Why the flu you had as a child may determine your risk decades later. And what it means for future outbreaks and vaccination strategies.
Study: Childhood immune imprinting group and duration shape influenza mortality.. Image Credit: PeopleImages/Shutterstock.com
A study in science advancement shows that population-level patterns consistent with strain-specific immunological imprinting by childhood influenza infection are associated with differences in the risk of lifetime mortality from influenza.
influenza virus antigen
Influenza A virus (IAV) has two surface antigens, hemagglutinin (HA) and neuraminidase (NA). These are the major antigens targeted by host antibodies and are major determinants of individual susceptibility to the virus.
Antigenic drift refers to changes in antigenicity due to accumulated mutations in these antigens, which contributes to immune evasion and recurrent infections. Antigenic shift, in contrast, refers to the recombination of these antigens to form new combinations that leads to the emergence of a new IAV subtype, causing epidemics.
Existing literature suggests that childhood influenza infection shapes the immune response to subsequent influenza infections. “Original antigenic sin” evokes the highest antibody titers. Furthermore, these individuals display protection patterns consistent with reduced risk of infection by seasonal influenza or novel avian influenza viruses that have similar HA phylogeny to earlier childhood virus strains.
They also exhibit antigenic seniority, consistently producing higher antibody levels against earlier childhood strains than later strains.
historical trends
The first H1N1 IAV pandemic of 1918–1920, the so-called “Spanish flu”, was followed by three phases of antigenic evolution, culminating with an “A-prime” variant circulating during 1946–1947.
In 1957, a major antigenic change occurred in H2N2, which displaced most variants and led to another pandemic. It was displaced by H3N2 in 1968, beginning the group 2 IAV virus pandemic. H3N2 viruses have shown the most rapid antigenic drift, causing large seasonal outbreaks and high mortality rates. H1N1 was reintroduced into the human population in 1977 and remains in circulation along with H3N2.
In 2009, H1N1pdm09 replaced seasonally circulating H1N1 strains globally. It shares HA epitopes most closely With the early 1918 H1N1 strains.
overall influenza mortality rate
The current study explored mortality by age and period in US birth cohorts between 1860 and 2020, by single year of age and by single season, covering the seasons from 1968–1969 to 2020–2021. The objective was to estimate model-based differences in childhood seasonal influenza mortality risk based on circulating strains.
According to the analysis, influenza mortality declined during 1968–2009 (with the emergence of H3N2). This was followed by an increase, indicating higher mortality during the H1N1pdm09 season compared to earlier H1N1 outbreaks. After 2010, the overall influenza mortality rate increased again. In 2020–2021, COVID-19-related public health measures led to a sharp decline in mortality.
The increased mortality after 2010 may reflect greater severity, better diagnosis, changes in death certificate coding, or population aging. During this period, nearly half of the deaths were among older adults (85 and older).
single-year age analysis
Age-stratified analyzes revealed two patterns. As expected, mortality was lower in younger groups across all influenza subtypes.
The results show that based on model-adjusted relative risk estimates, H1N1 seasons prior to 2009 were associated with approximately 97% lower mortality than H3N2 seasons. Since 2009, the H1N1pdm09 season had a higher mortality rate than the H1N1 season, but not the H3N2 season. Before 2009, mortality during the H1N1 season was similar between the H1N1 and H3N2 groups. During the H1N1pdm09 season, H1N1 clusters had lower mortality rates than H3N2-printed clusters.
During the H1N1pdm09 season, mortality was lower than expected in the 1940–1944 cohorts, likely consistent with increased protection imprinted by antigenically similar early H1N1 strains. A possible trade-off is suggested by the higher mortality rates, even after age adjustment, in older H1N1-imprinted groups compared to younger groups during the H1N2 season.
Mortality was higher in groups imprinted by later H1N1 variants, suggesting that the protective effects of imprinting were gradually weakening as antigenic changes continued.
The protective effect of H1N1 imprinting appears to be stronger and more consistent than against other strains, while protection against other subtypes is more limited or variable. H2N2-imprinted groups were Higher mortality than expected for their age, suggesting weak protection in HA level, although this remains an explanation rather than a definitive mechanism.
The mortality rate among H3N2-imprinted groups in the H1N2 season was only higher than among pre-1918 groups (which were not imprinted by the 1918–2020 H1N1 strains). The mortality rate from H3N2 was about 20% lower in several H1N1 and H2N2 groups during the H3N2 season, as shown in Regression-adjusted estimates rather than equal effects in all groups.
The authors offer possible explanations, including weak antibody response to group 2 HA stalk antigens (such as H3N2); Less unique H3N2 exposure in childhood, as H1N1 began to cocirculate within a decade, leading to weaker imprinting; More rapid antigenic evolution.
As a negative control, the authors used all-cause and pancreatic cancer mortality, confirming that the observed trajectories were specific for influenza mortality.
Estimates of future influenza mortality rates.
The authors projected a higher mortality risk for the aging H3N2- and H2N2-imprinted groups in future H1N1pdm09 seasons, that is, throughout most of their lives. This is likely to continue as long as H1N1pdm09 remains in circulation. Furthermore, the authors suggest that if avian H5N1 viruses begin to circulate among humans, H3N2 clusters may face higher mortality rates than older H1N1 clusters.
This strain-dependent protection emphasizes the importance of seasonal influenza vaccination, “which may provide protection against strains that do not match the strains that individuals are imprinted with in childhood.” Future studies are needed to identify 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 vaccinating naïve children in a way that ensures a strong H1N1 response, while maintaining protection against other seasonal strains, could provide broad protection throughout their lives.” Meanwhile, there remains demand for a universal influenza vaccine.
boundaries
The study has several important limitations. Imprinting was estimated from circulating strains and birth year rather than measured directly, and the analysis assumed constant risk of influenza exposure across seasons. Identification of dominant strains depends on viral sample testing, which may represent less severe variants, while the effects of neuraminidase (NA) and hemagglutinin (HA) imprinting cannot be distinguished.
Furthermore, the use of mortality data captures only the most severe cases and excludes mild infections that account for most of the burden of influenza.
The findings may also be influenced by potential misclassification or variations in death certificate coding, and the analysis does not take into account individual-level factors such as co-morbidities or health care-seeking behavior.
