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Past pandemic experience at an individual or population level may affect health outcomes in future pandemics. In this study, we focus on how the influenza pandemic of 1968 (H3N2), which killed up to 100,000 people in the US, may have produced differential COVID-19 (SARS-CoV-2) outcomes. Our analysis finds that areas with high influenza-related mortality in 1968 experienced 1-2% lower COVID-19 death rates. We employ an identification strategy that isolates variation in COVID-19 rates across age cohorts born before and after 1968. Locales in the US with high 1968 influenza mortality have lower COVID-19 death rates among older cohorts relative to younger ones. The relationship holds using county-level and patient-level data, as well as data from hospitals and nursing homes. Results do not appear to be driven by systemic or policy-related factors that would affect a population, but instead suggest a potential individual-level response to prior influenza pandemic exposure. The findings merit substantial further investigation into potential biological, immunological, or other mechanisms that can account for these differential outcomes.

Background Past pandemic experience at an individual or population level could affect health outcomes in future pandemics. In this paper we test whether people who lived through local outbreaks of the influenza pandemic of 1968 (H3N2), which resulted in 100,000 deaths in the US, experience better outcomes when infected by the SARS-CoV-2 virus.

Methods We employ econometric techniques on county-level and patient-level data, further validated by aggregated data from hospitals and nursing home, to explain differential COVID-19 outcomes. Given the cross-sectional nature of this study, we address endogeneity and omitted variable bias con-cerns in the relationship between the 1968 flu and COVID-19 outcomes by utilizing as our outcome variable the difference by age group in death rates, number of medical procedures, and hospital admissions. We choose the age cutoff based on whether someone was born before or after 1968 in an attempt to isolate those people more likely exposed to the 1968 pandemic.

Findings We find a persistent negative relationship between US locales’ ex-posure to the 1968 flu pandemic and COVID-19 mortality. This relationship is robust to various controls and holds across populations (i.e., county level aggregates, hospital admittees, and nursing home residents, subset of pa-tients), as well as specifications that exploit age-based variation in exposure. Further analysis supports a possible individual-level mechanism—rather than policy-related, systemic, or population-level factors—as drivers of this phenomenon.

Interpretation Results suggest a potential biological or immunological mechanism that may mitigate the severity of COVID-19 in individuals who survived the 1968 flu pandemic. Further research should explore possible explanations for this phenomenon in the hopes of uncovering new avenues of prevention and treatment.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This study did not receive any funding.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.


The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The IRB of the COVID-19 Research Database Consortium gave ethical approval for this work. The COVID-19 Research Database was established with IRB approval and an exemption from patient consent due to the use of HIPAA de-identified data, HIPAA limited data or non-HIPAA-covered data, along with the strong governance measures in place to control access to all data. This exemption covers all research performed within the COVID-19 Research Database.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.


I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as 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).


I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.


Paper in collection COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv

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