Abstract
Transcutaneous immunization (TCI) is easy to use, minimally invasive, and has excellent efficacy in vaccines against infections. We focused on toll-like receptor (TLR) ligands as applicable adjuvants for transcutaneous formulations and characterized immune responses. TCI was performed using poke-and-patch methods, in which puncture holes are formed with a polyglycolic acid microneedle on the back skin of mice. Various TLR ligands were applied to the puncture holes and covered with an ovalbumin-loaded hydrophilic gel patch. During the screening process, K3 (CpG-oligonucleotide) successfully produced more antigen-specific antibodies than other TLR ligands and induced T helper (Th) 1-type polarization. Transcutaneously administered K3 was detected in draining lymph nodes and was found to promote B cell activation and differentiation, suggesting a direct transcutaneous adjuvant activity on B cells. Furthermore, a human safety test of K3-loaded self-dissolving microneedles (sdMN) was performed. Although a local skin reaction was observed at the sdMN application site, there was no systemic side reaction. In summary, we report a K3-induced Th1-type immune response that is a promising adjuvant for transcutaneous vaccine formulations using MN and show that K3-loaded sdMN can be safely applied to human skin.
Highlights
Infectious diseases occur and spread widely and repeatedly worldwide, making them a leading cause of death in developing countries
These results suggested that the immune cells and keratinocytes present in the skin were involved in the induction of innate immunity by detecting the invasion of foreign substances via toll-like receptor (TLR)
Intradermal immunization (ID) with the hepatitis B vaccine, influenza vaccine, or Bacille de Calmette et Guérin has been reported to be superior to immune induction and dose sparing compared to subcutaneous immunization (SC) or intramuscular immunization [22,23]
Summary
Infectious diseases occur and spread widely and repeatedly worldwide, making them a leading cause of death in developing countries. As a solution to these challenges, we have developed novel transcutaneous administration devices such as self-dissolving (sdMN) and biodegradable polyglycolic acid (PGA-MN) microneedles [3,4] These devices are easy to use, minimally invasive, and may not require a cold-chain handling, suggesting that these devices could promote vaccine availability in developing countries. We have already demonstrated the safety and efficacy of MN loaded or coated with the influenza hemagglutinin (HA) vaccine or tetanus toxoid/diphtheria toxoid (DT) in animal experiments and clinical studies [5,6,7,8] To put these transcutaneous vaccine formulations into practical use and to spread the vaccine in developing countries, it is necessary to lower the cost by reducing vaccination dose and number of administrations and to induce stable immune responses.
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