While H5 viruses have never circulated widely (in modern times, anyway), the $64 question surrounding any potential HPAI H5N1 pandemic is whether there is any preexisting `immunity' in the general population against the virus, and what community cohorts might have greater or lesser degrees of protection.
The CDC original assessment (see July 14th, 2024 H5N1 Update) that `. . . that there is extremely low to no population immunity to clade 2.3.4.4b A(H5N1) viruses in the United States', has been challenged by a few studies suggesting there may be some limited immunity; particularly in those born before 1968.Initially, the focus was on HA immune imprinting (see Nature: Declan Butler On How Your First Bout Of Flu Leaves A Lasting Impression), where the HA group (1 or 2) you are first exposed to (see chart above) can provide some degree of protection against other HAs in that group.
How much real-world protection early or past H1/H2 exposure might offer against H5Nx - or how long it might last - are unknown, but it has been suggested it might provide an `edge' against severe disease.More recently, we've seen attempts to quantify the impact of the first NA (Neuraminidase) one is exposed to (see last December's Nature Comms: Pre-existing Cross-reactive Immunity to HPAI 2.3.4.4b A(H5N1) Virus in the United States).
This study found`very low levels of pre-existing binding antibodies to the HA head of the HPAI A(H5N1) 2.3.4.4b virus', but slightly more encouragingly, `. . . substantial cross-reactive binding antibodies to N1 neuraminidase (NA) of 2.3.4.4b A(H5N1).
The `very low levels' of HA binding antibodies were highest in those over 70 years of age, which correlates with early childhood exposures to HA Group 1 viruses (H2N2 and H1N1) in the 1950's and 1960s.
Regarding the the value of cross-reactive antibodies to the N1 Neuraminidase, the authors wrote:
Neuraminidase antibodies have been considered as an independent correlate to protect against influenza 20. Although they cannot prevent infection, neuraminidase antibodies can prevent virus egress, reduce viral shedding, and thus could attenuate disease and lessen disease severity 21,22,23.
Last summer, in Preprint: Neuraminidase Imprinting and the Age-related Risk of Zoonotic Influenza, we looked at a hypothesis by the authors of today's study, which proposed:
Here we review the complex immuno-epidemiological interactions underpinning influenza risk assessment and extend the imprinting hypothesis to include a potential role for cross-protective neuraminidase (NA) imprinting.
We compare H5N1 distributions and case fatality ratios by age and birth cohort (as proxy for HA2 and/or NA imprinting epoch) not only to H7N9 but also H5N6 and H9N2 avian influenza, representing more varied conditions of zoonotic influenza relatedness to human subtypes of the past century.
We show homosubtypic NA imprinting likely further modulates the age-related risk of zoonotic H5N1 and H9N2, with implications for pandemic risk assessment and response.Taking this idea one step further, these authors gathered convenience blood samples collected from 575 people (ages 1 to 80) in British Columbia in 2024 and tested them for antibodies against the (N1) neuraminidase from 2.3.4.4b H5N1 avian strain, A/RT-Hawk/ON/FAV-0473-4/2022.
They found roughly 70% of the population had detectable anti-N1 titres (>10), and around half had titres (>40) that might offer some (unknown) degree of protection.
Specifically, the authors report:
- Anti-N1 titres were highest among young adults born 1997-2003 who were school-aged children during the 2009 H1N1 pandemic.
- Anti-N1 titres were lowest among the `youngest and least influenza-experienced pediatric cohorts'; those born after 2015 and in middle-aged adults born during the 1957-1967 H2N2 era
Of course, if H5N5, or some other NA type (H5N6, H5N8, H5N9) should emerge as a pandemic threat, then all bets are off.
I've posted the link, abstract, and a brief excerpt from the study. Follow the link to read it in its entirety.
Cross-reactive H5N1 neuraminidase antibodies by age and influenza A imprinting cohorts of the past century: population-based serosurvey, British Columbia, Canada
Open Access
Danuta M Skowronski, MD , Charlene Ranadheera, PhD , Samantha E Kaweski, MSc , Suzana Sabaiduc, BSc , Lea Separovic, MSc , Gaby Makowski, BSc , Johnny Ung, BSc , Romina C Reyes, MD , Bonnie Henry, MD , Arianne Albert, PhD ... Show more
The Journal of Infectious Diseases, jiag030, https://doi.org/10.1093/infdis/jiag030
Published:
16 January 2026 Article history
Abstract
Background
Pre-existing immunity to emerging influenza viruses informs pandemic risk assessment. We compared cross-reactive neuraminidase (NA) antibody levels against avian influenza A(H5N1) by age and birth (imprinting) cohorts defined by periods of human influenza A subtype (H1N1, H2N2 or H3N2) circulation over the past century.
Methods
We used anonymized, residual sera collected from ten age groups spanning one to >80 years during an August 2024 cross-sectional serosurvey conducted in British Columbia, Canada. We assessed NA inhibition antibody titres by enzyme-linked lectin assay against clade 2.3.4.4b H5N1, and 2009 H1N1pdm09 and 1968 H3N2 pandemic strains
Results
Among 575 participants with median age 32 (IQR: 15-62) years, 404 (70%) had detectable anti-N1 titres >10 against H5N1, with 260 (45%), 182 (32%) and 98 (17%) having titres >40, >80 and >160, respectively. Anti-N1 titres against 2009 H1N1pdm09 and H5N1 were strongly correlated (r=0.86; 95%CI: 0.82-0.89), with both highest among young adults born 1997-2003 who were school-aged children during the 2009 H1N1 pandemic (427.9, 100.8), lowest among the youngest and least influenza-experienced pediatric cohorts born 2015-2023 (20.7, 6.8) and middle-aged adults born during the 1957-1967 H2N2 era (25.1, 10.7), thereafter increasing toward a similar secondary peak among the oldest cohorts born during the pre-1947 H1N1 era (387.3, 81.0).
Conclusions
A substantial proportion of the population has pre-existing anti-N1 against H5N1, with age-related variation reflecting H1N1 imprinting and exposure opportunities. Through heightened attack rates and shifts in immunological hierarchies, historic pandemics shape and expand the immune repertoire with implications for pre-immunity to emerging zoonotic threats.
(SNIP)
DISCUSSION
With H5N1 expansion but without endemicity in humans, we report cross-reactive anti-N1 antibodies to this emerging zoonosis in more than two-thirds of population-based serosurvey participants ranging one to >80 years of age, including half with titres >40, one-third >80 and nearly 20% >160. Anti-N1 titres to H1N1pdm09 and H5N1 were strongly correlated, with both varying by age and birth cohort, highest among young adults born 1997-2003, declining to lows among the youngest children born 2015-2023 and middle-aged adults born 1957-1967, thereafter increasing to a similar secondary peak among the oldest adults born pre-1947. We interpret this variation within a unifying hypothesis incorporating both age and imprinting effects, emphasizing the role of historic influenza pandemics in expanding and refining the immune repertoire through heightened attack rates and shifts in immunological hierarchies.
