Colocalization of Cell Death with Antigen Deposition in Skin Enhances Vaccine Immunogenicity

Depelsenaire, Alexandra C. I.; Meliga, Stefano C.; McNeilly, Celia L.; Pearson, Frances E.; Coffey, Jacob W.; Haigh, Oscar; Flaim, C.; Frazer, Ian H.; Kendall, M. A. F.

doi:10.1038/jid.2014.174

Cited by 87 publications

(130 citation statements)

References 53 publications

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“…However, skin immunization has not been broadly adopted to date, due to lack of safe adjuvants and technical difficulties in injecting vaccines into the ultrathin (<2 mm) skin tissue (3,4). We have demonstrated that controllable skin injury can serve as safe "adjuvant" for cutaneous vaccination and similar observations have been also made by other investigators (5)(6)(7). Treatment of the inoculation site with nonablative fractional laser (NAFL) generates an array of microthermal zones (MTZs) beneath the stratum corneum (8).…”

supporting

confidence: 77%

Effective and lesion-free cutaneous influenza vaccination

Wang

2015

Proc. Natl. Acad. Sci. U.S.A.

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The current study details efficient lesion-free cutaneous vaccination via vaccine delivery into an array of micropores in the skin, instead of bolus injection at a single site. Such delivery effectively segregated vaccine-induced inflammation, resulting in rapid resolution of the inflammation, provided that distances between any two micropores were sufficient. When the inoculation site was treated by FDA-approved nonablative fractional laser (NAFL) before insertion of a PR8 model influenza vaccine-packaged, biodegradable microneedle array (MNs), mice displayed vigorous antigenuptake, eliciting strong Th1-biased immunity. These animals were completely protected from homologous viral challenges, and fully or partially protected from heterologous H1N1 and H3N2 viral challenges, whereas mice receiving MNs alone suffered from severe illnesses or died of similar viral challenges. NAFL-mediated adjuvanicity was ascribed primarily to dsDNA and other "danger" signals released from laser-damaged skin cells. Thus, mice deficient in dsDNA-sensing pathway, but not Toll like receptor (TLR) or inflammasome pathways, showed poor responses to NAFL. Importantly, with this novel approach both mice and swine exhibited strong protective immunity without incurring any appreciable skin irritation, in sharp contrast to the overt skin irritation caused by intradermal injections. The effective lesion-free cutaneous vaccination merits further clinical studies.biodegradable microneedle | nonablative fractional laser | dsDNA S ubstantial evidence has shown that skin is a more potent site for vaccination than muscle because the former contains a large number of antigen presenting cells (APCs) and abundant network of lymphatic vessels. Moreover, skin offers potential for painless, needle-free, and self-applicable immunization, which would particularly benefit annual influenza vaccination of large populations (1, 2). However, skin immunization has not been broadly adopted to date, due to lack of safe adjuvants and technical difficulties in injecting vaccines into the ultrathin (<2 mm) skin tissue (3,4). We have demonstrated that controllable skin injury can serve as safe "adjuvant" for cutaneous vaccination and similar observations have been also made by other investigators (5-7). Treatment of the inoculation site with nonablative fractional laser (NAFL) generates an array of microthermal zones (MTZs) beneath the stratum corneum (8). The dying cells in the MTZs release "danger" signals that provoke sterile inflammation that is however constrained within individual MTZs. This array of microsterile inflammatory zones is resolved quickly, effectively averting skin lesion, provided that affected and unaffected areas of the skin are adequately balanced (8). Importantly, despite fast resolution, the microinflammation zones prove sufficient in augmentation of adaptive immune responses against the vaccine (5). In addition, this standalone adjuvant does not affect the volume of administration or formulation of the vaccine, which are serious hurdles for...

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supporting

confidence: 77%

Effective and lesion-free cutaneous influenza vaccination

Wang

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…This finding correlated well with the results presented in this doctoral thesis [344]. Cell death resulting from ballistic delivery of micro-particles to the skin was recently reported [242].…”

Section: Adjuvants and Cell Deathsupporting

confidence: 91%

“…(Figure 4.5), and more antigen co-localised with dead cells following NP than i.d. immunisations (Figure 7.4) [344]. However, it was not clear whether co-localisation of antigen with dead cells interspersed with live cells was essential for enhanced antibody production.…”

Section: Co-localising Nanopatch™-mediated Cell Death Adjacent Live mentioning

confidence: 99%

“…Lastly, while some MN vaccine delivery techniques use commercially available vaccines [309,344,345] or some with minor reformulation of the vaccine through adding a vaccine stabiliser, e.g. trehalose [296,346,347]), it is likely that these changes may require pre-clinical, and clinical device that could affect their translation into humans.…”

Section: Hollow Microneedlesmentioning

confidence: 99%

“…Based on published acceptability data of 750 µm long steel MNs applied to human study subjects [273], the NP is likely to be well tolerated based on the shorter NP projection length, unlikely to reach nerve endings in the human dermis triggering pain. Initially designed to deliver antigen and other molecules to target specifically the APCs within the VE and dermis based on probabilistic models [345], more recent evidence however suggests that additional factors other than APCs are essential for improved immune responses [344]. Specifically, that a combination between cell death inflicted by the projections, co-localising with antigen, danger signals and live cells [344] and possibly increased dermal antigen delivery to dDCs (unpublished observations) are favourable in mounting enhanced immune responses when compared with i.d.…”

Section: The Nanopatch™mentioning

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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Lytic Polyplex Vaccines Enhance Antigen‐Specific Cytotoxic T Cell Response through Induction of Local Cell Death

Peeler

Yen

Luera

et al. 2021

Advanced Therapeutics

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Endosomolytic vaccine nanocarriers can potentiate cellular immune responses by enhancing cross-presentation. A cationic polymer-lytic peptide conjugate (VIPER) that greatly improves endosomal escape and intracellular activity of nucleic acid cargoes is recently developed; furthermore, it is hypothesized that VIPER's unique mechanism of endosomal disruption can increase cytoplasmic delivery of other biomacromolecules (e.g., peptides). Herein, VIPER is formulated as a polyplex subunit vaccine composed of conjugated peptide antigens and electrostatically complexed poly(I:C) nucleic acid adjuvant and is evaluated to determine whether the presence of the lytic peptide melittin conjugated to the pH-responsive micelle core improves vaccination outcomes. Although VIPER delivers peptide antigens intracellularly, disrupts endosomes in antigen-presenting cells (APCs) in vitro, and generates strong antigen-specific cytotoxic T cell responses in vivo, significantly enhanced cross-presentation is only observed in conjunction with VIPER-induced local cell death. While these results demonstrate that VIPER is a useful platform technology for the study of vaccine delivery, full elucidation of how endosomal disruption by VIPER improves vaccination outcomes will require decoupling of endosomolysis from cytotoxicity, as well as precise targeting of VIPER vaccine formulations to APC populations in vivo.

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Colocalization of Cell Death with Antigen Deposition in Skin Enhances Vaccine Immunogenicity

Cited by 87 publications

References 53 publications

Effective and lesion-free cutaneous influenza vaccination

Effective and lesion-free cutaneous influenza vaccination

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

Lytic Polyplex Vaccines Enhance Antigen‐Specific Cytotoxic T Cell Response through Induction of Local Cell Death

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