Low-Temperature Multiple Micro-Dispensing on Microneedles for Accurate Transcutaneous Smallpox Vaccination.

Smallpox is an acute contagious disease caused by the variola virus. According to WHO guidelines, the smallpox vaccine is administrated by scarification into the epidermis using a bifurcated needle moistened with a vaccine solution. However, this invasive vaccination method involving multiple skin punctures requires a special technique to inoculate, as well as a cold chain for storage and distribution of vaccine solutions containing a live virus. Here, we report a transcutaneous smallpox vaccination using a live vaccinia-coated microneedle (MN) patch prepared by a low-temperature multiple nanoliter-level dispensing system, enabling accurate transdermal delivery of live vaccines and maintenance of bioactivity. The live vaccinia in hyaluronic acid (HA) solutions was selectively coated on the solid MN tips, and the coating amount of the vaccine was precisely controlled through a programmed multiple dispensing process with high accuracy under low temperature conditions (2-8 °C) for smallpox vaccination. Inoculation of mice (BALB/C mouse) with the MN patch coated with the second-generation smallpox vaccine increased the neutralizing antibody titer and T cell immune response. Interestingly, the live vaccine-coated MN patch maintained viral titers at -20 °C for 4 weeks and elevated temperature (37 °C) for 1 week, highlighting improved storage stability of the live virus formulated into coated MN patches. This coated MN platform using contact dispensing technique provides a simple and effective method for smallpox vaccination.