Rotavirus vaccines in low-income settings

Thesis (Ph.D.)--University of Washington, 2018Background: An estimated 200,000 deaths due to rotavirus diarrhea occur annually in children with most of the burden in low-income settings. Rotavirus is a double stranded RNA virus transmitted via the fecal-oral route. Without a vaccine, nearly all children <5 years old become infected with rotavirus and recurrent infection is common. Rotavirus vaccines continue to be the key intervention needed to reduce the global burden of severe rotavirus diarrhea. Two rotavirus vaccines are used worldwide (Rotarix [RV1]) and (RotaTeq [RV5]). Large multi-site randomized controlled trials (RCTs) of both vaccines in sub-Saharan Africa and Asia demonstrated moderate vaccine efficacy (VE) against severe rotavirus diarrhea during the first year of life. As of March 2018, 93 countries, including 43 Gavi-eligible countries, have introduced a rotavirus vaccine into its immunization schedule. This dissertation sought to evaluate the test-negative design as an appropriate epidemiologic study design to measure rotavirus vaccine effectiveness in low-income settings (Aim 1), estimate the population-level impact of rotavirus vaccine introduction in Matlab, Bangladesh (Aim 2), and assess the role of host genetic determinants in rotavirus vaccine failure (Aim 3). Methods: Each aim of the dissertation uses a separate data source. For Aim 1, test-negative vaccine effectiveness (VE-TND) estimates were derived from three large randomized placebo-controlled trials of RV1 and RV5 in sub-Saharan Africa and Asia. Derived VE-TND estimates were compared to the original RCT vaccine efficacy estimates (VE-RCTs). The core assumption of the TND (i.e., rotavirus vaccine has no effect on rotavirus-negative diarrhea) was also assessed. For Aim 2, interrupted time series were used to estimate the impact of RV1 introduction in Matlab, Bangladesh among children <2 years of age. Analyses were conducted using diarrheal surveillance data collected between 2000 and 2014 within the two service delivery areas (icddr,b service area [ISA] and government service area [GSA]) of the Matlab Health and Demographic Surveillance System. Age-group specific incidence rates were calculated for both rotavirus-positive (RV+) and rotavirus-negative (RV-) diarrhea. For Aim 3, conditional logistic regression was used to assess the relationship between Secretor and Lewis phenotypes and rotavirus vaccine failure. Analyses were conducted among children 3-