Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD and TB Prevention, US Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA.
School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
Vaccine. 2023 Jun 1;41(24):3663-3672. doi: 10.1016/j.vaccine.2023.05.005. Epub 2023 May 11.
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.
使用可溶解微针贴片（dMNP）进行乙型肝炎疫苗接种可以减少疫苗接种、冷藏储存和生物危害锐器废物安全处置所需的专业知识，从而增加出生时接种疫苗的机会。在这项研究中，我们开发了一种 dMNP，用于以 5µg、10µg 和 20µg 的剂量接种乙型肝炎表面抗原（HBsAg）无佐剂单价疫苗（AFV），并将其免疫原性与以 10µg 标准单价 HBsAg 进行肌肉内（IM）注射进行比较，无论是以 AFV 还是铝佐剂疫苗（AAV）的形式接种。在小鼠中，在 0、3 和 9 周的三个剂量方案中，以及在恒河猴中，在 0、4 和 24 周的三个剂量方案中进行了接种。dMNP 接种在所有三种研究的 HBsAg 剂量下，均可诱导小鼠和恒河猴产生保护性水平的抗-HBs 抗体反应（≥10 mIU/ml）。dMNP 递送的 HBsAg 诱导的抗-HBsAg 抗体（抗-HBs）反应高于小鼠和恒河猴中的 10µg IM AFV，但低于 10µg IM AAV。在所有疫苗组中均检测到 HBsAg 特异性 CD4+和 CD8+T 细胞反应。此外，我们分析了与每种疫苗接种组相关的差异基因表达谱，发现组织应激、T 细胞受体信号和 NFκB 信号通路在所有组中均被激活。这些结果表明，dMNP、IM AFV 和 IM AAV 递送的 HBsAg 具有诱导先天和适应性免疫反应的相似信号通路。我们进一步证明，dMNP 在室温（20°C-25°C）下可稳定保存 6 个月，保持 67±6%的 HBsAg 效力。这项研究提供了证据，表明通过 dMNP 接种 10µg（出生剂量）AFV 可在小鼠和恒河猴中诱导保护性水平的抗体反应。本研究中开发的 dMNPs 可用于提高资源有限地区乙型肝炎出生时接种疫苗的覆盖率水平，以实现和维持乙型肝炎的消除。
