Sequence Diversity of the Factor H Binding Protein Vaccine Candidate in Epidemiologically Relevant Strains of Serogroup B<i>Neisseria meningitidis</i>

Murphy, Ellen; Andrew, Lubomira; Lee, Kwok Leung; Dilts, Deborah A.; Nuñez, Lorna; Fink, Pamela S.; Ambrose, Karita; Borrow, Raymond; Findlow, Jamie; Taha, Muhamed-Kheir; Deghmane, Ala Eddine; Kriz, Paula; Musílek, Martin; Kalmusová, J.; Caugant, Dominique A.; Alvestad, Torill; Mayer, Leonard W.; Sacchi, Cláudio Tavares; Wang, Xin; Martin, Diana; Gottberg, Anne von; Plessis, Mignon du; Klugman, Keith P.; Anderson, Annaliesa S.; Jansen, Kathrin U.; Zlotnick, Gary W.; Hoiseth, Susan K.

doi:10.1086/600141

Cited by 182 publications

(191 citation statements)

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“…All nine were ST11 isolates that were not linked by geography as they were present in 5 ABC sites. An identical deletion resulting in the same frameshift and premature truncation was reported in a single meningococcus serogroup B isolate, 4 although the two alleles, B139_001 and B110_001, differ at 6 nucleotides in the N-terminal domain. Meningococcus serogroup C isolates carrying variants with the identical deletion at nucleotide 365 but also carrying compensating single nucleotide insertions that restore the correct reading frame within 7-9 amino acids were also identified (B140, 3 isolates in this collection, and B138 [GenBank accession HM588652]), as shown in Figure 3.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tsupporting

confidence: 52%

“…In contrast, the subfamily distribution in US serogroup B isolates during these years, weighted to account for the epidemic in Oregon, 9 was 42% subfamily A and 58% subfamily B, 4 and 39% subfamily A and 61% subfamily B in a larger study encompassing the years 2000-2008. 16 Compared to our survey of 1,814 serogroup B isolates in the US and Europe, 4,10 there was more population diversity with respect to fHBP among the US MnC isolates than among the larger MnB collection: 43 unique fHBP variants within the 116 serogroup C isolates compared to 198 different fHBP variants in the larger serogroup B collection. Of the 43 fHBP variants in the MnC isolates, 23 were new protein sequences not represented among the of 1,814 serogroup B isolates.…”

Section: Methodsmentioning

confidence: 86%

“…1) revealed that all fHBPs were grouped into one of the two subfamilies observed in a comprehensive prevalence-based study of more than 1,800 invasive disease serogroup B isolates. 4,10 In the current analysis of the fhbp …”

Section: Diversity Of Meningococcal Serogroup C Isolates Of the 116mentioning

confidence: 99%

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Preclinical evidence for the potential of a bivalent fHBP vaccine to preventNeisseria meningitidisSerogroup C Disease

et al. 2011

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Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tsupporting

confidence: 52%

Section: Methodsmentioning

confidence: 86%

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Preclinical evidence for the potential of a bivalent fHBP vaccine to preventNeisseria meningitidisSerogroup C Disease

et al. 2011

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“…Given the fact that the two fHbp subfamilies share similar hfH binding property, it is likely that the conformations of the hfH binding sites in the two subfamilies are similar. The hfH binding sites contain large numbers of subfamily-defining residues (25,26). The regions that are largely composed of conserved residues are expected to be also similar.…”

Section: Discussion the Polypeptide And Lipid Domains Of Trumenba Lipmentioning

confidence: 99%

The Dual Role of Lipids of the Lipoproteins in Trumenba, a Self-Adjuvanting Vaccine Against Meningococcal Meningitis B Disease

Luo

Friese

Runnels

et al. 2016

AAPS J

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ABSTRACT.Trumenba (bivalent rLP2086) is a vaccine licensed for the prevention of meningococcal meningitis disease caused by Neisseria meningitidis serogroup B (NmB) in individuals 10-25 years of age in the USA. The vaccine is composed of two factor H binding protein (fHbp) variants that were recombinantly expressed in Escherichia coli as native lipoproteins: rLP2086-A05 and rLP2086-B01. The vaccine was shown to induce potent bactericidal antibodies against a broad range of NmB isolates expressing fHbp that were different in sequence from the fHbp vaccine antigens. Here, we describe the characterization of the vaccine antigens including the elucidation of their structure which is characterized by two distinct motifs, the polypeptide domain and the N-terminal lipid moiety. In the vaccine formulation, the lipoproteins self-associate to form micelles driven by the hydrophobicity of the lipids and limited by the size of the folded polypeptides. The micelles help to increase the structural stability of the lipoproteins in the absence of bacterial cell walls. Analysis of the lipoproteins in Toll-like receptor (TLR) activation assays revealed their TLR2 agonist activity. This activity was lost with removal of the O-linked fatty acids, similar to removal of all lipids, demonstrating that this moiety plays an adjuvant role in immune activation. The thorough understanding of the structure and function of each moiety of the lipoproteins, as well as their relationship, lays the foundation for identifying critical parameters to guide vaccine development and manufacture.

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“…FHbp sequence variants in variant group 2 are prevalent among invasive strains in Europe (12) and North America (ID 19) (13) and Africa (ID 22) (14). These two sequence variants were reported to have low thermal stability for the amino-(N-) terminal domain (15,16), whereas FHbp from variant groups 1 and 3 had high thermal stability (15,17,18).…”

mentioning

confidence: 99%

A meningococcal vaccine antigen engineered to increase thermal stability and stabilize protective epitopes

Konar

Pajón

Beernink

2015

Proc. Natl. Acad. Sci. U.S.A.

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Factor H binding protein (FHbp) is part of two vaccines recently licensed for prevention of sepsis and meningitis caused by serogroup B meningococci. FHbp is classified in three phylogenic variant groups that have limited antigenic cross-reactivity, and FHbp variants in one of the groups have low thermal stability. In the present study, we replaced two amino acid residues, R130 and D133, in a stable FHbp variant with their counterparts (L and G) from a less stable variant. The single and double mutants decreased thermal stability of the amino- (N-) terminal domain compared with the wild-type protein as measured by scanning calorimetry. We introduced the converse substitutions, L130R and G133D, in a less stable wild-type FHbp variant, which increased the transition midpoint (Tm) for the N-terminal domain by 8 and 12 °C; together the substitutions increased the Tm by 21 °C. We determined the crystal structure of the double mutant FHbp to 1.6 Å resolution, which showed that R130 and D133 mediated multiple electrostatic interactions. Monoclonal antibodies specific for FHbp epitopes in the N-terminal domain had higher binding affinity for the recombinant double mutant by surface plasmon resonance and to the mutant expressed on meningococci by flow cytometry. The double mutant also had decreased binding of human complement Factor H, which in previous studies increased the protective antibody responses. The stabilized mutant FHbp thus has the potential to stabilize protective epitopes and increase the protective antibody responses to recombinant FHbp vaccines or native outer membrane vesicle vaccines with overexpressed FHbp.

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Sequence Diversity of the Factor H Binding Protein Vaccine Candidate in Epidemiologically Relevant Strains of Serogroup BNeisseria meningitidis

Abstract: The diversity of strains observed underscores the importance of studying the distribution of the vaccine antigen itself rather than relying on common epidemiological surrogates such as MLST.

Cited by 182 publications

References 33 publications

Preclinical evidence for the potential of a bivalent fHBP vaccine to preventNeisseria meningitidisSerogroup C Disease

Preclinical evidence for the potential of a bivalent fHBP vaccine to preventNeisseria meningitidisSerogroup C Disease

The Dual Role of Lipids of the Lipoproteins in Trumenba, a Self-Adjuvanting Vaccine Against Meningococcal Meningitis B Disease

A meningococcal vaccine antigen engineered to increase thermal stability and stabilize protective epitopes

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