Note: Those already familiar with immune imprinting may wish to skim, or skip, my rather lengthy intro.
#18,399
A little over 18 years ago, in A Predilection For The Young, I wrote about the disturbing (but curious) skewing of H5N1 cases (and deaths) among younger individuals (see WHO Chart above).While there are no records of humans ever having dealt with an H5 influenza pandemic (going back 130+ years), those who were born before before 1967 appeared far less susceptible to the virus - and those born before 1958 - even more so.
A lot of theories were proposed, but answers were elusive. Then, in 2013 an equally novel avian H7N9 virus emerged in China - sparking 5 years of seasonal infections - which skewed dramatically toward those over 40 (see comparison chart below).
And during the 2009 H1N1 pandemic, we saw a similar age shift, where people in their 40's were hardest hit. Here is what the CDC had to say about the impact of the virus in 2012's First Global Estimates of 2009 H1N1 Pandemic Mortality Released by CDC-Led Collaboration.
2009 H1N1 Pandemic Hits the Young Especially HardBy early in the last decade many researchers were convinced that the first flu you are exposed to early in life `primes' your immune system to preferentially fight similar influenza infections.
This study estimated that 80% of 2009 H1N1 deaths were in people younger than 65 years of age which differs from typical seasonal influenza epidemics during which 80-90% of deaths are estimated to occur in people 65 years of age and older.
- Those born prior to the mid-1960s were almost certainly first exposed to Group 1 flu viruses (H1N1 or H2N2)
- Those born after 1968 and before 1977 would have been exposed to Group 2 (H3N2)
- After 1977, both Group 1 and 2 viruses co-circulated, meaning the first exposure could have been to either one.
While none of this is likely to make one fully immune to H5 infection, it could reduce the severity of infection, and decrease mortality.
All of which brings us to a preprint- published yesterday - from researchers at the CDC and the University of Wisconsin - on potential preexisting population immunity against the HPAI H5 2.3.4.4b virus.
The good news is this research seems to support previous studies which have suggested that past (age related) H1N1/H2N2 exposure and seasonal flu vaccines may provide some limited protection against severe H5 infection.
This is a lengthy and detailed report, and so I've just posted the link, abstract, and some excerpts. I'll have a brief postscript after the break.
Population Immunity to Hemagglutinin Head, Stalk and Neuraminidase of Highly Pathogenic Avian Influenza 2.3.4.4b A(H5N1) viruses in the United States and the Impact of Seasonal Influenza on A(H5N1) Immunity
zhu-nan Li, Feng Liu, Yu-Jin Jung, Stacie Jefferson, Crystal Holiday, F Liaini Gross, Wen-pin Tzeng, Paul Carney, Ashely Kates, Ian York, Nasia Safdar, C Todd Davis, James Stevens, Terrence Tumpey, Min Levine
doi: https://doi.org/10.1101/2025.03.30.25323419
This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
Preview PDF
Abstract
The unprecedented 2.3.4.4b A(H5N1) outbreak in dairy cattle, poultry, and spillover to humans in the United States (US) poses a major public health threat. Population immunity is a critical component of influenza pandemic risk assessment.We conducted a comprehensive assessment of the population immunity to 2.3.4.4b A(H5N1) viruses and analyzed 1794 sera from 723 people (0.5-88 yrs) in multiple US geographic regions during 2021-2024. Low pre-existing neutralizing and hemagglutinin (HA) head binding antibodies and substantial cross reactive binding antibodies to N1 neuraminidase (NA) of 2.3.4.4b A(H5N1) were detected in US population.Antibodies to group 1 HA stalk were also prevalent with an age-related pattern. A(H1N1)pdm09 infection and influenza vaccination did not induce neutralizing antibodies but induced significant rise of NA inhibition (NAI) antibodies to N1 of 2.3.4.4b A(H5N1), and group 1 HA stalk antibodies. Understanding population susceptibility to novel influenza is essential for pandemic preparedness.
(SNIP)
Age-stratified scatter plot of antibodies to group 1 HA stalk in 2023-24, 327 sera were collected from 234 participants from 8 age groups.
Discussion
Population immunity against new emerging novel viruses is a key factor for influenza pandemic risk assessment16. Amid the ongoing A(H5N1) outbreaks in cattle and poultry and the continued spillover to humans, our study provides a timely and comprehensive assessment of the population immunity in the US to 2.3.4.4b A(H5N1) viruses.
Results from the current study demonstrate that the levels of the pre-existing neutralizing antibodies and the HA head binding antibodies to 2.3.4.4b A(H5) viruses in the US population are low, consistent with previous reports of low seroprevalence (mostly measured by HI antibodies) even in populations at increased risk of A(H5) exposure (e.g., poultry workers)12.
However, our study revealed that the population in the US was not completely immunologically naive to the 2.3.4.4b A(H5N1) viruses: there were substantial levels of preexisting antibodies to the N1 NA of 2.3.4.4b A(H5N1) virus, and group 1 HA stalk antibodies in an age-related pattern.
Furthermore, these pre-existing cross-reactive immunities to A(H5N1) virus (group 1) were mostly likely from past exposures to seasonal A(H1N1)pdm09 (group 1), not A(H3N2) (group 2) viruses.
While neutralizing antibodies targeting the HAs of the influenza virus are the main correlate of protection in reducing the risk of influenza virus infections, multiple immune mechanisms can contribute to protection from influenza13. Although seasonal influenza A(H1N1)pdm09 virus infection and influenza vaccination did not induce neutralizing and HA head binding antibodies to A(H5N1) viruses (Fig 3-4), both could induce significant rise of cross-reactive functional NAI antibodies to the N1 NA of 2.3.4.4b A(H5N1) (Fig 6).
Sequence analysis showed that there is significant genetic distance between the HA head of the 2.3.4.4b A(H5N1) and A(H1N1)pdm09 viruses, with amino acid homology at approximately only 53%, and differences across multiple antigenic sites (Extended Table S3 and Extended Fig 2). In contrast, there is a higher level of amino acid sequence homology (86-88%) between the N1 NA sequences of 2.3.4.4b A(H5N1) and recent circulating seasonal A(H1N1)pdm09 viruses (Extended Table S4).
As we've discussed previously (see SCI AM - A Bird Flu Vaccine Might Come Too Late to Save Us from H5N1), our options during the opening months of a novel pandemic will be limited. Antivirals may be in short supply (or ineffective), and a well-matched vaccine could be 6 months to a year away.
While not ideal - and with the caveat that it is always possible that H5 swaps out its NA gene for something less compatible - there may be some value in getting the seasonal flu vaccine in the opening days of an H5 pandemic.
Although the oft-quoted 50% CFR (Case Fatality Rate) of H5N1 is probably greatly exaggerated (see discussions here and here), even a more reasonable 2%-5% CFR would represent a public health crisis unlike anything we've seen in the modern era.
