Electroporation as a vaccine delivery system and a natural adjuvant to intradermal administration of plasmid DNA in macaques

Biliana Todorova (1) , Lucille Adam (2) , Slobodan Culina (2) , Raphaël Boisgard (3) , Frédéric Martinon (2) , Antonio Cosma (2) , Mart Ustav (4) , Thierry Kortulewski (5) , Roger Le Grand (1) , Catherine Chapon (6, 1)

1 IMVA - U1184 - Immunologie des Maladies Virales et Autoimmunes
2 IMETI - Institut des Maladies Emergentes et des Thérapies Innovantes
3 SHFJ - Service Hospitalier Frédéric Joliot
4 Institute of Technology [Tartu, Estonia]
5 IRCM - Institut de Radiobiologie Cellulaire et Moléculaire
6 VRI - Vaccine Research Institute [Créteil, France]

In vivo electroporation (EP) is used to enhance the uptake of nucleic acids and its association with DNA vaccination greatly stimulates immune responses to vaccine antigens delivered through the skin. However, the effect of EP on cutaneous cell behavior, the dynamics of immune cell recruitment and local inflammatory factors, have not been fully described. Here, we show that intradermal DNA vaccination combined with EP extends antigen expression to the epidermis and the subcutaneous skin muscle in non-human primates. In vivo fibered confocal microscopy and dynamic ex vivo imaging revealed that EP promotes the mobility of Langerhans cells (LC) and their interactions with transfected cells prior to their migration from the epidermis. At the peak of vaccine expression, we detected antigen in damaged keratinocyte areas in the epidermis and we characterized recruited immune cells in the skin, the hypodermis and the subcutaneous muscle. EP alone was sufficient to induce the production of pro-inflammatory cytokines in the skin and significantly increased local concentrations of Transforming Growth Factor (TGF)-alpha and IL-12. Our results show the kinetics of inflammatory processes in response to EP of the skin, and reveal its potential as a vaccine adjuvant. Among the various vaccination approaches against infectious diseases such as human immunodeficiency virus (HIV), deoxyribonucleic acid (DNA) vaccines have several advantages: they are easily produced, provide opportunities for molecular engineering, lack anti-vector immunity, and have the potential to promote both cellular and humoral immune responses 1. However, despite their high immunogenicity in murine models, DNA vaccines have shown poor efficacy in large animal models and humans 2. New strategies to improve DNA vaccines include the optimization of transcriptional control elements and codons 3-5 , the use of adjuvants, such as Toll-like receptor (TLR) ligands 6 , cytokine expressing plasmids 7-9 or apoptosis-based adjuvants 10-12 and the choice of an appropriate delivery system such as local electroporation (EP) 13-15. In particular, EP has been largely used to enhance plasmid DNA uptake and increase the number of antigen-producing cells 16, 17. In addition, EP modifies blood vessel permeability and facilitates leukocyte extrava-sation in the exposed area 18. However, the effects of EP on cutaneous antigen presenting cells (APCs) and on the dynamics of cell recruitment at the vaccine site have not been fully described. In a previous study, we demonstrated that intradermal (id) administration of the auxo-GTU ®-multiHIV plasmid (GTU for Gene Transport Unit) combined with noninvasive EP induces a strong and persistent poly-functional T-cell response in macaques 19. Here, we investigated the early events that occur in the skin and the 1 CEA-Université Paris Sud 11-INSERM U1184, DRF/Jacob/Immunology of Viral infections and Autoimmune Diseases (IMVA), IDMIT infrastructure, 92265, Fontenay-aux-Roses,

Domaines: Sciences du Vivant [q-bio]; Immunologie

Biliana Todorova, Lucille Adam, Slobodan Culina, Raphaël Boisgard, Frédéric Martinon, et al.. Electroporation as a vaccine delivery system and a natural adjuvant to intradermal administration of plasmid DNA in macaques. Scientific Reports, 2017, 7 (1), pp.4122. ⟨10.1038/s41598-017-04547-2⟩. ⟨inserm-02437890⟩