Sunday, July 16, 2017

H2N2: Everything Old Is Flu Again

Buried Lede Alert: H2N2 isolated from a muskrat in Western Siberia - Study


Although the first infections were reported in the Far East in February of 1957, it was 60 years ago this summer when the first U.S. pandemic H2N2 cases were reported, with the initial wave eventually peaking in October.  
Dubbed the `Asian Flu', H2N2 was the first subtype change in seasonal flu in nearly 4 decades, and while milder than the 1918 H1N1 pandemic, it still claimed 70,000 lives in the United States (at a time when the U.S. population was 45% lower than today).
While its evolutionary path to becoming a pandemic virus is still a bit murky, this pdmH2N2 virus appears to have been the product of a reassortment between seasonal H1N1 and an avian H2N2 virus (cite Adaptation of Pandemic H2N2 Influenza A Viruses in Humans).

An examination of the ECDC pandemic history chart at the top of this blog shows that H2N2 is believed to have sparked a pandemic around 1890, only to be replaced by an H3(N8?) pandemic in 1895, and by H1N1 in 1918.
Those under the age of 65 (in 1957) had never been exposed to an H2 virus, and were therefore the most susceptible to infection.
The H2N2 `Asian Flu' was supplanted in 1968 by H3N2 (which still circulates today) after a relatively short 11 year run, which means those born after 1968 would have very little immunity should an H2N2 pandemic come around again.

The progression of human influenza pandemics over the past 130 years is believed to have been H2, H3, H1, H2, H3, H1, H1 . . .
  • H2N2 sparked two pandemics (1898 and 1957) roughly 69 years apart.   
  • H3 viruses unleashed two pandemics (1900 and 1968) roughly 68 years apart
  • And H1N1 caused the great 1918 pandemic only to return in the pseudo-pandemic of 1977, 59 years later (and then reinvented itself in the 2009 Pandemic).
While we keep a wary eye on avian H5 and H7, this repeating pattern of the H1, H2, H3 pandemics is hard to ignore, even if the sample size is small (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?). Granted, we've no clue what influenza subtypes might have circulated in humans before 1890, and there is some guesswork surrouding those prior to 1918.  
Past performance is often a spectacularly poor predictor of the future, particularly when the data set is so limited, so a heavy dose of Caveat Predictor is warranted here.
But over the years we've examined a number of studies that have looked at H2N2 viruses in the wild, their pandemic potential, and what we might do to mitigate the risks.

In 2011, after the furor over the 2009 H1N1 pandemic had finally died down, some researchers suggested it might make sense to add an H2N2 component to the seasonal vaccine to head off the `next' pandemic (see Nature: A Preemptive H2N2 Vaccine Strike?)
While it sparked some academic discussions, this controversial proposal never went anywhere, the concensus being it was impossible to pick the `next' pandemic subtype with any confidence. 
In 2012, in H2N2: What Went Around, Could Come Around Again, we looked at a study conducted by scientists working at St. Jude Children's Research Hospital - published in the Journal of Virology - that concluded that H2N2 could well pose a threat to humanity once again.

A press release on this research warned:
1950s pandemic influenza virus remains a health threat, particularly to those under 50

St. Jude Children's Research Hospital scientists report that avian H2N2 influenza A viruses related to 1957-1958 pandemic infect human cells and spread among ferrets; may aid identification of emerging threats
Two years ago, in October of 2015, Russian (and Eastern European) media went ballistic   over a story that quoted Russian virologist Vladimir Blinov as predicting the return of pandemic H2N2 in 2017 (see When H2N2 Predictions Go Viral), based primarily on a supposed 60-year recurrence cycle.
Bombastic predictions out of Russia are nothing new, of course. In 2006 Dimitri Lvov predicted 1 billion deaths from an expected H5N1 pandemic (see From Russia, With Lvov (Again)), so I take these sorts of stories with a large grain of Siberian salt.
But the fact is, H2N2 still exists in the wild - and since H2 viruses have sparked pandemics in the past - we pay attention whenever an H2 avian virus shows any signs of jumping species. Again.

One recent example is published in The Journal Of Veterinary Medical Science, which details the finding of H2N2 in Siberian Muskrats.
Genetic characterization of an H2N2 influenza virus isolated from a muskrat in Western Siberia
Marina GULYAEVA1) 2), Kirill SHARSHOV2), Mizuho SUZUKI3), Ivan SOBOLEV2), Yoshihiro SAKODA3) 4), Alexander ALEKSEEV2), Mariya SIVAY2), Lidia SHESTOPALOVA1), Michael SHCHELKANOV5) 6), Alexander SHESTOPALOV2)

Released 2017/07/10 

 Full Text PDF [814K]

Thirty-two muskrats (Ondatra zibethicus) were captured for surveillance of avian influenza virus in wild waterfowl and mammals near Lake Chany, Western Siberia, Russia. A/muskrat/Russia/63/2014 (H2N2) was isolated from an apparently healthy muskrat using chicken embryos.
Based on phylogenetic analysis, the hemagglutinin and neuraminidase genes of this isolate were classified into the Eurasian avian-like influenza virus clade and closely related to low pathogenic avian influenza viruses (LPAIVs) isolated from wild water birds in Italy and Sweden, respectively. Other internal genes were also closely related to LPAIVs isolated from Eurasian wild water birds.
Results suggest that interspecies transmission of LPAIVs from wild water birds to semiaquatic mammals occurs, facilitating the spread and evolution of LPAIVs in wetland areas of Western Siberia.
Since 1968, influenza H2N2 viruses have not been detected in humans; therefore, most individuals younger than 50 years lack humoral immunity to the H2 antigen [19]. Although there are no influenza H2N2 viruses in the human population at the moment, H2 influenza viruses are often isolated from wild birds and  poultry [18]. The H2 influenza viruses in wild bird populations have been detected in combination with all nine NA subtypes. The AIV of the H2N3 subtype was also isolated from swine and the environment [1, 17, 20]. Therefore, it is of great interest to conduct studies on the interspecies transmission of H2 influenza viruses between avian and mammalians, because they have a high degree of genetic and antigenic similarity to the ancestral viruses that contributed genes to the 1957 H2N2 pandemic virus.

(Continue . . . )

You'll note that these samples were collected in 2014, which suggests that whatever H2N2 might be doing in small acquatic animals in Siberia, it is doing so slowly.  And indeed, muskrats may prove to be a dead-end host for the virus.
But as long as suitable reservoir hosts are available in the wild, old viral threats can return, even after decades of relative obscurity.
While the last H2 pandemic was paired with an N2 neuraminidase, H2 could always return with a different partner next time.

In 2007 the flu world was abuzz (see The Reassortment Tango) over the discovery of a mammalian-adapted H2N3 virus, isolated in swine at two separate Missouri farms in 2006. Previously, the H2N3 virus had only been known to infect birds. 
This was the first detection of an H2 influenza virus in a mammalian host since 1968, when the human H2N2 virus was supplanted by the the H3N2 pandemic virus.
In 2012, a PLoS One article (Recently Emerged Swine Influenza A Virus (H2N3) Causes Severe Pneumonia in Cynomolgus Macaques) found this swine H2N3 produced greater pathogenicity in a non-human primate than did the human H2N2 virus.

And just over a year ago, in Virus Genes: A Novel Reassortant H2N8 In China, we saw a study that warned:
Although this reassortant strain exhibited low pathogenicity in mice, it was able to replicate in the lungs of the mice without prior adaptation. Continued surveillance of domestic ducks in LPMs is required for early detection of AIV outbreaks in poultry and humans.
None of this means that H2 will spark the next pandemic, only that H2 remains a viable candidate, even if it has flown beneath the radar almost a half a century.