Self-Adjuvanting Lipopeptide Vaccines

Abstract

Despite the important role of adjuvants for vaccine development, relatively few adjuvants have been successfully incorporated into vaccines intended for human administration. This is in part due to the high toxicity associated with many experimental adjuvants. This lack of choice effectively hinders the ability to produce vaccines against many diseases, or to improve current vaccine formulations. The conjugation of immunostimulatory lipids to peptide antigens, to produce self-adjuvanting lipopeptide vaccines, has been tested in human clinical trials. These systems appear to have a number of advantages over more traditional adjuvants (e.g. alum salts) including the capacity for these vaccines to be administered via mucosal routes (e.g. orally or nasally) instead of by injection, elicitation of antigen-specific cytotoxic T-lymphocytes and mucosal immunity, as well as little-to-no observed toxicity. Several lipopeptide vaccine systems have been described in the literature, ranging from the conjugation of single fatty acid chains, to the conjugation of more complex lipids and glycolipids onto peptide antigens. The following review provides an overview of the most studied lipopeptide vaccine systems grouped into the following categories: 1) bacterial lipopeptides, including tri-palmitoyl-S-glyceryl cysteine (Pam3Cys) and di-palmitoyl-S--glyceryl cysteine (Pam2Cys); 2) the lipid-core peptide (LCP) and multiple antigen lipophilic adjuvant carrier (MALAC) systems; 3) single-chain palmitoylated peptides; and 4) glycolipids (e.g. monophosphoryl lipid A). The review also discusses the potential mechanisms of action for lipopeptide and glycolipopeptide vaccines, as well as structure activity relationships, and provides examples of studies utilising each system.

The Dual Role of Lipids of the Lipoproteins in Trumenba, a Self-Adjuvanting Vaccine Against Meningococcal Meningitis B Disease

“…The mechanism for the immune-enhancing effect studied with other bacterial lipopeptides and lipoproteins suggests lipoprotein recognition of TLR receptors on cells of the innate immune system (20)(21)(22)(23). In this study, the interactions of rLP2086 with TLR2 and/or TLR2/TLR1 complexes on cell surfaces, and the subsequent cell activation, were confirmed using HEK293 hTLR2 cells that express human TLR2 and TLR1.…”

“…This effect was enabled by induction of neutralizing antibodies (28,29) and by in vivo priming of epitope-specific cytotoxic T cells and memory T cells (30)(31)(32). Since antibodies to the lipid moieties are not generated in vivo, the immune-enhancing effect of the lipids is believed to be similar to that of a conventional adjuvant, and thus, bacterial lipoprotein/lipopeptidecontaining vaccines are recognized as one category of selfadjuvanting vaccines (21)(22)(23)33). Other categories include lipid-core peptides, single-chain palmitoylated peptides, and glycolipid analogues of bacterial lipopolysaccharides (21).…”

“…It was perceived in early days that the lipids simply anchor the lipoproteins/lipopeptides to the surface membrane of immune cells to facilitate the internalization. Recent research suggested that the lipid moieties interact with various TLRs, a type of membranebound pattern recognition receptors (PRRs), to drive the endocytosis of the lipoproteins by antigen-presenting cells (34) and induce various immune responses (21,22,32). PRR is a key component of the innate immune system to identify pathogen-associated molecular patterns (PAMPs) (35).…”

Advances in Peptide-based Human Papillomavirus Therapeutic Vaccines

“…Another strategy to enhance the potency of peptide-based vaccines is the conjugation of immunostimulatory lipids to a peptide antigen. Lipidic carriers have been used extensively for vaccine delivery and can act as self-adjuvanting moieties [108][109][110][111]. The lipid core peptide (LCP), a vaccine delivery system incorporating lipoamino acids, was used to produce vaccine candidates against HPV-16 [104].…”

Active immunisation of mice with GnRH lipopeptide vaccine candidates: Importance of T helper or multi-dimer GnRH epitope

“…The lipid moieties in the lipopeptide system serve to mimic the action of bacterial adjuvants such as Pam 3 Cys and Pam 2 Cys. 21 Lipopeptide constructs have been found to mediate significant immunogenic effects without additional adjuvants. 22,23 The development of a GnRH-based subunit lipopeptide vaccine for use as an immunocontraceptive therapy has previously received attention.…”