scholarly journals A Large Portion of Meningococcal Antigen Typing System-Negative Meningococcal Strains from Spain Is Killed by Sera from Adolescents and Infants Immunized with 4CMenB

2015 ◽  
Vol 22 (4) ◽  
pp. 357-360 ◽  
Author(s):  
R. Abad ◽  
A. Biolchi ◽  
M. Moschioni ◽  
M. M. Giuliani ◽  
M. Pizza ◽  
...  
Keyword(s):  
Large Scale ◽  
Vaccine Coverage ◽  
Surrogate Marker ◽  
Factor H ◽  
Enzyme Linked Immunosorbent Assay ◽  
Heparin Binding ◽  
Protein Vaccine ◽  
Typing System ◽  
Meningococcal Group ◽  
Group B

ABSTRACTA new vaccine (the 4CMenB 4-component protein vaccine [Bexsero], which includes PorA, factor H-binding protein [fHbp], neisserial heparin-binding antigen [NHBA], andNeisseriaadhesin A [NadA]) against serogroup B meningococci has recently been approved for use in people older than age 2 months in Europe, Australia, and Canada. Preapproval clinical efficacy studies are not feasible for invasive meningococcal disease because its incidence is low/very low, and the serum bactericidal antibody (SBA) titer (or the human SBA [hSBA] titer when human complement is used in the assay) has been used as a surrogate marker of protection. However, the hSBA assay cannot be used on a large scale, and therefore, a meningococcal antigen typing system (MATS) was developed. MATS combines conventional PorA genotyping with an enzyme-linked immunosorbent assay (ELISA) that quantifies both the expression and the cross-reactivity of antigenic variants. The assay has been used to evaluate the potential of the 4CMenB meningococcal group B vaccine to cover group B strains in several countries. Some recent data suggest that MATS is a conservative predictor of strain coverage. We used pooled sera from adolescents and infants to test by the hSBA assay 10 meningococcal group B strains isolated in Spain that were negative for the 3 antigens (n= 9) or that had very low levels of the 3 antigens (n= 1) by MATS. We found that all strains were killed by sera from adolescents and that 5 of the 10 strains were also killed, although at a low titer, by sera from infants. Our data confirm that MATS underestimates vaccine coverage.

scholarly journals Meningococcal Antigen Typing System (MATS)-Based Neisseria meningitidis Serogroup B Coverage Prediction for the MenB-4C Vaccine in the United States

mSphere ◽  
2017 ◽  
Vol 2 (6) ◽  
Author(s):  
Gowrisankar Rajam ◽  
Maria Stella ◽  
Ellie Kim ◽  
Simon Paulos ◽  
Giuseppe Boccadifuoco ◽  
...  
Keyword(s):  
United States ◽  
Vaccine Coverage ◽  
Binding Protein ◽  
The United States ◽  
Factor H ◽  
Enzyme Linked Immunosorbent Assay ◽  
Immune Reactivity ◽  
Content Type ◽  
Efficacy Trials ◽  
Typing System

ABSTRACT The meningococcal antigen typing system (MATS) is an enzyme-linked immunosorbent assay (ELISA)-based system that assesses the levels of expression and immune reactivity of the three recombinant MenB-4C antigens and, in conjunction with PorA variable 2 (VR2) sequencing, provides an estimate of the susceptibility of NmB isolates to killing by MenB-4C-induced antibodies. MATS assays or similar antigen phenotype analyses assume importance under conditions in which analyses of vaccine coverage predictions are not feasible with existing strategies, including large efficacy trials or functional antibody screening of an exhaustive strain panel. MATS screening of a panel of NmB U.S. isolates (n = 442) predicts high MenB-4C vaccine coverage in the United States. Neisseria meningitidis is the most common cause of bacterial meningitis in children and young adults worldwide. A 4-component vaccine against N. meningitidis serogroup B (MenB) disease (MenB-4C [Bexsero]; GSK) combining factor H binding protein (fHBP), neisserial heparin binding protein (NHBA), neisserial adhesin A (NadA), and PorA-containing outer membrane vesicles was recently approved for use in the United States and other countries worldwide. Because the public health impact of MenB-4C in the United States is unclear, we used the meningococcal antigen typing system (MATS) to assess the strain coverage in a panel of strains representative of serogroup B (NmB) disease in the United States. MATS data correlate with killing in the human complement serum bactericidal assay (hSBA) and predict the susceptibility of NmB strains to killing in the hSBA, the accepted correlate of protection for MenB-4C vaccine. A panel of 442 NmB United States clinical isolates (collected in 2000 to 2008) whose data were down weighted with respect to the Oregon outbreak was selected from the Active Bacterial Core Surveillance (ABCs; CDC, Atlanta, GA) laboratory. MATS results examined to determine strain coverage were linked to multilocus sequence typing and antigen sequence data. MATS predicted that 91% (95% confidence interval [CI95], 72% to 96%) of the NmB strains causing disease in the United States would be covered by the MenB-4C vaccine, with the estimated coverage ranging from 88% to 97% by year with no detectable temporal trend. More than half of the covered strains could be targeted by two or more antigens. NHBA conferred coverage to 83% (CI95, 45% to 93%) of the strains, followed by factor H-binding protein (fHbp), which conferred coverage to 53% (CI95, 46% to 57%); PorA, which conferred coverage to 5.9%; and NadA, which conferred coverage to 2.5% (CI95, 1.1% to 5.2%). Two major clonal complexes (CC32 and CC41/44) had 99% strain coverage. The most frequent MATS phenotypes (39%) were fHbp and NHBA double positives. MATS predicts over 90% MenB-4C strain coverage in the United States, and the prediction is stable in time and consistent among bacterial genotypes. IMPORTANCE The meningococcal antigen typing system (MATS) is an enzyme-linked immunosorbent assay (ELISA)-based system that assesses the levels of expression and immune reactivity of the three recombinant MenB-4C antigens and, in conjunction with PorA variable 2 (VR2) sequencing, provides an estimate of the susceptibility of NmB isolates to killing by MenB-4C-induced antibodies. MATS assays or similar antigen phenotype analyses assume importance under conditions in which analyses of vaccine coverage predictions are not feasible with existing strategies, including large efficacy trials or functional antibody screening of an exhaustive strain panel. MATS screening of a panel of NmB U.S. isolates (n = 442) predicts high MenB-4C vaccine coverage in the United States.

scholarly journals Genomic Characterization of Invasive Meningococcal Serogroup B Isolates and Estimation of 4CMenB Vaccine Coverage in Finland

mSphere ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Margherita Bodini ◽  
Alessandro Brozzi ◽  
Maria Giuliani ◽  
Hanna Nohynek ◽  
Anni Vainio ◽  
...  
Keyword(s):  
Genetic Variability ◽  
Neisseria Meningitidis ◽  
Meningococcal Disease ◽  
Vaccine Coverage ◽  
Factor H ◽  
Invasive Meningococcal Disease ◽  
Heparin Binding ◽  
Protein Variant ◽  
Content Type ◽  
Typing System

ABSTRACT Invasive meningococcal disease (IMD) caused by Neisseria meningitidis is a significant cause of morbidity and mortality worldwide. In Finland, the incidence rate of IMD is low, with meningococcal serogroup B (MenB) accounting for around one-third of IMD cases annually. The aim of this study was to investigate the genetic variability of invasive MenB isolates collected in Finland between 2010 and 2017 (n = 81), including the genes encoding the 4-component MenB vaccine (4CMenB; Bexsero; GSK) antigens and their promoters, and to evaluate the 4CMenB potential coverage. Whole-genome sequencing was performed. The meningococcal antigen typing system (MATS) was used to characterize MenB isolates and predict the potential coverage of 4CMenB. MATS was complemented by genetic MATS (gMATS) through association of antigen genotyping and phenotypic MATS results. Multilocus sequence typing revealed predominance of the ST-41/44 clonal complex among which sequence type (ST)-303 was the most common and was predicted to be covered by 4CMenB. Of the 4 major vaccine antigens, the factor H-binding protein variant 1, neisserial heparin binding antigen peptide 2, and the PorA P1.4 antigen were predominant, whereas Neisseria adhesin A was present in only 4% of the 81 isolates. MATS and gMATS 4CMenB strain coverage predictions were 78% and 86%, respectively, in a subpanel of 60 isolates collected during 2010 to 2014, with a gMATS prediction of 84% for all 81 isolates. The results suggest that 4CMenB could reduce the burden of IMD in Finland and that gMATS could be applied to monitor vaccine strain coverage and predict vaccine effectiveness. IMPORTANCE 4CMenB is a 4-component vaccine used against invasive meningococcal disease (IMD) caused by Neisseria meningitidis serogroup B (MenB). We investigated the genetic variability of MenB in Finland and evaluated 4CMenB strain coverage by 2 different methods: MATS (meningococcal antigen typing system) and gMATS (genetic MATS). In a set of MenB isolates, 78% (MATS) and 86% (gMATS) were predicted as covered by 4CMenB, suggesting that use of 4CMenB would help reduce IMD incidence in Finland. MATS has been used in 13 countries worldwide, generating information on phenotypic characteristics that could infer protection by 4CMenB. Based on these data and genetic information, gMATS coverage predictions can be made. gMATS predicts coverage consistent with MATS for about 94% of tested strains. Unlike MATS, gMATS does not require live isolates, thus allowing the analysis also of noncultivable strains, making the coverage predictions more accurate. Therefore, gMATS can replace MATS to assess 4CMenB coverage, including in regions with no prior MATS data.

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.

scholarly journals Epitopes Recognized by a Nonautoreactive Murine Anti-N-Propionyl Meningococcal Group B Polysaccharide Monoclonal Antibody

2005 ◽  
Vol 73 (4) ◽  
pp. 2123-2128 ◽  
Author(s):  
Gregory R. Moe ◽  
Apurva Dave ◽  
Dan M. Granoff
Keyword(s):  
Monoclonal Antibody ◽  
Capsular Polysaccharide ◽  
Polysialic Acid ◽  
Enzyme Linked Immunosorbent Assay ◽  
Ionization Time ◽  
Protein Carriers ◽  
Protein Conjugate ◽  
Meningococcal Group ◽  
Group B ◽  
Antigenic Targets

ABSTRACT The capsular polysaccharide of Neisseria meningitidis group B (MBPS) is a polymer of alpha (2→8) N-acetyl neuraminic acid. The polysaccharide is chemically identical to an autoantigen, polysialic acid (PSA), and is a poor immunogen, even when conjugated to protein carriers. Immunization of mice with MBPS-protein conjugate vaccines, in which N-acetyl groups have been replaced by propionyl groups (N-Pr MBPS), elicits serum bactericidal antibodies. A subpopulation of these antibodies do not cross-react with human PSA. The reasons for the increased immunogenicity of N-Pr MBPS and the antigenic targets of the bactericidal nonautoreactive antibodies are unknown. In this study, we investigated the antigenic targets of a protective murine monoclonal antibody (MAb) prepared against a N-Pr MBPS-tetanus toxoid conjugate vaccine. Binding of the MAb to N-Pr MBPS (as demonstrated by an enzyme-linked immunosorbent assay) and bactericidal activity were inhibited by de-N-acetylated MBPS and re-N-acetylated MBPS, which indicate that N-propionyl groups are not obligatory determinants for binding. The results of affinity selection from a preparation of N-Pr MBPS and matrix-assisted laser desorption ionization-time of flight mass spectroscopic analysis indicated that the minimal epitope recognized by the MAb is a MBPS disaccharide containing one de-N-acetylated residue. Thus, the bacterial capsular epitope recognized by this bactericidal, nonautoreactive, anti-group-B MAb likely contains de-N-acetyl residues.

scholarly journals M Protein of the Group A StreptococcusBinds to the Seventh Short Consensus Repeat of Human Complement Factor H

1998 ◽  
Vol 66 (4) ◽  
pp. 1427-1431 ◽  
Author(s):  
Timothy K. Blackmore ◽  
Vincent A. Fischetti ◽  
Tania A. Sadlon ◽  
Helena M. Ward ◽  
David L. Gordon
Keyword(s):  
Protein Binding ◽  
Binding Site ◽  
Regulatory Protein ◽  
Factor H ◽  
M Protein ◽  
Protein Binding Site ◽  
Enzyme Linked Immunosorbent Assay ◽  
Complement Factor ◽  
Heparin Binding ◽  
Protein Factor

ABSTRACT Streptococcus pyogenes evades complement by binding the complement-regulatory protein factor H (fH) via the central conserved C-repeat region of M protein. However, the corresponding binding region within fH has not previously been precisely localized. fH is composed of 20 conserved modules called short consensus repeats (SCRs), each of which contains approximately 60 amino acids. A series of fH truncated and deletion mutants were prepared, and their interaction with M6 protein was examined. The M protein binding site was initially localized to SCRs 6 to 15 as demonstrated by ligand dot blotting, chemical cross-linking, and enzyme-linked immunosorbent assay. SCR 7 was then shown to contain the M protein binding site, as a construct consisting of the first seven SCRs bound M protein but a construct containing the first six SCRs did not bind. In addition, deletion of SCR 7 from full-length fH abolished binding to M protein. SCR 7 is known to contain a heparin binding domain, and binding of fH to M6 protein was almost totally inhibited in the presence of 400 U of heparin per ml. These results localize the M6 protein binding site of fH to SCR 7 and indicate that it is in close proximity to the heparin binding site.

scholarly journals Prevalence of Factor H–Binding Protein Variants and NadA among Meningococcal Group B Isolates from the United States: Implications for the Development of a Multicomponent Group B Vaccine

2007 ◽  
Vol 195 (10) ◽  
pp. 1472-1479 ◽  
Author(s):  
Peter T. Beernink ◽  
Jo Anne Welsch ◽  
Lee H. Harrison ◽  
Arunas Leipus ◽  
Sheldon L. Kaplan ◽  
...  
Keyword(s):  
United States ◽  
Binding Protein ◽  
The United States ◽  
Factor H ◽  
Meningococcal Group ◽  
Group B ◽  
Protein Variants

scholarly journals Ex Vivo Model of Meningococcal Bacteremia Using Human Blood for Measuring Vaccine-Induced Serum Passive Protective Activity

2009 ◽  
Vol 16 (6) ◽  
pp. 785-791 ◽  
Author(s):  
Joyce S. Plested ◽  
Jo Anne Welsch ◽  
Dan M. Granoff
Keyword(s):  
Human Blood ◽  
Ex Vivo ◽  
Factor H ◽  
Antibody Activity ◽  
Complement Factor ◽  
Human Complement ◽  
Protective Activity ◽  
Protein Vaccine ◽  
Ex Vivo Model ◽  
Group B

ABSTRACT The binding of complement factor H (fH) to meningococci was recently found to be specific for human fH. Therefore, passive protective antibody activity measured in animal models of meningococcal bacteremia may overestimate protection in humans, since in the absence of bound fH, complement activation is not downregulated. We developed an ex vivo model of meningococcal bacteremia using nonimmune human blood to measure the passive protective activity of stored sera from 36 adults who had been immunized with an investigational meningococcal multicomponent recombinant protein vaccine. Before immunization, human complement-mediated serum bactericidal activity (SBA) titers of ≥1:4 against group B strains H44/76, NZ98/254, and S3032 were present in 19, 11, and 8% of subjects, respectively; these proportions increased to 97, 22, and 36%, respectively, 1 month after dose 3 (P < 0.01 for H44/76 and S3032). Against the two SBA-resistant strains, NZ98/254 and S3032, passive protective titers of ≥1:4 were present in 11 and 42% of sera before immunization, respectively, and these proportions increased to 61 and 94% after immunization (P < 0.001 for each strain). Most of the sera with SBA titers of <1:4 and passive protective activity showed a level of killing in the whole-blood assay (>1 to 2 log10 decreases in CFU/ml during a 90-min incubation) similar to that of sera with SBA titers of ≥1:4. In conclusion, passive protective activity was 2.6- to 2.8-fold more frequent than SBA after immunization. The ability of SBA-negative sera to kill Neisseria meningitidis in human blood where fH is bound to the bacteria provides further evidence that SBA titers of ≥1:4 measured with human complement may underestimate meningococcal immunity.

scholarly journals Interlaboratory Standardization of the Sandwich Enzyme-Linked Immunosorbent Assay Designed for MATS, a Rapid, Reproducible Method for Estimating the Strain Coverage of Investigational Vaccines

2012 ◽  
Vol 19 (10) ◽  
pp. 1609-1617 ◽  
Author(s):  
Brian D. Plikaytis ◽  
Maria Stella ◽  
Giuseppe Boccadifuoco ◽  
Lisa M. DeTora ◽  
Mauro Agnusdei ◽  
...  
Keyword(s):  
Immunosorbent Assay ◽  
Mixed Model ◽  
Pearson Correlation ◽  
Correlation Coefficients ◽  
Cross Reactivity ◽  
Factor H ◽  
Enzyme Linked Immunosorbent Assay ◽  
Heparin Binding ◽  
Mixed Model Analysis ◽  
Consensus Values

ABSTRACTThe meningococcal antigen typing system (MATS) sandwich enzyme-linked immunosorbent assay (ELISA) was designed to measure the immunologic cross-reactivity and quantity of antigens in target strains of a pathogen. It was first used to measure the factor H-binding protein (fHbp), neisserial adhesin A (NadA), and neisserial heparin-binding antigen (NHBA) content of serogroup B meningococcal (MenB) isolates relative to a reference strain, or “relative potency” (RP). With the PorA genotype, the RPs were then used to assess strain coverage by 4CMenB, a multicomponent MenB vaccine. In preliminary studies, MATS accurately predicted killing in the serum bactericidal assay using human complement, an accepted correlate of protection for meningococcal vaccines. A study across seven laboratories assessed the reproducibility of RPs for fHbp, NadA, and NHBA and established qualification parameters for new laboratories. RPs were determined in replicate for 17 MenB reference strains at laboratories A to G. The reproducibility of RPs among laboratories and against consensus values across laboratories was evaluated using a mixed-model analysis of variance. Interlaboratory agreement was very good; the Pearson correlation coefficients, coefficients of accuracy, and concordance correlation coefficients exceeded 99%. The summary measures of reproducibility, expressed as between-laboratory coefficients of variation, were 7.85% (fHbp), 16.51% (NadA), and 12.60% (NHBA). The overall within-laboratory measures of variation adjusted for strain and laboratory were 19.8% (fHbp), 28.8% (NHBA), and 38.3% (NadA). The MATS ELISA was successfully transferred to six laboratories, and a further laboratory was successfully qualified.

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