To elicit protective adaptive immune responses, vaccines must efficiently trigger the innate immune system. It is becoming increasingly apparent that microbial and host nucleic acids serve as important activators of the innate immune system in both currently available and experimental vaccines.
Microbial and host nucleic acids may be recognized, respectively, as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) by a complex machinery of innate immune receptors. The activation of these receptors either directly or indirectly has an impact on the activity of antigen-presenting cells and on subsequent adaptive immune responses.
The deconstruction of the mechanisms of action of many live attenuated vaccines is revealing that the sensing of microbial nucleic acids makes an important contribution to the immunogenicity of these vaccines.
Innate immune detection of host DNA and of the nucleic acid metabolite uric acid may have a role in the adjuvant properties of aluminium salts, the most widely used type of vaccine adjuvant.
Nucleic acid-sensing mechanisms may be directly harnessed by novel adjuvant molecules. Several vaccines containing such molecules are currently in the preclinical and early clinical stages of development.
The demand is currently high for new vaccination strategies, particularly to help combat problematic intracellular pathogens, such as HIV and malarial parasites. In the past decade, the identification of host receptors that recognize pathogen-derived nucleic acids has revealed an essential role for nucleic acid sensing in the triggering of immunity to intracellular pathogens. This Review first addresses our current understanding of the nucleic acid-sensing immune machinery. We then explain how the study of nucleic acid-sensing mechanisms not only has revealed their central role in driving the responses mediated by many current vaccines, but is also revealing how they could be harnessed for the design of new vaccines.
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The authors thank F. Bureau, C. Coban and T. Marichal for critical reading of the manuscript. C.J.D. is supported by the Fonds National de la Recherche Scientifique (FRS-FNRS, Belgium; Fonds pour la Recherche Scientifique Médicale grant). K.J.I. is supported by a Health and Labour Sciences Research Grant of the Japanese Ministry of Health, Labour and Welfare and by the Core Research Evolutionary Science and Technology (CREST) programme at the Japan Science and Technology Agency.
The authors declare no competing financial interests.
Substances that facilitate, enhance and/or modulate the host immune response to an antigen.
- Conventional dendritic cells
(cDCs). Phagocytes that are resident in lymphoid and non-lymphoid tissues and are specialized in the presentation of antigens to T cells.
- Plasmacytoid dendritic cells
(pDCs). A DC subtype specialized in producing large amounts of type I interferons in response to nucleic acids from pathogens.
- RNase L
A ribonuclease that is induced in response to type I interferons and degrades all the RNA within the cell.
A multiprotein signalling complex, the activation and assembly of which leads to the recruitment and activation of caspase 1, resulting in the cleavage of pro-IL-1β and pro-IL-18 into their biologically active forms.
(Polyinosinic–polycytidylic acid). A substance that is used as a mimic of viral double-stranded RNA.
- CpG-B and CpG-A oligodeoxynucleotides
Synthetic oligodeoxynucleotides that contain immunostimulatory unmethylated dinucleotide CpG motifs. CpG-A oligodeoxynucleotides are based on a mixed phosphodiester–phosphorothioate backbone, contain a single CpG motif within a palindromic sequence and have a 3′ polyG tail, whereas CpG-B oligodeoxynucleotides are based on a phosphorothioate backbone and contain multiple CpG motifs.
A process by which certain antigen-presenting cells may take up and process extracellular antigens and present them on MHC class I molecules to CD8+ T cells.
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Desmet, C., Ishii, K. Nucleic acid sensing at the interface between innate and adaptive immunity in vaccination. Nat Rev Immunol 12, 479–491 (2012). https://doi.org/10.1038/nri3247
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