H2N2 Pandemic Waves - NEJM 2009
Although our understanding and identification of humanized influenza viruses only goes back about a century, in our limited experience only three subtypes of influenza (H1, H2, H3) have circulated widely in humans. Yes, occasionally we’ve seen one-off infections and small clusters of H5 and H7 avian strains, but so far (knock on wood), these remain primarily avian-centric pathogens.
Currently, and for almost the past 40 years, the two humanized flu strains have been the H1N1 and H3N2 varieties. But in 1957, after roughly 40 years of flu dominance by the H1N1 descendants of the Spanish Flu of 1918, a new H2N2 flu virus emerged from China and sparked a pandemic.
For the next decade – until 1968 – H2N2 influenza reigned supreme, supplanting the old H1N1 strain, and causing millions of flu related deaths. It was replaced in 1968 by the last pandemic strain of the 20th century – H3N2 – and has not been seen in the human population in the last 45 years.
Which means that a substantial portion of the world’s population – particularly those under the age of 50 – have little or no immunity to the H2N2 influenza virus, making them an easy target for the virus should it re-emerge. For now the virus resides quietly (primarily) in aquatic birds, but that status could change as it did in the 1950s.
While we don’t have any good data on what flu viruses may have circulated in the 19th century or earlier, some scientists believe that they were likely of the H1, H2, or H3 variety – as they are the ones best adapted to human hosts. All of which suggests that the next pandemic virus could well come from a reassortment of an H1, H2, or H3 virus.
In 2011, in Nature: A Preemptive H2N2 Vaccine Strike?, we looked at an article in Nature, where authors Gary J. Nabel,Chih-Jen Wei & Julie E. Ledgerwood discuss the idea of possibly heading off the next pandemic by launching a preemptive strike against the H2N2 virus.
And in 2007, friend and fellow flu blogger Scott McPherson broached the subject of H2 returning as a pandemic virus way back in 2007 in the following blog:
Posted on Wednesday, December 19, 2007
Earlier this year, in MIT: The Risks Of An Emerging H3N2 Pandemic Virus, we looked at concerns over seeing a reassorted H3N2 virus emerge from swine. And the surprise H1N1 pandemic of 2009 proved that a reassorted H1 virus – a cousin to the most durable human flu virus of the past century – could indeed spark a global outbreak.
All of which serves as prelude to a new study, which appears in the Journal of Virology, that takes the most detailed look at H2N2 viruses in the wild to date, and concludes that this virus could well pose a threat to humanity again. First a link, and some excerpts from the abstract, then part of the press release from St. Jude Children's Research Hospital.
Jeremy C. Jones, Tatiana Baranovich, Bindumadhav M. Marathe, Angela F. Danner, Jon P. Seiler, John Franks, Elena A. Govorkova, Scott Krauss and Robert G. Webster#
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA
H2N2 influenza A viruses were the cause of the 1957-1958 pandemic. Historical evidence demonstrates they arose from avian virus ancestors, and while the H2N2 subtype has disappeared from humans, it persists in wild and domestic birds. Re-emergence of H2N2 in humans is a significant threat due to the absence of humoral immunity in individuals under the age of 50. Thus, examination of these viruses, particularly those from the avian reservoir, must be addressed through surveillance, characterization, and antiviral testing.
The data presented here are a risk assessment of 22 avian H2N2 viruses isolated from wild and domestic birds over 6 decades. Our data showed that they have a low rate of genetic and antigenic evolution and remained similar to isolates circulating near the time of the pandemic. Most isolates replicated in mice and human bronchial epithelial cells, but replication in swine tissues was low or absent. Multiple isolates replicated in ferrets, and 3 viruses were transmitted to direct-contact cagemates. Markers of mammalian adaptation in HA and PB2 proteins were absent from all isolates, and they retained a preference for avian-like α2-3 linked sialic acid receptors.
Most isolates remained antigenically similar to pandemic A/Singapore/1/57 (H2N2) virus, suggesting they could be controlled by the pandemic vaccine candidate. All viruses were susceptible to neuraminidase inhibitors and adamantanes. Nonetheless, the sustained pathogenicity of avian H2N2 viruses in multiple mammalian models elevates their risk potential for human infections and stresses the need for continual surveillance as a component of pre-pandemic planning.
While this study is behind a pay wall, we have a press release from St. Jude Children's Research Hospital to provide additional detail. Follow the link to read it in its entirety, after which I’ll return with a bit more.
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
(MEMPHIS, TENN. – December 3, 2013) St. Jude Children's Research Hospital scientists have evidence that descendants of the H2N2 avian influenza A virus that killed millions worldwide in the 1950s still pose a threat to human health, particularly to those under 50. The research has been published in an advance online edition of the Journal of Virology.
The study included 22 H2N2 avian viruses collected from domestic poultry and wild aquatic birds between 1961 and 2008, making it the most comprehensive analysis yet of avian H2N2 viruses.
Researchers reported the viruses could infect human respiratory cells. Several strains also infected and spread among ferrets, which are susceptible to the same flu viruses as humans. Based on those and other indicators, one virus was classified as posing a high risk for triggering a pandemic.
Researchers found evidence the viruses were susceptible to current antiviral medications and could likely be controlled with an available prototype vaccine.
Such protection was unavailable in 1957 when an H2N2 virus that included genes from avian flu viruses emerged. Federal health officials estimate the 1957-58 pandemic killed 1 to 2 million people worldwide. While the H2N2 strain disappeared from flu viruses circulating in humans in 1968, it has persisted in the world's bird population.
"This study suggests H2N2 has the characteristics necessary to re-emerge as a significant threat to human health in part because most individuals under the age of 50 lack immunity to the virus," said corresponding author Robert Webster, Ph.D., a member of the St. Jude Department of Infectious Diseases. "This highlights the importance of continued surveillance of viruses circulating in animals and additional research to enhance our ability to identify viruses that are emerging health threats."
In early 1976, after an absence of nearly two decades, a never-before-seen strain of H1N1 swine flu appeared at Ft. Dix, New Jersey – prompting a national emergency response for its expected return in the fall. While that virus failed to return (see Deja Flu, All Over Again), the following year we were blindsided by the abrupt return of the H1N1 virus last seen in the mid-1950s.
Although those over the age of 20 carried some immunity to the virus, it slammed kids and teenagers very hard, and today is viewed as a `pseudo-pandemic’ (see Pseudo Pandemics And Viral Interlopers).
While we understandably watch novel flu strains like H5N1 and H7N9 with a certain amount of trepidation – if you base your risk assessment on pandemics past – then we should be preparing for a variation of one of the H1, H2, H3 viruses which actually have a track record of sparking a pandemic.
Or to put it another way, those who forget their viral history may well be doomed to repeat it.