Vaccine antigen, Factor H binding protein, is typically a non-lipidated precursor that localises to the meningococcal surface by Slam

Abstract

Meningococcal surface lipoprotein, Factor H binding protein (FHbp), is the sole antigen of the Trumenba vaccine (Pfizer) and one of four antigens of the Bexsero vaccine (GSK) targeting Neisseria meningitidis serogroup B isolates. Lipidation of FHbp is assumed to occur for all isolates and its surface localisation is conducted by surface lipoprotein assembly modulator, Slam. We show in 91% of a collection of UK isolates (1742/1895) non-synonymous single nucleotide polymorphisms (SNPs) in the signal peptide of FHbp. A single SNP, common to all, alters a polar amino acid that abolishes processing, including lipidation and signal peptide cleavage. Rather than the toxic accumulation of the precursor in the periplasm as expected from disrupting the canonical processing pathway, remarkably the FHbp precursor is translocated to the outer membrane and surfacelocalised by Slam. Thus we show Slam is not lipoprotein-specific. In a panel of isolates expressing precursor FHbp at the surface, we investigated their binding to human factor H and their susceptibility to antibody-mediated killing. Our findings have implications for Trumenba and Bexsero and provide key insights for lipoprotein-based vaccines in development..

Variant Signal Peptides of Vaccine Antigen, FHbp, Impair Processing Affecting Surface Localization and Antibody-Mediated Killing in Most Meningococcal Isolates

“…New algorithms can now be deployed to predict whether other preprolipoproteins are processed to become mature lipoproteins or remain as precursors. This manuscript has been released as a Pre-Print at BioRxiv (da Silva et al, 2019). FIGURE 1 | Model pathway for translocation, processing, sorting, and export of FHbp in Neisseria meningitidis.…”