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      High-density microprojection array delivery to rat skin of low doses of trivalent inactivated poliovirus vaccine elicits potent neutralising antibody responses

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          Abstract

          To secure a polio-free world, the live attenuated oral poliovirus vaccine (OPV) will eventually need to be replaced with inactivated poliovirus vaccines (IPV). However, current IPV delivery is less suitable for campaign use than OPV, and more expensive. We are progressing a microarray patch delivery platform, the Nanopatch, as an easy-to-use device to administer vaccines, including IPV. The Nanopatch contains an ultra-high density array (10,000/cm 2) of short (~230 μm) microprojections that delivers dry coated vaccine into the skin. Here, we compare the relative immunogenicity of Nanopatch immunisation versus intramuscular injection in rats, using monovalent and trivalent formulations of IPV. Nanopatch delivery elicits faster antibody response kinetics, with high titres of neutralising antibody after just one (IPV2) or two (IPV1 and IPV3) immunisations, while IM injection requires two (IPV2) or three (IPV1 and IPV3) immunisations to induce similar responses. Seroconversion to each poliovirus type was seen in 100% of rats that received ~1/40th of a human dose of IPV delivered by Nanopatch, but not in rats given ~1/8th or ~1/40th dose by IM injection. Ease of administration coupled with dose reduction observed in this study suggests the Nanopatch could facilitate inexpensive IPV vaccination in campaign settings.

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          Potent Immunity to Low Doses of Influenza Vaccine by Probabilistic Guided Micro-Targeted Skin Delivery in a Mouse Model

          Background Over 14 million people die each year from infectious diseases despite extensive vaccine use [1]. The needle and syringe—first invented in 1853—is still the primary delivery device, injecting liquid vaccine into muscle. Vaccines could be far more effective if they were precisely delivered into the narrow layer just beneath the skin surface that contains a much higher density of potent antigen-presenting cells (APCs) essential to generate a protective immune response. We hypothesized that successful vaccination could be achieved this way with far lower antigen doses than required by the needle and syringe. Methodology/Principal Findings To meet this objective, using a probability-based theoretical analysis for targeting skin APCs, we designed the Nanopatch™, which contains an array of densely packed projections (21025/cm2) invisible to the human eye (110 µm in length, tapering to tips with a sharpness of <1000 nm), that are dry-coated with vaccine and applied to the skin for two minutes. Here we show that the Nanopatches deliver a seasonal influenza vaccine (Fluvax® 2008) to directly contact thousands of APCs, in excellent agreement with theoretical prediction. By physically targeting vaccine directly to these cells we induced protective levels of functional antibody responses in mice and also protection against an influenza virus challenge that are comparable to the vaccine delivered intramuscularly with the needle and syringe—but with less than 1/100th of the delivered antigen. Conclusions/Significance Our results represent a marked improvement—an order of magnitude greater than reported by others—for injected doses administered by other delivery methods, without reliance on an added adjuvant, and with only a single vaccination. This study provides a proven mathematical/engineering delivery device template for extension into human studies—and we speculate that successful translation of these findings into humans could uniquely assist with problems of vaccine shortages and distribution—together with alleviating fear of the needle and the need for trained practitioners to administer vaccine, e.g., during an influenza pandemic.
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            Priming after a fractional dose of inactivated poliovirus vaccine.

            To reduce the costs of maintaining a poliovirus immunization base in low-income areas, we assessed the extent of priming immune responses after the administration of inactivated poliovirus vaccine (IPV). We compared the immunogenicity and reactogenicity of a fractional dose of IPV (one fifth of a full dose) administered intradermally with a full dose administered intramuscularly in Cuban infants at the ages of 4 and 8 months. Blood was collected from infants at the ages of 4 months, 8 months, 8 months 7 days, and 8 months 30 days to assess single-dose seroconversion, single-dose priming of immune responses, and two-dose seroconversion. Specimens were tested with a neutralization assay. A total of 320 infants underwent randomization, and 310 infants (96.9%) fulfilled the study requirements. In the group receiving the first fractional dose of IPV, seroconversion to poliovirus types 1, 2, and 3 occurred in 16.6%, 47.1%, and 14.7% of participants, respectively, as compared with 46.6%, 62.8%, and 32.0% in the group receiving the first full dose of IPV (P<0.008 for all comparisons). A priming immune response to poliovirus types 1, 2, and 3 occurred in 90.8%, 94.0%, and 89.6% of participants, respectively, in the group receiving the fractional dose as compared with 97.6%, 98.3%, and 98.1% in the group receiving the full dose (P=0.01 for the comparison with type 3). After the administration of the second dose of IPV in the group receiving fractional doses, cumulative two-dose seroconversion to poliovirus types 1, 2, and 3 occurred in 93.6%, 98.1%, and 93.0% of participants, respectively, as compared with 100.0%, 100.0%, and 99.4% in the group receiving the full dose (P<0.006 for the comparisons of types 1 and 3). The group receiving intradermal injections had the greatest number of adverse events, most of which were minor in intensity and none of which had serious consequences. This evaluation shows that vaccinating infants with a single fractional dose of IPV can induce priming and seroconversion in more than 90% of immunized infants. (Funded by the World Health Organization and the Pan American Health Organization; Australian New Zealand Clinical Trials Registry number, ACTRN12610001046099.).
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              Improving the reach of vaccines to low-resource regions, with a needle-free vaccine delivery device and long-term thermostabilization.

              Dry-coated microprojections can deliver vaccine to abundant antigen-presenting cells in the skin and induce efficient immune responses and the dry-coated vaccines are expected to be thermostable at elevated temperatures. In this paper, we show that we have dramatically improved our previously reported gas-jet drying coating method and greatly increased the delivery efficiency of coating from patch to skin to from 6.5% to 32.5%, by both varying the coating parameters and removing the patch edge. Combined with our previous dose sparing report of influenza vaccine delivery in a mouse model, the results show that we now achieve equivalent protective immune responses as intramuscular injection (with the needle and syringe), but with only 1/30th of the actual dose. We also show that influenza vaccine coated microprojection patches are stable for at least 6 months at 23°C, inducing comparable immunogenicity with freshly coated patches. The dry-coated microprojection patches thus have key and unique attributes in ultimately meeting the medical need in certain low-resource regions with low vaccine affordability and difficulty in maintaining "cold-chain" for vaccine storage and transport. Copyright © 2011 Elsevier B.V. All rights reserved.
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                Author and article information

                Contributors
                d.muller4@uq.edu.au
                m.kendall@uq.edu.au
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                3 October 2017
                3 October 2017
                2017
                : 7
                : 12644
                Affiliations
                [1 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Delivery of Drugs and Genes Group (D2G2) Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, ; Brisbane, Queensland QLD 4072 Australia
                [2 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, Australian Infectious Diseases Research Centre, The University of Queensland, ; Brisbane, Queensland Australia
                [3 ]ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Queensland, Australia
                [4 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, School of Chemistry and Molecular Biosciences, The University of Queensland, ; Brisbane, Queensland Australia
                [5 ]GRID grid.479585.2, Vaxxas Pty Ltd, Translational Research Institute, ; Brisbane, Queensland 4102 Australia
                [6 ]ISNI 0000 0000 9230 4992, GRID grid.419260.8, Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, ; Atlanta, Georgia USA
                Article
                13011
                10.1038/s41598-017-13011-0
                5626768
                28974777
                e9fd986d-d23b-4856-9931-e70392ed67a5
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                : 5 May 2017
                : 12 September 2017
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