Immune response and reactogenicity of an unadjuvanted intradermally delivered human papillomavirus vaccine using a first generation Nanopatch™ in rhesus macaques: An exploratory, pre-clinical feasibility assessment

Abstract

The human papillomavirus (HPV) 9-valent, recombinant vaccine (Gardasil™9) helps protect young adults (males and females) against anogenital cancers and genital warts caused by certain HPV genotypes (ref. Gardasil™9 insert). This vaccine is administered intramuscularly (IM). The aim of this study was to determine preclinically whether intradermal (ID) vaccination with an unadjuvanted 9-valent recombinant HPV vaccine using a first-generation ID delivery device, the Nanopatch™, could enhance vaccine immunogenicity compared with the traditional ID route (Mantoux technique). IM injection of HPV VLPs formulated with Merck & Co., Inc., Kenilworth, NJ, USA Alum Adjuvant (MAA) were included in the rhesus study for comparison. The Nanopatch™ prototype contains a high-density array comprised of 10,000 microprojections/cm 2 , each 250 µm long. It was hypothesized the higher density array with shallower ID delivery may be superior to the Mantoux technique. To test this hypothesis, HPV VLPs without adjuvant were coated on the Nanopatch™, stability of the Nanopatch™ with unadjuvanted HPV VLPs were evaluated under accelerated conditions, skin delivery was verified using radiolabelled VLPs or FluoSpheres®, and the immune response and skin site reaction with the Nanopatch™ was evaluated in rhesus macaques. The immune response induced by Nanopatch™ administration, measured as HPV-specific binding antibodies, was similar to that induced using the Mantoux technique. It was also observed that a lower dose of unadjuvanted HPV VLPs delivered with the first-generation Nanopatch™ and applicator or Mantoux technique resulted in an immune response that was significantly lower compared to a higher-dose of alum adjuvanted HPV VLPs delivered IM in rhesus macaques. The study also indicated unadjuvanted HPV VLPs could be delivered with the first-generation Nanopatch™ and applicator to the skin in 15 s with a transfer efficiency of approximately 20%. This study is the first demonstration of patch administration in non-human primates with a vaccine composed of HPV VLPs.

Microneedles: A New Generation Vaccine Delivery System

“…Different methods have been used to enhance the coating of antigens on the surface of solid microneedles. Solid microneedles coated with multilayers of charge reversal pH-sensitive copolymers enhanced the delivery of the DNA vaccine to antigen-presenting cells, thus producing enhanced immune response [ 42 ]. The Mantoux technique is the traditional intradermal administration method; however, an improved or first-generation intradermal administration technique involving solid microneedles in a Nanopatch™ comprising 10,000 micro projections/cm 2 each 250 µm long enhanced the antigenicity of the HPV vaccine administered.…”

Engineering Micro–Nanomaterials for Biomedical Translation

“…Due to the high density of projections the patch needs to be applied using an applicator. [ 53 ] The technology has been recently tested in two clinical trials using microneedle arrays coated with monovalent influenza vaccine and manufactured by means of an aseptically validated process. [ 47,54 ] Microneedle arrays without a vaccine have been tested for safety and tolerability in humans, and data on the acceptability of the delivery system have been generated.…”

Engineering Microneedles for Therapy and Diagnosis: A Survey

“…Besides clinical trials, many commercial MN products have been developed for vaccination and are available nowadays. These commercial products, for example, Nanopatch TM [159], Fluzone Intradermal ® [160], and Intanza ® [161], have been published in journals, and contributed to public health against pestilence [162,163].…”