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Proposal 1141

Title of the Proposed Research

Multivariate methods for meta-analysis of vaccine studies with multiple correlated outcomes

Lead Researcher

Merryn Voysey

Affiliation

Nuffield Department of Primary Care Health Sciences
University of Oxford

Funding Source

Applications for funding for this PhD are being submitted to the NIHR and the University of Oxford.

Potential Conflicts of Interest

Professor Pollard has received grants from Pfizer vaccines, Novartis vaccines, and GSK vaccines; and is the Chair of the UK Departments of Health’s Joint Committee on Vaccination and Immunisation.

Data Sharing Agreement Date

22 July 2015

Lay Summary

Vaccines protect people in the UK from many diseases. They are quick and cheap ways of providing protection for large numbers of people and work best when everyone receives their vaccines at the right times. There is a list of which vaccines each person in the UK should receive and at what age, starting from the age of 2 months old. This list does not change very often but has changed in recent years. It is important that when changes are made to the list these decisions are based on high quality information. It is also important that when people decide to receive a vaccine, their decision is based on the best information. This research will look at how we can improve our analysis of vaccine data to understand them better.

Modern vaccines often protect against more than one disease (e.g. diphtheria, tetanus and whooping cough are combined into one vaccine). Studies which measure the benefit of vaccines therefore measure more than one disease at the same time. This is done by taking one blood sample and testing it many times using different tests. The way a person responds to the vaccination of one disease (e.g. diphtheria) relates to the way they respond to the vaccination of another (e.g. tetanus) when given at the same time. These relationships are important but are not generally included in current analyses. In order to include them, a different type of analysis can be used called 'multivariate analysis'.

This research will look at new ways to analyse these vaccine data using the 'multivariate' method. It will compare the old and new methods to see if the newer methods give us better information. The new methods will then be used to answer two further questions about vaccines: whether girls respond differently to vaccination than boys, and what ages are best for giving vaccines to infants. In the UK infants are given vaccines at 2, 3, and 4 months of age; in other countries they are given at different time such as at ages 2, 4 and 6 months. The timing of a vaccine can affect a person’s response to it, and therefore how well they are protected against disease. In the UK we have never tested which is the best time to give vaccines to children. They may therefore be less protected than they could be.

Study Data Provided

Study GSK-110478: Immunogenicity and reactogenicity study of a new formulation of GSK Biologicals' DTPa-HBV-IPV/Hib vaccine administered as a booster dose to 18-23 months old children
Study GSK-112157: Immunogenicity and safety study of GlaxoSmithKline Biologicals’ GSK2202083A vaccine in healthy infants at 2, 3 and 4 months of age
Study GSK-113978: Immunogenicity and safety study of GlaxoSmithKline Biologicals’ GSK2202083A vaccine administered as a booster dose in 12-18 months old healthy children
Study GSK-104567: Phase IIIb, multicentre study to assess safety & immunogenicity of GSK Biologicals’ combined DTPa/Hib (Infanrix/Hib) vaccine vs separate administration of DTPa (Infanrix) & Hib (Hiberix) vaccines in healthy infants 3,4,&5 months of age as compared with the separate administration of DTPa and Hib vaccines at different injection sites.
Study GSK-111535: Immunogenicity and reactogenicity study of GlaxoSmithKline Biologicals' Infanrix™/Hib vaccine administered as a booster dose to 18-24 months old children
Study GSK-107137: Prophylactic antipyretic treatment in children receiving booster dose of pneumococcal vaccine GSK1024850A and DTPa-HBV-IPV/Hib vaccine (Infanrix hexa) and assessment of impact of pneumococcal vaccination on nasopharyngeal carriage
Study GSK-109509: Booster vaccination course with the pneumococcal vaccine GSK 1024850A, DTPw-HBV/Hib and OPV or IPV in children who completed the primary vaccination course in study 107007
Study GSK-109661: Primary vaccination course in children receiving the pneumococcal vaccine GSK 1024850A, Infanrix hexa and Rotarix
Study GSK-110031: Phase II, observer-blind follow-up study to assess reacto-and immunogenicity of GSK Biologicals' pneumococcal conjugate vaccine (GSK1024850A), when given as booster in primed children or as 2-dose catch-up in unprimed children.
Study GSK-110521: Primary vaccination course in children receiving the pneumococcal vaccine GSK 1024850A co-administered with Zilbrix™ Hib and Polio Sabin™
Study GSK-113166: Safety, reactogenicity and immunogenicity study of GSK Biologicals’ pneumococcal vaccine GSK1024850A, given either as a booster dose or as a 2-dose catch-up immunization in healthy Malian children
Study GSK-113199: Safety, reactogenicity and immunogenicity study of GSK Biologicals’ pneumococcal vaccine GSK1024850A, given either as a booster dose or as a 2-dose catch-up immunization in healthy Nigerian children
Study GSK-111344: Immunogenicity and reactogenicity of GSK Biologicals' DTPa-HBV-IPV/Hib vaccine when given as a booster dose.
Study GSK-105910: Compare immunogenicity & reactogenicity of 2 formulations of GSK Biologicals’ DTPa-HBV-IPV/Hib vaccine (new vs current) given in healthy infants. The DTPa-HBV-IPV vaccine (new formulation) will also be assessed in a 3rd group of subjects
Study GSK-217744/077 (DTPa-HBV-IPV-077): A phase III, double-blind, randomized, multicenter primary vaccination study to bridge the DTPa-HBV-IPV vaccine manufactured according to the large scale manufacturing process with the DTPa-HBV-IPV vaccine manufactured by the small scale manufacturing process when administered intramuscularly to infants at 2, 4 and 6 months of age, co-administered with Merck's Hib conjugate vaccine (Liquid PedvaxHIB®) in a separate injection at 2 and 4 months of age
Study GSK-217744/084 (DTPa-Hep B-IPV-084): A phase III, open labeled, randomized, multicenter, clinical study of the safety of a primary series of GlaxoSmithKline Biologicals' (GSK Biologicals') DTaP-HepB-IPV combined candidate vaccine coadministered with HibTITER® and Prevnar® to healthy infants at 2, 4, and 6 months of age as compared to the separate administration of Infanrix® + Engerix-B®+ IPOL® + HibTITER + Prevnar
Study GSK-217744/085 (DTPa-Hep B-IPV-085): A phase III, open labeled, randomized, multicenter, clinical study of the safety and immunogenicity of a primary series of GlaxoSmithKline Biologicals' (GSK Biologicals') DTaP-HepBIPV candidate vaccine coadministered with HibTITER® and Prevnar® to healthy infants at 2, 4, and 6 months of age as compared to the separate administration of Infanrix® + Engerix-B® + IPOL® + HibTITER + Prevnar and to GSK Biologicals' DTaP-HepB-IPV candidate vaccine coadministered with HibTITER
Study GSK-217744/097 (DTPa-HBV-IPV-097): Study to assess immunogenicity and reactogenicity of three doses of GSK Bio’s combined Hib-MenC vaccine co-admind with GSK Bio’s DTPa-HBV-IPV vaccine and of two doses of Baxters meningococcal C conjugate vaccine co-admind with GSK Bio’s DTPa-HBV-IPV/Hib vaccine
Study GSK-106786: A study to evaluate the immunogenicity and safety of a new formulation of GSK Biologicals' DTPa-HBV-IPV/Hib vaccine as compared to the currently licensed Infanrix hexa in healthy infants (2,3,4 M)
Study GSK-217744/076 (DTPa-HBV-IPV-076): An open, multicenter, phase IV clinical trial to assess the immunogenicity and reactogenicity of three doses of GSK Biologicals’ combined DTPa-HBV-IPV/Hib vaccine in healthy infants at 2, 4 and 6 months of age, when co-administered with Wyeth-Lederle’s meningococcal group C conjugate vaccine.
Study GSK-217744/078 (DTPa-HBV-IPV-078): An open, multicentre, phase IV clinical trial to assess the immunogenicity and reactogenicity of GSK Biologicals’ combined DTPa-HBV-IPV/Hib vaccine, when co-administered at 3-4-5 Mth of age with Wyeth-Lederle's seven-valent pneumococcal conjugate vaccine at a different injection site during the same visit
Study GSK-217744/081 (DTPa-HBV-IPV-081): An open, multicentre, phase IV booster vaccination study to assess the immunogenicity and reactogenicity of a 4th dose of GSK Biologicals’ combined DTPa-HBV-IPV/Hib vaccine, co-administered with Wyeth's seven-valent Pneumococcal conjugate vaccine at a different injection site during the same visit in healthy children
Study GSK-217744/083 (DTPa-HBV-IPV-083): Study to assess immunogenicity and reactogenicity of GSK Bio’s combined DTPa-HBV-IPV/Hib vaccine in pre-term infants in comparison with term infants, administered as a booster dose to children who previously were primed with 3 doses of GSK Biologicals combined DTPa-HBV-IPV/Hib vaccine
Study GSK-217744/086 (DTPa-HBV-IPV-086): Single-blind, multicentre, phase IV clinical trial to assess and compare the immunogenicity and reactogenicity of GSK Biologicals’ DTPa-HBV-IPV/Hib vaccine (Infanrix hexa™) and Aventis Pasteur’s DTPa-HBV-IPV-Hib vaccine (Hexavac™) given as a primary vaccination course at 2, 4 and 6 months of age.
Study GSK-217744/090 (DTPa-HBV-IPV-090): A phase IV, open, multicentre study to assess the immunogenicity and reactogenicity of GlaxoSmithKline Biologicals’ DTPa-HBV-IPV/Hib vaccine (Infanrix hexa() given as a primary vaccination course at 2, 4 and 6 months of age to pre-term infants.
Study GSK-217744/094: Study to assess and compare the immunogenicity and reactogenicity of GlaxoSmithKline Biologicals’ DTPa-HBV-IPV/Hib vaccine (INFANRIX™ HEXA) and Aventis Pasteur MSD’s DTPa-HBV-IPV-Hib vaccine (HEXAVAC™) given at 3, 5 and 11-12 months of age
Study GSK-101197 (DTPa -127): An open, multicentric, phase IV clinical trial to assess the immunogenicity and reactogenicity of GlaxoSmithKline Biologicals’ combined diphtheria-tetanus-acellular pertussis vaccine (Infanrix™) administered to healthy infants at 2, 4 and 6 months of age.
Study GSK-104871: A multicentric study to compare the immunogenicity, safety & reactogenicity of GSK Biologicals' DTPa-IPV vaccine vs. co-administration of GSK's DTPa vaccine & Sanofi-Pasteurs' IPV vaccine at different injection sites, to healthy children
Study GSK-208355/125 (APV-125): A phase III, open, multicenter study of the safety of Infanrix® when administered as a booster dose at 15 to 18 months of age following primary immunization in studies 217744/084 and 217744/085 (Subjects from DTaP-HepB-IPV-084 and DTaP-HepB-IPV-085)
Study GSK-106208: To assess reactogenicity and immunogenicity of GSK Biologicals’ 10-valent pneumococcal conjugate vaccine, when co-administered with GSK Biologicals’ DTPa-HBV-IPV/Hib vaccine (Infanrix™ hexa) at 2, 4 and 6 months of age.
Study GSK-105539: An open, randomized, phase IIIa study to evaluate the safety and immunogenicity of GSK Biologicals' 10-valent pneumococcal conjugate vaccine, when administered intramuscularly according to a 2-4-11 months vaccination schedule
Study GSK-107737: Study to assess the safety and immunogenicity of GSK Biologicals 10-valent pneumococcal conjugate vaccine when Co-administered with DTPa-HBV-IPV/Hib (Infanrix-Hexa) vaccine in preterm infants as a 3-dose primary immunization course during the first 6 months of life.
Study GSK-110142: Non-inferiority of co-administration of GSK Biologicals’pneumococcal conjugate vaccine GSK1024850A with DTPa-IPV-Hib versus co-administration with DTPa-HBV-IPV/Hib.
Study GSK-107017: Multicentre study to assess the effect of prophylactic antipyretic treatment on the rate of febrile reactions following concomitant administration of GSK Biologicals’ 10-valent pneumococcal conjugate, Infanrix hexa and Rotarix vaccines
Study GSK-111053: Non-inferiority of co-administration of GSK Biologicals’pneumococcal conjugate vaccine GSK1024850A with DTPa-IPV-Hib versus co-administration with DTPa-HBV-IPV/Hib.
Study GSK-114260: Immunogenicity and safety of GlaxoSmithKline Biologicals’ DTPa-IPV/Hib (Infanrix™-IPV+Hib) vaccine in healthy Korean infants
Study GSK-104065: Immune memory of GSK's DTPw-HBV/Hib vaccine by giving Plain PRP polysaccharide at 10 mths. Immunogenicity & reactogenicity of a booster dose of DTPw-HBV/Hib or DTPw-HBV or DTPw-HBV+Hib at 15-18 mths in infants previously primed with DTPw-HBV/Hib
Study GSK-104489: Study to assess immunogenicity and safety of GlaxoSmithKline Biologicals Kft’s DTPw-HBV/Hib vs DTPwCSL-HBV/Hib Kft and vs concomitant administration of CSL’s Triple Antigen and GlaxoSmithKline Biologicals’ Hiberix, to infants at 2, 4, 6 months of age, after a birth dose of hepatitis B
Study GSK-106602: Immunogenicity, Reactogenicity & Safety of a Booster Dose of GSK Biologicals’ DTPw-HBV/Hib Kft Vaccine Vs GSK Biologicals’ DTPw-HBV/Hib Vaccine, in Infants Who Received a 3-Dose Primary Vaccination Course With the Same Vaccines.
Study GSK-105553: Assess lot-to-lot consistency of 3 lots (double blind design) of GlaxoSmithKline Biologicals' 10-valent pneumococcal vaccine and evaluate non-inferiority to Prevenar™ (single blind design) when administered as 3-dose primary immunization course before 6 months of age
Study GSK-107005: To assess safety, reactogenicity and immunogenicity of GSK Biologicals’ 10-valent pneumococcal conjugate vaccine, when co-administered with DTPa-combined vaccines and MenC or Hib-MenC vaccines during the first 6 months of age.
Study GSK-107007: To assess the safety, reactogenicity and immunogenicity of GSK Biologicals' pneumococcal conjugate vaccine compared to Prevenar™, co-administered with DTPw-HBV/Hib & OPV or IPV vaccines as a 3-dose primary immunization course during the first 6 months of age
Study GSK-107046: To assess the safety, reactogenicity & immunogenicity of a 4th dose of GSK Biologicals’ pneumococcal vaccine or Prevenar™ in children (12-18 months) previously vaccinated in the primary study 105553 with either pneumococcal vaccine or Prevenar™
Study GSK-101222: Study to demonstrate the non-inferiority of GSK Biologicals' DTPw-HBV/Hib Kft. vaccine compared to GSK Biologicals' Tritanrix™-HepB/Hiberix™ vaccine and to separate administration of DTPw-HBV Kft. and Hiberix™ vaccines with respect to the immunogenicity of all antigens, when administered to healthy infants.
Study GSK-101223: Study to assess the lot-to-lot consistency of the production method of GSK Biologicals' DTPw-HBV/ Hib Kft. vaccine and to compare to GSK Biologicals' Tritanrix™-HepB/Hiberix™ vaccine, when administered as a primary vaccination course.
Study GSK-217744/070 (DTPa-HBV-IPV-070): An open clinical study to assess the immunogenicity and safety of GSK Biologicals' DTPa-HBV-IPV vaccine mixed in one syringe with Hib vaccine, as a primary vaccination course to pre-term infants (<37 weeks) at 2, 4 and 6 months of age in comparison with infants born after normal gestation period
Study GSK-217744/095 (DTPa-HBV-IPV-095): Study to assess immunogenicity and reactogenicity of GSK Biologicals' DTPa-HBV-IPV/Hib vaccine when given as a booster dose to children previously primed at 2-4-6 months of age either with Aventis Pasteurs' DTPa-HBV-IPV-Hib vaccine or GSK Biologicals' DTPa-HBV-IPV/Hib vaccine in study DTPa-HBV-IPV-086
Study GSK-109507: Booster Vaccination With Pneumococcal Vaccine GSK1024850A, a DTPa-Combined and MenC or Hib-MenC Vaccines
Study GSK-101518 (DTPa-HBV-IPV-103): A phase IV, open, multicentre study to assess the immunogenicity and reactogenicity of GSK Biologicals’ DTPa-HBV-IPV/Hib vaccine (Infanrix-hexa) given as a booster at 18-24 months of age to children who have received a three-dose primary immunisation course with the same vaccine in a previous study

Statistical Analysis Plan

Publication Citation

http://jamanetwork.com/journals/jamapediatrics/fullarticle/2627571