A cationic vaccine adjuvant based on a saturated quaternary ammonium lipid have different in vivo distribution kinetics and display a distinct CD4 T cell-inducing capacity compared to its unsaturated analog

Dennis Christensen, Malou Henriksen-Lacey, Arun T. Kamath, Thomas Lindenstrøm, Karen S. Korsholm, Jan P. Christensen, Anne-Francoise Rochat, Paul-Henri Lambert, Peter Andersen, Claire-Anne Siegrist, Yvonne Perrie, Else Marie Agger

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Adjuvants are often composed of different constituents that can be divided into two groups based on their primary activity: the delivery system which carries and presents the vaccine antigen to antigen-presenting cells, and the immunostimulator that activates and modulates the ensuing immune response. Herein, we have investigated the importance of the delivery system and in particular its physical characteristics by comparing the delivery properties of two lipids which differ only in the degree of saturation of the acyl chains, rendering the liposomes either rigid (DDA, dimethyldioctadecylammonium) or highly fluid (DODA, dimethyldioleoylammonium) at physiological temperature. We show that these delivery systems are remarkably different in their ability to prime a Th1-directed immune response with the rigid DDA-based liposomes inducing a response more than 100 times higher compared to that obtained with the fluid DODA-based liposomes. Upon injection with a vaccine antigen, DDA-based liposomes form a vaccine depot that results in a continuous attraction of antigen-presenting cells that engulf a high amount of adjuvant and are subsequently efficiently activated as measured by an elevated expression of the co-stimulatory molecules CD40 and CD86. In contrast, the fluid DODA-based liposomes are more rapidly removed from the site of injection resulting in a lower up-regulation of co-stimulatory CD40 and CD86 molecules on adjuvant-positive antigen-presenting cells. Additionally, the vaccine antigen is readily dissociated from the DODA-based liposomes leading to a population of antigen-presenting cells that are antigen-positive but adjuvant-negative and consequently are not activated. These studies demonstrate the importance of studying in vivo characteristics of the vaccine components and furthermore show that physicochemical properties of the delivery system have a major impact on the vaccine-induced immune response.

LanguageEnglish
Pages468-476
Number of pages9
JournalJournal of Controlled Release
Volume160
Issue number3
DOIs
Publication statusPublished - 28 Jun 2012

Fingerprint

Ammonium Compounds
Liposomes
Vaccines
Antigen-Presenting Cells
T-Lymphocytes
Lipids
Antigens
Injections
Up-Regulation
Temperature
Population
dimethyldioctadecylammonium

Keywords

  • dimethyldioctadecylammonium
  • DDA
  • DODA
  • dimethyldioleoylammonium
  • adjuvant
  • depot effect

Cite this

Christensen, Dennis ; Henriksen-Lacey, Malou ; Kamath, Arun T. ; Lindenstrøm, Thomas ; Korsholm, Karen S. ; Christensen, Jan P. ; Rochat, Anne-Francoise ; Lambert, Paul-Henri ; Andersen, Peter ; Siegrist, Claire-Anne ; Perrie, Yvonne ; Agger, Else Marie. / A cationic vaccine adjuvant based on a saturated quaternary ammonium lipid have different in vivo distribution kinetics and display a distinct CD4 T cell-inducing capacity compared to its unsaturated analog. In: Journal of Controlled Release. 2012 ; Vol. 160, No. 3. pp. 468-476.
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title = "A cationic vaccine adjuvant based on a saturated quaternary ammonium lipid have different in vivo distribution kinetics and display a distinct CD4 T cell-inducing capacity compared to its unsaturated analog",
abstract = "Adjuvants are often composed of different constituents that can be divided into two groups based on their primary activity: the delivery system which carries and presents the vaccine antigen to antigen-presenting cells, and the immunostimulator that activates and modulates the ensuing immune response. Herein, we have investigated the importance of the delivery system and in particular its physical characteristics by comparing the delivery properties of two lipids which differ only in the degree of saturation of the acyl chains, rendering the liposomes either rigid (DDA, dimethyldioctadecylammonium) or highly fluid (DODA, dimethyldioleoylammonium) at physiological temperature. We show that these delivery systems are remarkably different in their ability to prime a Th1-directed immune response with the rigid DDA-based liposomes inducing a response more than 100 times higher compared to that obtained with the fluid DODA-based liposomes. Upon injection with a vaccine antigen, DDA-based liposomes form a vaccine depot that results in a continuous attraction of antigen-presenting cells that engulf a high amount of adjuvant and are subsequently efficiently activated as measured by an elevated expression of the co-stimulatory molecules CD40 and CD86. In contrast, the fluid DODA-based liposomes are more rapidly removed from the site of injection resulting in a lower up-regulation of co-stimulatory CD40 and CD86 molecules on adjuvant-positive antigen-presenting cells. Additionally, the vaccine antigen is readily dissociated from the DODA-based liposomes leading to a population of antigen-presenting cells that are antigen-positive but adjuvant-negative and consequently are not activated. These studies demonstrate the importance of studying in vivo characteristics of the vaccine components and furthermore show that physicochemical properties of the delivery system have a major impact on the vaccine-induced immune response.",
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author = "Dennis Christensen and Malou Henriksen-Lacey and Kamath, {Arun T.} and Thomas Lindenstr{\o}m and Korsholm, {Karen S.} and Christensen, {Jan P.} and Anne-Francoise Rochat and Paul-Henri Lambert and Peter Andersen and Claire-Anne Siegrist and Yvonne Perrie and Agger, {Else Marie}",
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Christensen, D, Henriksen-Lacey, M, Kamath, AT, Lindenstrøm, T, Korsholm, KS, Christensen, JP, Rochat, A-F, Lambert, P-H, Andersen, P, Siegrist, C-A, Perrie, Y & Agger, EM 2012, 'A cationic vaccine adjuvant based on a saturated quaternary ammonium lipid have different in vivo distribution kinetics and display a distinct CD4 T cell-inducing capacity compared to its unsaturated analog' Journal of Controlled Release, vol. 160, no. 3, pp. 468-476. https://doi.org/10.1016/j.jconrel.2012.03.016

A cationic vaccine adjuvant based on a saturated quaternary ammonium lipid have different in vivo distribution kinetics and display a distinct CD4 T cell-inducing capacity compared to its unsaturated analog. / Christensen, Dennis; Henriksen-Lacey, Malou; Kamath, Arun T.; Lindenstrøm, Thomas; Korsholm, Karen S.; Christensen, Jan P.; Rochat, Anne-Francoise; Lambert, Paul-Henri; Andersen, Peter; Siegrist, Claire-Anne; Perrie, Yvonne; Agger, Else Marie.

In: Journal of Controlled Release, Vol. 160, No. 3, 28.06.2012, p. 468-476.

Research output: Contribution to journalArticle

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T1 - A cationic vaccine adjuvant based on a saturated quaternary ammonium lipid have different in vivo distribution kinetics and display a distinct CD4 T cell-inducing capacity compared to its unsaturated analog

AU - Christensen, Dennis

AU - Henriksen-Lacey, Malou

AU - Kamath, Arun T.

AU - Lindenstrøm, Thomas

AU - Korsholm, Karen S.

AU - Christensen, Jan P.

AU - Rochat, Anne-Francoise

AU - Lambert, Paul-Henri

AU - Andersen, Peter

AU - Siegrist, Claire-Anne

AU - Perrie, Yvonne

AU - Agger, Else Marie

N1 - Copyright © 2012 Elsevier B.V. All rights reserved.

PY - 2012/6/28

Y1 - 2012/6/28

N2 - Adjuvants are often composed of different constituents that can be divided into two groups based on their primary activity: the delivery system which carries and presents the vaccine antigen to antigen-presenting cells, and the immunostimulator that activates and modulates the ensuing immune response. Herein, we have investigated the importance of the delivery system and in particular its physical characteristics by comparing the delivery properties of two lipids which differ only in the degree of saturation of the acyl chains, rendering the liposomes either rigid (DDA, dimethyldioctadecylammonium) or highly fluid (DODA, dimethyldioleoylammonium) at physiological temperature. We show that these delivery systems are remarkably different in their ability to prime a Th1-directed immune response with the rigid DDA-based liposomes inducing a response more than 100 times higher compared to that obtained with the fluid DODA-based liposomes. Upon injection with a vaccine antigen, DDA-based liposomes form a vaccine depot that results in a continuous attraction of antigen-presenting cells that engulf a high amount of adjuvant and are subsequently efficiently activated as measured by an elevated expression of the co-stimulatory molecules CD40 and CD86. In contrast, the fluid DODA-based liposomes are more rapidly removed from the site of injection resulting in a lower up-regulation of co-stimulatory CD40 and CD86 molecules on adjuvant-positive antigen-presenting cells. Additionally, the vaccine antigen is readily dissociated from the DODA-based liposomes leading to a population of antigen-presenting cells that are antigen-positive but adjuvant-negative and consequently are not activated. These studies demonstrate the importance of studying in vivo characteristics of the vaccine components and furthermore show that physicochemical properties of the delivery system have a major impact on the vaccine-induced immune response.

AB - Adjuvants are often composed of different constituents that can be divided into two groups based on their primary activity: the delivery system which carries and presents the vaccine antigen to antigen-presenting cells, and the immunostimulator that activates and modulates the ensuing immune response. Herein, we have investigated the importance of the delivery system and in particular its physical characteristics by comparing the delivery properties of two lipids which differ only in the degree of saturation of the acyl chains, rendering the liposomes either rigid (DDA, dimethyldioctadecylammonium) or highly fluid (DODA, dimethyldioleoylammonium) at physiological temperature. We show that these delivery systems are remarkably different in their ability to prime a Th1-directed immune response with the rigid DDA-based liposomes inducing a response more than 100 times higher compared to that obtained with the fluid DODA-based liposomes. Upon injection with a vaccine antigen, DDA-based liposomes form a vaccine depot that results in a continuous attraction of antigen-presenting cells that engulf a high amount of adjuvant and are subsequently efficiently activated as measured by an elevated expression of the co-stimulatory molecules CD40 and CD86. In contrast, the fluid DODA-based liposomes are more rapidly removed from the site of injection resulting in a lower up-regulation of co-stimulatory CD40 and CD86 molecules on adjuvant-positive antigen-presenting cells. Additionally, the vaccine antigen is readily dissociated from the DODA-based liposomes leading to a population of antigen-presenting cells that are antigen-positive but adjuvant-negative and consequently are not activated. These studies demonstrate the importance of studying in vivo characteristics of the vaccine components and furthermore show that physicochemical properties of the delivery system have a major impact on the vaccine-induced immune response.

KW - dimethyldioctadecylammonium

KW - DDA

KW - DODA

KW - dimethyldioleoylammonium

KW - adjuvant

KW - depot effect

U2 - 10.1016/j.jconrel.2012.03.016

DO - 10.1016/j.jconrel.2012.03.016

M3 - Article

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JO - Journal of Controlled Release

T2 - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

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ER -