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The Wide World of Vaccines

March 2019

Microneedle Patch to Deliver Vaccines? Not Just Pie in the Sky

 

Christopher J. Harrison, MD, FAAP, FPIDS | Director, Infectious Diseases Research Laboratory | Director, Vaccine and Treatment Evaluation Unit | Professor of Pediatrics, UMKC School of Medicine

A few years ago, we mentioned microneedle patch technology as a vaccine delivery system. It was a “gee-whiz” moment. But are we now closer to a practical and safe microneedle patch?

What has taken so long to get to the point of testing in humans?

  1. Microneedles, foreign bodies, allow adherence of organisms and act as avenues for bacteria/fungi to traverse the skin.
  2. The longer the needles stay in place, the greater the likelihood of secondary infection.
  3. Early models were stiff and did not flex with body surfaces.
  4. The amount of deliverable vaccine was limited, causing concern over adequacy of immune responses.

Now, Australian investigators may have developed an ingenious patch composed of carboxymethyl cellulose (CMC).1 CMC is an inexpensive and safe viscosity modifier/thickener, often used to stabilize various products, including ice cream and toothpaste. CMC patches can be produced so that at room temperature they are soft, but solid. CMC can be liquified to pour into molds rendering patch manufacturing relatively simple. Patches are stable and store well.

What makes this cool is that CMC is very water soluble, i.e., dissolves quickly.
Figure 1.  Cartoon of microneedles in a CMC patch dissolving (in seconds).

So, the dozens of microneedles in a patch will dissolve in about 1 minute when applied to the skin, but still deposit the vaccine subcutaneously. What’s more, the microneedles produce minimal pain, require no special equipment to apply them, and are easily removed.

Another cool aspect of this technology is that the investigators impregnated the microneedles with silver nanoparticles. Silver is antimicrobial so the silver particles render the patch “self-sterilizing.” In other words, any organisms trying to sneak in during the minute that the needles are dissolving are eliminated by the effects of the silver in the needles. The patches have been tested and effectively kill many pathogens, including S. aureus, coagulase negative staphylococcus, E. coli, and P. aeruginosa. The mechanism of action is twofold: 1. Silver particles bind to pathogen cell membranes and disrupt cell walls, and 2. Free radical silver anions damage DNA and destabilize ribosomal protein production. The antimicrobial effects last one to two days. Of note, microneedle-induced “pores” heal over in <12 hours.

The second silver nanoparticle function is acting as an adjuvant.2 This means smaller vaccine amounts can induce the desired immune response. While adjuvants can be reactogenic (extra local reactions), silver does not appear proinflammatory (not reactogenic). In vitro, microneedle silver particles do not induce TNF-a or IL-8, the major innate immune responses that are proinflammatory. Also, the silver does not injure fibroblasts, surrogates for the subcutaneous tissue, so toxicity to skin structures should not be an issue.   

Patches are light-weight, and ship and store easily. There is no “sharps” waste or chance for inadvertent health care-related inadvertent punctures. The system’s limits are related to stability of vaccine formulations, not the patch. Influenza vaccine seems an ideal target for the patches.

While minute amounts of a “heavy metal” entering the body may raise concern in some, per patch concentrations are six times less than local silver toxic concentrations. It is unknown if skin conditions e.g., eczema, will be an issue. Use in young children needs additional study given their more sensitive skin.

Testing needed for approval likely will take a few more years, but I am looking forward to my influenza vaccine being a patch on my arm for a minute. Patches might get enough people immunized to establish herd immunity to influenza for the first time.

References:

1. Self-Sterilizing Antibacterial Silver-Loaded Microneedles. Gonzalez Garcia LN, MacGregor MN, Visalakshan RM, et al. Chem. Commun., 2019, 55, 171 † Laura E.

2. Green Synthesis and Evaluation of Silver Nanoparticles as Adjuvant in Rabies Veterinary Vaccine.  Asgary V, Shoari A, Baghbani-Arani F, et al. Int. J. Nanomed., 2016, 11, 3597–3605.