Transdermal Influenza Immunization with Vaccine-Coated Microneedle Arrays

Dimitrios G Koutsonanos,Richard W Compans,Ioanna Skountzou,Sean P Sullivan,Maria Del Pilar Martin,Vladimir G Zarnitsyn,Mark R Prausnitz,Derya Unutmaz

doi:10.1371/journal.pone.0004773

Dimitrios G Koutsonanos, Richard W Compans + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0004773

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Journal: PLoS ONE	Publication Date: Mar 10, 2009
Citations: 221	License type: CC BY 4.0

Affiliation: Emory University, Georgia Institute of Technology

Abstract

BackgroundInfluenza is a contagious disease caused by a pathogenic virus, with outbreaks all over the world and thousands of hospitalizations and deaths every year. Due to virus antigenic drift and short-lived immune responses, annual vaccination is required. However, vaccine coverage is incomplete, and improvement in immunization is needed. The objective of this study is to investigate a novel method for transdermal delivery using metal microneedle arrays (MN) coated with inactivated influenza virus to determine whether this route is a simpler and safer approach than the conventional immunization, capable to induce robust immune responses and confer protection against lethal virus challenge.Methodology/Principal FindingsInactivated A/Aichi/2/68 (H3N2) influenza virus was coated on metal microneedle arrays and applied to mice as a vaccine in the caudal dorsal skin area. Substantial antibody titers with hemagglutination inhibition activity were detected in sera collected two and four weeks after a single vaccine dose. Challenge studies in mice with 5×LD50 of mouse adapted Aichi virus demonstrated complete protection. Microneedle vaccination induced a broad spectrum of immune responses including CD4+ and CD8+ responses in the spleen and draining lymph node, a high frequency of antigen-secreting cells in the lung and induction of virus-specific memory B-cells. In addition, the use of MN showed a dose-sparing effect and a strong Th2 bias when compared to an intramuscular (IM) reference immunization.Conclusions/SignificanceThe present results show that delivery of inactivated influenza virus through the skin using metal microneedle arrays induced strong humoral and cellular immune responses capable of conferring protection against virus challenge as efficiently as intramuscular immunization, which is the standard vaccination route. In view of the convenience of delivery and the potential for self-administration, vaccine-coated metal microneedles may provide a novel and highly effective immunization method.

Highlights

Transdermal delivery of bioactive compounds on the skin has been used for thousands of years for therapeutic or prophylactic purposes, and more than one billion patches are sold annually for delivery of small molecule drugs [1]
Conclusions/Significance: The present results show that delivery of inactivated influenza virus through the skin using metal microneedle arrays induced strong humoral and cellular immune responses capable of conferring protection against virus challenge as efficiently as intramuscular immunization, which is the standard vaccination route
After immunization at the lower dose (3 mg), we observed a marked increase in the hemagglutination inhibition (HAI) titers of the microneedle arrays (MN) group, close to 80, which remained elevated at 28 days (Figure 2A)

Summary

Introduction

Transdermal delivery of bioactive compounds on the skin has been used for thousands of years for therapeutic or prophylactic purposes, and more than one billion patches are sold annually for delivery of small molecule drugs [1]. The skin is extremely dense in innate immune cell populations whose role is to recognize, uptake and present foreign antigens to T and B cells in the draining lymph nodes to initiate adaptive immune responses. These antigen-presenting cells (APCs) include large numbers of Langerhans cells (LCs), dermal dendritic cells (DCs), macrophages and monocytes as well as accessory cells such as keratinocytes [6,7,8,9]. Vaccines administered to the skin have been shown to require a lower dose and/or generate stronger immune responses compared to conventional intramuscular or subcutaneous injection [5,10]. The objective of this study is to investigate a novel method for transdermal delivery using metal microneedle arrays (MN) coated with inactivated influenza virus to determine whether this route is a simpler and safer approach than the conventional immunization, capable to induce robust immune responses and confer protection against lethal virus challenge

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