Designing a new antifungal glycoconjugate vaccine

Abstract

Bacterial capsular polysaccharides have been used as effective vaccines for adults but infants and seniors respond poorly to these immunogens because pure polysaccharides are unable to activate T-cells resulting in antibodies of low affinity and poor immunological memory. These deficiencies are addressed by conjugate vaccines composed of bacterial polysaccharide covalently attached to protein carriers such as tetanus or diphtheria toxoids. These vaccines activate T-cells and have been hugely effective in reducing the incidence of dangerous infectious diseases such as bacterial meningitis in infants and adults. The methods of conjugation often produce conjugate vaccines that contain polysaccharides with several cross links to one or more protein carrier molecules. Synthesis of large oligosaccharides derivatized to achieve single site attachment to protein has established the minimal size of an oligosaccharide that is required to produce protective antibody. Several examples are described where such oligosaccharides range in size from 8 to 16 monosaccharides. A more limited set of examples show that protective antibodies may be elicited by conjugate vaccines composed of tri and tetrasaccharide epitopes. One example is the β-mannan present in the phosphomannan glycoprotein of Candida albicans. Reverse engineering a protective antibody that recognizes this oligosaccharide revealed that a disaccharide was the minimal epitope. Further epitope mapping by functional group modification established that the internal mannose residue of a disaccharide was involved in the most important antibody-disaccharide interactions. NMR binding studies in combination with homology modeling of the bound β-mannan antigen suggested an optimum oligosaccharide for inclusion in a conjugate vaccine. Several conjugate vaccines were developed to test these conclusions. Immunization of mice or rabbits with conjugates containing disaccharide or trisaccharide conjugated to immunogenic proteins followed by live challenge experiments showed that the vaccines reduced fungal burden. The results of these and other studies suggest new approaches to novel synthetic conjugate vaccines.

A Convergent Synthesis of 6‐O‐Branched β‐Glucan Oligosaccharides

“…[2] For antifungal vaccine development, the unique polysaccharides, [3] especially β-1,3-linked glucans (known as β-glucans), [4] on the surface of fungal cells are attractive antigens. [5] Studies have shown that β-glucans are not only exposed but also consistently expressed and highly conserved on the cell surface of all pathogenic fungi.…”

“…[5] Studies have shown that β-glucans are not only exposed but also consistently expressed and highly conserved on the cell surface of all pathogenic fungi. [6] It has also been shown that β-glucans could induce strong immune responses [4] and that a vaccine composed of natural β-glucans could engender effective protection against Candida albican and Aspergillus fumigatus infections in mouse. [7] In addition, the CRM 197 protein conjugates of β-glucan oligosaccharides have been revealed to elicit immune responses comparable to that induced by the conjugates of natural β-glucans, [8] demonstrating that the oligosaccharide analogs of natural β-glucans are useful for antifungal vaccine development.…”

6-O-Branched Oligo-β-glucan-Based Antifungal Glycoconjugate Vaccines

“…For antifungal vaccine development, polysaccharides, 7 such as β-glucans, 8, 9 in the cell wall glycocalyx of pathogenic fungi are attractive targets, 10 as they are exposed on cells and can elicit strong immune response. 8, 9 β-Glucans 7, 11 are a class of polysaccharides composed of ca .…”

From Immunologically Archaic to Neoteric Glycovaccines

“…Even though antibodies may discriminate very small molecules (around one square nanometer surface), the usual antibody footprint is five to twenty square nanometers and covers an area in the range of a tetra-up to a deca-saccharide [12]. These structural constraints indicate that the smaller a PS the fewer potential immune epitopes it contains.…”

“…The main cause of candidiasis, Candida albicans , expresses the phosphomannan glycoprotein that is linked to β-mannan. Protective vaccination was achieved by phosphomannan disaccharide structures eliciting protective antibody responses in mice [12]. More impressively, this study described a hybrid vaccine composed of (1) a β-mannan trisaccharide; (2) a 14 amino acid peptide of the fructose-bisphosphate aldolase of C. albicans ; and (3) TT that did not require any adjuvant [181].…”