Abstract
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 the majority of a collection of United Kingdom isolates (1742/1895) non-synonymous single nucleotide polymorphisms (SNPs) in the signal peptide (SP) of FHbp. A single SNP, common to all, alters a polar amino acid that abolishes processing: lipidation and SP 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-localized by Slam. Thus we show Slam is not lipoprotein-specific. In a panel of isolates tested, the overall reduced surface localization of the precursor FHbp, compared to isolates with an intact SP, 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.
Highlights
Neisseria meningitidis is a leading cause of bacterial meningitis and sepsis with high fatality and high frequency of severe sequelae (Rappuoli et al, 2018)
Our work has focused on bacterial-cell-intrinsic molecular factors, which govern the processing and localization of Factor H binding protein (FHbp) to the surface (Figure 1) which is key for target recognition following immunization with FHbpbased vaccines
The FHbps of both MC58 and L91543 are classified as subfamily B (Fletcher et al, 2004; Beernink and Granoff, 2009) (Masignani et al, 2003) and, as we previously reported, they share nucleotide and amino acid (AA) identities of 95 and 93% respectively (Karlyshev et al, 2015)
Summary
Neisseria meningitidis is a leading cause of bacterial meningitis and sepsis with high fatality (up to 50% when untreated) and high frequency (more than 10%) of severe sequelae (Rappuoli et al, 2018). The amino acid sequence of FHbp varies with identities as low as 60% between isolates which led to the classification of this lipoprotein into subfamily A (subdivided into variant groups 2 and 3) and subfamily B (variant group 1) (Masignani et al, 2003; Fletcher et al, 2004; Frontiers in Microbiology | www.frontiersin.org da Silva et al. Most Meningococci Present Non-lipidated FHbp. Brehony et al, 2009; Jiang et al, 2010). 2009; Jiang et al, 2010) Despite this variation, FHbp emerged as a promising vaccine candidate due to its ability to stimulate a strong serum bactericidal antibody (SBA) response capable of killing diverse group B isolates (Fletcher et al, 2004). It is thought that FHbp-specific antibodies promote bactericidal killing by the classical pathway and via amplification of the alternative pathway, by preventing fH from binding to FHbp (Giuntini et al, 2011)
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