Credit CDC
#17,822
Although the media tends to lump all HPAI H5 viruses into one basket, there is a huge amount of diversity among avian H5Nx viruses circulating around the world; different subtypes, different clades and subclades, and within each of these sub-divisions, numerous genotypes.
Admittedly, it can get a bit overwhelming. But even minor variations can make a huge difference in the threat an H5 virus may pose to birds, humans, or other mammals.
We've an intriguing report today from researchers at The University of Hong Kong on similarities between the NA gene of H5N1 Clade 2.3.4.4b and the (now) seasonal H1N1 virus which emerged in 2009.
Since all of this involves wending our way through some fairly technical jargon, and I've recently received a request of a basic primer on the influenza virus, I've put together a brief overview.
If you are familiar with the structure of the flu virus, antigenic drift, and antigenic shift, feel free to skip ahead to the study below.
With 18 HA (hemagglutinin) subtypes and 11 different NA (neuraminidase) subtypes there are nearly 200 possible influenza subtypes (e.g. H1N1, H5N1, H7N8, etc.). To date, more than 130 have already been detected in nature.
Each subtype (based on the HA gene) is further classified by its clade - grouped by their similarity - and clades can be further divided into multiple subclades (see chart below). This alone can yield thousands of variations.
In order to thrive, a new subtype/clade/genotype must be able to compete against the existing panoply of flu viruses. Luckily most are evolutionary failures, but occasionally a more biologically `fit' virus emerges, often with dramatic effect.
All of this genetic evolution and diversity is why we must update the flu vaccine every year, and why the WHO and CDC have created literally dozens of candidate vaccine viruses (CVVs) against an array of novel viruses (H5N1, H7N9, H9N2, etc.) over the years.
It also helps to explain how the H5N1 clade 2.3.2.1c virus in Cambodia appears to be much deadlier to humans than the H5N1 clade 2.3.4.4b clade which is currently spreading globally. The 2.3.4.4b clade, however, is far better adapted to migratory birds, which has enabled it to spread far and wide.
All of which brings us to today's report, which find the NA (neuraminidase) gene segment in our seasonal H1N1 virus is antigenically similar to the NA gene segment in the clade 2.3.4.4b H5N1 virus.
While flu vaccines are currently based on the HA gene segment (i.e. H1 or H3 or H5), there has been research suggesting that the NA gene might be a useful target for a `universal flu vaccine' (see Influenza neuraminidase as a vaccine antigen).
Blood samples collected and tested in Hong Kong in 2020 show high titers of cross-reactive NA inhibition antibodies to the H5N1 clade 2.3.4.4b virus. Unknown, at least for now, is how useful those cross reactive antibodies might be in preventing or reducing the severity of infection from H5N1.
First the link, and some excerpts, from the EID Journal report. After which I'll return with a bit more.
Dispatch
Avian Influenza A(H5N1) Neuraminidase Inhibition Antibodies in Healthy Adults after Exposure to Influenza A(H1N1)pdm09
Pavithra Daulagala, Samuel M.S. Cheng, Alex Chin, Leo L.H. Luk, Kathy Leung, Joseph T. Wu, Leo L.M. Poon, Malik Peiris1, and Hui-Ling Yen1
Abstract
We detected high titers of cross-reactive neuraminidase inhibition antibodies to influenza A(H5N1) virus clade 2.3.4.4b in 96.8% (61/63) of serum samples from healthy adults in Hong Kong in 2020. In contrast, antibodies at low titers were detected in 42% (21/50) of serum samples collected in 2009. Influenza A(H1N1)pdm09 and A(H5N1) titers were correlated.
(SNIP)
Highly pathogenic avian influenza A(H5N1) virus has not yet achieved efficient transmissibility in humans, but the current epidemiology of H5N1 2.3.4.4b lineage raises concerns of possible pandemic potential. Population immunity to an emerging influenza virus is one of the key parameters considered in assessing its pandemic risk according to the Centers for Disease Control and Prevention influenza risk assessment tool (LINK) and the World Health Organization tool for influenza pandemic risk assessment (LINK).
Neutralizing antibodies targeting the HA receptor-binding domain and antibodies that inhibit neuraminidase (NA) activity have been shown to correlate with protection against influenza infection (5,6).
We evaluated whether healthy adults possess cross-reactive hemagglutination inhibition (HAI) and neuraminidase inhibition (NAI) antibodies to H5N1 virus through previous exposure to seasonal influenza infections.
(SNIP)
Conclusion
We detected high titers of cross-reactive NAI antibodies to clade 2.3.4.4b H5N1 virus, Spoonbill/HK/22, in samples collected from healthy adults 18–73 years of age in 2020. The N1 antibody cross-reactivity also extended to an H6N1 avian influenza virus isolated from wild bird samples in Hong Kong. Our results confirm and extend the findings from a recent study reporting cross-reactive NAI antibody responses to clade 2.3.4.4b H5N1 virus in healthy blood donors (12). The use of monospecific archival ferret antiserum against seasonal H1N1 and pH1N1 influenza showed that cross-reactive NAI response to H5N1 were elicited by pH1N1 but not by seasonal H1N1 viruses circulating during 1977–2007. The pH1N1 virus derived its NA protein from the avian-origin Eurasian-avian swine viruses (13) and appeared antigenically more closely related to the N1 of H5N1 and H6N1 avian influenza viruses but not to a N4 of H6N4 avian influenza virus. The use of serum samples collected from healthy blood donors in 2009 further confirmed that exposure to pH1N1 might have contributed to the cross-reactive NAI antibodies against H5N1.
HAI titer of >1:40 has long been established to correspond with a 50% reduction in influenza infection risk, which might be used to model the effects of cross-reactive HAI antibody titers on reducing the basic reproduction number (R0) of novel zoonotic viruses with pandemic potential (14). NAI antibodies have also been shown to protect against infection, reduce symptoms, and shorten the duration of viral shedding (5,6); however, the NAI antibody threshold that corresponds with protection has not been clearly defined.
In summary, we detected high titers of cross-reactive NAI antibodies against influenza A(H5N1) clade 2.3.4.4b virus in serum samples collected from healthy adults in 2020 but not detected in serum samples collected in 2009. Further studies are needed to confirm whether cross-reactive NAI antibodies confer protection against H5N1 infection or modulate disease severity, but our results suggest that the antibodies against H5N1) and H6N1 viruses might derive from exposure to the conserved epitopes shared between the avian-origin pH1N1 virus and avian N1 proteins.
Dr. Daulagala is a researcher at the School of Public Health, University of Hong Kong. Her primary research interest is understanding the role of neuraminidase antibodies in influenza infections.
While the media remains fixated on the `worst-case' 50% case fatality rate of H5N1, nearly all of those fatal cases (primarily from Indonesia, Egypt, Vietnam, Cambodia, China etc.) were from older clades, many of which haven't been reported in years (note: H5N1 clade 2.3.2.1c has made a surprise comeback in 2023).
And as we've discussed numerous times, that devastating fatality rate was among those who were sick enough to be hospitalized. Since we don't have a good handle on the denominator - the total number of people infected - we can't reliably calculate the CFR.
We've also seen patterns of infection with both H5N1 and H7N9 which suggest that one's first exposure to seasonal flu viruses may provide some protection against infection and/or severe disease from novel viruses (see Nature: Declan Butler On How Your First Bout Of Flu Leaves A Lasting Impression).
- 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.
There are obviously a lot of moving parts, many of which we are only starting to understand. Some may cancel each other out, while others may have a synergistic effect.
The impact of having high titers of cross-reactive NA inhibition antibodies to the H5N1 clade 2.3.4.4b virus are currently unknown, but it is certainly possible it might help reduce the impact of the virus should it ever become a pandemic.
Admittedly, that impact might be small. But in a viral storm, we can use any advantage we can get.
