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Infection and Immunity, September 2003, p. 5210-5218, Vol. 71, No. 9
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.9.5210-5218.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Liposomal Meningococcal B Vaccination: Role of Dendritic Cell Targeting in the Development of a Protective Immune Response

Carmen Arigita,1,2 Lisette Bevaart,3 Linda A. Everse,1 Gerben A. Koning,1 Wim E. Hennink,1 Daan J. A. Crommelin,1 Jan G. J. van de Winkel,3 Martine J. van Vugt,3 Gideon F. A. Kersten,2 and Wim Jiskoot1*

Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University,1 Immunotherapy Laboratory, Department of Immunology, University Medical Center Utrecht, Utrecht,3 Laboratory for Product and Process Development, Netherlands Vaccine Institute, Bilthoven, The Netherlands2

Received 14 March 2003/ Returned for modification 1 May 2003/ Accepted 20 June 2003

The effect of targeting strategies for improving the interaction of liposomal PorA with dendritic cells (DC) on the immunogenicity of PorA was investigated. PorA, a major antigen of Neisseria meningitidis, was purified and reconstituted in different types of (targeted) liposomes, i.e., by using mannose or phosphatidylserine as targeting moieties, or with positively charged liposomes. We studied the efficiency of liposome uptake and its effect on the maturation of and interleukin 12 (IL-12) production by murine DC. Moreover, mice were immunized subcutaneously to study the localization and immunogenicity of PorA liposomes. Uptake of liposomes by DC was significantly increased for targeted liposomes and resulted in the maturation of DC, but to various degrees. Maturation markers (i.e., CD80, CD86, major histocompatibility complex class II, and CD40) showed enhanced expression on DC incubated with targeted PorA liposomes relative to those incubated with nontargeted PorA liposomes. Moreover, only the uptake of targeted PorA liposomes induced production of IL-12 by DC, with levels similar to those produced by lipopolysaccharide (LPS)-pulsed DC. Mannose-targeted PorA liposomes administered subcutaneously had an increased localization in draining lymph nodes compared to nontargeted PorA liposomes. Liposomes in draining lymph nodes interacted preferentially with antigen-presenting cells, an effect that was enhanced with targeted PorA liposomes. Immunization studies showed an improvement of the bactericidal antibody response (i.e., increased number of responders) generated by targeted PorA liposomes compared to that generated by nontargeted ones or LPS-containing outer membrane vesicles. In conclusion, the use of targeted PorA liposomes results in an improved uptake by and activation of DC and an increased localization in draining lymph nodes. These effects correlate with an enhanced immune response toward the vaccine.

* Corresponding author. Mailing address: Department of Pharmaceutics, Utrecht University, P.O. Box 80082 3508 TB Utrecht, The Netherlands. Phone: 31-30-253-69-70. Fax: 31-30-251-78-39. E-mail: W.Jiskoot{at}pharm.uu.nl.

Editor: J. N. Weiser

Infection and Immunity, September 2003, p. 5210-5218, Vol. 71, No. 9
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.9.5210-5218.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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