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Vaccines
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Mucosal Immunity and Vaccine
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Mucosal Immunity and Vaccine

A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "Vaccines, Clinical Advancement, and Associated Immunology".

Deadline for manuscript submissions: closed (30 June 2026) | Viewed by 11320

Editors

Prof. Dr. Xingmin Sun

E-Mail Website
Guest Editor
Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Boulevard, MDC07, Tampa, FL 33612, USA
Interests: vaccinology; immunology; applied immunology; mucosal immunology; vaccine platforms; bacterial pathogenesis
Dr. Yongqun He (Oliver)

E-Mail Website
Guest Editor
Unit for Lab Animal Medicine and Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, USA
Interests: vaccine; brucellosis; host-pathogen interaction; precision medicine; nephrology; ontology; bioinformatics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mucosal surfaces are the first line of defense against numerous infectious agents, yet the development of vaccines targeting these sites has historically been challenging. This Special Issue will address the latest advancements and challenges in inducing robust mucosal immune responses through vaccination, with implications for preventing infections such as respiratory, gastrointestinal, and sexually transmitted diseases.

This Special Issue will focus on the critical role of mucosal immunity in vaccine development, exploring how vaccines can be designed to elicit effective immune responses at mucosal surfaces—the primary entry points for many pathogens. In this Special Issue, original research articles, reviews, short communications, and perspectives are welcome.

Topic areas may include (but are not limited to) the following:

  • Mechanisms of mucosal immune responses to vaccines.
  • Development of mucosal vaccines: oral, nasal, and other routes of administration.
  • Comparative efficacy of mucosal versus systemic immunity in infection control.
  • Mucosal adjuvants and delivery systems for enhancing vaccine efficacy.
  • Role of secretory IgA and other mucosal antibodies in vaccine-induced protection.
  • Immune memory and long-term protection conferred by mucosal vaccines.
  • Case studies on mucosal vaccines in clinical trials (e.g., for influenza, rotavirus, and HIV).
  • Challenges in developing mucosal vaccines for emerging pathogens.
  • Computational modeling and bioinformatics in mucosal vaccine design.

We look forward to receiving your contributions.

Dr. Xingmin Sun
Dr. Yongqun He (Oliver)
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-anonymized 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

  • mucosal immunity
  • vaccine
  • mucosal adjuvant

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Published Papers (5 papers)

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Research

Jump to: Review

20 pages, 2868 KB  
Article
Potential Roles of Gamma-Delta T Cells in a Bacterial Immun-Ization Model
by Lee Anne Talbot, Raffi Manjikian and Constantine Bitsaktsis
Vaccines 2026, 14(7), 590; https://doi.org/10.3390/vaccines14070590 - 1 Jul 2026
Viewed by 247
Abstract
Background/Objective: Francisella tularensis is a highly infectious intracellular pathogen that causes severe pulmonary tularemia following aerosol exposure, yet no licensed vaccine exists. Because infection initiates at the respiratory mucosa, understanding mechanisms of protective pulmonary immunity is critical for mucosal vaccine development. This study [...] Read more.
Background/Objective: Francisella tularensis is a highly infectious intracellular pathogen that causes severe pulmonary tularemia following aerosol exposure, yet no licensed vaccine exists. Because infection initiates at the respiratory mucosa, understanding mechanisms of protective pulmonary immunity is critical for mucosal vaccine development. This study investigated the role of lung-resident γδ T cells following intranasal immunization with inactivated F. tularensis (iFt) and subsequent lethal challenge with live vaccine strain (LVS). Methods: Mice were intranasally immunized with iFt and later challenged with lethal LVS. Pulmonary immune responses were evaluated using flow cytometry and cytokine analysis. Recruitment of γδ and αβ T cells, production of IL-17 and IFN-γ, neutrophil infiltration, and γδ T cell memory phenotypes were assessed in naïve and immunized mice following infection. Results: Primary LVS infection induced rapid recruitment of γδ T cells to the lung beginning on Day 2 post-infection, preceding significant αβ T cell accumulation. Increased pulmonary IL-17 and IFN-γ correlated with expansion of IL-17– and IFN-γ–associated γδ T cell populations. Following iFt immunization, mice demonstrated enhanced survival after lethal LVS challenge, accompanied by early increases in pulmonary IL-17 and IL-17 producing γδ T cells. Immunized mice also exhibited expansion of effector memory and central memory γδ T cell populations associated with IL-17 production. Conclusions: These findings identify IL-17 producing γδ T cells as contributors to early mucosal immunity following intranasal vaccination against F. tularensis and suggest that targeting lung-resident γδ T cells may support the development of next-generation mucosal vaccines against respiratory pathogens. Full article
(This article belongs to the Special Issue Mucosal Immunity and Vaccine)
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18 pages, 2678 KB  
Article
Mucosal Delivery of Recombinant SARS-CoV-2 Spike Receptor-Binding Domain Antigen Containing Immune-Stimulating Peptides Induces Protective Immune Responses Against Viral Infection in huACE2 Mice
by Byeol-Hee Cho, Ju Kim and Yong-Suk Jang
Vaccines 2026, 14(5), 421; https://doi.org/10.3390/vaccines14050421 - 7 May 2026
Viewed by 5188
Abstract
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through the interaction between the spike protein receptor-binding domain (RBD) and the human angiotensin-converting enzyme 2 (hACE2) receptor, which is expressed on epithelial cells in various tissues, including the respiratory tract. [...] Read more.
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells through the interaction between the spike protein receptor-binding domain (RBD) and the human angiotensin-converting enzyme 2 (hACE2) receptor, which is expressed on epithelial cells in various tissues, including the respiratory tract. Therefore, mucosal immunity in the respiratory tract plays a key role in protection against viral infection. Previously, we demonstrated that intranasal administration of antigens (Ags) conjugated with the M cell-targeting peptide Co4B enhances both mucosal and systemic immune responses. That conjugation with human β-defensin 2 (HBD2) increases neutralizing antibody (Ab) responses. Methods: A recombinant antigen conjugate incorporating both Co4B and HBD2 was designed to enhance immunogenicity. Its immunogenicity was evaluated in mice following intranasal immunization. Antigen-specific antibody responses were measured in serum and bronchoalveolar lavage fluid. T-cell responses were evaluated in lungs and spleens. Protective efficacy was assessed using SARS-CoV-2-susceptible hACE2 knock-in mice. Results: Ag-specific Ab levels increased in both serum and bronchoalveolar lavage fluid of mice immunized intranasally with the conjugate. Especially, T-cell responses were significantly enhanced in the lungs and spleens of immunized hACE2 knock-in mice. In challenge experiments, intranasal administration of the conjugate reduced viral load. Moreover, Siglec F was identified as a potential receptor for Co4B, a previously uncharacterized M cell-targeting ligand. Conclusions: A recombinant viral Ag containing Co4B and HBD2 induces virus-specific humoral and cellular immune responses. Although further optimization of the vaccine formulation and administration strategy is needed, this conjugate shows potential as a platform for improving mucosal and systemic immunity. Full article
(This article belongs to the Special Issue Mucosal Immunity and Vaccine)
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15 pages, 2786 KB  
Article
Effect of Anti-Programmed Cell Death-1 Antibody on Middle Ear Mucosal Immune Response to Intranasal Administration of Haemophilus influenzae Outer Membrane Protein
by Kazuhiro Yoshinaga, Takashi Hirano, Shingo Umemoto, Yoshinori Kadowaki, Takayuki Matsunaga and Masashi Suzuki
Vaccines 2025, 13(3), 313; https://doi.org/10.3390/vaccines13030313 - 13 Mar 2025
Cited by 1 | Viewed by 1655
Abstract
Background/Objectives: Acute otitis media is a common pediatric infection caused primarily by nontypeable Haemophilus influenzae. With rising antibiotic resistance, vaccines are essential for combating this public health issue. Although the PD-1/PD-L1 pathway has been extensively studied for its role in tumor [...] Read more.
Background/Objectives: Acute otitis media is a common pediatric infection caused primarily by nontypeable Haemophilus influenzae. With rising antibiotic resistance, vaccines are essential for combating this public health issue. Although the PD-1/PD-L1 pathway has been extensively studied for its role in tumor immunity, its impact on mucosal immunity, particularly in vaccine responses, is unclear. Methods: BALB/c mice were intranasally immunized with nontypeable H. influenzae outer membrane protein and treated with anti-PD-L1 antibodies. Immune responses were evaluated in middle ear mucosa (MEM), the cervical lymph node, and the spleen using an enzyme-linked immunosorbent assay, an enzyme-linked immunospot assay, and flow cytometry. The effects on CD4+ T cells, T follicular helper (Tfh) cells, and B-cell differentiation were analyzed. Results: Anti-PD-L1 antibody treatment increased CD3+CD4+CD185+ (CXCR5+) Tfh cells in MEM, which play a crucial role in supporting B-cell activation and antibody production. This correlated with a significant increase in IgA- and IgG-producing cells in MEM, which enhanced local bacterial clearance. Although B-cell activation and differentiation into plasmablasts were observed in MEM, no significant changes were noted in the cervical lymph node and spleen, suggesting a localized enhancement of mucosal immunity. Conclusions: Anti-PD-L1 antibodies promoted Tfh cell expansion and B-cell differentiation in MEM, leading to enhanced antibody production and improved bacterial clearance. These findings suggest that PD-L1 blockade can potentiate mucosal vaccine-induced immunity by strengthening local humoral responses. This supports its potential application in developing intranasal vaccines for acute otitis media. Full article
(This article belongs to the Special Issue Mucosal Immunity and Vaccine)
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16 pages, 2640 KB  
Article
Oral Administration of Zinc Sulfate with Intramuscular Foot-and-Mouth Disease Vaccine Enhances Mucosal and Systemic Immunity
by Min Ja Lee, Seokwon Shin, Hyeong Won Kim, Mi-Kyeong Ko, So Hui Park, Su-Mi Kim and Jong-Hyeon Park
Vaccines 2024, 12(11), 1268; https://doi.org/10.3390/vaccines12111268 - 9 Nov 2024
Cited by 1 | Viewed by 2607
Abstract
Background/Objectives: Foot-and-mouth disease (FMD) remains a significant global threat to livestock farming. Current commercial FMD vaccines present several challenges, including the risk of infection and adverse injection site reactions due to oil-based adjuvants. The complex immune environment of the gut-associated lymphoid tissue [...] Read more.
Background/Objectives: Foot-and-mouth disease (FMD) remains a significant global threat to livestock farming. Current commercial FMD vaccines present several challenges, including the risk of infection and adverse injection site reactions due to oil-based adjuvants. The complex immune environment of the gut-associated lymphoid tissue has the potential to induce broad and diverse immune responses. Therefore, we aimed to explore the potential of zinc sulfate as an oral adjuvant to enhance intestinal mucosal immunity and complement the effects of intramuscular (IM) FMD vaccination. Methods: We conducted serological analyses on mice and pigs, measuring secretory IgA (sIgA) levels and evaluating the expression of mucosal immunity-related genes in pigs. These assessments were used to investigate the systemic and mucosal immune responses induced by oral zinc sulfate administration in combination with an IM FMD vaccine. Results: This combination strategy significantly increased structural protein antibody titers and virus neutralization titers in experimental animals (mice) and target animals (pigs) across early, mid-, and long-term periods. Additionally, this approach enhanced the expression of key cytokines associated with mucosal immunity and increased sIgA levels, which are critical markers of mucosal immunity. Conclusions: Oral zinc sulfate administration may synergize with inactivated FMD vaccines, leading to sustained and enhanced long-term immune responses. This novel strategy could reduce the frequency of required vaccinations or allow for a lower antigen dose in vaccines, effectively stimulating the mucosal immune system and boosting systemic immunity. This approach has the potential to improve the overall efficacy of commercial FMD vaccines. Full article
(This article belongs to the Special Issue Mucosal Immunity and Vaccine)
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Review

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22 pages, 4708 KB  
Review
Engineered mRNA Nanoparticle Platforms for Respiratory Mucosal Delivery
by Rui Jin, Bao-Zhong Wang and Wandi Zhu
Vaccines 2026, 14(7), 596; https://doi.org/10.3390/vaccines14070596 - 4 Jul 2026
Viewed by 289
Abstract
Respiratory mucosal vaccination can induce robust humoral and cellular immune responses, as well as effective mucosal immunity at the primary site of pathogen entry, and has been shown to provide superior protection against respiratory viral infections compared with traditional approaches. Among current vaccine [...] Read more.
Respiratory mucosal vaccination can induce robust humoral and cellular immune responses, as well as effective mucosal immunity at the primary site of pathogen entry, and has been shown to provide superior protection against respiratory viral infections compared with traditional approaches. Among current vaccine technologies, mRNA vaccines offer unique advantages, including rapid development, flexible antigen design, and potent immunogenicity. However, efficient mucosal delivery of mRNA remains challenging due to biological barriers within the respiratory tract, including mucus clearance, limited cellular uptake, and instability during aerosolization. Furthermore, mRNA formulations intended for respiratory mucosal delivery require more stringent safety and tolerability profiles. Recent advances in nanoparticle engineering have accelerated the development of mRNA delivery systems optimized for respiratory mucosal immunization. This review aims to evaluate how nanoparticle engineering strategies can overcome respiratory mucosal barriers and improve the safety, stability, delivery efficiency, extrahepatic expression, and immunogenicity of mRNA vaccines and therapeutics. We summarize recent progress in engineered mRNA nanoparticle platforms for respiratory mucosal immunity, encompassing modified lipid nanoparticles (LNPs), polymer-based mRNA nanoparticles, and hybrid nanoparticle systems, including lipid-inorganic, polymeric hybrid, and lipid-extracellular vesicle (EV) nanoparticles. We further discuss optimization strategies for mucosal mRNA delivery, including the incorporation of appropriate adjuvants, the development of polyethylene glycol (PEG) alternatives, and advanced delivery approaches. Finally, we highlight current challenges and future directions for the rational design of next-generation mRNA nanoparticle platforms that can induce durable and broadly protective mucosal immunity against respiratory viral infections. Full article
(This article belongs to the Special Issue Mucosal Immunity and Vaccine)
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