Note: Since Immune Imprinting is a topic we've covered extensively before, anyone already familiar with the concept may wish to skip today's intro.
Nine years ago, in Science: Protection Against Novel Flu Subtypes Via Childhood HA Imprinting, we looked at new research which suggested the influenza HA Group type (see chart above) you are first exposed to can provide some (probably small) degree of cross immunity against other subtypes in that same HA group.
Any `protection' afforded by a first childhood exposure to HA Group 1 viruses is likely to be quite limited, while the prospect of a pandemic virus that preferentially targets children and adolescents is particularly harrowing.
2009 H1N1 Pandemic Hits the Young Especially Hard
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.
Last summer, in CDC A(H5N1) Update: Population Immunity to A(H5N1) clade 2.3.3.4b Viruses, the CDC reported finding extremely low to no population immunity, even among those who recently received a seasonal flu vaccine.
It has also been suggested that repeated receipt of the seasonal flu shot might provide some degree of protection, due to the similarity of the H1N1 and H5N1 NA gene segment (see EID Journal: A(H5N1) NA Inhibition Antibodies in Healthy Adults after Exposure to Influenza A(H1N1)pdm09).
At least, that's the hope.
To this growing list of studies we can add the following research report, published yesterday in Emerging Microbes & Infections - conducted by researchers at the University of Hong Kong - which disappointingly finds only limited evidence of pre-existing immunity in those > 60, and scant evidence that receipt of the seasonal flu vaccines provides protection against H5.
I've only posted the link, abstract, and discussion, so follow the link to read it in its entirety. I'll have a brief postscript after the break.
Research Article
Risk assessment of 2024 cattle H5N1 using age-stratified serosurveillance data
Lin-Lei Chen,Xiaojuan Zhang,Kang Zhang,Brian Pui-Chun Chan,Jacqueline Kwan Yuk Yuen,Kwok-Yung Yuen,Pui Wang,Yuhe R. Yang,Honglin Chen & Kelvin Kai-Wang To
Accepted author version posted online: 22 Apr 2025
https://doi.org/10.1080/22221751.2025.2497304
ABSTRACT
The highly pathogenic avian influenza virus A(H5N1) clade 2.3.4.4b has caused a human outbreak in North America since March 2024. Here, we conducted a serosurveillance study to determine the risk of A(H5N1) clade 2.3.4.4b (2024 cattle H5N1) to general population.
In the initial screening of 180 serum specimens encompassing all age groups, 2.2% (4/180) had detectable neutralizing antibody (nAb) titers against reverse genetics-derived 2024 cattle H5N1, with all collected from older adults aged ≥60 years old. Further screening showed that 4.2% (19/450) of adults aged ≥60 years old had detectable nAb titers against the 2024 cattle H5N1. 80% (4/5) serum specimens with nAb titer of ≥40 had detectable HI titer, and there was a positive correlation between nAb titer and HA binding (r = 0.3325, 95% confidence interval 0.2477 to 0.4123; P < 0.0001).
The nAb titer against seasonal H1N1 virus was 4.2-fold higher for ≥60 years old individuals with detectable H5N1 nAb titer than those ≥60 years old ones without (geometric mean titer: 89.3 [95% CI 42.9-185.7]) vs 21.3 [95% CI 17.3-26.1], P < 0.0001), but there was no statistically significant difference between H5N1 and H3N2 nAb titer. There was no difference in demographics, comorbidities and clinical frailty scores between individuals with detectable H5N1 nAb and those without.
Our findings suggest that most individuals lack nAb response against 2024 cattle H5N1 and there is an urgency to develop and evaluate H5N1 vaccine or prophylactic monoclonal antibodies. Immune imprinting may be responsible for the cross neutralization between H5N1 and H1N1 among older adults.
DISCUSSIONSerosurveillance has been an indispensable tool to understand population immunity during the A(H1N1)pdm09 and the COVID-19 pandemic [29,30]. In this study, we utilized serosurveillance to evaluate the risk posed by the 2024 clade 2.3.4.4b cattle H5N1 to the general public. Our initial screening of 180 anonymized serum specimens obtained from various age groups revealed that only 2.2% had detectable nAb titers against the 2024 cattle H5N1. These findings underscore the vulnerability of our population to H5N1. Consequently, if the H5N1 were to become more transmissible among humans, there is a possibility of rapid surge in patients that could potentially overwhelm the healthcare system, similar to the situation for A(H1N1)pdm09 and COVID-19 pandemics.H1N1, but not H3N2, nAb titer was statistically significantly higher among those with detectable H5N1 nAb. Our results suggest that there are cross reactive nAb in these serum specimens that neutralize both H1N1 and H5N1. Both HA and neuraminidase (NA) can be the target of broadly reactive nAb. For HA, previous studies demonstrated that the stalk region and the vestigial esterase domain of the HA protein are the targets of broadly reactive Ab that neutralizes both H5N1 and H1N1 [31,32]. For NA, prophylactic treatment with anti-NA monoclonal antibodies, which targets the lateral face of NA, could protect mice against lethal H1N1 or H5N1 infection [33]. NA is also a target of broadly neutralizing monoclonal antibodies which can protect mice from both H1N1 and clade 2.3.4.4b H5N1 virus [34]. Future studies should assess the role of NA nAb in the neutralization of H5N1 viruses.Age-stratified analysis indicated that all serum specimens with detectable cattle H5N1 nAb were obtained from individuals aged 60 years or above, while none of the 120 individuals aged between 0 and 59 years old had detectable cattle H5N1 nAb. Our results suggest that immune imprinting due to childhood exposure to H1N1 or H2N2 may elicit nAb that cross neutralize H5N1.
Our results are consistent with the observations in previous studies. Gostic et al demonstrated that childhood imprinting with H1N1 was associated with 75% protection against severe H5N1 infection [35]. A recent study by Garretson et al demonstrated that individuals born before 1968 had higher levels of H5N1 HA binding Ab [36]. Supporting this, a study in ferrets showed that immune imprinting with H1N1 increases the survival rates for H5N1 infection [37]. Similarly, in mice infected with H5N1, those primed with H1 HA had less weight loss when compared to those primed with H3 HA [38].Another possible reason for having H5N1 nAb is repeated vaccination against influenza virus. Using pseudovirus neutralization test, Wang et al showed that 36% of adults aged 48-64 years old who have received multiple seasonal influenza vaccines from 2004 to 2009 had nAb of ≥160 against the H5N1 Vietnam/1203/04, though none had nAb of ≥160 against several other H5N1 strains isolated from 2002-2006 [28]. However, in our study, we did not observe any statistically significant difference among individuals who have received influenza vaccine and those who did not. Therefore, it is unlikely that repeated seasonal influenza vaccination can reliably elicit H5 nAb.There are several limitations. First, this study was conducted in HKSAR where H5N1 and other subtypes of avian influenza viruses exposure may be more frequent than places without H5N1 circulation, especially before the implementation of stringent live poultry market measures [2]. Hence, there is a possibility that some individuals may indeed have prior exposure to H5N1 or H5Nx. However, it should be noted that low levels of H5N1 nAb can be found in individuals recruited for studies in the United States before the 2024 H5N1 outbreak [36]. Second, caution is warranted when comparing our results from those of others, as different assays were employed. In our current study, we used a conventional live virus neutralization test. However, other studies have used pseudovirus neutralization test or HI assay only [13,14]. Third, we have not explored the role of NA in immune imprinting.Our serosurveillance study showed that our general population is vulnerable to H5N1 infection. A small proportion of older adults have cross-neutralizing antibody against H5N1, likely due to childhood immune imprinting. Currently, 2 of 65 (3.1%) of cases in the North American clade 2.3.4.4b outbreak require critical care. The clade 2.3.4.4b H5N1 virus can cause fatal infection in ferrets and mice [15,39]. There is an urgent need to develop and evaluate H5N1 vaccine against the clade 2.3.4.4b before this virus becomes pandemic.
We've also seen warnings that our current influenza antivirals may be lacking (see St. Jude Researchers: Current Antivirals Likely Less Effective Against Severe Infection Caused by Bird Flu in Cows’ Milk) and signs of growing antiviral resistance in avian flu (see Emerg. Microbes & Inf: Oseltamivir Resistant H5N1 (Genotype D1.1) found On 8 Canadian Poultry Farms).
As Maggie Fox explained last year in SCI AM - A Bird Flu Vaccine Might Come Too Late to Save Us from H5N1, our pharmaceutical options during the opening months of any pandemic will be limited.
Five months ago, in A Personal Pre-Pandemic Plan, I wrote about some of the practical things you and your family can do now to prepare for a possible pandemic in the months or years ahead.
While we are hopefully still years away from the next pandemic, it is always better to prepare for an emergency a year too early, than a day too late.
