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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.

Original publication

DOI

10.1073/pnas.2005857117

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

08/09/2020

Volume

117

Pages

24443 - 24449

Addresses

Technology Platform Unit, GSK Vaccines Institute for Global Health (GVGH), 53100 Siena, Italy.

Keywords

B-Lymphocytes, T-Lymphocytes, Animals, Humans, Mice, Salmonella typhi, Typhoid Fever, Polysaccharides, Bacterial, Bacterial Proteins, Immunoglobulin G, Salmonella Vaccines, Vaccines, Conjugate, Antibodies, Bacterial, Female, Male