The changing shape of vaccination: improving immune responses through geometrical variations of a microdevice for immunization

Abstract

Micro-device use for vaccination has grown in the past decade, with the promise of ease-of-use, painless application, stable solid formulations and greater immune response generation. However, the designs of the highly immunogenic devices (e.g. the gene gun, Nanopatch or laser adjuvantation) require significant energy to enter the skin (30–90 mJ). Within this study, we explore a way to more effectively use energy for skin penetration and vaccination. These modifications change the Nanopatch projections from cylindrical/conical shapes with a density of 20,000 per cm2 to flat-shaped protrusions at 8,000 per cm2, whilst maintaining the surface area and volume that is placed within the skin. We show that this design results in more efficient surface crack initiations, allowing the energy to be more efficiently be deployed through the projections into the skin, with a significant overall increase in penetration depth (50%). Furthermore, we measured a significant increase in localized skin cell death (>2 fold), and resultant infiltrate of cells (monocytes and neutrophils). Using a commercial seasonal trivalent human influenza vaccine (Fluvax 2014), our new patch design resulted in an immune response equivalent to intramuscular injection with approximately 1000 fold less dose, while also being a practical device conceptually suited to widespread vaccination.

A low inflammatory, Langerhans cell-targeted microprojection patch to deliver ovalbumin to the epidermis of mouse skin

“…Projection designs included conical-shaped, 207 µm ± 5 µm tall projections at 10,000 (10k) projections/cm 2 (p/cm 2 ), herein referred to as conical-MPA ( Figure 1A) or slit shaped, 110 µm ± 3 µm tall projections at 7k p/cm 2 ( Figure 1B), herein referred to as slit-MPA. A similar conical-MPA design was first reported in Depelsenaire et al [33] (previously named 'Nanopatch') and slit-MPA design in Crichton et al [40] (previously named 'Transdermal patch'). Silicon MPAs were imaged using secondary scanning electron microscopic (SEM) imaging (Hitachi, SU3500).…”

“…For example, when Crichton et al [44], used a similar application energy (26 mJ), the conical-MPA penetrated into the dermis of ear skin. Conversely, the slit-MPAs were initially reported to increase penetration depth into mouse skin [40]. Yet, using polycarbonate slit-MPAs with a larger (blunter) tip surface area ( Figure 1F), led to reduced penetration into the skin that could be maintained at a lower application energy (Figure 3), thus generating less cell death ( Figure 6) and ultimately less skin inflammation (Figure 4 and Figure 5).…”

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

“…This enhancement was further boosted by the addition of an adjuvant [12]. These enhanced immune responses were observed in live-attenuated [13], DNA [14], inactivated [15,16], virus-like particle [17], conjugated [18], and split-virion vaccines [19,20].…”

Innate local response and tissue recovery following application of high density microarray patches to human skin

“…Dermaroller™), diagnostic 16 , 17 , drug delivery 18 – 20 through to the most promising and most studied area, vaccine delivery 21 . In small animal models comparative dose matched studies with standard injection methods, HD-MAPs have routinely been shown to produce enhanced immune responses with enhanced kinetics of IgG induction with a fractional dose compared to needle and syringe for a wide range of vaccines from inactivated virus 22 , 23 , split virus 24 , conjugated 25 , DNA 26 and virus like particle vaccines 27 . This enhanced response has largely been attributed to the induced cell death around each projection causing a mixture of damage and pathogen (vaccine) danger signals 28 .…”