Abstract
The development of lipopeptides (lipidated peptides) for vaccines is discussed, including their role as antigens and/or adjuvants. Distinct classes of lipopeptide architectures are covered including simple linear and ligated constructs and lipid core peptides. The design, synthesis, and immunological responses of the important class of glycerol-based Toll-like receptor agonist lipopeptides such as Pam3CSK4, which contains three palmitoyl chains and a CSK4 hexapeptide sequence, and many derivatives of this model immunogenic compound are also reviewed. Self-assembled lipopeptide structures including spherical and worm-like micelles that have been shown to act as vaccine agents are also described. The work discussed includes examples of lipopeptides developed with model antigens, as well as for immunotherapies to treat many infectious diseases including malaria, influenza, hepatitis, COVID-19, and many others, as well as cancer immunotherapies. Some of these have proceeded to clinical development. The research discussed highlights the huge potential of, and diversity of roles for, lipopeptides in contemporary and future vaccine development.
Highlights
Vaccination has been a highly successful life-saving method to prevent viral infections, since its development by Jenner in 1796 to treat smallpox, which has been eradicated
The roles of lipopeptides as antigens and/or adjuvants is the focus of the current Review, and it includes the important class of self-adjuvanting lipopeptides, which incor
The architecture with pendant PamnCSS linked via the ε-amine group of lysine (Scheme 9) is most effective in stimulating dendritic cells (DCs) maturation via TLR2.104 This was confirmed in a study using lipopeptides with this architecture bearing a Th sequence ALNNRFQIKGVELKS from influenza hemeagglutinin that elicits CD4+ T cells and a CTL peptide epitope TYQRTRALV, i.e., NP147−155, derived from the nucleoprotein of the influenza virus which is the dominant CD8+ T cell epitope recognized by BALB/c mice in all type A influenza strains.[104]
Summary
Vaccination has been a highly successful life-saving method to prevent viral infections, since its development by Jenner in 1796 to treat smallpox, which has been eradicated. Later developments include oil-in-water emulsions such as Freund’s complete adjuvant which contains heat-killed Mycobacterium tuberculosis (incomplete Freund’s adjuvant lacks the mycobacteria) or squalene oil-in-water emulsions AS03 or MF59 (squalene is more readily metabolized than paraffin, used in Freund’s adjuvants).[21,22] Alum and emulsion adjuvants are generally considered to have good safety profiles.[21,30,31] Freund’s aduvant contains many innate immune stimulants and can cause side serious effects; use of both Freund’s complete and incomplete adjuvants was discontinued for this reason.[22,31−33] Organic adjuvants such as those based on peptides, proteins, lipids, polysaccharides, and lipopeptides offer scope to tailor more specific immune responses and are the focus of considerable interest in the development of new vaccines.
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