Meningococcal Factor H–Binding Protein Variants Expressed by Epidemic Capsular Group A, W‐135, and X Strains from Africa

Beernink, Peter T.; Caugant, Dominique A.; Welsch, Jo Anne; Koeberling, Oliver; Granoff, Dan M.

doi:10.1086/597806

Cited by 70 publications

(50 citation statements)

References 49 publications

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“…For example, isolated epidemic strains from serogroups A, W, and X (a recently identified cause of IMD in Africa, for which no vaccine exists), express fHbp proteins that share significant sequence homology with the fHbp antigen used in the 4CMenB vaccine and, therefore, may be susceptible to the bactericidal activity of 4CMenB-induced antibodies. 28,29 Indeed, results of an analysis of the bactericidal activity of sera from 4CMenB-vaccinated individuals against a panel of serogroup X epidemic strains indicated that 4CMenB may indeed confer protection against strains of this serogroup, and that this protection is likely attributable to fHbp-specific antibody responses. 30 While 4CMenB coverage of non-serogroup B strains has not been studied extensively, the susceptibility of any meningococcal strain to bactericidal antibodies elicited by 4CMenB is dependent upon both the degree of similarity between vaccine antigens and the respective target proteins, as well as the expression level of the target proteins, in each strain.…”

Section: Discussionmentioning

confidence: 99%

Immunogenicity and safety of investigational vaccine formulations against meningococcal serogroups A, B, C, W, and Y in healthy adolescents

Sáez-Llorens

Vaca²,

Abarca

et al. 2015

Human Vaccines & Immunotherapeutics

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This phase 2 study assessed the immunogenicity, safety, and reactogenicity of investigational formulations of meningococcal ABCWY vaccines, consisting of recombinant proteins (rMenB) and outer membrane vesicle (OMV) components of a licensed serogroup B vaccine, combined with components of a licensed quadrivalent meningococcal glycoconjugate vaccine (MenACWY-CRM). A total of 495 healthy adolescents were randomized to 6 groups to receive 2 doses (Months 0, 2) of one of 4 formulations of rMenB antigens, with or without OMV, combined with MenACWY-CRM, or 2 doses of rMenB alone or one dose of MenACWY-CRM then a placebo. Immunogenicity was assessed by serum bactericidal assay with human complement (hSBA) against serogroups ACWY and serogroup B test strains; solicited reactions and any adverse events (AEs) were assessed. Two MenABCWY vaccinations elicited robust ACWY immune responses, with higher seroresponse rates than one dose of MenACWY-CRM. Bactericidal antibody responses against the rMenB antigens and OMV components were highest in subjects who received 2 doses of OMV-containing MenABCWY formulations, with 68% of subjects achieving hSBA titers 5 against each of the serogroup B test strains. After the first dose, solicited local reaction rates were higher in the MenABCWY or rMenB groups than the MenACWY-CRM group, but similar across groups after the second dose, consisting mainly of transient injection site pain. Fever ( 38.0 C) was rare and there were no vaccine-related serious AEs. In conclusion, investigational MenABCWY formulations containing OMV components elicited highly immunogenic responses against meningococcal serogroups ACWY, as well as serogroup B test strains, with an acceptable safety profile. [NCT01210885]

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Section: Discussionmentioning

confidence: 99%

Immunogenicity and safety of investigational vaccine formulations against meningococcal serogroups A, B, C, W, and Y in healthy adolescents

Sáez-Llorens

Vaca²,

Abarca

et al. 2015

Human Vaccines & Immunotherapeutics

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“…We chose FHbp ID 22, as this sequence variant was prevalent in invasive isolates from Africa (14,20) and the immunogenicity of vaccines containing FHbp ID 22 previously had been tested in mice (6,14,16,21). The L130R substitution increased the T m of the N-terminal domain by 7.7°C (Fig.…”

Section: Resultsmentioning

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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“…The same study also evaluated the distribution of fHBP proteins in other meningococcal serogroups (MnC, MnY, and MnW135) and showed that for these other serogroups the proportion of fHBP subfamily A variants was also increased. Relatively more subfamily A disease has also been identified for MnC isolates from South Africa and for W135 isolates from the sub-Saharan meningitis belt in Africa (36,38,39). Conversely, in South Africa, MnW135 is dominated by a higher proportion of fHBP subfamily B variants.…”

Section: Distribution and Diversity Of Fhbpmentioning

confidence: 99%

Role of Factor H Binding Protein in Neisseria meningitidis Virulence and Its Potential as a Vaccine Candidate To Broadly Protect against Meningococcal Disease

McNeil

Zagursky

Lin

et al. 2013

Microbiol Mol Biol Rev

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SUMMARY Neisseria meningitidis is a Gram-negative microorganism that exists exclusively in humans and can cause devastating invasive disease. Although capsular polysaccharide-based vaccines against serogroups A, C, Y, and W135 are widely available, the pathway to a broadly protective vaccine against serogroup B has been more complex. The last 11 years has seen the discovery and development of the N. meningitidis serogroup B (MnB) outer membrane protein factor H binding protein (fHBP) as a vaccine component. Since the initial discovery of fHBP, a tremendous amount of work has accumulated on the diversity, structure, and regulation of this important protein. fHBP has proved to be a virulence factor for N. meningitidis and a target for functional bactericidal antibodies. fHBP is critical for survival of meningococci in the human host, as it is responsible for the primary interaction with human factor H (fH). Binding of hfH by the meningococcus serves to downregulate the host alternative complement pathway and helps the organism evade host innate immunity. Preclinical studies have shown that an fHBP-based vaccine can elicit serum bactericidal antibodies capable of killing MnB, and the vaccine has shown very encouraging results in human clinical trials. This report reviews our current knowledge of fHBP. In particular, we discuss the recent advances in our understanding of fHBP, its importance to N. meningitidis , and its potential role as a vaccine for preventing MnB disease.

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Meningococcal Factor H–Binding Protein Variants Expressed by Epidemic Capsular Group A, W‐135, and X Strains from Africa

Cited by 70 publications

References 49 publications

Immunogenicity and safety of investigational vaccine formulations against meningococcal serogroups A, B, C, W, and Y in healthy adolescents

Immunogenicity and safety of investigational vaccine formulations against meningococcal serogroups A, B, C, W, and Y in healthy adolescents

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

Role of Factor H Binding Protein in Neisseria meningitidis Virulence and Its Potential as a Vaccine Candidate To Broadly Protect against Meningococcal Disease

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