Carbohydrate vaccines: developing sweet solutions to sticky situations?

Abstract

Recent technological advances in glycobiology and glycochemistry are paving the way for a new era in carbohydrate vaccine design. This is enabling greater efficiency in the identification, synthesis and evaluation of unique glycan epitopes found on a plethora of pathogens and malignant cells. Here, we review the progress being made in addressing challenges posed by targeting the surface carbohydrates of bacteria, protozoa, helminths, viruses, fungi and cancer cells for vaccine purposes.

Figure 1. A diverse array of disease-causing agents and glycan antigens are targeted by existing and developmental carbohydrate vaccines

Bacteria: capsular polysaccharide repeats associated with particular species (and serotypes). Fungi: β-glucan (Candida, Cryptococcus and Aspergillus), β-mannan (Candida), common GXM motifs for serotypes A-D (Cryptococcus). Parasites: synthetic GPI motif (Plasmodium falciparum), common tyvelose-containing Ag (Trichinella), LDN(F) (Schistosoma), common LPG (Leishmania). Viruses: high mannose, GlcNAc₂Man₉ (HIV). Tumours: common glycan antigens associated with glycolipids (Globo H, Fucosyl GM1, Le^Y) and glycoproteins (TF, Le^Y, Tn, sTn and PSA) found on various malignant tissues, see Table 3. * Mannose residues may be 6O-acetylated.

Figure 2. Schematic representation of glycoconjugate immunogen design

Starting from activated glycans (* denotes activated group) from natural or synthetic sources, the production of three categories of glycoconjugate immunogens are shown: protein conjugates, lipid conjugates and polyvalent scaffold conjugates. The requirement for both polyvalent display and T helper epitopes, critical for achieving strong, long-lasting and class-switched Ab responses, are satisfied in each category. For protein conjugates, activated glycans are covalently attached to immunogenic protein carriers (e.g. KLH), which provide T helper epitopes and enable polyvalent display. Lipid conjugates, made by covalent linkage of activated glycans to T helper peptides attached to lipid moieties, allow polyvalency through formulation into lipid membranes. In addition, activated glycans may first be conjugated to synthetic polyvalent scaffolds (e.g. dendron, MAG and RAFT) which may then be used to make protein and lipid conjugates. Alternatively, polyvalent scaffold conjugates may be made through addition of T helper peptides alone. Adjuvants are usually included in the final glycoconjugate vaccine formulations (e.g. Alum and QS-21). Note: Pam₃Cys also has adjuvant properties. MAG: multiple antigen glycopeptides. RAFT: regioselectively addressable functionalized templates

Figure 3. Synthetic glycoconjugate immunogens

This figure shows examples of synthetic carbohydrate immunogens used in vaccine development. Hib: polyribosylribitol-TT (QuimiHib®); Candida: Man₃-TT; Plasmodium: GPI-KLH. HIV: Man₉ glycodendron BSA conjugate and Qβ-Man₉ (overall representations also depicted), GlcNAc₂Man₉ divalent glycopeptide OMPC conjugate (outer membrane protein complex, derived from N. meningitidis); Cancer: KLH-Globo H, KLH-clustered Tn, unimolecular pentavalent KLH conjugate.