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

Wyeth Vaccines Research, Pearl River, New York 10965, USA.
The Journal of Infectious Diseases (Impact Factor: 6). 07/2009; 200(3):379-89. DOI: 10.1086/600141
Source: PubMed


Recombinant forms of Neisseria meningitidis human factor H binding protein (fHBP) are undergoing clinical trials in candidate vaccines against invasive meningococcal serogroup B disease. We report an extensive survey and phylogenetic analysis of the diversity of fhbp genes and predicted protein sequences in invasive clinical isolates obtained in the period 2000-2006.
Nucleotide sequences of fhbp genes were obtained from 1837 invasive N. meningitidis serogroup B (MnB) strains from the United States, Europe, New Zealand, and South Africa. Multilocus sequence typing (MLST) analysis was performed on a subset of the strains.
Every strain contained the fhbp gene. All sequences fell into 1 of 2 subfamilies (A or B), with 60%-75% amino acid identity between subfamilies and at least 83% identity within each subfamily. One fHBP sequence may have arisen via inter-subfamily recombination. Subfamily B sequences were found in 70% of the isolates, and subfamily A sequences were found in 30%. Multiple fHBP variants were detected in each of the common MLST clonal complexes. All major MLST complexes include strains in both subfamily A and subfamily B.
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.

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Available from: Jamie Findlow, Jul 18, 2014
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    • "Lipoprotein LP2086, a human factor H-binding protein (fHBP), was identified as a vaccine candidate [5]. The LP2086 gene is highly conserved, with >83% sequence identity within the 2 identified subfamilies , labeled A and B, and is present in all strains included in a database of 1837 invasive MnB isolates [6]. Few strains have been identified to date that do not express fHBP [7] [8]. "
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    ABSTRACT: Background: Neisseria meningitidis serogroup B (MnB) is a major cause of invasive meningococcal disease in infants. A conserved, surface-exposed lipoprotein, LP2086 (a factor H-binding protein [fHBP]), is a promising MnB vaccine target. A bivalent, recombinant vaccine targeting the fHBP (rLP2086) of MnB was developed. Methods: This phase 1/2 clinical study was designed to assess the immunogenicity, safety, and tolerability of a 4-dose series of the rLP2086 vaccine at 20-, 60-, 120-, or 200-μg dose levels in vaccine-naive infants when given with routine childhood vaccines. The study was to consist of two phases: a single-blind sentinel phase and an open-label full enrollment phase. During the sentinel phase, randomization of subjects to the next higher dose was delayed pending a 14-day safety review of dose 1 of the preceding dose cohort. The full enrollment phase was to occur after completion of the sentinel phase. Results: Local reactions were generally mild and adverse events infrequent; however, after only 46 infants were randomized into the study, fever rates were 64% and 90% in subjects receiving one 20- or 60-μg rLP2086 dose, respectively. Most fevers were <39.0°C. Only 2 subjects in the 20-μg group and 1 subject in the 60-μg group experienced fevers >39.0°C; no fevers were >40.0°C. Due to these high fever rates, the study was terminated early. No immunogenicity data were collected. This report discusses the safety and acceptability of rLP2086 in infants after one 20- or 60-μg dose. Conclusion: Due to the high fever rate experienced in the 20- and 60-μg groups, rLP2086 in the current formulation may not be acceptable for infants.
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    • "Efficacy studies are mostly conducted after vaccine introduction due to the low incidence of disease. Strain coverage is assessed by the analysis of protein expression in a representative strain panel and by determination of the allelic diversity (Bambini et al., 2009; Lucidarme et al., 2009; Murphy et al., 2009). Serum bactericidal assays are a major effort for MenB vaccines, as in contrast to polysaccharide vaccines, several strains have to be tested. "
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    ABSTRACT: Meningococcal disease is communicable by close contact or droplet aerosols. Striking features are high case fatality rates and peak incidences of invasive disease in infants, toddlers and adolescents. Vaccine development is hampered by bacterial immune evasion strategies including molecular mimicry.As for Haemophilus influenzae and Streptococcus pneumoniae, no vaccine has therefore been developed that targets all serogroups of Neisseria meningitidis. Polysaccharide vaccines available both in protein conjugated and non-conjugated form, have been introduced against capsular serogroups A, C,W-135 and Y, but are ineffective against serogroup B meningococci, which cause a significant burden of disease in many parts of the world. Detoxified outer membrane vesicles are used since decades to elicit protection against epidemic serogroup B disease. Genome mining and biochemical approaches have provided astounding progress recently in the identification of immunogenic, yet reasonably conserved outer membrane proteins. As subcapsular proteins nevertheless are unlikely to immunize against all serogroup B variants, thorough investigation by surrogate assays and molecular epidemiology approaches are needed prior to introduction and post-licensure of protein vaccines. Research currently addresses the analysis of life vaccines, meningococcus B polysaccharide modifications and mimotopes, as well as the use of N. lactamica outer membrane vesicles.
    Preview · Article · May 2010 · Microbial Biotechnology
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    ABSTRACT: Meningococcal serogroup C conjugate immunization was introduced in the Dutch national immunization schedule at the age of 14 months, together with a large catch-up campaign in 2002. After introduction of this MenC immunization, the incidence of MenC completely disappeared from the immunized population and a large reduction of disease was observed in the non-immunized population. Little information was present on the longevity of immunity following a single MenC immunization. In this PhD thesis the immunity of the Dutch population was assessed before and after introduction of the vaccine. The study reveals that a single immunization is beneficial over naturally induced immunity against MenC and reveals that the persistence of MenC-specific antibodies gradually increases in relation with the age at the time of immunization. Therefore, the main success of the MenC immunization programme is mainly due to the large herd effect that was introduced after the mass catch-up campaign. However, children that receive a single MenC immunization at the age of 14 months may be at risk when they enter the adolescent age and therefore an additional immunization may be necessary. Furthermore, studies on the transfer of maternal antibodies from mother to neonate were performed and the kinetics of antibody responses following primary or secondary MenC conjugate vaccination were studied.
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