Avian Flu Diary: Eurosurveillance: Novel influenza A(H1N2) Seasonal Reassortant Virus Identified in a Patient, Sweden, April 2025

#18,830

Influenza reassortment - also known as Antigenic Shift - is something we've discussed often in the blog, albeit mostly in regards to avian or swine influenza. This reshuffling of influenza genes is the primary force behind the creation of novel or pandemic flu viruses (see NIAID Video: How Influenza Pandemics Occur).

Shift can occur inside any host capable of being simultaneously infected with two or more influenza A viruses; even humans (see Preprint: Intelligent Prediction & Biological Validation of the High Reassortment Potential of Avian H5N1 and Human H3N2 Influenza Viruses).

While nearly everyone today thinks of seasonal flu as being a mix of H1N1 and H3N2 subtypes, between 1918 and 1957, it was solely H1N1. Between 1957 and 1968, H2N2 reigned, and in 1968 it gave way to H3N2 (both initially introduced as pandemic viruses).

H1N1 mysteriously returned in 1977-78 after a 20 year absence, and for nearly 6 decades this viral H1/H3 tag-team has all but defined human seasonal flu (excluding swine-variant viruses).

There have been some notable exceptions:

In 1988-1989 China reported a handful of novel H1N2 infections (see Human influenza A (H1N2) viruses isolated from China)

In 2000-2001 another novel H1N2 emerged, with legs enough to spread internationally (cite), before disappearing in 2003.

Over 2018-2019 we saw a spate of isolated detections across Europe (Netherlands, Denmark, and Sweden).

Note: In 2019 the CDC also detected a rare H3N1 reassortment in a 13-year-old from Idaho (see 2020 blog on MMWR report), and today's Eurosurveillance references two recent H3N2 reassortants (internal genes largely from H1N1pdm) from the Netherlands in February 2025.

So while rare, shift happens.

Although it seems likely that a reassortant derived from two existing seasonal flu strains would have less impact than one involving a zoonotic flu virus, there are no guarantees it would be benign.

Detecting these reassortants, much like detecting novel swine or avian flu viruses, is often a matter of luck. Only a tiny fraction of flu-like illnesses are subtyped, and an even smaller percentage end up sequenced.

All of which brings us to yesterday's Eurosurviellance report on a novel H1N2 virus isolated from a patient in Sweden last April. This is a lengthy and detailed report, which many will want to read it its entirety.

A few key points:

This virus was initially identified as H1N1 by PCR

It was only identified as H1N2 because additional sequencing was performed.

Sequencing revealed it carried 7 genes (including HA) from seasonal A(H1N1)pdm09 and 1 gene (neuraminidase, NA) from seasonal A(H3N2)

There was no evidence of `mixed' infection (sample negative for both H3 and N1), suggesting this reassortment occurred in another host

Out of > 24,200 lab-confirmed flu cases in Sweden in 2024-2025, only 227 have been characterized by WGS (whole-genome sequencing)

Some excerpts from the report follow, after which I'll have a brief postscript.

Novel influenza A(H1N2) seasonal reassortant virus identified in a patient, Sweden, April 2025
Dorina Ujvari1 , Tove Samuelsson Hagey1 , AnnaSara Carnahan2 , Neus Latorre-Margalef1
A reassortant seasonal influenza A(H1N2) virus was detected in Sweden in a routine sentinel surveillance sample from an infected patient. Here we describe this case and the characterisation of the virus.
Case description
During early April 2025 (week 14 2025) in southern Sweden, a male patient of the 40–49-year age group, without underlying conditions consulted a primary care physician following 6 days of influenza-like illness (ILI). A nasopharyngeal swab was taken within the national sentinel surveillance system [1].
The sample was forwarded to the Public Health Agency of Sweden, where the diagnosis of influenza A virus infection was established by an in-house multiplex real-time PCR targeting the matrix protein (MP) gene of influenza A and B viruses. The sample was subtyped as A(H1)pdm09 by an in-house multiplex real-time PCR targeting the haemagglutinin (HA) gene of A(H1)pdm09 and A(H3) subtypes of influenza A virus.
The patient had not been vaccinated against influenza during 2023/24 or 2024/25 and had not travelled abroad in the 14 days before ILI onset. The patient did not require hospitalisation or antiviral treatment and has fully recovered.

(SNIP)

Sporadic cases of zoonotic influenza viruses in humans arising from animal-to-human spillover are increasing, especially due to A(H5N1) outbreaks in domestic birds and mammals worldwide [14]. Co-infection with different seasonal and zoonotic influenza strains might lead to the formation of influenza viruses with novel constellations of gene segments. Reassortment also imposes a strong selection pressure on the virus, provoking a transient increase in the rate of amino acid replacements – a burst of positively selected adaptive changes.

This might lead to emergence of variant viruses with post-reassortment adaptation to the new environment, i.e. acquiring the ability to efficiently spread among humans and cause epidemics or pandemics [15]. Therefore, it is of high importance that reference laboratories, via molecular surveillance of circulating influenza strains, can detect new reassortant viruses and that the potential public health impact of reassortant viruses is assessed.

This study has some limitations. No case finding or contact tracing was possible, so there may have been related cases that remain undetected, particularly in individuals with mild symptoms. Sampling for influenza in Sweden is confined to medically attended influenza infection, meaning those with mild or no symptoms are unlikely to be sampled. In addition, only approximately 25% of all laboratory-confirmed influenza A cases detected nationally are subtyped. As such, reassortant cases may be missed.

Conclusion

The occurrence of the H1N2 reassortant of influenza A virus detected during routine surveillance activities in Sweden, underscores the importance for sustained systematic testing alongside genomic characterisation. Given the pandemic potential of influenza viruses of different origin, surveillance systems and analysis tools are crucial for timely and effective public health responses.

Sweden's GHS (Global Health Security) Index ranks among the top 10 globally (see map below) - but less than 1% of their lab-confirmed flu isolates are fully sequenced - a surveillance gap that provides opportunities for novel viruses to spread undetected.

For much of the rest of the world, however, the chances of detecting the emergence of a novel virus are far slimmer.

While we've seen agencies like the WHO and ECDC promoting increased surveillance (see ECDC: Updated Reporting Protocol for Zoonotic Influenza Virus) - for numerous and varied economic and political reasons - the sharing of data only seems to be getting worse (see From Here To Impunity).