Vaccine 19 (2001) 1373 – 1380 Immunostimulatory effect of IL-18-encoding plasmid in DNA vaccination against murine Schistosoma mansoni infection Loı ¨c Dupre ´ a, *, Laurent Kremer b , Isabelle Wolowczuk c , Gilles Riveau a , Andre ´ Capron a , Camille Locht b a Laboratoire des Relations Ho ˆtes -Parasite et Strate ´gies Vaccinales, INSERM U 167, Institut Pasteur de Lille, F -59019 Lille Cedex, France b Laboratoire de Microbiologie Ge ´ne ´tique et Mole ´culaire, INSERM U447, Institut Pasteur de Lille, F -59019 Lille Cedex, France c UMR CNRS 8527, Institut Pasteur de Lille, F -59019 Lille Cedex, France Received 31 May 2000; accepted 19 September 2000 Abstract In vivo delivery of DNA encoding antigens is a simple tool to induce immune responses against pathogens. This approach to vaccination also offers the possibility to codeliver plasmids encoding immunomodulatory molecules in order to drive immune responses towards optimal protective effects. In the murine model of Schistosoma mansoni infection, vaccination inducing a Th1 profile has been shown to be protective. In this study, we used a plasmid encoding the Th1-promoting cytokine IL-18, since we observed that percutaneous infection of Balb/c mice strongly induced the production of IL-18 mRNA in the skin. Intradermal injection of the IL-18-encoding plasmid prior to infection did not interfere with parasite migration through the skin although it led to a local and transient cellular infiltration. When the IL-18-encoding plasmid was codelivered with a S. mansoni glutathione S -transferase (Sm28GST)-encoding plasmid, a 30-fold increase of antigen-specific IFN- secretion by spleen cells was observed in comparison to spleen cells from mice that had received only the Sm28GST-encoding plasmid. This immunostimulatory effect was related to a significant protective effect (28% reduction in egg laying and 23% reduction in worm burden) which was attributed to a cooperative effect between both plasmids. Therefore, this study shows that codelivery of an IL-18-encoding plasmid with an antigen-encoding plasmid can stimulate specific cellular responses and induce protective effects against S. mansoni infection. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: DNA vaccination; IL-18; Schistosoma mansoni www.elsevier.com/locate/vaccine 1. Introduction The development of vaccine strategies against para- site infections represents a difficult and exciting chal- lenge particularly because of the complexity of the life cycles of parasites within their hosts and because of the complexity of the immune responses they elicit. In Schistosoma mansoni infections, the parasite larvae (cer- cariae) enter the body by active penetration through the skin and reach the lungs via the systemic circulation within a few days [1]. In the lungs, the young parasites (schistosomula) undergo morphological transforma- tions and in approximately 2 weeks, start to gather in the portal system where they mature into adult worms. In the murine model, infection first induces a Th1 type immune response (generally characterized by the secre- tion of IFN- and IL-12). After the onset of egg laying, a radical shift towards a Th2 type immune response occurs (generally characterized by the secretion of IL-4 and IL-10) [2]. S. mansoni eggs are only partially ex- creted via the feces and numerous eggs are trapped in the liver and the intestine, where they induce granu- loma formation and fibrosis which are at the origin of the pathology. In an effort to reduce the infection intensity before the development of egg-induced pathology, a possible approach would be to strengthen the immune responses naturally occurring early in the infection. This ap- proach was used successfully by co-administering IL- 12, a cytokine capable of promoting a Th1 response, as * Corresponding author. Present address: Telethon Institute for Gene Therapy, San Raffaele Biomedical Science Park, via Olgettina 58, 20132 Milan, Italy. Tel.: +39-2-21277212; fax: +39-2-26434668. 0264-410X/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII:S0264-410X(00)00363-7