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Proposal 1731

Title of the Proposed Research

Host characteristics impacting Rotarix immunogenicity and correlates of protection for rotavirus gastroenteritis, a multi-site pooled analysis of individual-level clinical trial data

Lead Researcher

Julia M. Baker

Affiliation

Department of Epidemiology, Rollins School of Public Health, Emory University

Funding Source

Julia Baker’s work will be funded by her current PhD studentship stipend. Dr. Ben Lopman will contribute time through established rotavirus research grants. Dr. Michael Haber will be providing guidance throughout the research with financial support for his time from the Department of Biostatistics and Bioinformatics at Emory University or another source.

Potential Conflicts of Interest

None

Data Sharing Agreement Date

5 June 2017

Lay Summary

Extensive evaluations of two rotavirus vaccines, Rotarix (GlaxoSmithKline) and RotaTeq (Merck), have demonstrated their dramatic role in reducing the risk of severe rotavirus disease among young children.(1–5) Despite this progress, rotavirus remains the leading cause of severe diarrheal disease among children under 5 years of age globally, responsible for 215,000 deaths annually.(6)

A central impediment to further reducing the rotavirus burden is the relatively low efficacy of the vaccines in settings where the incidence of severe disease and death is highest.(6,7) Vaccine efficacy ranges from 80-90% in areas of low child mortality and only 40-60% in settings with high child mortality.(1,8) The mechanisms behind this variation are not fully understood(9) with possible hypotheses including differences in circulating strains(10) or host characteristics such as breastfeeding and nutrition, and co-infection with other pathogens.(1,11) Identification of factors that contribute to vaccine immunogenicity may provide insight into potentially modifiable factors for improving vaccine efficacy.

Anti-rotavirus immunoglobulin A (IgA) antibodies are being explored as possible markers for protection(12) and have proven valuable as possible predictors of vaccine efficacy on the aggregate level, when comparing countries by income level.(13) Findings related to individual-level correlates of protection, however, have been inconsistent(14–17) and require further exploration.

To promote optimal rotavirus vaccine strategies and evaluation of new interventions, this study aims to investigate host characteristics that contribute to immune response and, based upon these findings, identify correlates of protection for rotavirus gastroenteritis at the individual level.

This pooled analysis will utilize individual-level data on infants from countries of varying levels of income who participated in GlaxoSmithKline’s Rotarix phase II and phase III clinical trials. All relevant demographic, social and behavioral host characteristics available in the data (eg. gender, age at first dose, nutritional status, breastfeeding status, and country of residence) will be evaluated via regression analysis to determine their association with clinical endpoints for immunogenicity, measured by serum anti-rotavirus IgA antibody titer and anti-rotavirus IgA antibody seroconversion. To identify correlates of protection, post-immunization serum IgA antibody data will be analyzed to identify a cutoff at which vaccination provides protection from severe rotavirus gastroenteritis within one and two years after administration of the vaccine. The findings from this research will be communicated to the public through peer-reviewed literature to help guide relevant programmatic and policy decisions.

Study Data Provided

GSK-106481: Phase IIIb, Double Blind, Randomised, Placebo-Controlled, Multi-Country/Centre, Study to Assess Safety, Reactogenicity & Immunogenicity of 2 Doses of GSK Biologicals' Oral Live Attenuated Human Rotavirus (HRV) Vaccine in Pre-Term Infants
GSK-107625: Efficacy, safety, reactogenicity and immunogenicity study of the lyophilised formulation of Rotarix vaccine in healthy Japanese infants
GSK-109216: Immunogenicity and safety of two doses of GlaxoSmithKline (GSK) Biologicals’ oral live attenuated human rotavirus (HRV) liquid vaccine (GSK 357941A) in healthy infants
GSK-444563/023: A placebo-controlled, multi-country & multi-center study to assess the efficacy, safety & immunogenicity of 2 doses of GSK Biologicals’ oral live attenuated human rotavirus (HRV) vaccine in healthy infants
GSK-101555: A phase II, double-blind, randomized, placebo-controlled study to compare the immunogenicity, reactogenicity and safety of 2 different formulations of GSK Biologicals’ live attenuated human rotavirus (HRV) vaccine given as a two-dose primary vaccination in healthy infants previously uninfected with HRV
GSK-444563/013: A phase II, randomized, double-blind, placebo-controlled study of safety, reactogenicity and immunogenicity of 2 or 3 doses of GSK Biologicals’ oral live attenuated human rotavirus vaccine at 10E6.5 CCID50 viral concentration in healthy infants (approximately 5-10 weeks old) in the Republic of South Africa
GSK-444563/022: A phase II, double-blind, randomized, placebo-controlled study to assess the safety, reactogenicity and immunogenicity of three doses of GlaxoSmithKline (GSK) Biologicals’ oral live attenuated human rotavirus (HRV) vaccine administered to human immunodeficiency virus (HIV) infected infants at 6, 10 and 14 weeks of age in South Africa.
GSK-444563/024: A multi-country & multi-center study to assess the efficacy, immunogenicity & safety of two doses of GSK Biologicals' oral live attenuated HRV vaccine given concomitantly with routine EPI vaccinations including OPV in healthy infants
GSK-444563/028: A phase III, double-blind, randomized, placebo-controlled, multi-country and multi-center study to assess the efficacy and safety of two doses of GSK Biologicals’ oral live attenuated human rotavirus (HRV) vaccine in healthy infants
GSK-107070: A phase III, double-blind, randomized, placebo-controlled, multi-country and multi-center study to assess the efficacy and safety of two doses of GSK Biologicals' oral live attenuated human rotavirus (HRV) vaccine in healthy infants.
GSK-444563/029: A phase III, double-blind, randomized, placebo-controlled, multi-country and multi-center study to assess the efficacy and safety of two doses of GSK Biologicals’ oral live attenuated human rotavirus (HRV) vaccine in healthy infants
GSK-107072: A phase III, double-blind, randomized, placebo-controlled, multi-country and multi-center study to assess the efficacy and safety of two doses of GSK Biologicals' oral live attenuated human rotavirus (HRV) vaccine in healthy infants.
GSK-444563/030: A phase III, double-blind, randomized, placebo-controlled, multi-country and multi-center study to assess the efficacy and safety of two doses of GSK Biologicals’ oral live attenuated human rotavirus (HRV) vaccine in healthy infants
GSK-107076: A phase III, double-blind, randomized, placebo-controlled, multi-country and multi-center study to assess the efficacy and safety of two doses of GSK Biologicals' oral live attenuated human rotavirus (HRV) vaccine in healthy infants.
GSK-444563/033: Study to assess the clinical consistency of three production lots of GSK Biologicals’ HRV vaccine in terms of immunogenicity and safety when given to healthy infants at 2 and 4 months of age
GSK-102247: A multi-country & multi-center study to assess the efficacy, safety & immunogenicity of 2 doses of GSK Biologicals’ oral live attenuated human rotavirus (HRV) vaccine in healthy infants in co-administration with specific childhood vaccines
GSK-109810: To assess long-term efficacy & safety of subjects approximately 3 years after priming with 2 doses of GlaxoSmithKline (GSK) Biologicals’ oral live attenuated human rotavirus (HRV) vaccine (Rotarix) in the primary vaccination study (102247).
GSK-102248: Multi-Center Study to Assess the Efficacy, Safety and Immunogenicity of 2 or 3 Doses of GSK Biologicals' Oral Live Attenuated Human Rotavirus (HRV) Vaccine Given Concomitantly With Routine EPI Vaccinations in Healthy Infants
GSK-111274: Multi-Center Study to Assess the Efficacy, Safety and Immunogenicity of 2 or 3 Doses of GSK Biologicals' Oral Live Attenuated Human Rotavirus (HRV) Vaccine Given Concomitantly With Routine EPI Vaccinations in Healthy Infants
GSK-103478: Assess the immunogenicity, safety & reactogenicity of 2 doses of GSK Biologicals’ oral live attenuated human rotavirus (HRV) vaccine in healthy infants (6-12 weeks of age at first dose) previously uninfected with human rotavirus
GSK-103992: Evaluate immunogenicity, reactogenicity & safety of 2 doses of GSK Biologicals’ oral live attenuated HRV vaccine (RIX4414 at 106.5 CCID50) when given concomitantly with OPV versus given alone (HRV vaccine dose given 15 days after the OPV dose) in healthy infants in Bangladesh
GSK-105722: A placebo-controlled study to evaluate the immunogenicity, reactogenicity and safety of two doses of GSK Biologicals' oral live attenuated human rotavirus (HRV) liquid vaccine, when given to healthy infants, in Vietnam
GSK-113808: Efficacy, immunogenicity and safety of two doses of GlaxoSmithKline (GSK) Biologicals' Oral Live Attenuated Liquid Human Rotavirus (HRV) Vaccine (444563), in healthy infants
GSK-444563/007 (rota-007): Study to assess efficacy, immunogenicity, reactogenicity and safety of two doses of GSK Biologicals' oral live attenuated human rotavirus vaccine at different viral concentrations in healthy infants previously uninfected with human rotavirus and approximately 3 months of age
GSK-444563/004: A study to assess the efficacy, immunogenicity and safety of two doses of oral live attenuated human rotavirus (HRV) vaccine (Rotarix) in healthy infants.
GSK-444563/005 (rota-005): Phase II, double-blind, randomized, placebo-controlled study of 2 doses of GSK Biologicals’ live attenuated human rotavirus vaccine at different virus concentrations (10 5.2 and 10 6.4 ffu) in healthy infants following a 0, 2 month schedule and previously uninfected with human rotavirus
GSK-444563/006: To assess the efficacy, immuno & safety of 2 doses of GSK HRV vaccine at different virus concentrations in healthy infants aged 2 months & previously uninfected with HRV, concurrently given with DTPw-HBV, Hib.
GSK-103792: A multicenter study of the immunogenicity & safety of 2 doses of GSK Biologicals’ oral live attenuated human rotavirus vaccine (RIX4414) as primary dosing of healthy infants in India aged approximately 8 wks at the time of the first dose

Statistical Analysis Plan

Publication Citation

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Summary Results

Results summary or link will be posted when available.