| Summary: | Abstract The present study aimed to estimate the infection fatality risk (IFR) and ascertainment bias of SARS-CoV-2 for six epidemic waves in Japan from February 2020 to January 2022. We used two types of datasets: (i) surveillance-based datasets containing the cumulative numbers of confirmed cases and deaths in each epidemic wave and (ii) seroepidemiological datasets conducted in a serial cross-sectional manner. Smoothing spline function was employed to reconstruct the age-specific cumulative incidence of infection. We found that IFR was highest during the first wave, and the second highest during the fourth wave, caused by the Alpha variant. Once vaccination became widespread, IFR decreased considerably among adults aged 40 years plus during the fifth wave caused by the Delta variant, although the epidemic size of fifth wave was the largest before the Omicron variant emerged. We also found that ascertainment bias was relatively high during the first and second waves and, notably, RT-PCR testing capacity during these early periods was limited. Improvements in the ascertainment were seen during the third and fourth waves. Once the Omicron variant began spreading, IFR diminished while ascertainment bias was considerably elevated.
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