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

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posted on 07.05.2020, 09:07 by RAG da Silva, AV Karlyshev, NJ Oldfield, KG Wooldridge, CD Bayliss, A Ryan, R 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.

Funding

The funding for this work was received from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (201521/2015-6) for a 4-year Ph.D. program for RS. Additional funding for consumables was provided by the School of Life Sciences, University of Nottingham as part of a start-up package for RG.

History

Citation

Frontiers in Microbiology, 2019, 10:2847

Author affiliation

Department of Genetics and Genome Biology

Version

VoR (Version of Record)

Published in

Frontiers in Microbiology

Volume

10

Pagination

2847

Publisher

Frontiers Media

eissn

1664-302X

Acceptance date

25/11/2019

Copyright date

2019

Publisher version

https://www.frontiersin.org/articles/10.3389/fmicb.2019.02847/full#h1

Language

eng

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