Inactivated polio vaccination using a microneedle patch is immunogenic in the rhesus macaque
Introduction
Due largely to the efforts of the Global Polio Eradication Initiative (GPEI), worldwide confirmed polio cases have reached their lowest level in history [1], and the current target for eradication of the disease is fast approaching [2]. This progress has been achieved primarily through mass vaccination using the oral polio vaccine (OPV), which is a live-attenuated vaccine administered orally [3]. Vaccination using OPV offers the advantages of administration by minimally trained personnel in mass campaigns (fixed post or house-to-house); generation of no sharps waste; small package size for simplified storage, transportation and waste disposal; low-cost vaccine; and generation of mucosal immunity.
However, OPV has a major disadvantage: it carries a risk of genetic reversion to a virulent form, which can result in the emergence and transmission of vaccine-derived polioviruses (VDPVs) [4], which now account for a large fraction of polio cases [5]. To achieve the ultimate goal of eradication, OPV needs to be replaced with inactivated polio vaccine (IPV), which does not carry the risk of paralysis in the recipient or transmission in the community [6].
Plans to switch to IPV are being developed, with the goal of eliminating use of OPV worldwide by 2019 after worldwide introduction of IPV [7]. This is currently underway with the phased withdrawal of OPV type 2 and the transition to bivalent OPV, which will be followed by the complete withdrawal of OPV. However, while IPV overcomes OPV's major disadvantage of genetic reversion to virulent forms, it also introduces many new disadvantages, such as the need for trained healthcare professionals to administer injections; generation of sharps waste; larger package size of vials, needles and syringes for storage, transport and disposal; multi-dose presentation that leads to vaccine wastage; order of magnitude higher vaccine cost; and poor generation of mucosal immunity on its own [8], [9], [10]. Recent studies have found IPV to be a better booster of intestinal immunity in OPV primed persons than an additional dose of OPV, suggesting mass campaigns with IPV could be especially beneficial to the polio endgame [11].
In this study, we propose the use of a microneedle patch to administer IPV by an approach that seeks to capture the safety advantages of IPV without losing the logistical advantages of OPV. Microneedle patches can be applied to the skin in a simple manner, such that microscopic needles painlessly puncture the skin to administer IPV without the need for hypodermic needles [12]. Microneedle patches have previously been used to administer other vaccines in preclinical studies, such as influenza, measles, HPV and others [13], [14], [15], [16], [17], [18], [19], [20], [21], but have not yet been studied for IPV vaccination.
IPV vaccination using a microneedle patch can eliminate the need for trained healthcare professionals to administer injections, thereby enabling the use of minimally trained personnel to efficiently administer vaccine in house-to-house campaigns in a cost-effective manner. In addition, IPV vaccination using microneedle patches may reduce vaccine cost by possible dose sparing enabled by skin vaccination, as seen for intradermal injection of IPV and other vaccines [22] and generation of improved immunity, as seen for microneedle vaccination using other vaccines [23], [24], [25].
Given these motivations, this study developed a dissolving microneedle patch for IPV vaccination and measured the immune response to IPV delivery in the rhesus macaque using the microneedle patch compared to conventional intramuscular injection. This is the first study to assess IPV vaccination using a microneedle patch.
Section snippets
Concentration of inactivated polio vaccine
Unformulated, monovalent, bulk inactivated polio vaccine was kindly provided by GlaxoSmithKline Biologicals (Rixensart, Belgium). The starting antigen concentration was measured by us as described below to be 2023, 831 and 1081 d-antigen units/mL for IPV types 1, 2 and 3, respectively. The bulk IPV was concentrated using Amicon Ultra centrifuge spin filters with a 100 kDa molecular weight cutoff (EMD Millipore, Billerica, MA). The stock IPV solutions were each concentrated approximately 38-fold
Microneedle fabrication: vaccine filling
Molds consisting of a 10 × 10 array of 300 × 300 × 600 μm pyramidal microneedles were fabricated as previously described [26], [27]. The concentrated poliovirus vaccine stock was mixed into a casting solution containing 15% w/v sucrose and 300 mM threonine (Sigma–Aldrich, St. Louis, MO) and ∼20 μL was applied to the microneedle mold, to which vacuum at a pressure of −93.1 kPa was then applied for 20 min. After that, the mold was allowed to further dry in a chemical fume hood for 60 min. Adhesive tape was
Microneedle patch design
Microneedle patches were designed to be inexpensive to manufacture, have a small package size, be simple to administer, and generate no sharps waste in order to meet the needs of mass vaccination campaigns in developing countries. The resulting microneedle patches are shown in Fig. 1. They contain a 10 × 10 array of pyramidal microneedles measuring approximately 650 μm in height. With the addition of the supporting backing layer, each microneedle patch has a footprint of 1.27 cm2 and a total volume
Discussion
The WHO has recommended that member countries begin introducing IPV prior to OPV withdrawal as eradication progresses, to reduce the risk of emergence of vaccine-derived polioviruses [7]. IPV is currently delivered using a needle and syringe, which introduces a number of drawbacks when compared to the oral delivery route utilized by OPV. Hypodermic injection generally requires trained healthcare personnel at fixed-post clinics and increases the risk of disease transmission due to generation of
Acknowledgements
The authors would like to thank Ryan Johnson and Dr. Robyn Engel for their assistance in bleeding and anesthetizing the animals; William Hendley, Sharla McDonald, Deborah Moore and Yiting Zhang for conducting the serum neutralization assays; Marcus Collins for his help with protocol development and sample collection; and Dr. Paul Rota for acquiring the rhesus macaques and making them available for use in this study. We also thank Dr. James Norman for his help with statistical analyses and Donna
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