Glycan Microarrays Decode Candida Antibodies to Unlock New Diagnostics and Vaccines

Invasive candidiasis affects over 1.5 million people annually, causing roughly one million deaths and ranking among the most dangerous nosocomial bloodstream infections. Despite this burden, no approved antifungal vaccine exists, and current diagnostics—including serum β-D-glucan assays and mannan antigen tests—suffer from poor sensitivity, specificity, and long turnaround times. The WHO has designated C. albicans and C. auris as critical priority pathogens, underscoring the urgent need for better tools.

This study harnessed glycan microarray technology to systematically map antibody responses to Candida cell wall polysaccharides. The arrays were populated with chemically pure, synthetic glycans replicating structures found on the fungal surface: α-(1,2)-, α-(1,3)-, β-(1,2)-, β-(1,6)-, and α-(1,6)-linked mannose units, phosphodiester-linked mannosides, and β-(1,3)/β-(1,6)-glucan fragments. Sera from Candida-infected patients and mouse infection models were screened alongside uninfected controls, and both IgG and IgM antibody binding profiles were quantified across the array.

Key temporal dynamics emerged. Shortly after infection, IgM antibodies predominantly targeted β-glucan epitopes. As infection persisted, the antibody response evolved, with IgM and IgG antibodies shifting to recognize oligomannose structures. This sequential pattern mirrors the transition from innate-like to adaptive humoral immunity and provides a framework for interpreting serological findings at different infection stages.

Three glycan structures were identified as lead biomarker and vaccine candidates. The tetrasaccharide β-(1,2)Man-α-(1,2)Man-α-(1,2)Man-α-(1,2)Man and the pentasaccharide α-(1,2)Man-α-(1,3)Man-α-(1,2)Man-α-(1,2)Man-α-(1,2)Man demonstrated strong, infection-specific IgG recognition, making them attractive antigens for glycoconjugate vaccines. A branched β-glucan pentasaccharide, β-(1,3)Glc-β-(1,3)Glc-β-(1,3)Glc-[β-(1,6)Glc]-β-(1,3)Glc, was similarly highlighted. Additionally, the β-(1,2)-mannose monomer and phosphodiester-linked mannosides showed differential binding across Candida species, suggesting their utility in species-discriminating lateral flow diagnostic tests.

These findings provide a molecular roadmap for translating fungal immunology into actionable clinical tools. The identified epitopes could underpin monoclonal antibody-based lateral flow assays for rapid bedside diagnosis and serve as haptens in glycoconjugate vaccines designed to protect immunocompromised patients—the population most at risk for invasive candidiasis.