The influenza virus that wreaked worldwide havoc in 1918-1919 founded a
viral dynasty that persists to this day, according to scientists from
the National Institute of Allergy and Infectious Diseases (NIAID), part
of the National Institutes of Health. In an article published online on
June 29 by the New England Journal of Medicine, authors Anthony
S. Fauci, M.D., Jeffery K. Taubenberger, M.D., Ph.D., and David M.
Morens, M.D., argue that we have lived in an influenza pandemic era
since 1918, and they describe how the novel 2009 H1N1 virus now
circling the globe is yet another manifestation of this enduring viral
"The 1918-1919 influenza pandemic was a defining event in the
history of public health," says NIAID Director Dr. Fauci. "The legacy
of that pandemic lives on in many ways, including the fact that the
descendents of the 1918 virus have continued to circulate for nine
Influenza viruses have eight genes, two of which code for
virus surface proteins - hemagglutinin (H) and neuraminidase (N) - that
allow the virus to enter a host cell and spread from cell to cell.
There are 16 H subtypes and 9 N subtypes, and, therefore, 144 possible
HN combinations. However, only three (H1N1, H2N2 and H3N2) have ever
been found in influenza viruses that are fully adapted to infect
humans. Other combinations, such as avian influenza H5N1, occasionally
infect people, but they are bird viruses, not human viruses.
"The eight influenza genes can be thought of as players on a
team: Certain combinations of players may arise through chance and
endow the virus with new abilities, such as the ability to infect a new
type of host," says Dr. Morens, Senior Advisor to the NIAID Director.
That is likely what happened to spark the 1918 pandemic, he adds.
Scientists have shown that the founding virus was an avian-like virus.
The virus had a novel set of eight genes and - through still-unknown
mechanisms - gained the ability to infect people and spread readily
from person to person.
Not only did the 1918 H1N1 virus set off an explosive pandemic
in which tens of millions died, during the pandemic the virus was
transmitted from humans to pigs, where - as it does in people - it
continues to evolve to this day. "Ever since 1918, this tenacious virus
has drawn on a bag of evolutionary tricks to survive in one form or
another…and to spawn a host of novel progeny viruses with novel gene
constellations, through the periodic importation or exportation of
viral genes," write the NIAID authors.
"All human-adapted influenza A viruses of today - both
seasonal variations and those that caused more dramatic pandemics - are
descendents, direct or indirect, of that founding virus," notes Dr.
Taubenberger, Senior Investigator in NIAID's Laboratory of Infectious
Diseases. "Thus we can be said to be living in a pandemic era that
began in 1918."
How exactly do new influenza gene teams make the leap from
aquatic birds to a new host, such as people or other mammals? What
factors determine whether infection in a new host yields a dead-end
infection or sustained, human-to-human transmission, as happened in
1918? Research on such topics is intense, but at this time definitive
answers remain elusive, notes Dr. Morens.
It is known that the human immune system mounts a defense
against the influenza virus's H and N proteins, primarily in the form
of antibodies. But as population-wide immunity to any new variant of
flu arises, the virus reacts by changing in large and small ways that
make it more difficult for antibodies to recognize it. For nearly a
century, then, the immune system has been engaged in a complicated pas
de deux with the 1918 influenza virus and its progeny, say the NIAID
authors. The partners in this dance are linked in an endless effort to
take the lead from the other.
While the dynasty founded by the virus of 1918 shows little
evidence of being overthrown, the NIAID authors note that there may be
some cause for optimism. When viewed through a long lens of many
decades, it does appear that successive pandemics and outbreaks caused
by later generations of the 1918 influenza dynasty are decreasing in
severity, notes Dr. Morens. This is due in part to advances in medicine
and public health measures, he says, but this trend also may reflect
viral evolutionary pathways that favor increases in the virus's ability
to spread from host to host, combined with decreases in its tendency to
kill those hosts.
"Although we must be prepared to deal with the possibility of
a new and clinically severe influenza pandemic caused by an entirely
new virus, we must also understand in greater depth, and continue to
explore, the determinants and dynamics of the pandemic era in which we
live," conclude the authors.
DM Morens et al. The persistent legacy of the 1918 influenza virus. New England Journal of Medicine. DOI: 10.1056/NEJMp0904819 (2009).