The threat of pandemic
influenza and other public health needs motivate the development of better
vaccine delivery systems. To address this need, microneedles have been developed as micron-scale needles fabricated using low-cost manufacturing methods that administer
vaccine into the skin using a simple device that may be suitable for
self-administration. Delivery using solid or hollow microneedles can be accomplished by (1) piercing the skin and then applying a
vaccine formulation or patch onto the permeabilized skin, (2) coating or encapsulating
vaccine onto or within microneedles for rapid, or delayed, dissolution and release in the skin, and (3) injection into the skin using a modified syringe or pump. Extensive clinical experience with
smallpox, TB, and other
vaccines has shown that
vaccine delivery into the skin using conventional
intradermal injection is generally safe and effective and often elicits the same immune responses at lower doses compared to
intramuscular injection. Animal experiments using microneedles have shown similar benefits. Microneedles have been used to deliver whole, inactivated virus; trivalent split
antigen vaccines; and
DNA plasmids encoding the
influenza hemagglutinin to rodents, and strong antibody responses were elicited. In addition,
ChimeriVax-JE against
yellow fever was administered to nonhuman primates by microneedles and generated protective levels of
neutralizing antibodies that were more than seven times greater than those obtained with subcutaneous delivery;
DNA plasmids encoding
hepatitis B surface antigen were administered to mice and antibody and T cell responses at least as strong as hypodermic
injections were generated; recombinant protective
antigen of Bacillus anthracis was administered to rabbits and provided complete protection from lethal
aerosol anthrax spore challenge at a lower dose than
intramuscular injection; and
DNA plasmids encoding four vaccinia virus genes administered to mice in combination with electroporation generated
neutralizing antibodies that apparently included both Th1 and Th2 responses. Dose sparing with microneedles was specifically studied in mice with the model
vaccine ovalbumin. At low dose (1 microg), specific antibody titers from microneedles were one order of magnitude greater than
subcutaneous injection and two orders of magnitude greater than
intramuscular injection. At higher doses, antibody responses increased for all delivery methods. At the highest levels (20-80 microg), the route of administration had no significant effect on the immune response. Concerning safety, no
infections or other serious adverse events have been observed in well over 1,000 microneedle insertions in human and animal subjects.
Bleeding generally does not occur for short microneedles (<1 mm). Highly localized, mild, and transient
erythema is often observed. Microneedle
pain has been reported as nonexistent to mild, and always much less than a
hypodermic needle control. Overall, these studies suggest that microneedles may provide a safe and effective method of delivering
vaccines with the possible added attributes of requiring lower
vaccine doses, permitting low-cost manufacturing, and enabling simple distribution and administration.