The stratum corneum can be split into four layers. Clearly, there are few vaccine strategies that match these specifications. Typically, lipophilic molecules with a molecular weight below 500 Dalton and which have less than three hydrogen bonding groups are able to pass through the stratum corneum. The stratum corneum is comprised of 10–20 layers of dead keratinocytes and intracellular lipids, proteins, and humectants. The stratum corneum has a thickness averaging at around 20 µm, with the whole epidermis being around 85 µm thick, and it is the first and most formidable barrier against exposure to foreign substances and pathogens. Schematic representation of the skin, the distribution of a variety of immune cells, and potential routes to bypass the stratum corneum. In this review paper, the different routes of, and technologies for, vaccination will be explored, and the rationale behind developments in transcutaneous delivery and how these approaches are shaping the current vaccine landscape will be discussed. Especially, as many of the means of improving patient acceptance may also provide enhancements to both safety and efficacy compared to the current rather outdated paradigm of needle and syringe (N&S)-based vaccine delivery strategies. Improving the patient experience of vaccination will be an equally important part of ensuring effective preparation for, and reaction to, pathogenic disease. However, amidst this fervent vaccine development activity, the second of those global challenges identified by the WHO, i.e., ‘vaccine hesitancy’, should not be forgotten. This impressive reaction will doubtless improve future readiness for, and response to, a wide range of potentially pandemic pathogens. A range of new vaccine technologies as well as processes to accelerate their development, testing, and implementation have emerged out of the remarkable global response to coronavirus disease (COVID-19). In 2019, the WHO identified an ‘influenza pandemic’ and ‘vaccine hesitancy’ as two of the top ten challenges to global health. These include needle and syringe techniques, microneedles, DNA tattooing, jet and ballistic delivery, and skin permeabilization techniques, including thermal ablation, chemical enhancers, ablation, electroporation, iontophoresis, and sonophoresis. This review will provide an overview of the diverse range of vaccination techniques available to target the dermal compartment, as well as their current state, challenges, and prospects, and touch upon the formulations that have been developed to maximally benefit from these new techniques. Vaccination into this dermal compartment offers a way of addressing both of the challenges presented by the WHO, as well as opening up avenues for novel vaccine formulation and dose-sparing strategies to enter the clinic. The skin is a unique vaccination site, due to its immune-rich milieu, which is evolutionarily primed to respond to challenge, and its ability to induce both humoral and cellular immunity. In 2019, an ‘influenza pandemic’ and ‘vaccine hesitancy’ were listed as two of the top 10 challenges to global health by the WHO.
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