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

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.

cGAMP/Saponin Adjuvant Combination Improves Protective Response to Influenza Vaccination by Microneedle Patch in an Aged Mouse Model

“…The aim of this study was to investigate the possibility of using cGAMP/Quil-A as a combination adjuvant with influenza vaccine in MNP format to enhance immune responses in aged mice. MNPs possess the unique property of “physical adjuvancy” which arises from the physical puncture of skin by microneedles during application of MNPs, which in turn induces limited (and painless) cell damage leading to inflammation at the site of application ( 35 ). Physical adjuvantation may also come from formulation of the MNPs using a water-soluble polymer that forms a gel upon contact with interstitial fluid in the skin.…”

Efficient Delivery of Dengue Virus Subunit Vaccines to the Skin by Microprojection Arrays

“…To overcome the weakly immunogenic nature of the E protein, we included Quil-A adjuvant, which we have previously shown significantly enhances immune responses in small animal models [12,18,31,32]. The formulated vaccines were then dry-coated on the nanopatch for delivery.…”

Microarray patches enable the development of skin-targeted vaccines against COVID-19

“…Importantly, this local cell death increased the immunogenicity of the vaccine, as evidenced by increasing humoral responses, up to a certain level of cell death [ 354 ]. Collectively, these pre-clinical studies suggest that optimal MAP designs and application conditions can generate transient mechanical stress to induce controlled cell death and a pro-inflammatory skin microenvironment to enhance antigen-specific humoral immune responses [ 354 , 355 ]. However, the effects of skin cell death generated by diverse MAP designs on cutaneous immune mechanisms and adaptive immune responses have yet to be elucidated with diverse vaccine candidates.…”