Variant signal peptides of meningococcal vaccine antigen, FHbp, impairs processing affecting surface localisation and antibody-mediated killing.

Meningococcal 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. 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: lipidation and signal peptide cleavage. Whilst some of the FHbp precursor is retained in the cytoplasm due to reduced binding to SecA, remarkably some is translocated and further surface-localised by Slam. Thus we show Slam is not lipoprotein-specific. In a panel of isolates tested, the overall reduced surface localisation of the precursor FHbp, compared to isolates with an intact signal peptide, corresponded with decreased susceptibility to antibody-mediated killing. Our findings shed new light on the canonical pathway for lipoprotein processing and translocation of important relevance for lipoprotein-based vaccines in development and in particular for Trumenba.