title: Comparison of two-dose priming plus 9-month booster with a standard three-dose priming schedule for a ten-valent pneumococcal conjugate vaccine in Nepalese infants: a randomised, controlled, open-label, non-inferiority trial.
abstract: BACKGROUND
  Use of pneumococcal conjugate vaccines (PCVs) in resource-poor countries has focused on early infant immunisation with little emphasis on protection in late infancy and beyond. Boosting of the immune response later in infancy might provide improved persistence of immunogenicity into early childhood, however data are scarce. The aim of this study was to investigate if a two-dose prime with booster at age 9 months compared with a three-dose prime-only PCV schedule provided non-inferior immunogenicity in early infancy and superior persistence of antibody responses in early childhood.
  
  
  METHODS
  We did an open-label, randomised, parallel group, controlled trial in healthy infants aged 40-60 days from Kathmandu, Nepal. Participants were randomly allocated (4:4:5 ratio) to receive PCV10 in addition to routine immunisations either as a two-dose prime and boost (2+1), three-dose prime (3+0), or two doses after completion of the initial study phase (0+2). We used a computer generated randomisation list with randomly varying block sizes. We followed up participants at age 2-4 years together with a group of unvaccinated controls. Sera were analysed for opsonophagocytic activity, protein D, and PCV10 serotype-specific IgG. Laboratory staff was masked to intervention group assignment. The primary outcome measure was to determine the proportion of participants in the 2+1 group at age 10 months with specific IgG for serotypes 1, 5, and 14 of at least 0·2 μg/mL in the per-protocol population. The secondary outcomes were non-inferiority (within 10% levels) at age 18 weeks for the proportion of participants in the 2+1 group compared with the 3+0 group with serotypes 1, 5, and 14 specific IgG of at least 0·2 μg/mL; the proportion of participants with PCV10 serotype-specific IgG of at least 0·2 μg/mL and opsonophagocytic activity reciprocal titre of at least 8 at ages 18 weeks and 10 months; and nasopharyngeal pneumococcal serotype-specific carriage rates at age 9 months in each study group. In the follow-up study, the primary outcome measure was the proportion of participants with IgG of at least 0·2 μg/mL for PCV10 serotypes at age 2-4 years in children previously immunised with a 3+0 schedule compared with a 2+1 schedule. The trial is registered with Current Controlled Trials, registration number ISRCTN56766232.
  
  
  RESULTS
  Between May 10, 2010, and Jan 7, 2011, 390 children were randomly assigned to each group: 119 to the 2+1 group, 120 to the 3+0 group, and 151 to the 0+2 group. At age 10 months, the proportions of 2+1 participants with IgG of at least 0·2 μg/mL were 99·0% (95% CI 94·2-100·0) for serotype 1, 100% (96·2-100·0) for serotype 5, and 97·9% (92·5-99·7) for serotype 14. At age 18 weeks, non-inferiority (within 10% levels) of the 2+1 group was shown compared with the 3+0 group, and there was no difference between the 2+1 and 3+0 groups for the proportion with IgG of at least 0·2 μg/mL for any of the PCV10 serotypes. At age 10 months, proportions with IgG of at least 0·2 μg/mL for serotypes 1, 5, 6B, and 23F, were higher in the 2+1 group than in the 3+0 group. At age 18 weeks, there were no differences in opsonophagocytic activity between the 2+1 and 3+0 groups for reciprocal titres of at least 8, but at age 10 months, proportions with an opsonophagocytic reciprocal titre of at least 8 for serotypes 1, 4, 5, 6B, 18C, 19F and 23F were higher in the 2+1 group than in the 3+0 group. At age 2-4 years, there were higher proportions in the 2+1 group versus the 3+0 group with IgG of at least 0·2 μg/mL for serotypes 1, 5, 6B, and 18C.
  
  
  CONCLUSIONS
  Use of a 2+1 PCV schedule with booster at age 9 months in a resource-poor setting improved antibody persistence through early childhood without compromising antibody responses in early infancy. This schedule is now recommended by WHO for progressive introduction across Nepal, with PCV10 introduction having commenced on Jan 18, 2015. Concurrent pre-implementation and post-implementation surveillance is being done by a GAVI Alliance funded study.
  
  
  BACKGROUND
  This study was supported by funding from the National Institute for Public Health and the Environment, The Netherlands; Oxford Vaccine Group, University of Oxford, UK; and GlaxoSmithKline Biologicals, Belgium.
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, UK.
authors.forename: Mainga
authors.initials: M
authors.lastname: Hamaluba
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, UK. Electronic address: rama.kandasamy@paediatrics.ox.ac.uk.
authors.forename: Rama
authors.initials: R
authors.lastname: Kandasamy
authors.affiliation: Child Health Division, Department of Health Services, Ministry of Health, Kathmandu, Nepal.
authors.forename: Shyam R
authors.initials: SR
authors.lastname: Upreti
authors.affiliation: National Immunization Program, Department of Health Services, Ministry of Health, Kathmandu, Nepal.
authors.forename: Giri R
authors.initials: GR
authors.lastname: Subedi
authors.affiliation: Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Shrijana
authors.initials: S
authors.lastname: Shrestha
authors.affiliation: Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Shiva
authors.initials: S
authors.lastname: Bhattarai
authors.affiliation: Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Meeru
authors.initials: M
authors.lastname: Gurung
authors.affiliation: Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Rahul
authors.initials: R
authors.lastname: Pradhan
authors.affiliation: Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.
authors.forename: Merryn
authors.initials: M
authors.lastname: Voysey
authors.affiliation: Programme for Immunization Preventable Diseases, World Health Organization, Kathmandu, Nepal.
authors.forename: Santosh
authors.initials: S
authors.lastname: Gurung
authors.affiliation: Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Shachi
authors.initials: S
authors.lastname: Pradhan
authors.affiliation: Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Anushil K
authors.initials: AK
authors.lastname: Thapa
authors.affiliation: Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Maharjan
authors.affiliation: Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Usha
authors.initials: U
authors.lastname: Kiran
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, UK.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Kerridge
authors.affiliation: Division of Clinical Sciences, St George's, University of London, London, UK.
authors.forename: Jason
authors.initials: J
authors.lastname: Hinds
authors.affiliation: National Institute for Public Health and the Environment, Bilthoven, Utrecht, The Netherlands.
authors.forename: Fiona
authors.initials: F
authors.lastname: van der Klis
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, UK.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Snape
authors.affiliation: Department of Pathology, University of Otago, Christchurch, New Zealand.
authors.forename: David R
authors.initials: DR
authors.lastname: Murdoch
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kelly
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, UK.
authors.forename: Dominic F
authors.initials: DF
authors.lastname: Kelly
authors.affiliation: Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Neelam
authors.initials: N
authors.lastname: Adhikari
authors.affiliation: Paediatric Research Unit, Patan Academy of Health Sciences, Kathmandu, Nepal.
authors.forename: Stephen
authors.initials: S
authors.lastname: Thorson
authors.affiliation: Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pollard
mesh_terms: D000907:Antibodies, Bacterial / Q000097:blood*; D002675:Child, Preschool; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007115:Immunization Schedule; D007074:Immunoglobulin G / Q000097:blood; D007223:Infant; D008297:Male; D009390:Nepal; D009895:Opsonin Proteins / Q000097:blood; D010587:Phagocytosis; D022242:Pneumococcal Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D016896:Treatment Outcome; D014611:Vaccination / Q000379:methods
chemical_list: C586648:10-valent pneumococcal conjugate vaccine; D000907:Antibodies, Bacterial; D007074:Immunoglobulin G; D009895:Opsonin Proteins; D022242:Pneumococcal Vaccines