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

Proposal
1141

Title of Proposed Research

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

None

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

[{ "PostingID": 135, "Title": "GSK-110478", "Description": "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

Medicine: Combined Diphtheria, Tetanus, Acellular Pertussis Adsorbed, Hepatitis B (Recombinant), Inactivated Polio Vaccine, Condition: Acellular pertussis; Diphtheria; Hepatitis B; Poliomyelitis; Tetanus, Phase: 4, Clinical Study ID: 110478, Sponsor: GSK" },{ "PostingID": 136, "Title": "GSK-112157", "Description": "Immunogenicity and safety study of GlaxoSmithKline Biologicals' GSK2202083A vaccine in healthy infants at 2, 3 and 4 months of age

Medicine: Combined Diphtheria, Tetanus, Acellular Pertussis, Hepatitis B, Inactivated Polio, Haemophilus influenzae Type b Vaccine, Condition: Acellular Pertussis; Diphtheria; Haemophilus influenzae type b; Hepatitis B; Poliomyelitis; Tetanus, Phase: 2, Clinical Study ID: 112157, Sponsor: GSK" },{ "PostingID": 137, "Title": "GSK-113978", "Description": "Immunogenicity and safety study of GlaxoSmithKline Biologicals' GSK2202083A vaccine administered as a booster dose in 12-18 months old healthy children

Medicine: Combined Diphtheria, Tetanus, Acellular Pertussis, Hepatitis B, Inactivated Polio, Haemophilus influenzae Type b Vaccine, Condition: Acellular Pertussis; Diphtheria; Haemophilus influenzae type b; Hepatitis B; Poliomyelitis; Tetanus, Phase: 2, Clinical Study ID: 113978, Sponsor: GSK" },{ "PostingID": 153, "Title": "GSK-104567", "Description": "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.

Medicine: Diphtheria, Tetanus, Acellular Pertussis Vaccine Adsorbed, Condition: Acellular pertussis; Diphtheria; Tetanus, Phase: 3, Clinical Study ID: 104567, Sp" },{ "PostingID": 154, "Title": "GSK-111535", "Description": "Immunogenicity and reactogenicity study of GlaxoSmithKline Biologicals' Infanrix™/Hib vaccine administered as a booster dose to 18-24 months old children

Medicine: Diphtheria, Tetanus, Acellular Pertussis Vaccine Adsorbed, Condition: Acellular pertussis; Diphtheria; Tetanus, Phase: 3, Clinical Study ID: 111535, Sponsor: GSK" },{ "PostingID": 253, "Title": "GSK-107137", "Description": "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

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 3, Clinical Study ID: 107137, Sponsor: GSK" },{ "PostingID": 254, "Title": "GSK-109509", "Description": "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

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 3, Clinical Study ID: 109509, Sponsor: GSK" },{ "PostingID": 256, "Title": "GSK-109661", "Description": "Primary vaccination course in children receiving the pneumococcal vaccine GSK 1024850A, Infanrix hexa and Rotarix

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 3, Clinical Study ID: 109661, Sponsor: GSK" },{ "PostingID": 257, "Title": "GSK-110031", "Description": "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.

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 2, Clinical Study ID: 110031, Sponsor: GSK" },{ "PostingID": 258, "Title": "GSK-110521", "Description": "Primary vaccination course in children receiving the pneumococcal vaccine GSK 1024850A co-administered with Zilbrix™ Hib and Polio Sabin™

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 3, Clinical Study ID: 110521, Sponsor: GSK" },{ "PostingID": 264, "Title": "GSK-113166", "Description": "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

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 3, Clinical Study ID: 113166, Sponsor: GSK" },{ "PostingID": 265, "Title": "GSK-113199", "Description": "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

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 3, Clinical Study ID: 113199, Sponsor: GSK" },{ "PostingID": 280, "Title": "GSK-111344", "Description": "Immunogenicity and reactogenicity of GSK Biologicals' DTPa-HBV-IPV/Hib vaccine when given as a booster dose.

Medicine: Combined Diphtheria, Tetanus, Acellular Pertussis, Hepatitis B, Inactivated Polio, Haemophilus influenzae Type b Vaccine, Condition: Acellular pertussis; Diphtheria; Haemophilus influenzae type b; Hepatitis B; Poliomyelitis; Tetanus, Phase: 2, Clinical Study ID: 111344, Sponsor: GSK" },{ "PostingID": 333, "Title": "GSK-105910", "Description": "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

Medicine: Combined Diphtheria, Tetanus, Acellular Pertussis Adsorbed, Hepatitis B (Recombinant), Inactivated Polio Vaccine, Condition: Acellular pertussis; Diphtheria; Hepatitis B; Poliomyelitis; Tetanus, Phase: 3, Clinical Study ID: 105910, Sponsor: GSK" },{ "PostingID": 334, "Title": "GSK-217744/077 (DTPa-HBV-IPV-077)", "Description": "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

Medicine: Combined Diphtheria, Tetanus, Acellular Pertu" },{ "PostingID": 335, "Title": "GSK-217744/084 (DTPa-Hep B-IPV-084)", "Description": "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

Medicine: Combined Diphtheria, Tetanus, Acellular Pertussis Adsorbed, Hepatitis B (Recombinant), Inactivated Polio Vaccine, Cond" },{ "PostingID": 336, "Title": "GSK-217744/085 (DTPa-Hep B-IPV-085)", "Description": "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

Medicine: Combined Diphtheria, Te" },{ "PostingID": 337, "Title": "GSK-217744/097 (DTPa-HBV-IPV-097)", "Description": "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

Medicine: Combined Diphtheria, Tetanus, Acellular Pertussis Adsorbed, Hepatitis B (Recombinant), Inactivated Polio Vaccine, Condition: Acellular pertussis; Diphtheria; Hepatitis B; Poliomyelitis; Tetanus, Phase: 3, Clinical Study ID: 217744/097 (D" },{ "PostingID": 342, "Title": "GSK-106786", "Description": "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)

Medicine: Combined Diphtheria, Tetanus, Acellular Pertussis, Hepatitis B, Inactivated Polio, Haemophilus influenzae Type b Vaccine, Condition: Acellular pertussis; Diphtheria; Haemophilus influenzae type b; Hepatitis B; Poliomyelitis; Tetanus, Phase: 2, Clinical Study ID: 106786, Sponsor: GSK" },{ "PostingID": 343, "Title": "GSK-217744/076 (DTPa-HBV-IPV-076)", "Description": "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.

Medicine: Combined Diphtheria, Tetanus, Acellular Pertussis, Hepatitis B, Inactivated Polio, Haemophilus influenzae Type b Vaccine, Condition: Acellular pertussis; Diphtheria; Haemophilus influenzae type b; Hepatiti" },{ "PostingID": 344, "Title": "GSK-217744/078 (DTPa-HBV-IPV-078)", "Description": "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

Medicine: Combined Diphtheria, Tetanus, Acellular Pertussis, Hepatitis B, Inactivated Polio, Haemophilus influenzae Type b Vaccine, Condition: Acellular pertussis; Diphtheria; Haemophilus influenzae typ" },{ "PostingID": 345, "Title": "GSK-217744/081 (DTPa-HBV-IPV-081)", "Description": "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

Medicine: Combined Diphtheria, Tetanus, Acellular Pertussis, Hepatitis B, Inactivated Polio, Haemophilus influenzae Type b Vaccine, Condition: Acellular pertussis; Diphtheria; Haemophilus in" },{ "PostingID": 346, "Title": "GSK-217744/083 (DTPa-HBV-IPV-083)", "Description": "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

Medicine: Combined Diphtheria, Tetanus, Acellular Pertussis, Hepatitis B, Inactivated Polio, Haemophilus influenzae Type b Vaccine, Condition: Acellular pertussis; Diphtheria; Haemophilus influenzae type b; Hepatitis B; Pol" },{ "PostingID": 347, "Title": "GSK-217744/086 (DTPa-HBV-IPV-086)", "Description": "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.

Medicine: Combined Diphtheria, Tetanus, Acellular Pertussis, Hepatitis B, Inactivated Polio, Haemophilus influenzae Type b Vaccine, Condition: Acellular pertussis; Diphtheria; Haemophilus influenzae type b; Hepa" },{ "PostingID": 348, "Title": "GSK-217744/090 (DTPa-HBV-IPV-090)", "Description": "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.

Medicine: Combined Diphtheria, Tetanus, Acellular Pertussis, Hepatitis B, Inactivated Polio, Haemophilus influenzae Type b Vaccine, Condition: Acellular pertussis; Diphtheria; Haemophilus influenzae type b; Hepatitis B; Poliomyelitis; Tetanus, Phase: 4, Clinical S" },{ "PostingID": 349, "Title": "GSK-217744/094", "Description": "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

Medicine: Combined Diphtheria, Tetanus, Acellular Pertussis, Hepatitis B, Inactivated Polio, Haemophilus influenzae Type b Vaccine, Condition: Acellular pertussis; Diphtheria; Haemophilus influenzae type b; Hepatitis B; Poliomyelitis; Tetanus, Phase: 4, Clinical Study" },{ "PostingID": 359, "Title": "GSK-101197 (DTPa -127)", "Description": "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.

Medicine: Diphtheria, Tetanus, Acellular Pertussis Vaccine Adsorbed, Condition: Acellular pertussis; Diphtheria; Tetanus, Phase: 4, Clinical Study ID: 101197 (DTPa -127), Sponsor: GSK" },{ "PostingID": 361, "Title": "GSK-104871", "Description": "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

Medicine: Diphtheria, Tetanus, Acellular Pertussis Vaccine Adsorbed, Condition: Acellular pertussis; Diphtheria; Tetanus, Phase: 3, Clinical Study ID: 104871, Sponsor: GSK" },{ "PostingID": 363, "Title": "GSK-208355/125 (APV-125)", "Description": "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)

Medicine: Diphtheria, Tetanus, Acellular Pertussis Vaccine Adsorbed, Condition: Acellular pertussis; Diphtheria; Tetanus, Phase: 3, Clinical Study ID: 208355/125 (APV-125), Sponsor: GSK" },{ "PostingID": 436, "Title": "GSK-106208", "Description": "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.

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 2, Clinical Study ID: 106208, Sponsor: GSK" },{ "PostingID": 464, "Title": "GSK-105539", "Description": "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

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 3, Clinical Study ID: 105539, Sponsor: GSK" },{ "PostingID": 469, "Title": "GSK-107737", "Description": "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.

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 3, Clinical Study ID: 107737, Sponsor: GSK" },{ "PostingID": 470, "Title": "GSK-110142", "Description": "Non-inferiority of co-administration of GSK Biologicals'pneumococcal conjugate vaccine GSK1024850A with DTPa-IPV-Hib versus co-administration with DTPa-HBV-IPV/Hib.

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 3, Clinical Study ID: 110142, Sponsor: GSK" },{ "PostingID": 509, "Title": "GSK-107017", "Description": "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

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 3, Clinical Study ID: 107017, Sponsor: GSK" },{ "PostingID": 1545, "Title": "GSK-111053", "Description": "Non-inferiority of co-administration of GSK Biologicals'pneumococcal conjugate vaccine GSK1024850A with DTPa-IPV-Hib versus co-administration with DTPa-HBV-IPV/Hib.

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 3, Clinical Study ID: 111053, Sponsor: GSK" },{ "PostingID": 1691, "Title": "GSK-114260", "Description": "Immunogenicity and safety of GlaxoSmithKline Biologicals' DTPa-IPV/Hib (Infanrix™-IPV+Hib) vaccine in healthy Korean infants

Medicine: Combined Diphtheria, Tetanus, Acellular Pertussis, Inactivated Polio, Haemophilus influenzae Type b Conjugate Vaccine, Condition: Acellular pertussis; Diphtheria; Haemophilus influenzae type b; Poliomyelitis; Tetanus, Phase: 3, Clinical Study ID: 114260, Sponsor: GSK" },{ "PostingID": 2158, "Title": "GSK-104065", "Description": "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

Medicine: Combined Diphtheria, Tetanus, Whole Cell Pertussis, Hepatitis B, Haemophilus influenzae Type b Vaccine (KFT), Condition: Diphtheria; Haemophilus influenzae type b; Hepatitis B; Tetanus; Whole Cell Pertussis, Phase: 3, Clinical Study ID: 104065, Spon" },{ "PostingID": 2159, "Title": "GSK-104489", "Description": "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

Medicine: Combined Diphtheria, Tetanus, Whole Cell Pertussis, Hepatitis B, Haemophilus influenzae Type b Vaccine (KFT), Condition: Diphtheria; Haemophilus influenzae type b; Hepatitis B; Tetanus; Whole Cell Pertussis, Phase" },{ "PostingID": 2160, "Title": "GSK-106602", "Description": "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.

Medicine: Combined Diphtheria, Tetanus, Whole Cell Pertussis, Hepatitis B, Haemophilus influenzae Type b Vaccine (KFT), Condition: Diphtheria; Haemophilus influenzae type b; Hepatitis B; Tetanus; Whole Cell Pertussis, Phase: 3, Clinical Study ID: 106602, Sponsor: GSK" },{ "PostingID": 2209, "Title": "GSK-105553", "Description": "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

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 3, Clinical Study ID: 105553, Sponsor: GSK" },{ "PostingID": 2210, "Title": "GSK-107005", "Description": "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.

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 3, Clinical Study ID: 107005, Sponsor: GSK" },{ "PostingID": 2211, "Title": "GSK-107007", "Description": "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

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 3, Clinical Study ID: 107007, Sponsor: GSK" },{ "PostingID": 2212, "Title": "GSK-107046", "Description": "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™

Medicine: Pneumococcal Polysaccharide Conjugate Vaccine (Adsorbed), Condition: Infections, Streptococcal, Phase: 3, Clinical Study ID: 107046, Sponsor: GSK" },{"PostingID":2757,"Title":"GSK-101222","Description":"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, Sponsor: GSK"},{"PostingID":2758,"Title":"GSK-101223","Description":"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., Sponsor: GSK"},{"PostingID":3227,"Title":"GSK-217744/070 (DTPa-HBV-IPV-070)","Description":"An open clinical study to assess the immunogenicity and safety of GSK Bio's 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, Sponsor: GSK"},{"PostingID":3233,"Title":"GSK-217744/095 (DTPa-HBV-IPV-095)","Description":"Study to assess immunogenicity and reactogenicity of GSK Bio's 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 Bio's DTPa-HBV-IPV/Hib vaccine in study DTPa-HBV-IPV-086 Medicine or Vaccine (generic name), Sponsor: GSK"},{"PostingID":134,"Title":"GSK-109507","Description":"Booster Vaccination With Pneumococcal Vaccine GSK1024850A, a DTPa-Combined and MenC or Hib-MenC Vaccines, Sponsor: GSK"},{"PostingID":339,"Title":"GSK-101518 (DTPa-HBV-IPV-103)","Description":"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, Sponsor: GSK"}]

Statistical Analysis Plan

1.0 Title

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

2.0 Aims

* To investigate the benefits of multivariate methods of meta-analysis for studies with multiple correlated outcomes;
* To use multivariate meta-analysis to answer current questions regarding responses to infant vaccination in: a) girls compared to boys, and b) accelerated timing schedules (2, 3, 4 months) compared to other timing schedules.

3.0 Background

Immunisation is a safe, quick and effective way to protect people against vaccine preventable diseases and is one of the most cost-effective investments that any government or health system can make in improving the health of its population.

Changes to the schedule of vaccinations in the UK do not occur often. Changes to polio vaccination (from an oral vaccine to an injected vaccine) occurred in 2004 and pneumococcal conjugate vaccine (PCV) was added to the routine immunisation schedule in September 2006. The 2013-14 period has seen the greatest number of changes to the UK vaccination schedule in its history with the introduction of shingles vaccine, a nasal spray influenza vaccination in young children, rotavirus vaccine for infants and changes to the number of vaccinations required against human papilloma virus (HPV) for girls and meningococcal C for infants. Meningococcal B vaccine has also been recommended for addition to the schedule in the near future.

Vaccinations work when given to the whole population of at-risk people thus inducing ‘herd immunity' and effectively removing the disease from circulation. Herd immunity occurs when there are sufficient numbers of people vaccinated such that the disease has too few people left who can be infected and is thus is prevented from spreading. The World Health Organisation (WHO) recommends at least 95% of children should receive vaccines as scheduled to reduce the risk of disease in all children. This does not always happen. Current newly introduced recommendations for all young children to be vaccinated with a nasal spray influenza vaccine are not being achieved with only a third of 2 year olds receiving the vaccine as scheduled. Negative press surrounding flawed and fraudulent research on the measles, mumps and rubella vaccine (MMR) resulted in a sharp drop in the rate of vaccine uptake in the UK. Outbreaks of entirely preventable diseases occurred resulting in disability and death.

The Joint Committee on Vaccination and Immunisation (JCVI) advises the UK health departments on immunisations for the prevention of infections and/or disease after review of the available evidence from randomised controlled trials and epidemiological studies. Systematic reviews or meta-analyses are not always available for the JCVI to consider when making recommendations for policy and there is no JCVI budget for commissioning such reviews.

It is vital that both policy makers and the public have access to the best quality research when making decisions on vaccinations.

The very first vaccines were developed in the late 18th and 19th century and were specific to one disease only (e.g. small pox, tuberculosis, cholera). With the change in technology since then, vaccines have become multi- component multi-dose interventions. Infants from the age of 2 months old in the UK receive combination vaccines which protect against 5 separate diseases - diphtheria, tetanus, pertussis, polio and Haemophilus influenza type b (Hib) disease (DTP-IPV/Hib) - and 13 different serotypes of pneumococcal disease (PCV13). Due to the multi-component nature of vaccine interventions, vaccine randomised controlled trials usually have multiple primary outcomes - one for each vaccine component. Antibody concentrations are used to assess immune response to a vaccine and are measured simultaneously from one blood sample. Thus a trial of PCV13 vaccine might have 13 primary outcomes. Responses to different components of a vaccine can be highly correlated yet randomised controlled trials generally treat each component as if it is independent of all other components and assess effectiveness separately at the 5% significant level without adjusting for multiple comparisons. This increases the chance of finding falsely significant results (type 1 error bias). There is currently no guidance or general consensus on how or which trial endpoints should be controlled for multiple testing. Methods are available for controlling type 1 error when multiple comparisons are independent of each other but for situations where outcomes are highly correlated there is no simple method for adjusting the results as the extent of bias is related to the underlying correlation structure in the data.

Meta-analysis is a well-established method of combining information from multiple clinical trials or observational studies to obtain more precise estimates of treatment effects or differences. Meta-analyses are almost entirely conducted using univariate methods i.e. each outcome is analysed independently even though outcomes may be related and thus treatment effects on outcomes could be correlated. Recently methods and software for conducting meta-analyses under a multivariate framework have become readily available enabling the correlation between study treatment effects to be controlled. Multivariate meta-analysis has the potential to reduce the type 1 error bias which occurs when multiple outcomes are treated as independent, as the correlation structure of the data can be modelled. Additionally multivariate meta-analysis has the potential to reduce other forms of bias. Outcome reporting bias occurs in meta-analysis when some included trials did not measure all relevant outcomes. Univariate meta-analyses of necessity have to exclude such trials but multivariate meta-analysis can still include them as long as other related outcomes were measured in the study. This adds significant power to an analysis.

4.0 Plan of Investigation

This project focusses on two main areas; a methodological assessment of multivariate meta-analysis methods followed by utilisation of methods to answer current questions in the field of vaccine research. Recommendations for the conduct, analysis and meta-analysis of vaccine studies will be made which will improve the quality of the evidence available to policy makers and the public.

4.1 Assessment of methods

A methods review of multivariate meta-analysis will be conducted, reviewing the different options available for conducting meta-analysis under a multivariate framework. This will include (but not be limited to) one-stage models (using multi-level modelling), two-stage models (using summary statistics) and different methods of specifying both types of analyses. It will also include a review of available software for conducting such analyses (R, SAS and Stata) as different statistical programs have different options.

Using individual patient data from multiple vaccine trials multivariate treatment effect estimates will be compared to univariate treatment effects by analysing the data using each method. Estimates of treatment differences calculated using univariate (standard) meta-analysis will be compared to multivariate estimates to determine if false-positive results are more likely under a univariate framework. The correlation between responses to each vaccine component will also be assessed as part of this research to determine whether there is a pattern in the way children respond to vaccination. The question of which vaccine components produce immune responses which are more highly correlated and whether children who respond well to one component also respond well to others will be addressed. These studies will be used to illustrate how the difference between multivariate vs univariate estimates changes under a different correlation structure and a different treatment effect size from a different disease and treatment area.

Individual participant data meta-analyses from these analyses will provide estimates of the underlying correlation structure of the study treatment effects which can then be used in simulation models to characterise the gain in precision of estimates of efficacy due to the multivariate methods. This will provide estimates under perfectly controlled scenarios. Simulations will be conducted for plausible situations; varying the degree of correlation between outcomes and varying the size of the underlying treatment effect.

Since vaccine trials have multiple endpoints it may be beneficial to be able to combine all endpoints into one metric for analysis. A global metric (using ranks) will be developed to compare overall response across endpoints rather than component-specific response and simulations conducted to determine the performance of this metric. Data will be simulated from the vaccine trials data so that the simulated data has the same underlying correlation structure.

4.2 Application of methods

The first part of this research plan (section 4.1) assessed the methods available to address current questions. The second part of the research (section 4.2) will put those methods shown to work best into practice in order to provide robust and reliable conclusions to currently unanswered questions.

4.2.1 Sex-differential responses to vaccination

In recent years controversy has arisen surrounding differences in response to vaccination in girls compared to boys. Researchers have claimed that higher overall mortality rates can be observed in girls compared to boys due to vaccination with diphtheria-tetanus-pertussis after vaccination with the Bacille Calmette-Guerin (BCG) vaccine. This constitutes a non-specific effect as the differences seen in mortality rates were higher than would be expected due to deaths caused by the diseases covered by the vaccines. These claims led the WHO to commission independent reviews to determine if the current evidence is sufficient to lead to adjustments in policy recommendations for infant immunisations or to warrant further scientific investigation. I was privileged to be a part of the team providing a review of the available immunological evidence presented at the WHO Strategic Advisory Group of Experts on Immunization meeting in Geneva in 2014. Most of the data available for review were observational studies or small lab-based technical studies. Both the epidemiological and immunological reviews of the potential non-specific effects of vaccination concluded that the evidence available in the published and grey literature which can be used to assess this question is poor in methodological rigour and open to high or extreme risk of various forms of bias. The question of sex-differential responses to vaccination has therefore still not been answered and the controversy continues.

If it is true that there are sex-specific differences in responses to vaccinations it should be possible to demonstrate this by re-analysing data from previous randomised controlled trials. The questions which will be therefore addressed in this section are:

Is there a plausible difference in the immunological response to vaccination in girls compared to boys?

Are sex-specific differences in vaccine response limited to certain antigens or vaccines only or is it a general phenomenon? and,

Does previous vaccination with BCG in the first week of life affect the immune response to subsequent vaccination with diphtheria-tetanus-pertussis vaccines in early infancy and if so, does this vary according to sex?

4.2.2 Vaccination Timing Policy

In 1990 the UK infant schedule for DTP vaccination changed from a 3, 5, 9 month schedule to a 2, 3, 4 month schedule in order to increase protection against pertussis in younger, more vulnerable children. There has never been a randomised controlled trial in the UK to compare how timing affects immune responses however early observational research suggested that the 2, 3, 4 schedule was less immunogenic. This schedule was later altered to incorporate a booster dose.

Infant vaccination schedules vary greatly from country to country. Australia, Ireland, Canada, USA and some European countries vaccinate at 2, 4, and 6 months of age; Sweden, Iceland, Norway, Italy recommend a 2 dose infant schedule at 3 and 5 months of age. The WHO recommends a 6, 10, and 14 week schedule for DTP vaccines. There are no trials comparing different schedules in the UK and very limited information from trials in other countries. No meta-analysis of trials has been conducted to assess this issue. The UK schedule is effective in preventing disease yet may still not be optimal. Schedules with wider spacing of doses, and, counter-intuitively, schedules with fewer early vaccine doses may result in similar immunogenicity in the first 6 months of life and better immunogenicity after a 12 month booster dose.

As more life-saving vaccinations are added to the UK schedule it is becoming crowded with little room available for adding new, multiple-dose vaccines such as the proposed new meningococcal B vaccine which requires 3-4 separate injections. When new vaccines become available and the schedule is reviewed, the effect of the timing of the vaccinations becomes crucial since timing effects both the immune response and the acceptability for parents. Timing of vaccinations in infants can have large effects on the infant immune response. For example recent trials in Nepal have shown that two infant vaccinations with pneumococcal vaccine followed by one booster dose is far more immunogenic than three doses given in infancy. These findings resulted in changes to the Nepalese vaccination policy to increase protection in children without adding any further costs to the health system and without increasing the burden of vaccination on children. Other studies have shown that sometimes in the world of infant immunisation ‘less is more' - one infant dose of meningococcal C vaccine followed by a booster has been shown to be better than two infant doses followed by a booster.

Using the same data from section 4.2.1 I will compare immune responses in infants vaccinated under different policies by grouping data from trials conducted in different countries with varying policies. The antibody levels in children in response to vaccination can be compared between schedules in a multivariate meta-analysis framework. Data will be compared from trials of a 2, 4, 6 month schedule; a 3, 4, 5 month schedule; 2, 3, 4 month schedule and the 6, 10, 14 week schedule. Analyses will adjust for the country in which the trial was conducted and receipt of BCG vaccination at birth.

Publication Citation

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