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

tel-00827710, version 1 - 29 May 2013
we can suppose that co-administration with adjuvant would most likely be the optimal
formulation in this case.
1) Peptide vaccine
In agreement with our predictions, it is well established that adjuvant co-administered with
short peptides enhances the specific response. Indeed, uptake and processing of this antigen is
not the rate-limiting steps as peptide interacts directly with MHC molecule. Thus, it is
reasonable to assume that co-administration of antigen and adjuvant would be optimal (Table
6).
2) Protein vaccine
Protein or synthetic long peptides require endocytosis and processing prior to presentation.
This slight delay suggests that adjuvant should be delivered a short time after immunization.
An interesting comparison can be made concerning vaccination with the NY-ESO protein and
adjuvant for the treatment of melanoma patients. In a previous study, Nair and colleagues
demonstrated that injection of immature DCs into skin pretreated with the TLR7 agonist,
imiquimod, allowed a better activation of anti-tumor response compared to delivery of ex vivo
mature DCs into untreated skin (Nair et al., 2003). Following from these results, a clinical
trial was performed using NY-ESO protein injected locally in imiquimod-pretreated skin of
melanoma patients. However, in this case, only a limited CD4 + T cell response and no CD8 +
T cell responses were observed (Adams et al., 2008). In contrast, the same antigen injected
simultaneously with another adjuvant, CpG and formulated with Montanide gave much better
results (Valmori et al., 2007). This difference in the efficiency of the immune response may
be due to the different timing of adjuvant application. Pretreatment of skin with adjuvant prior
to immunization does not appear as the optimal timing for adjuvant delivery.
In the case of synthetic long peptides, there are ongoing trials that are examining the
feasibility of specific epitopes linked to TLR ligands, in order to favor the simultaneous
detection of antigen and the danger signal adjuvant.
Additionally, recent reports have highlighted that uptake of soluble antigens through
pinocytosis or receptor-mediated phagocytosis can be independent of DC maturation in some
cases (Drutman and Trombetta, 2010; Platt et al., 2010). Thus, some of the mechanisms of
adjuvant-mediated inhibition for cell-associated antigen (i.e. the inverse relationship between
DC maturation and antigen uptake ability) may not apply to mounting an immune response to
162