Formulation and coating of microneedles with inactivated influenza virus to improve vaccine stability and immunogenicity

Abstract

Microneedle patches coated with solid-state influenza vaccine have been developed to improve vaccine efficacy and patient coverage. However, dip coating microneedles with influenza vaccine can reduce antigen activity. In this study, we sought to determine the experimental factors and mechanistic pathways by which inactivated influenza vaccine can lose activity, as well as develop and assess improved microneedle coating formulations that protect the antigen from activity loss. After coating microneedles using a standard vaccine formulation, antigenicity was reduced to just 2%, as measured by hemagglutination activity. The presence of carboxymethylcellulose, which was added to increase viscosity of the coating formulation, was shown to contribute to vaccine activity loss. After screening a panel of candidate stabilizers, the addition of trehalose to the coating formulation was shown to protect the antigen and retain 48–82% antigen activity for all three major strains of seasonal influenza: H1N1, H3N2 and B. Influenza vaccine coated in this way also exhibited thermal stability, such that activity loss was independent of temperature over the range of 4 – 37°C for 24 h. Dynamic light scattering measurements showed that antigen activity loss was associated with virus particle aggregation, and that stabilization using trehalose largely blocked this aggregation. Finally, microneedles using an optimized vaccine coating formulation were applied to the skin to vaccinate mice. Microneedle vaccination induced robust systemic and functional antibodies and provided complete protection against lethal challenge infection similar to conventional intramuscular injection. Overall, these results show that antigen activity loss during microneedle coating can be largely prevented through optimized formulation and that stabilized microneedle patches can be used for effective vaccination.

Intradermal delivery of vaccines: potential benefits and current challenges

“…Encouraging preclinical data have been obtained with several formats of this type of device. [38][39][40] Challenges remain in producing solid formulations of different types of vaccine antigens, developing methods for coating sufficient antigen onto the microneedles and controlling the reproducibility of antigen delivery. If these can be overcome, microneedle patches could provide several benefits in addition to dose-sparing, including small-packaged volumes and simplicity of use.…”

Formulation of Microneedles Coated with Influenza Virus-like Particle Vaccine

“…The coating solution was composed of 0.25-1.0% (w/v) carboxymethylcellulose (CMC) sodium salt (USP grade, Carbo-Mer, San Diego, California, USA), 0.5% (w/v) Lutrol F-68 NF (BASF, Mt. Olive, New Jersey, USA) in PBS as described previously (32,33). Additional studies used other viscosity-enhancing agents, including 1% (w/v) alginic acid, polyvinylpyrrolidone, gum ghatti, karaya gum (Sigma-Aldrich, St. Louis, Missouri, USA), and xanthan gum (Fluka, Buchs, Switzerland).…”

Microneedles: an emerging transdermal drug delivery system

“…These challenges can be overcome by use of microneedles. Highly hydrophilic drug formulations like PEGylated naltrexone or hydrophobic formulations of drugs like ketoprofen, show a many-fold increase in area under the curve (AUC) and maximum drug concentration [58][59][60] Coat and poke Adjuvant increases cellular immunogenicity, safety and self life. Hepatitis B vaccine [61] Poke and release Antigenicity was maintained at high temperature.…”