Childhood Flu Exposure Shapes Lifelong Risk, Study Finds

A new analysis of over five decades of U.S. mortality data reveals that the first influenza strain a person encounters in childhood can have a profound and lasting impact on their future risk of dying from the flu.

The research suggests patterns consistent with "immune imprinting," where the first influenza strain a person encounters shapes their immune response to future strains.

Published in Science Advances, the study examined mortality data from 1968 to 2021, analyzing birth cohorts from 1860 to 2020. The findings highlight how a person's initial "imprinting" to a flu virus influences their susceptibility for the rest of their life.

Key Findings on Strain-Specific Risk

The study uncovered distinct patterns of risk based on the subtype of the first childhood influenza infection:

• Cohorts whose first childhood exposure was to an H1N1 strain showed approximately 97% lower mortality rates during H1N1 seasons prior to 2009, compared to H3N2 seasons.
• During H1N1pdm09 seasons (post-2009), cohorts imprinted by early H1N1 strains had lower-than-expected mortality, suggesting enhanced protection.
• Cohorts imprinted by H3N2 strains had the highest mortality rates during H3N2 seasons.
• The protective effect of H1N1 imprinting appeared stronger and more consistent than for other strains. Protection from H2N2 imprinting was weaker or more variable.
• A possible trade-off was noted: older H1N1-imprinted cohorts had higher mortality rates during H3N2 seasons compared to younger cohorts, even after age adjustment.

Historical Context of Virus Evolution

To understand these findings, it's important to know how influenza viruses change. Influenza A viruses have surface proteins called hemagglutinin (H) and neuraminidase (N), which are key targets for our antibodies.

• Antigenic drift refers to gradual mutations in these proteins.
• Antigenic shift is a major change that creates a new subtype, often causing pandemics.

Major shifts in the 20th century include:

• The 1918 H1N1 pandemic.
• A shift to H2N2 in 1957.
• A shift to H3N2 in 1968.
• The reintroduction of H1N1 in 1977.
• The emergence of the new H1N1pdm09 strain in 2009.

A person's birth year determines which of these strains was likely circulating during their early childhood, setting their lifelong immune imprint.

Implications and Future Projections

The study's authors used their model to project future risks:

• Aging H3N2- and H2N2-imprinted cohorts may face higher mortality risk in future H1N1pdm09 seasons.
• If avian H5N1 viruses began circulating in humans, H3N2-imprinted cohorts might suffer greater mortality than older H1N1-imprinted cohorts.
• The findings emphasize the critical role of seasonal vaccination in providing protection against strains that are mismatched to an individual's childhood imprinting.
• Future research is needed to compare vaccine-induced and infection-related imprinting in infants.

Study Limitations

The authors listed several important limitations to their work:

• Imprinting was inferred from birth year and circulating strains, not directly measured in individuals.
• The analysis assumed a constant risk of influenza exposure across seasons.
• Viral specimen data may underrepresent less severe variants.
• The effects of H and N imprinting could not be separated.
• Mortality data captures only severe, fatal cases, excluding the majority of influenza infections.
• The analysis did not account for individual-level factors like comorbidities.
• Findings could be influenced by variations in how deaths are recorded on certificates.