Courtney Jarrahian

Delivery systems for intradermal vaccination.

Intradermal (ID) vaccination can offer improved immunity and simpler logistics of delivery, but its use in medicine is limited by the need for simple, reliable methods of ID delivery. ID injection by the Mantoux technique requires special training and may not reliably target skin, but is nonetheless used currently for BCG and rabies vaccination. Scarification using a bifurcated needle was extensively used for smallpox eradication, but provides variable and inefficient delivery into the skin. Recently, ID vaccination has been simplified by introduction of a simple-to-use hollow microneedle that has been approved for ID injection of influenza vaccine in Europe. Various designs of hollow microneedles have been studied preclinically and in humans. Vaccines can also be injected into skin using needle-free devices, such as jet injection, which is receiving renewed clinical attention for ID vaccination. Projectile delivery using powder and gold particles (i.e., gene gun) have also been used clinically for ID vaccination. Building off the scarification approach, a number of preclinical studies have examined solid microneedle patches for use with vaccine coated onto metal microneedles, encapsulated within dissolving microneedles or added topically to skin after microneedle pretreatment, as well as adapting tattoo guns for ID vaccination. Finally, technologies designed to increase skin permeability in combination with a vaccine patch have been studied through the use of skin abrasion, ultrasound, electroporation, chemical enhancers, and thermal ablation. The prospects for bringing ID vaccination into more widespread clinical practice are encouraging, given the large number of technologies for ID delivery under development.

Improved DNA vaccination by skin-targeted delivery using dry-coated densely-packed microprojection arrays

HSV-2-gD2 DNA vaccine was precisely delivered to immunologically sensitive regions of the skin epithelia using dry-coated microprojection arrays. These arrays delivered a vaccine payload to the epidermis and the upper dermis of mouse skin. Immunomicroscopy results showed that, in 43 ± 5% of microprojection delivery sites, the DNA vaccine was delivered to contact with professional antigen presenting cells in the epidermal layer. Associated with this efficient delivery of the vaccine into the vicinity of the professional antigen presenting cells, we achieved superior antibody responses and statistically equal protection rate against an HSV-2 virus challenge, when compared with the mice immunized with intramuscular injection using needle and syringe, but with less than 1/10th of the delivered antigen.

DNA vaccine delivery by densely-packed and short microprojection arrays to skin protects against vaginal HSV-2 challenge

There is an unmet medical need for a prophylactic vaccine against herpes simplex virus (HSV). DNA vaccines and cutaneous vaccination have been tried for many applications, but few reports combine this vaccine composition and administration route. We compared DNA administration using the Nanopatch™, a solid microprojection device coated with vaccine comprised of thousands of short (110 μm) densly-packed projections (70 μm spacing), to standard intramuscular DNA vaccination in a mouse model of vaginal HSV-2 infection. A dose-response relationship was established for immunogenicity and survival in both vaccination routes. Appropriate doses administered by Nanopatch™ were highly immunogenic and enabled mouse survival. Vaginal HSV-2 DNA copy number day 1 post challenge correlated with survival, indicating that vaccine-elicited acquired immune responses can act quickly and locally. Solid, short, densely-packed arrays of microprojections applied to the skin are thus a promising route of administration for DNA vaccines.

Intradermal delivery for vaccine dose sparing: Overview of current issues

There is a wide range of methods and technologies aimed at improving human vaccine products and the way they are delivered. Some of these have the potential to increase vaccine effectiveness in specific populations and may furthermore help to increase vaccine access, reduce costs, and ease the logistical burdens of immunization programs, especially in low-resource settings. One strategy under evaluation is the use of intradermal (ID) delivery of vaccines, which has been shown to result in dose sparing with some vaccines. Novel ID delivery devices could enable needle-free and therefore safer and more reliable ID administration than current ID injection methods, facilitating ID delivery and dose sparing with existing or new vaccines. There are promising clinical data with some vaccines that highlight the potential of reduced-dose immunization via the ID route. And more studies are under way. However, a number of clinical and technical research as well as operational challenges exist, including establishing the optimal doses for different vaccines, reformulating to adjust antigen concentration or add preservatives, matching vaccine vial volume to session size, working with vaccine manufacturers to achieve regulatory clearance for ID delivery, and developing ID delivery devices suitable for the varying scenarios of use of different vaccines. These will need to be addressed before the benefits of ID delivery and the impact of novel ID delivery technologies on human health are fully realized.

Opportunities and challenges in delivering influenza vaccine by microneedle patch.

INTRODUCTION Simple and efficacious delivery methods for influenza vaccines are needed to improve health outcomes and manage possible pandemics both in the United States and globally. One approach to meeting these needs is the microneedle patch (MNP), a small array of micron-scale needles that is applied to the skin like a bandage. METHODS To inform additional technical developments and the eventual introduction of MNPs for influenza vaccination, we interviewed key opinion leaders in the United States for insights into the opportunities and challenges associated with this technology, particularly its potential for self-administration. RESULTS All interviewees expressed high support for administration of influenza vaccine in MNPs by health care providers and for self-administration in groups supervised by a provider. Self-administration via prescription and over-the-counter purchase of MNPs received lower levels of support. Interviewees also highlighted priorities that should be considered in the ongoing development of an influenza vaccine MNP, such as confirming efficacy and ensuring safety for self-administration. For patient and health care provider acceptability, important attributes are ease of use, short wear times, and an easily accessible application site. DISCUSSION AND CONCLUSIONS Stakeholders agreed that using MNPs can help increase coverage, facilitate easy and safe delivery, reduce the cost of vaccination, and decrease the global morbidity and mortality associated with influenza. Another opportunity for this delivery method is the potential for self-administration. The prospect of reduced provider training requirements, increased thermostability, and high patient and provider acceptability makes it an attractive option for use in remote and low-resource settings worldwide. However, in addition to the technological challenges associated with producing the patch, developers must be mindful of cost considerations and key product attributes or requirements, such as usability, wear time, and proper disposal, that can affect how the product will be received in the marketplace.

An economic model assessing the value of microneedle patch delivery of the seasonal influenza vaccine.

BACKGROUND New vaccine technologies may improve the acceptability, delivery (potentially enabling self-administration), and product efficacy of influenza vaccines. One such technology is the microneedle patch (MNP), a skin delivery technology currently in development. Although MNPs hold promise in preclinical studies, their potential economic and epidemiologic impacts have not yet been evaluated. METHODS We utilized a susceptible-exposed-infectious-recovered (SEIR) transmission model linked to an economic influenza outcomes model to assess the economic value of introducing the MNP into the current influenza vaccine market in the United States from the third-party payer and societal perspectives. We also explored the impact of different vaccination settings, self-administration, the MNP price, vaccine efficacy, compliance, and MNP market share. Outcomes included costs, quality-adjusted life years (QALYs), cases, and incremental cost-effectiveness ratios (ICERs; cost/QALY). RESULTS With healthcare provider administration, MNP introduction would be cost-effective (ICERs ≤

Needle-free jet injector intradermal delivery of fractional dose inactivated poliovirus vaccine: Association between injection quality and immunogenicity

23,347/QALY) at all MNP price points (

A randomized clinical trial in adults and newborns in South Africa to compare the safety and immunogenicity of bacille Calmette-Guérin (BCG) vaccine administration via a disposable-syringe jet injector to conventional technique with needle and syringe

9.50-

Transdermal delivery of gentamicin using dissolving microneedle arrays for potential treatment of neonatal sepsis

30) and market shares (10-60%) assessed, except when compliance and efficacy were assumed to be the same as existing vaccines and the MNP occupied a 10% market share. If MNP self-administration were available (assuming the same efficacy as current technologies), MNP compliance or its efficacy would need to increase by ≥3% in order to be cost-effective (ICERs ≤

Immunogenicity and safety of measles-mumps-rubella vaccine delivered by disposable-syringe jet injector in healthy Brazilian infants: A randomized non-inferiority study

1401/QALY), assuming a 2% reduction in administration success with unsupervised self-administration. Under these conditions, MNP introduction would be cost-effective for all price points and market shares assessed. CONCLUSIONS When healthcare providers administered the MNP, its introduction would be cost-effective or dominant (i.e., less costly and more effective) in the majority of scenarios assessed. If self-administration were available, MNP introduction would be cost-effective if it increased compliance enough to overcome any decrease in self-administration success or if the MNP presentation afforded an increase in efficacy over current delivery methods for influenza vaccines.