleotides, enzymes, and lipid nanoparticles (LNP), that are produced by a limited number of global suppliers. These dependencies, combined with platform-specific manufacturing processes and stringent cold chain requirements, introduce vulnerabilities across production, distribution, and regulatory oversight. This narrative review examines the distinctive features of mRNA vaccine supply chains and identifies key challenges and opportunities across three interconnected domains: manufacturing systems, logistics and distribution, and regulatory governance. Drawing on literature published between January 2021 and March 2026, the review synthesizes evidence on supply chain bottlenecks revealed during the COVID-19 pandemic, including upstream raw-material dependencies, limitations in manufacturing scale-up, cold chain constraints, and regulatory fragmentation. Particular attention is given to the implications of these challenges for low- and middle-income countries, where infrastructure, technical capacity, and regulatory resources may limit participation in mRNA vaccine production and deployment. The review also highlights emerging strategies to strengthen supply chain resilience, including diversification of input suppliers, development of regional manufacturing hubs, improvements in vaccine thermostability, regulatory harmonization initiatives, and the use of digital technologies for supply chain management. By integrating insights from manufacturing, logistics, and regulatory perspectives, this study contributes to a better understanding of the structural characteristics shaping mRNA vaccine supply chains and identifies priority areas for strengthening global preparedness for future health emergencies. Full article
(This article belongs to the Special Issue The Development of mRNA Vaccines)
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