Hepatitis B vaccine delivered by microneedle patch: Immunogenicity in mice and rhesus macaques.

Vaccination against hepatitis B using a dissolving microneedle patch (dMNP) could increase access to the birth dose by reducing expertise needed for vaccine administration, refrigerated storage, and safe disposal of biohazardous sharps waste. In this study, we developed a dMNP to administer hepatitis B surface antigen (HBsAg) adjuvant-free monovalent vaccine (AFV) at doses of 5 µg, 10 µg, and 20 µg, and compared its immunogenicity to vaccination with 10 µg of standard monovalent HBsAg delivered by intramuscular (IM) injection either in an AFV format or as aluminum-adjuvanted vaccine (AAV). Vaccination was performed on a three dose schedule of 0, 3, and 9 weeks in mice and 0, 4, and 24 weeks in rhesus macaques. Vaccination by dMNP induced protective levels of anti-HBs antibody responses (≥10 mIU/ml) in mice and rhesus macaques at all three HBsAg doses studied. HBsAg delivered by dMNP induced higher anti-HBsAg antibody (anti-HBs) responses than the 10 µg IM AFV, but lower responses than 10 µg IM AAV, in mice and rhesus macaques. HBsAg-specific CD4+ and CD8+ T cell responses were detected in all vaccine groups. Furthermore, we analyzed differential gene expression profiles related to each vaccine delivery group and found that tissue stress, T cell receptor signaling, and NFκB signaling pathways were activated in all groups. These results suggest that HBsAg delivered by dMNP, IM AFV, and IM AAV have similar signaling pathways to induce innate and adaptive immune responses. We further demonstrated that dMNP was stable at room temperature (20 °C-25 °C) for 6 months, maintaining 67 ± 6 % HBsAg potency. This study provides evidence that delivery of 10 µg (birth dose) AFV by dMNP induced protective levels of antibody responses in mice and rhesus macaques. The dMNPs developed in this study could be used to improve hepatitis B birth dose vaccination coverage levels in resource limited regions to achieve and maintain hepatitis B elimination.

Co-Delivery of M2e Virus-Like Particles with Influenza Split Vaccine to the Skin Using Microneedles Enhances the Efficacy of Cross Protection.

It is a high priority to develop a simple and effective delivery method for a cross-protective influenza vaccine. We investigated skin immunization by microneedle (MN) patch with human influenza split vaccine and virus-like particles containing heterologous M2 extracellular (M2e) domains (M2e5x virus-like particles (VLP)) as a cross-protective influenza vaccine candidate. Co-delivery of influenza split vaccine and M2e5x VLP to the skin by MN patch was found to confer effective protection against heterosubtypic influenza virus by preventing weight loss and reducing lung viral loads. Compared to intramuscular immunization, MN-based delivery of combined split vaccine and M2e5x VLPs shaped cellular immune responses toward T helper type 1 responses increasing IgG2a isotype antibodies as well as IFN-γ producing cells in mucosal and systemic sites. This study provides evidence that potential immunological and logistic benefits of M2e5x VLP with human influenza split vaccine delivered by MN patch can be used to develop an easy-to-administer cross-protective influenza vaccine.