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

Background Meningococcal 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. Methods In 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). Results At 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. Conclusion 4CMenB 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. Disclosures Alessia 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)

Community outbreak of serogroup B invasive meningococcal disease in Beaujolais, France, February to June 2016: from alert to targeted vaccination

In February and March 2016, four cases of serogroup B invasive meningococcal disease (IMD) occurred over 3 weeks in a small area north of Lyon in the Auvergne-Rhône-Alpes region, France. There were no deaths but two cases had sequelae. This community outbreak was caused by a rare meningococcal strain of the clonal complex ST-32, covered by the 4CMenB/Bexsero vaccine. The incidence rate for serogroup B IMD in this area was 22.5 per 100,000 inhabitants, which is above the epidemic threshold (10/100,000). The number of cases observed was significantly higher than expected in the age group of 0–24 year-olds (standardised incidence ratio: 96). These results suggested the potential emergence of this invasive strain in this sub-population. In accordance with French recommendations, it was decided to vaccinate the population aged between 2 months and 24 years, living, working or studying in the epidemic area. The vaccination campaign took place from April to September 2016. Vaccination coverage was estimated at 47% for one dose and 40% for two doses. The lowest coverage estimations were observed for the age groups younger than 3 and 15–19 years. Enhanced epidemiological and microbiological surveillance reported a fifth case in June 2016, outside the epidemic area.

Establishment of the European meningococcal strain collection genome library (EMSC-GL) for the 2011 to 2012 epidemiological year

Invasive meningococcal disease surveillance in Europe combines isolate characterisation and epidemiological data to support public health intervention. A representative European Meningococcal Strain Collection (EMSC) of IMD isolates was obtained, and whole genome sequenced to characterise 799 EMSC isolates from the epidemiological year July 2011–June 2012. To establish a genome library (GL), the isolate information was deposited in the pubMLST.org/neisseria database. Genomes were curated and annotated at 2,429 meningococcal loci, including those defining clonal complex, capsule, antigens, and antimicrobial resistance. Most genomes contained genes encoding B (n = 525; 65.7%) or C (n = 163; 20.4%) capsules; isolates were genetically highly diverse, with >20 genomic lineages, five of which comprising 60.7% (n = 485) of isolates. There were >350 antigenic fine-types: 307 were present once, the most frequent (P1.7-2,4:F5-1) comprised 8% (n = 64) of isolates. Each genome was characterised for Bexsero Antigen Sequence Typing (BAST): 25.5% (n = 204) of isolates contained alleles encoding the fHbp and/or the PorA VR1 vaccine component, but most genomes (n = 513; 64.2%) did not contain the NadA component. EMSC-GL will support an integrated surveillance of disease-associated genotypes in Europe, enabling the monitoring of hyperinvasive lineages, outbreak identification, and supporting vaccine programme implementation.

Organization or Community-Based Outbreak? Responding to Cases of Meningitis Under Epidemiologic Uncertainty

Six cases of serogroup C invasive meningococcal disease were identified in Treviso district, Veneto region, Italy between December 13 and 15, 2007. The afflicted patients were found to have attended the same Latin-dance clubs on the same nights, and chemoprophylaxis was provided to potentially exposed individuals. Despite these efforts, 2 cases caused by the same meningococcal strain subsequently occurred in the same area, without any apparent epidemiological correlation to the initial cases. This may have resulted from a failure to neutralize the meningococcal carrier/s. The root cause analysis method applied to public health emergency preparedness was used to analyze the response to this critical incident. The root cause analysis revealed a need to develop regional guidelines for the classification and management of a meningococcal outbreak and for developing risk-communication strategies that include the identification of appropriate channels of communication for differing segments of the population. (Disaster Med Public Health Preparedness. 2019;13:368–371)

Immunogenicity and Safety of a Combination of Two Serogroup B Meningococcal Outer Membrane Vesicle Vaccines

ABSTRACT MenBvac and MeNZB are safe and efficacious vaccines against serogroup B meningococcal disease. MenBvac is prepared from a B:15:P1.7,16 meningococcal strain (strain 44/76), and MeNZB is prepared from a B:4:P1.7-2,4 strain (strain NZ98/254). At 6-week intervals, healthy adults received three doses of MenBvac (25 μg), MeNZB (25 μg), or the MenBvac and MeNZB (doses of 12.5 μg of each vaccine) vaccines combined, followed by a booster 1 year later. Two-thirds of the subjects who received a monovalent vaccine in the primary schedule received the other monovalent vaccine as a booster dose. The immune responses to the combined vaccine were of the same magnitude as the homologous responses to each individual vaccine observed. At 6 weeks after the third dose, 77% and 87% of the subjects in the combined vaccine group achieved serum bactericidal titers of ≥4 against strains 44/76 and NZ98/254, respectively, and 97% and 93% of the subjects achieved a fourfold or greater increase in opsonophagocytic activity against strains 44/76 and NZ98/254, respectively. For both strains, a trend of higher responses after the booster dose was observed in all groups receiving at least one dose of the respective strain-specific vaccine. Local and systemic reactions were common in all vaccine groups. Most reactions were mild or moderate in intensity, and there were no vaccine-related serious adverse events. The safety profile of the combined vaccine was not different from those of the separate monovalent vaccines. In conclusion, use of either of the single vaccines or the combination of MenBvac and MeNZB may have a considerable impact on the serogroup B meningococcal disease situation in many countries.

MyD88-Dependent Signaling Affects the Development of Meningococcal Sepsis by Nonlipooligosaccharide Ligands

ABSTRACT The Toll-like receptors (TLRs) and the adaptor myeloid differentiation factor 88 (MyD88) are important in the innate immune defenses of the host to microbial infections. Meningococcal ligands signaling via TLRs control inflammatory responses, and stimulation can result in fulminant meningococcal sepsis. In this study, we show that the responses to nonlipooligosaccharide (non-LOS) ligands of meningococci are MyD88 dependent. An isogenic LOS-deficient mutant of the serogroup C meningococcal strain FAM20 caused fatal disease in wild type C57BL/6 mice that was not observed in MyD88−/− mice. Fatality correlated with high proinflammatory cytokine and C5a levels in serum, high neutrophil numbers in blood, and increased bacteremia at 24 h postinfection in the wild-type mice. Infection with the parent strain FAM20 resulted in fatality in 100% of the wild-type mice and 50% of the MyD88−/− mice. We conclude that both LOS and another neisserial ligand cause meningococcal sepsis in an in vivo mouse model and confirm that meningococcal LOS can act via both the MyD88- dependent and -independent pathways, while the non-LOS meningococcal ligand(s) acts only via the MyD88-dependent pathway.

Characterization of MspA, an Immunogenic Autotransporter Protein That Mediates Adhesion to Epithelial and Endothelial Cells in Neisseria meningitidis

ABSTRACT A novel putative autotransporter protein (NMB1998) was identified in the available genomic sequence of meningococcal strain MC58 (ET-5; ST-32). The mspA gene is absent from the genomic sequences of meningococcal strain Z2491 (ET-IV; ST-4) and the gonococcal strain FA1090. An orthologue is present in the meningococcal strain FAM18 (ET-37; ST-11), but the sequence contains a premature stop codon, suggesting that the protein may not be expressed in this strain. MspA is predicted to be a 157-kDa protein with low cysteine content, and it exhibits 36 and 33% identity to the meningococcal autotransporter proteins immunoglobulin A1 (IgA1) protease and App, respectively. Search of the Pfam database predicts the presence of IgA1 protease and autotransporter β-barrel domains. MspA was cloned, and a recombinant protein of the expected size was expressed and after being affinity purified was used to raise rabbit polyclonal monospecific antiserum. Immunoblot studies showed that ca. 125- and 95-kDa fragments of MspA are secreted in meningococcal strain MC58, which are absent from the isogenic mutant. Secretion of MspA was shown to be modified in an AspA isogenic mutant. A strain survey showed that MspA is expressed by all ST-32 and ST-41/44 (lineage 3) strains, but none of the ST-8 (A4) strains examined. Sera from patients convalescing from meningococcal disease were shown to contain MspA-specific antibodies. In bactericidal assays, anti-MspA serum was shown to kill the homologous strain (MC58) and another ST-32 strain. Escherichia coli-expressing recombinant MspA was shown to adhere to both human bronchial epithelial cells and brain microvascular endothelial cells.