Micoli, FrancescaBjarnarson, Stefania P.Arcuri, MelissaPind, Audur Anna AradottirMagnusdottir, Gudbjorg J.Necchi, FrancescaDi Benedetto, RobertaCarducci, MartinaSchiavo, FabiolaGiannelli, CarloPisoni, IvanMartin, Laura B.Del Giudice, GiuseppeMacLennan, Calman A.Rappuoli, RinoJonsdottir, IngileifSaul, Allan2025-11-202025-11-202020-09-29Micoli, F, Bjarnarson, S P, Arcuri, M, Pind, A A A, Magnusdottir, G J, Necchi, F, Di Benedetto, R, Carducci, M, Schiavo, F, Giannelli, C, Pisoni, I, Martin, L B, Del Giudice, G, MacLennan, C A, Rappuoli, R, Jonsdottir, I & Saul, A 2020, 'Short Vi-polysaccharide abrogates T-independent immune response and hyporesponsiveness elicited by long Vi-CRM 197 conjugate vaccine', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 39, pp. 24443-24449. https://doi.org/10.1073/pnas.20058571170027-842436967242f7813d2d-692b-4693-a8d2-6353f806bad68509228914132900928https://hdl.handle.net/20.500.11815/6274Publisher Copyright: © 2020 National Academy of Sciences. All rights reserved.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.7142520424443-24449eninfo:eu-repo/semantics/openAccessConjugate vaccinePolysaccharideSalmonella TyphiT-dependent responseT-independent responseMultidisciplinary/dk/atira/pure/researchoutput/researchoutputtypes/contributiontojournal/article10.1073/pnas.2005857117