title: 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: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Novartis Vaccines and Diagnostics.
authors.affiliation: Departamento de Pediatría, Hospital Dr Luis Calvo Mackenna, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: María Elena
authors.initials: ME
authors.lastname: Santolaya
authors.forename: Miguel L
authors.initials: ML
authors.lastname: O'Ryan
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Valenzuela
authors.forename: Valeria
authors.initials: V
authors.lastname: Prado
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Vergara
authors.forename: Alma
authors.initials: A
authors.lastname: Muñoz
authors.forename: Daniela
authors.initials: D
authors.lastname: Toneatto
authors.forename: Gabriela
authors.initials: G
authors.lastname: Graña
authors.forename: Huajun
authors.initials: H
authors.lastname: Wang
authors.forename: Ralf
authors.initials: R
authors.lastname: Clemens
authors.forename: Peter M
authors.initials: PM
authors.lastname: Dull
mesh_terms: D000293:Adolescent; D000704:Analysis of Variance; D002648:Child; D002677:Chile; D005260:Female; D006801:Humans; D008297:Male; D008589:Meningococcal Infections / Q000276:immunology / Q000517:prevention & control*; D022401:Meningococcal Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology*; D038541:Neisseria meningitidis, Serogroup B / Q000276:immunology*; D016037:Single-Blind Method; D016896:Treatment Outcome; D014611:Vaccination / Q000379:methods
chemical_list: C570015:4CMenB vaccine; D022401:Meningococcal Vaccines