title: Hepatitis B immune memory in children primed with hexavalent vaccines and given monovalent booster vaccines: an open-label, randomised, controlled, multicentre study.
abstract: BACKGROUND
  In 2000, hexavac and infanrix hexa were licensed in Europe for primary immunisation of children against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, and invasive infections caused by Haemophilus influenzae b. In 2005, hexavac was suspended because of concerns about the long-term immunogenicity of its hepatitis B component. We aimed to assess the duration of immunity and need for booster injections in children primed with these vaccines.
  
  
  METHODS
  In an open-label, randomised, controlled, multicentre study in six local health units and at the Bambino Gesù Paediatric Research Hospital in Italy, antibody concentrations were measured 5 years after immunisation of infants with hexavac or infanrix hexa. Children with concentrations of antibodies to hepatitis B surface antigen (anti-HBs) lower than 10 mIU/mL were randomly assigned by simple randomisation to receive a booster of HBVaxPro or engerix B monovalent hepatitis B vaccine and tested 2 weeks later. Primary endpoints were the proportion of children with anti-HBs concentrations of at least 10 mIU/mL, geometric mean concentrations (GMCs) of antibody 5 years after vaccination, and the proportion of children with anti-HBs concentrations lower than 10 mIU/mL who had anamnestic response to booster. The study is registered with Agenzia Italiana del Farmaco, code FARM67NFPN.
  
  
  RESULTS
  1543 children were enrolled, 833 had received hexavac and 710 infanrix hexa. 831 children who received hexavac and 709 who received infanrix hexa were included in the analysis. 319 children who received hexavac (38.4%, 95% CI 35.1-41.7) had anti-HBs concentrations of at least 10 mIU/mL compared with 590 who received infanrix hexa (83.2%, 80.5-86.0; p<0.0001). GMCs before booster were 4.5 mIU/mL in the hexavac group compared with 61.3 mIU/mL in the infanrix hexa group (p<0.0001). After booster 409 (92.1%, 89.6-94.6) of 444 children primed with hexavac and 99 (94.3%, 89.8-98.7) of 105 primed with infanrix hexa had anti-HBs concentrations of at least 10 mIU/mL (p=0.4); GMCs were 448.7 mIU/mL and 484.9 mIU/mL (p=0·6). The two booster vaccine groups did not differ in number of side-effects; no serious adverse events were reported.
  
  
  CONCLUSIONS
  5 years after immunisation with hexavalent vaccines, immunological memory seems to persist in children with anti-HBs concentrations lower than 10 mIU/mL, suggesting that booster doses are not needed. Additional follow-up is needed.
  
  
  BACKGROUND
  Agenzia Italiana del Farmaco.
authors.affiliation: Department of Public Health-Microbiology-Virology, University of Milan, Milan, Italy. alessandro.zanetti@unimi.it
authors.forename: Alessandro Remo
authors.initials: AR
authors.lastname: Zanetti
authors.forename: Luisa
authors.initials: L
authors.lastname: Romanò
authors.forename: Cristina
authors.initials: C
authors.lastname: Giambi
authors.forename: Anna
authors.initials: A
authors.lastname: Pavan
authors.forename: Vito
authors.initials: V
authors.lastname: Carnelli
authors.forename: Guglielmino
authors.initials: G
authors.lastname: Baitelli
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Malchiodi
authors.forename: Edgardo
authors.initials: E
authors.lastname: Valerio
authors.forename: Antonella
authors.initials: A
authors.lastname: Barale
authors.forename: Maria Anna
authors.initials: MA
authors.lastname: Marchisio
authors.forename: Domenico
authors.initials: D
authors.lastname: Montù
authors.forename: Alberto Eugenio
authors.initials: AE
authors.lastname: Tozzi
authors.forename: Fortunato
authors.initials: F
authors.lastname: D'Ancona
mesh_terms: D002648:Child; D002675:Child, Preschool; D015721:Diphtheria-Tetanus-Pertussis Vaccine / Q000008:administration & dosage / Q000276:immunology*; D022681:Diphtheria-Tetanus-acellular Pertussis Vaccines / Q000008:administration & dosage / Q000276:immunology*; D005260:Female; D006509:Hepatitis B / Q000276:immunology* / Q000517:prevention & control; D006510:Hepatitis B Antibodies / Q000097:blood*; D006514:Hepatitis B Surface Antigens / Q000276:immunology; D017325:Hepatitis B Vaccines / Q000008:administration & dosage / Q000276:immunology*; D006801:Humans; D007117:Immunization, Secondary / Q000379:methods*; D007156:Immunologic Memory; D007558:Italy; D008297:Male; D011054:Poliovirus Vaccine, Inactivated / Q000008:administration & dosage / Q000276:immunology*; D017778:Vaccines, Combined / Q000008:administration & dosage / Q000276:immunology
chemical_list: D015721:Diphtheria-Tetanus-Pertussis Vaccine; D022681:Diphtheria-Tetanus-acellular Pertussis Vaccines; C075654:Engerix-B; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D017325:Hepatitis B Vaccines; C426944:Hexavac; D011054:Poliovirus Vaccine, Inactivated; D017778:Vaccines, Combined