Why the flu you got as a child may determine your risk decades later. and what it means for future epidemics and vaccination strategies.
Study: Childhood immune imprinting shapes influenza mortality across cohorts and time periods. Image credit: PeopleImages/Shutterstock.com
research in scientific progress suggest that population-level patterns consistent with strain-specific immunological imprinting due to childhood influenza infection are associated with differential lifetime mortality risk from influenza.
influenza virus antigen
Influenza A virus (IAV) has two surface antigens: hemagglutinin (HA) and neuraminidase (NA). These are the primary antigens targeted by host antibodies and are important determinants of an individual’s susceptibility to the virus.
Antigenic drift refers to changes in antigenicity caused by accumulated mutations in these antigens, contributing to immune evasion and recurrent infections. In contrast, antigenic shift refers to the reassortment of these antigens to create new combinations, leading to the emergence of new IAV subtypes and causing pandemics.
Existing literature indicates that childhood influenza infection shapes the immune response to subsequent influenza infections. “Original antigen sin” causes the highest antibody titers. Furthermore, these individuals tend to exhibit a pattern of protection consistent with a reduced risk of infection by seasonal influenza or novel avian influenza viruses that have the same HA lineage as the initial childhood viral strain.
They also exhibit antigenic seniority, producing persistently higher antibody levels against initial childhood strains than against subsequent strains.
historical trends
The first H1N1 IAV pandemic of 1918–1920, the so-called “Spanish flu,” then underwent three stages of antigenic evolution, ending with the “A-Prime” variant that circulated in 1946–1947.
In 1957, H2N2 underwent a major antigenic change, replacing most variants and causing another pandemic. It was replaced by H3N2 in 1968, marking the beginning of the group 2 IAV virus pandemic. H3N2 viruses exhibit the most rapid antigenic variation and cause seasonal outbreaks and high mortality rates. H1N1 was reintroduced to humans in 1977 and remains in circulation alongside H3N2.
In 2009, H1N1pdm09 replaced the H1N1 strain that is seasonally circulating around the world. Most commonly share HA epitopes In the earliest 1918 H1N1 strain.
Overall influenza mortality rate
In this study, we investigated age-specific, period-specific, single-age, and single-season mortality rates in U.S. birth cohorts from 1860 to 2020, covering seasons from 1968-1969 to 2020-2021. The objective was to estimate model-based differences in seasonal influenza mortality risk in a cohort likely to have been imprinted in childhood, based on circulating strains.
The analysis shows that influenza mortality rates decreased from 1968 to 2009 (due to the emergence of H3N2). It subsequently increased, suggesting that mortality rates during the H1N1pdm09 season were higher than during the earlier H1N1 epidemic. Since 2010, overall influenza mortality rates have increased again. From 2020 to 2021, public health measures related to the novel coronavirus disease (COVID-19) led to a sharp decline in mortality rates.
The increase in mortality since 2010 may reflect increased severity, improved diagnosis, changes in death certificate coding, or an aging population. Almost half of the deaths during this period were among the elderly (85 years and older).
Single year age analysis
Analysis by age group revealed two patterns. As expected, mortality rates were lower in the younger cohort across all influenza subtypes.
The results suggest that the pre-2009 H1N1 season had approximately 97% lower mortality compared to the H3N2 season, based on model-adjusted relative risk estimates. Since 2009, mortality rates in the H1N1pdm09 season were higher than in the H1N1 season, but not higher than in the H3N2 season. Prior to 2009, mortality rates during the H1N1 season were similar between the H1N1 and H3N2 cohorts. During the H1N1pdm09 season, mortality rates in the H1N1 cohort were lower than in the H3N2-imprinted cohort.
During the H1N1pdm09 season, mortality was lower than expected in the 1940–1944 cohort, likely due to imprinting by antigenically similar early H1N1 strains, consistent with enhanced protection. A possible trade-off is suggested by the higher mortality rate of H1N1-imprinted older cohorts compared to younger cohorts during the H3N2 season, even after adjusting for age.
Mortality was higher in cohorts imprinted by late H1N1 variants, suggesting that the protective effect of imprinting is gradually weakening as antigenic change persists.
The protective effects of H1N1 imprinting appear to be stronger and more consistent than those of other strains, whereas the protective effects against other subtypes are more limited or variable. The H2N2 imprinted cohort is Mortality rate is higher than expected for age, suggesting weak protection from HA However, this remains an interpretation rather than a definitive mechanism.
Only the pre-1918 cohort (which was not imprinted by H1N1 strains from 1918 to 2020) exceeded the mortality rate of the H3N2-imprinted cohort in the H3N2 season. Several H1N1 and H2N2 cohorts had approximately 20% lower H3N2 mortality during the H3N2 season, as reflected below. Regression-adjusted estimates rather than uniform effects across all cohorts.
The authors offer possible explanations, including weak antibody responses to group 2 HA stalk antigens (such as H3N2). Within 10 years, H1N1 began to cocirculate, reducing the specific exposure to H3N2 during childhood and weakening imprinting. and more rapid antigen evolution.
The authors used all-cause and pancreatic cancer mortality as negative controls and confirmed that the observed trajectory was specific to influenza mortality.
Prediction of future influenza mortality
The authors predict that older H3N2 and H2N2-imprinted cohorts will be at increased risk of death during future H1N1pdm09 seasons, and thus for most of their lives. This is likely to continue as long as H1N1pdm09 remains prevalent. Additionally, the authors suggest that if avian H5N1 viruses begin to circulate among humans, mortality rates in the H3N2 cohort may be higher than in older H1N1 cohorts.
This strain-dependent protection underscores the importance of seasonal influenza vaccination, which “can provide protection against strains that are mismatched to those with which an individual was imprinted in childhood.” Future studies are needed to determine the differences between vaccine-induced and infection-related imprinting in infants who are often vaccinated before their first infection.
If they are found to be equivalent, “our results suggest that it may be possible to provide broader lifelong protection to unvaccinated children in a way that ensures a strong H1N1 response while preserving protection against other seasonal strains.” Meanwhile, universal influenza vaccines continue to be sought after.
Restrictions
This study has several important limitations. Imprinting is not directly measured but inferred from circulating strains and year of birth, and the analysis assumes a constant risk of exposure to influenza across seasons. Identification of the predominant strain relied on viral specimen testing, which may have underestimated less severe variants, while the effects of neuraminidase (NA) and hemagglutinin (HA) imprinting could not be separated.
Additionally, using mortality data captures only the most severe cases and excludes mild infections, which make up the majority of influenza cases.
The findings may also be influenced by potential misclassification and variation in death certificate coding, and the analysis did not take into account individual-level factors such as comorbidities and health care seeking behavior.
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