Multicomponent meningococcal serogroup B vaccination elicits cross-reactive immunity in infants against genetically diverse serogroup C, W and Y invasive disease isolates.

Background: The multicomponent meningococcal serogroup B vaccine (4CMenB) is currently indicated for active immunization against invasive meningococcal disease caused by Neisseria meningitidis serogroup B (MenB). However, genes encoding the 4CMenB antigens are also variably present and expressed in strains belonging to other meningococcal serogroups. In this study, we evaluated the ability of antibodies raised by 4CMenB immunisation to induce complement-mediated bactericidal killing of non-MenB strains.

Genetic Meningococcal Antigen Typing System (gMATS): A genotyping tool that predicts 4CMenB strain coverage worldwide.

Background: The Meningococcal Antigen Typing System (MATS) was developed to identify meningococcus group B strains with a high likelihood of being covered by the 4CMenB vaccine, but is limited by the requirement for viable isolates from culture-confirmed cases. We examined if antigen genotyping could complement MATS in predicting strain coverage by the 4CMenB vaccine.

Methods: From a panel of 3912 MATS-typed invasive meningococcal disease isolates collected in England and Wales in 2007-2008, 2014-2015 and 2015-2016, and in 16 other countries in 2000-2015, 3481 isolates were also characterized by antigen genotyping.

Predicted Strain Coverage of a New Meningococcal Multicomponent Vaccine (4CMenB) in Spain: Analysis of the Differences with Other European Countries.

Background: A novel meningococcal multicomponent vaccine, 4CMenB (Bexsero®), has been approved in Europe, Canada, Australia and US. The potential impact of 4CMenB on strain coverage is being estimated by using Meningococcal Antigen Typing System (MATS), an ELISA assay which measures vaccine antigen expression and diversity in each strain. Here we show the genetic characterization and the 4CMenB potential coverage of Spanish invasive strains (collected during one epidemiological year) compared to other European countries and discuss the potential reasons for the lower estimate of coverage in Spain.

Neisseria meningitidis factor H-binding protein fHbp: a key virulence factor and vaccine antigen.

Neisseria meningitidis is a leading cause of meningitis and sepsis worldwide. The first broad-spectrum multicomponent vaccine against serogroup B meningococcus (MenB), 4CMenB (Bexsero(®)), was approved by the EMA in 2013, for prevention of MenB disease in all age groups, and by the US FDA in January 2015 for use in adolescents. A second protein-based MenB vaccine has also been approved in the USA for adolescents (rLP2086, Trumenba(®)).

Neisseria adhesin A variation and revised nomenclature scheme.

Neisseria adhesin A (NadA), involved in the adhesion and invasion of Neisseria meningitidis into host tissues, is one of the major components of Bexsero, a novel multicomponent vaccine licensed for protection against meningococcal serogroup B in Europe, Australia, and Canada. NadA has been identified in approximately 30% of clinical isolates and in a much lower proportion of carrier isolates. Three protein variants were originally identified in invasive meningococci and named NadA-1, NadA-2, and NadA-3, whereas most carrier isolates either lacked the gene or harbored a different variant, NadA-4.

Diversity of Greek meningococcal serogroup B isolates and estimated coverage of the 4CMenB meningococcal vaccine.

Background: Serogroup B meningococcal (MenB) isolates currently account for approximately 90% of invasive meningococcal disease (IMD) in Greece with ST-162 clonal complex predominating. The potential of a multicomponent meningococcal B vaccine (4CMenB) recently licensed in Europe was investigated in order to find whether the aforementioned vaccine will cover the MenB strains circulating in Greece. A panel of 148 serogroup B invasive meningococcal strains was characterized by multilocus sequence typing (MLST) and PorA subtyping.

Molecular and serological diversity of Neisseria meningitidis carrier strains isolated from Italian students aged 14 to 22 years.

Neisseria meningitidis is an obligate human commensal that commonly colonizes the oropharyngeal mucosa. Carriage is age dependent and very common in young adults. The relationships between carriage and invasive disease are not completely understood.

Variability of genes encoding surface proteins used as vaccine antigens in meningococcal endemic and epidemic strain panels from Norway.

Surface-expressed protein antigens such as factor H-binding protein (fHbp), Neisserial adhesin A (NadA), Neisserial heparin-binding antigen (NHBA) and Porin protein A (PorA); all express sequence variability that can affect their function as protective immunogens when used in meningococcal serogroup B vaccines like the recently-approved 4CMenB (Bexsero(®)). We assessed the sequence variation of genes coding for these proteins and two additional proteins ("fusion partners" to fHbp and NHBA) in pathogenic isolates from a recent low incidence period (endemic situation; 2005-2006) in Norway. Findings among strains from this panel were contrasted to what was found among isolates from a historic outbreak (epidemic situation; 1985-1990).

An analysis of the sequence variability of meningococcal fHbp, NadA and NHBA over a 50-year period in the Netherlands.

Studies of meningococcal evolution and genetic population structure, including the long-term stability of non-random associations between variants of surface proteins, are essential for vaccine development. We analyzed the sequence variability of factor H-binding protein (fHbp), Neisserial Heparin-Binding Antigen (NHBA) and Neisseria adhesin A (NadA), three major antigens in the multicomponent meningococcal serogroup B vaccine 4CMenB. A panel of invasive isolates collected in the Netherlands over a period of 50 years was used.

Predicted strain coverage of a meningococcal multicomponent vaccine (4CMenB) in Europe: a qualitative and quantitative assessment.

Background: A novel multicomponent vaccine against meningococcal capsular group B (MenB) disease contains four major components: factor-H-binding protein, neisserial heparin binding antigen, neisserial adhesin A, and outer-membrane vesicles derived from the strain NZ98/254. Because the public health effect of the vaccine, 4CMenB (Novartis Vaccines and Diagnostics, Siena, Italy), is unclear, we assessed the predicted strain coverage in Europe.

Methods: We assessed invasive MenB strains isolated mainly in the most recent full epidemiological year in England and Wales, France, Germany, Italy, and Norway.

Could the multicomponent meningococcal serogroup B vaccine (4CMenB) control Neisseria meningitidis capsular group X outbreaks in Africa?

A new vaccine, 4CMenB, is composed of surface proteins of Neisseria meningitidis and is aimed to target serogroup B (MenB) isolates. The vaccine components are present in meningococcal isolates of other serogroups allowing potential use against meningococcal isolates belonging to non-B serogroups. Isolates of serogroup X (MenX) have been emerged in countries of the African meningitis belt.

Rational design of a meningococcal antigen inducing broad protective immunity.

The sequence variability of protective antigens is a major challenge to the development of vaccines. For Neisseria meningitidis, the bacterial pathogen that causes meningitis, the amino acid sequence of the protective antigen factor H binding protein (fHBP) has more than 300 variations. These sequence differences can be classified into three distinct groups of antigenic variants that do not induce cross-protective immunity.

Prevalence and genetic diversity of candidate vaccine antigens among invasive Neisseria meningitidis isolates in the United States.

Neisseria meningitidis (Nm) serogroups B, C and Y are the major causes of meningococcal diseases in the United States. NmB accounts for ∼1/3 of the disease but no licensed vaccine is yet available. Two candidate vaccines are being developed specifically to target NmB, but may also provide protection against other serogroups.

Neisseria meningitidis is structured in clades associated with restriction modification systems that modulate homologous recombination.

Molecular data on a limited number of chromosomal loci have shown that the population of Neisseria meningitidis (Nm), a deadly human pathogen, is structured in distinct lineages. Given that the Nm population undergoes substantial recombination, the mechanisms resulting in the evolution of these lineages, their persistence in time, and the implications for the pathogenicity of the bacterium are not yet completely understood. Based on whole-genome sequencing, we show that Nm is structured in phylogenetic clades.

Characterization of diverse subvariants of the meningococcal factor H (fH) binding protein for their ability to bind fH, to mediate serum resistance, and to induce bactericidal antibodies.

Neisseria meningitidis is a commensal of the human nasopharynx but is also a major cause of septicemia and meningitis. The meningococcal factor H binding protein (fHbp) binds human factor H (fH), enabling downregulation of complement activation on the bacterial surface. fHbp is a component of two serogroup B meningococcal vaccines currently in clinical development.

Influence of sequence variability on bactericidal activity sera induced by Factor H binding protein variant 1.1.

Factor H binding protein (fHbp), one of the main antigens of new vaccines against serogroup B meningococcus, varies in amino acid sequence and level of expression in different clinical isolates. To evaluate the contribution of amino acid sequence variability to vaccine coverage, we constructed a strain that is susceptible to bactericidal killing only by anti-fHbp antibodies and engineered it to express equal levels of 10 different fHbp sub-variants from a constitutive promoter. Testing of these isogenic strains showed that sera from mice or adult volunteers vaccinated with fHbp variant 1.

Qualitative and quantitative assessment of meningococcal antigens to evaluate the potential strain coverage of protein-based vaccines.

A unique multicomponent vaccine against serogroup B meningococci incorporates the novel genome-derived proteins fHbp, NHBA, and NadA that may vary in sequence and level of expression. Measuring the effectiveness of such vaccines, using the accepted correlate of protection against invasive meningococcal disease, could require performing the serum bactericidal assay (SBA) against many diverse strains for each geographic region. This approach is impractical, especially for infants, where serum volumes are very limited.

Characterization of fHbp, nhba (gna2132), nadA, porA, and sequence type in group B meningococcal case isolates collected in England and Wales during January 2008 and potential coverage of an investigational group B meningococcal vaccine.

Invasive disease caused by meningococcal capsular groups A, C, W-135, and Y is now preventable by means of glycoconjugate vaccines that target their respective polysaccharide capsules. The capsule of group B meningococci (MenB) is poorly immunogenic and may induce autoimmunity. Vaccines based on the major immunodominant surface porin, PorA, are effective against clonal epidemics but, thus far, have a limited scope of coverage against the wider MenB population at large.

Characterization of fHbp, nhba (gna2132), nadA, porA, sequence type (ST), and genomic presence of IS1301 in group B meningococcal ST269 clonal complex isolates from England and Wales.

Highly effective glycoconjugate vaccines exist against four of the five major pathogenic groups of meningococci: A, C, W-135, and Y. An equivalent vaccine against group B meningococci (menB) has remained elusive due to the poorly immunogenic capsular polysaccharide. A promising alternative, the investigational recombinant menB (rMenB)- outer membrane vesicle (OMV) vaccine, contains fHBP, NHBA (previously GNA2132), NadA, and outer membrane vesicles (OMVs) from the New Zealand MeNZB vaccine.

Distribution and genetic variability of three vaccine components in a panel of strains representative of the diversity of serogroup B meningococcus.

With the aim of studying the molecular diversity of the antigens of a new recombinant vaccine against meningococcus serogroup B, the three genes coding for the main vaccine components GNA (Genome-derived Neisseria Antigen) 1870 (fHbp, factor H Binding Protein), GNA1994 (NadA, Neisseria adhesin A) and GNA2132 were sequenced in a panel of 85 strains collected worldwide and selected as representative of the serogroup B meningococcal diversity. No correlations were found between vaccine antigen variability and serogroup, geographic area and year of isolation. Although a relevant clustering was found with MLST clonal complexes, each showing an almost specific antigen variant repertoire, the prediction of the antigen assortment was not possible on the basis of MLST alone.

HadA is an atypical new multifunctional trimeric coiled-coil adhesin of Haemophilus influenzae biogroup aegyptius, which promotes entry into host cells.

The Oca (Oligomeric coiled-coil adhesin) family is a subgroup of the bacterial trimeric autotransporter adhesins, which includes structurally related proteins, such as YadA of Yersinia enterocolitica and NadA of Neisseria meningitidis. In this study, we searched in silico for novel members of this family in bacterial genomes and identified HadA (Haemophilus adhesin A), a trimeric autotransporter expressed only by Haemophilus influenzae biogroup aegyptius causing Brazilian purpuric fever (BPF), a fulminant septicemic disease of children. By comparative genomics and sequence analysis we predicted that the hadA gene is harboured on a mobile genetic element unique to BPF isolates.

Prevalence and sequence variations of the genes encoding the five antigens included in the novel 5CVMB vaccine covering group B meningococcal disease.

During the recent years, projects are in progress for designing broad-range non-capsular-based meningococcal vaccines, covering also serogroup B isolates. We have examined three genes encoding antigens (NadA, GNA1030 and GNA2091) included in a novel vaccine, i.e.

Epitope mapping of a bactericidal monoclonal antibody against the factor H binding protein of Neisseria meningitidis.

The factor H binding protein (fHbp) is a 27-kDa membrane-anchored lipoprotein of Neisseria meningitidis that allows the survival of the bacterium in human plasma; it is also a major component of a universal vaccine against meningococcus B. In this study, we used nuclear magnetic resonance spectroscopy, mutagenesis, and in silico modeling to map the epitope recognized by MAb502, a bactericidal monoclonal antibody elicited by fHbp. The data show that the antibody recognizes a conformational epitope within a well-defined area of the immunodominant C-terminal domain of the protein that is formed by two loops connecting different beta-strands of a beta-barrel and a short alpha-helix brought in spatial proximity by the protein folding.

Fine antigenic specificity and cooperative bactericidal activity of monoclonal antibodies directed at the meningococcal vaccine candidate factor h-binding protein.

No broadly protective vaccine is available for the prevention of group B meningococcal disease. One promising candidate is factor H-binding protein (fHbp), which is present in all strains but often sparsely expressed. We prepared seven murine immunoglobulin G monoclonal antibodies (MAbs) against fHbp from antigenic variant group 2 (v.

A universal vaccine for serogroup B meningococcus.

Meningitis and sepsis caused by serogroup B meningococcus are two severe diseases that still cause significant mortality. To date there is no universal vaccine that prevents these diseases. In this work, five antigens discovered by reverse vaccinology were expressed in a form suitable for large-scale manufacturing and formulated with adjuvants suitable for human use.