The Development of Peptide-Based Vaccines

A special issue of Vaccines (ISSN 2076-393X).

Deadline for manuscript submissions: 30 September 2026 | Viewed by 9799

Special Issue Editors


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Guest Editor
Biotechnology of Macromolcules, Instituto de Productos Naturales y Agrobiología, CSIC, 28006 Madrid, Spain
Interests: biotechnology; macromolecules; antimicrobials; IgY antibodies; peptides; epitopes
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
1. SaBio, IREC (CSIC-UCLM-JCCM), Ciudad Real, Spain
2. Department of Veterinary Pathobiology, CVHS, Oklahoma State University, Stillwater, OK, USA
Interests: infectious diseases; molecular biology of host-vector-pathogen interactions; gene regulation; pathogenesis; functional genomics; evolution and immunology; systems biology; ticks and tick-borne diseases; intracellular bacteria (Rickettsia, Anaplasma, Mycobacterium); vaccinology; biotechnology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue covers a wide range of topics, including the design and synthesis of peptide antigens, strategies to enhance immunogenicity, and innovative delivery systems. We invite contributions that go beyond predicted outcomes, specifically focusing on experimental evidence demonstrating that immunogens are immunogenic and elicit an appropriate immune response. Papers addressing the molecular mechanisms underlying the efficacy of peptide vaccines, the role of adjuvants, and the challenges of translating preclinical findings into clinical applications are particularly welcome.

This Special Issue will also highlight the emerging use of peptide vaccines in combating infectious diseases, cancer, and autoimmune diseases. Special attention will be given to novel approaches such as multi-epitope and personalized peptide vaccines, as well as the integration of computational tools in peptide vaccine development. This Special Issue aims to bring together researchers from diverse fields to foster interdisciplinary collaboration and provide a platform for the exchange of cutting-edge research that demonstrates real-world efficacy, paving the way for the next generation of peptide vaccines.

Dr. José Manuel Pérez De La Lastra
Prof. Dr. José de la Fuente
Guest Editors

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Keywords

  • peptide antigens
  • vaccine design
  • immunogenicity
  • epitope mapping
  • adjuvants
  • multi-epitope vaccines
  • personalized peptide vaccines
  • vaccine delivery systems
  • computational vaccine design
  • synthetic peptides

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Published Papers (6 papers)

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Research

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25 pages, 5590 KB  
Article
Construction of the Multi-Epitope HFMD Vaccine Based on an Attenuated CVB3 Vector and Evaluation of Immunological Responses in Mice
by Jiayi Zheng, Huixiong Deng, Zhuangcong Liu, Hengyao Zhang, Guangzhi Liu, Yanlei Li, Jiacheng Zhu, Liming Gu, Dongdong Qiao, Gefei Wang and Rui Li
Vaccines 2026, 14(4), 294; https://doi.org/10.3390/vaccines14040294 - 26 Mar 2026
Viewed by 879
Abstract
Background/Objectives: Hand, foot, and mouth disease (HFMD) is a major public health concern primarily caused by human enterovirus A71 (EV-A71), coxsackievirus A16 (CVA16), coxsackievirus A6 (CVA6), and certain coxsackievirus B serotypes. Currently available EV-A71 vaccines lack cross-protective efficacy against other serotypes, highlighting the [...] Read more.
Background/Objectives: Hand, foot, and mouth disease (HFMD) is a major public health concern primarily caused by human enterovirus A71 (EV-A71), coxsackievirus A16 (CVA16), coxsackievirus A6 (CVA6), and certain coxsackievirus B serotypes. Currently available EV-A71 vaccines lack cross-protective efficacy against other serotypes, highlighting the urgent need for multivalent and broadly effective enterovirus vaccines. Methods: Immunoinformatics approaches were used to predict highly immunogenic B-cell and T-cell epitopes, which were assembled to construct a novel multivalent epitope vaccine, rCV-A3V, followed by in silico validation. Recombinant protein expression was confirmed by Western blotting and immunofluorescence assays. The immunogenicity was evaluated in Balb/c mice following intranasal immunization. Results: A preliminary safety evaluation demonstrated that the rCV-A3V vaccine was well tolerated in the mouse model, with no abnormal changes in body weight observed after immunization. In addition, the target protein was successfully expressed. Intranasal immunization induced a strong Th1-biased immune response, robust serum neutralizing and IgG antibody responses, and pronounced mucosal immunity, including elevated sIgA and IgG levels in nasal lavage fluid, sIgA in feces, and substantial sIgA responses in milk. Dominant epitope peptides were also identified. Conclusions: The intranasal live attenuated rCV-A3V vaccine successfully induced humoral, mucosal, and cellular immune responses against EV-A71, CVA16, CVA6, and CVB3, demonstrating broad immunogenicity. These findings provide experimental evidence supporting its potential as a candidate vaccine for HFMD. Full article
(This article belongs to the Special Issue The Development of Peptide-Based Vaccines)
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14 pages, 3007 KB  
Article
Generation and Evaluation of a Multi-Epitope Vaccine Against Acinetobacter baumannii, a Nosocomial Bacterial Pathogen
by Nicolas D. Prather, Jadelynn Aki, Sean Jeffreys, Bernard P. Arulanandam, Chiung-Yu Hung and Jieh-Juen Yu
Vaccines 2026, 14(3), 275; https://doi.org/10.3390/vaccines14030275 - 20 Mar 2026
Viewed by 750
Abstract
Background/Objectives: Multidrug-resistant (MDR) Acinetobacter baumannii (Ab) has emerged as a significant bacterial pathogen responsible for nosocomial infections. The most common clinical manifestations of Ab infection include ventilator-associated pneumonia and catheter-related bloodstream/urinary infections. Given the extensive MDR phenotype of Ab, preventive [...] Read more.
Background/Objectives: Multidrug-resistant (MDR) Acinetobacter baumannii (Ab) has emerged as a significant bacterial pathogen responsible for nosocomial infections. The most common clinical manifestations of Ab infection include ventilator-associated pneumonia and catheter-related bloodstream/urinary infections. Given the extensive MDR phenotype of Ab, preventive vaccination strategies are crucial for protecting susceptible populations. Methods: We utilized immunoinformatics to identify candidate peptides containing both putative B- and T-cell epitopes from proteins associated with Ab pathogenesis. Subsequently, we designed novel Acinetobacter Multi-Epitope Vaccines (AMEVs), each comprising an Ab thioredoxin A (TrxA) leader protein, five to seven of the identified peptide antigens, and a C-terminal His(6x)-tag to facilitate protein purification. Results: Subcutaneous vaccination of C57BL/6 mice with AMEV1 or AMEV2, formulated with TiterMax adjuvant, conferred 60% and 80% protection, respectively, against intraperitoneal Ab challenge. AMEV vaccination induced a robust antibody response to each corresponding whole protein and most of its component peptides. We then constructed an improved vaccine, AMEV5, which included the Ab TrxA protein and seven confirmed B-cell epitope peptides. Subcutaneous immunization of BALB/c mice (n = 10 per group) with rAMEV5 emulsified in Adda03 adjuvant activated antigen-specific IL-5-secreting T cells and antibody-producing B cells. Evaluation of vaccine efficacy demonstrated that AMEV2- and AMEV5-immunized mice were protected from a lethal intraperitoneal Ab challenge, with survival rates of 70% and 90%, respectively. Conclusions: These study results provide insights into the application of reverse vaccinology to combat the rise of MDR Acinetobacter infection. Full article
(This article belongs to the Special Issue The Development of Peptide-Based Vaccines)
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Review

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24 pages, 1480 KB  
Review
Future Perspectives on the Application of Systems Biology and Generative Artificial Intelligence in the Design of Immunogenic Peptides for Vaccines
by José M. Pérez de la Lastra, Isidro Sobrino, Víctor M. Rodríguez Borges and José de la Fuente
Vaccines 2026, 14(2), 177; https://doi.org/10.3390/vaccines14020177 - 13 Feb 2026
Cited by 1 | Viewed by 1377
Abstract
Peptide-based vaccines offer a modular and readily manufacturable platform for both prophylactic and therapeutic immunization. However, their broader translation has been constrained by the limited capacity to predict protective immunity directly from sequence-level features. Recent advances in systems vaccinology and high-throughput immune profiling [...] Read more.
Peptide-based vaccines offer a modular and readily manufacturable platform for both prophylactic and therapeutic immunization. However, their broader translation has been constrained by the limited capacity to predict protective immunity directly from sequence-level features. Recent advances in systems vaccinology and high-throughput immune profiling have substantially expanded the experimental evidence, while generative artificial intelligence now enables de novo design of peptide immunogens and multi-epitope antigens under precisely controlled constraints. This review approaches how these complementary developments are transforming peptide vaccine research, moving beyond classical reverse vaccinology and conventional epitope prediction toward integrated, data-driven design frameworks. We discuss key generative model architectures and conditioning strategies aligned with vaccine objectives, including approaches that account for structural presentation, antigen processing and population-level human leukocyte antigen (HLA) diversity. Central to this perspective is the requirement for rigorous experimental validation and for strengthening the computational–experimental feedback loop through iterative in vitro and in vivo testing informed by systems-level immune readouts. We highlight representative applications spanning infectious diseases, cancer immunotherapy and vector-borne vaccinology, and we outline major technical and translational challenges that must be addressed to enable robust real-world deployment. Finally, we propose future directions for precision peptide vaccinology, emphasizing standardized functional benchmarks, the development of richer curated datasets linking sequence space to immune outcomes, and the early incorporation of formulation and delivery constraints into generative design pipelines. Full article
(This article belongs to the Special Issue The Development of Peptide-Based Vaccines)
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13 pages, 533 KB  
Review
Peptide Vaccines for Pediatric High-Grade Glioma and Diffuse Midline Glioma: Current Progress and Future Perspectives
by Aron K. Mebrahtu, Vatsal Jain, Eliese M. Moelker, Alexandra M. Hoyt-Miggelbrink, Katayoun Ayasoufi and Eric M. Thompson
Vaccines 2025, 13(12), 1215; https://doi.org/10.3390/vaccines13121215 - 30 Nov 2025
Viewed by 1659
Abstract
High-grade gliomas (HGGs) and diffuse midline gliomas (DMGs) in pediatric patients carry a poor prognosis, necessitating the rapid development of novel therapies. Peptide vaccines represent a safe, repeatable, and rational immunotherapeutic modality aimed at inducing potent, tumor-specific T-cell responses. In this review, we [...] Read more.
High-grade gliomas (HGGs) and diffuse midline gliomas (DMGs) in pediatric patients carry a poor prognosis, necessitating the rapid development of novel therapies. Peptide vaccines represent a safe, repeatable, and rational immunotherapeutic modality aimed at inducing potent, tumor-specific T-cell responses. In this review, we define the scope of current progress by arguing that immunogenicity in children with HGG/DMG hinges on three factors: appropriate antigen class (neoantigen vs. TAA), the use of potent immunoadjuvants, and successful navigation of immune suppression. To address the gap between biological promise and clinical reality, we analyze clinical trials targeting shared tumor-associated antigens (e.g., CMV pp65, Survivin) and specific shared neoantigens (H3.3K27M). Crucially, we highlight pivotal data from the PNOC007 trial, where the magnitude of H3.3K27M-specific T-cell expansion correlated directly with significantly longer overall survival (OS), establishing a causal link between pharmacodynamics and clinical benefit. However, the unique challenges of the immunosuppressive tumor microenvironment and the detrimental effect of necessary corticosteroids remain paramount barriers. Future success relies on multi-modal combination strategies, the development of next-generation personalized neoantigen vaccines, and the application of advanced neuroimaging to accurately assess treatment response. Full article
(This article belongs to the Special Issue The Development of Peptide-Based Vaccines)
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18 pages, 1162 KB  
Review
Shaping Antitumor Immunity with Peptide Vaccines: Implications of Immune Modulation at the Vaccine Site
by Amrita Sarkar, Emily Pauline Rabinovich and Craig Lee Slingluff, Jr.
Vaccines 2025, 13(11), 1150; https://doi.org/10.3390/vaccines13111150 - 11 Nov 2025
Cited by 1 | Viewed by 1587
Abstract
Cancer vaccines have emerged as a class of therapeutics designed to harness the immune system to stimulate durable anti-tumor responses with lower systemic toxicity than conventional therapies. Many platforms have been explored, including protein, peptide, DNA, RNA, and cell-based vaccines. Within this landscape, [...] Read more.
Cancer vaccines have emerged as a class of therapeutics designed to harness the immune system to stimulate durable anti-tumor responses with lower systemic toxicity than conventional therapies. Many platforms have been explored, including protein, peptide, DNA, RNA, and cell-based vaccines. Within this landscape, peptide vaccines remain a promising approach. Most clinical trials have examined peripheral immune responses and clinical outcomes, but there is growing interest in the vaccine site microenvironment (VSME) as a window to understand local immune activation and its implications for systemic immunity and tumor control. Studies of the VSME have investigated the effects of adjuvants, local immune cell dynamics, and their correlation with systemic responses and outcomes. Local adjuvants typically enhance immune cell infiltration, though there are concerns regarding VSME sequestration or dysfunction of immune cells, which could impact systemic efficacy. Repeated vaccination at a single site may improve antigen presentation and immune responses, but factors such as injection site location may be linked to variability in clinical outcomes. Current studies are limited by substantial variability in sampling, timing, and analyses used in VSME assessment. This limits the comparability of findings and broader inferences regarding the influence of vaccine site dynamics on therapeutic efficacy. Standardized VSME assessment as part of future vaccine trials may improve evaluation of immune responses and provide a more consistent surrogate for vaccine effectiveness. This refinement may inform optimal vaccine strategies and further support the development of next-generation cancer immunotherapies. Full article
(This article belongs to the Special Issue The Development of Peptide-Based Vaccines)
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Other

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10 pages, 1220 KB  
Case Report
Case Report: A Multi-Peptide Vaccine Targeting Individual Somatic Mutations Induces Tumor Infiltration of Neoantigen-Specific T Cells in a Patient with Metastatic Colorectal Cancer
by Armin Rabsteyn, Henning Zelba, Borong Shao, Lisa Oenning, Christina Kyzirakos, Simone Kayser, Tabea Riedlinger, Johannes Harter, Magdalena Feldhahn, Dirk Hadaschik, Florian Battke, Veit Scheble, Alfred Königsrainer and Saskia Biskup
Vaccines 2025, 13(9), 960; https://doi.org/10.3390/vaccines13090960 - 11 Sep 2025
Cited by 1 | Viewed by 2540
Abstract
Background/Objectives: Fully personalized peptide vaccines targeting tumor-specific mutations are a promising treatment option for patients in an adjuvant but also advanced/metastatic disease situation in addition to non-personalized standard therapies. Here, we report a patient’s case with advanced metastatic colorectal cancer (mCRC) who was [...] Read more.
Background/Objectives: Fully personalized peptide vaccines targeting tumor-specific mutations are a promising treatment option for patients in an adjuvant but also advanced/metastatic disease situation in addition to non-personalized standard therapies. Here, we report a patient’s case with advanced metastatic colorectal cancer (mCRC) who was treated with a neoantigen-derived multi-peptide vaccine in addition to standard of care. Methods: Tumor-specific mutations were identified by whole exome and transcriptome sequencing. An individualized peptide vaccine was designed using an in-house developed epitope prediction and vaccine design platform. In this case, the vaccine consisted of 20 peptides targeting 18 distinct mutations. The vaccine was administered according to a prime-boost scheme for a total of 12 vaccinations. Vaccine immunogenicity was determined by stimulation of patient T cells with vaccinated peptides and subsequent intracellular cytokine staining (ICS). Tumor-infiltrating lymphocytes (TIL) were analyzed by ICS and T cell receptor beta chain (TCRβ) sequencing. Results: The patient survived for 41 months since initial diagnosis despite continuous disease progression under all therapeutic interventions. The vaccination induced multiple neoantigen-specific T cell responses in the patient without notable side effects. Two liver metastases were resected five months after the start of vaccination, and TIL were extracted and cultured. Analysis of TIL cultures revealed tumor infiltration by vaccine-induced neoantigen-specific T cells in only one of the metastases. TCRβ sequencing of neoantigen-specific T cells and tumor tissues supported this finding. Vaccine-targeted variants were reduced or absent in the metastasis with vaccine-specific T cell infiltration. Conclusions: This case demonstrates immunogenicity of a neoantigen-derived peptide vaccine and highlights tumor-infiltrating capabilities and potential cytotoxicity of vaccine-induced T cells in mCRC. Full article
(This article belongs to the Special Issue The Development of Peptide-Based Vaccines)
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