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Vaccines
Special Issues
Evaluating the Immune Response to RNA Vaccine
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Evaluating the Immune Response to RNA Vaccine

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: 31 March 2026 | Viewed by 3142

Special Issue Editors

Dr. Ang Lin

E-Mail Website
Guest Editor
Vaccine Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
Interests: mRNA vaccine; infectious disease; novel vaccine platform; adjuvant; immune mechanism
Dr. Huajun Zhao

E-Mail Website
Guest Editor
School of Pharmaceutical Sciences, Shandong University, Jinan, China
Interests: infectious disease; HBV; HCC; innate immunity; adjuvant

Special Issue Information

Dear Colleagues,

RNA technology has demonstrated numerous advantages in vaccine development and is widely recognized for its versatility. Specifically, it can be utilized in the development of new vaccines or therapeutics for various types of infectious or non-infectious diseases by manipulating the mRNA cargo and the lipid-based delivery system.

However, we still lack a comprehensive understanding of how these vaccines work, particularly regarding their interactions with the immune system and the underlying mechanism of action implicated in the generation of high-quality vaccine responses.

In this Special Issue, we seek original research articles and review articles that address the immune mechanisms of RNA vaccines. This includes, but is not limited to, innate immune signatures, the magnitude and quality of antibody responses, and the regulation of B cell and T cell compartments. These investigations provide essential guidance for the rational design of RNA vaccines.

Dr. Ang Lin
Dr. Huajun Zhao
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 100 words) can be sent to the Editorial Office for announcement on this website.

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

  • RNA vaccine
  • mechanism of action
  • immune regulation
  • innate immunity
  • adaptive vaccine response

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Published Papers (4 papers)

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Research

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19 pages, 4424 KiB  
Article
Humoral and Memory B Cell Responses Following SARS-CoV-2 Infection and mRNA Vaccination
by Martina Bozhkova, Ralitsa Raycheva, Steliyan Petrov, Dobrina Dudova, Teodora Kalfova, Marianna Murdjeva, Hristo Taskov and Velizar Shivarov
Vaccines 2025, 13(8), 799; https://doi.org/10.3390/vaccines13080799 - 28 Jul 2025
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Abstract
Background: Understanding the duration and quality of immune memory following SARS-CoV-2 infection and vaccination is critical for informing public health strategies and vaccine development. While waning antibody levels have raised concerns about long-term protection, the persistence of memory B cells (MBCs) and T [...] Read more.
Background: Understanding the duration and quality of immune memory following SARS-CoV-2 infection and vaccination is critical for informing public health strategies and vaccine development. While waning antibody levels have raised concerns about long-term protection, the persistence of memory B cells (MBCs) and T cells plays a vital role in sustaining immunity. Materials and Methods: We conducted a longitudinal prospective study over 12 months, enrolling 285 participants in total, either after natural infection or vaccination with BNT162b2 or mRNA-1273. Peripheral blood samples were collected at four defined time points (baseline, 1–2 months, 6–7 months, and 12–13 months after vaccination or disease onset). Immune responses were assessed through serological assays quantifying anti-RBD IgG and neutralizing antibodies, B-ELISPOT, and multiparameter flow cytometry for S1-specific memory B cells. Results: Both mRNA vaccines induced robust B cell and antibody responses, exceeding those observed after natural infection. Memory B cell frequencies peaked at 6 months and declined by 12 months, but remained above the baseline. The mRNA-1273 vaccine elicited stronger and more durable humoral and memory B-cell-mediated immunity compared to BNT162b2, likely influenced by its higher mRNA dose and longer prime-boost interval. Class-switched memory B cells and S1-specific B cells were significantly expanded in vaccine recipients. Natural infection induced more heterogeneous immune memory. Conclusions: Both mRNA vaccination and natural SARS-CoV-2 infection induce a comparable expansion of memory B cell subsets, reflecting a consistent pattern of humoral immune responses across all studied groups. These findings highlight the importance of vaccination in generating sustained immunological memory and suggest that the vaccine platform and dosage influence the magnitude and durability of immune responses against SARS-CoV-2. Full article
(This article belongs to the Special Issue Evaluating the Immune Response to RNA Vaccine)
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Review

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32 pages, 2027 KiB  
Review
Harnessing the Loop: The Perspective of Circular RNA in Modern Therapeutics
by Yang-Yang Zhao, Fu-Ming Zhu, Yong-Juan Zhang and Huanhuan Y. Wei
Vaccines 2025, 13(8), 821; https://doi.org/10.3390/vaccines13080821 (registering DOI) - 31 Jul 2025
Abstract
Circular RNAs (circRNAs) have emerged as a transformative class of RNA therapeutics, distinguished by their closed-loop structure conferring nuclease resistance, reduced immunogenicity, and sustained translational activity. While challenges in pharmacokinetic control and manufacturing standardization require resolution, emerging synergies between computational design tools and [...] Read more.
Circular RNAs (circRNAs) have emerged as a transformative class of RNA therapeutics, distinguished by their closed-loop structure conferring nuclease resistance, reduced immunogenicity, and sustained translational activity. While challenges in pharmacokinetic control and manufacturing standardization require resolution, emerging synergies between computational design tools and modular delivery platforms are accelerating clinical translation. In this review, we synthesize recent advances in circRNA therapeutics, with a focused analysis of their stability and immunogenic properties in vaccine and drug development. Notably, key synthesis strategies, delivery platforms, and AI-driven optimization methods enabling scalable production are discussed. Moreover, we summarize preclinical and emerging clinical studies that underscore the potential of circRNA in vaccine development and protein replacement therapies. As both a promising expression vehicle and programmable regulatory molecule, circRNA represents a versatile platform poised to advance next-generation biologics and precision medicine. Full article
(This article belongs to the Special Issue Evaluating the Immune Response to RNA Vaccine)
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Other

Jump to: Research, Review

10 pages, 2440 KiB  
Brief Report
Leveraging an mRNA Platform for the Development of Vaccines Against Egg Allergy
by Xianyu Shao, Lijing Liu, Changzhen Weng, Kun Guo, Zhutao Lu, Lulu Huang, Zhenhua Di, Yixuan Guo, Guorong Di, Renmei Qiao, Jingyi Wang, Yong Yang, Shiyu Sun, Shentian Zhuang and Ang Lin
Vaccines 2025, 13(5), 448; https://doi.org/10.3390/vaccines13050448 - 24 Apr 2025
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Abstract
Background: Food allergy (FA) poses a major global health issue due to the increasing prevalence and lack of effective prevention strategies. Allergen-specific immunotherapy (AIT) has emerged as a disease-modifying therapy for FA. However, due to long-term treatment duration and unexpected adverse reactions, only [...] Read more.
Background: Food allergy (FA) poses a major global health issue due to the increasing prevalence and lack of effective prevention strategies. Allergen-specific immunotherapy (AIT) has emerged as a disease-modifying therapy for FA. However, due to long-term treatment duration and unexpected adverse reactions, only a minority of patients benefit from AIT. Therefore, effective prophylactic interventions are urgently needed for FA patients. Methods: In this proof-of-concept study, using a well-established mRNA platform, we developed mRNA vaccine candidates encoding for the major egg white allergen Gal d2 and comprehensively evaluated their prophylactic efficacy against anaphylaxis in a Gal d2-induced allergic mouse model. Results: Two vaccine formulations, Gal d2 mRNA vaccine and Gal d2-IL-10 mRNA vaccine, both demonstrated potent ability in inducing allergen-specific IgG and Th1-type T cells. Importantly, the two vaccine formulations showed promise in preventing the onset of allergic disease, which is indicated by prevention of body temperature decline during anaphylaxis. Conclusions: We provided preliminary proof-of-concept evidence showing that the mRNA platform is unique and holds promise for the development of anti-allergy vaccines. This is largely attributed to the capacities of mRNA vaccines in eliciting an allergen-blocking antibody, shifting Th2 towards Th1 immunity, as well as in generating peripheral tolerance. However, further investigations are required to better understand the mode of action. Full article
(This article belongs to the Special Issue Evaluating the Immune Response to RNA Vaccine)
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12 pages, 2225 KiB  
Brief Report
Development and Evaluation of the Immunogenic Potential of an Unmodified Nucleoside mRNA Vaccine for Herpes Zoster
by Shun Zhang, Xiaojie Wang, Tongyi Zhao, Chen Yang and Lulu Huang
Vaccines 2025, 13(1), 68; https://doi.org/10.3390/vaccines13010068 - 13 Jan 2025
Cited by 2 | Viewed by 1606
Abstract
Background/Objectives: Approved mRNA vaccines commonly use sequences modified with pseudouridine to enhance translation efficiency and mRNA stability. However, this modification can result in ribosomal frameshifts, reduced immunogenicity, and higher production costs. This study aimed to explore the potential of unmodified mRNA sequences for [...] Read more.
Background/Objectives: Approved mRNA vaccines commonly use sequences modified with pseudouridine to enhance translation efficiency and mRNA stability. However, this modification can result in ribosomal frameshifts, reduced immunogenicity, and higher production costs. This study aimed to explore the potential of unmodified mRNA sequences for varicella-zoster virus (VZV) and evaluate whether codon optimization could overcome the limitations of pseudouridine modification. Methods: We utilized artificial intelligence (AI) to design several unmodified gE mRNA sequences for VZV, considering factors such as codon preference and secondary structure. The optimized mRNA sequences were assessed for protein expression levels in vitro and were subsequently used to develop a vaccine, named Vac07, encapsulated in a lipid nanoparticle (LNP) delivery system. The immunogenicity of Vac07 was evaluated in mice. Results: Codon-optimized mRNA sequences showed significantly higher protein expression levels in vitro compared to wild-type (WT) sequences. Vaccination with Vac07 demonstrated immunogenicity in mice that was comparable to, or even superior to, the licensed Shingrix vaccine, characterized by a stronger Th1-biased antibody response and a slightly more robust Th1-type cellular response. Conclusions: Codon-optimized unmodified mRNA sequences may also represent a viable approach for mRNA vaccine development. These optimized sequences have the potential to lower production costs while possibly enhancing the immunogenicity of mRNA vaccines. Vac07, developed using this method, shows promise as a potentially more efficient and cost-effective mRNA vaccine candidate for VZV. Full article
(This article belongs to the Special Issue Evaluating the Immune Response to RNA Vaccine)
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