Recent Advances in Design and Synthesis of Self-Adjuvanting Lipopeptide Vaccines Istvan Toth Æ Pavla Simerska Æ Yoshio Fujita Accepted: 15 August 2008 / Published online: 8 September 2008 Ó Springer Science+Business Media, LLC 2008 Abstract Synthetic lipopeptide vaccines are being increasingly investigated mainly because of the advantages they offer over traditional vaccines, including safety of use in humans, high specificity in eliciting immune responses, greater purity and large scale/cost-effective production capacity. Moreover, a number of lipopeptide vaccines designed to possess self-adjuvanting properties have been developed and tested in vitro and in vivo. Producing high levels of serum-specific antibodies against incorporated peptide epitopes, they are showing their potential as effective vaccine candidates without the need for a co- administered adjuvant and/or carrier protein, often associ- ated with undesirable effects in humans. This review presents recent insights on lipopeptide vaccine research and development, particularly on (1) the influence of the orientation of peptide epitopes and lipids on immune responses, (2) the use of carbohydrates for vaccine target- ing, adjuvanting or as peptide epitope carriers, and (3) synthetic approaches to highly pure, multi-epitopic vaccine molecules using native chemical ligation techniques. Incorporation of different types of antigens within the same lipopeptide construct could provide a lipopeptide vaccine candidate suitable for safe and effective mucosal admin- istration, which is a comfortable way of drug delivery. Keywords Vaccine Á Adjuvant Á Peptide Á Lipid Á Carbohydrate Introduction Preventive vaccines are widely acknowledged as effective protection providers against a wide range of diseases. However, the use of killed, inactivated or live-attenuated pathogens in traditional vaccines is often a source of problems, especially a risk of infections and inadequate immune responses. Subunit antigens such as glycoproteins, recombinant proteins, and synthetic peptides are more suitable for the development of effective and safe vaccines (Baldwin et al. 2008; Golovkin et al. 2007; Peduzzi et al. 2008; Singh et al. 2006). Unfortunately, they are less immunogenic than those employing attenuated microor- ganisms and require the co-administration of a powerful adjuvant (Arnon 1991; Kwissa et al. 2007). Even though adjuvants are available experimentally (e.g. complete Freund’s adjuvant, lipid A), only a few of them such as aluminium salt-based adjuvants are non-toxic and suitable for human use (Gupta et al. 1993; Gupta and Siber 1995; Guy 2007; Pashine et al. 2005). Resent research has focused on the development of synthetic peptide antigens conjugated to carrier proteins; although these systems allow the induction of strong immune responses, they are associated with undesirable effects, e.g. the production of antibodies against carrier proteins (Herzenberg et al. 1980; Schutze et al. 1985). Therefore, defining an appropriate carrier/adjuvant system that enhances both the immuno- genicity and stability of free antigenic, short peptides is one of the main challenges in the design and development of peptide vaccines. The lipidation of peptide antigens may improve their immunogenicity and offers long-lasting protection by activation of the antigen-presenting cells (APCs) and B- cells and stimulation of innate immunity via interaction with Toll-like receptor families expressed on the APCs. I. Toth (&) Á P. Simerska Á Y. Fujita School of Molecular and Microbial Sciences (SMMS), The University of Queensland, St Lucia 4072, QLD, Australia e-mail: i.toth@uq.edu.au 123 Int J Pept Res Ther (2008) 14:333–340 DOI 10.1007/s10989-008-9147-y