Predicted strain coverage of a meningococcal multicomponent vaccine (4CMenB) in Europe: a qualitative and quantitative assessment
TL;DR: MATS analysis showed that a multicomponent vaccine could protect against a substantial proportion of invasive MenB strains isolated in Europe, however, monitoring of antigen expression will be needed in the future.
Abstract: Summary 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. Meningococcal antigen typing system (MATS) results were linked to multilocus sequence typing and antigen sequence data. To investigate whether generalisation of coverage applied to the rest of Europe, we also assessed isolates from the Czech Republic and Spain. Findings 1052 strains collected from July, 2007, to June, 2008, were assessed from England and Wales, France, Germany, Italy, and Norway. All MenB strains contained at least one gene encoding a major antigen in the vaccine. MATS predicted that 78% of all MenB strains would be killed by postvaccination sera (95% CI 63–90, range of point estimates 73–87% in individual country panels). Half of all strains and 64% of covered strains could be targeted by bactericidal antibodies against more than one vaccine antigen. Results for the 108 isolates from the Czech Republic and 300 from Spain were consistent with those for the other countries. Interpretation MATS analysis showed that a multicomponent vaccine could protect against a substantial proportion of invasive MenB strains isolated in Europe. Monitoring of antigen expression, however, will be needed in the future. Funding Novartis Vaccines and Diagnostics.
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TL;DR: The plasmid-mediated colistin resistance gene, mcr-1, was detected in an Escherichia coli isolate from a Danish patient with bloodstream infection and in five E. coli isolates from imported chicken meat.
Abstract: The plasmid-mediated colistin resistance gene, mcr-1, was detected in an Escherichia coli isolate from a Danish patient with bloodstream infection and in five E. coli isolates from imported chicken meat. One isolate from chicken meat belonged to the epidemic spreading sequence type ST131. In addition to IncI2*, an incX4 replicon was found to be linked to mcr-1. This report follows a recent detection of mcr-1 in E. coli from animals, food and humans in China.
381 citations
TL;DR: The two-dose 4CMenB priming schedule was highly effective in preventing MenB disease in infants, and cases in vaccine-eligible infants halved in the first 10 months of the programme.
227 citations
TL;DR: Findings support evidence that routine MCC vaccination was the driving force behind the decreasing SgC trend, and highlight the need for high-quality surveillance data to accurately assess the changing epidemiology of IMD, the effectiveness and impact of implemented vaccines, and the needs for future vaccines.
144 citations
Cites background from "Predicted strain coverage of a meni..."
...Some context-specific factors include the IMD and age group-specific serogroup burden in a country, estimation of strain coverage of the vaccine (particularly concerning 4CMenB), and vaccination coverage [9,35]....
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TL;DR: The 4CMenB program was associated with continued positive effect against meningococcal group B disease in children in England, and protection after three doses of the vaccine was sustained for at least 2 years.
Abstract: Background In September 2015, the United Kingdom introduced the multicomponent meningococcal group B vaccine (4CMenB, Bexsero) into its publicly funded national immunization program at a r...
133 citations
TL;DR: MATS is a conservative predictor of strain coverage by the 4CMenB vaccine in infants and adolescents, and is experimentally validated against strains representative of a specific epidemiologic setting.
130 citations
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TL;DR: The impact of recombination varies between bacterial species but in many species is sufficient to obliterate the phylogenetic signal in gene trees.
Abstract: The identification of clones within bacterial populations is often taken as evidence for a low rate of recombination, but the validity of this inference is rarely examined. We have used statistical tests of congruence between gene trees to examine the extent and significance of recombination in six bacterial pathogens. For Neisseria meningitidis, Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus, the congruence between the maximum likelihood trees reconstructed using seven house-keeping genes was in most cases no better than that between each tree and trees of random topology. The lack of congruence between gene trees in these four species, which include both naturally transformable and nontransformable species, is in three cases supported by high ratios of recombination to point mutation during clonal diversification (estimates of this parameter were not possible for Strep. pyogenes). In contrast, gene trees constructed for Hemophilus influenzae and pathogenic isolates of Escherichia coli showed a higher degree of congruence, suggesting lower rates of recombination. The impact of recombination therefore varies between bacterial species but in many species is sufficient to obliterate the phylogenetic signal in gene trees.
506 citations
TL;DR: Children and adult recipients of either meningococcal vaccine were more likely than controls to develop an immune response to the heterologous epidemic strain, and epidemic strain-specific vaccines homologous for class 1 OMP are promising candidates for the control of epidemic serogroup B menedococcal disease.
Abstract: ContextMeningococcal disease occurs worldwide, and serogroup
B disease accounts for a large proportion of cases. Although persons
younger than 4 years are at greatest risk for serogroup B meningococcal
disease, vaccine efficacy has not been demonstrated in this age group.ObjectiveTo evaluate serum bactericidal activity (SBA) against
homologous vaccine type strains and a heterologous Chilean epidemic
strain of Neisseria meningitidis as a potential correlate for
vaccine efficacy.DesignDouble-blind, randomized controlled trial conducted between
March 14 and July 20, 1994. All blood samples were taken by December
1994.SettingSantiago, Chile, where a clonal serogroup B meningococcal
disease epidemic began in 1993.ParticipantsInfants younger than 1 year (n=187),
children aged 2 to 4 years (n=183), and adults aged 17
to 30 years (n=173).InterventionParticipants received 3 doses of outer-membrane
protein (OMP) meningococcal vaccine developed in either Cuba or Norway
or a control vaccine, with each dose given 2 months apart. Blood
samples were obtained at baseline, prior to dose 3, and at 4 to 6 weeks
after dose 3.Main Outcome MeasureImmune response, defined as a 4-fold or
greater rise in SBA titer 4 to 6 weeks after dose 3 compared with
prevaccination titer.ResultsChildren and adult recipients of either
meningococcal vaccine were more likely than controls to develop an
immune response to the heterologous epidemic strain. After 3 doses of
vaccine, 31% to 35% of children responded to the vaccine vs 5% to
placebo; 37% to 60% of adults responded to vaccine vs 4% to placebo
(P<.05 vs control for all). Infants, however, did not
respond. In contrast, against homologous vaccine type strains, the
response rate was 67% or higher among children and adults and 90% or
higher among infants (P<.001 vs control for all). Subsequent
SBA against 7 isogenic homologous target strains identified class 1 OMP
as the immunodominant antigen.ConclusionsThese data suggest that neither serogroup B OMP
meningococcal vaccine would confer protection during a heterologous
epidemic. However, epidemic strain–specific vaccines homologous for
class 1 OMP are promising candidates for the control of epidemic
serogroup B meningococcal disease.
401 citations
TL;DR: The meningococcal antigen typing system (MATS) is developed by combining a unique vaccine antigen-specific ELISA, which detects qualitative and quantitative differences in antigens, with PorA genotyping information, and the ELISA correlates with killing of strains by SBA and measures both immunologic cross-reactivity and quantity of the antigen NHBA, NadA, and fHbp.
Abstract: 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.
302 citations
TL;DR: In this article, the immunogenicity and reactogenicity of a multicomponent Meningitidis vaccine (4CMenB) and routine infant vaccines when given either concomitantly or separately was evaluated.
Abstract: Context In the absence of an effective vaccine, serogroup B Neisseria meningitidis (MenB) remains a major cause of invasive disease in early childhood in developed countries. Objective To determine the immunogenicity and reactogenicity of a multicomponent MenB vaccine (4CMenB) and routine infant vaccines when given either concomitantly or separately. Design, Setting, and Participants Phase 2b, multicenter, open-label, parallel-group, randomized controlled study of 1885 infants enrolled at age 2 months from August 2008 to July 2010 in Europe. Intervention Participants were randomized 2:2:1:1 to receive (1) 4CMenB at 2, 4, and 6 months with routine vaccines (7-valent pneumococcal and combined diphtheria, tetanus, acellular pertussis, inactivated polio, hepatitis B, Haemophilus influenzae type b vaccines); (2) 4CMenB at 2, 4, and 6 months and routine vaccines at 3, 5, and 7 months; (3) 4CMenB with routine vaccines at 2, 3, and 4 months; or (4) routine vaccines alone at 2, 3, and 4 months. Main Outcome Measures Percentage of participants with human complement serum bactericidal activity (hSBA) titer of 1:5 or greater against 3 MenB strains specific for vaccine antigens (NZ98/254, 44/76-SL, and 5/99). Results After three 4CMenB vaccinations, 99% or more of infants developed hSBA titers of 1:5 or greater against strains 44/76-SL and 5/99. For NZ98/254, this proportion was 79% (95% CI, 75.2%-82.4%) for vaccination at 2, 4, and 6 months with routine vaccines, 86.1% (95% CI, 82.9%-89.0%) for vaccination at 2, 4, and 6 months without routine vaccines, and 81.7% (95% CI, 76.6%-86.2%) for vaccination at 2, 3, and 4 months with routine vaccines. Responses to routine vaccines given with 4CMenB were noninferior to routine vaccines alone for all antigens, except for the responses to pertactin and serotype 6B pneumococcal polysaccharide. Fever was seen following 26% (158/602) to 41% (247/607) of 4CMenB doses when administered alone, compared with 23% (69/304) to 36% (109/306) after routine vaccines given alone and 51% (306/605) to 61% (380/624) after 4CMenB and routine vaccines administered together. Conclusion A 4CMenB vaccine is immunogenic against reference strains when administered with routine vaccines at 2, 4, and 6 or at 2, 3, and 4 months of age, producing minimal interference with the response to routine infant vaccinations. Trial Registration clinicaltrials.gov Identifier: NCT00721396
263 citations
Journal Article•
TL;DR: A 4CMenB vaccine is immunogenic against reference strains when administered with routine vaccines at 2, 4, and 6 years of age, producing minimal interference with the response to routine infant vaccinations.
260 citations