TY - JOUR

T1 - The administration route is decisive for the ability of the vaccine adjuvant CAF09 to induce antigen-specific CD8(+) T-cell responses

T2 - The immunological consequences of the biodistribution profile

AU - Schmidt, Signe Tandrup

AU - Khadke, Swapnil

AU - Korsholm, Karen Smith

AU - Perrie, Yvonne

AU - Rades, Thomas

AU - Andersen, Peter

AU - Foged, Camilla

AU - Christensen, Dennis

N1 - Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

PY - 2016/8/26

Y1 - 2016/8/26

N2 - A prerequisite for vaccine-mediated induction of CD8(+) T-cell responses is the targeting of dendritic cell (DC) subsets specifically capable of cross-presenting antigen epitopes to CD8(+) T cells. Administration of a number of cationic adjuvants via the intraperitoneal (i.p.) route has been shown to result in strong CD8(+) T-cell responses, whereas immunization via e.g. the intramuscular (i.m.) or subcutaneous (s.c.) routes often stimulate weak CD8(+) T-cell responses. The hypothesis for this is that self-drainage of the adjuvant/antigen to the lymphoid organs, which takes place upon i.p. immunization, is required for the subsequent activation of cross-presenting lymphoid organ-resident CD8α(+) DCs. In contrast, s.c. or i.m. immunization usually results in the formation of a depot at the site of injection (SOI), which hinders the self-drainage and targeting of the vaccine to cross-presenting CD8α(+) DCs. We investigated this hypothesis by correlating the biodistribution pattern and the adjuvanticity of the strong CD8(+) T-cell inducing liposomal cationic adjuvant formulation 09 (CAF09), which is composed of dimethyldioctadecylammonium bromide/monomycoloyl glycerol liposomes with polyinosinic:polycytidylic acid electrostatically adsorbed to the surface. Biodistribution studies with radiolabeled CAF09 and a surface-adsorbed model antigen [ovalbumin (OVA)] showed that a significantly larger fraction of the vaccine dose localized in the draining lymph nodes (dLNs) and the spleen 6h after i.p. immunization, as compared to after i.m. immunization. Studies with fluorescently labelled OVA+CAF09 demonstrated a preferential association of OVA+CAF09 to DCs/monocytes, as compared to macrophages and B cells, following i.p. immunization. Administration of OVA+CAF09 via the i.p. route did also result in DC activation, whereas no DC activation could be measured within the same period with unadjuvanted OVA and OVA+CAF09 administered via the s.c. or i.m. routes. In the dLNs, the highest level of activated, cross-presenting CD8α(+) DCs was detected at 24h post immunization, whereas an influx of activated, migrating and cross-presenting CD103(+) DCs to the dLNs could be measured after 48h. This suggests that the CD8α(+) DCs are activated by self-draining OVA+CAF09 in the lymphoid organs, whereas the CD103(+) DCs are stimulated by the OVA+CAF09 at the SOI. These results support the hypothesis that the self-drainage of OVA+CAF09 to the draining LNs is required for the activation of CD8α(+) DCs, while the migratory CD103(+) DCs may play a role in sustaining the subsequent induction of strong CD8(+) T-cell responses.

AB - A prerequisite for vaccine-mediated induction of CD8(+) T-cell responses is the targeting of dendritic cell (DC) subsets specifically capable of cross-presenting antigen epitopes to CD8(+) T cells. Administration of a number of cationic adjuvants via the intraperitoneal (i.p.) route has been shown to result in strong CD8(+) T-cell responses, whereas immunization via e.g. the intramuscular (i.m.) or subcutaneous (s.c.) routes often stimulate weak CD8(+) T-cell responses. The hypothesis for this is that self-drainage of the adjuvant/antigen to the lymphoid organs, which takes place upon i.p. immunization, is required for the subsequent activation of cross-presenting lymphoid organ-resident CD8α(+) DCs. In contrast, s.c. or i.m. immunization usually results in the formation of a depot at the site of injection (SOI), which hinders the self-drainage and targeting of the vaccine to cross-presenting CD8α(+) DCs. We investigated this hypothesis by correlating the biodistribution pattern and the adjuvanticity of the strong CD8(+) T-cell inducing liposomal cationic adjuvant formulation 09 (CAF09), which is composed of dimethyldioctadecylammonium bromide/monomycoloyl glycerol liposomes with polyinosinic:polycytidylic acid electrostatically adsorbed to the surface. Biodistribution studies with radiolabeled CAF09 and a surface-adsorbed model antigen [ovalbumin (OVA)] showed that a significantly larger fraction of the vaccine dose localized in the draining lymph nodes (dLNs) and the spleen 6h after i.p. immunization, as compared to after i.m. immunization. Studies with fluorescently labelled OVA+CAF09 demonstrated a preferential association of OVA+CAF09 to DCs/monocytes, as compared to macrophages and B cells, following i.p. immunization. Administration of OVA+CAF09 via the i.p. route did also result in DC activation, whereas no DC activation could be measured within the same period with unadjuvanted OVA and OVA+CAF09 administered via the s.c. or i.m. routes. In the dLNs, the highest level of activated, cross-presenting CD8α(+) DCs was detected at 24h post immunization, whereas an influx of activated, migrating and cross-presenting CD103(+) DCs to the dLNs could be measured after 48h. This suggests that the CD8α(+) DCs are activated by self-draining OVA+CAF09 in the lymphoid organs, whereas the CD103(+) DCs are stimulated by the OVA+CAF09 at the SOI. These results support the hypothesis that the self-drainage of OVA+CAF09 to the draining LNs is required for the activation of CD8α(+) DCs, while the migratory CD103(+) DCs may play a role in sustaining the subsequent induction of strong CD8(+) T-cell responses.

U2 - 10.1016/j.jconrel.2016.08.034

DO - 10.1016/j.jconrel.2016.08.034

M3 - Journal article

C2 - 27574990

VL - 239

SP - 107

EP - 117

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

ER -