Credit NIAID
#18,867
During the 2009 H1N1 pandemic younger people were much harder hit than the elderly, with the average age of flu-related death temporarily plummeting from 76 (see Study: Years Of Life Lost Due To 2009 Pandemic) to just 41 (cite CDC).
In 2010's EID Journal: Original Antigenic Sin And Pandemic H1N1, we looked at a highly plausible explanation; that the first flu subtype one is exposed to early in life creates a lasting impression on your immune system.
We saw a similar pattern during 1977 return of the `Russian (H1N1) flu' which, primarily affected those under the age of 20.
Over the past 15 years it has become increasingly apparent that the first influenza subtype you are exposed to makes the biggest, and most lasting, impression on your immune system (see Nature: Declan Butler On How Your First Bout Of Flu Leaves A Lasting Impression).
At first, it was assumed that the HA subtype (H1, H2, or H3) was the main driver of immunity, but about a decade ago a new idea emerged; that the HA Group (1 or 2) could provide some degree of cross-protection as well.There are 18 known HA (hemagglutinin) subtypes,which are divided into two major HA groups. Depending from which group your first exposure came, you may carry some degree of cross-protection against novel flu viruses of that same group.
In other words, if your first influenza exposure was to H1N1 or H2N2 (group 1), you may carry some degree of immunity to the H5 viruses (H5N1, H5N6, etc.). If, however, your first exposure was to H3N2 (group 2), you may carry some protection against H7N9 instead.
But there is still a lot left to unravel when it comes to the complex human immune response to novel flu subtypes.
Over the past couple of years, we increasingly seen the idea that one's first exposure to the other influenza A surface protein - the NA (neuraminidase) - may also play an important role in long-term immunity.
All of which brings us to a new preprint which seems to add weight to that argument. While there are still a great many unknowns (including whether all N1 neuraminidases are created equal), this study suggests that an NA match may overshadow the HA group match when it comes to antibody responses.
When it comes to influenza immunity, everything is relative.
Whatever small advantage there may be against H5N1 to those born prior to 1957 may well be negated by other factors, including advancing age and declining immune systems.
And while this study would suggest that those born between 1968 and 1977 (1st exposure likely to H3N2) might be the most susceptible to an H5N1 virus, how much more is difficult to say.
I've reproduced the abstract and some excerpts from the preprint. Follow the link to read it in its entirety. I'll have a postscript after the break.
Cross-reactive human antibody responses to H5N1 influenza virus neuraminidase are shaped by immune history
Jordan T. Ort, Ashley Sobel Leonard, Shuk Hang Li, Reilly K. Atkinson, Lydia M. Mendoza, Marcos Costa Vieira, Sydney Gang, Sarah Cobey, Scott E. Hensley
doi: https://doi.org/10.1101/2025.09.02.25334929
This article is a preprint and has not been certified by peer review [what does this mean?].
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Abstract
H5N1 highly pathogenic avian influenza viruses have spread globally and pose a risk for a human pandemic. Prior studies suggest that early life exposures to group 1 influenza viruses (H1N1 and H2N2) prime antibodies that cross-react to the hemagglutinin of H5N1, which is also a group 1 virus.
Less is known about how immune history affects antibody responses against the neuraminidase (NA) of H5N1 viruses. Here, we measured NA inhibition antibodies against multiple H5N1 viruses using sera from 155 individuals born between 1927 and 2016.
We found that individuals primed in childhood with H1N1 viruses were more likely to possess higher levels of antibodies that cross-react with the NA of H5N1 viruses compared to individuals primed in childhood with H2N2 or H3N2 viruses. While young children rarely possessed cross-reactive NA antibodies, we found that childhood infections with contemporary H1N1, but not H3N2, viruses can elicit them.
These data suggest that immune history greatly impacts the generation of cross-reactive NA antibodies that can inhibit H5N1 viruses.
These studies indicate that immune imprinting affects the priming of NA antibody responses across the human population, which may impact differential H5N1 risks between age groups. Our data are consistent with recent work that suggest that in addition to HA group-level imprinting, homosubtypic NA imprinting can further modulate the risk of zoonotic influenza infection, including between H5N1 and H5N6 viruses which differ only by NA subtype 34. This has far-reaching implications, as our studies predict that H5 viruses may cause differential levels of disease in the human population after reassortment with a novel NA.While we found that initial exposure to an H1N1 virus confers high levels of cross-reactive N1 antibodies, and others have examined the role of NA imprinting in shaping age-specific seasonal influenza infection patterns35,36, further longitudinal studies are necessary to fully ascertain the importance and contribution of early-life infections.(SNIP)Although we identified similar patterns of cross-reactivity to each of the tested H5N1 NAs— including the reassorted NA of the D1.1 genotype—determining the epitopes targeted by these antibodies will be key to understanding their potential breadth. Given the diversity of N1 genes in wild birds39, and the propensity of H5 viruses to undergo reassortment 1,40, it will be important to establish if certain N1 lineages could escape pre-existing immunity.
A better understanding of how immune imprinting affects cross-reactive antibody responses within diverse human populations will be useful for risk assessment of new viral strains with pandemic potential.
For more on this topic, you may wish to revisit:
Preprint: Neuraminidase Imprinting and the Age-related Risk of Zoonotic Influenza
Preprint: Population Immunity to HPAI 2.3.4.4b A(H5N1) Viruses in the United States and the Impact of Seasonal Influenza on A(H5N1) Immunity
Preprint: Pre-existing H1N1 Immunity Reduces Severe Disease with Cattle H5N1 Influenza Virus
