The administration route is decisive for the ability of the vaccine adjuvant CAF09 to induce antigen-specific CD8+ T-cell responses: the immunological consequences of the biodistribution profile

Signe Tandrup Schmidt; Swapnil Khadke; Karen Smith Korsholm; Yvonne Perrie; Thomas Rades; Peter Andersen; Camilla Foged; Dennis Christensen

doi:10.1016/j.jconrel.2016.08.034

The administration route is decisive for the ability of the vaccine adjuvant CAF09 to induce antigen-specific CD8⁺ T-cell responses: the immunological consequences of the biodistribution profile

Signe Tandrup Schmidt, Swapnil Khadke, Karen Smith Korsholm, Yvonne Perrie, Thomas Rades, Peter Andersen, Camilla Foged, Dennis Christensen

Strathclyde Institute Of Pharmacy And Biomedical Sciences

Research output: Contribution to journal › Article

20 Citations (Scopus)

Abstract

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 6 h 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 24 h post immunization, whereas an influx of activated, migrating and cross-presenting CD103⁺ DCs to the dLNs could be measured after 48 h. 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.

Language	English
Pages	107-117
Number of pages	11
Journal	Journal of Controlled Release
Volume	239
Early online date	26 Aug 2016
DOIs	10.1016/j.jconrel.2016.08.034
Publication status	Published - 10 Oct 2016

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CD8 Antigens

Ovalbumin

Vaccines

T-Lymphocytes

Immunization

Dendritic Cells

Drainage

Lymph Nodes

Antigens

Poly I-C

Injections

Liposomes

Epitopes

Monocytes

B-Lymphocytes

Spleen

Macrophages

Keywords

liposome
subunit vaccine
biodistribribution
cross-presentation
adjuvant
nanomedicine

Cite this

Schmidt, S. T., Khadke, S., Korsholm, K. S., Perrie, Y., Rades, T., Andersen, P., ... Christensen, D. (2016). The administration route is decisive for the ability of the vaccine adjuvant CAF09 to induce antigen-specific CD8⁺ T-cell responses: the immunological consequences of the biodistribution profile. Journal of Controlled Release, 239, 107-117. https://doi.org/10.1016/j.jconrel.2016.08.034

Schmidt, Signe Tandrup ; Khadke, Swapnil ; Korsholm, Karen Smith ; Perrie, Yvonne ; Rades, Thomas ; Andersen, Peter ; Foged, Camilla ; Christensen, Dennis. / The administration route is decisive for the ability of the vaccine adjuvant CAF09 to induce antigen-specific CD8⁺ T-cell responses : the immunological consequences of the biodistribution profile. In: Journal of Controlled Release. 2016 ; Vol. 239. pp. 107-117.

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abstract = "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 6 h 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 24 h post immunization, whereas an influx of activated, migrating and cross-presenting CD103+ DCs to the dLNs could be measured after 48 h. 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.",

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Schmidt, ST, Khadke, S, Korsholm, KS, Perrie, Y, Rades, T, Andersen, P, Foged, C & Christensen, D 2016, 'The administration route is decisive for the ability of the vaccine adjuvant CAF09 to induce antigen-specific CD8⁺ T-cell responses: the immunological consequences of the biodistribution profile' Journal of Controlled Release, vol. 239, pp. 107-117. https://doi.org/10.1016/j.jconrel.2016.08.034

The administration route is decisive for the ability of the vaccine adjuvant CAF09 to induce antigen-specific CD8⁺ T-cell responses : the immunological consequences of the biodistribution profile. / Schmidt, Signe Tandrup; Khadke, Swapnil; Korsholm, Karen Smith; Perrie, Yvonne; Rades, Thomas; Andersen, Peter; Foged, Camilla; Christensen, Dennis.

In: Journal of Controlled Release, Vol. 239, 10.10.2016, p. 107-117.

Research output: Contribution to journal › Article

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 - Journal of Controlled Release

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

PY - 2016/10/10

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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 6 h 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 24 h post immunization, whereas an influx of activated, migrating and cross-presenting CD103+ DCs to the dLNs could be measured after 48 h. 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 6 h 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 24 h post immunization, whereas an influx of activated, migrating and cross-presenting CD103+ DCs to the dLNs could be measured after 48 h. 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.

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KW - biodistribribution

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KW - adjuvant

KW - nanomedicine

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