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

da Silva, Ronni A.G.; Karlyshev, Andrey V.; Oldfield, Neil J.; Wooldridge, Karl G.; Bayliss, Christopher D.; Ryan, Ali; Griffin, Ruth

Authors

Ronni A.G. da Silva

Andrey V. Karlyshev

Neil J. Oldfield

Karl G. Wooldridge

Christopher D. Bayliss

Ali Ryan

Ruth Griffin



Abstract

© Copyright © 2019 da Silva, Karlyshev, Oldfield, Wooldridge, Bayliss, Ryan and Griffin. 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.

Journal Article Type Article
Publication Date Dec 19, 2019
Journal Frontiers in Microbiology
Electronic ISSN 1664-302X
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 10
Article Number 2847
APA6 Citation da Silva, R. A., Karlyshev, A. V., Oldfield, N. J., Wooldridge, K. G., Bayliss, C. D., Ryan, A., & Griffin, R. (2019). Variant Signal Peptides of Vaccine Antigen, FHbp, Impair Processing Affecting Surface Localization and Antibody-Mediated Killing in Most Meningococcal Isolates. Frontiers in Microbiology, 10, https://doi.org/10.3389/fmicb.2019.02847
DOI https://doi.org/10.3389/fmicb.2019.02847
Keywords Meningoccocus; FHbp; Vaccine; Signal peptide; Lipoprotein; Lnt; Slam
Publisher URL https://www.frontiersin.org/articles/10.3389/fmicb.2019.02847/full

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