Glycoconjugate vaccines provide enormous health benefits against bacterial pathogens, yet conjugation of polysaccharides to proteins has often been a “black art,” with poorly defined chemistry resulting in inadequately characterized conjugates. Especially problematic has been the lack of appreciation of the molecular and cellular interactions by which the immune system processes these complex antigens. We reported the most comprehensive study to date on the immune mechanisms involved in glycoconjugate vaccine activation of adaptive immune machinery (Nature Medicine 17, 1602; Nature Protocols 7, 2180). We demonstrated for the first time that carbohydrates that were previously considered to be “T cell independent” antigens can indeed be specifically recognized by T cells (i.e., Tcarbs) (Fig. 1). Our conclusions are a major departure from the traditional understanding that the T cells can only recognize peptides presented by the MHC proteins. Using the knowledge gained from our mechanistic studies, we designed and synthesized a model new-generation glycoconjugate vaccine with much greater immunogenicity than its traditional counterpart (Fig. 2). Data in our article map out a conceptual framework on which to base future investigations of vaccine immunogenicity and vaccine design based on carbohydrate antigens found not only in bacterial pathogens but also in other pathogens (e.g., parasites, viruses) and cancer cells.

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