Ravulizumab facilitates reduced burden of vascular access, a major benefit in paediatric atypical haemolytic uraemic syndrome.

BACKGROUND: Atypical haemolytic uraemic syndrome (aHUS) is a rare thrombotic microangiopathy resulting from dysregulation of the alternative complement pathway, leading to multi-organ dysfunction and chronic kidney disease. Eculizumab is an anti-C5 monoclonal antibody therapy that has significantly improved aHUS disease control and patient outcomes, however it requires fortnightly intravenous dosing. This often necessitates long term central access and a high hospital attendance burden. Ravulizumab is a novel, next-generation anti-C5 monoclonal antibody engineered from eculizumab to reduce endosomal degradation of the antibody, increasing the dosing interval up to 8 weeks. CASE SERIES: In this retrospective case series we present the transition of three children with aHUS from eculizumab to ravulizumab from a single tertiary paediatric nephrology service. All patients underwent genomic and immunological work up for aHUS, with no cause found. After stabilisation with eculizumab, two patients developed macrovascular thrombotic complications associated with indwelling central vascular catheters, ultimately leading to central access failure. All patients were transitioned from eculizumab to ravulizumab without relapse of aHUS. One patient successfully underwent deceased donor kidney transplantation with ravulizumab for complement inhibition. All patients have transitioned to peripheral access for infusions given the reduced frequency of dosing, maintaining good control of aHUS for 2-4 years. CONCLUSION: Ravulizumab permits sufficiently reduced frequency of infusion to allow for administration by peripheral cannulation - removing the risks of long term central vascular access often required to deliver eculizumab to paediatric patients.

Pneumococcal IgG Antibody Responses to 23vPPV in Healthy Controls Using an Automated ELISA.

Measurement of pre- and post-pneumococcal antibody levels after immunization with the 23-valent capsular polysaccharide pneumococcal vaccine (23vPPV) is indicative of a T-independent antibody response. The World Health Organisation ELISA is considered gold standard yet is labor-intensive and technically difficult to perform. Interpretation criteria defining an adequate response to 23vPPV remain controversial. The diagnostic Immunology Laboratory at The Royal Children's Hospital, Melbourne (RCH), performs an in-house multi-serotype automated ELISA. The primary objective of this study was to verify RCH interpretation criteria for the laboratory's automated ELISA. Forty pneumococcal conjugate vaccine (PCV)-naïve healthy adults aged 18 to 25 years and 22 PCV-primed healthy children aged 2 to 5 years were immunized with 23vPPV. A serum sample was collected immediately prior and 28 to 42 (± 7) days post immunization. Samples were analyzed on the Tecan Freedom Evo 200 ELISA with adequate response defined as post-immunization antibody level of 1.3 µg/mL or fourfold rise from baseline in ≥ 10/15 serotypes in adult participants and ≥ 4/8 serotypes in pediatric participants. Thirty-nine (97.5%) adults and 22 (100%) children achieved an adequate response to 23vPPV. In PCV-naïve adults, serotypes contained within the conjugate vaccines were less immunogenic, with 12 (30%) adults not achieving an adequate antibody response when only PCV serotypes were used for interpretation. Our diagnostic laboratory has verified the interpretation criteria used for an automated multi-serotype pneumococcal ELISA method. Clinical Trial Registration: ANZCTR registration number ACTRN12618000822280.

Marginal zone B cells acquire dendritic cell functions by trogocytosis.

Marginal zone (MZ) B cells produce broad-spectrum antibodies that protect against infection early in life. In some instances, antibody production requires MZ B cells to display pathogen antigens bound to major histocompatibility complex class II (MHC II) molecules to T cells. We describe the trogocytic acquisition of these molecules from conventional dendritic cells (cDCs). Complement component 3 (C3) binds to murine and human MHC II on cDCs. MZ B cells recognize C3 with complement receptor 2 (CR2) and trogocytose the MHC II-C3 complexes, which become exposed on their cell surface. The ubiquitin ligase MARCH1 limits the number of MHC II-C3 complexes displayed on cDCs to prevent their elimination through excessive trogocytosis. Capture of C3 by MHC II thus enables the transfer of cDC-like properties to MZ B cells.