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      High coverage of diverse invasive meningococcal serogroup B strains by the 4-component vaccine 4CMenB in Australia, 2007–2011: Concordant predictions between MATS and genetic MATS

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          ABSTRACT

          Meningococcal serogroup B (MenB) accounts for an important proportion of invasive meningococcal disease (IMD). The 4-component vaccine against MenB (4CMenB) is composed of factor H binding protein (fHbp), neisserial heparin-binding antigen (NHBA), Neisseria adhesin A (NadA), and outer membrane vesicles of the New Zealand strain with Porin 1.4. A meningococcal antigen typing system (MATS) and a fully genomic approach, genetic MATS (gMATS), were developed to predict coverage of MenB strains by 4CMenB. We characterized 520 MenB invasive disease isolates collected over a 5-year period (January 2007–December 2011) from all Australian states/territories by multilocus sequence typing and estimated strain coverage by 4CMenB. The clonal complexes most frequently identified were ST-41/44 CC/Lineage 3 (39.4%) and ST-32 CC/ET-5 CC (23.7%). The overall MATS predicted coverage was 74.6% (95% coverage interval: 61.1%–85.6%). The overall gMATS prediction was 81.0% (lower–upper limit: 75.0–86.9%), showing 91.5% accuracy compared with MATS. Overall, 23.7% and 13.1% (MATS) and 26.0% and 14.0% (gMATS) of isolates were covered by at least 2 and 3 vaccine antigens, respectively, with fHbp and NHBA contributing the most to coverage. When stratified by year of isolate collection, state/territory and age group, MATS and gMATS strain coverage predictions were consistent across all strata. The high coverage predicted by MATS and gMATS indicates that 4CMenB vaccination may have an impact on the burden of MenB-caused IMD in Australia. gMATS can be used in the future to monitor variations in 4CMenB strain coverage over time and geographical areas even for non-culture confirmed IMD cases.

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          Multilocus sequence typing: A portable approach to the identification of clones within populations of pathogenic microorganisms

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            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. Through acquisition of specific genes and through insertions and rearrangements, each clade has acquired and remodeled specific genomic tracts, with the potential to impact on the commensal and virulence behavior of Nm. Despite this clear evidence of a structured population, we confirm high rates of detectable recombination throughout the whole Nm chromosome. However, gene conversion events were found to be longer within clades than between clades, suggesting a DNA cleavage mechanism associated with the phylogeny of the species. We identify 22 restriction modification systems, probably acquired by horizontal gene transfer from outside of the species/genus, whose distribution in the different strains coincides with the phylogenetic clade structure. We provide evidence that these clade-associated restriction modification systems generate a differential barrier to DNA exchange consistent with the observed population structure. These findings have general implications for the emergence of lineage structure and virulence in recombining bacterial populations, and they could provide an evolutionary framework for the population biology of a number of other bacterial species that show contradictory population structure and dynamics.
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              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. To address this, we developed the meningococcal antigen typing system (MATS) by combining a unique vaccine antigen-specific ELISA, which detects qualitative and quantitative differences in antigens, with PorA genotyping information. The ELISA correlates with killing of strains by SBA and measures both immunologic cross-reactivity and quantity of the antigens NHBA, NadA, and fHbp. We found that strains exceeding a threshold value in the ELISA for any of the three vaccine antigens had ≥80% probability of being killed by immune serum in the SBA. Strains positive for two or more antigens had a 96% probability of being killed. Inclusion of multiple different antigens in the vaccine improves breadth of coverage and prevents loss of coverage if one antigen mutates or is lost. The finding that a simple and high-throughput assay correlates with bactericidal activity is a milestone in meningococcal vaccine development. This assay allows typing of large panels of strains and prediction of coverage of protein-based meningococcal vaccines. Similar assays may be used for protein-based vaccines against other bacteria.
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                Author and article information

                Journal
                Hum Vaccin Immunother
                Hum Vaccin Immunother
                Human Vaccines & Immunotherapeutics
                Taylor & Francis
                2164-5515
                2164-554X
                13 April 2021
                2021
                13 April 2021
                : 17
                : 9
                : 3230-3238
                Affiliations
                [a ]Queensland Paediatric Infectious Disease Laboratory, Children’s Health Queensland Hospitals and Health Service, Queensland Children’s Hospital; , Brisbane, Australia
                [b ]Child Health Research Centre, The University of Queensland; , Brisbane, Australia
                [c ]Pathology Queensland, Forensic & Scientific Services; , Brisbane, Australia
                [d ]Public Health England, Meningococcal Reference Unit, Manchester Royal Infirmary; , Manchester, United Kingdom
                [e ]GSK; , Siena, Italy
                [f ]GSK; , Melbourne, Australia
                Author notes
                CONTACT Michael D. Nissen theniss@ 123456uq.edu.au Child Health Research Centre, The University of Queensland; , 62 Graham Street, South Brisbane, QLD 4101, Australia.
                Author information
                https://orcid.org/0000-0002-3001-7642
                https://orcid.org/0000-0003-4308-9335
                https://orcid.org/0000-0001-5969-3161
                https://orcid.org/0000-0002-0691-6568
                https://orcid.org/0000-0003-0924-7758
                https://orcid.org/0000-0001-6041-2603
                https://orcid.org/0000-0002-1050-9439
                https://orcid.org/0000-0002-6530-5951
                https://orcid.org/0000-0002-7622-0355
                https://orcid.org/0000-0003-4113-2512
                https://orcid.org/0000-0002-8635-6424
                https://orcid.org/0000-0002-7800-1404
                https://orcid.org/0000-0003-1643-1908
                https://orcid.org/0000-0003-1686-3313
                Article
                1904758
                10.1080/21645515.2021.1904758
                8381844
                33847225
                c6811083-de49-4a34-b2a3-db5ae9dad7b5
                © 2021 GlaxoSmithKline Biologicals S.A. Published with license by Taylor & Francis Group, LLC.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Page count
                Figures: 5, Tables: 1, References: 38, Pages: 9
                Categories
                Research Article
                Research Paper

                Molecular medicine
                meningococcal serogroup b,4cmenb,mats,gmats,strain coverage,australia
                Molecular medicine
                meningococcal serogroup b, 4cmenb, mats, gmats, strain coverage, australia

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