Expression of tak1 and tram induces synergistic pro-inflammatory signalling and adjuvants DNA vaccines.
Improving vaccine immunogenicity remains a major challenge in the fight against developing country diseases like malaria and AIDS. We describe a novel strategy to identify new DNA vaccine adjuvants. We have screened components of the Toll-like receptor signalling pathways for their ability to activate pro-inflammatory target genes in transient transfection assays and assessed in vivo adjuvant activity by expressing the activators from the DNA backbone of vaccines. We find that a robust increase in the immune response necessitates co-expression of two activators. Accordingly, the combination of tak1 and tram elicits synergistic reporter activation in transient transfection assays. In a mouse model this combination, but not the individual molecules, induced approximately twofold increases in CD8+ T-cell immune responses. These results indicate that optimal immunogenicity may require activation of distinct innate immune signalling pathways. Thus this strategy offers a novel route to the discovery of a new generation of adjuvants.
Larsen
Karen Colbjørn
KC
The Jenner Institute, University of Oxford, Oxford OX3 7DQ, United Kingdom. karen.colbjorn@googlemail.com
Spencer
Alexandra J
AJ
Goodman
Anna L
AL
Gilchrist
Ashley
A
Furze
Julie
J
Rollier
Christine S
CS
Kiss-Toth
Endre
E
Gilbert
Sarah C
SC
Bregu
Migena
M
Soilleux
Elizabeth J
EJ
Hill
Adrian V S
AV
Wyllie
David H
DH
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism*; D019444:Vaccines, DNA / Q000276:immunology*; D000099151:MAP Kinase Kinase Kinase 7
D000276:Adjuvants, Immunologic; D007371:Interferon-gamma; D020930:MAP Kinase Kinase Kinases; D018123:Receptors, Interleukin; D019444:Vaccines, DNA; D000099151:MAP Kinase Kinase Kinase 7; C476416:Ticam2 protein, mouse