Recent progress concerning CpG DNA and its use as a vaccine adjuvant

Abstract

CpG Oligonucleotides (ODN) are immunomodulatory synthetic oligonucleotides designed to specifically agonize Toll-like receptor 9. Here, we review recent progress in understanding the mechanism of action of CpG ODN and provide an overview of human clinical trial results using CpG ODN to improve the vaccines for cancer, allergy and infectious disease.

Keywords::

• allergy
• cancer
• CpG oligonucleotide
• infection
• Toll-like receptor
• vaccine adjuvant

Acknowledgments

This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. The assertions herein are the private ones of the authors and are not to be construed as official or as reflecting the views of the National Cancer Institute at large.

Financial & competing interests disclosure

DM Klinman and members of his laboratory are inventors/co-inventors on a number of patents pertaining to CpG ODN. All rights to these patents have been assigned to the Federal Government. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. 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.

Key issues

• Toll-like receptor 9 (TLR9) responds to the unmethylated CpG motifs present at high frequency in bacterial DNA. TLR9 engagement triggers a protective immune response involving plasmacytoid dendritic cells and B lymphocytes that improves host elimination of infectious pathogens.

• TLR9 is expressed in early and late endosomes. The precise location of receptor interaction with CpG oligonucleotides (ODN) determines the nature of the ensuing response.

• To optimize immunogenicity, APCs should be exposed to CpG ODN plus antigen simultaneously. Co-delivery of CpG ODN plus antigen increases the speed, magnitude and duration of the resultant immune response.

• The activity of CpG ODN can be further improved by combining them with other adjuvants and TLR agonists. For example, combining CpG ODN with cholera toxin improve the response induced by mucosal vaccines.

• Clinical trials demonstrate that CpG-adjuvanted vaccines induce stronger and faster immune responses against both HBV and anthrax.

• The ability of CpG ODN to induce a Th1-biased immmune response supports their use in vaccines targeting allergens. However, clinical results using a CpG-adjuvanted vaccine against ragweed were inconsistent.

• CpG ODN have been evaluated in a number of cancer trials. Their ability to boost immunity sufficiently to eradicate established cancers remains unclear.

• CpG ODN have a good safety profile when used as vaccine adjuvants.