Background: Cross-country and cross-period variation in COVID-19 age-adjusted case fatality rates (ad-CFRs) has not been clarified. We aim to identify the country-specific effects of booster vaccination and other features that may affect heterogeneity on ad-CFR, and predict the impact of increasing booster vaccination rates on future CFR.

Method: We used the machine learning algorithm to identify risk features affecting ad-CFRs in 32 countries, considering the 35 factors. Next, we simulated the impact of increasing booster vaccination rates by 1% to 30% in each country on ad-CFRs.

Results: Across 32 countries, COVID-19 ad-CFRs ranged from 110 to 5,112 deaths per 100,000 cases from Feb 4, 2020 to Jan 31, 2022. The importance of booster vaccination on ad-CFRs increased from Alpha to Omicron period (Fig 1). The Omicron period model revealed that low GDP per capita and low booster vaccination rates were key risk factors for countries with higher ad-CFRs than crude CFR, while high dietary risks and low physical activity were key risk factors for the opposite group (Fig 1). Increasing booster vaccination rates by 17% would reduce CFRs in 24 countries, but not in the remaining 6 countries where booster vaccination was increased up to 30% (Fig 1).

Conclusions: Boosters reduce ad-CFRs, but addressing country-specific risks and implementing joint intervention strategies are also crucial.