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

2019 ◽  
Author(s):  
RAG da Silva ◽  
AV Karlyshev ◽  
NJ Oldfield ◽  
KG Wooldridge ◽  
CD Bayliss ◽  
...  
Keyword(s):  
Signal Peptide ◽  
Human Factor ◽  
Binding Protein ◽  
Factor H ◽  
Vaccine Antigen ◽  
Nucleotide Polymorphisms ◽  
Polar Amino Acid ◽  
Single Nucleotide ◽  
Peptide Cleavage ◽  
Lipoprotein Assembly

AbstractMeningococcal 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) targetingNeisseria meningitidisserogroup 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 surface-localised 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.

scholarly journals Vitamin D receptor, vitamin D binding protein and CYP27B1 single nucleotide polymorphisms and susceptibility to viral infections in infants

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria Zacharioudaki ◽  
Ippokratis Messaritakis ◽  
Emmanouil Galanakis
Keyword(s):  
Vitamin D ◽  
Single Nucleotide Polymorphisms ◽  
Viral Infection ◽  
Vitamin D Receptor ◽  
Viral Infections ◽  
Binding Protein ◽  
Genotypic Differences ◽  
Nucleotide Polymorphisms ◽  
Vitamin D Binding Protein ◽  
Single Nucleotide

AbstractThe role of vitamin D in innate and adaptive immunity is recently under investigation. In this study we explored the potential association of genetic variances in vitamin D pathway and infections in infancy. Τhis prospective case–control study included infants 0–24 months with infection and age-matched controls. The single nucleotide polymorphisms of vitamin D receptor (VDR) gene (BsmI, FokI, ApaI, TaqI), vitamin D binding protein (VDBP) (Gc gene, rs7041, rs4588) and CYP27B1 (rs10877012) were genotyped by polymerase chain reaction-restriction fragment length polymorphism. In total 132 infants were enrolled, of whom 40 with bacterial and 52 with viral infection, and 40 healthy controls. As compared to controls, ΤaqI was more frequent in infants with viral infection compared to controls (p = 0.03, OR 1.96, 95% CI 1.1–3.58). Moreover, Gc1F was more frequent in the control group compared to infants with viral infection (p = 0.007, OR 2.7, 95% CI 1.3–5.6). No significant differences were found regarding the genetic profile for VDR and VDBP in infants with bacterial infection compared to the controls and also regarding CYP27B1 (rs10877012) between the studied groups. Genotypic differences suggest that vitamin D pathway might be associated with the host immune response against viral infections in infancy.

scholarly journals Impaired Immunogenicity of a Meningococcal Factor H-Binding Protein Vaccine Engineered To Eliminate Factor H Binding

2010 ◽  
Vol 17 (7) ◽  
pp. 1074-1078 ◽  
Author(s):  
Peter T. Beernink ◽  
Jutamas Shaughnessy ◽  
Sanjay Ram ◽  
Dan M. Granoff
Keyword(s):  
Binding Protein ◽  
Factor H ◽  
Vaccine Antigen ◽  
Mouse Strains ◽  
Enzyme Linked Immunosorbent Assay ◽  
Complement Factor ◽  
Protein Vaccine ◽  
Wild Type ◽  
Bacterial Surface ◽  
Cast Doubt

ABSTRACT Meningococcal factor H-binding protein (fHbp) is a promising antigen that is part of two vaccines in clinical development. The protein specifically binds human complement factor H (fH), which downregulates complement activation on the bacterial surface and enables the organism to evade host defenses. In humans, the vaccine antigen forms a complex with fH, which may affect anti-fHbp antibody repertoire and decrease serum bactericidal activity by covering important fHbp epitopes. In a recent study, fHbp residues in contact with fH were identified from a crystal structure. Two fHbp glutamate residues that mediated ion-pair interactions with fH were replaced with alanine, and the resulting E218A/E239A mutant no longer bound the fH fragment. In the present study, we generated the E218A/E239A mutant recombinant protein and confirmed the lack of fH binding. By enzyme-linked immunosorbent assay (ELISA), the mutant fHbp showed similar respective concentration-dependent inhibition of binding of four bactericidal anti-fHbp monoclonal antibodies (MAbs) to fHbp, compared with inhibition by the soluble wild-type protein. In two mouse strains, the mutant fHbp elicited up to 4-fold-lower IgG anti-fHbp antibody titers and up to 20-fold-lower serum bactericidal titers than those elicited by the wild-type fHbp vaccine. Thus, although introduction of the two alanine substitutions to eliminate fH binding did not appear to destabilize the molecule globally, the mutations resulted in decreased immunogenicity in mouse models in which neither the mutant nor the wild-type control vaccine bound fH. These results cast doubt on the vaccine potential in humans of this mutant fHbp.

Human factor H and C4b-binding protein serve as factor I-cofactors both encompassing inactivation of C3b and C4b

1995 ◽  
Vol 32 (5) ◽  
pp. 355-360 ◽  
Author(s):  
Tsukasa Seya ◽  
Kimiyo Nakamura ◽  
Takahisa Masaki ◽  
Chikako Ichihara-Itoh ◽  
Misako Matsumoto ◽  
...  
Keyword(s):  
Human Factor ◽  
Binding Protein ◽  
Factor H ◽  
Factor I

scholarly journals Single Nucleotide Polymorphisms in the Gc Gene for Vitamin D Binding Protein in Common Cancers in Thailand

2015 ◽  
Vol 16 (8) ◽  
pp. 3339-3344 ◽  
Author(s):  
Wanwisa Maneechay ◽  
Teeranut Boonpipattanapong ◽  
Samornmas Kanngurn ◽  
Puttisak Puttawibul ◽  
Sarayut Lucien Geater ◽  
...  
Keyword(s):  
Vitamin D ◽  
Single Nucleotide Polymorphisms ◽  
Binding Protein ◽  
Nucleotide Polymorphisms ◽  
Vitamin D Binding Protein ◽  
Single Nucleotide ◽  
Gc Gene

Prediction of the affinity of the TATA-binding protein to TATA boxes with single nucleotide polymorphisms

2009 ◽  
Vol 43 (3) ◽  
pp. 472-479 ◽  
Author(s):  
P. M. Ponomarenko ◽  
M. P. Ponomarenko ◽  
I. A. Drachkova ◽  
M. V. Lysova ◽  
T. V. Arshinova ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Binding Protein ◽  
Tata Binding Protein ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

scholarly journals Characterization of Neisseria meningitidis Isolates That Do Not Express the Virulence Factor and Vaccine Antigen Factor H Binding Protein

2011 ◽  
Vol 18 (6) ◽  
pp. 1002-1014 ◽  
Author(s):  
Jay Lucidarme ◽  
Lionel Tan ◽  
Rachel M. Exley ◽  
Jamie Findlow ◽  
Ray Borrow ◽  
...  
Keyword(s):  
Neisseria Meningitidis ◽  
Binding Protein ◽  
Factor H ◽  
Negative Regulator ◽  
Vaccine Antigen ◽  
Natural Immunity ◽  
Content Type ◽  
Reading Frame ◽  
Flanking Sequences

ABSTRACTNeisseria meningitidisremains a leading cause of bacterial sepsis and meningitis. Complement is a key component of natural immunity against this important human pathogen, which has evolved multiple mechanisms to evade complement-mediated lysis. One approach adopted by the meningococcus is to recruit a human negative regulator of the complement system, factor H (fH), to its surface via a lipoprotein, factor H binding protein (fHbp). Additionally, fHbp is a key antigen in vaccines currently being evaluated in clinical trials. Here we characterize strains ofN. meningitidisfrom several distinct clonal complexes which do not express fHbp; all strains were recovered from patients with disseminated meningococcal disease. We demonstrate that these strains have either a frameshift mutation in thefHbpopen reading frame or have entirely lostfHbpand some flanking sequences. No fH binding was detected to other ligands among thefHbp-negative strains. The implications of these findings for meningococcal pathogenesis and prevention are discussed.

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