Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study.
ABSTRACT Effective glycoconjugate vaccines against Neisseria meningitidis serogroups A, C, W-135, and Y have been developed, but serogroup B remains a major cause of severe invasive disease in infants and adolescents worldwide. We assessed immunogenicity and tolerability of a four-component vaccine (4CMenB) in adolescents.
We did a randomised, observer-blind, placebo-controlled, study at 12 sites in Santiago and Valparaíso, Chile. Adolescents aged 11-17 years received one, two, or three doses of 4CMenB at 1 month, 2 month, or 6 month intervals. Immunogenicity was assessed as serum bactericidal activity using human complement (hSBA) against three reference strains for individual vaccine antigens, and assessed by ELISA against the fourth strain. Local and systemic reactions were recorded 7 days after each vaccination, and adverse events were monitored throughout the study. Participants were initially randomised to five groups (3:3:3:3:1) during the primary phase to receive either one dose, two doses 1 or 2 months apart, or three doses of 4CMenB, or three doses of placebo, with an additional three groups generated for the booster phase. All subjects received at least one dose of 4CMenB. Geometric mean titres, proportions of participants with serum bactericidal antibody titres of 4 or more, and Clopper-Pearson 95% CIs were calculated. The study is registered with ClinicalTrials.gov, number NCT00661713.
Overall, 1631 adolescents (mean age 13·8 [SD 1·9] years) received at least one dose of 4CMenB. After two or three doses, 99-100% of recipients had hSBA titres of 4 or more against test strains, compared with 92-97% after one dose (p<0·0145) and 29-50% after placebo. At 6 months 91-100% of participants still had titres of 4 or more for each strain after two or three doses, but only 73-76% after one dose; seroresponse rates reached 99-100% for each strain after second or third doses at 6 months. Local and systemic reaction rates were similar after each 4CMenB injection and did not increase with subsequent doses, but remained higher than placebo. No vaccine-related serious adverse events were reported and no significant safety signals were identified.
On the basis of immunogenicity responses this study provides evidence for an adolescent 4CMenB vaccine schedule of two doses, 1-6 months apart, to provide protection against meningococcal B infection. The extent of this protection against meningococcus B variants circulating worldwide will be determined by national surveys.
Novartis Vaccines and Diagnostics.
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ABSTRACT: Despite the widespread use of polysaccharide and conjugate vaccines against disease caused by several serogroups of Neisseria meningitidis, vaccines targeting meningococci expressing the serogroup B capsule (MenB) have focused on subcapsular antigens, due to crossreactivity of the polysaccharide with human glycoproteins. Protein vaccines composed of outer membrane vesicles have been used successfully to control epidemics of MenB disease in several countries; however, these are specific for epidemic strains. Currently, a single serogroup B vaccine, aiming to provide comprehensive coverage, has been approved for use, and several others are undergoing clinical trials. Data on potential new vaccine candidates, from discovery to initial preclinical evaluation, are regularly published. In this review, the data required to progress from preclinical to clinical development of MenB vaccines are outlined, with reference to relevant regulatory guidelines. The issues caused by a lack of reliable animal models, particularly with respect to determination of protective efficacy, are also discussed.Expert Review of Vaccines 01/2013; 12(1):31-42. · 4.22 Impact Factor
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ABSTRACT: This study examined the antigenic and genetic diversity of serogroup B Neisseria meningitidis (MenB) recovered from invasive meningococcal disease (IMD) cases in Ontario, Canada for the 10 year period of 2001 to 2010 during which no MenB outbreaks had occurred. MenB was found to be responsible for 39% of all IMD cases, with the remaining cases mainly caused by serogroup Y (28%), serogroup C (24%), and serogroup W135 (8%). One hundred and ninety-three individual MenB case isolates were collected and characterized. Of the 88 sequence types (STs) identified, 75 were grouped into 14 known clonal complexes (CCs) while 13 STs were not assigned to any known CC. Fifty-seven different PorA genotypes and 88 STs defined the diversity of invasive MenB in Ontario, which supported the endemic nature of MenB disease in Ontario. Despite the presence of the hyper-virulent ST-41/44 and ST-32 CCs, no single ST was predominant and responsible for a large number of IMD cases. Although the Québec outbreak clone of ST-269 was also found in Ontario, the 20 case isolates were genetically diverse, grouped into 7 STs and without a predominant PorA genotype. eBURST analysis identified a new CC responsible for 14.5% of the MenB case isolates. The 6 most common PorA VR2 genotypes (VR2-9, 4, 14, 16, 13-1, and 16-3) were found in 67% of invasive MenB isolates.Journal of Medical Microbiology 10/2012; · 2.30 Impact Factor
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ABSTRACT: Septic shock caused by Neisseria meningitidis is typically rapidly evolving and often fatal despite antibiotic therapy. Further understanding of the mechanisms underlying the disease is necessary to reduce fatality rates. Postmortem samples from the characteristic purpuric rashes of the infection show bacterial aggregates in close association with microvessel endothelium but the species specificity of N. meningitidis has previously hindered the development of an in vivo model to study the role of adhesion on disease progression. Here we introduced human dermal microvessels into SCID/Beige mice by xenografting human skin. Bacteria injected intravenously exclusively associated with the human vessel endothelium in the skin graft. Infection was accompanied by a potent inflammatory response with the secretion of human inflammatory cytokines and recruitment of inflammatory cells. Importantly, infection also led to local vascular damage with hemostasis, thrombosis, vascular leakage and finally purpura in the grafted skin, replicating the clinical presentation for the first time in an animal model. The adhesive properties of the type IV pili of N. meningitidis were found to be the main mediator of association with the dermal microvessels in vivo. Bacterial mutants with altered type IV pili function also did not trigger inflammation or lead to vascular damage. This work demonstrates that local type IV pili mediated adhesion of N. meningitidis to the vascular wall, as opposed to circulating bacteria, determines vascular dysfunction in meningococcemia.PLoS Pathogens 01/2013; 9(1):e1003139. · 8.14 Impact Factor