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

Proposal
1731

Title of Proposed Research

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

[{ "PostingID": 271, "Title": "GSK-106481", "Description": "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" },{ "PostingID": 272, "Title": "GSK-107625", "Description": "Efficacy, safety, reactogenicity and immunogenicity study of the lyophilised formulation of Rotarix vaccine in healthy Japanese infants" },{ "PostingID": 273, "Title": "GSK-109216", "Description": "Immunogenicity and safety of two doses of GlaxoSmithKline (GSK) Biologicals' oral live attenuated human rotavirus (HRV) liquid vaccine (GSK 357941A) in healthy infants." },{ "PostingID": 510, "Title": "GSK-444563/023", "Description": "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" },{ "PostingID": 1283, "Title": "GSK-101555", "Description": "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" },{ "PostingID": 1284, "Title": "GSK-444563/013", "Description": "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" },{ "PostingID": 1285, "Title": "GSK-444563/022", "Description": "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" },{ "PostingID": 1286, "Title": "GSK-444563/024", "Description": "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" },{ "PostingID": 1287, "Title": "GSK-444563/028", "Description": "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" },{ "PostingID": 1288, "Title": "GSK-107070", "Description": "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." },{ "PostingID": 1289, "Title": "GSK-444563/029", "Description": "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" },{ "PostingID": 1290, "Title": "GSK-107072", "Description": "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." },{ "PostingID": 1291, "Title": "GSK-444563/030", "Description": "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" },{ "PostingID": 1292, "Title": "GSK-107076", "Description": "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." },{ "PostingID": 1293, "Title": "GSK-444563/033", "Description": "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" },{ "PostingID": 1294, "Title": "GSK-102247", "Description": "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" },{ "PostingID": 1295, "Title": "GSK-109810", "Description": "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)." },{ "PostingID": 1296, "Title": "GSK-102248", "Description": "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" },{ "PostingID": 1297, "Title": "GSK-111274", "Description": "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" },{ "PostingID": 1299, "Title": "GSK-103478", "Description": "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" },{ "PostingID": 1300, "Title": "GSK-103992", "Description": "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" },{ "PostingID": 1302, "Title": "GSK-105722", "Description": "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" },{ "PostingID": 1546, "Title": "GSK-113808", "Description": "Efficacy, immunogenicity and safety of two doses of GlaxoSmithKline (GSK) Biologicals' Oral Live Attenuated Liquid Human Rotavirus (HRV) Vaccine (444563), in healthy infants" },{ "PostingID": 3308, "Title": "GSK-444563/007 (rota-007)", "Description": "Study to assess efficacy, immunogenicity, reactogenicity and safety of two doses of GSK Bio's oral live attenuated human rotavirus vaccine at different viral concentrations in healthy infants previously uninfected with human rotavirus and approximately 3 months of age" },{ "PostingID": 3347, "Title": "GSK-444563/004", "Description": "A study to assess the efficacy, immunogenicity and safety of two doses of oral live attenuated human rotavirus (HRV) vaccine (Rotarix) in healthy infants." },{ "PostingID": 3348, "Title": "GSK-444563/005 (rota-005)", "Description": "Phase II, double-blind, randomized, placebo-controlled study of 2 doses of GSK Bios' 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" },{ "PostingID": 3349, "Title": "GSK-444563/006", "Description": "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." },{ "PostingID": 4670, "Title": "GSK-103792", "Description": "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

The statistical analysis plan to achieve Aim 1 will differ slightly based upon the outcome measure of interest. Linear regression of log transformed data is proposed for analysis of the IgA antibody titer (continuous outcome) while logistic regression is appropriate for seroconversion (dichotomous outcome). Both types of models will incorporate host characteristics as predictors and control for potential confounders, which will be selected based on the availability of data and existing literature. The effect measures of interest estimated by our models will be rate ratios and corresponding 95% confidence intervals for the linear regression models and odds ratios and corresponding 95% confidence intervals for the logistic regression models.For Aim 2, the dichotomous outcomes of interest (occurrence of severe rotavirus gastroenteritis within 1 and 2 years of vaccination; occurrence of rotavirus gastroenteritis of any severity within 1 and 2 years of vaccination) will be analyzed as time to event variables using survival analysis methods. The predictors of interest will be IgA antibody titers at specified cut-off values selected based on the distribution of the titers. Hazard ratios (and corresponding 95% confidence intervals) will be estimated using Cox proportional hazard regression analysis for each specified level of IgA antibodies and each outcome. For Aim 2, participants will be censored at the end of the follow-up period or when the individual was lost to follow-up (a method to address missing data).Data will be analyzed in SAS. Julia Baker, trained in epidemiology, will be conducting the statistical procedures under the guidance of Dr. Michael Haber and Dr. Benjamin Lopman of Emory University.There are important challenges and limitations of this proposed research. Using data collected under the stringent monitoring necessary for a clinical trial means that the results produced may not perfectly reflect the findings that would have occurred under more routine, real world conditions. Further, it is anticipated that there will be limited data available on maternal, socioeconomic and environmental factors that may play a role in individual-level immune response to vaccination and time to first episode of rotavirus gastroenteritis, potentially introducing residual or uncontrolled confounding in our models. An especially important and anticipated potential confounder is rotavirus infections that occur prior to vaccination (pre-vaccine seropositivity). The effects of seropositivity on rotavirus vaccine efficacy and immunogenicity is currently being investigated by Joann Gruber of the University of North Carolina using some of these same data from GSK's Rotarix trials and, based on her findings, will be addressed accordingly in this proposed research. The proposed study has several notable strengths. The first is the use of individual-level pooled data from similarly conducted randomized clinical trials. This not only allows for a larger sample size than would be available from individual trials alone, but also provides high quality data on the exposures, outcomes and potential confounders of interest. Including data from countries of various levels of economic development will facilitate analyses and production of results specific to country-income level but that are also generalizable. The two, related aims of this study may provide important insight into the pathways in which host characteristics influence immunogenicity which in turn impacts clinical disease.

Publication Citation

http://ars.samrc.ac.za/ARS%202019/ARS%20posters/Baker%20Oral%20polio%20vaccine%20interferes%20.pdf

http://ars.samrc.ac.za/ARS%202019/ARS%20posters/Baker%20Assessing%20serum%20anti.pdf