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tel-00827710, version 1 - 29 May 2013 2) In which circumstances does splenocyte engulfment occur? Figure 51. Intradermal versus intravenous injections: conditions of immunization. Differences between are highlighted in yellow: formation (i.d.) or absence (i.v.) of an antigen depot (1), damage associated with injection (i.d.) or not (i.v.) (2), different DC subsets involved (3), different levels of danger depending on where antigen is delivered (4). 146

tel-00827710, version 1 - 29 May 2013 (a) Depot formation after i.d. immunization When we injected bioluminescent splenocytes in vivo, we observed that they formed an antigen depot afer i.d. immunization at the site of injection, that persisted for several days (Figure 33). After i.v. immunization, such a depot was not observed. Previous studies have already demonstrated that the presence of a depot facilitates the development of a better immune response. Moreover, the antigen depot is a well-known characteristic of empirically developed adjuvants such as oil-in-water emulsions or aluminum salts, which may partially explain their effectiveness (Coffman et al., 2010). Finally proteins formulated with this kind of adjuvant or a protein anchored to a cell membrane are not dramatically different – a protein antigen in combination with lipids in both cases – with either cellular membrane or adjuvant, allowing for the formation of a depot. This depot formation and resulting antigen persistence could explain why a more robust cross-priming is observed upon i.d. immunization (Figure 51, (1)). (b) Tissue damage induced after i.d. immunization Inflammation can be induced at the site of injection (Figure 51, (2)): however, i.v. and i.d. immunizations would probably not trigger the same tissue damage and inflammation. As it is being delivered directly to the bloodstream, an intravenous injection should not induce as much inflammation. This is completely different for an intradermal immunization, in which the full volume of injection is pushed into an organized tissue, which is characterized by its structural integrity. Injection will lead to damage of the local tissues and capillaries, including the necrotic cell death of neighbouring cells. This type of damage would induce the release of danger signals, activation of immune cells within the skin and the initiation of a local inflammatory response. In fact, we can observe the skin visibly distending during i.d. injection. Interestingly adjuvants previously described as favoring the formation of a depot were recently “re-discovered”, as they were thought to maybe play a role also in inflammasome activation or induction of necrosis (Coffman et al., 2010). Because of these points, the i.d. route can be considered as a more inflammatory than i.v. injection. This observation can also be confirmed by the results obtained in DNA vaccination trials. Although exciting data were obtained in mouse models of DNA vaccination, the results in humans were disappointing. One justification of this inconsistency was the volume of injection used (Rice et al., 2008). The volume used in mice was relatively high probably allowing for increased transfection of host cells and, potentially, more damage at the site of infection leading to increased inflammatory responses, as discussed here. Unfortunately, the proportional volume was far too large to be used in humans and was reduced for clinical Page 147 of 256

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