Can a DNA vaccine protect against Chagas disease? A systematic review of preclinical studies.

DNA Vaccines: A Review

Background: Patients with HER2-overexpressing breast cancer often exhibit reduced immunity to the HER2 antigen. Therapeutic vaccines can enhance cytotoxic T cell responses against tumor-associated antigens, enabling selective tumor destruction. Both peptide- and DNA-based platforms have been explored for vaccine delivery, but direct comparisons of their safety and immunogenicity remain limited. We hypothesize that DNA-based vaccines may generate more robust and durable HER2-specific immunity than other vaccine platforms due to prolonged antigen expression from persistent plasmid presence in host tissues. Methods: We retrospectively analyzed 66 patients from a phase 1 DNA-vaccine trial and 38 from a phase 2 peptide-vaccine trial, all with stage III or IV HER2-positive breast cancer and either no evidence of disease or stable bone-only disease at enrollment. Both vaccines targeted HER2 intracellular domain (ICD) epitopes. Immunogenicity was assessed via IFN-γ ELISpot assays on cryopreserved PBMCs stimulated with HER2 ICD or extracellular domain (ECD) peptides as an indicator of epitope spreading. Changes in T-cell responses from baseline to peak post-vaccination were evaluated using the Wilcoxon test, and between-trial differences using the Mann-Whitney test. Patients were stratified by baseline HER2 immunity and immunologic responder status. Adverse events were recorded per NCI CTCAE v4.0. Results: The magnitude of T-cell immunity achieved to the HER2 ICD varied between the two modes of vaccination and was dependent on whether patients had preexisting immunity to HER2 when entering the study. Patients receiving the DNA vaccine showed significant increases in HER2 ICD immunity regardless of preexisting HER2 immunity (p=0.005 with, p<0.001 without), while those receiving the peptide vaccine showed elevated responses only in patients without preexisting immunity (p<0.001; p=0.76 with immunity). Both vaccines induced intramolecular epitope spreading, that is a broadening of the immune response to the HER2 ECD, representing the induction of endogenous immunity. DNA-vaccine recipients showed significant ECD immune responses both in those with (p=0.03) and without (p<0.001) baseline HER2 immunity. In contrast, peptide-vaccine recipients showed increased ECD immunity only in those without baseline immunity (p=0.04; p=0.33 with immunity). The DNA group had higher ECD immunity at baseline (p=0.02) and post-vaccination (p=0.005). The elevation in T-cell immunity from baseline to peak post-vaccination was comparable between vaccine types for both HER2 ICD (p=0.37) and ECD (p=0.13), including among responders (p=0.35 for ICD, p=0.44 for ECD). However, among non-responders, DNA-vaccine recipients demonstrated greater increases in both HER2 ICD (p=0.005) and ECD (p=0.04) immunity. One grade 3 ALT elevation occurred in the DNA-vaccine trial; no grade 3–5 events were observed in the peptide-vaccine trial. Conclusion: Both DNA- and peptide-based HER2 vaccines were well tolerated and capable of inducing HER2-specific T-cell responses in patients with advanced HER2-positive breast cancer. However, the DNA vaccine elicited broader and more consistent immune activation, including stronger epitope spreading to HER2 ECD and greater responses among patients without preexisting immunity. Notably, DNA-vaccine recipients demonstrated enhanced immunity even among non-responders, suggesting a more robust platform for overcoming baseline immune tolerance. Citation Format: Y. Liu, S. Huang, Y. Dang, M. L. Disis. Dna-based HER2 vaccine induces broader and more durable t-cell responses than peptide vaccine in advanced HER2-positive breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-01-17.

Engineering DNA vaccines against infectious diseases

Gene-based vaccines.

DNA Technology May Revolutionize Vaccine

Phase 1 clinical trials of the safety and immunogenicity of adjuvanted plasmid DNA vaccines encoding influenza A virus H5 hemagglutinin

Glioblastoma (GBM) is the most common malignant central nervous system (CNS) tumor in adults. Despite multimodality treatment including surgery, radiation, and chemotherapy, patients with GBM have a median survival of less than 2 years. Recent clinical trials have reported promising results using cancer vaccines to stimulate a tumor-directed immune response in several histologies. The majority of trials targeted tumor neoantigens derived from a single tumor sample, which limits the antigen pool in spatially heterogeneous cancers like GBM. Our group previously implemented multisector sequencing into the design of personalized peptide vaccines to increase the candidate pool of targetable neoantigens (NCT03422094). Although the peptide vaccine treatment was successful in stimulating an effector T cell response, it was limited by a long turnaround time from vaccine design to administration and a low peptide production rate. Therefore, we incorporated multisector sampling into the design of a personalized DNA-based GBM vaccine (NCT04015700). An average of 33% of the candidate targetable neoantigens were spatially restricted to a single sampled region, which would have been missed without multisector sequencing. DNA-based vaccines are potentially advantageous over peptide-based vaccines because they enable a higher neoantigen payload and faster manufacturing time with potent immunogenicity. Here, we report the results from 9 subjects enrolled onto the study. Spatially distinct tumor regions were subjected to whole exome sequencing (WES) and RNA-sequencing (RNA-seq), data from which were used to identify neoantigens through the pVACseq algorithm (http://pvactools.org). An average of 32 neoantigens were included in each DNA vaccine, compared to an average of only 9 for the peptide vaccine, and the turnaround time from date of surgery to administration of the DNA vaccine was about half the time. Three subjects had radiographic evidence of tumor progression prior to vaccination, highlighting the aggressive nature of GBM and the need for short manufacturing timeframes. PBMCs pre- and post-DNA vaccination were collected from 7/9 subjects. All subjects presented detectable responses and 6/7 tested revealed a sustained increment in T cell reactivity against tumor neoantigens post-treatment by IFN-γ ELISpot. Intracellular staining showed a neoantigen-specific antitumor CD8/CD4 T cell cytolytic (CD69+, CD107a+) and proliferative (Ki67+) profile. Post-vaccination tumor resections were performed for 2 subjects who also were treated with PD1 blockade upon progression, providing an opportunity to explore vaccine-induced changes in the tumor microenvironment. Herein, we demonstrate the advantages of incorporating multisector sequencing into the development of DNA-based GBM vaccines and provide insights into the resulting immune responses. Citation Format: Elizabeth A. Garfinkle, Katherine E. Miller, Alexandra J. Livingstone, Renzo Perales-Linares, Neil Cooch, Alfredo Perales-Puchalt, Sarah Rochestie, Joann Peters, Niranjan Y. Sardesai, William E. Gillanders, Elaine R. Mardis, Gavin P. Dunn, Tanner M. Johanns. Incorporation of multisector analysis into the design of personalized DNA vaccines for patients with newly diagnosed glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1174.

DNA vaccines join the fight against COVID-19

DNA-based vaccination is a novel technique to efficiently stimulate humoral (antibody) and cellular (T cell) immune responses to protein antigens. In DNA-based vaccination, immunogenic proteins are expressed in in vivo transfected cells of the vaccine recipients in their native conformation with correct posttranslational modifications from antigen-encoding expression plasmid DNA. This ensures the integrity of antibody-defined epitopes and supports the generation of protective (neutralizing) antibody titers. Plasmid DNA vaccination is furthermore an exceptionally potent strategy to stimulate CD8+ cytotoxic T lymphocyte (CTL) responses because antigenic peptides are efficiently generated by endogenous processing of intracellular protein antigens. These key features make DNA-based immunization an attractive strategy for prophylactic and therapeutic vaccination against extra- and intracellular pathogens. In this brief review, we summarize the current state of expression vector design, DNA delivery strategies, priming immune responses to intracellular or secreted antigens by DNA vaccines and unique advantages of DNA- versus recombinant protein-based vaccines using the hepatitis B surface antigen (HBsAg) as a model antigen.

Transgene expression and local tissue distribution of naked and polymer-condensed plasmid DNA after intradermal administration in mice

Immuno-oncology has revolutionized cancer treatment and has opened up new opportunities for developing vaccination methods. DNA-based cancer vaccines have emerged as a promising approach to activating the bodily immune system against cancer. Plasmid DNA immunizations have shown a favorable safety profile and there occurs induction of generalized as well as tailored immune responses in preclinical and early-phase clinical experiments. However, these vaccines have notable limitations in immunogenicity and heterogeneity and these require refinements. DNA vaccine technology has been focusing on improving vaccine efficacy and delivery, with parallel developments in nanoparticle-based delivery systems and gene-editing technologies such as CRISPR/Cas9. This approach has showcased great promise in enhancing and tailoring the immune response to vaccination. Strategies to enhance the efficacy of DNA vaccines include the selection of appropriate antigens, optimizing insertion in a plasmid, and studying combinations of vaccines with conventional strategies and targeted therapies. Combination therapies have attenuated immunosuppressive activities in the tumor microenvironment and enhanced the capability of immune cells. This review provides an overview of the current framework of DNA vaccines in oncology and focuses on novel strategies, including established combination therapies and those still under development.The challenges that oncologists, scientists, and researchers need to overcome to establish DNA vaccines as an avant-garde approach to defeating cancer, are also emphasized. The clinical implications of the immunotherapeutic approaches and the need for predictive biomarkers have also been reviewed upon. We have also tried to extend the role of Neutrophil extracellular traps (NETs) to the DNA vaccines. The clinical implications of the immunotherapeutic approaches have also been reviewed upon. Ultimately, refining and optimizing DNA vaccines will enable harnessing the immune system's natural ability to recognize and eliminate cancer cells, leading the world towards a revolution in cancer cure.

Synergism Between Chemotherapy with 6-Mercaptopurine and DNA Vaccination Against Ph+ Acute Lymphoblastic Leukemia In Syngeneic Mice

Wound contraction rate in excised and unexcised burn wounds with laser photobiomodulation: Systematic review and meta-analysis of preclinical studies

Immunotherapy of Angiogenesis with DNA Vaccines

Synergism Between Imatinib Mesylate and a BCR-ABL-Specific DNA Vaccine against Pre-Established Ph + Acute Lymphoblastic Leukemia in Syngeneic Mice.