INFLUENZA PANDEMIC (H1N1) 2009 (04): PANDEMIC ORIGINS

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[1]
Date: Mon 13 Jul 2009
Source: Rehabpub, Reuters Health Stories [edited]



In a review of the genotypes of viruses responsible for the 3 major
influenza pandemics in the 20th century, scientists in China have
found clues indicating that viral precursors probably circulated for
several years in animal and human hosts before the pandemic strains
emerged.

"The evolutionary history of these 3 pandemic viruses remains unclear,
and that lack of understanding hinders the recognition of and
preparedness for future influenza pandemics," senior author Dr. Yi
Guan and associates at The University of Hong Kong write in the 14 Jul
2009 issue of the Proceedings of the National Academy of Sciences [see
part (3) below].

To clarify the mechanisms underlying pandemic emergence, Dr. Guan's
team compared amino acid similarities of all 8 gene segments of all
available viruses associated with the emergence of the A/Brevig
Mission/1/1918 virus (BM/1918), H2N2/1957, and H3N2/1968 pandemic
strains.

"These pandemics were initiated by the introduction and successful
adaptation of a novel hemagglutinin subtype to humans from an animal
source, resulting in antigenic shift," the investigators say.
Estimates for the times of most recent common ancestors to the BM/1918
strain indicate that the they ranged from 1903 for the PB2 gene to
1916 for the HA gene, suggesting that the virus genes were present in
swine or human hosts 2 to 15 years prior to the pandemic. "It is
unlikely," the authors state, "that the BM/1918 virus could have
resulted from adaptation of an entire avian virus introduced directly
into humans shortly before the pandemic. More likely, it was generated
by reassortment between previously circulating swine and human strains
and introduced avian viruses over a period of years." They estimate
that 3 H1N1 variants co-circulated in 1918, BM/1918 and precursors of
seasonal and classic swine H1N1.

Phylogenies showed that the H2N2/1957 resulted from the genetic
reassortment between already circulating human and avian viruses and 3
genes derived from a Eurasian avian source. These genes were
introduced into human populations 2 to 6 years before the pandemic.
Their data point to a similar process for the H3N1 pandemic. Dr.
Guan's team concludes that if future pandemics arise in a similar
manner -- generated through reassortment events in unknown mammalian
hosts and involving multiple avian viruses preceding pandemic
recognition -- appropriate surveillance strategies for detection of
precursor viruses may abort future pandemics.

Furthermore, they believe that high-throughput characterization of all
8 gene segments of human virus isolates will be necessary for early
warning of an incipient pandemic.

--
Communicated by:
ProMED-mail

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[2]
Date: Tue 14 Jul 2009
Source: Fort Frances times, The Canadian Press [edited]



The precursors of pandemic flu viruses may circulate in humans for
years before picking up all the genetic changes needed to ignite a
pandemic, a new study suggests. The authors argue that the last 3
pandemics -- including the infamous 1918 Spanish flu -- emerged in
this gradual manner. They also say their findings contradict the
notion that the Spanish flu virus jumped directly from birds into
people. Instead, they say, it evolved in a gradual manner over years,
with some of the genes likely coming from the virus responsible for
the pandemic that preceded 1918. That pandemic, which occurred in
1889, is believed to have been caused by an H3 virus.

"It's always been contentious," lead author Gavin Smith said of the
theory that the Spanish flu virus came directly and intact from birds
rather than through a series of gene-swapping events known as
reassortments. "It's never been a consensus view of people in the
research community." However, the researcher who led the effort to
find and sequence the 1918 virus said this new work, done by
calculations drawn from virus family trees -- a process called
phylogenetics -- can only generate hypotheses about how the Spanish
flu virus emerged.

"The fundamental problem in terms of dating the emergence of the 1918
virus with all of these models ... (is) that the crucial data that we
would need to understand the origin of the 1918 flu are influenza
samples from before 1918," said Jeffery Taubenberger, an influenza
researcher at the U.S. National Institutes of Allergy and Infectious
Diseases. "And until such time that those sequences are available, I
think that phylogenetics is not going to be able to answer with
specificity the question about the origin of the 1918 virus."

The new paper, published in the journal Proceedings of the National
Academy of Sciences, is by researchers from the University of Hong
Kong, Shantou University in China, and St. Jude Children's Research
Hospital in Memphis, Tenn. USA [see (3) below]. Smith is an
evolutionary biologist and virologist at the University of Hong Kong.
He was also lead author of a paper published last month [June 2009] in
Nature that estimated the new swine flu virus has been circulating in
people probably since about January of this year [2009]. The current
research used the same techniques as were employed in the Nature
paper. Smith and his colleagues looked at gene sequences for all 8
genes in the flu viruses responsible for the 1918, 1957 and 1968
pandemics, tracing back their lineages through the available banked
sequence data. Smith said the work suggests all 3 of the pandemics of
the 20th century emerged through reassortment, the swapping of genes
that can occur when an animal or a human is infected with 2 different
strains of flu at the same time.

While it is widely accepted that the 1957 and 1968 strains were
reassortant viruses, some contend the 1918 virus was an avian virus
that mutated to the point where it was able to infect people. Smith
and his co-authors also compared the viruses to current seasonal H1N1
viruses and H1N1 viruses known to circulate in pigs and came to a
somewhat startling conclusion. Current seasonal H1N1 viruses and swine
viruses are not the distant offspring of the 1918 virus, they said.
Rather, the gene dating techniques suggest the 1918 H1N1, current
seasonal H1N1s and the H1N1s circulating in pigs all had a common
ancestor, making them more like cousins or distant relatives.

If they are right, that suggests those viruses were all circulating
during the 1918 pandemic, which could explain uneven patterns of
disease seen at the time. "There was variation in the severity of the
pandemic," Smith explained in an interview from Hong Kong. "Some areas
had more severe (disease) and others didn't. So it sort of fits into
that idea. But again it is inference. And unless you've got a lot of
isolates from that period, I think it's always going to be impossible
to say definitely."

Taubenberger remains skeptical, noting that if modern science can't
say where and when the current pandemic virus evolved, it has less
chance of cracking the mysteries of 1918. "Even in this time and age
of extraordinary influenza surveillance and rapid genetic analysis, we
actually don't know with specificity when that reassortment event
(that produced the pandemic virus) occurred, in what species, in what
location geographically. We don't know that ... in something that just
happened right now, in a molecular virology era," he said from
Bethesda, Md. "Since we don't know what happened in 2008 or 2009 in
the emergence of this new H1 (virus), we really don't know what
happened in 1918 where so much data is not available and probably will
never become available."

[Byline: Helen Branswell]

--
Communicated by:
ProMED-mail Rapporteur Mary Marshall

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[3]
Date: 13 Jul 2009
Source: Proceedings of the National Academy of Sciences [edited]



Dating the emergence of pandemic influenza viruses. By Gavin J. D.
Smitha, Justin Bahla, Dhanasekaran Vijaykrishnaa, Jinxia Zhanga, Leo
L. M. Poona, Honglin Chena, Robert G. Webstera, J. S. Malik Peirisa,
and Yi Guana. At: State Key Laboratory of Emerging Infectious Diseases
& Department of Microbiology, Li Ka Shing Faculty of Medicine, The
University of Hong Kong, Pokfulam, Hong Kong SAR, China; International
Institute of Infection and Immunity, Shantou University, Shantou,
Guangdong 515031, China; Virology Division, Department of Infectious
Diseases, St. Jude Children's Research Hospital, Memphis, TN 38015;
and HKU-Pasteur Research Centre, The University of Hong Kong,
Pokfulam, Hong Kong SAR, China.

Abstract
----------
Pandemic influenza viruses cause significant mortality in humans. In
the 20th century, 3 influenza viruses caused major pandemics: the 1918
H1N1 virus, the 1957 H2N2 virus, and the 1968 H3N2 virus. These
pandemics were initiated by the introduction and successful adaptation
of a novel hemagglutinin subtype to humans from an animal source,
resulting in antigenic shift.

Despite global concern regarding a new pandemic influenza, the
emergence pathway of pandemic strains remains unknown. Here we
estimated the evolutionary history and inferred date of introduction
to humans of each of the genes for all 20th century pandemic influenza
strains.

Our results indicate that genetic components of the 1918 H1N1 pandemic
virus circulated in mammalian hosts, i.e., swine and humans, as early
as 1911 and was not likely to be a recently introduced avian virus.
Phylogenetic relationships suggest that the A/Brevig Mission/1/1918
virus (BM/1918) was generated by reassortment between mammalian
viruses and a previously circulating human strain, either in swine or,
possibly, in humans. Furthermore, seasonal and classic swine H1N1
viruses were not derived directly from BM/1918, but their precursors
co-circulated during the pandemic.

Mean estimates of the time of most recent common ancestor also suggest
that the H2N2 and H3N2 pandemic strains may have been generated
through reassortment events in unknown mammalian hosts and involved
multiple avian viruses preceding pandemic recognition. The possible
generation of pandemic strains through a series of reassortment events
in mammals over a period of years before pandemic recognition suggests
that appropriate surveillance strategies for detection of precursor
viruses may abort future pandemics.

--
Communicated by:
ProMED-mail

[These authors have carried out phylogenetic analyses of all available
influenza virus sequences by an alternate methodology. In the case of
influenza genome sequences, establishing the times of most recent
common ancestor (TMRCA) can provide an estimate of when virus genes
emerged in a given host that allows the time of interspecies
transmission to be inferred. The authors have used this approach to
investigate the possible date of introduction to humans of each of the
genes for all available 20th century pandemic influenza strains. The
mean TMRCA estimates of each gene segment of H1N1 viruses shows that
the components of the 1918 pandemic strain were circulating in
mammalian hosts, i.e., swine and humans, at least 2 to 15 years prior
to the pandemic. The phylogenetic analyses suggest that the 1918 H1N1
pandemic virus most likely was generated by reassortment between
mammalian viruses and a previous human strain and was not a pure avian
virus, likewise that seasonal and classic swine H1N1 viruses were not
derived directly from the 1918 virus but rather their precursors
co-circulated during the pandemic. Furthermore, mean TMRCA estimates
also suggest that the avian-derived genes of the H2N2 and H3N2
pandemic strains may have been introduced to humans on multiple
occasions over a number of years.

These conclusions regarding the origin of the pandemic viruses of the
20th century are somewhat different from the outcome of previous
analyses, and in the absence of isolates from earlier years, are
likely to remain controversial. - Mod.CP]

[see also:
Influenza pandemic (H1N1) 2009 (03): vaccine 20090713.2505
Influenza pandemic (H1N1) 2009 (03): official nomenclature -- to be archived
Influenza pandemic (H1N1) 2009 (02): obesity risk factor 20090711.2482
Influenza pandemic (H1N1) 2009 - Viet Nam: patient data 20090708.2450
Influenza A (H1N1) - worldwide (86): official nomenclature 20090706.2430]
...........................................................cp/msp/jw
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