Short Vi-polysaccharide abrogates T-independent immune response and hyporesponsiveness elicited by long Vi-CRM197 conjugate vaccine
| العنوان: | Short Vi-polysaccharide abrogates T-independent immune response and hyporesponsiveness elicited by long Vi-CRM197 conjugate vaccine |
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| المؤلفون: | Calman A. MacLennan, Ivan Pisoni, Giuseppe Del Giudice, Stefania P. Bjarnarson, Fabiola Schiavo, Allan Saul, Gudbjorg Julia Magnusdottir, Francesca Micoli, Carlo Giannelli, Rino Rappuoli, Laura B. Martin, Roberta Di Benedetto, Martina Carducci, Melissa Arcuri, Francesca Necchi, Audur Anna Aradottir Pind, Ingileif Jonsdottir |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | National Academy of Sciences, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Salmonella Vaccines, T-Lymphocytes, T cell, Spleen, T-dependent response, Microbiology, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Bacterial Proteins, Antigen, Conjugate vaccine, medicine, Animals, Humans, 030212 general & internal medicine, Typhoid Fever, B-Lymphocytes, Vaccines, Conjugate, Multidisciplinary, Chemistry, Immunogenicity, Polysaccharides, Bacterial, Biological Sciences, Salmonella typhi, Antibodies, Bacterial, Molecular biology, 030104 developmental biology, medicine.anatomical_structure, polysaccharide, Immunoglobulin G, conjugate vaccine, Female, Bone marrow, T-independent response, Conjugate |
| الوصف: | Significance Our results suggest a rational way of designing and developing an improved typhoid conjugate vaccine and, by extension, to conjugate vaccines in general: first, modify a T-independent polysaccharide so that it no longer induces a T-independent response, then conjugate the polysaccharide to a suitable carrier protein restoring immunogenicity, thus creating a pure T-dependent antigen that induces a strongly boostable and long-lived response at an early age. 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. |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::578a5124365b0596bb093cfbc0b95a49Test https://doi.org/10.1073/pnas.2005857117Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....578a5124365b0596bb093cfbc0b95a49 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |