Anti-staphylococcus aureus adaptive immunity is impaired in end-stage renal disease patients on hemodialysis: one-year longitudinal study.

Introduction: Patients with end-stage renal disease (ESRD) display defects in adaptive and innate immunity, increasing susceptibility to infection. Staphylococcus aureus (S. aureus) is a major cause of bacteraemia in this population and is associated with increased mortality. More information on the immune response to S. aureus in these patients is needed to inform effective vaccine development. Methods: A longitudinal prospective study was carried out at two medical centers and included 48 ESRD patients who started chronic hemodialysis (HD) treatment ≤3 months before inclusion. Control samples were taken from 62 consenting healthy blood donors. Blood samples were obtained from ESRD patients at each visit, on month (M) 0 (beginning of HD), M6 and M12. Around 50 immunological markers of adaptive and innate immunity were assessed to compare immune responses to S. aureus in ESRD patients versus controls to document the changes on their immune profile during HD. Results: S. aureus survival in whole blood was significantly higher in ESRD patients than in controls at M0 (P=0.049), while impaired oxidative burst activity was observed in ESRD patients at all timepoints (P<0.001). S. aureus-specific immunoglobulin G (IgG) responses to iron surface determinant B (IsdB) and S. aureus α hemolysin (Hla) antigens were lower in ESRD patients than in healthy donors at M0 (P=0.003 and P=0.007, respectively) and M6 (P=0.05 and P=0.03, respectively), but were restored to control levels at M12. Moreover, S. aureus-specific T-helper cell responses were comparable to controls for IsdB but were impaired for Hla antigen at all timepoints: 10% of ESRD patients responded to Hla at M0, increasing to 30% at M12, compared with 45% of healthy donors. B-cell and T-cell concentrations in blood were significantly reduced (by 60% and 40%, respectively) compared with healthy controls. Finally, upregulation of Human Leucocyte Antigen-DR (HLA-DR) and C-C chemokine Receptor type 2 (CCR2) was impaired at M0 but was restored during the first year of HD. Conclusion: All together, these results show that adaptive immunity was largely impaired in ESRD patients, whereas innate immunity was less impacted and tended to be restored by HD.

Improvement of immunogenicity of meningococcal lipooligosaccharide by coformulation with lipidated transferrin-binding protein B in liposomes: implications for vaccine development.

Among various meningococcal antigens, lipooligosaccharide (LOS) and recombinant lipidated transferrin-binding protein B (rlip-TbpB) are considered to be putative vaccine candidates against group B Neisseria meningitidis. In the present work, we report the development of a new liposome-based vaccine formulation containing both rlip-TbpB and L8 LOS. The endotoxic activity of the liposomal LOS was evaluated in vitro using the Limulus Amebocyte Lysate assay and compared to the endotoxic activity of free LOS. Above a 250:1 lipid/LOS molar ratio, liposomes were shown to effectively detoxify the LOS as the endotoxic activity of the LOS was reduced by more than 99%. Immunogenicity studies in rabbits showed that the presence of rlip-TbpB dramatically increased the immunogenicity of the LOS. While the formulation raised a strong anti-TbpB response, it elicited a higher anti-LOS IgG level than the liposomal LOS alone. Sera from rabbits immunized with rlip-TbpB/liposomal LOS displayed increased ability to recognize LOS on live bacteria expressing the L8 immunotype and increased anti-LOS-specific bactericidal activity compared to sera from rabbits immunized with liposomal LOS alone. Measurement of interleukin-8 (IL-8) produced by HEK293 cells transfected with Toll-like receptor (TLR) after stimulation with rlip-TbpB showed that the protein is a TLR2 agonist, which is in accordance with the structure of its lipid. Furthermore, an in vivo study demonstrated that the lipid moiety is not only required for its adjuvant effect but also has to be linked to the protein. Overall, the rlip-TbpB/LOS liposomal formulation was demonstrated to induce an effective anti-LOS response due to the adjuvant effect of rlip-TbpB on LOS.