Rotavirus vaccines in low-income settings

BACKGROUND

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-<24 months of age enrolled within the Vaccine Impact on Diarrhea in Africa (VIDA) study, a large case-control study in The Gambia, Mali, and Kenya assessing diarrheal etiologies.

RESULTS

For Aim 1, TND vaccine effectiveness estimates were nearly equivalent to original RCT estimates. Neither rotavirus vaccine had a substantial effect on rotavirus-negative diarrhea. For Aim 2, we observed a downward trend in RV+ diarrhea incidence among children from ISA villages presenting to Matlab Hospital during approximately 3.5 years of routine RV1 use. Significant impact of RV1 on RV+ diarrhea incidence among children from GSA villages was not observed. Differences in population-level impact between ISA and GSA villages may be due to lower rotavirus vaccine coverage in GSA villages and a lower presentation rate to the hospital. For Aim 3, preliminary results demonstrated null phenotypes reduced the risk of rotavirus vaccine failure in a population with mostly P[8] infections, but serotype-specific results could not be estimated.

CONCLUSIONS

The findings of this dissertation support the TND as an appropriate epidemiologic study design to measure rotavirus vaccine effectiveness in low-income settings, provide additional evidence of a decrease in rotavirus diarrhea burden in Asia after vaccine introduction, and explored a preliminary analysis of the relationship between host genetic determinants and rotavirus vaccine failure. Together these results show the public health success of rotavirus vaccines in reducing averting severe rotavirus diarrhea cases in regions with the greatest burden. The results also highlight the need for additional research to understand the effectiveness and population-level impact of these vaccines in understudied regions and the interplay of risk factors contributing to moderate vaccine effectiveness.