Short Vi-polysaccharide abrogates T-independent immune response and hyporesponsiveness elicited by long Vi-CRM197 conjugate vaccine.
Francesca MicoliStefania P BjarnarsonMelissa ArcuriAudur Anna Aradottir PindGudbjorg J MagnusdottirFrancesca NecchiRoberta Di BenedettoMartina CarducciFabiola SchiavoCarlo GiannelliIvan PisoniLaura B MartinGiuseppe Del GiudiceCalman A MacLennanRino RappuoliIngileif JonsdottirAllan SaulPublished in: Proceedings of the National Academy of Sciences of the United States of America (2020)
Polysaccharide-protein conjugates have been developed to overcome the T-independent response, hyporesponsiveness to repeated vaccination, and poor immunogenicity in infants of polysaccharides. To address the impact of polysaccharide length, typhoid conjugates made with short- and long-chain fractions of Vi polysaccharide with average sizes of 9.5, 22.8, 42.7, 82.0, and 165 kDa were compared. Long-chain-conjugated Vi (165 kDa) induced a response in both wild-type and T cell-deficient mice, suggesting that it maintains a T-independent response. In marked contrast, short-chain Vi (9.5 to 42.7 kDa) conjugates induced a response in wild-type mice but not in T cell-deficient mice, suggesting that the response is dependent on T cell help. Mechanistically, this was explained in neonatal mice, in which long-chain, but not short-chain, Vi conjugate induced late apoptosis of Vi-specific B cells in spleen and early depletion of Vi-specific B cells in bone marrow, resulting in hyporesponsiveness and lack of long-term persistence of Vi-specific IgG in serum and IgG+ antibody-secreting cells in bone marrow. We conclude that while conjugation of long-chain Vi generates T-dependent antigens, the conjugates also retain T-independent properties, leading to detrimental effects on immune responses. The data reported here may explain some inconsistencies observed in clinical trials and help guide the design of effective conjugate vaccines.
Keyphrases
- immune response
- wild type
- bone marrow
- cancer therapy
- clinical trial
- high glucose
- mesenchymal stem cells
- dendritic cells
- heat shock protein
- cell cycle arrest
- drug induced
- magnetic resonance
- machine learning
- adipose tissue
- computed tomography
- drug delivery
- induced apoptosis
- cell proliferation
- photodynamic therapy
- endoplasmic reticulum stress
- water soluble
- electronic health record
- small molecule
- inflammatory response
- insulin resistance
- skeletal muscle
- high fat diet induced
- protein protein
- artificial intelligence
- double blind