Meningococcal Strains Research Articles

Meningococcal Infection in Novosibirsk: Changes in Epidemiology and Prevention Problems

Relevance. Meningococcal disease is a relatively rare but still potentially fatal and disabling infection, affecting primarily healthy people of all age groups, and remains an important public health problem.Aims. The aim of the study was to analyze the long-term dynamics of the incidence of MI in the Novosibirsk region (NSO; identification and study of the factors that determined the change in the incidence of MI in 2019 in the region.Materials & Methods. A retrospective comparative epidemiological analysis of the incidence of the population of the Novosibirsk region in 1992–2019 was carried out. using statistical reporting forms No. 2 «Information on infectious and parasitic diseases»; state reports «On the state of sanitary and epidemiological well-being ofthe population oftheRussian Federation» for 1998–2015, and according to the NSO for 2005–2019.Results. An analysis of the epidemiological patterns of MI in the NSO revealed the presence of significant fluctuations in the incidence rates with multiple replacements of the leading strains of meningococcus, in the absence of immunity to all the main pathogens of MI in the vast majority of the region's inhabitants (from 60% to 82.92% of the population in different years remained seronegative to meningococcus serogroup A, 100% of the examined are seronegative to serogroup C). Simultaneously with the change in the epidemic situation in MI in the NSO in 2019, a tendency towards an increase in the incidence of MI was registered during 2016–2019 and in all regions ofCentral Asia, from where the influx oflabor migrants with their families continues. As anti-epidemic measures in risk groups, vaccination was used mainly against meningococcus serogroup A in combination with chemoprophylaxis in contact persons.Conclusion. The NSO (Novosibirsk) is characterized by: dynamic changes in the circulating serogroups of meningococcus, the presence of refugees and migrants with a high risk of infection with local strains and the introduction of new ones, including hypervirulent strains from regions on the transit route; high risk of repeated outbreaks and further complication of the epidemic situation. It is necessary to form a regional vaccine prophylaxis program, taking into account the variability of the etiology of MI and the most effective prevention strategies.

Surface architecture of Neisseria meningitidis capsule and outer membrane as revealed by atomic force microscopy

An extensive morphological analysis of the Neisseria meningitidis cell envelope, including serogroup B capsule and outer membrane, based on atomic force microscopy (AFM) together with mechanical characterization by force spectroscopic measurements, has been carried out. Three meningococcal strains were used: the encapsulated serogroup B strain B1940, and the isogenic mutants B1940 siaD(+C) (lacking capsule), and B1940 cps (lacking both capsule and lipooligosaccharide outer core). AFM experiments with the encapsulated strain B1940 provided unprecedented images of the meningococcal capsule, which seems to be characterized by protrusions (“bumps”) with the lateral dimensions of about 30 nm. Measurement of the Young's modulus provided quantitative assessment of the property of the capsule to confer resistance to mechanical stress. Moreover, Raman spectroscopy gave a fingerprint by which it was possible to identify the specific molecular species of the three strains analyzed, and to highlight major differences between them.

Deconvolution of intergenic polymorphisms determining high expression of Factor H binding protein in meningococcus and their association with invasive disease.

Neisseria meningitidis is a strictly human pathogen and is the major cause of septicemia and meningitis worldwide. Factor H binding protein (fHbp) is a meningococcal surface-exposed lipoprotein that binds the human Complement factor H allowing the bacterium to evade the host innate immune response. FHbp is also a key antigen in two vaccines against N. meningitidis serogroup B. Although the fHbp gene is present in most circulating meningococcal strains, level of fHbp expression varies among isolates and has been correlated to differences in promoter sequences upstream of the gene. Here we elucidated the sequence determinants that control fHbp expression in globally circulating strains. We analyzed the upstream fHbp intergenic region (fIR) of more than 5800 strains representative of the UK circulating isolates and we identified eleven fIR sequence alleles which represent 88% of meningococcal strains. By engineering isogenic recombinant strains where fHbp expression was under the control of each of the eleven fIR alleles, we confirmed that the fIR sequence determines a specific and distinct level of expression. Moreover, we identified the molecular basis for variation in expression through polymorphisms within key regulatory regions that are known to affect fHbp expression. We experimentally established three expression groups, high-medium-low, that correlated directly with the susceptibility to killing mediated by anti-fHbp antibodies and the ability of the meningococcal strain to survive within human serum. By using this sequence classification and information about the variant, we predicted fHbp expression in the panel of UK strains and we observed that strains with higher expressing fIR alleles are more likely associated with invasive disease. Overall, our findings can contribute to understand and predict vaccine coverage mediated by fHbp as well as to shed light on the role of this virulence factor in determining an invasive phenotype.

Serogroup B invasive meningococcal disease (IMD) outbreak at a Japanese high school dormitory: An outbreak investigation report from the first IMD outbreak in decades

PurposeThe first outbreak of invasive meningococcal disease (IMD) in decades occurred in a high school dormitory in 2011. This report aims to describe the results of the IMD outbreak investigation and to discuss current issues of IMD in Japan. MethodsWe conducted an epidemiological and microbiological investigation against the IMD outbreak of serogroup B among students and staff in a high school dormitory. Information on patients was collected to analyze risk factors for IMD. Control measures and public health actions were summarized. ResultsThree cases of meningitis and two cases of bacteremia were identified. Freshmen (15–16 years old) living in the dormitory with preceding cough were high-risk populations in this outbreak. Pulsed-field gel electrophoresis, multilocus sequence typing, and porA gene sequencing results revealed that all isolates were closely related to each other and had deep similarities to the domestic circulating meningococcal strain. The outbreak was terminated after promptly implementing control measures. Based on the results of our investigation, from April 2013, national infectious disease surveillance started to target meningococcal bacteremia as part of IMD, in addition to meningococcal meningitis, which was newly designated as a category II school infectious disease under the School Health and Safety Act. ConclusionsThis outbreak has enhanced public health measures against IMD in Japan. The development of national guidelines for appropriate public health interventions on the IMD outbreak response including chemoprophylaxis is still needed.

Molecular characterization of invasive serogroup B Neisseria meningitidis isolates from Spain during 2015–2018: Evolution of the vaccine antigen factor H binding protein (FHbp)

108, 103, 87 and 112 invasive MenB strains isolated during 2015-2018, respectively, were received at NRL. The strains were whole genome sequenced, and porA, fetA, MLST and fHbp variability was analyzed. Potential impact on MenB vaccines coverage was also assessed. A total of 42, 38 and 3 different FHbp subfamily A, B and A/B hybrid peptides, respectively, were found. FHbp subfamily A peptides were harboured by most of the strains (65.9%), being the most prevalent peptide 45 which was associated with genosubtype 22,14 and cc213. FHbp subfamily B peptides were harboured by 32.4% of the strains, and 6 strains harbouring subfamily A/B hybrid peptides were also found. The 64.15% of the strains showed FHbp variants "exact-match" or "cross-reactive" to the FHbp variants included in rLP2086 vaccine according to hSBA assays in the rLP2086 clinical development, and 15.85% showed FHbp peptides defined as predictors of FHbp-coverage for 4CMenB vaccine by gMATS. Due to invasive meningococcal strains temporal variability (eg prevalence of the cc213 increased from 3.6% in 2007 to 33% in 2018) affecting to the presence and distribution of the vaccine antigens, continuous detailed meningococcal surveillance and monitoring of the vaccine antigens is needed to determine the degree and durability of coverage provided by these protein vaccine.

Immunogenicity of the UK group B meningococcal vaccine (4CMenB) schedule against groups B and C meningococcal strains (Sched3): outcomes of a multicentre, open-label, randomised controlled trial

The use of the multicomponent meningococcal vaccine 4CMenB in the UK schedule at 2, 4, and 12 months of age has been shown to be 59·1% effective at preventing invasive group B meningococcal disease. Here, we report the first data on the immunogenicity of this reduced-dose schedule to help to interpret this effectiveness estimate. In this multicentre, parallel-group, open-label, randomised clinical trial, infants aged up to 13 weeks due to receive their primary immunisations were recruited via child health database mailouts in Oxfordshire and via general practice surgeries in Gloucestershire and Hertfordshire. Infants were randomly assigned (1:1) with permuted block randomisation to receive a 2 + 1 (2, 4, and 12 months; group 1) or 1 + 1 (3 and 12 months; group 2) schedule of the 13-valent pneumococcal conjugate vaccine (PCV13). All infants also received 4CMenB at 2, 4, and 12 months of age, and had blood samples taken at 5 and 13 months. Participants and clinical trial staff were not masked to treatment allocation. Proportions of participants with human complement serum bactericidal antibody (hSBA) titres of at least 4 were determined for group B meningococcus (MenB) reference strains 5/99 (Neisserial Adhesin A [NadA]), NZ98/254 (porin A), and 44/76-SL (factor H binding protein [fHbp]). Geometric mean titres (GMTs) with 95% CIs were also calculated, and concomitant vaccine responses (group C meningococcus [MenC], Haemophilus influenzae b [Hib], tetanus, diphtheria, and pertussis) were compared between groups. The primary outcome was PCV13 immunogenicity, with 4CMenB immunogenicity and reactogenicity as secondary outcomes. All individuals by randomised group with a laboratory result were included in the analysis. The study is registered on the EudraCT clinical trials database, 2015-000817-32, and ClinicalTrials.gov, NCT02482636, and is complete. Between Sept 22, 2015, and Nov 1, 2017, of 376 infants screened, 213 were enrolled (106 in group 1 and 107 in group 2). 204 samples post-primary immunisation and 180 post-boost were available for analysis. The proportion of participants with hSBA of at least 4 was similar in the two study groups. For strain 5/99, all participants developed hSBA titres above 4 in both groups and at both timepoints. For strain 44/76-SL, these proportions were 95·3% (95% CI 88·5-98·7) or above post-priming (82 of 86 participants in group 1), and 92·4% (84·2-97·2) or above post-boost (73 of 79 participants in group 1). For strain NZ98/254, these proportions were 86·5% (78·0-92·6) or above post-priming (83 of 96 participants in group 2) and 88·6% (79·5-94·7) or above post-boost (70 of 79 participants in group 1). The MenC rabbit complement serum bactericidal antibody (rSBA) titre in group 1 was significantly higher than in group 2 (888·3 vs 540·4; p=0·025). There was no significant difference in geometric mean concentrations between groups 1 and 2 for diphtheria, tetanus, Hib, and pertussis post-boost. A very small number of children did not have a protective response against 44/76-SL and NZ98/254. Local and systemic reactions were similar between the two groups, apart from the 3 month timepoint when one group received an extra dose of PCV13 and recorded more systemic reactions. These data support the recent change to the licensed European schedule for 4CMenB to add an infant 2 + 1 schedule, as used in the routine UK vaccine programme with an effectiveness of 59·1%. When compared with historical data, our data do not suggest that effectiveness would be higher with a 3 + 1 schedule, however a suboptimal boost response for bactericidal antibodies against vaccine antigen fHbp suggests a need for ongoing surveillance for vaccine breakthroughs due to fHbp-matched strains. Changing from a 2 + 1 to a 1 + 1 schedule for PCV13 for the UK is unlikely to affect protection against diphtheria, tetanus, and Hib, however an unexpected reduction in bactericidal antibodies against MenC seen with the new schedule suggests that ongoing surveillance for re-emergent MenC disease is important. Bill & Melinda Gates Foundation and the National Institute for Health Research.

Клинико-микробиологические особенности менингококковой инфекции у детей

The threat of a pandemic of meningococcal infection, the severity of the disease and the unpredictability of outcomes necessitate monitoring of the characteristics of the disease course and the circulating serotypes of meningococcus. The purpose — to study the features of the clinical manifestations of meningococcal infection in children depending on the serogroup of N. meningitidis, as well as the phenotypic and genotypic characteristics of the pathogen. Material and methods. 97 children with invasive meningococcal infection with the established serogroup N. meningitidis, hospitalized in 2014–2020, were under observation at PRCCID. We also analyzed 15 discharge epicrises of children with invasive meningococcal infection caused by N. meningitidis W, hospitalized in hospitals in Moscow (Infectious Diseases Hospital No. 2 and Children’s City Clinical Hospital named after Z.A. Bashlyaeva) in 2017–2019. The study of the phenotypic and genotypic characteristics of the pathogen was carried out by the analysis of 34 strains of meningococcus isolated at PRCCID. Results. It was found that in the disease caused by NmW, in 29% of cases (n = 9), there was a subacute onset of the disease with a delayed appearance of an abundant hemorrhagic rash with a predominant localization on the distal extremities (p < 0,01). Also, with NmW in 22,6% (n = 7) cases, the development of convulsive syndrome is noted in 22,6% (n = 7) cases (p < 0,01). NmB is characterized (65,3%, n = 34) by multiple elements of hemorrhagic rash and the formation of soft tissue neuroses (46,2%, n = 24). Focal neurological symptoms were predominantly observed in children with HFMI caused by NmC (23,5%, n = 4) and NmW (13,3%, n = 4). It is noteworthy that among the atypical manifestations of meningococcal infection in NmW, diarrhea, pain in the abdomen and joints, myalgia were most often noted, and conjunctivitis in NmC. Intracranial complications are observed mainly in children with the disease caused by NmB (36,0%, n = 9) and NmC (24%, n = 6), extracranial — by NmB (50%, n = 5), and intracranial + extracranial — by NmW (26,8%, n = 11) and NmB (51,2%, n = 21). Analysis of the phenotypic and genotypic features of invasive meningococcal infection, depending on the pathogen, revealed meningococcal strains (54,1%, n = 20) with reduced sensitivity to antibacterial drugs, as well as 12 NmW strains (ST-11, cc11), closely located to Anglo-French and Swedish subgroup of the Hajj cluster. Conclusion. The features of the clinical manifestations of meningococcal infection in children largely depend on the serotype of the causally significant meningococcus, the timely diagnosis of which makes it possible to predict the course of the disease. It has been established that currently among circulating meningococci there are meningococcal strains with reduced sensitivity to antibacterial drugs (54,1%, n = 20), as well as NmW strains (ST-11, cc11), close to Anglo-French and Swedish subgroups of the Hajj cluster (35,3%, n = 12). This situation requires continuous monitoring of the phenotypic and genotypic characteristics of the microorganism to optimize management tactics.

Modelling the Impact of COVID-19 on Meningococcal Carriage and Disease in the UK

Background: Enforced country-wide social distancing and suspension of most non-emergency medical care due to the COVID-19 pandemic will undoubtedly affect public health in multiple ways. While non-pharmaceutical interventions are expected to reduce transmission of several infectious diseases, severe disruptions to healthcare systems have hampered diagnosis, treatment, and routine vaccination. We examine the effect of this disruption on meningococcal disease and vaccination in the UK.Methods: By adapting an existing mathematical model for meningococcal carriage and disease, we address the following questions: a) What is the predicted impact of social distancing on infection rates? b) What effect might reductions in vaccine uptake have on future infection rates? c) Will catch-up vaccination campaigns be necessary for the adolescent MenACWY vaccine?Findings: Model findings indicate that COVID-19 social distancing is expected to have caused significant reductions in the carriage prevalence of meningococcal strains A, C, W, and Y. In all scenarios modelled, pandemic social mixing assumptions outweighed potential falls in vaccine uptake (of 10%, 34%, and 50%). Furthermore, a return to pre-pandemic carriage prevalence is expected to be slow, greater than 20 years.Interpretation: COVID-19 social distancing is expected to have caused significant reductions in the carriage prevalence of meningococcal strains A, C, W, and Y. It seems unlikely that a MenACWY catch-up campaign is necessary due to the persisting low carriage prevalence we predict. Funding Information: Wellcome Trust; NIHR Health Protection Research Unit in Immunisation.Declaration of Interests: Authors have no competing interests to declare.

Immunogenicity of antigens from outer membrane vesicles of Neisseria meningitidis associated with bilayer fragment of dioctadecyldimethylammonium in Swiss adult mice.

PurposeIn the present study, meningococcal serogroup B outer membrane vesicles (OMVs) were associated with bilayer fragments of a cationic lipid, dioctadecyldimethylammonium (DDA-BF), used as adjuvant, in an antigenic preparation tested in adult female outbred mice. This adjuvant was compared to the traditional adjuvant aluminum hydroxide.Materials and MethodsThe potential in generating humoral response was evaluated by enzyme-linked immunosorbent assay (ELISA). Individual serum was collected and immunoglobulin G (IgG), IgG1, IgG2a, and IgG2b were quantified. Analyses were carried out 15 and 60 days after immunization. Antibodies avidity index were also analyzed by ELISA. Immunoblot and dot-ELISA were carried out to evaluate specific reaction for homologous strains and cross-reactive antigens present in other meningococcal strains isolated in 2011–2012 year, in Brazil. Delayed type hypersensitivity was used as indicative of cellular immunity and compared between two experimental groups, 24 hours after homologous strain challenge.ResultsThe OMVs of Neisseria meningitidis, and N. lactamica (related species) were characterized by electrophoretic separation of proteins in 13% polyacrylamide gel. The strains presented antigens in the range of 8 to 130 kDa, showing a heterogeneous protein migration pattern. In the group immunized with OMVs/DDA-BF, we found no significant production of total IgG 15 days after the first immunization. On the other hand, 60 days after first immunization both adjuvants act benefiting total IgG production similarly. The antibodies of the IgG isotype produced by animals immunized after one or two doses after first immunization, showed intermediate and high avidity, independent on the adjuvant used. In both experimental groups the swelling of the footpads was significantly higher than those of the controls, suggesting that only one dose was enough to stimulate the generation of cellular immunity.ConclusionThe use of this cationic adjuvant for N. meningitidis OMVs preparation revealed good potential for future new antigen preparation for N. meningitidis vaccine.

7. Two-Dose 4CMenB Vaccination in Adolescents Elicits a Bactericidal Activity against 15 Outbreak-Representative Meningococcal Strains

BackgroundMeningococcal outbreaks have often been associated with N. meningitidis serogroup B (MenB) in high-income countries. We examined whether antibodies elicited by the 4-component MenB vaccine (4CMenB) in adolescents could induce complement-mediated bacterial killing of a panel of 14 genetically diverse MenB strains representative of outbreaks that occurred from 2001 to 2016 (11 from the US, 2 from the UK, and 1 from France). One N. meningitidis serogroup W (MenW) hyperendemic strain (UK, 2011) was also included in the analysis.MethodsIn a previous multicenter study (NCT02212457), adolescents aged 10-18y received 2 4CMenB doses 2 months apart. We tested individual sera collected from a subgroup of 20 US participants at pre-vaccination and 1 month post-second dose in a serum bactericidal assay with human complement (hSBA) against the meningococcal strain panel. Similarly, sera collected from 23 Chilean adolescents aged 11-17y (NCT00661713) were tested in a hSBA against a subset of 4 strains (3 from the US, 1 from the UK).ResultsAt baseline, the percentage of US subjects with seroprotective titers (hSBA ≥ 1:4) ranged from 5% to 35%. One month after 4CMenB series completion, 65% to 100% had seroprotective titers (hSBA ≥ 1:4) against 11 out of the 14 MenB tested strains. The seroprotection rate was 45%, 25%, and 15% against the 3 remaining MenB strains. Against MenW, the percentage of adolescents with hSBA titers ≥ 1:4 was 15% at baseline and 95% one month after series completion. No significant changes in the percentage of subjects were observed when analysing hSBA titers ≥ 1:8. Moreover, the subset analysis indicated similar results for US and Chilean subjects for 3 out of 4 strains: the percentage of US vs Chilean subjects with hSBA titers ≥ 1:4 was 100% vs 100%; 80% vs 74%; 45% vs 52%. For the 4th strain, 65% of US subjects vs 91% of Chilean subjects showed a hSBA ≥ 1:4.Conclusion4CMenB elicited bactericidal antibodies against a panel of 14 outbreak-representative MenB strains and 1 MenW hyperendemic strain in US adolescents. No major differences were detected in the bactericidal activity of Chilean subjects vaccinated with 4CMenB when tested against a subset of 4 MenB outbreak strains, suggesting that the immune response to 4CMenB is comparable in adolescents from different geographic areas.DisclosuresAlessia Biolchi, n/a, GSK (Employee) Sara Tomei, n/a, GSK (Employee) Laura Santini, n/a, GSK (Employee) Rita La Gaetana, n/a, GSK Vaccines (Employee, Shareholder) Elena Mori, n/a, GSK (Employee) Patricia Novy, PhD, GSK (Employee, Shareholder) Rino Rappuoli, PhD, GSK (Employee) Rafik Bekkat-Berkani, M.D, GSK (Employee, Shareholder) Marzia Monica Giuliani, n/a, GSK (Employee, Shareholder) Mariagrazia Pizza, Biological Sciences, PhD, GSK Vaccines (Employee)

Molecular insights into meningococcal carriage isolates from Burkina Faso 7 years after introduction of a serogroup A meningococcal conjugate vaccine.

In 2010, Burkina Faso completed the first nationwide mass-vaccination campaign of a meningococcal A conjugate vaccine, drastically reducing the incidence of disease caused by serogroup A meningococci. Since then, other strains, such as those belonging to serogroups W, X and C, have continued to cause outbreaks within the region. A carriage study was conducted in 2016 and 2017 in the country to characterize the meningococcal strains circulating among healthy individuals following the mass-vaccination campaign. Four cross-sectional carriage evaluation rounds were conducted in two districts of Burkina Faso, Kaya and Ouahigouya. Oropharyngeal swabs were collected for the detection of Neisseria meningitidis by culture. Confirmed N. meningitidis isolates underwent whole-genome sequencing for molecular characterization. Among 13 758 participants, 1035 (7.5 %) N . meningitidis isolates were recovered. Most isolates (934/1035; 90.2 %) were non-groupable and primarily belonged to clonal complex (CC) 192 (822/934; 88 %). Groupable isolates (101/1035; 9.8 %) primarily belonged to CCs associated with recent outbreaks in the region, such as CC11 (serogroup W) and CC10217 (serogroup C); carried serogroup A isolates were not detected. Phylogenetic analysis revealed several CC11 strains circulating within the country, several of which were closely related to invasive isolates. Three sequence types (STs) were identified among eleven CC10217 carriage isolates, two of which have caused recent outbreaks in the region (ST-10217 and ST-12446). Our results show the importance of carriage studies to track the outbreak-associated strains circulating within the population in order to inform future vaccination strategies and molecular surveillance programmes.

4CMenB Immunization Induces Serum Bactericidal Antibodies Against Non-SerogroupB Meningococcal Strains in Adolescents.

IntroductionInvasive meningococcal disease (IMD) is an important public health concern. In developed countries, most IMD is caused by meningococcal serogroup B (MenB) and two protein-based MenB vaccines are currently available: the four-component vaccine 4CMenB (Bexsero, GSK) and the bivalent vaccine MenB-FHbp (Trumenba, Pfizer). Genes encoding the 4CMenB vaccine antigens are also present in strains belonging to other meningococcal serogroups.MethodsTo evaluate the potential of 4CMenB vaccination to protect adolescents against non-MenB IMD, we tested the bactericidal activity of sera from immunized adolescents on 147 (127 European and 20 Brazilian) non-MenB IMD isolates, with a serum bactericidal antibody assay using human complement (hSBA). Serum pools were prepared using samples from randomly selected participants in various clinical trials, pre- and post-vaccination: 12 adolescents who received two doses of 4CMenB 2 months apart, and 10 adolescents who received a single dose of a MenACWY conjugate vaccine (as positive control).Results4CMenB pre-immune sera killed 7.5% of the 147 non-MenB isolates at hSBA titers ≥ 1:4. In total, 91 (61.9%) tested isolates were killed by post-dose 2 pooled sera at hSBA titers ≥ 1:4, corresponding to 44/80 (55.0%) MenC, 26/35 (74.3%) MenW, and 21/32 (65.6%) MenY isolates killed.Conclusion4CMenB vaccination in adolescents induces bactericidal killing of non-MenB isolates, suggesting that mass vaccination could impact IMD due to serogroups other than MenB.

The Level of Meningococcal Carriage and Genotyping of N. meningitidis Strains in the Group of Labor Migrants

Relevance. Population migration can play a crucial role in the spread of invasive strains of meningococcus, initiating outbreaks of meningococcal infection, and changing the incidence at the local level.Aim. To assess the prevalence of meningococcal carriage among migrants arriving in Moscow and to characterize the antigenic and genetic properties of carrier strains of meningococcus.Materials and methods. The study was conducted in March 2020 at the bases of the Multifunctional Migration Center of Moscow and the Federal Budget Institution of Science «Central Research Institute of Epidemiology». Samples of nasopharyngeal mucus were collected from 352 people. Nasopharyngeal strains of meningococcus were identified and identified using microbiological, serological, and molecular biological methods.Results. The overall level of the carriage was 5.7%. Of the twenty selected strains, 10 have a serogroup defined: Y – 5 strains, W - 3, A, and B – 1 each. The obtained genetic and antigenic characteristics do not allow talking about the import into the RF of representatives of known hypervirulent clonal complexes. In this study, strains were identified that are part of the clonal complex ST-175 complex, which has not been previously described in the Russian Federation.Conclusion. It seems promising to continue the dynamic monitoring of carriage of meningococcus in various groups, including among people entering the country to obtain a migration patent, as well as identifying risk factors for acquiring carriage. The data obtained will supplement current information on the incidence of the generalized form of meningococcal infection and will be crucial for determining the epidemiology at the country level, the population groups responsible for the transmission of the disease, and the need for targeted vaccination.

Predicted coverage by 4CMenB vaccine against invasive meningococcal disease cases in the Netherlands

Neisseria meningitidis serogroup B is a major cause of invasive meningococcal disease in Europe. In the absence of a conjugate serogroup B vaccine, a subcapsular 4CMenB vaccine was developed. Data on 4CMenB vaccine efficacy is still limited. Recently, genomic MATS (Meningococcal Antigen Typing System) was developed as a tool to predict strain coverage, using vaccine antigens sequence data. We characterized all invasive meningococcal isolates received by the Netherlands Reference Laboratory for Bacterial Meningitis (NRLBM) in two epidemiological years 2017–2019 using whole-genome sequencing and determined serogroup, clonal complex (cc) and estimated 4CMenB vaccine coverage by gMATS. Of 396 cases of invasive meningococcal disease, corresponding to an incidence of 1.22 cases/105 inhabitants, 180 (45%) were serogroup W, 155 (39%) serogroup B, 46 (12%) serogroup Y, 10 (3%) serogroup C, 2 non-groupable (0.5%) and 3 (0.7%) unknown. The incidence was the highest among 0–4 years olds (4 cases/105 inhabitants), and 57/72 (79%) of these cases were serogroup B. Serogroup W predominated among persons 45 years of age or older with 110/187 (59%) cases. Serogroup B isolates comprised 11 different clonal complexes, with 103/122 (84%) isolates belonging to 4 clonal complexes: cc32, cc41/44, cc269 and cc213. In contrast, serogroup W isolates were genetically similar with 95% belonging to cc11. Of 122 serogroup B isolates, 89 (73%; 95% CI: 64–80%) were estimated to be covered by 4CMenB and the degree of coverage varied largely by clonal complex and age. Among the 0–4 year olds, 25 of 43 (58%; 95% CI: 43–72%) MenB isolates were estimated to be covered. Since the coverage of the 4CMenB vaccine is dependent on circulating clonal complexes, our findings emphasize the need for surveillance of circulating meningococcal strains. In addition, estimation of age specific coverage is relevant to determine the right target age group for vaccination.

4CMenB vaccine induces elite cross-protective human antibodies that compete with human factor H for binding to meningococcal fHbp.

Neisseria meningitidis serogroup B (MenB) is the leading cause of meningococcal meningitis and sepsis in industrialized countries, with the highest incidence in infants and adolescents. Two recombinant protein vaccines that protect against MenB are now available (i.e. 4CMenB and MenB-fHbp). Both vaccines contain the Factor H Binding Protein (fHbp) antigen, which can bind the Human Factor H (fH), the main negative regulator of the alternative complement pathway, thus enabling bacterial survival in the blood. fHbp is present in meningococcal strains as three main variants which are immunologically distinct. Here we sought to obtain detailed information about the epitopes targeted by anti-fHbp antibodies induced by immunization with the 4CMenB multicomponent vaccine. Thirteen anti-fHbp human monoclonal antibodies (mAbs) were identified in a library of over 100 antibody fragments (Fabs) obtained from three healthy adult volunteers immunized with 4CMenB. Herein, the key cross-reactive mAbs were further characterized for antigen binding affinity, complement-mediated serum bactericidal activity (SBA) and the ability to inhibit binding of fH to live bacteria. For the first time, we identified a subset of anti-fHbp mAbs able to elicit human SBA against strains with all three variants and able to compete with human fH for fHbp binding. We present the crystal structure of fHbp v1.1 complexed with human antibody 4B3. The structure, combined with mutagenesis and binding studies, revealed the critical cross-reactive epitope. The structure also provided the molecular basis of competition for fH binding. These data suggest that the fH binding site on fHbp v1.1 can be accessible to the human immune system upon immunization, enabling elicitation of human mAbs broadly protective against MenB. The novel structural, biochemical and functional data are of great significance because the human vaccine-elicited mAbs are the first reported to inhibit the binding of fH to fHbp, and are bactericidal with human complement. Our studies provide molecular insights into the human immune response to the 4CMenB meningococcal vaccine and fuel the rationale for combined structural, immunological and functional studies when seeking deeper understanding of the mechanisms of action of human vaccines.

MenB-FHbp Vaccine Protects Against Diverse Meningococcal Strains in Adolescents and Young Adults: Post Hoc Analysis of Two Phase 3 Studies.

IntroductionTwo phase 3 studies in adolescents and young adults demonstrated that MenB-FHbp, a meningococcal serogroup B (MenB) vaccine, elicits protective immune responses after 2 or 3 doses based on serum bactericidal antibody assays using human complement (hSBA) against 4 primary and 10 additional diverse, vaccine-heterologous MenB test strains. Lower limits of quantitation (LLOQs; titers 1:8 or 1:16; titers ≥ 1:4 correlate with protection) were used to evaluate responses to individual strains and all 4 primary strains combined (composite response). A post hoc analysis evaluated percentages of subjects with protective responses to as many as 8 strains combined (4 primary plus additional strains).MethodsImmune responses were measured using hSBAs against 4 primary strains in adolescents (n = 1509, MenB-FHbp; n = 898, hepatitis A virus vaccine/saline) and young adults (n = 2480, MenB-FHbp; n = 824, saline) receiving MenB-FHbp or control at 0, 2, and 6 months. Ten additional strains were evaluated in subsets of subjects from approximately 1800 MenB-FHbp recipients across both studies. Percentages of subjects with hSBA titers ≥ LLOQ for different numbers of primary strains or primary plus additional strains combined (7 or 8 strains total per subset) were determined before vaccination, 1 month post-dose 2, and 1 month post-dose 3.ResultsAcross the panel of primary plus additional strains, at 1 month post-dose 3, titers ≥ LLOQ were elicited in 93.7–95.7% of adolescents and 91.7–95.0% of young adults for ≥ 5 test strains combined and in 70.5–85.8% of adolescents and 67.5–81.4% of young adults for ≥ 7 strains combined. Among adolescents, 99.8%, 99.0%, 92.8%, and 82.7% had titers ≥ LLOQ against at least 1, 2, 3, and all 4 primary strains, respectively; corresponding percentages for young adults were 99.7%, 97.7%, 94.0%, and 84.5%.ConclusionsResults support the ability of MenB-FHbp to provide broad coverage against MenB strains expressing diverse FHbp variants.Trial RegistrationClinicalTrials.gov identifiers NCT01830855, NCT01352845.Electronic supplementary materialThe online version of this article (10.1007/s40121-020-00319-0) contains supplementary material, which is available to authorized users.

Polymorphism at variable regions (VRs) of porA gene from Neisseria meningitidis strains isolated in Northern Vietnam

Meningococcal bacterium Neisseria meningitidis is one of the major causes of meningitis worldwide. Currently in Vietnam, N. meningitidis B and C are the most prevalent invasive serogroups. N. meningitidis expresses two major transmembrane proteins, PorA and PorB, of which PorA showed high levels of polymorphism among strains and has been studied as one component of vaccines against N. meningitidis B. Polymorphisms in porA gene clustered into three variable regions VR1, VR2 and VR3. In this study, we sequenced the entired porA gene of 19 N. meningitidis strains isolated from military units in northern Vietnam during the period 2008 – 2017 in order to: (1) evaluate the polymorphism of porA gene at nucleotide level and predict its immuno-reactivity from annotated amino acide sequences; and (2) compare porA variants of Vietnamese strains with known strains worldwide. Our results showed a high level of polymorphisms among Vietnamese strains, with the highest polymorphism found in VR1, followed by VR2 and VR3. Notably, 5/19 strains in this study showed novel variants at VR2 with unknown immunological reactivity. This result suggested potential novel immunological characteristics of meningococcal strains from Vietnam.

Epidemiological Characteristics of Meningococcal Infection in Moscow

Aims. The purpose of this study was to identify current epidemiological features of meningococcal infection in Moscow.Materials and methods. Cases of invasive meningococcal disease in Moscow from 2014 to 2018 and the biomaterial from patients with an invasive meningococcal disease were analyzed.Results. The features of the epidemic process of meningococcal disease in Moscow were revealed: increasing in the incidence rate involving teenagers and young adults into the epidemic process; meningococcal strains of serogroups W and A increased in the etiology of the invasive meningococcal disease; high mortality rate.Conclusions. It seems reasonable to recommend vaccination against meningococcal disease by including adolescents, young adults and persons over 65 years old.

Epidemiological Characteristics of Meningococcal Infection in Moscow

Aims. The purpose of this study was to identify current epidemiological features of meningococcal infection in Moscow.Materials and methods. Cases of invasive meningococcal disease in Moscow from 2014 to 2018 and the biomaterial from patients with an invasive meningococcal disease were analyzed.Results. The features of the epidemic process of meningococcal disease in Moscow were revealed: increasing in the incidence rate involving teenagers and young adults into the epidemic process; meningococcal strains of serogroups W and A increased in the etiology of the invasive meningococcal disease; high mortality rate.Conclusions. It seems reasonable to recommend vaccination against meningococcal disease by including adolescents, young adults and persons over 65 years old.

Immunogenicity and Reactogenicity of a Reduced Schedule of a 4-component Capsular Group B Meningococcal Vaccine: A Randomized Controlled Trial in Infants.

The 4-component capsular group B meningococcal vaccine (4CMenB) was licensed as a 4-dose infant schedule but introduced into the United Kingdom as 3 doses at 2, 4, and 12 months of age. We describe the immunogenicity and reactogenicity of the 2 + 1 schedule in infants. Infants were randomized to receive 4CMenB with routine immunizations (test group) at 2, 4, and 12 months or 4CMenB alone at 6, 8, and 13 months of age (control group). Serum bactericidal antibody (SBA) assay against a serogroup B meningococcal reference strain (44/76-SL), memory B-cell responses to factor H binding protein, Neisseria adhesion protein A, Neisseria heparin binding antigen, Porin A (PorA), and reactogenicity was measured. One hundred eighty-seven infants were randomized (test group: 94; control group: 93). In the test group, 4CMenB induced SBA titers above the putative protective threshold (1:4) after primary and booster doses in 97% of participants. Postbooster, the SBA GMT (72.1; 95% confidence interval [CI], 51.7-100.4) was numerically higher than the serum bactericidal antibody geometric mean titre (SBA GMT) determined post-primary vaccination (48.6; 95% CI, 37.2-63.4). After primary immunizations, memory B-cell responses did not change when compared with baseline controls, but frequencies significantly increased after booster. Higher frequency of local and systemic adverse reactions was associated with 4CMenB. A reduced schedule of 4CMenB was immunogenic and established immunological memory after booster.