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Review
. 2012 Feb;11(2):189-209.
doi: 10.1586/erv.11.188.

Technologies for enhanced efficacy of DNA vaccines

Fadi Saade  1 , Nikolai Petrovsky
Affiliations
Review

Technologies for enhanced efficacy of DNA vaccines

Fadi Saade et al. Expert Rev Vaccines. 2012 Feb.

Abstract

Despite many years of research, human DNA vaccines have yet to fulfill their early promise. Over the past 15 years, multiple generations of DNA vaccines have been developed and tested in preclinical models for prophylactic and therapeutic applications in the areas of infectious disease and cancer, but have failed in the clinic. Thus, while DNA vaccines have achieved successful licensure for veterinary applications, their poor immunogenicity in humans when compared with traditional protein-based vaccines has hindered their progress. Many strategies have been attempted to improve DNA vaccine potency including use of more efficient promoters and codon optimization, addition of traditional or genetic adjuvants, electroporation, intradermal delivery and various prime-boost strategies. This review summarizes these advances in DNA vaccine technologies and attempts to answer the question of when DNA vaccines might eventually be licensed for human use.

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Conflict of interest statement

Financial & competing interests disclosure

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1
Figure 1. DNA vaccines: from preparation to the induction of immune responses
Antigen sequence is obtained following isolation from the pathogen (step 1), followed by identification by sequencing (step 2). The sequence of interest can be amplified by PCR or generated by chemical synthesis. The DNA sequence is then cloned into the multiple cloning site of a eukaryotic plasmid following an enzymatic reaction (step 3). Competent bacteria are transformed by the constructed plasmid and are grown into specific media (step 4). Ultra-pure plasmid is obtained using anion-exchange column following cell lysis (step 5). Plasmid can be formulated with conventional adjuvants or coadministered with genetic adjuvants (step 6). Plasmid is delivered to the inoculation site intradermally, subcutaneously, topically or intramuscularly (step 7). Following intramuscular injection, muscle cells are the main transfected cells. Resident APCs are also directly transfected by the plasmid. Plasmid enters the nucleus of transfected cells and initiates gene transcription (step 8). Antigenic protein is produced in the cytoplasm and is submitted to post-translational modification similarly to the native protein in natural infection. APCs can also be activated by cross-priming, following the capture of antigen secreted by muscle cells or the capture of apoptotic muscle cells loaded with the antigen. APCs then migrate to the proximal lymph nodes, where they present the antigenic peptides to CD4+ T cells via MHC-II and the T-cell receptor and to CD8+ T cells by MHC-I and the T-cell receptor (step 9). Activated CD4+ T cells trigger the differentiation of specific B cells, which can also be activated by secreted antigen that arrives to the lymph node. Primed lymphocytes (CD4+ and CD8+ T cells, and B cells) could be restimulated and further expanded at the immunization site by presentation of the peptide–MHC complexes displayed by transfected muscle cells (step 10). Thus, DNA vaccination induces both humoral and cellular immune responses specific for the microbial antigen. TLR: Toll-like receptor.
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