Induction of potent CD8+ T cell responses through the delivery of subunit protein vaccines to skin antigen-presenting cells using densely packed microprojection arrays

Ng, Hwee-Ing; Fernando, Germain J. P.; Kendall, M. A. F.

doi:10.1016/j.jconrel.2012.07.024

Cited by 40 publications

(46 citation statements)

References 75 publications

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“…Nevertheless, this method of delivery differs from intradermal administration by microneedles. On the other hand, some previous studies on model subunit vaccines using microneedles, such as nanopatches to deliver non-encapsulated TLR adjuvants or pH sensitive microneedles arrays loaded with high doses of protein induced CD8 + T cell responses [39][40][41]. However, in these studies using microneedles none of the vaccine antigens were encapsulated in nanoparticles.…”

Section: Discussionmentioning

confidence: 96%

Hollow microneedle-mediated intradermal delivery of model vaccine antigen-loaded PLGA nanoparticles elicits protective T cell-mediated immunity to an intracellular bacterium

Groot

Mönkäre

et al. 2017

Journal of Controlled Release

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A B S T R A C TThe skin is an attractive organ for immunization due to the presence of a large number of epidermal and dermal antigen-presenting cells. Hollow microneedles allow for precise and non-invasive intradermal delivery of vaccines. In this study, ovalbumin (OVA)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles with and without TLR3 agonist poly(I:C) were prepared and administered intradermally by hollow microneedles. The capacity of the PLGA nanoparticles to induce a cytotoxic T cell response, contributing to protection against intracellular pathogens, was examined. We show that a single injection of OVA-loaded PLGA nanoparticles, compared to soluble OVA, primed both adoptively transferred antigen-specific naïve transgenic CD8 + and CD4 + T cells with markedly high efficiency. Applying a triple immunization protocol, PLGA nanoparticles primed also endogenous OVA-specific CD8 + T cells. Immune response, following immunization with in particular anionic PLGA nanoparticles co-encapsulated with OVA and poly(I:C), provided protection against a recombinant strain of the intracellular bacterium Listeria monocytogenes, secreting OVA. Taken together, we show that PLGA nanoparticle formulation is an excellent delivery system for protein antigen into the skin and that protective cellular immune responses can be induced using hollow microneedles for intradermal immunizations.

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Section: Discussionmentioning

confidence: 96%

Hollow microneedle-mediated intradermal delivery of model vaccine antigen-loaded PLGA nanoparticles elicits protective T cell-mediated immunity to an intracellular bacterium

Groot

Mönkäre

et al. 2017

Journal of Controlled Release

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“…Others have reported enhanced stability of trivalent influenza vaccine when formulated with trehalose for 1 month at 4 °C and 25 °C, however this was not seen when stored at 37 °C as assessed by HA activity [346]. Induction of CD8 + T-cell responses, important for protection in immunisations were successfully achieved with unadjuvanted OVA or adjuvanted (QA or CPG) OVA [350]. Enhanced T-cell responses were also seen with live viral vector malaria vaccine that were comparable to i.d.…”

Section: The Nanopatch™mentioning

confidence: 99%

“…antigens and plasmids such as sulphur rodamine, Coomassie Blue [280,349], OVA [280,349,350], trivalent split virion influenza [3,280,345,350], HPV [304], West Nile viral plasmid [303], whole Chikungunya virus [303], DNA vaccine encoding for HSV-2-gD2 [306,307], as well as live viral vector malaria vaccine [347] amongst several other antigens.…”

Section: The Nanopatch™mentioning

confidence: 99%

“…A highly efficient adjuvant, it produces predominantly Th2 responses but also enhances Th1 responses, along with strong CD8 + T-cell responses to coadministered antigens [350,[408][409][410][411]. However, its toxicity and side effects do not allow its use as an adjuvant in humans, prompting local reactions and irritations, granulomas [412] as well as haemolysis of cells through pore formation in the cell membranes [413].…”

Section: Saponins: Quil-a and Qs-21mentioning

confidence: 99%

“…By contrast, Sun et al concluded that saponin's side chains and the glycosyl groups could affect haemolytic activities, adjuvanticity and type of immune responses [416]. Moreover, saponins in general have been shown to cause local reactions and inflammation [406] along with enhanced cytokine productions [345,350,410]. A more purified and less toxic version of QA is QS-21 [415], which was shown to induce high antibody-specific responses as well as CD8 + T-cell responses against several pathogens including HIV-1 and other antigens, and has also been delivered i.d.…”

Section: Saponins: Quil-a and Qs-21mentioning

confidence: 99%

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Investigation of cell death caused by the Nanopatch™ and its role in vaccine delivery as a physical immune enhancer

Depelsenaire¹

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Since the introduction of vaccines, millions of lives have been saved. Yet, infectious diseases continue to contribute to deaths in underdeveloped countries, with over 2 million children dying per year from preventable diseases such as diphtheria, pertussis and tetanus. Despite the advantages of vaccines, there are also some risks and disadvantages associated with vaccines and their delivery such as the need for medical personnel for administration, refrigeration of the vaccine, disease transmission associated with needles and potential adverse side effects due to adjuvants. While intramuscular and subcutaneous injections are most frequently used for vaccine administration, these sites are poor in antigen-presenting cells. The skin, the largest immunological organ, by contrast contains a dense network of antigen-presenting cells, important in the uptake of antigen and presentation to naive T-cells, and has received increased interest as a target site for vaccine delivery. Intradermal immunisations have achieved significant dose-sparing over conventional immunisation routes. However, using existing needle designs, intradermal injections can be difficult to administer into the thin dermal layer due to the proportionally large scale of the needle. This has led to the development of alternative skin-based delivery methods, such as microneedle arrays.Here, the Nanopatch™ is an array containing 3364 microprojections of ~110 µm in length, which was used to deliver the vaccine into the viable epidermis and dermis of the skin. With an unprecedented >100-fold dose-sparing reported by the Nanopatch™ in comparison to conventional immunisation strategies with an influenza split virion vaccine, the mechanisms behind this skin- The extent of cell death after Nanopatch™ application and intradermal injection was investigated, characterised and quantified by Confocal/ Multiphoton microscopy, Western Blot and flow cytometry. A distinct pattern of dead cells was obtained with significantly higher levels (~65-fold) of cell death in murine ear skin following Nanopatch™ treatment than intradermal injection.ii | P a g e Measured skin cell death was tuneable by changing projection density but not shapes, and was associated with modelled stresses of ≥1 MPa.Immunogenicity studies demonstrated consistently and statistically significantly higher anti-IgG endpoint titres (up to 50-fold higher) in Nanopatch™ than intradermally injected groups after delivery of a split virion influenza vaccine, with a 10-fold dose-sparing effect. Importantly, colocalisation of delivered antigen with both, live and dead cells was necessary for immunogenicity enhancement. Overall, higher inflammatory responses and longer-lasting antigen depot formation were associated with Nanopatch™ immunisations but not with intradermal injections. The findings indicated a correlation between co-localisation of antigen cell death caused by the Nanopatch™ and enhanced immunogenicity with split virion influenza vaccine as model antigen.Collectively, the data presented wi...

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An Ultrahigh‐Density Microneedle Array for Skin Vaccination: Inducing Epidermal Cell Death by Increasing Microneedle Density Enhances Total IgG and IgG1 Immune Responses

Coffey

Burg

Rananakomol

et al. 2022

Advanced NanoBiomed Research

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Many types of microneedle (MN) arrays have been tested for delivery of vaccines to the skin. However, the effect of MN geometry/array design on antibody production is still unclear. Reports suggest that systemic immune responses may be affected by how MN arrays “mechanically” deliver vaccines, which can induce cell damage and act as an adjuvant. This includes parameters such as MN length/insertion depth, delivery energy/velocity, MN shape, and density. However, these effects have not been systematically investigated. Herein, the effect of MN density on antibody responses to influenza vaccination is assessed, keeping all other variables constant. MN arrays are manufactured within the “high‐density range” from 5 k microneedles cm−2 (n cm−2) to the “ultrahigh” 30 k n cm−2. Prior to this study, the highest MN density used for vaccination is 20 k n cm−2. Thus, MN array vaccination is evaluated over an unprecedented range. Cell viability is assessed in the skin after application and antibody responses at days 21/63. It is demonstrated that increasing MN density from 5 to 30 k n cm−2 increases both epidermal cell death and anti‐influenza IgG1, without an increase in anti‐influenza IgG2a. This suggests that MN density has a direct adjuvant effect on immune responses through Th2‐mediated signalling—a response critical for human vaccination.

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Induction of potent CD8+ T cell responses through the delivery of subunit protein vaccines to skin antigen-presenting cells using densely packed microprojection arrays

Cited by 40 publications

References 75 publications

Hollow microneedle-mediated intradermal delivery of model vaccine antigen-loaded PLGA nanoparticles elicits protective T cell-mediated immunity to an intracellular bacterium

Hollow microneedle-mediated intradermal delivery of model vaccine antigen-loaded PLGA nanoparticles elicits protective T cell-mediated immunity to an intracellular bacterium

Investigation of cell death caused by the Nanopatch™ and its role in vaccine delivery as a physical immune enhancer

An Ultrahigh‐Density Microneedle Array for Skin Vaccination: Inducing Epidermal Cell Death by Increasing Microneedle Density Enhances Total IgG and IgG1 Immune Responses

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