Intradermal Synthetic DNA Vaccination Generates Leishmania -Specific T Cells in the Skin and Protection against Leishmania major

Abstract

Vaccination remains one of the greatest medical breakthroughs in human history and has resulted in the near eradication of many formerly lethal diseases in many countries, including the complete eradication of smallpox. However, there remain a number of diseases for which there are no or only partially effective vaccines. There are numerous hurdles in vaccine development, of which knowing the appropriate immune response to target is one of them. Recently, tissue-resident T cells have been shown to mediate high levels of protection for several infections, although the best way to induce these cells is still unclear. Here we compare the ability to generate skin-resident T cells in sites distant from the immunization site following intramuscular and intradermal injection using optimized synthetic DNA vaccines. We found that mice immunized intradermally with a synthetic consensus DNA HIV envelope vaccine by electroporation (EP) are better able to maintain durable antigen-specific cellular responses in the skin than mice immunized by the intramuscular route. We extended these studies by delivering a synthetic DNA vaccine encoding Leishmania glycosomal phosphoenolpyruvate carboxykinase (PEPCK) by EP and again found that the intradermal route was superior to the intramuscular route for generating skin-resident PEPCK-specific T cells. We observed that when challenged with Leishmania major parasites, mice immunized intradermally exhibited significant protection, while mice immunized intramuscularly did not. The protection seen in intradermally vaccinated mice supports the viability of this platform not only to generate skin-resident T cells but also to promote durable protective immune responses at relevant tissue sites.

Intradermal delivery of a synthetic DNA vaccine protects macaques from Middle East respiratory syndrome coronavirus

“…This trend can be seen in this study with a MERS DNA vaccine (Figure 1), as well as in recent clinical studies of DNA vaccines targeting HIV (11) and Ebola (10). In addition, it could be that there is a different induction of T cell trafficking induced by ID vs IM immunization such as has recently been reported in a leishmania model system (22). One hypothesis is that different cell populations are transfected between the muscle (myocytes) and skin (keratinocytes, fibroblasts, dendritic-like cells, adipocytes, and potentially some myocytes)(23), resulting in different recruitment profiles for antigen presenting cells to the site of immunization.…”

Staphylococcus aureus-Specific Tissue-Resident Memory CD4+ T Cells Are Abundant in Healthy Human Skin

“…Most importantly, Tsrm cells contribute to localized protection against re-infection with cutaneous pathogens (4)(5)(6)(7)(8)(9). In addition, Trm cell development has been tracked in mice following vaccination and was positively correlated with vaccination efficacy (10)(11)(12)(13), making Trm cells a promising target for vaccination (14)(15)(16)(17)(18)(19).…”

Leishmania Immunity: Advancing Immunotherapy and Vaccine Development

“…Recently, Lumena et al showed that mice immunized intradermally with PEPCK were superior in generating skin-resident PEPCK-specific T cells when compared to mice immunized intramuscularly. They further observed that when challenged with Leishmania major parasites, intradermal immunization led to significant protection, which was not observed after intramuscular immunization [106].…”