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Novel Vaccine Designs to Enhance the Engagement of Innate and Adaptive Immunity

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A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "Vaccine Design, Development, and Delivery".

Deadline for manuscript submissions: 30 November 2026 | Viewed by 19898

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Prof. Dr. Martin H. Bluth

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Guest Editor

1. Blood Transfusion and Donor Services, Maimonides Medical Center, Brooklyn, NY, USA
2. Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA
Interests: biomarker discovery; clinical pathology; inflammation; immunotherapeutics; IgE/IgG antibody regulation; ADCC
Special Issues, Collections and Topics in MDPI journals

Dr. Fangfeng Yuan

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Guest Editor

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Building 76-243, Cambridge, MA 02139-4307, USA
Interests: novel vaccine development

Special Issue Information

Dear Colleagues,

Vaccination remains one of the most effective ways to prevent diseases. It has greatly reduced or eliminated numerous infectious conditions that previously caused significant morbidity and mortality. Antigen-presenting cells have a critical role in vaccine-induced immune activation. Antibody-modulated immunity can block pathogen infection of host cells, while cellular - based immunity can recognize and kill virus-infected cells. This special issue seeks insights into novel strategies to enhance vaccination-induced immunity. The topics include but are not limited to novel delivery tools to enhance antigen presentation, nucleic acid/protein engineering for immune enhancement, targeted delivery, novel adjuvants, strategies for genetically modified live vaccines and the immune related activities engaged in such approaches. We welcome original articles, perspectives, and reviews on vaccine development against infectious diseases affecting humans and animals.

Prof. Dr. Martin H. Bluth
Dr Fangfeng Yuan
Guest Editors

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Keywords

vaccine
innate immunity
adaptive immunity
infectious disease
novel strategy
antigen delivery
protein engineering
adjuvants

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Published Papers (9 papers)

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Research

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17 pages, 2362 KB

Open AccessArticle

Inactivated Klebsiella pneumoniae Induces Metabolic and Hematopoietic Reprogramming to Promote Trained Immunity and Heterologous Antibacterial Protection

by Xiang Cheng, Shaoqiong Huang, Zhidong Hu and Xiaoyong Fan

Vaccines 2026, 14(4), 300; https://doi.org/10.3390/vaccines14040300 - 27 Mar 2026

Viewed by 808

Abstract

Background: Infections caused by multidrug-resistant bacteria and inadequate vaccine coverage against opportunistic pathogens highlight the need for interventions that broadly and durably enhance host defense beyond antigen-specific adaptive immunity. Trained immunity, driven by metabolic and epigenetic reprogramming of innate immune cells, has been predominantly characterized using Bacille Calmette–Guérin and β-glucan, whereas its induction by Gram-negative bacteria remains poorly defined. To address this gap, we aimed to determine whether heat-killed Klebsiella pneumoniae (HK Kp) induces trained immunity through metabolic and hematopoietic reprogramming to confer heterologous antibacterial protection. Methods: HK Kp-trained murine bone marrow-derived macrophages and HK Kp-immunized C57BL/6 mice were employed to interrogate functional, metabolic, and transcriptomic reprogramming in vitro, hematopoietic progenitor remodeling in vivo, and protective efficacy against systemic Salmonella Typhimurium and Staphylococcus aureus infection. Results: HK Kp-trained macrophages showed markedly enhanced IL-1β secretion across all restimulation conditions, stimulus-dependent amplification of TNF-α responses, increased phagocytosis, and improved intracellular control of S. typhimurium, together with sustained upregulation of the glycolytic enzymes-encoding genes Hk2 and Pfkfb3. Transcriptomic profiling revealed extensive reprogramming enriched in glycolysis/gluconeogenesis and hematopoietic cell lineage pathways. In vivo, HK Kp immunization shifted bone marrow stem/progenitor compartments toward a myeloid-biased state. HK Kp-trained mice challenged with lethal S. typhimurium or S. aureus exhibited less weight loss, improved survival rates, and reduced bacterial burdens. Conclusions: Inactivated K. pneumoniae orchestrates metabolic and hematopoietic reprogramming to establish enhanced innate immune responsiveness and confer heterologous protection in murine S. typhimurium and S. aureus sepsis models, supporting its potential as a potent inducer of trained immunity. These findings establish HK Kp-based trained immunity as a promising strategy for combating multidrug-resistant and vaccine-evading pathogens. Full article

(This article belongs to the Special Issue Novel Vaccine Designs to Enhance the Engagement of Innate and Adaptive Immunity)

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17 pages, 1683 KB

Open AccessArticle

Development and Evaluation of Immunoprotective Efficacy of Membrane Protein Vaccine Against Scuticociliatosis

by Qingmeihui Sun, Bingchen Wu, Yaoqi Ao, Xiaoyu Meng, Xiaohang Wang and Ruijun Li

Vaccines 2026, 14(2), 142; https://doi.org/10.3390/vaccines14020142 - 29 Jan 2026

Viewed by 778

Abstract

Objective: To develop a novel and efficient vaccine for controlling scuticociliatosis in turbot (Scophthalmus maximus), this study targeted the parasitic ciliate Pseudocohnilembus persalinus for membrane protein vaccine preparation. Methods: The immunoprotective efficacy and underlying molecular mechanisms of the vaccine were systematically evaluated through immunization–challenge experiments, immune parameter detection, and transcriptomic analysis. Results: Results showed that the serum IgM level in turbot immunized with the membrane protein vaccine reached its peak one week after the second immunization, which was significantly higher than that in the control group and the whole-cell protein vaccine group (p < 0.05). Additionally, the activities of serum peroxidase (POD), total superoxide dismutase (T-SOD), acetylcholinesterase (ACH), and lysozyme (LZM) were significantly enhanced (p < 0.05). At 24 h and 48 h post-challenge, the relative parasite reduction rates at the wound sites in the membrane protein vaccine group were 87.79% and 74.17%, respectively. Transcriptomic analysis revealed 1063 differentially expressed genes (DEGs) in the spleen tissue of turbot immunized with the membrane protein vaccine, including 734 upregulated and 329 downregulated genes. These DEGs were significantly enriched in pathways such as glycine, serine and threonine metabolism and one carbon pool by folate, which are involved in immune responses by regulating immune cell proliferation, antioxidant defense, and immune substance synthesis. Conclusions: This study successfully developed a P. persalinus membrane protein vaccine with excellent immunoprotective efficacy and elucidated its molecular mechanisms of protection. It provides a novel vaccine candidate for the green control of turbot scuticociliatosis and offers a theoretical basis and technical support for the development of fish parasite subunit vaccines. Full article

(This article belongs to the Special Issue Novel Vaccine Designs to Enhance the Engagement of Innate and Adaptive Immunity)

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14 pages, 4488 KB

Open AccessArticle

From Bovine Immune Milk Profiling to Multi-Antigen Vaccine Design: Enhanced Humoral Responses Against H. pylori with a Flagellin and Urease Subunit Cocktail

by Hongru Li, Enhao Zhang, Jingyuan Ning, Yushan Lin, Guanyuan Wang, Hong Zhang, Cuixia Ma, Jiachao Wang, Miao Li, Xue Gao, Chenhui Li, Lin Wei, Xian Wang and Cuiqing Ma

Vaccines 2026, 14(2), 110; https://doi.org/10.3390/vaccines14020110 - 23 Jan 2026

Viewed by 645

Abstract

Objective: The aim of this study was to develop and evaluate non-antibiotic strategies against Helicobacter pylori by establishing a bovine immune milk platform and designing a synergistic multi-antigen immunogen to enhance humoral immune responses. Methods: Inactivated Helicobacter pylori (H. pylori) was used to immunize dairy cows, and the resulting immune milk was characterized for antibody specificity, acid stability, and target antigens via ELISA, Western blot, agglutination assays, and mass spectrometry. Key identified antigens (UreA, UreB, UreE, UreG, HypA, FlaA, and FlaB) were produced as recombinant proteins. Their immunogenicity was evaluated in a murine model, comparing single antigens with various protein combinations. Immune responses were assessed by antigen-specific IgG ELISA, bacterial agglutination titers, flow cytometry for T-cell activation, and histopathology for safety. Results: Immune milk contained high-titer, acid-stable IgG antibodies targeting multiple H. pylori virulence factors. In mice, while single proteins induced specific IgG, a multi-antigen cocktail (FlaA + FlaB + HypA + UreA + UreB + UreE + UreG) elicited significantly higher serum agglutination titers (~7 × 10³) than single antigens or inactivated whole-cell vaccine, alongside robust CD4⁺ T-cell activation. No formulations showed any hepatorenal or splenic toxicity. Conclusion: Bovine immune milk is a viable platform for acid-stable antibody delivery. A rationally designed multi-antigen cocktail synergistically enhances functional humoral immunity in vivo, providing a promising foundation for developing antibody-based or subunit vaccine strategies against H. pylori. Full article

(This article belongs to the Special Issue Novel Vaccine Designs to Enhance the Engagement of Innate and Adaptive Immunity)

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20 pages, 1661 KB

Open AccessArticle

Structure-Guided Engineering of Protein VP2 from Epizootic Hemorrhagic Disease Virus Maximizes Production and Confers Complete Protection as Subunit Vaccine

by Samuel Jurado, Luis Jiménez-Cabello, María del Carmen Nuñez, Sergio Utrilla-Trigo, Eva Calvo-Pinilla, Iván Mazuecos-Aragonés, José Ramón Gutierrez, Ana Falcón, Javier Ortego and José M. Escribano

Vaccines 2026, 14(1), 7; https://doi.org/10.3390/vaccines14010007 - 20 Dec 2025

Viewed by 1150

Abstract

Epizootic hemorrhagic disease (EHD) is an important livestock disease caused by Epizootic hemorrhagic disease virus (EHDV). The recent incursion and wide distribution of EHDV in Europe have increased the need for effective vaccine candidates. Background/Objectives: The VP2 protein of EHDV forms the outer capsid layer of the virion and is essential for viral assembly and host cell entry. Owing to its antigenic properties, VP2 represents a major target for vaccine development. However, the recombinant production of VP2 is limited by low stability and poor yields, representing a significant barrier for the generation of safe and effective subunit vaccines. Methods: To overcome these limitations, the VP2 protein from EHDV serotype 8 (EHDV-8) was rationally engineered with targeted modifications at both the amino and carboxyl termini of its coding sequence. Recombinant expression was performed using a baculovirus vector-mediated system in Trichoplusia ni pupae (CrisBio^® technology), employed as living biofactories. Results: The engineering of VP2 resulted in up to a tenfold increase in protein yields compared with the wild-type sequence, while maintaining the trimeric structural integrity of the recombinant protein. Both wild-type and engineered VP2 protein variants were formulated and used to immunize IFNAR(−/−) mice, a model susceptible to EHDV infection. Both engineered and wild-type VP2 formulations elicited comparable neutralizing antibody responses in vaccinated animals. Furthermore, immunization with either formulation conferred full protection against lethal EHDV-8 challenge. Conclusions: In this work, we demonstrated that the rational engineering of the VP2 protein significantly improved recombinant expression yields in a baculovirus-based system without compromising structural integrity or immunogenicity. These findings additionally demonstrate the feasibility of producing high-quality VP2 antigens in T. ni pupae using CrisBio^® technology and support their potential application in the development of subunit vaccines against EHDV. Full article

(This article belongs to the Special Issue Novel Vaccine Designs to Enhance the Engagement of Innate and Adaptive Immunity)

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18 pages, 3875 KB

Open AccessArticle

A QS21 + CpG-Adjuvanted Trivalent HSV-2 Vaccine and Trivalent HSV-2 mRNA Vaccine Induce a Strong Immune Response, Protect Against HSV-2 Infection, and Cross-Protect Against HSV-1 Infection in Mice

by Han Cao, Xiaolong Zhang, Jishuai Cheng, Yang Li, Ning Luan, Jingping Hu, Bingyan Liang, Haihao Zhang, Dandan Gao, Zhentao Lei, Yufeng Yao and Cunbao Liu

Vaccines 2025, 13(5), 497; https://doi.org/10.3390/vaccines13050497 - 6 May 2025

Cited by 5 | Viewed by 3873

Abstract

Background: HSV-2 infection continues to be a significant global health concern, as there are no approved vaccines despite numerous attempts at development. Methods: This study explored the immunogenicity and protective efficacy of aluminum- or QS21 + CpG-adjuvanted trivalent HSV-2 vaccines and a trivalent HSV-2 mRNA vaccine incorporating the gC2, gD2, and gE2 antigens. Results: Our results demonstrated that the QS21 + CpG-adjuvanted subunit vaccine and mRNA vaccines successfully induced robust antigen-specific humoral and cellular immune responses and provided significant protection against both HSV-2 and HSV-1 infection. These vaccines showed remarkable efficiency in reducing the viral load and preventing clinical symptoms in mice, highlighting their potential for clinical application. Conversely, the aluminum-adjuvanted vaccine exhibited limited effectiveness, emphasizing the superiority of the QS21 + CpG-adjuvanted and mRNA vaccines. Conclusions: These findings provide valuable insights for the continued development of effective HSV vaccines and suggest promising strategies for preventing both HSV-2 and HSV-1 infection. Full article

(This article belongs to the Special Issue Novel Vaccine Designs to Enhance the Engagement of Innate and Adaptive Immunity)

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27 pages, 2149 KB

Open AccessEditor’s ChoiceArticle

Inflammatory and Humoral Immune Responses to Commercial Autogenous Salmonella Bacterin Vaccines in Light-Brown Leghorn Pullets: Primary and Secondary Vaccine Responses

by Chrysta N. Beck, Jossie M. Santamaria and Gisela F. Erf

Vaccines 2025, 13(3), 311; https://doi.org/10.3390/vaccines13030311 - 13 Mar 2025

Cited by 4 | Viewed by 2009

Abstract

Background/Objectives: Commercial poultry flocks undergo Salmonella vaccinations to manage salmonellosis outbreaks. Due to reports of severe injection site reactions to Salmonella bacterins, assessment of local inflammatory responses is necessary. The objective was to assess local inflammatory and systemic humoral immune responses to commercial autogenous Salmonella bacterin vaccines (SV1 or SV2) following primary or secondary intradermal (i.d.) vaccination in Light-Brown Leghorns (LBLs). Methods: LBL pullets received primary (14 wks) or secondary (19 wks) vaccination by i.d. growing feather (GF) pulp injection of SV1, SV2, Salmonella Enteritidis (SE) lipopolysaccharide (LPS), or water–oil–water emulsion (V). Local leukocyte levels and relative cytokine mRNA expression were monitored before (0 d) and at 6 h, 1 d, 2 d, 3 d, 5 d, and 7 d post-GF pulp injection (p.i.). Blood was collected through 28 d post-primary or -secondary vaccination, and SE-specific antibodies were quantified via ELISA. Results: Primary vaccine administration increased local heterophil and macrophage levels and increased IL-6 and IL-8 mRNA expressions at 6 h p.i., independent of treatment. Secondary administration extended these local immune activities through 3 d p.i. and included prolonged IL-17A mRNA expression. Primary and secondary GF-pulp injection with V resulted in rapid lymphocyte recruitment by 6 h p.i., comprised primarily of CD4⁺ and γδ T cells. SV1 and SV2 also produced a T-dependent systemic humoral immune response, as indicated by the IgM-to-IgG isotype switch, along with a memory phenotype in the secondary response. Conclusions: These commercial-killed Salmonella vaccines, when prepared in water–oil–water emulsions, stimulated prolonged innate and T helper (Th) 17-type inflammatory responses at the injection site and produced a classic systemic humoral immune response after a second vaccination. Further research is needed to determine if extended inflammation influences adaptive immune responses in eliminating Salmonella infection. Full article

(This article belongs to the Special Issue Novel Vaccine Designs to Enhance the Engagement of Innate and Adaptive Immunity)

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14 pages, 2149 KB

Open AccessArticle

Differential Adjuvant Activity by Flagellins from Escherichia coli, Salmonella enterica Serotype Typhimurium, and Pseudomonas aeruginosa

by Shengmei Pang, Mei Liu, Longlong Wang, Mingqing Shao, Guoqiang Zhu and Qiangde Duan

Vaccines 2024, 12(11), 1212; https://doi.org/10.3390/vaccines12111212 - 25 Oct 2024

Cited by 8 | Viewed by 2362

Abstract

(1) Background: The adjuvant properties of flagellin from various bacterial species have been extensively studied; however, a systematic comparison of the immunoadjuvant effects of flagellins from different bacterial species is lacking. This study aims to analyze the amino acid sequences and structural features of flagellins from Escherichia coli (FliC_E.C), Salmonella enterica serotype Typhimurium (FliC_S.T), and Pseudomonas aeruginosa (FliC_P.A), and to evaluate their adjuvant activities in terms of Toll-like receptor 5 (TLR5) activation, antibody production, and cytokine responses in a murine model. (2) Methods: Bioinformatics analysis was conducted to compare the amino acid sequences and structural domains (D0, D1, D2, and D3) of flagellins from the three bacterial species. PyMol atomic models were used to confirm structural differences. Toll-like receptor 5 (TLR5) activation assays were performed to measure IL-8 and TNF-α production in vitro. The IgG antibody titers against the model antigen FaeG and cytokine responses, including IL-4 and TNF-α secretion were evaluated in a murine model. (3) Results: Bioinformatics analysis revealed that the D0 and D1 domains are highly conserved, whereas the D2 and D3 domains exhibit significant variability across the three species. Structural analysis via PyMol confirmed these differences, particularly in the D2 and D3 domains. TLR5 activation assays showed that FliC_S.T and FliC_P.A induced higher levels of IL-8 and TNF-α production compared to FliC_E.C, indicating species-specific variations in TLR5 activation. In the murine model, FliC_S.T as an adjuvant produced higher antibody titers against FaeG and increased IL-4 secretion in splenocytes compared to FliC_E.C and FliC_P.A. FliC_P.A induced higher TNF-α expression than FliC_S.T and FliC_E.C, suggesting FliC_S.T and FliC_P.A are more effective at inducing T-cell responses. (4) Conclusions: This study highlights the potential of FliC_S.T and FliC_P.A as potent vaccine adjuvants. The results provide insights into the structure–function relationships of these flagellins and support their application in enhancing immune responses against diverse pathogens. Full article

(This article belongs to the Special Issue Novel Vaccine Designs to Enhance the Engagement of Innate and Adaptive Immunity)

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Review

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25 pages, 686 KB

Open AccessReview

Optimizing Humoral Immunity for Durable and Broad Protection in Flavivirus Vaccines

by Jae-Yeon Park and Hye-Mi Lee

Vaccines 2025, 13(12), 1182; https://doi.org/10.3390/vaccines13121182 - 21 Nov 2025

Cited by 1 | Viewed by 1766

Abstract

Flavivirus infections, including dengue, Zika, West Nile, and Japanese encephalitis, remain a major global health concern. Although several vaccines are licensed, the durability and qualitative features of vaccine-induced antibodies differ substantially across platforms, leading to incomplete cross-protection and the risk of antibody-dependent enhancement. Long-term durability is exemplified by YF-17D, which induces protective antibodies that have been detectable for decades, whereas the JE SA14-14-2 vaccine has achieved program-level reductions in disease in endemic regions. In contrast, CYD-TDV shows serostatus-dependent outcomes, and the investigational TAK-003 vaccine has demonstrated antibody persistence for at least four years. Recent studies have clarified how preserving quaternary envelope epitopes, minimizing prM-associated non-neutralizing specificity, and sustaining germinal center activity determine antibody affinity, breadth, and persistence. Advances in adjuvant formulations and delivery platforms have shown that engaging defined innate pathways and prolonging antigen availability enhance affinity maturation and long-lived plasma cell formation. Booster scheduling and baseline serostatus further shape the antibody quality, highlighting the importance of immune imprinting and cross-reactivity in vaccine design. Together, these findings outline the design principles for next-generation flavivirus vaccines, including stabilization of neutralization-sensitive epitopes, use of adjuvants that sustain germinal center responses, optimization of antigen persistence, and tailoring of dosing strategies to immune history to elicit durable and broadly protective humoral immunity. Full article

(This article belongs to the Special Issue Novel Vaccine Designs to Enhance the Engagement of Innate and Adaptive Immunity)

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27 pages, 1281 KB

Open AccessReview

Novel Strategies for Developing Next-Generation Vaccines to Combat Infectious Viral Diseases

by Fangfeng Yuan and Martin H. Bluth

Vaccines 2025, 13(9), 979; https://doi.org/10.3390/vaccines13090979 - 17 Sep 2025

Cited by 1 | Viewed by 5209

Abstract

The development of viral vaccines faces persistent scientific and logistical challenges, particularly in the wake of the COVID-19 pandemic. This review critically examines emerging strategies to overcome key barriers in viral vaccine design and deployment. We focus on four major areas: (1) structure-guided antigen engineering to stabilize conformations; (2) the mRNA platform and its delivery system; (3) advanced adjuvant systems that enhance cellular and humoral immunity; and (4) approaches to mitigate immune imprinting and antigenic variability, such as chimeric antigens and glycan shielding. We also explore anti-idiotypic vaccination strategies and the limitations of current animal models in predicting human immune responses. In addition, to address vaccine hesitancy and inequitable access, we advocate for global collaboration in manufacturing, distribution, and public education to ensure inclusive immunization strategies. By integrating molecular insights with platform technologies, we aim to inform the rational design of future vaccines with improved efficacy and public acceptance. Full article

(This article belongs to the Special Issue Novel Vaccine Designs to Enhance the Engagement of Innate and Adaptive Immunity)

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