Vaccine 19 (2001) 4363–4372 Review Towards the rational design of Th1 adjuvants P. Moingeon *, J. Haensler, A. Lindberg Aentis Pasteur, Department of Research and Deelopment, Campus Me ´rieux, 1541 aenue Marcel Me ´rieux, 69280 Marcy l’Etoile, France Received 26 February 2001; received in revised form 17 May 2001; accepted 22 May 2001 Abstract Finding adjuvants in order to enhance immune responses against target immunogens has been a major and recurrent issue for the vaccine industry. It is yet to be solved, most particularly in the context of a growing interest in designing new types of vaccines capable of eliciting Th1 immune responses. A review of synthetic adjuvants which have been (or are being) tested in clinical studies is presented. Importantly, recent advances in our understanding of the physiology of immune responses offer new avenues to design and test candidate adjuvants, based on either synthetic or natural molecules, with the aim to mimic and recapitulate pro-inflammatory signals initiating both innate and adaptative immune effector mechanisms. Thus, adjuvants of the future might be a mixture of molecules selected singularly for a capacity to attract, target or activate professional antigen presenting cells. Used as a combination, such molecules should facilitate antigen presentation by professional APCs and lead to a potent induction of T cell-mediated effector and immune memory mechanisms. © 2001 Published by Elsevier Science Ltd. Keywords: Adjuvant; Vaccine design; Th1 response www.elsevier.com/locate/vaccine 1. Why do we need new adjuvants? Conventional vaccines based on either inactivated pathogens, live attenuated pathogens and, more re- cently, subcellular components such as purified capsular polysaccharides isolated from bacteria, virus proteins, or recombinant proteins, have been successfully used to induce neutralizing antibodies against surface molecules in order to prevent infection. To this aim, adjuvant preparations containing aluminum salts (Alum) have been used to adsorb bacterial or viral antigens [1]. In such formulations both electrostatic and hydrophobic interactions were shown to contribute to the adsorption of antigens onto aluminium-based adjuvants [2]. Expec- tations for new vaccines have changed dramatically in recent years. Vaccines based on live attenuated or inac- tivated pathogens might still have a role to play in the future of vaccination. However, in the context of a tougher regulatory environment, most experimental vaccines which are currently being tested in humans are based on recombinant viruses, recombinant proteins, DNA, purified subunits, peptides, etc., targeting well- identified antigens. Changes in the nature of vaccine components and routes of administration are imposing a need for new adjuvants to be developed. There is also now a major interest in designing vaccines capable of eliciting strong cellular immune responses of the Th1 type. The latter encompasses both the induction of cytotoxic and Th1 helper cellular responses leading to the activation of immune effector mechanisms, as well as the production of immuno-stimulatory cytokines such as -interferon. The induction of such Th1 re- sponses is for example highly desirable for vaccines targeting either chronic viral diseases, infections linked to intracellular pathogens or cancer (therapeutic vac- cines) [3]. In addition, induction by vaccines of local (e.g. mucosal) or polarized (i.e. Th1 or Th2) immune responses is needed in a number of circumstances. An additional requirement is that adjuvants should not elicit unacceptable local reactions, when used as part of prophylactic vaccines, but also of therapeutic vaccines. Abbreiations: APC, antigen presenting cell(s); DC, dendridic cell(s); LPS, lipopolysaccharide; TLR, Toll-like receptor(s). * Corresponding author. Tel.: +33-4-3737-3807; fax: +33-4-3737- 3582. E-mail address: philippe.moingeon@aventis.com (P. Moingeon). 0264-410X/01/$ - see front matter © 2001 Published by Elsevier Science Ltd. PII: S0264-410X(01)00193-1