Molecular mechanisms for enhanced DNA vaccine immunogenicity

Abstract

In the two decades since their initial discovery, DNA vaccines technologies have come a long way. Unfortunately, when applied to human subjects inadequate immunogenicity is still the biggest challenge for practical DNA vaccine use. Many different strategies have been tested in preclinical models to address this problem, including novel plasmid vectors and codon optimization to enhance antigen expression, new gene transfection systems or electroporation to increase delivery efficiency, protein or live virus vector boosting regimens to maximise immune stimulation, and formulation of DNA vaccines with traditional or molecular adjuvants. Better understanding of the mechanisms of action of DNA vaccines has also enabled better use of the intrinsic host response to DNA to improve vaccine immunogenicity. This review summarizes recent advances in DNA vaccine technologies and related intracellular events and how these might impact on future directions of DNA vaccine development.

Keywords: DNA vaccine; immunogenicity; molecular adjuvant; plasmid; vaccine delivery.

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Figure 1. Mechanisms of DNA vaccine sensing in transfected immune or non-immune cells

(A) DNA vaccines transfect myocytes, keratinocytes or dendritic cells (DC). DCs are able to present antigens directly while myocytes or keratinocytes rely on cross-presentation pathways. (B) Molecular events are summarized for DC vaccines. TLR9 is not critical for DNA vaccine action, although it may still play a contributory role given the CpG motifs in most DNA vector backbones. Recent studies showed that STING/TBK1/IRF3 pathways and the AIM2 inflammasome are important to DNA vaccine action. Other innate immune receptors playing a role in DNA vaccine sensing include cyclic-GMP-AMP (cGAMP) synthase (cGAS), AIM2, DHX29 and RIG-I. Additional potential DNA sensors are now under study, including DDX41, IFI16, DNA-PK and MRE11. Molecular adjuvants that represent ligands of the above sensors and signalling proteins are currently being tested for their ability to improve DNA vaccine immunogenicity.

Figure 2. Summary of human clinical trials involving DNA vaccines

Number of clinical trials of DNA vaccines carried out in different time periods, clinical trial phases and the diseases being targeted are summarized for all 162 DNA vaccine trials registered in the ClinicalTrial.gov database.