Improved influenza vaccination in the skin using vaccine coated microneedles

Kim, Yeu Chun; Quan, Fu‐Shi; Yoo, Dae-Goon; Compans, Richard W.; Kang, Sang‐Moo; Prausnitz, Mark R.

doi:10.1016/j.vaccine.2009.08.108

Cited by 116 publications

(75 citation statements)

References 36 publications

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“…It is noteworthy that in comparison to our previous work with subcutaneous vaccination, the MN immunization with the trimeric HA induced similar serum IgG and HAI titers and induced the same level of protection against lethal challenge as that in the s.c. vaccinated mice. Comparisons between intramuscular, intranasal, subcutaneous, and microneedle vaccinations using virus-like particles (VLP) and inactivated virus antigens have all demonstrated the enhanced immunogenicity of the transdermal route (16,17,23). Taken together, the results emphasize the conclusion that the delivery route as well as the nature of the vaccine antigen is important in determining the efficacy of an influenza vaccine.…”

Section: Discussionmentioning

confidence: 90%

Microneedle Vaccination with Stabilized Recombinant Influenza Virus Hemagglutinin Induces Improved Protective Immunity

Weldon¹,

Martı́n²,

Zarnitsyn³

et al. 2011

Clin. Vaccine Immunol.

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The emergence of the swine-origin 2009 influenza pandemic illustrates the need for improved vaccine production and delivery strategies. Skin-based immunization represents an attractive alternative to traditional hypodermic needle vaccination routes. Microneedles (MNs) can deliver vaccine to the epidermis and dermis, which are rich in antigen-presenting cells (APC) such as Langerhans cells and dermal dendritic cells. Previous studies using coated or dissolvable microneedles emphasized the use of inactivated influenza virus or virus-like particles as skin-based vaccines. However, most currently available influenza vaccines consist of solubilized viral protein antigens. Here we test the hypothesis that a recombinant subunit influenza vaccine can be delivered to the skin by coated microneedles and can induce protective immunity. We found that mice vaccinated via MN delivery with a stabilized recombinant trimeric soluble hemagglutinin (sHA) derived from A/Aichi/2/68 (H3) virus had significantly higher immune responses than did mice vaccinated with unmodified sHA. These mice were fully protected against a lethal challenge with influenza virus. Analysis of postchallenge lung titers showed that MN-immunized mice had completely cleared the virus from their lungs, in contrast to mice given the same vaccine by a standard subcutaneous route. In addition, we observed a higher ratio of antigen-specific Th1 cells in trimeric sHA-vaccinated mice and a greater mucosal antibody response. Our data therefore demonstrate the improved efficacy of a skin-based recombinant subunit influenza vaccine and emphasize the advantage of this route of vaccination for a protein subunit vaccine.

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Section: Discussionmentioning

confidence: 90%

Microneedle Vaccination with Stabilized Recombinant Influenza Virus Hemagglutinin Induces Improved Protective Immunity

Weldon¹,

Martı́n²,

Zarnitsyn³

et al. 2011

Clin. Vaccine Immunol.

Self Cite

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show abstract

“…In contrast, microneedles inherently target delivery to the skin using a simple device, which can ultimately lead to local effects on depositing vaccines within the skin and systemic effects on transferring vaccines to the draining lymph nodes through the vasculature or lymphatics after uptake by antigen presenting cells such as dendritic and/or Langerhans cells. Animal studies have shown that microneedles coated with inactivated influenza vaccine can generate stronger humoral and cellular immune responses than intramuscular vaccination (25,26). Microneedles have also been shown to be painless and well tolerated in humans subjects (27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

Formulation of Microneedles Coated with Influenza Virus-like Particle Vaccine

et al. 2010

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Abstract. Mortality due to seasonal and pandemic influenza could be reduced by increasing the speed of influenza vaccine production and distribution. We propose that vaccination can be expedited by (1) immunizing with influenza virus-like particle (VLP) vaccines, which are simpler and faster to manufacture than conventional egg-based inactivated virus vaccines, and (2) administering vaccines using microneedle patches, which should simplify vaccine distribution due to their small package size and possible self-administration. In this study, we coated microneedle patches with influenza VLP vaccine, which was released into skin by dissolution within minutes. Optimizing the coating formulation required balancing factors affecting the coating dose and vaccine antigen stability. Vaccine stability, as measured by an in vitro hemagglutination assay, was increased by formulation with increased concentration of trehalose or other stabilizing carbohydrate compounds and decreased concentration of carboxymethylcellulose (CMC) or other viscosity-enhancing compounds. Coating dose was increased by formulation with increased VLP concentration, increased CMC concentration, and decreased trehalose concentration, as well as increased number of dip coating cycles. Finally, vaccination of mice using microneedles stabilized by trehalose generated strong antibody responses and provided full protection against high-dose lethal challenge infection. In summary, this study provides detailed analysis to guide formulation of microneedle patches coated with influenza VLP vaccine and demonstrates effective vaccination in vivo using this system.

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“…Indeed, Sullivan et al and Kim et al reported that administration of influenza vaccine using microneedles could elicit stronger immune responses than those of intramuscular injections in mice without adjuvant substances. 45,46) Moreover, it is important to ensure the safety of vaccine adjuvant in addition to vaccine efficacy after administration. Recently, it has been reported that some adjuvant substances provoked critical adverse effects.…”

Section: Discussionmentioning

confidence: 99%

Application of Microneedles to Skin Induces Activation of Epidermal Langerhans Cells and Dermal Dendritic Cells in Mice

Takeuchi

Nomoto

Watanabe

et al. 2016

Biological & Pharmaceutical Bulletin

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An adequate immune response to percutaneous vaccine application is generated by delivery of sufficient amounts of antigen to skin and by administration of toxin adjuvants or invasive skin abrasion that leads to an adjuvant effect. Microneedles penetrate the stratum corneum, the outermost layer of the skin, and enable direct delivery of vaccines from the surface into the skin, where immunocompetent dendritic cells are densely distributed. However, whether the application of microneedles to the skin activates antigen-presenting cells (APCs) has not been demonstrated. Here we aimed to demonstrate that microneedles may act as a potent physical adjuvant for successful transcutaneous immunization (TCI). We prepared samples of isolated epidermal and dermal cells and analyzed the expression of major histocompatibility complex (MHC) class II and costimulatory molecules on Langerhans or dermal dendritic cells in the prepared samples using flow cytometry. The expression of MHC class II and costimulatory molecules demonstrated an upward trend in APCs in the skin after the application of 500-and 300-µm microneedles. In addition, in the epidermal cells, application of microneedles induced more effective activation of Langerhans cells than did an invasive tapestripping (positive control). In conclusion, the use of microneedles is likely to have a positive effect not only as an antigen delivery system but also as a physical technique inducing an adjuvant-like effect for TCI.

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Improved influenza vaccination in the skin using vaccine coated microneedles

Cited by 116 publications

References 36 publications

Microneedle Vaccination with Stabilized Recombinant Influenza Virus Hemagglutinin Induces Improved Protective Immunity

Microneedle Vaccination with Stabilized Recombinant Influenza Virus Hemagglutinin Induces Improved Protective Immunity

Formulation of Microneedles Coated with Influenza Virus-like Particle Vaccine

Application of Microneedles to Skin Induces Activation of Epidermal Langerhans Cells and Dermal Dendritic Cells in Mice

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