Colocalization of cell death with antigen deposition in skin enhances vaccine immunogenicity.
Vaccines delivered to the skin by microneedles-with and without adjuvants-have increased immunogenicity with lower doses than standard vaccine delivery techniques such as intramuscular or intradermal injection. However, the mechanisms underlying this skin-mediated "adjuvant" effect are not clear. Here, we show that the dynamic application of a microprojection array (the Nanopatch) to skin generates localized transient stresses invoking cell death around each projection. Nanopatch application caused significantly higher levels (∼65-fold) of cell death in murine ear skin than i.d. injection using a hypodermic needle. Measured skin cell death is associated with modeled stresses ∼1-10 MPa. Nanopatch-immunized groups also yielded consistently higher anti-immunoglobulin G endpoint titers (up to 50-fold higher) than i.d. groups after delivery of a split virion influenza vaccine. Importantly, colocalization of cell death with nearby live skin cells and delivered antigen was necessary for immunogenicity enhancement. These results suggest a correlation between cell death caused by the Nanopatch with increased immunogenicity. We propose that the localized cell death serves as a "physical immune enhancer" for the adjacent viable skin cells, which also receive antigen from the projections. This natural immune enhancer effect has the potential to mitigate or replace chemical-based adjuvants in vaccines.
D2G2, The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia.
Alexandra C I
ACI
Depelsenaire
D2G2, The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia.
Stefano C
SC
Meliga
D2G2, The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia.
Celia L
CL
McNeilly
D2G2, The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia.
Frances E
FE
Pearson
D2G2, The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia.
Jacob W
JW
Coffey
D2G2, The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia.
Oscar L
OL
Haigh
D2G2, The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia.
Christopher J
CJ
Flaim
The University of Queensland, Diamantina Institute for Cancer, Brisbane, Queensland, Australia.
Ian H
IH
Frazer
D2G2, The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland, Australia; The University of Queensland, Diamantina Institute for Cancer, Brisbane, Queensland, Australia; Faculty of Medicine and Biomedical Sciences, The University of Queensland, Centre for Clinical Research, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia. Electronic address: m.kendall@uq.edu.au.
Mark A F
MAF
Kendall
D000279:Administration, Cutaneous; D000818:Animals; D016923:Cell Death / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000494:pharmacology*; D007271:Injections, Intradermal; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D049329:Nanostructures; D012867:Skin / Q000276:immunology*; D014611:Vaccination / Q000379:methods*; D064166:Vaccine Potency
D007252:Influenza Vaccines