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A mechanism for glycoconjugate vaccine activation of the adaptive immune system and its implications for vaccine design

2011; Nature Portfolio; Volume: 17; Issue: 12 Linguagem: Inglês

10.1038/nm.2535

1546-170X

Fikri Y. Avci, Xiangming Li, Moriya Tsuji, Dennis L. Kasper,

Neonatal and Maternal Infections

Glycoconjugate vaccines—such as those targeting some bacteria—couple a glycan to a protein to provide T cell help to B cells and induce polysaccharide-specific IgGs. T cell help has been thought to be conferred by recognition of the protein portion by T cells. Dennis Kasper and his colleagues now report that a glycan-peptide conjugate can induce T cells specific for the glycan moiety, which could help inform future glycoconjugate vaccine development. Glycoconjugate vaccines have provided enormous health benefits globally, but they have been less successful in some populations at high risk for developing disease. To identify new approaches to enhancing glycoconjugate effectiveness, we investigated molecular and cellular mechanisms governing the immune response to a prototypical glycoconjugate vaccine. We found that in antigen-presenting cells a carbohydrate epitope is generated upon endolysosomal processing of group B streptococcal type III polysaccharide coupled to a carrier protein. In conjunction with a carrier protein–derived peptide, this carbohydrate epitope binds major histocompatibility class II (MHCII) and stimulates carbohydrate-specific CD4+ T cell clones to produce interleukins 2 and 4—cytokines essential for providing T cell help to antibody-producing B cells. An archetypical glycoconjugate vaccine that we constructed to maximize the presentation of carbohydrate-specific T cell epitopes is 50–100 times more potent and substantially more protective in a neonatal mouse model of group B Streptococcus infection than a vaccine constructed by methods currently used by the vaccine industry. Our discovery of how glycoconjugates are processed resulting in presentation of carbohydrate epitopes that stimulate CD4+ T cells has key implications for glycoconjugate vaccine design that could result in greatly enhanced vaccine efficacy.