Antibody dependent complement activation is critical for boosting opsonophagocytosis of Staphylococcus epidermidis in an extremely preterm human whole blood model

Staphylococcus epidermidis is a major cause of late onset sepsis in extremely preterm neonates. Antibody therapies are considered as an interesting strategy to prevent sepsis. However, previous clinical trials with intravenous immunoglobulin (IVIG) and a monoclonal antibody (mAb) targeting staphylococcal lipoteichoic acid (LTA) (Pagibaximab) failed to show significant protection from invasive infections in extremely preterm neonates. Here we use an age-specific in vitro platform to compare immune protection by Pagibaximab with two other mAbs recognizing invasive S. epidermidis in the context of the neonatal immune system. We demonstrate poor activity of Pagibaximab in inducing complement C3b opsonization and neutrophil opsonophagocytosis in neonatal plasma. MAbs CR5133 and CR6453 [recognizing wall teichoic acid (WTA)] potently induced S. epidermidis opsonophagocytosis in an (extreme) preterm reconstituted whole blood model, especially after introduction of hexamer-enhancing mutations in the IgG-Fc tail. In conclusion, using age-specific in vitro assays, we show that mAbs with strong complement-inducing potential may be effective in preventing neonatal bacterial sepsis in extreme preterm neonates.