The direct effectiveness of infant rotavirus vaccination implemented in 2006 in the United States has been evaluated extensively, however, understanding of population-level vaccine effectiveness (VE) is still incomplete. Methods: We analyzed time series data on rotavirus gastroenteritis (RVGE) and all-cause acute gastroenteritis (AGE) hospitalization rates in the United States from the MarketScan® Research Databases for July 2001-June 2016. Individuals were grouped into ages 0-4, 5-9, 10-14,

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... 24, 25-44, and 45-64 years. Negative binomial regression models were fitted to monthly RVGE and AGE data to estimate the direct, indirect, overall, and total VE. Results: A total of 9211 RVGE and 726,528 AGE hospitalizations were analyzed. Children 0-4 years of age had the largest declines in RVGE hospitalizations with direct VE of 87% (95% CI: 83, 90%). Substantial indirect effects were observed across age groups and generally declined in each older group. Overall VE against RVGE hospitalizations for all ages combined was 69% (95% CI: 62, 76%). Total VE was highest among young children; a vaccinated child in the post-vaccine era has a 95% reduced risk of RVGE hospitalization compared to a child in the pre-vaccine era. We observed higher direct VE in odd post-vaccine years and an opposite pattern for indirect VE. Conclusions: Vaccine benefits extended to unvaccinated individuals in all age groups, suggesting infants are important drivers of disease transmission across the population. Imperfect disease classification and changing disease incidence may lead to bias in observed direct VE. Trial registration: Not applicable.