What you need to know about Influenza Virus and Immunity!

[Guest guest]

There is so much BAD information circulating about the flu virus presence today.

Here's just one article explaining some history of flu epidemics. It's very

important to understand the 1918 flu epidemic to put this current outbreak into

perspective. Seems like most of the TV and media experts can't study history!

Will Winter

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

1918 Influenza: the Mother of All Pandemics

Jeffery K. Taubenberger* and M. Morens†

*Armed Forces Institute of Pathology, Rockville, land, USA; and †National

Institutes of Health, Bethesda, land, USA

S

The " Spanish " influenza pandemic of 1918–1919, which caused & #8776;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 tissues. 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! " cried Alice

Carroll, Alice's Adventures in Wonderland, 1865

An estimated one third of the world's population (or & #8776;500 million persons)

were infected and had clinically apparent illnesses (1,2) during the 1918–1919

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 & #8776;50 million (5–7) and were arguably as high as 100

million (7).

The impact of this pandemic was not limited to 1918–1919. All influenza A

pandemics since that time, and indeed almost all cases of influenza A worldwide

(excepting 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 incorporated avian influenza genes that code

for novel surface 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 descendants of 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 lineage, 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 uncommonly infect humans, and the human H1N1 and H3N2

lineages have both been associated with substantially lower rates of illness and

death than the virus of 1918. In fact, current 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 substantially

lowered death rates. Did some critical viral genetic event produce a 1918 virus

of remarkable pathogenicity and then other 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 (11–17) and a number of reviews covering different aspects of

the 1918 pandemic have recently been published (18–20) 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 origin 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 & #8776;12-month period in 1918–1919, in Europe,

Asia, and North America (the first wave was best described in the United States

in March 1918). Historical and epidemiologic data are inadequate 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 (19).

Figure 1

Click to view enlarged image

Figure 1. Three pandemic waves: weekly combined influenza and pneumonia

mortality, United Kingdom, 1918–1919 (21).

Figure 2

Click to view enlarged image

Figure 2. " U- " and " W- " shaped combined influenza and pneumonia mortality, by

age at death, per 100,000 persons...

Figure 3

Click to view enlarged image

Figure 3. Influenza plus pneumonia (combined) age-specific incidence rates per

1,000 persons per age group...

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 succession by much more fatal

second and third waves in the fall and winter of 1918–1919, respectively (Figure

1). Is it possible that a poorly-adapted H1N1 virus was already beginning to

spread in 1915, causing some serious illnesses but not yet sufficiently fit to

initiate a pandemic? Data consistent 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 causing 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 partially immunoprotected. " Herald " events in 1915,

1916, and possibly even in early 1918, if they occurred, would be difficult to

identify.

The 1918 influenza pandemic had another unique feature, the simultaneous (or

nearly simultaneous) infection of humans and swine. The virus of the 1918

pandemic likely 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

neuraminidase (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 conclusion. Regression analyses of human and swine influenza

sequences obtained from 1930 to the present place the initial circulation of the

1918 precursor virus in humans at approximately 1915–1918 (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 1918–1919 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 universal or highly susceptible

human population. Thereafter, confronted by the selection pressures of

population immunity, these pandemic viruses begin to drift genetically and

eventually settle into a pattern of annual epidemic recurrences caused by the

drifted virus variants.

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 second 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 similarities 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 pandemic and in prior interpandemic years. In

retrospect, even the rapid progressions from uncomplicated influenza infections

to fatal pneumonia, a hallmark of the 1918–1919 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 frequency 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 recurrent

annual outbreaks, are driven by viral antigenic drift, with an antigenic variant

virus emerging to become dominant 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 environmental

temperatures and human nasal temperatures (beneficial to thermolabile viruses

such as influenza), optimal humidity, increased crowding indoors, and imperfect

ventilation due to closed windows and suboptimal airflow.

However, such factors cannot explain the 3 pandemic waves of 1918–1919, which

occurred in the spring-summer, 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 periods 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 susceptible

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 having

occurred, such mutated viruses normally take months to spread around the world.

At the beginning of other " off season " influenza pandemics, 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 recurrences in 1889–1892, however, were spread over >3 years, in

contrast to 1918–1919, when the sequential waves seen in individual countries

were typically compressed into & #8776;8–9 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 (16), 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 protected

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 little to resolve the question of whether the first wave was caused by

the same virus or whether major genetic evolutionary events were occurring even

as the pandemic exploded and progressed. Only influenza RNA–positive 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 contrary, 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

of fixed specimens of wild 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 of

viruses 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 compare

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 subjected 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 synonymous 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 differences from those of wild-bird strains to have spent many years

adapting only in a human or swine intermediate 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 pandemic 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

mechanism—reassortment 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 offer 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 & #945; (2–3) linked sugars (27–29). Human-adapted

influenza viruses are thought to preferentially bind receptors with & #945; (2–6)

linkages. The switch from this avian receptor configuration requires of the

virus only 1 amino acid change, 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 of 5 1918 HA sequences have it (16).

This means that at least 2 H1N1 receptor-binding variants 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 chronologic

indication exists to suggest that one of these variants was the precursor of the

other, nor are there consistent differences between the case histories or

histopathologic features 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 influenza 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 proteins, 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 Adults?

The curve of influenza deaths by age at death has historically, 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 & #8776;20–40 years of age.

Influenza and pneumonia death rates for those 15–34 years of age in 1918–1919,

for example, were >20 times higher than in previous years (35). Overall, nearly

half of the influenza-related deaths in the 1918 pandemic were in young adults

20–40 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 1918–1919.

In comparison, the <65-year age group accounted for 36% of all excess

influenza-related deaths in the 1957 H2N2 pandemic and 48% in the 1968 H3N2

pandemic (33).

A sharper perspective emerges when 1918 age-specific influenza morbidity rates

(21) are used to adjust the W-shaped mortality curve (Figure 3, panels, A, B,

and C [35,37]). Persons <35 years of age in 1918 had a disproportionately high

influenza incidence (Figure 3, panel A). But even after adjusting age-specific

deaths by age-specific clinical attack rates (Figure 3, panel , 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., 1928–1929 (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, tempered 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 theory would present an additional paradox: an obscure precursor 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 evidence for the emergence of an antigenically novel

influenza 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 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 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 persons 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 1911–1917. 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 pattern, 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

extraordinary 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 recombinant 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 Administration–approved antiinfluenza

drugs rimantadine and oseltamivir.

However, some characteristics of the 1918 pandemic appear unique: most notably,

death rates were 5–20 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 understanding them will also require examination

of host and environmental 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 current

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 pathogenic outbreak in domestic poultry, and no highly pathogenic 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 emergence,

is unknown for any influenza virus. The 1918 virus acquired this trait, but we

do not know how, and we currently 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 pandemic 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 factors, 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 differences 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 genetic

basis of host adaptation and the extent of the natural reservoir of influenza

viruses. Understanding influenza pandemics in general requires understanding the

1918 pandemic 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, land. His research interests

include the molecular pathophysiology and evolution of influenza viruses.

Dr Morens is an epidemiologist with a long-standing interest in emerging

infectious diseases, virology, tropical medicine, and medical history. Since

1999, he has worked at the National Institute of Allergy and Infectious

Diseases.

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Suggested citation for this article:

Taubenberger JK, Morens DM. 1918 influenza: the mother of all pandemics. Emerg

Infect Dis [serial on the Internet]. 2006 Jan [date cited]. Available from

http://www.cdc.gov/ncidod/EID/vol12no01/05-0979.htm

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