title: Modelling the immunological response to a tetravalent dengue vaccine from multiple phase-2 trials in Latin America and South East Asia.
abstract: BACKGROUND
  The most advanced dengue vaccine candidate is a live-attenuated recombinant vaccine containing the four dengue viruses on the yellow fever vaccine backbone (CYD-TDV) developed by Sanofi Pasteur. Several analyses have been published on the safety and immunogenicity of the CYD-TDV vaccine from single trials but none modelled the heterogeneity observed in the antibody responses elicited by the vaccine.
  
  
  METHODS
  We analyse the immunogenicity data collected in five phase-2 trials of the CYD-TDV vaccine. We provide a descriptive analysis of the aggregated datasets and fit the observed post-vaccination PRNT50 titres against the four dengue (DENV) serotypes using multivariate regression models.
  
  
  RESULTS
  We find that the responses to CYD-TDV are principally predicted by the baseline immunological status against DENV, but the trial is also a significant predictor. We find that the CYD-TDV vaccine generates similar titres against all serotypes following the third dose, though DENV4 is immunodominant after the first dose.
  
  
  CONCLUSIONS
  This study contributes to a better understanding of the immunological responses elicited by CYD-TDV. The recent availability of phase-3 data is a unique opportunity to further investigate the immunogenicity and efficacy of the CYD-TDV vaccine, especially in subjects with different levels of pre-existing immunity against DENV. Modelling multiple immunological outcomes with a single multivariate model offers advantages over traditional approaches, capturing correlations between response variables, and the statistical method adopted in this study can be applied to a variety of infections with interacting strains.
authors.affiliation: MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, Norfolk Place, W2 1PG London, United Kingdom. Electronic address: i.dorigatti@imperial.ac.uk.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Dorigatti
authors.affiliation: MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, Norfolk Place, W2 1PG London, United Kingdom.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Aguas
authors.affiliation: MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, Norfolk Place, W2 1PG London, United Kingdom.
authors.forename: Christl A
authors.initials: CA
authors.lastname: Donnelly
authors.affiliation: Sanofi Pasteur, 2 Avenue Pont Pasteur, Lyon Cedex 07 69367, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Guy
authors.affiliation: Sanofi Pasteur, 2 Avenue Pont Pasteur, Lyon Cedex 07 69367, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Coudeville
authors.affiliation: Sanofi Pasteur, 2 Avenue Pont Pasteur, Lyon Cedex 07 69367, France.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Jackson
authors.affiliation: Sanofi Pasteur, 2 Avenue Pont Pasteur, Lyon Cedex 07 69367, France.
authors.forename: Melanie
authors.initials: M
authors.lastname: Saville
authors.affiliation: MRC Centre for Outbreak Analysis and Modelling, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, Norfolk Place, W2 1PG London, United Kingdom.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Ferguson
mesh_terms: D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000097:blood*; D001210:Asia, Southeastern; D002648:Child; D002675:Child, Preschool; D017322:Clinical Trials, Phase II as Topic; D053059:Dengue Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology*; D005260:Female; D006801:Humans; D007223:Infant; D007843:Latin America; D008297:Male; D015233:Models, Statistical; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; C000603176:CYD-TDV vaccine; D053059:Dengue Vaccines
keywords: CYD-TDV dengue vaccine; Multivariate regression; PRNT50 antibody titres; Serotype interactions