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Review
. 2024 Nov;17(11):e70053.
doi: 10.1111/1751-7915.70053.

New insights for the development of efficient DNA vaccines

Simone Berger  1 , Yanira Zeyn  2 , Ernst Wagner  1 , Matthias Bros  2
Affiliations
Review

New insights for the development of efficient DNA vaccines

Simone Berger et al. Microb Biotechnol. 2024 Nov.

Abstract

Despite the great potential of DNA vaccines for a broad range of applications, ranging from prevention of infections, over treatment of autoimmune and allergic diseases to cancer immunotherapies, the implementation of such therapies for clinical treatment is far behind the expectations up to now. The main reason is the poor immunogenicity of DNA vaccines in humans. Consequently, the improvement of the performance of DNA vaccines in vivo is required. This mini-review provides an overview of the current state of DNA vaccines and the various strategies to enhance the immunogenic potential of DNA vaccines, including (i) the optimization of the DNA construct itself regarding size, nuclear transfer and transcriptional regulation; (ii) the use of appropriate adjuvants; and (iii) improved delivery, for example, by careful choice of the administration route, physical methods such as electroporation and nanomaterials that may allow cell type-specific targeting. Moreover, combining nanoformulated DNA vaccines with other immunotherapies and prime-boost strategies may help to enhance success of treatment.

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Conflict of interest statement

The authors declare no conflict of interest and no competing financial interest.

Figures

FIGURE 1
FIGURE 1
Mechanisms of DNA vaccine‐induced adaptive immune responses. Upon transfection of somatic cells, antigen (illustrated as orange dots) may be released via exosomes or apoptotic bodies that are internalized by antigen presenting cells (APCs). Depending on the delivery route and formulation, a considerable number of APCs may be transfected directly. After processing, protein‐derived oligopeptides (illustrated as red dots) can be presented both via major histocompatibility complex class I (MHC‐I) to CD8+ T cells and via MHC‐II to CD4+ T cells, by this triggering T cells whose T‐cell receptor (TCR) binds the MHC/antigen complex with sufficient affinity. T‐cell activation requires concomitant co‐stimulation by APCs via co‐stimulatory signals such as CD86/CD28 interaction. Activated CD4+ T cells support the differentiation of activated CD8+ T cells towards cytotoxic T lymphocytes (CTLs). CTLs recognize infected or malignant cells that present the same antigen via MHC‐I and kill these by various cytotoxins. B cells are triggered when their B‐cell receptor (BCR) engages protein antigen, and pre‐activated antigen‐specific CD4+ T cells confer B‐cell co‐activation. Derived plasma cells secrete antibodies, which in turn bind protein on the surface of pathogens and infected or malignant cells. The antibodies' constant Fc part may trigger classical complement activation and via innate immune cells antibody‐dependent cellular cytotoxicity (ADCC).
FIGURE 2
FIGURE 2
Nanoparticle (NP) engineering for improved delivery of DNA vaccines—overview of the various adjustment screws. Passive targeting of NPs is largely determined by their surface characteristics like size, charge and hydrophobicity, all determining the composition of the protein corona in vivo. However, NP surface shielding with polyethylene glycol (PEG) at high density may strongly decrease its formation. Active cell targeting may be achieved by conjugation of a cell surface receptor binding moiety such as an antibody or a carbohydrate. In general, the rigidity and shape of the NP may modulate the extent of its cellular uptake. The bioactivity of the NP's cargo is determined by the time course of release also with regard to endosomal escape. The impact of the different modifications is NP‐dependent. Further information as well as examples are provided in the text.
FIGURE 3
FIGURE 3
Overview of parameters for the improvement of DNA vaccines. Besides optimization of the vector backbone, including the deletion of prokaryotic sequences and the attachment of nuclear localization signals (NLS) to promote nuclear plasmid DNA entry for transcription, choosing a eukaryotic promoter may be important in case that long‐lasting transgene expression is required and if transcriptional targeting is intended, respectively. Furthermore, careful selection of proper antigen(s) and the design of the antigen‐encoding sequences, for example, in terms of codon optimization are important parameters. The induction and shaping of antigen‐specific adaptive immune responses requires co‐administration of adequate adjuvants. This can be realized by co‐delivery in nanoparticles. The delivery method as well as the application route further impact the efficacy of DNA vaccines. APC, antigen presenting cell.
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