Santolaya, M.E. et al. 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. Lancet 379, 617-624

Departamento de Pediatría, Hospital Dr Luis Calvo Mackenna, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
The Lancet (Impact Factor: 45.22). 02/2012; 379(9816):617-24. DOI: 10.1016/S0140-6736(11)61713-3
Source: PubMed


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, 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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Available from: Miguel Oryan, Oct 27, 2015
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    • "The low rate of withdrawals from the V72P10 study and the similarity of the reactogenicity profiles between 4CMenB and placebo indicate that 4CMenB was generally well tolerated in adolescents [29]. Although 4CMenB vaccinations were associated with higher reactogenicity than placebo injections, local and systemic reactions were mostly of mild or moderate severity. "
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    ABSTRACT: Recently approved in Europe and Australia, the multi-component meningococcal B vaccine, 4CMenB (Bexsero(®), Novartis Vaccines and Diagnostics), contains three surface-exposed recombinant proteins (fHbp, NadA, and NHBA) and New Zealand strain outer membrane vesicles (NZ OMV) with PorA 1.4 antigenicity. This comprehensive review of the 4CMenB clinical development program covers pivotal phase I/IIb/III studies in over 7,000 adults, adolescents, and infants. The immunological correlate for clinical protection used was human complement-mediated serum bactericidal activity titers ≥4 or 5 against indicator strains for individual antigens. Based on achievement of protective titers, a four-dose schedule (three primary doses and one booster dose) for infants and a two-dose schedule for adolescents provided the best results. Observed increases in injection site pain/tenderness and fever in infants, and injection site pain, malaise, and headache in adolescents compared with routine vaccines, were mostly mild to moderate; frequencies of rare events (Kawasaki disease, juvenile arthritis) were not significantly different from non-vaccinated individuals. 4CMenB is conservatively estimated to provide 66-91 % coverage against meningococcal serogroup B strains worldwide.
    Full-text · Article · Dec 2013 · Drugs
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    • "Serum samples before and after immunization were obtained from the following clinical trials. Study 1 was a phase 2b/3 clinical trial conducted in healthy adolescents , aged 11–17 years [19]. Two pooled sera preparations were derived from 13 subjects (1) before vaccination and (2) 30 days after the second dose of 4CMenB vaccine, administered 2 months after the first dose. "
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    ABSTRACT: 4CMenB (Bexsero), a vaccine developed against invasive meningococcal disease caused by capsular group B strains (MenB), was recently licensed for use by the European Medicines Agency. Assessment of 4CMenB strain coverage in specific epidemiologic settings is of primary importance to predict vaccination impact on the burden of disease. The Meningococcal Antigen Typing System (MATS) was developed to predict 4CMenB strain coverage, using serum bactericidal antibody assay with human complement (hSBA) data from a diverse panel of strains not representative of any specific epidemiology. To experimentally validate the accuracy of MATS-based predictions against strains representative of a specific epidemiologic setting. We used a stratified sampling method to identify a representative sample from all MenB disease isolates collected from England and Wales in 2007-2008, tested the strains in the hSBA assay with pooled sera from infant and adolescent vaccinees, and compared these results with MATS. MATS predictions and hSBA results were significantly associated (P=0.022). MATS predicted coverage of 70% (95% CI, 55-85%) was largely confirmed by 88% killing in the hSBA (95% CI, 72-95%). MATS had 78% accuracy and 96% positive predictive value against hSBA. MATS is a conservative predictor of strain coverage by the 4CMenB vaccine in infants and adolescents.
    Full-text · Article · Aug 2013 · Vaccine
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    • "While a conjugate meningococcal vaccine for serogroups A, C, Y, and W-135 has shown reductions in meningococcal disease in some populations [3], development of an effective vaccine against serogroup B has been difficult. Recent trials have shown promise in the use of a new multicomponent serogroup B vaccine [7] [8], but currently the lack of a widely available, effective vaccination against N. meningitidis B, as well as the lack of access to vaccinations in populations at risk of epidemics, such as in sub-Saharan Africa, means that N. meningitidis still remains a significant cause of bacterial meningitis [6]. "
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    ABSTRACT: Paediatric bacterial meningitis is a neurological emergency which, despite advances in medical management, still has a significant morbidity and mortality. Over recent decades new vaccines have led to a change in epidemiology of the disease; however, it remains a condition that requires a high index of suspicion, prompt diagnosis, and early management in the emergency department. New laboratory techniques and clinical tools are aiding the diagnosis of bacterial meningitis, yet some controversies still exist in its management. This paper outlines the changing epidemiology of the disease, current diagnostic techniques as well as controversies and advances in the management of bacterial meningitis in the paediatric population.
    Full-text · Article · Sep 2012
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