Main author: Stefanía P Bjarnarson
Institution or Company: University of Iceland, Faculty of Medicine, Biomedical Center, and Department of Immunology, Landspítali, The National University Hospital of Iceland
Co-Authors, Institution or Company:
Francesca Micoli, Technology Platform Unit, GSK Vaccines Institute for Global Health (GVGH), Siena, Italy.. Melissa Arcuri, Technology Platform Unit, GSK Vaccines Institute for Global Health (GVGH), Siena, Italy.. Auður Anna Aradóttir Pind, University of Iceland, Faculty of Medicine and Department of Immunology, Landspítali, The National University Hospital of Iceland. Francesca Necchi, Technology Platform Unit, GSK Vaccines Institute for Global Health (GVGH), Siena, Italy.. Roberta Di Benedetto, Technology Platform Unit, GSK Vaccines Institute for Global Health (GVGH), Siena, Italy.. Martina Carducci, Technology Platform Unit, GSK Vaccines Institute for Global Health (GVGH), Siena, Italy.. Fabiola Schiavo, Technology Platform Unit, GSK Vaccines Institute for Global Health (GVGH), Siena, Italy.. Carlo Giannelli, Technology Platform Unit, GSK Vaccines Institute for Global Health (GVGH), Siena, Italy.. Ivan Pisoni, R&D Centre, GSK Vaccines, Siena, Italy.. Laura B Martin, Technology Platform Unit, GSK Vaccines Institute for Global Health (GVGH), Siena, Italy.. Giuseppe Del Giudice, R&D Centre, GSK Vaccines, Siena, Italy.. Calman A MacLennan, Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.. Rino Rappuoli, R&D Centre, GSK Vaccines, 53100 Siena, Italy and Faculty of Medicine, Imperial College, London, United Kingdom. Allan Saul, Technology Platform Unit, GSK Vaccines Institute for Global Health (GVGH), Siena, Italy.. Ingileif Jónsdóttir, University of Iceland, Faculty of Medicine, Biomedical Center, and Department of Immunology, Landspítali, The National University Hospital of Iceland.
Introduction: Polysaccharide-protein conjugates have been developed to overcome the T-independent responses, hyporesponsiveness to repeated vaccination, and poor immunogenicity in infants of polysaccharides (PS). In a conjugate vaccine development against typhoid fever, Salmonella typhi, 164kDa-full-length Vi-PS was conjugated to CRM197 but did not induce a booster response in clinical Phase 2 trials. To address the impact of PS-length, conjugates were made with different Vi size-fragments, 9.5, 22.8, 42.7, 82.0 and 165kDa, and compared.
Methods: Wild-type and T-cell-deficient adult mice were immunized twice with different fragments of unconjugated/conjugated Vi-PS at 4 weeks interval. Neonatal mice were immunized twice with 43kDaVi-CRM197/165kDaVi-CRM197+alum at 3 weeks interval, and a booster 2 weeks later; saline, plain 43kDa-fVi, 165kDa-Vi or conjugate.
Results: Long-chain-conjugated 165kDaVi induced a response in both wild-type and T cell-deficient mice, suggesting that the conjugate maintains T-independent properties. In contrast, short-chain Vi conjugates (up to 42.7kDa) induced no response in T cell-deficient mice, only in wild-type mice. Mechanistically, this was explained in neonatal mice, where long-chain 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.
Conclusion: 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.
