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

Financial & competing interests disclosure

The authors of this work were supported by funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under Contract No HHSN272201400053C and HHSN272200800039C. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. 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.

Key issues

• DNA vaccines have the benefits of being able to express antigens in their native conformation inside cells and thereby induce CD8+ T-cell responses.

• Currently, >150 human DNA vaccine trials are ongoing or completed.

• Animal and human trial data has showed good tolerance and safety of DNA vaccines.

• Codon optimization and strong viral promoters do not always enhance DNA vaccine immunogenicity.

• Minicircle DNA or mini-intronic plasmid systems are promising for bacterial element-free DNA vaccine production.

• Molecular adjuvants including plasmid-encoded cytokines and signaling molecules and RNA knockdown strategy can be used to enhance DNA vaccine immunogenicity.

• Needle-free skin delivery or pulmonary delivery methods may be promising directions for future use.