Microneedle-based vaccines

Abstract

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.

Fig. 1

Solid microneedles used either to pierce or to scrape microscopic holes in the skin. Shown from left to right: platinum-coated silicon microneedle measuring 170 µm in height (image courtesy of James Birchall, Cardiff University); metal microneedles measuring 700 µm in height (image courtesy of Harvinder Gill, Georgia Institute of Technology); dissolving polymer microneedles measuring 650 µm in height (image courtesy of Sean Sullivan, Georgia Institute of Technology); blunt-tip polymer microneedles measuring 150 µm in height to scrape the skin (image courtesy of John Mikszta, BD Technologies).

Fig. 2

Solid microneedles coated with model compounds. Shown from left to right: metal microneedles measuring 225 µm in height coated with approximately (a) 1.4 ng and (b) 19 ng of ovalbumin and viewed from above, looking from their tips down their shafts (images courtesy of Michel Cormier, Alza Corporation); metal microneedles measuring 700 µm in height each coated with approximately 2 µg vitamin B (image courtesy of Harvinder Gill, Georgia Institute of Technology).

Fig. 3

Dissolving or degrading polymer microneedles that encapsulate model compounds. Shown from left to right: dissolving polymer microneedles measuring 600 µm in height encapsulating sulforhodamine (image courtesy of Jeong Woo Lee, Georgia Institute of Technology); biodegradable polymer microneedles measuring 600 µm in height encapsulating calcein (image courtesy of Jung-Hwan Park, Georgia Institute of Technology); array of biodegradable polymer microneedles held between two fingers (image courtesy of Gary Meek, Georgia Institute of Technology).

Fig. 4

Hollow microneedles for injection into the skin. Shown from left to right: metal hypodermic needle protruding 1.5 mm from a specially designed hub for intradermal delivery (image courtesy of John Mikszta, BD Technologies); metal microneedle measuring 150 µm in height (image courtesy of Devin McAllister, Georgia Institute of Technology); silicon microneedle measuring 200 µm in height (image courtesy of Yotam Levin, NanoPass Technologies).

Fig. 5

Antibody response to influenza vaccines in rats. Data represent a subset of those originally reported in reference [4]. (A) Antibody response to whole, inactivated influenza virus following immunization with either a high dose or low dose of vaccine. Data represent day 56 ELISA titers following immunization on day 0, day 21 and day 42. (B) Antibody response to influenza virus following immunization with either a high dose or low dose of plasmid DNA encoding influenza virus hemagglutinin. Data represent day 56 ELISA titers following immunization on day 0, day 21 and day 42. (C) Antibody response to the H1N1 strain of influenza virus following immunization with either a high dose or low dose of trivalent, split virion vaccine. Data represent day 21 ELISA titers following a single immunization. (D) Antibody response to the H3N2 strain of influenza virus following immunization with either a high dose or low dose of trivalent, split virion vaccine. Data represent day 21 ELISA titers following a single immunization.

Fig. 6

Anti-ovalbumin antibody response to ovalbumin immunization in hairless guinea pigs. Each animal received a primary immunization followed by a secondary immunization (booster) 4 weeks later with the same ovalbumin dose [54]. The routes of administration were intracutaneous using coated microneedle arrays, ID, SC, and IM injection. The serum samples were collected 1 week after the booster immunization and evaluated for the presence of anti-ovalbumin IgG antibodies by ELISA. The results are expressed as end-point antibody titers relative to non-immunized control sera.