Validating the test-negative case-control design for estimating rotavirus vaccine effectiveness using gold-standard randomized controlled trial data from South Africa and Malawi (Rota-037)

Validating the test-negative case-control design for estimating rotavirus vaccine effectiveness using gold-standard randomized controlled trial data from South Africa and Malawi (Rota-037)

Gates Foundation to PATH with subcontract to Fred Hutchinson Cancer Research Center and additional NIH/NIAID Grant Funding

Merck (HPV Vaccine Scientific Advistory Committee)- no conflict
Sanofi Pasteur (Dengue Vaccine) - no conflict

Rotavirus is the leading cause of severe diarrhea in children worldwide. Annually there are about 453,000 deaths attributable to rotavirus diarrhea in children. Most of these deaths occur in sub-Saharan Africa and south Asia. Recently low-income countries have introduced rotavirus vaccine into national immunization schedules. After introduction of a new vaccine case-control studies are conducted to assess vaccine effectiveness in a particular setting. The classical case-control study for rotavirus vaccine includes rotavirus diarrheal cases ascertained at a hospital or through surveillance, and controls include subjects without diarrhea but from the same hospital for a different disease or healthy subjects from a nearby community. Researchers have begun to conduct test-negative case-control studies for rotavirus vaccine. In these studies, cases include laboratory confirmed rotavirus-diarrhea but the controls are those with diarrhea caused by a pathogen other than rotavirus. The test-negative case-control design has been validated for influenza vaccines by analyzing RCT data as if it were collected through an observational case-control study (De Serres 2013). A similar validation method could be used for rotavirus vaccine. This can be accomplished by analyzing the dataset from the Rotarix-037 vaccine clinical trial.

Aims:
1. Compare original estimates of efficacy of Rotarix from the 037 trial to those generated using a test-negative case-control design.
2. Explore estimates of vaccine effectiveness (VE) using participant and specimen-based analyses.
3. Explore the sensitivity of estimates to different methods of case capture.
4. Explore sensitivity of estimates under the test-negative design to various precision variables, such as country, age, sex, race, clinic, month of hospital/clinic admission.

The main analysis (Aim 1) includes assessment of the RCT as if it were a test-negative case control study. Cases will include subjects with severe rotavirus gastroenteritis and controls will include subjects who tested rotavirus negative at any time within the study period. Vaccine effectiveness will be calculated and compared to original vaccine efficacy estimates. In Aim 2 we explore additional analyses including participant-based analysis with censoring for rotavirus where controls are rotavirus negative throughout the entire study period. A specimen-based analysis will also be conducted. For Aim 3 we will calculate separate VE estimates when cases are obtained through weekly home visits and through health clinics. In Aim 4 we will explore the sensitivity of the test-negative case-control study by adjusting for precision covariates. Adjusting for these covariates may lead to more precise and less biased estimates if these variables are prognostic of severe rotavirus gastroenteritis.

Findings: We will publish the results in a peer-reviewed scientific journal. Results will inform future studies on the effectiveness of rotavirus vaccine.

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