1918 Influenza: the Mother of All Pandemics

Jeffery K. Taubenberger" and David M. Morens1-

The “Spanish" influenza pandemic of 1918—1919,
which caused :50 million deaths worldwide, remains an
ominous warning to public health. Many questions about its
origins, its unusual epidemiologic features, and the basis of
its pathogenicity remain unanswered. The public health
implications of the pandemic therefore remain in doubt
even as we now grapple with the feared emergence of a
pandemic caused by H5N1 or other virus. However, new
information about the 1918 virus is emerging, for example,
sequencing of the entire genome from archival autopsy tis-
sues. But, the viral genome alone is unlikely to provide
answers to some critical questions. Understanding the
1918 pandemic and its implications for future pandemics
requires careful experimentation and in-depth historical
analysis.

 

”Curiouser and curiouser/ ” criedAlice
Lewis Carroll, Alice’s Adventures in Wonderland, 1865

An estimated one third of the world’s population (or
z500 million persons) were infected and had clinical-
ly apparent illnesses (1,2) during the 191871919 inﬂuenza
pandemic. The disease was exceptionally severe. Case-
fatality rates were >2.5%, compared to <0.1% in other
inﬂuenza pandemics (3,4). Total deaths were estimated at
z50 million (577) and were arguably as high as 100 mil-
lion (7).

The impact of this pandemic was not limited to
191871919. All inﬂuenza A pandemics since that time, and
indeed almost all cases of inﬂuenza A worldwide (except-
ing human infections from avian Viruses such as H5N1 and
H7N7), have been caused by descendants of the 1918
Virus, including “drifted” H1N1 Viruses and reassorted
H2N2 and H3N2 Viruses. The latter are composed of key
genes from the 1918 Virus, updated by subsequently-incor—
porated avian inﬂuenza genes that code for novel surface

 

*Armed Forces Institute of Pathology, Rockville, Maryland, USA;
and TNational Institutes of Health, Bethesda, Maryland, USA

proteins, making the 1918 Virus indeed the “mother” of all
pandemics.

In 1918, the cause of human inﬂuenza and its links to
avian and swine inﬂuenza were unknown. Despite clinical
and epidemiologic similarities to inﬂuenza pandemics of
1889, 1847, and even earlier, many questioned whether
such an explosively fatal disease could be inﬂuenza at all.
That question did not begin to be resolved until the 1930s,
when closely related inﬂuenza Viruses (now known to be
H1N1 Viruses) were isolated, ﬁrst from pigs and shortly
thereafter from humans. Seroepidemiologic studies soon
linked both of these viruses to the 1918 pandemic (8).
Subsequent research indicates that descendants of the 1918
Virus still persists enzootically in pigs. They probably also
circulated continuously in humans, undergoing gradual
antigenic drift and causing annual epidemics, until the
1950s. With the appearance of a new H2N2 pandemic
strain in 1957 (“Asian ﬂu”), the direct H1N1 Viral descen-
dants 0f the 1918 pandemic strain disappeared from human
circulation entirely, although the related lineage persisted
enzootically in pigs. But in 1977, human H1N1 Viruses
suddenly “reemerged” from a laboratory freezer (9). They
continue to circulate endemically and epidemically.

Thus in 2006, 2 major descendant lineages of the 1918
H1N1 Virus, as well as 2 additional reassortant lineages,
persist naturally: a human epidemic/endemic H1N1 line-
age, a porcine enzootic H1N1 lineage (so-called classic
swine ﬂu), and the reassorted human H3N2 Virus lineage,
which like the human H1N1 Virus, has led to a porcine
H3N2 lineage. None of these Viral descendants, however,
approaches the pathogenicity of the 1918 parent Virus.
Apparently, the porcine H1N1 and H3N2 lineages uncom-
monly infect humans, and the human H1N1 and H3N2 lin-
eages have both been associated with substantially lower
rates ofillness and death than the virus of 1918. In fact, cur-
rent H1N1 death rates are even lower than those for H3N2
lineage strains (prevalent from 1968 until the present).
H1N1 Viruses descended from the 1918 strain, as well as 
H3N2 Viruses, have now been cocirculating worldwide for
29 years and show little evidence of imminent extinction.

Trying To Understand What Happened

By the early 1990s, 75 years of research had failed to
answer a most basic question about the 1918 pandemic:
why was it so fatal? No Virus from 1918 had been isolated,
but all of its apparent descendants caused substantially
milder human disease. Moreover, examination of mortality
data from the 1920s suggests that within a few years after
1918, inﬂuenza epidemics had settled into a pattern of
annual epidemicity associated with strain drifting and sub-
stantially lowered death rates. Did some critical Viral genet-
ic event produce a 1918 Virus of remarkable pathogenicity
and then another critical genetic event occur soon after the
1918 pandemic to produce an attenuated H1N1 Virus?

In 1995, a scientiﬁc team identiﬁed archival inﬂuenza
autopsy materials collected in the autumn of 1918 and
began the slow process of sequencing small Viral RNA
fragments to determine the genomic structure of the
causative inﬂuenza Virus (10). These efforts have now
determined the complete genomic sequence of 1 Virus and
partial sequences from 4 others. The primary data from the
above studies (11717) and a number of reviews covering
different aspects of the 1918 pandemic have recently been
published ([8720) and conﬁrm that the 1918 Virus is the
likely ancestor of all 4 of the human and swine H1N1 and
H3N2 lineages, as well as the “extinct” H2N2 lineage. No
known mutations correlated with high pathogenicity in
other human or animal inﬂuenza Viruses have been found
in the 1918 genome, but ongoing studies to map Virulence
factors are yielding interesting results. The 1918 sequence
data, however, leave unanswered questions about the ori-
gin of the Virus (19) and about the epidemiology of the
pandemic.

When and Where Did the 1918 Inﬂuenza
Pandemic Arise?

Before and after 1918, most inﬂuenza pandemics
developed in Asia and spread from there to the rest of the
world. Confounding deﬁnite assignment of a geographic
point of origin, the 1918 pandemic spread more or less
simultaneously in 3 distinct waves during an z12-month
period in 191871919, in Europe, Asia, and North America
(the ﬁrst wave was best described in the United States in
March 1918). Historical and epidemiologic data are inade-
quate to identify the geographic origin of the Virus (21),
and recent phylogenetic analysis of the 1918 Viral genome
does not place the Virus in any geographic context ([9).

Although in 1918 inﬂuenza was not a nationally
reportable disease and diagnostic criteria for inﬂuenza and
pneumonia were vague, death rates from inﬂuenza and
pneumonia in the United States had risen sharply in 1915
and 1916 because of a major respiratory disease epidemic
beginning in December 1915 (22). Death rates then dipped
slightly in 1917. The ﬁrst pandemic inﬂuenza wave
appeared in the spring of 1918, followed in rapid succes-
sion by much more fatal second and third waves in the fall
and winter of 191871919, respectively (Figure 1). Is it pos-
sible that a poorly-adapted H1N1 Virus was already begin-
ning to spread in 1915, causing some serious illnesses but
not yet sufﬁciently ﬁt to initiate a pandemic? Data consis-
tent with this possibility were reported at the time from
European military camps (23), but a counter argument is
that if a strain with a new hemagglutinin (HA) was caus-
ing enough illness to affect the US national death rates
from pneumonia and inﬂuenza, it should have caused a
pandemic sooner, and when it eventually did, in 1918,
many people should have been immune or at least partial-
ly immunoprotected. “Herald” events in 1915, 1916, and
possibly even in early 1918, if they occurred, would be dif-
ﬁcult to identify.

The 1918 inﬂuenza pandemic had another unique fea-
ture, the simultaneous (or nearly simultaneous) infection
of humans and swine. The Virus of the 1918 pandemic like-
ly expressed an antigenically novel subtype to which most
humans and swine were immunologically naive in 1918
(12,20). Recently published sequence and phylogenetic
analyses suggest that the genes encoding the HA and neu-
raminidase (NA) surface proteins of the 1918 Virus were
derived from an avianlike inﬂuenza Virus shortly before
the start of the pandemic and that the precursor Virus had
not circulated widely in humans or swine in the few
decades before (12,15, 24). More recent analyses of the
other gene segments of the Virus also support this conclu-
sion. Regression analyses of human and swine inﬂuenza
sequences obtained from 1930 to the present place the ini-
tial circulation of the 1918 precursor Virus in humans at
approximately 191571918 (20). Thus, the precursor was
probably not circulating widely in humans until shortly
before 1918, nor did it appear to have jumped directly
from any species of bird studied to date (19). In summary,
its origin remains puzzling.

Were the 3 Waves in 1918—1 919 Caused
by the Same Virus? If So, How and Why?
Historical records since the 16th century suggest that
new inﬂuenza pandemics may appear at any time of year,
not necessarily in the familiar annual winter patterns of
interpandemic years, presumably because newly shifted
inﬂuenza Viruses behave differently when they ﬁnd a uni-
versal or highly susceptible human population. Thereafter,
confronted by the selection pressures of population immu-
nity, these pandemic Viruses begin to drift genetically and
eventually settle into a pattern of annual epidemic recur-
rences caused by the drifted Virus variants.

Figure 1. Three pandemic waves: weekly combined inﬂuenza and
pneumonia mortality, United Kingdom, 1918—1919 (21).

In the 1918-1919 pandemic, a ﬁrst or spring wave
began in March 1918 and spread unevenly through the
United States, Europe, and possibly Asia over the next 6
months (Figure 1). Illness rates were high, but death rates
in most locales were not appreciably above normal. A sec-
ond or fall wave spread globally from September to
November 1918 and was highly fatal. In many nations, a
third wave occurred in early 1919 (21). Clinical similari-
ties led contemporary observers to conclude initially that
they were observing the same disease in the successive
waves. The milder forms of illness in all 3 waves were
identical and typical of inﬂuenza seen in the 1889 pandem-
ic and in prior interpandemic years. In retrospect, even the
rapid progressions from uncomplicated inﬂuenza infec-
tions to fatal pneumonia, a hallmark of the 191871919 fall
and winter waves, had been noted in the relatively few
severe spring wave cases. The differences between the
waves thus seemed to be primarily in the much higher fre-
quency of complicated, severe, and fatal cases in the last 2
waves.

But 3 extensive pandemic waves of inﬂuenza within 1
year, occurring in rapid succession, with only the briefest
of quiescent intervals between them, was unprecedented.
The occurrence, and to some extent the severity, of recur-
rent annual outbreaks, are driven by Viral antigenic drift,
with an antigenic variant Virus emerging to become domi-
nant approximately every 2 to 3 years. Without such drift,
circulating human inﬂuenza Viruses would presumably
disappear once herd immunity had reached a critical
threshold at which further Virus spread was sufﬁciently
limited. The timing and spacing of inﬂuenza epidemics in
interpandemic years have been subjects of speculation for
decades. Factors believed to be responsible include partial
herd immunity limiting Virus spread in all but the most
favorable circumstances, which include lower environ-
mental temperatures and human nasal temperatures (bene-
ﬁcial to thermolabile Viruses such as inﬂuenza), optimal
humidity, increased crowding indoors, and imperfect ven-
tilation due to closed windows and suboptimal airﬂow.

However, such factors cannot explain the 3 pandemic
waves of 1918-1919, which occurred in the spring-sum-
mer, summer—fall, and winter (of the Northern
Hemisphere), respectively. The ﬁrst 2 waves occurred at a
time of year normally unfavorable to inﬂuenza Virus
spread. The second wave caused simultaneous outbreaks
in the Northern and Southern Hemispheres from
September to November. Furthermore, the interwave peri-
ods were so brief as to be almost undetectable in some
locales. Reconciling epidemiologically the steep drop in
cases in the ﬁrst and second waves with the sharp rises in
cases of the second and third waves is difﬁcult. Assuming
even transient postinfection immunity, how could suscep-
tible persons be too few to sustain transmission at 1 point,
and yet enough to start a new explosive pandemic wave a
few weeks later? Could the Virus have mutated profoundly
and almost simultaneously around the world, in the short
periods between the successive waves? Acquiring Viral
drift sufﬁcient to produce new inﬂuenza strains capable of
escaping population immunity is believed to take years of
global circulation, not weeks of local circulation. And hav-
ing occurred, such mutated Viruses normally take months
to spread around the world.

At the beginning of other “off season” inﬂuenza pan-
demics, successive distinct waves within a year have not
been reported. The 1889 pandemic, for example, began in
the late spring of 1889 and took several months to spread
throughout the world, peaking in northern Europe and the
United States late in 1889 or early in 1890. The second
recurrence peaked in late spring 1891 (more than a year
after the ﬁrst pandemic appearance) and the third in early
1892 (21 ). As was true for the 1918 pandemic, the second
1891 recurrence produced of the most deaths. The 3 recur-
rences in 1889-1892, however, were spread over >3 years,
in contrast to 191871919, when the sequential waves seen
in individual countries were typically compressed into
z879 months.

What gave the 1918 Virus the unprecedented ability to
generate rapidly successive pandemic waves is unclear.
Because the only 1918 pandemic Virus samples we have
yet identiﬁed are from second-wave patients ([6), nothing
can yet be said about whether the ﬁrst (spring) wave, or for
that matter, the third wave, represented circulation of the
same Virus or variants of it. Data from 1918 suggest that
persons infected in the second wave may have been pro-
tected from inﬂuenza in the third wave. But the few data
bearing on protection during the second and third waves
after infection in the ﬁrst wave are inconclusive and do lit-
tle to resolve the question of whether the ﬁrst wave was
caused by the same Virus or whether major genetic evolu-
tionary events were occurring even as the pandemic
exploded and progressed. Only inﬂuenza RNAipositive
human samples from before 1918, and from all 3 waves,
can answer this question.

What Was the Animal Host
Origin of the Pandemic Virus?

Viral sequence data now suggest that the entire 1918
Virus was novel to humans in, or shortly before, 1918, and
that it thus was not a reassortant Virus produced from old
existing strains that acquired 1 or more new genes, such as
those causing the 1957 and 1968 pandemics. On the con-
trary, the 1918 Virus appears to be an avianlike inﬂuenza
Virus derived in toto from an unknown source (17,19), as
its 8 genome segments are substantially different from
contemporary avian inﬂuenza genes. Inﬂuenza Virus gene
sequences from a number ofﬁxed specimens ofwild birds
collected circa 1918 show little difference from avian
Viruses isolated today, indicating that avian Viruses likely
undergo little antigenic change in their natural hosts even
over long periods (24,25).

For example, the 1918 nucleoprotein (NP) gene
sequence is similar to that ofviruses found in wild birds at
the amino acid level but very divergent at the nucleotide
level, which suggests considerable evolutionary distance
between the sources of the 1918 NP and of currently
sequenced NP genes in wild bird strains (13,19). One way
of looking at the evolutionary distance of genes is to com-
pare ratios of synonymous to nonsynonymous nucleotide
substitutions. A synonymous substitution represents a
silent change, a nucleotide change in a codon that does not
result in an amino acid replacement. A nonsynonymous
substitution is a nucleotide change in a codon that results
in an amino acid replacement. Generally, a Viral gene sub-
jected to immunologic drift pressure or adapting to a new
host exhibits a greater percentage of nonsynonymous
mutations, while a Virus under little selective pressure
accumulates mainly synonymous changes. Since little or
no selection pressure is exerted on synonymous changes,
they are thought to reﬂect evolutionary distance.

Because the 1918 gene segments have more synony-
mous changes from known sequences of wild bird strains
than expected, they are unlikely to have emerged directly
from an avian inﬂuenza Virus similar to those that have
been sequenced so far. This is especially apparent when
one examines the differences at 4-fold degenerate codons,
the subset of synonymous changes in which, at the third
codon position, any of the 4 possible nucleotides can be
substituted without changing the resulting amino acid. At
the same time, the 1918 sequences have too few amino acid
diﬁerences from those of wild-bird strains to have spent
many years adapting only in a human or swine intermedi-
ate host. One possible explanation is that these unusual
gene segments were acquired from a reservoir of inﬂuenza
Virus that has not yet been identiﬁed or sampled. All of
these ﬁndings beg the question: where did the 1918 Virus
come from?

In contrast to the genetic makeup of the 1918 pandem-
ic Virus, the novel gene segments of the reassorted 1957
and 1968 pandemic Viruses all originated in Eurasian avian
Viruses (26); both human Viruses arose by the same mech-
anismireassortment of a Eurasian wild waterfowl strain
with the previously circulating human H1N1 strain.
Proving the hypothesis that the Virus responsible for the
1918 pandemic had a markedly different origin requires
samples of human inﬂuenza strains circulating before
1918 and samples of inﬂuenza strains in the wild that more
closely resemble the 1918 sequences.

What Was the Biological Basis for
1918 Pandemic Virus Pathogenicity?

Sequence analysis alone does not oﬁer clues to the
pathogenicity of the 1918 Virus. A series of experiments
are under way to model Virulence in Vitro and in animal
models by using Viral constructs containing 1918 genes
produced by reverse genetics.

Inﬂuenza Virus infection requires binding of the HA
protein to sialic acid receptors on host cell surface. The HA
receptor-binding site conﬁguration is different for those
inﬂuenza Viruses adapted to infect birds and those adapted
to infect humans. Inﬂuenza Virus strains adapted to birds
preferentially bind sialic acid receptors with 01 (273) linked
sugars (27729). Human-adapted inﬂuenza Viruses are
thought to preferentially bind receptors with 01 (2%) link-
ages. The switch from this avian receptor conﬁguration
requires of the Virus only 1 amino acid change (30), and
the HAs of all 5 sequenced 1918 Viruses have this change,
which suggests that it could be a critical step in human host
adaptation. A second change that greatly augments Virus
binding to the human receptor may also occur, but only 3
of5 1918 HA sequences have it (16).

This means that at least 2 H1N1 receptor-binding vari-
ants cocirculated in 1918: 1 with high—afﬁnity binding to
the human receptor and 1 with mixed-afﬁnity binding to
both avian and human receptors. No geographic or chrono-
logic indication eXists to suggest that one of these variants
was the precursor of the other, nor are there consistent dif-
ferences between the case histories or histopathologic fea-
tures of the 5 patients infected with them. Whether the
Viruses were equally transmissible in 1918, whether they
had identical patterns of replication in the respiratory tree,
and whether one or both also circulated in the ﬁrst and
third pandemic waves, are unknown.
In a series of in Vivo experiments, recombinant inﬂuen-
za Viruses containing between 1 and 5 gene segments of
the 1918 Virus have been produced. Those constructs
bearing the 1918 HA and NA are all highly pathogenic in

mice (31). Furthermore, expression microarray analysis
performed on whole lung tissue of mice infected with the
1918 HA/NA recombinant showed increased upregulation
of genes involved in apoptosis, tissue injury, and oxidative
damage (32). These ﬁndings are unexpected because the
Viruses with the 1918 genes had not been adapted to mice;
control experiments in which mice were infected with
modern human Viruses showed little disease and limited
Viral replication. The lungs of animals infected with the
1918 HA/NA construct showed bronchial and alveolar
epithelial necrosis and a marked inﬂammatory inﬁltrate,
which suggests that the 1918 HA (and possibly the NA)
contain Virulence factors for mice. The Viral genotypic
basis of this pathogenicity is not yet mapped. Whether
pathogenicity in mice effectively models pathogenicity in
humans is unclear. The potential role of the other 1918 pro-
teins, singularly and in combination, is also unknown.
Experiments to map further the genetic basis of Virulence
of the 1918 Virus in various animal models are planned.
These experiments may help deﬁne the Viral component to
the unusual pathogenicity of the 1918 Virus but cannot
address whether speciﬁc host factors in 1918 accounted for
unique inﬂuenza mortality patterns.

Why Did the 1918 Virus Kill So Many Healthy
Young Ad ults?

The curve of inﬂuenza deaths by age at death has histor-
ically, for at least 150 years, been U-shaped (Figure 2),
exhibiting mortality peaks in the very young and the very
old, with a comparatively low frequency of deaths at all
ages in between. In contrast, age-speciﬁc death rates in the
1918 pandemic exhibited a distinct pattern that has not been
documented before or since: a “W—shaped” curve, similar to
the familiar U-shaped curve but with the addition of a third
(middle) distinct peak of deaths in young adults z20410
years of age. Inﬂuenza and pneumonia death rates for those
1534 years of age in 191871919, for example, were
20 times higher than in previous years (35). Overall, near-
ly half of the inﬂuenza—related deaths in the 1918 pandem-
ic were in young adults 20410 years of age, a phenomenon
unique to that pandemic year. The 1918 pandemic is also
unique among inﬂuenza pandemics in that absolute risk of
inﬂuenza death was higher in those <65 years of age than in
those >65; persons <65 years of age accounted for >99% of
all excess inﬂuenza—related deaths in 191871919. In com-
parison, the <65-year age group accounted for 36% of all
excess inﬂuenza—related deaths in the 1957 H2N2 pandem-
ic and 48% in the 1968 H3N2 pandemic (33).
A sharper perspective emerges when 1918 age-speciﬁc
inﬂuenza morbidity rates (21) are used to adj ust the W-
shaped mortality curve (Figure 3, panels, A, B, and C
[35,37]). Persons 65 years of age in 1918 had a dispro-
portionately high inﬂuenza incidence (Figure 3, panel A).

But even after adjusting age-speciﬁc deaths by age-specif—
ic clinical attack rates (Figure 3, panel B), a W—shaped
curve with a case-fatality peak in young adults remains and
is signiﬁcantly different from U-shaped age-speciﬁc case-
fatality curves typically seen in other inﬂuenza years, e.g.,
192871929 (Figure 3, panel C). Also, in 1918 those 5 to 14
years of age accounted for a disproportionate number of
inﬂuenza cases, but had a much lower death rate from
inﬂuenza and pneumonia than other age groups. To explain
this pattern, we must look beyond properties of the Virus to
host and environmental factors, possibly including
immunopathology (e.g., antibody-dependent infection
enhancement associated with prior Virus exposures [38])
and exposure to risk cofactors such as coinfecting agents,
medications, and environmental agents.

One theory that may partially explain these ﬁndings is
that the 1918 Virus had an intrinsically high Virulence, tem-
pered only in those patients who had been born before
1889, e.g., because of exposure to a then-circulating Virus
capable of providing partial immunoprotection against the
1918 Virus strain only in persons old enough (>35 years) to
have been infected during that prior era (35). But this the-
ory would present an additional paradox: an obscure pre-
cursor Virus that left no detectable trace today would have
had to have appeared and disappeared before 1889 and
then reappeared more than 3 decades later.

Epidemiologic data on rates of clinical inﬂuenza by
age, collected between 1900 and 1918, provide good evi-
dence for the emergence of an antigenically novel inﬂuen-
za Virus in 1918 (21). Jordan showed that from 1900 to
1917, the 5- to 15-year age group accounted for 11% of
total inﬂuenza cases, while the >65-year age group
accounted for 6 % of inﬂuenza cases. But in 1918, cases in

Figure 2. “U-” and “W—” shaped combined inﬂuenza and pneumo-
nia mortality, by age at death, per 100,000 persons in each age
group, United States, 1911—1918. Influenza- and pneumonia-
speciﬁc death rates are plotted for the interpandemic years
1911—1917 (dashed line) and for the pandemic year 1918 (solid
line) (33,34).

Incidence male per 1 .nao persunslage group
Mortality per 1.000 persunslige group

+ Case—fataiity rale 1918—1919 

Case fatalily par 100 persons ill wilh P&I pel age group

Figure 3. Influenza plus pneumonia (P&l) (combined) age-specific
incidence rates per 1,000 persons per age group (panel A), death
rates per 1,000 persons, ill and well combined (panel B), and
case-fatality rates (panel C, solid line), US Public Health Service
house-to-house surveys, 8 states, 1918 (36). A more typical curve
of age-specific influenza case-fatality (panel C, dotted line) is
taken from US Public Health Service surveys during 1928—1929
(37).

the 5 to 15-year-old group jumped to 25% of inﬂuenza
cases (compatible with exposure to an antigenically novel
Virus strain), while the >65-year age group only accounted
for 0.6% of the inﬂuenza cases, ﬁndings consistent with
previously acquired protective immunity caused by an
identical or closely related Viral protein to which older per-
sons had once been exposed. Mortality data are in accord.
In 1918, persons >75 years had lower inﬂuenza and

pneumonia case-fatality rates than they had during the
prepandemic period of 191171917. At the other end of the
age spectrum (Figure 2), a high proportion of deaths in
infancy and early childhood in 1918 mimics the age pat-
tern, if not the mortality rate, of other inﬂuenza pandemics.

Could a 1918-like Pandemic Appear Again?
If So, What Could We Do About It?

In its disease course and pathologic features, the 1918
pandemic was different in degree, but not in kind, from
previous and subsequent pandemics. Despite the extraordi-
nary number of global deaths, most inﬂuenza cases in
1918 (>95% in most locales in industrialized nations) were
mild and essentially indistinguishable from inﬂuenza cases
today. Furthermore, laboratory experiments with recombi-
nant inﬂuenza Viruses containing genes from the 1918
Virus suggest that the 1918 and 1918-like Viruses would be
as sensitive as other typical Virus strains to the Food and
Drug Administrationiapproved antiinﬂuenza drugs riman-
tadine and oseltamivir.

However, some characteristics of the 1918 pandemic
appear unique: most notably, death rates were 5 7 20 times
higher than expected. Clinically and pathologically, these
high death rates appear to be the result of several factors,
including a higher proportion of severe and complicated
infections of the respiratory tract, rather than involvement
of organ systems outside the normal range of the inﬂuenza
Virus. Also, the deaths were concentrated in an unusually
young age group. Finally, in 1918, 3 separate recurrences
of inﬂuenza followed each other with unusual rapidity,
resulting in 3 explosive pandemic waves within a year’s
time (Figure 1). Each of these unique characteristics may
reﬂect genetic features of the 1918 Virus, but understand-
ing them will also require examination of host and envi-
ronmental factors.

Until we can ascertain which of these factors gave rise
to the mortality patterns observed and learn more about the
formation of the pandemic, predictions are only educated
guesses. We can only conclude that since it happened once,
analogous conditions could lead to an equally devastating
pandemic.

Like the 1918 Virus, H5N1 is an avian Virus (39),
though a distantly related one. The evolutionary path that
led to pandemic emergence in 1918 is entirely unknown,
but it appears to be different in many respects from the cur-
rent situation with H5N1. There are no historical data,
either in 1918 or in any other pandemic, for establishing
that a pandemic “precursor” Virus caused a highly patho-
genic outbreak in domestic poultry, and no highly patho-
genic avian inﬂuenza (HPAI) Virus, including H5N1 and a
number of others, has ever been known to cause a major
human epidemic, let alone a pandemic. While data bearing
on inﬂuenza Virus human cell adaptation (e.g., receptor
binding) are beginning to be understood at the molecular
level, the basis for Viral adaptation to efﬁcient human-to-
human spread, the chief prerequisite for pandemic emer-
gence, is unknown for any inﬂuenza Virus. The 1918 Virus
acquired this trait, but we do not know how, and we cur-
rently have no way of knowing whether H5N1 Viruses are
now in a parallel process of acquiring human-to-human
transmissibility. Despite an explosion of data on the 1918
Virus during the past decade, we are not much closer to
understanding pandemic emergence in 2006 than we were
in understanding the risk of H1N1 “swine ﬂu” emergence
in 1976.

Even with modern antiviral and antibacterial drugs,
vaccines, and prevention knowledge, the return of a pan-
demic Virus equivalent in pathogenicity to the Virus of
1918 would likely kill >100 million people worldwide. A
pandemic Virus with the (alleged) pathogenic potential of
some recent H5N1 outbreaks could cause substantially
more deaths.

Whether because of Viral, host or environmental fac-
tors, the 1918 Virus causing the ﬁrst or ‘spring’ wave was
not associated with the exceptional pathogenicity of the
second (fall) and third (winter) waves. Identiﬁcation of an
inﬂuenza RNA-positive case from the ﬁrst wave could
point to a genetic basis for Virulence by allowing differ-
ences in Viral sequences to be highlighted. Identiﬁcation of
pre-1918 human inﬂuenza RNA samples would help us
understand the timing of emergence of the 1918 Virus.
Surveillance and genomic sequencing of large numbers of
animal inﬂuenza Viruses will help us understand the genet-
ic basis of host adaptation and the extent of the natural
reservoir of inﬂuenza Viruses. Understanding inﬂuenza
pandemics in general requires understanding the 1918 pan-
demic in all its historical, epidemiologic, and biologic
aspects.

Dr Taubenberger is chair of the Department of Molecular
Pathology at the Armed Forces Institute of Pathology, Rockville,
Maryland. His research interests include the molecular patho-
physiology and evolution of inﬂuenza Viruses.

Dr Morens is an epidemiologist with a long-standing inter-
est in emerging infectious diseases, Virology, tropical medicine,
and medical history. Since 1999, he has worked at the National
Institute of Allergy and Infectious Diseases.

References

1. Frost WH. Statistics of inﬂuenza morbidity. Public Health Rep.
19203558497.
2. Bumet F, Clark E. Inﬂuenza: a survey ofthe last 50 years in the light
of modern work on the Virus of epidemic inﬂuenza. Melbourne:
MacMillan; 1942.
3. Marks G, Beatty WK. Epidemics. New York: Scribners, 1976.
4. Rosenau MJ, Last JM. Maxcy-Rosenau preventative medicine and
public health. New York: Appleton-Century-Crofts; 1980.
5. Crosby A. America’s forgotten pandemic. Cambridge (UK):
Cambridge University Press;1989.
6. Patterson KD, Pyle GF. The geography and mortality of the 1918
influenza pandemic. Bull Hist Med. 1991;65:4–21.
7. Johnson NPAS, Mueller J. Updating the accounts: global mortality of
the 1918–1920 “Spanish” influenza pandemic. Bull Hist Med
2002;76:105–15.
8. Shope RE. The incidence of neutralizing antibodies for swine
influenza virus in the sera of human beings of different ages. J Exp
Med. 1936;63:669–84.
9. Kendal AP, Noble GR, Skehel JJ, Dowdle WR. Antigenic similarity
of influenza A (H1N1) viruses from epidemics in 1977–1978 to
“Scandinavian” strains isolated in epidemics of 1950–1951. Virology.
1978;89:632–6.
10. Taubenberger JK, Reid AH, Krafft AE, Bijwaard KE, Fanning TG.
Initial genetic characterization of the 1918 “Spanish” influenza virus.
Science. 1997;275:1793–6.
11. Basler CF, Reid AH, Dybing JK, Janczewski TA, Fanning TG, Zheng
H, et al. Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses
bearing the 1918 NS genes. Proc Natl Acad Sci U S A
2001;98:2746–51.
12. Reid AH, Fanning TG, Hultin JV, Taubenberger JK. Origin and evolution of the 1918 “Spanish” influenza virus hemagglutinin gene.
Proc Natl Acad Sci U S A 1999;96:1651–6.
13. Reid AH, Fanning TG, Janczewski TA, Lourens RM, and
Taubenberger JK. Novel origin of the 1918 pandemic influenza virus
nucleoprotein gene segment. J Virol. 2004;78:12462–70.
14. Reid AH, Fanning TG, Janczewski TA, McCall S, Taubenberger JK.
Characterization of the 1918 “Spanish” influenza virus matrix gene
segment. J Virol. 2002;76:10717–23.
15. Reid AH, Fanning TG, Janczewski TA, Taubenberger JK.
Characterization of the 1918 “Spanish” influenza virus neuraminidase gene. Proc Natl Acad Sci U S A 2000;97:6785–90.
16. Reid AH, Janczewski TA, Lourens RM, Elliot AJ, Daniels RS, Berry
CL, et al. 1918 influenza pandemic caused by highly conserved viruses with two receptor-binding variants. Emerg Infect Dis.
2003;9:1249–53.
17. Taubenberger JK, Reid AH, Lourens RM, Wang R, Jin G, Fanning
TG. Characterization of the 1918 influenza virus polymerase genes.
Nature. 2005;437:889–93.
18. Reid AH, Taubenberger JK. The 1918 flu and other influenza pandemics: “over there” and back again. Lab Invest. 1999;79:95–101.
19. Reid AH, Taubenberger JK, Fanning TG. Evidence of an absence: the
genetic origins of the 1918 pandemic influenza virus. Nat Rev
Microbiol. 2004;2:909–14.
20. Taubenberger JK, Reid AH, Fanning TG. The 1918 influenza virus: a
killer comes into view. Virology. 2000;274:241–5.
21. Jordan E. Epidemic influenza: a survey. Chicago: American Medical
Association, 1927.
22. Capps J, Moody A. The recent epidemic of grip. JAMA.
1916;67:1349–50.
33. Oxford JS, Sefton A, Jackson R, Innes W, Daniels RS, Johnson NP.
World War I may have allowed the emergence of “Spanish” influenza. Lancet Infect Dis. 2002;2:111–4.
24. Fanning TG, Slemons RD, Reid AH, Janczewski TA, Dean J,
Taubenberger JK. 1917 avian influenza virus sequences suggest that
the 1918 pandemic virus did not acquire its hemagglutinin directly
from birds. J Virol. 2002;76:7860–2.
25. Reid AH, Fanning TG, Slemons RD, Janczewski TA, Dean J,
Taubenberger JK. Relationship of pre-1918 avian influenza HA and
NP sequences to subsequent avian influenza strains. Avian Dis.
2003;47:921–5.
26. Bean W, Schell M, Katz J, Kawaoka Y, Naeve C, Gorman O, et al.
Evolution of the H3 influenza virus hemagglutinin from human and
nonhuman hosts. J Virol. 1992;66:1129–38.
27. Weis W, Brown JH, Cusack S, Paulson JC, Skehel JJ, Wiley DC.
Structure of the influenza virus haemagglutinin complexed with its
receptor, sialic acid. Nature. 1988;333:426–31.
28. Gambaryan AS, Tuzikov AB, Piskarev VE, Yamnikova SS, Lvov DK,
Robertson JS, et al. Specification of receptor-binding phenotypes of
influenza virus isolates from different hosts using synthetic sialylglycopolymers: non-egg-adapted human H1 and H3 influenza A and
influenza B viruses share a common high binding affinity for 6′-sialyl(N-acetyllactosamine). Virology. 1997;232: 345–50.
29. Matrosovich M, Gambaryan A, Teneberg S, Piskarev VE, Yamnikova
SS, Lvov DK, et al. Avian influenza A viruses differ from human
viruses by recognition of sialyloigosaccharides and gangliosides and
by a higher conservation of the HA receptor-binding site. Virology.
1997;233:224–34.
30. Glaser L, Stevens J, Zamarin D, Wilson IA, Garcia-Sastre A, Tumpey
TM, et al. A single amino acid substitution in the 1918 influenza virus
hemagglutinin changes the receptor binding specificity. J Virol.
2005;79:11533–6.
31. Kobasa D, Takada A, Shinya K, Hatta M, Halfmann P, Theriault S, et
al. Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus. Nature. 2004;431:703–7.
32. Kash JC, Basler CF, Garcia-Sastre A, Carter V, Billharz R, Swayne
DE, et al. Global host immune response: pathogenesis and transcriptional profiling of type A influenza viruses expressing the hemagglutinin and neuraminidase genes from the 1918 pandemic virus. J Virol.
2004;78:9499–511.
33. Grove RD, Hetzel AM. Vital statistics rates in the United States:
1940–1960. Washington: US Government Printing Office, 1968.
34. Linder FE, Grove RD. Vital statistics rates in the United States:
1900–1940. Washington: US Government Printing Office, 1943.
35. Simonsen L, Clarke MJ, Schonberger LB, Arden NH, Cox NJ,
Fukuda K. Pandemic versus epidemic influenza mortality: a pattern
of changing age distribution. J Infect Dis 1998;178:53–60.
36. Frost WH. The epidemiology of influenza. Public Health Rep.
1919;34:1823–61.
37. Collins SD. Age and sex incidence of influenza and pneumonia morbidity and mortality in the epidemic of 1928-1929 with comparative
data for the epidemic of 1918–1919. Public Health Rep.
1931;46:1909–37.
38. Majde JA. Influenza: Learn from the past. ASM News. 1996;62:514.
39. Peiris JS, Yu WC, Leung CW, Cheung CY, Ng WF, Nicholls JM, et al.
Re-emergence of fatal human influenza A subtype H5N1 disease.
Lancet. 2004;363:617–9.

Address for correspondence: Jeffery K. Taubenberger, Department of
Molecular Pathology, Armed Forces Institute of Pathology, 1413
Research Blvd, Bldg 101, Rm 1057, Rockville, MD 20850-3125, USA;
fax. 301-295-9507; email: taubenberger@afip.osd.mil

The opinions expressed by authors contributing to this journal do
not necessarily reflect the opinions of the Centers for Disease
Control and Prevention or the institutions with which the authors
are affiliated.

Question: What are the circumstances that promote the spread of influenza virus?
Answer:  lower environ-
mental temperatures and human nasal temperatures (bene-
ﬁcial to thermolabile Viruses such as inﬂuenza), optimal
humidity, increased crowding indoors, and imperfect ven-
tilation due to closed windows and suboptimal airﬂow