Voie d'immunisation et séquence d'administration de l ... - TEL

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