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Author Notes:

Email Address:Mark R. Prausnitz : prausnitz@gatech.edu ;

Conceived and designed the experiments: HJC RWC SMK MRP. Performed the experiments: HJC JMS BJB.

Analyzed the data: HJC JMS BJB RWC SMK MRP. Wrote the paper: HJC JMS BJB RWC SMK MRP.

The authors wish to thank Dr. Toan T. Nguyen at Georgia Tech for useful discussions, James Norman for his assistance with statistical analysis, and Donna Bondy for her hard-working dedication to the administrative aspects of this research.

This work was carried out at the Institute for Bioengineering and Bioscience and the Center for Drug Design, Development and Delivery at Georgia Tech.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

M.R.P. serves as a consultant and is an inventor on patents licensed to companies developing microneedle-based products and has a significant financial interest in Micron Biomedical, a company developing microneedle-based products for drug and vaccine delivery to the skin.

This potential conflict of interest has been disclosed and is being managed by the Georgia Institute of Technology and Emory University.

This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

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Research Funding:

This research was financially supported by National Institutes of Health (NIH) grants EB006369 and EB012495 (M.R.P.) and AI0680003 (R.W.C.), and AI105170 and AI093772 (S.M.K.).

Effect of Osmotic Pressure on the Stability of Whole Inactivated Influenza Vaccine for Coating on Microneedles

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Journal Title:

PLoS ONE

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Volume 10, Number 7

Publisher:

, Pages e0134431-e0134431

Type of Work:

Article | Final Publisher PDF

Abstract:

Enveloped virus vaccines can be damaged by high osmotic strength solutions, such as those used to protect the vaccine antigen during drying, which contain high concentrations of sugars. We therefore studied shrinkage and activity loss of whole inactivated influenza virus in hyperosmotic solutions and used those findings to improve vaccine coating of microneedle patches for influenza vaccination. Using stopped-flow light scattering analysis, we found that the virus underwent an initial shrinkage on the order of 10% by volume within 5 s upon exposure to a hyperosmotic stress difference of 217 milliosmolarity. During this shrinkage, the virus envelope had very low osmotic water permeability (1 - 6×10-4 cm s-1) and high Arrhenius activation energy (Ea = 15.0 kcal mol-1), indicating that the water molecules diffused through the viral lipid membranes. After a quasi-stable state of approximately 20 s to 2 min, depending on the species and hypertonic osmotic strength difference of disaccharides, there was a second phase of viral shrinkage. At the highest osmotic strengths, this led to an undulating light scattering profile that appeared to be related to perturbation of the viral envelope resulting in loss of virus activity, as determined by in vitro hemagglutination measurements and in vivo immunogenicity studies in mice. Addition of carboxymethyl cellulose effectively prevented vaccine activity loss in vitro and in vivo, believed to be due to increasing the viscosity of concentrated sugar solution and thereby reducing osmotic stress during coating of microneedles. These results suggest that hyperosmotic solutions can cause biphasic shrinkage of whole inactivated influenza virus which can damage vaccine activity at high osmotic strength and that addition of a viscosity enhancer to the vaccine coating solution can prevent osmotically driven damage and thereby enable preparation of stable microneedle coating formulations for vaccination.

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© 2015 Choi et al.

This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits distribution of derivative works, making multiple copies, distribution, public display, and publicly performance, provided the original work is properly cited. This license requires copyright and license notices be kept intact, credit be given to copyright holder and/or author.

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