Understanding Variation in Rotavirus Vaccine Effectiveness Estimates in the United States: The Role of Rotavirus Activity and Diagnostic Misclassification.

Background: Estimates of rotavirus vaccine effectiveness (VE) in the United States appear higher in years with more rotavirus activity. We hypothesized rotavirus VE is constant over time but appears to vary as a function of temporal variation in local rotavirus cases and/or misclassified diagnoses.
Methods: We analyzed 6 years of data from eight US surveillance sites on 8- to 59-month olds with acute gastroenteritis symptoms. Children's stool samples were tested via enzyme immunoassay (EIA); rotavirus-positive results were confirmed with molecular testing at the US Centers for Disease Control and Prevention. We defined rotavirus gastroenteritis cases by either positive on-site EIA results alone or positive EIA with Centers for Disease Control and Prevention confirmation. For each case definition, we estimated VE against any rotavirus gastroenteritis, moderate-to-severe disease, and hospitalization using two mixed-effect regression models: the first including year plus a year-vaccination interaction, and the second including the annual percent of rotavirus-positive tests plus a percent positive-vaccination interaction. We used multiple overimputation to bias-adjust for misclassification of cases defined by positive EIA alone.
Results: Estimates of annual rotavirus VE against all outcomes fluctuated temporally, particularly when we defined cases by on-site EIA alone and used a year-vaccination interaction. Use of confirmatory testing to define cases reduced, but did not eliminate, fluctuations. Temporal fluctuations in VE estimates further attenuated when we used a percent positive-vaccination interaction. Fluctuations persisted until bias-adjustment for diagnostic misclassification.
Conclusions: Both controlling for time-varying rotavirus activity and bias-adjusting for diagnostic misclassification are critical for estimating the most valid annual rotavirus VE.
Competing Interests: Disclosure: J.A.E. has research support from Merck, Pfizer, and GlaxoSmithKline and consults for Sanofi Pasteur and Meissa Vaccines. G.A.W. received an honorarium from Merck for authorship of chapters in the Merck Manual. M.M.M. has laboratory agreements with Merck Sharp & Dohme and Sanofi. C.J.H. has research support from Merck, GlaxoSmithKline, Pfizer, and Astra-Zeneca and has received honoraria from Frontline Medical Communications for contributions to Pediatric News. J.E.S. has research support from Merck. T.L.L. is a member of the Amgen Methods Advisory Council, for which he receives consulting fees and travel support. B.A.L. reports grants and personal fees from Takeda Pharmaceuticals and personal fees from World Health Organization, outside the subject of the submitted work. The other authors report no conflicts of interest.
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