Impact of rotavirus genotype and local rotavirus gastroenteritis incidence on Rotarix vaccine efficacy estimates: a multi-site pooled analysis of individual-level clinical trial data

Proposal
10141

Title of Proposed Research

Lead Researcher

Avnika B. Amin

Affiliation

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

Funding Source

Potential Conflicts of Interest

Data Sharing Agreement Date

15 May 2020

Lay Summary

Extensive evaluations of Rotarix have demonstrated its efficacy against severe rotavirus gastroenteritis among young children. However, the relatively low vaccine efficacy in high-burden settings leaves the children most at risk of serious rotavirus outcomes with the least benefit from vaccination. Heterogeneity in nutritional deficiencies, gut flora, co-infections, maternally-acquired antibodies, and immune system immaturity may all reduce immune response to rotavirus infection or vaccination. Other factors and measurement errors may also affect efficacy estimates. Rotavirus diversity could partially explain the variation in efficacy estimates, with some evidence suggesting lowered vaccine protection against certain genotypes. Specifically, the effectiveness of rotavirus vaccines may be reduced against one specific genotype (G2P[4]) compared to protection against other rotavirus genotypes. High child mortality regions, which are also those with greater rotavirus burden, have much greater genotype diversity than low child mortality regions. In settings with greater genotype diversity, differing genotype-specific efficacies may explain why the ‘overall' efficacy is lower in high burden settings. A challenge to investigating this question is the limited statistical power available in most individual trials when data were stratified by rotavirus genotype. By pooling data from rigorously-conducted clinical trials, we can assess the extent to which lower overall efficacy in low income settings is a result of reduced protection against certain genotypes.The imperfectly immunizing nature of rotavirus infections and vaccination further complicates assessment of vaccine efficacy. Rotavirus infections are imperfectly immunizing in the sense that several infections are required for complete immunity, so more exposure to rotavirus results in faster acquisition of immunity. When rotavirus incidence is higher, the unvaccinated accumulate immunity faster than they would in a low incidence setting. Because incidence impacts the rate of change in individual susceptibility, comparing efficacy between settings with different incidence rates may result in different estimates of protection, even when biological protection offered by vaccine is the same. Only after accounting for incidence can study populations in different locations be considered comparable. Local incidence differences have not been extensively studied in the context of rotavirus, leaving the magnitude of bias on vaccine efficacy estimates uncertain.This extended analysis aims to evaluate the extent to which rotavirus genotype and local incidence rates influence vaccine efficacy estimates. The pooled analysis will use individual-level data collected for GSK's Rotarix Phase II and Phase III clinical trials. Regression analyses will be used to evaluate 1) genotype-specific vaccine efficacy, and 2) the relationship between local incidence rates and vaccine efficacy estimates. The findings from this research will be disseminated through publication in peer-reviewed journals to help guide current and future evaluation of rotavirus vaccines.

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": 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": 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

Aim 1 analyses will use hierarchical multinomial logistic regression. The first-level data come from the individuals in each trial, and the second-level data from study site(s) in each trial. We will first estimate a single pooled estimate of vaccine efficacy to represent the traditional approach to efficacy calculations. To estimate genotype-specific efficacy, we will use the same model but treat each genotype component of vaccine efficacy as having its own distribution. This allows for different estimates to be obtained based on rotavirus genotype. Each gastroenteritis endpoint will thus have two models (overall and genotype-specific efficacy).Aim 2 analyses will use hierarchical Poisson regression. As in Aim 1, the first-level data will come from the individuals in each trial, and the second-level data from study site(s) in each trial. The local incidence rate at each study site will be calculated using data from the unvaccinated group in each trial, then included as the main covariate of interest in the regression model. We will use the Poisson regression model to generate vaccine efficacy estimates, examining either the interaction between efficacy and incidence or vaccine efficacy as a function of incidence. Data will be analyzed in SAS and/or R. Avnika B. Amin, trained in epidemiology, will conduct the statistical analysis under the guidance of Dr. Benjamin A. Lopman and Dr. Lance Waller of Emory University.There are some key challenges and limitations to the proposed work. While the protocols used in the requested studies are similar, they are not exactly the same. This may result in loss of data when consistent definitions are applied across trials, as well as issues with interpreting results derived from a more heterogeneous population. Loss to follow-up may also be an issue over such a long period of follow-up time, and alternative methods to maximize use of person-time data may need to be employed. Substantial loss to follow-up may compromise the validity of the research results.The proposed work has several strengths as well. Use of individual-level pooled data from randomized clinical trials with similar protocols allows for data to be pooled, resulting in a larger sample size than those from individual trials. The high quality of the trial data will also reduce the likelihood of measurement and misclassification errors. Inclusion of data from countries at various points in their economic development will also allow for evaluation of genotype diversity and local incidence impacts across a wider range of settings.

Publication Citation

Amin AB, Tate JE, Waller LA, Lash TL, Lopman BA. Monovalent Rotavirus Vaccine Efficacy Against Different Rotavirus Genotypes: A Pooled Analysis of Phase II and III Trial Data. Clin Infect Dis. 2023 Feb 8;76(3)
DOI: 10.1093/cid/ciac699