Microprojection arrays applied to skin generate mechanical stress, induce an inflammatory transcriptome and cell death, and improve vaccine-induced immune responses

Hwee-Ing Ng,Ian H. Frazer,Stefano C. Meliga,Mark A. F. Kendall,Alexandra C. I. Depelsenaire,Zewen K. Tuong,Germain J. P. Fernando

doi:10.1038/s41541-019-0134-4

Abstract

Chemical adjuvants are typically used to improve immune responses induced by immunisation with protein antigens. Here we demonstrate an approach to enhance immune responses that does not require chemical adjuvants. We applied microprojection arrays to the skin, producing a range of controlled mechanical energy to invoke localised inflammation, while administering influenza split virus protein antigen. We used validated computational modelling methods to identify links between mechanical stress and energy generated within the skin strata and resultant cell death. We compared induced immune responses to those induced by needle-based intradermal antigen delivery and used a systems biology approach to examine the nature of the induced inflammatory response, and correlated this with markers of cell stress and death. Increasing the microprojection array application energy and the addition of QS-21 adjuvant were each associated with enhanced antibody response to delivered antigen and with induction of gene transcriptions associated with TNF and NF-κB signalling pathways. We concluded that microprojection intradermal antigen delivery inducing controlled local cell death could potentially replace chemical adjuvants to enhance the immune response to protein antigen.

Highlights

Adjuvants were first deployed in vaccines in the 1930s and have since been included as a component of many vaccines, delivered by needles to enhance systemic antibody responses to immunising proteins.[1,2,3] only a few chemical adjuvants are licensed for the use in human vaccines, including various Alum compounds, Monophosphoryl Lipid A and squalene-based MF59TM
This study demonstrated that a skin delivery device (NanopatchTM) applying mechanical energy could potentially replace the use of chemical adjuvant to improve vaccine-induced antibody response
Mathematical models simulating interaction of mechanical energy, applied by delivery devices to the skin resulting in spatial stress distribution in various skin layers, correlate consistently with cell death, with an estimated threshold of 30 MPa in the viable epidermis (VE) and 3 MPa in the dermis

Summary

Introduction

Adjuvants were first deployed in vaccines in the 1930s and have since been included as a component of many vaccines, delivered by needles to enhance systemic antibody responses to immunising proteins.[1,2,3] only a few chemical adjuvants are licensed for the use in human vaccines, including various Alum compounds, Monophosphoryl Lipid A and squalene-based MF59TM. We tested whether a vaccine delivery device targeting the skin could use the energy of application to induce localised physical inflammation that might circumvent the need for chemical adjuvants. Mechanical means of delivery of vaccines, including ballistic gene guns delivery of vaccines, have been explored since the 1990s, the effects of energy of application has not been investigated.[12,13] Making mechanical delivery devices suitable for practical vaccination programmes is challenging, as the design requirements, materials and energy sources are constrained by issues of costs and compactness

Methods

Results

Conclusion