www.medrxiv.orgAge-stratified infection fatality rate of COVID-19 in the non-elderly informed from pre-vaccination national seroprevalence studiesThe infection fatality rate (IFR) of COVID-19 among non-elderly people in the absence of vaccination or prior infection is important to estimate accurately, since 94% of the global population is younger than 70 years and 86% is younger than 60 years. In systematic searches in SeroTracker and PubMed (protocol: ), we identified 40 eligible national seroprevalence studies covering 38 countries with pre-vaccination seroprevalence data. For 29 countries (24 high-income, 5 others), publicly available age-stratified COVID-19 death data and age-stratified seroprevalence information were available and were included in the primary analysis. The IFRs had a median of 0.035% (interquartile range (IQR) 0.013 - 0.056%) for the 0-59 years old population, and 0.095% (IQR 0.036 - 0.125%,) for the 0-69 years old. The median IFR was 0.0003% at 0-19 years, 0.003% at 20-29 years, 0.011% at 30-39 years, 0.035% at 40-49 years, 0.129% at 50-59 years, and 0.501% at 60-69 years. Including data from another 9 countries with imputed age distribution of COVID-19 deaths yielded median IFR of 0.025-0.032% for 0-59 years and 0.063-0.082% for 0-69 years. Meta-regression analyses also suggested global IFR of 0.03% and 0.07%, respectively in these age groups. The current analysis suggests a much lower pre-vaccination IFR in non-elderly populations than previously suggested. Large differences did exist between countries and may reflect differences in comorbidities and other factors. These estimates provide a baseline from which to fathom further IFR declines with the widespread use of vaccination, prior infections, and evolution of new variants.
Highlights *Across 31 systematically identified national seroprevalence studies in the pre-vaccination era, the median infection fatality rate of COVID-19 was estimated to be 0.035% for people aged 0-59 years people and 0.095% for those aged 0-69 years.
*The median IFR was 0.0003% at 0-19 years, 0.003% at 20-29 years, 0.011% at 30-39 years, 0.035% at 40-49 years, 0.129% at 50-59 years, and 0.501% at 60-69 years.
*At a global level, pre-vaccination IFR may have been as low as 0.03% and 0.07% for 0-59 and 0-69 year old people, respectively.
*These IFR estimates in non-elderly populations are lower than previous calculations had suggested.
### Competing Interest Statement
The authors have declared no competing interest.
### Funding Statement
The work of John Ioannidis is supported by an unrestricted gift from Sue and Bob O Donnell. The work of Angelo Maria Pezzullo in this research has been supported by the European Network Staff Exchange for Integrating Precision Health in the Healthcare Systems project (Marie Skłodowska-Curie Research and Innovation Staff Exchange no. 823995). Cathrine Axfors has received funding outside this work from the Knut and Alice Wallenberg Foundation s Postdoctoral Fellowship (KAW 2019.0561) and postdoctoral grants from Uppsala University (E o R Borjesons stiftelse; Medicinska fakultetens i Uppsala stiftelse for psykiatrisk och neurologisk forskning), The Sweden-America Foundation, Foundation Blanceflor, Swedish Society of Medicine, and Marta och Nicke Nasvells fond. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
### Author Declarations
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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
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The protocol, data, and code used for this analysis will be made available at the Open Science Framework upon publication: https://osf.io/xvupr
