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Whether differences in BCG strain and administration (intradermal Danish-1331 vs transcutaneous Tokyo-172) translate into meaningful variation in safety remains uncertain. South Korea's dual BCG policy enables a head-to-head comparison. We conducted a nationwide retrospective cohort of all children born 2014–2018 who received BCG in infancy (N = 1,217,695; Danish/intradermal n = 457,063; Tokyo/transcutaneous n = 760,632). National immunization, tuberculosis surveillance, claims registries were deterministically linked. Children were followed from vaccination until outcome or 31 December 2023. Incidence rates (IRs) were calculated, and Cox models adjusted for birth year, sex, socio-economic status, and region estimated adjusted hazard ratios (aHRs). The study cohort comprised 1,217,690 infants born between 2014 and 2018 who received BCG vaccination in infancy. Of these, 457,063 (37.5 %) received intradermal BCG (Danish 1331 strain) and 760,632 (62.5 %) received transcutaneous BCG (Tokyo 172 strain). Lymphadenitis occurred more often after intradermal BCG (42,385/457,063; 9.27 %) than after transcutaneous BCG (67,466/760,632; 8.87 %) (p < 0.001), with an adjusted hazard ratio of 1.00 (95 % CI, 0.99–1.02). Osteitis was rare in both groups (142 vs. 209 cases; ∼0.03 % each; aHR = 1.01; 95 % CI, 0.80–1.26). In this large real-world cohort, intradermal BCG (Danish-1331) and transcutaneous BCG (Tokyo-172) provided equivalent protection against pediatric tuberculosis. Intradermal vaccination was associated with only a very small increase in lymphadenitis, while serious adverse events were uncommon with both methods. These findings support programmatic flexibility in BCG vaccination policy: both methods are safe and effective, so selection can be guided by vaccine supply, delivery logistics, and local preferences rather than expected differences in outcomes.

Injection using needle and syringe (N&S) is the most widely used method for vaccination, but requires trained healthcare workers. Fear of needles, risk of needle-stick injury, and the need to reconstitute lyophilised vaccines, are also drawbacks. The Nanopatch (NP) is a microarray skin patch comprised of a high-density array of microprojections dry-coated with vaccine that is being developed to address these shortcomings. Here we report a randomised, partly-blinded, placebo-controlled trial that represents the first use in humans of the NP to deliver a vaccine. Healthy volunteers were vaccinated once with one of the following: (1) NPs coated with split inactivated influenza virus (A/California/07/2009 [H1N1], 15 µg haemagglutinin (HA) per dose), applied to the volar forearm (NP-HA/FA), n = 15; (2) NPs coated with split inactivated influenza virus (A/California/07/2009 [H1N1], 15 µg HA per dose), applied to the upper arm (NP-HA/UA), n = 15; (3) Fluvax® 2016 containing 15 µg of the same H1N1 HA antigen injected intramuscularly (IM) into the deltoid (IM-HA/D), n = 15; (4) NPs coated with excipients only, applied to the volar forearm (NP-placebo/FA), n = 5; (5) NPs coated with excipients only applied to the upper arm (NP-placebo/UA), n = 5; or (6) Saline injected IM into the deltoid (IM-placebo/D), n = 5. Antibody responses at days 0, 7, and 21 were measured by haemagglutination inhibition (HAI) and microneutralisation (MN) assays. NP vaccination was safe and acceptable; all adverse events were mild or moderate. Most subjects (55%) receiving patch vaccinations (HA or placebo) preferred the NP compared with their past experience of IM injection with N&S (preferred by 24%). The antigen-vaccinated groups had statistically higher HAI titres at day 7 and 21 compared with baseline (p < 0.0001), with no statistical differences between the treatment groups (p > 0.05), although the group sizes were small. The geometric mean HAI titres at day 21 for the NP-HA/FA, NP-HA/UA and IM-HA/D groups were: 335 (189–593 95% CI), 160 (74–345 95% CI), and 221 (129–380 95% CI) respectively. A similar pattern of responses was seen with the MN assays. Application site reactions were mild or moderate, and more marked with the influenza vaccine NPs than with the placebo or IM injection. Influenza vaccination using the NP appeared to be safe, and acceptable in this first time in humans study, and induced similar immune responses to vaccination by IM injection.

•Various active and passive approaches available for cutaneous immunization.•Cutaneous immunization provides the potential to induce humoral, cellular and mucosal immune responses.•Adjuvants affect the type of immunity upon cutaneous immunization.•DNA vaccination successfully performed employing different cutaneous administration strategies. Technologies and strategies for cutaneous vaccination have been evolving significantly during the past decades. Today, there is evidence for increased efficacy of cutaneously delivered vaccines allowing for dose reduction and providing a minimally invasive alternative to traditional vaccination. Considerable progress has been made within the field of well-established cutaneous vaccination strategies: Jet and powder injection technologies, microneedles, microporation technologies, electroporation, sonoporation, and also transdermal and transfollicular vaccine delivery. Due to recent advances, the use of cutaneous vaccination can be expanded from prophylactic vaccination for infectious diseases into therapeutic vaccination for both infectious and non-infectious chronic conditions. This review will provide an insight into immunological processes occurring in the skin and introduce the key innovations of cutaneous vaccination technologies.

We previously reported the safety and efficacy in animal experiments of transcutaneous immunization (TCI) using a self-dissolving microneedle patch (MicroHyala; MH) made of hyaluronic acid and collagen. However, this MH was an unsuitable TCI device for the human skin, as collagen is suspected to induce inflammation. In this study, we developed an improved collagen-free MH (new-MH) and conducted clinical study to evaluate the fundamental properties and safety in human. Microneedle dissolution, skin irritation, and antigen-specific antibody production about new-MH were measured in mice and/or rats. On the basis of the results, the clinical study was conducted in healthy volunteers to evaluate local and systemic adverse events caused by new-MH application. We confirmed that the microneedles of new-MH, as well as those on our old-MH that contained collagen, could easily pierce stratum corneum without severe skin irritation, and that TCI using new-MH efficiently increased antibody titer with comparable to TCI using old-MH. Application of new-MH caused no severe adverse reactions in 20 healthy volunteers enrolled in a clinical study. These results verified that new-MH is a safe TCI device in human, and greatly encouraged us to advance PI/PII clinical studies of antigen-loaded new-MH.

Transcutaneous immunization (TCI) is an effective vaccination method that is easier and less painful than the conventional injectable vaccination method. We previously developed self-dissolving microneedle patches (sdMN) and demonstrated that this TCI method has a high vaccination efficacy in mice and humans. To elucidate the mechanism of immune response induction, which is the basis for the efficacy and safety of TCI with sdMN, we examined the local reaction of the skin where sdMN was applied and the kinetics and differentiation status of immune cells in the draining lymph nodes (DLNs). We found that gene expression of the proinflammatory cytokine Il1b and the downstream transcription factor Irf7 was markedly upregulated in skin tissues after sdMN application. Moreover, activation of Langerhans cells and CD207− dermal dendritic cells, which are subsets of antigen-presenting cells (APCs) in the skin, and their migration to the DLNs were promoted. Furthermore, the activated APC subsets promoted CD4+ T cell and B cell differentiation and the formation of germinal centers, which are the sites of high-affinity antibody production. These phenomena associated with sdMN application may contribute to the efficient production of antigen-specific antibodies after TCI using sdMN. These findings provide essential information regarding immune response induction mechanisms for the development and improvement of TCI preparations.

Transcutaneous immunization (TCI) systems that use the skin's immune function are promising needle-free, easy-to-use, and low-invasive vaccination alternative to conventional, injectable vaccination methods. To develop effective TCI systems, it is essential to establish fundamental techniques and technologies that deliver antigenic proteins to antigen-presenting cells in the epidermis and dermis while overcoming the barrier function of the stratum corneum. In this review, we provide an outline of recent trends in the development of techniques for the delivery of antigenic proteins and of the technologies used to enhance TCI systems. We also introduce basic and clinical research involving our TCI systems that incorporate several original devices.

The success of topically applied treatments on skin relies on the efficacy of skin penetration. In order to increase particle or product penetration, mild skin barrier disruption methods can be used. We previously described cyanoacrylate skin surface stripping as an efficient method to open hair follicles, enhance particle penetration, and activate Langerhans cells. We conducted ex vivo and in vivo measurements on human skin to characterize the biological effect and quantify barrier disruption-related inflammation on a molecular level. Despite the known immunostimulatory effects, this barrier disruption and hair follicle opening method was well accepted and did not result in lasting changes of skin physiological parameters, cytokine production, or clinical side effects. Only in ex vivo human skin did we find a discrete increase in IP-10, TGF-β, IL-8, and GM-CSF mRNA. The data underline the safety profile of this method and demonstrate that the procedure per se does not cause substantial inflammation or skin damage, which is also of interest when applied to non-invasive sampling of biomarkers in clinical trials.

A growing variety of biological macromolecules are in development for use as active ingredients in topical therapies and vaccines. Dermal delivery of biomacromolecules offers several advantages compared to other delivery methods, including improved targetability, reduced systemic toxicity, and decreased degradation of drugs. However, this route of delivery is hampered by the barrier function of the skin. Recently, a large body of research has been directed toward improving the delivery of macromolecules to the skin, ranging from nucleic acids (NAs) to antigens, using noninvasive means. In this review, we discuss the latest formulation‐based efforts to deliver antigens and NAs for vaccination and treatment of skin diseases. We provide a perspective of their advantages, limitations, and potential for clinical translation. The delivery platforms discussed in this review may provide formulation scientists and clinicians with a better vision of the alternatives for dermal delivery of biomacromolecules, which may facilitate the development of new patient‐friendly prophylactic and therapeutic medicines.

Virus-like particles (VLP) are inert, empty capsids of viruses, which contain no DNA/RNA from the virus itself. However they retain the structure of a virus and they can be engineered to have antigens attached. We have constructed VLP, derived from Rabbit hemorrhagic disease virus, and shown they are highly immunogenic. We tested the capacity of these engineered VLP to induce immune responses when they are administered to mice via the transcutaneous route. This route of vaccination is important, in order to generate mucosal protection. Our data showed that VLP are taken up by dendritic cells (DC), antigen-presenting cells that are essential to initiate acquired immune responses. The VLP induced an increase in expression of CD40, CD80 and CD86 but required an adjuvant, CpG DNA oligo-deoxy nucleotides (ODN) motifs, to enhance these responses. In vivo testing has also shown that the VLP, when wiped on to the skin in conjunction with immunostimulatory CpG, induce Ag-specific immune responses, typified by high levels of IFN-γ and IgG1.

Transcutaneous immunization aims at taking advantage of the skin's immune system for the purpose of immunoprotection. In the present study, we evaluated the potential of topical delivery of a recombinant melanoma protein, HR-gp100, derived from a shortened sequence of the native gp100 gene. The protein was applied on the skin, with and without the addition of two forms of heat labile enterotoxin (nLT and LTB). HR-gp100 fused to Haptide, a cell penetrating 20mer peptide (HR-gp100H) was also tested. Topical HR-gp100 and HR-gp100H application on the ears of mice elicited the production of specific antibodies, and transcutaneous delivery to intact human skin induced dose-dependent LC activation. nLT and LTB also activated LC, but did not further increase the activation induced by HR-gp100. These results show that HR-gp100, an antigenic tumor-derived protein, activates the immune system following transcutaneous delivery, as shown by both Langerhans cell activation and induction of antibody production.