White paper by John Barry on novel H1N1

[wotan]

White paper authored by Barry:

Massachusetts Institute of Technology
Engineering Systems Division
Working Paper Series
ESD-WP-2009-07

WHITE PAPER ON NOVEL H1N1

PREPARED FOR THE
MIT CENTER FOR ENGINEERING SYSTEMS FUNDAMENTALS

John M. Barry
Distinguished Scholar, Tulane University Center for Bioenvironmental Research
Member, Advisory Board, MIT Center for Engineering Systems Fundamentals
jvbarry@aol.com
July 2009
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White Paper On Novel H1N1
Prepared for the MIT Center for Engineering Systems Fundamentals
John M. Barry
Distinguished Scholar, Tulane University Center for Bioenvironmental Research
Member, Advisory Board, MIT Center for Engineering Systems Fundamentals
jvbarry@aol.com

Note: This paper’s purpose is to provide a relatively in-depth understanding of the
problem and the issues, now and as they change. Therefore, it omits an executive
summary.

Contents:
1. Background on the Influenza Virus
2. The Epidemiological Picture and Cross-Protection as of Late June 2009
3. Antivirals and Vaccines
4. Recent Non-Pharmaceutical Interventions and International Actions
5. Communication
6. The Past as Prologue: Waves and Patterns from Past Pandemics
7. The Future of Novel H1N1
8. Acknowledgements

1. Background on the Influenza Virus:

Influenza is an RNA virus with eight genes on a segmented genome. There are three
types of influenza viruses: A, B, and C. Although B can cause human disease, only
influenza A viruses threaten pandemics. The virus is identified by its most visible
antigens, hemagglutinin – H1 to H16 – and neuraminidase-N1 to N9, which are outside
the viral envelope and allow the virus to bind to and then escape a cell.

Birds are the natural reservoir for all influenza viruses, and in birds the virus is generally
a stable and benign intestinal virus. On occasion, highly pathogenic influenza viruses
such as A/H5N1 or just H5N1, emerge in birds. (The “A/” will be dropped in further
references to the virus; all subsequent viruses mentioned are influenza A.)
Influenza can jump species in two ways. One is a function of its extraordinarily rapid
mutation rate. About 8 hours after a single influenza virus infects a single cell, that single
cell will produce between 100,000 and 1,000,000 new virus particles, but it mutates so
rapidly that only 1 percent of these are actual viruses able to infect a cell and replicate.
That translates into between 1,000 and 10,000 functioning viruses, each of which is
different, produced by a single cell. All possible permutations of the virus are produced,
and that mutation rate allows an entire virus to jump from one species to another, as
happened with the original H1N1 virus of 1918 and as H5N1 threatens to do.

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Influenza can also jump species because of its “segmented genome” – that is, its genes
stand alone, individually. Genes of nearly all other organisms run continuously along a
strand of nucleic acid. This attribute allows influenza to jump species by “reassorting” its
genes, which occurs when different influenza viruses infect the same cell and all the
genes become shuffled together, much like a deck of cards, and a new virus is dealt out of
the cell with genes from each virus. The 1957 (H2N2) and 1968 (H3N2) pandemics were
caused by “reassortant” viruses; in both cases, the new viruses joined new genes to those
of the human virus that was already circulating.

Both seasonal and pandemic influenza usually burns through a community in 6-8 weeks.
The chief differences are morbidity and mortality. Seasonal flu infects about 10 percent
of the population. Pandemic flu, in contrast, can be expected to infect from 15 to 40
percent – and occasionally even more – because it presents the human population with
new antigens that the human immune system does not recognize. There have been at least
10 pandemics in the last 300 years, and probably many more going much further back in
history. All pandemics about which we know in any detail – 1889, 1918, 1957, and
1968 – have been caused by H1, H2, or H3 viruses. (Some virologists speculate that only
viruses with these three hemagglutinin can cause human pandemics; others dismiss this
speculation since it is based on so few samples.)

The influenza virus survives outside the body on hard surfaces, such as a doorknob, for
many hours at least, and sometimes for a day or longer-- in some circumstances, much
longer. It also survives best in low humidity and low temperatures; this fact, coupled with
human social behavior, helps account for the tendency of influenza to be more common
in cold weather. Compared to warmer times of the year, winter is when people are more
likely to crowd together indoors, in spaces where there is less circulating air (e.g., at a
basketball game rather than a baseball game). Nevertheless, influenza also can achieve
high morbidity in tropical countries with consistently higher temperatures.

Influenza infects a wide range of mammals, including dogs, cats, tigers, horses, seals, and
so on. In 1918, the original H1N1 virus – after first infecting humans – jumped to pigs,
and subsequently was reported in many wild animals, including moose. H1N1 has
survived in pigs ever since. Pigs have receptors for both avian and human influenza
viruses – they have long been referred to as “mixing bowls” – and therefore are
considered a likely path for avian and other influenza viruses to enter the human
population. Since 1998, triple reassortant viruses with genes derived from birds, humans,
and swine have caused illness in pigs, along with viruses descended from the 1918 H1N1
virus.

A 2007 survey found 37 additional reports in medical literature of swine influenza in
humans between 1958 and 2007. Between December 2005 and February 2009, 11 human
clinical cases caused by triple reassortant swine viruses were reported to CDC, 10 of
them being H1N1 viruses.

In 1976, an outbreak of so-called “swine flu” was completely contained within Fort Dix,
a U.S. Army base in New Jersey. It infected numerous soldiers, killed one, and resulted in
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13 clinical cases. Antibodies in blood showed that several hundred more soldiers were
exposed.

Since 1968, the dominant circulating influenza A virus has been H3N2, but for
approximately 30 years an H1N1 virus has co-circulated; existing vaccines against
seasonal influenza are designed to protect against H3N2, this older H1N1, and
influenza B. The novel H1N1 virus bears little resemblance beyond its name to the
currently circulating H1N1. The novel H1N1 which now threatens is a triple reassortant
of bird, human, and several different swine viruses with predecessors traced back to
1998. While the individual genes have all been seen before in other influenza viruses, the
present combination has not been seen.

In humans, influenza is generally limited to the respiratory tract, although in 1918
symptoms suggest it may have infected organs outside the respiratory system. H5N1 may
do so as well. Symptoms of novel H1N1 also suggest occasional abdominal infection;
symptoms are those common to influenza, plus diarrhea and vomiting in some cases.
These abdominal symptoms have occasioned concern that oral-fecal spread may be
possible with novel H1N1, which brings transmission through water into the picture – a
potential problem for the developing world. In birds, this transmission clearly occurs.

2. The Epidemiological Picture and Cross-Protection as of Late June
2009
Epidemiologists believe they have identified an index human case in Mexico dated
March 17, 2009, although other analysis (based on mutation rates) suggests the virus may
have begun to circulate in January 2009 and possibly as early as September 2008.
As of this writing, we do not have a good sense of R0 (the reproductive number, i.e., the
number of cases caused by one case). An R0 less than 1 means an outbreak will die out.
R0 for seasonal influenza ranges widely, with a mean of 1.3, although in 1951 – which
was not a pandemic virus, just a particularly bad seasonal one – R0 approached 2.0. As
R0 rises past 2.0, models that suggest non-pharmaceutical interventions (NPIs) could
mitigate morbidity or mortality become less useful, and an R0 over 3.0 makes them
useless. New work suggests the R0 in 1918 was well in excess of 2.0, and may have
approached 4.0.1

Estimates of R0 for novel H1N1 vary widely. On May 11, the World Health Organization
(WHO) announced that the disease seemed more infectious than seasonal influenza,
noting that while the secondary attack rate in households of seasonal flu is 5 to 15
percent, that rate for novel H1N1 was 22 to 33 percent. On May 20, the U.S. Centers for
Disease Control (CDC) contradicted this statement, asserting that attack rates
1 Andreasen, V, Viboud, C and Simonsen, L (2008), Epidemiologic characterization of the 1918 influenza
pandemic summer wave in Copenhagen: implications for pandemic control strategies, Journal of Infectious
Diseases 197(2), 270-8.

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approximated seasonal influenza. A third study put the R0 slightly higher than most
seasonal flu, at 1.4 to 1.6.2 A fourth study suggested an R0 range from 2.2 to 3.1,3 while a
fifth estimated R0 at 1.2.4

One problem is the case count, which is unknown. But we also do not know, for example,
the incubation period, which is a significant factor in an outbreak’s explosiveness and in
calculating the R0. Reasonable assumptions have been made that incubation is
comparable to seasonal influenza, but data from Spain suggests incubation is longer.5
Case mortality has been estimated from 0.1 percent – approximately the same as seasonal
influenza – to as high as 0.4 percent. However, a case fatality of even 0.1 percent for
those younger than age 65 represents a substantial increase in lethality in the non-elderly
population.

The number of cases worldwide is impossible to ascertain. In mid-May, when the official
count of confirmed U.S. cases was less than 5,000, CDC estimated 100,000 cases in the
United States. (On June 1, confirmed U.S. cases exceeded 10,000.) It was not surprisng
when Dr. Thomas Fleming, the public health director in Seattle and King County, said,
“We had widespread community illness before CDC posted a single confirmed case in
Seattle.”6 More recently, the New York City Health department estimated that cases
reached several hundred thousand in its jurisdiction.

Initial worldwide surveillance suggests that the virus has not spread nearly so widely in
other parts of the world as it has in the United States and Mexico. Although more than
70 countries had reported cases as of mid-June 2009, the confirmed case counts remain
less than 100 in roughly 80 percent of these countries. While there is significant underreporting
– Britain has been accused of under-reporting by a factor of 200-300 –there has,
nevertheless, been little sign around the world of truly explosive spread late June, in what
appears to be a first wave.

Two possibilities explain these figures: 1) R0 varies from country to country and from
setting to setting, probably due to many biological, social, and environmental factors;
2) the virus is still adapting to humans and has not yet reached maximum efficiency in
infecting people.

2 Fraser C, Donnelly CA, Cauchelmes S, Hanage WP, Van Kerkhove MD, Hollingsworth TD, et al.
Pandemic potential of a strain of influenza A (H1N1): early findings. Published 11 May 2009 on Science
Express. DOI: 10.1126/science.1176062. http://www.sciencemag.org/cgi/content/abstract/1176062
3 P Y Boëlle , P Bernillon, J C Desenclos, “A preliminary estimation of the reproduction ratio for new
influenza A(H1N1) from the outbreak in Mexico, March-April 2009,” Eurosurveillance, Volume 14, Issue
19, 14 May 2009
4 personal communication, Richard Larson, May 2009
5 Surveillance Group for New Influenza A(H1N1) Virus Investigation and Control in Spain. New influenza
A(H1N1) virus infections in Spain, April-May 2009. Euro Surveill . 2009; 14(19): p11=19209. Available
from: http://www.eurosurveillance.org/View...rticleId=19209
6Trust for America’s health report on early lessons, http://healthyamericans.org/assets/f...emic-flulesson.
pdf
5
Despite WHO’s delay in declaring “Stage 6,” a full-fledged pandemic, the technical
threshold for such a declaration was clearly passed by mid-May. Lack of flexibility in the
pandemic planning process, and the fact that plans failed to account either for a mild
pandemic or a mild first wave of a dangerous pandemic, explains WHO’s reluctance,
since Stage 6 would trigger certain responses – including shifting resources from
preparing vaccine for seasonal influenza to a vaccine for the pandemic strain – that may
not be appropriate for the current situation. Despite continued opposition to declaring
Stage 6, especially from Britain, WHO finally did so on June 11.

Based on ages of confirmed cases, it does seem that some cross-protection in older adults
exists. On May 22, CDC concluded that 64 percent of U.S. cases (and the United States
had more than half of all the world’s confirmed cases on that date) are ages 5 to 24.7 Only
1 percent of cases have occurred in people older than 65. These numbers reflect several
factors, such as that those over 65 are less likely to be exposed because of social habits.
But cross-protection is also a probable factor. Some 6 to 9 percent of unvaccinated adults
ages 18 to 64 showed antibody reactive against novel H1N1, while 33 percent of those
over 60 had antibody. (We recognize these numbers represent a shifting base; however,
that is the way CDC released the data.) It has not been established that the measured
antibody is sufficient to protect, but the epidemiology suggests that it is sufficient.
After vaccination with the trivalent seasonal flu, which includes a component of the
already-circulating H1N1 virus, 7 percent of adults ages 18 to 40, 25 percent of adults
ages 40 to 64, and 43 percent of those under age 60 had protective antibody against novel
H1N1.

There is also evidence that exposure to any influenza virus provides some crossprotection,
at least compared to a completely virgin population; children are much more
likely than adults not to have had any exposure to influenza.

3. Antivirals and Vaccines

As of this writing, H3N2 has shown some resistance to the neuraminadase inhibitors
oseltamivir and zanamivir (tamiflu and relenza), while previously circulating H1N1 has
shown nearly universal resistance to those drugs. So far novel H1N1 has shown
resistance to these drugs only in isolated cases. How rapidly resistance spreads is of
course the crucial factor in how useful these antivirals will be; it is already resistant to the
older antivirals rimantidine and amantadine.

In the United States, the Department of Health and Human Services (HHS) had
stockpiled 50 million courses of treatment of neuraminidase inhibitors, and states had
stockpiled another 23 million courses – enough to cover 25 percent of the U.S.
population. Early in this outbreak, when there was widespread fear that this virus might
be virulent, HHS released 25 percent of its stockpile to states and contracted for
replacement. European states have stockpiles for larger proportions of their populations.
7 MMWR, May 22, 2009 / 58(19);521-524
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The United States also shipped antivirals to Mexico, which was an important diplomatic
statement and precedent. (Japan and China also quickly donated masks, gloves, and
gowns; in the latter case, this may have been to make amends for aggressive actions
against Mexican nationals in China.)

Britain has used Tamiflu not only on cases but on those exposed to cases, in an effort to
snuff out the outbreak. This action is absurd, because the virus is too well established for
the strategy to succeed – and even in the extraordinarily unlikely event that Britain could
snuff out the initial outbreak, the virus would only reenter later. It is also dangerous,
because it increases the possibility of the virus developing resistance without any benefit.
As of mid-June, no resistance to neuraminidase inhibitors has been reported for novel
H1N1. But more than 90 percent of samples of both H3N2 and previously circulating
H1N1 have developed resistance.

HHS, WHO, and European governments have signed contracts with several vaccine
manufacturers using different technologies to produce vaccine against novel H1N1, and
seed virus has been provided. Traditional egg-based production will supply the
overwhelming bulk of the vaccine, cell-based production will supply some, and contracts
for “virus-like particles,” monoclonal antibodies, and other technologies have also been
signed.

In a best-case scenario, the virus will require no more antigen than a seasonal influenza
vaccine, only a single dose will be needed to provide protection, and adjuvant will cut in
half the amount of antigen needed. If all that occurs, sufficient vaccine could be available
to protect the entire U.S. population by October 2009. In a worst-case scenario, the virus
will grow more slowly than anticipated, more antigen will be required to generate an
immune response than for seasonal influenza, and – since this is a new virus – two doses
will be required as well. In that case, it could take a year or more to produce enough
vaccine for the entire population.

Only 31 percent of the vaccine needed is produced in the United States. This raises the
question of whether foreign governments would block the export of vaccine until their
own populations are fully protected. The more virulent the virus, the more likely it is that
foreign governments will intervene.

The same supply question applies to the developing world: how soon will advanced
countries export vaccine?

The final point on vaccine is that for most diseases, vaccines approach 100 percent
effectiveness. For influenza, however, a good vaccine is 70-percent effective and a great
vaccine is 90-percent effective. In the 2007-2008 flu season, the vaccine was only
44 percent effective. Producing a highly effective vaccine for a new virus, which may be
less stable than seasonal influenza, should be more difficult than for ordinary influenza.

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4. Recent Non-Pharmaceutical Interventions and International Actions

Several countries have undertaken various non-pharmaceutical interventions. These
include, but are not limited to school closings, airport screening of passengers, quarantine
of Mexicans visiting foreign countries, and quarantine of people returning from Mexico.
In the United States, there was initial pressure to close the border with Mexico from
people who with understanding of either the impact of such closing or its ineffectiveness.
In the United States, the decision to close schools is one of the most difficult for policy
makers, given the burden it imposes on working parents, employers, and children who get
their best meals in schools. Prior to this outbreak, CDC had determined that in a serious
pandemic it would recommend school closings. On Friday, May 1, CDC pushed far past
its own guidelines for a pandemic of the mildness that novel H1N1 had by then
demonstrated, and took the extreme position that a school with a single case should close
for 14 days, and that local officials should consider closing all neighboring and feeder
schools. This guidance was apparently designed to snuff out the outbreak entirely.
Recognizing the impossibility of this task, CDC reversed itself a few days later and
simultaneously declared that closing schools was not effective in stopping spread.
Since then, local officials have occasionally closed schools. In New York City, and
probably elsewhere, there has been political pressure to do so more aggressively.
Mayor Bloomberg finally responded by saying it might make sense to become exposed to
this virus because the attack was mild and it likely provided immunity against later
attacks. (The widow of an assistant principal who died from novel H1N1 attacked the
mayor for this statement.)

The question of whether school closing is worthwhile remains open. Models suggest that
it is, but for closing to be most effective it must be sustained for at least several weeks
and children cannot congregate in other venues. Both of these requirements are
problematic, and the press has reported on the difficulties of keeping children away from
each other during closures. It is unclear how much these problems undermine whatever
benefits may accrue from closure.

Seasonal influenza outbreaks, the 1957 pandemic, and experience this spring do seem to
demonstrate that schools are a major vehicle of spread. But there is solid contradictory
evidence from 1889, 1918, and 1920 that schools did not play a significant role in
transmitting infection. One speculative explanation for this contradictory data is that in
1918 and 1920, immune systems of adults and children were equal (we do not know
enough about 1889 to make any assertions). Because the 1918 virus came directly from
birds, no one had been previously exposed to it, and by 1920 everyone old enough for
school had been exposed. In seasonal flu, 1957, 1968, and today’s H1N1, a reassortant
virus caused illness. Adults therefore had some protection, while children had little or
none, making school transmission much more important.

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Whether this is the explanation, these data do support the conclusion that in some
outbreaks schools play an important role in transmission, while in others they do not.
This obviously makes contemporaneous analysis of data important. At any rate, data from
recent school closings are now being evaluated for their effectiveness and may yet yield
an answer at least for novel H1N1.

As far as other NPIs in the United States, advice to wash hands came seemingly every
five minutes on television. Messages regarding cough etiquette and for the ill to stay at
home did not come through nearly as well.

In Mexico City and in the neighboring state, all schools were closed on April 24. Two
days later, on April 26, the president of Mexico advised people to wear masks on public
transport, exercise cough etiquette, avoid crowded places, and wash their hands. Soldiers
handed out 6 million masks to the general public. In Mexico City, taxi and bus drivers
were required to wear masks and gloves (the latter order being nonsensical, since the
gloves would require constant changing).

One study concluded that mask usage on public transportation peaked at 65 percent for a
three-day period (the peak was April 29) and then declined to below 27 percent by May
4.8 This decline occurred even while the government was taking the extreme measure,
from May 1 to May 5, of closing all non-essential business and services in Mexico City.
Whether masks do any good, the decline in compliance does not portend well for
sustaining an NPI.

It is not clear whether these measures had any effect. Every model, including those which
conclude that social distancing measures could mitigate an outbreak, has also concluded
an intervention has to come very early if it is to succeed. By the time Mexico City closed
businesses (May 1 to May 5), the virus had already become widely distributed – in fact,
the epidemic had just peaked and was already waning. In addition, five days is not long
enough to interrupt spread. The fact that the outbreak in Mexico City did not flare up
again after the closing order was lifted is further evidence that the outbreak was already
in rapid decline.

Politics no doubt played a role in the Mexican reaction. Competing parties run Mexico
City (PRD) and the national government (PAN). Each ran competing news conferences
to release information about their jurisdictions, and each wanted to be seen as most
effective. Congressional elections are scheduled for July 2009.

International restrictions were significant, especially given that the WHO explicitly
recommended against trade or travel restrictions. The irrationality of many of these
responses is disturbing, and they do not portend well for a more serious outbreak.
Between April 24, when news first surfaced of the H1N1 outbreak in Mexico, and May 5,
25 nations took some action on trade with or travel from Mexico, not including
8 Condon, Bradley and Sinha Tapen, “The Use of Face Masks on Mexico City Public Transportation
During the 2009 Influenza A (H1N1) Outbreak, draft, personal communication from Tapen Sinha.
9
suggestions by governments, including the United States and the European Union (EU),
that non-essential travel be canceled. China was probably most aggressive, not only
imposing travel restrictions and quarantine of arriving passengers, but also quarantining
all Mexicans in the country. Argentina, Ecuador, and Peru suspended flights to Mexico.
France urged the EU to also suspend all flights to Mexico; the EU declined.9
On a related note, some countries imposed some form of quarantine. Historical data
clearly demonstrate that quarantine does not work unless it is absolutely rigid and
complete. In World War I, there was no statistical difference between the 83 percent of
U.S. Army training camps (N=99) that imposed quarantine and the 17 percent that did not
(N=21). While quarantine regulations varied from camp to camp, in most camps they
involved isolating companies when a soldier became sick, and also sealing off larger
organizations as disease spread beyond the individual company. If a military camp cannot
be successfully quarantined in wartime, it is highly unlikely a civilian community can be
quarantined during peacetime.10 (An investigator did see some success, at least in slowing
transmission, in a few camps where quarantine had no leakage.)

Some 20 countries also banned pork imports from Mexico, Canada, and/or several
U.S. states, and Russia also banned pork imports from Spain.

5. Communication

Candid communication is crucial in most crises, and this certainly includes a pandemic.11
In general, Mexico, the United States, and the WHO were extremely candid. Mexico
even overstated the threat, chiefly because it initially reported “suspect” cases, which
peaked at 2,498 on April 28. On April 29, when Mexico began reporting only confirmed
cases, the number dropped to 97. The same day, there were 109 confirmed U.S. cases.
Mexico clearly paid a price for candor. On April 30, Mexico’s secretary of finance
declared that the impact of the virus on the Mexican economy would be on the order of
magnitude of 0.3 to 0.5 percent of the Gross Domestic Product (GDP). In mid-June, the
World Bank estimated the impact would be 0.7 percent of GDP.

It is less clear that other countries have been candid, either in reporting or in
communicating to their publics. In fact, several either lied or failed utterly to understand
the threat. Indonesia’s health minister told his citizens they had no need to worry about
H1N1 because they lived in a tropical climate. Chinese Health Minister Chen Zhu
declared, “We are confident and capable of preventing and containing an H1N1 influenza
epidemic.”12 Some British epidemiologists have wondered aloud whether Britain’s under-
9Condon, Bradley, and Sinha, Tapen, Chronicle of a Pandemic Foretold: Lessons from the 2009 Influenza
Pandemic, available at SSRN: http://ssrn.com/abstract=1398445
10, Soper, G, “The influenza Pandemic in the Camps," undated draft report, US National Archives, Record
Group 112; BOX 394
11 See my commentary “Avoiding Mistakes of 1918” in May 21 Nature.
12 Peter Brown, “Swine Flu Tests Confidence in China, Japan,” Asia Times, May 8, 2009,
10

reporting was purposeful and have complained that Britain failed to release information
that later emerged only in a European report.

Although the United States generally did very well communicating, even it came close to
a blunder when the president spoke of “concern, but not a cause for alarm.”13 At the time,
no one knew what direction the virus might go, and he ran the risk of putting himself
behind the curve and having to reverse himself overnight.

6. The Past as Prologue: Waves and Patterns from Past Pandemics

1889

The 1889-1892 pandemic, an H2N2 virus, came in three extended waves. It first surfaced
in Turkestan in May 1889, took several months to reach Berlin and Paris, and then took
only a few more weeks to cross the ocean to the United States. By January 1890, what
was still considered the first wave had reached Hong Kong and Japan. Although this
wave spread worldwide, an observer noted, “In 1890 the influenza outbreaks were as a
rule single or isolated and occurred in only a few places in Europe, particularly in Lisbon,
Nuremberg, Paris, Copenhagen, London, etc.”14

By the time the second wave emerged, the virus had already seeded itself around the
world. A second observer noted, “The transfer of the disease by ships which played such
an important role in the first [wave] appeared to be insignificant in 1891.”15 This second
wave caused more widespread illness than the first, but it still did not achieve full
pandemic status. This did not occur until later that year, in a third wave. A contemporary
epidemiologist wrote, “The third real epidemic spread of influenza was a true pandemic
which began in October 1891 and lasted through the whole winter until the spring of
1892.”16

While transportation time and the fact that parts of the world were more isolated in 1889
than even in 1918 – and far, far more than today – may account for some of this
stretched-out pandemic progress, the behavior of the virus also suggests that it required
several years before it became fully efficient in infecting humans. The third wave also
was considered by contemporaries to be the most lethal, even in those places, such as
London, that experienced the first two waves.

Although good statistics for the 1889 pandemic are unavailable, extrapolating from
available statistics suggests it ranks second in severity, and was incrementally more
severe than 1957. Comparison is difficult, though, because in 1957 antibiotics were
available to treat secondary bacterial infections.

1918

13 Obama speech, National Academies of Science, April 27,. 2009
14 Vaughan, WT, Influenza: An epidemiologic study, American Journal of Hygiene, Baltimore, 1921, 45
15 Ibid, 46
16 Ibid, 45-46.
11
In 1918, the virus seems to have jumped species in January in Kansas (another hypothesis
suggests the virus jumped species as much as two years earlier), and the first wave began
to spread rapidly in U.S. Army camps, with intermittent spread in civilian communities in
March. By April, it was spreading through Europe. By late May, this first wave had
disappeared from the United States but was reaching Asian cities, and the first wave
continued through the summer in Europe. This wave was more mild even than seasonal
influenza, and articles in medical journals suggested it was so mild that it might be
another disease. A thorough 1927 study of epidemiological data also concluded that “a
striking feature of the first wave was that … it lacked the extreme diffusive vigor” of the
second wave and had “a tendency to die out.17

The first widespread outbreak of the lethal second wave occurred in late July in
Switzerland. By mid-October, most of the world’s cities had experienced this deadly
wave, and it did not die out. R0 almost certainly exceeded 2.0 and may have approached
4.0.

A third wave struck intermittently around the world from January-April 1919, and caused
about one-third of the total deaths. Exposure to the first wave did generate immune
protection to the second wave, but strangely evidence suggests neither first nor second
wave exposure protected against the third wave.18

Although case mortality in the developed world was 2 to 2.5 percent, even in the West,
certain subgroups suffered much higher numbers. Metropolitan Life found that
3.26 percent of U.S. industrial workers it insured ages 20-45 died, so case mortality in
that population had to be in the neighborhood of 10 percent. In total, the 1918 virus killed
between 1.9 and 5.5 percent of the total world population. As more than half the dead
were young adults, the percentage of that population killed was significantly higher.
Symptoms could be horrific, including bleeding from the eyes and ears. In some
countries, including the United States, society nearly broke down. My hypothesis is that
the government’s effort to reassure people became counterproductive, destroying trust
and alienating the public from those in authority and from each other. National public
health leaders had said, “This is ordinary influenza by another name,” and, “You have
nothing to worry about if proper precautions are taken.”19

Before discussing other pandemics, the point should be made that seasonal flu can turn
virulent at any time; in 1951, seasonal flu was more deadly, with a higher R0, than either
the 1957 or 1968 pandemics.

1957

17 Jordan, EO, Epidemic Influenza, American Medical Association, Chicago, 1927.
18 Barry, JM, Viboud, C, Simonsen, L,, Cross Protection Between Successive Waves of the 1918-19
Influenza Pandemic: Epidemiological Evidence from US Army Camps and Britain, J Infect Dis. 2008 Nov
15;198(10):1427-34.
19 For more on this, see my essay in May 21 Nature, op. cit.
12
The 1957 “Asian Flu” virus, H2N2, was first identified in late February in China, and by
April 12 was epidemic in Hong Kong. On April 25, it reached Japan and by June 1 it was
“all over the country.”20 An epidemic peaked by mid-June and disappeared by July;
disease was mild, affecting primarily children, with low mortality. By late June, the first
wave in Indonesia had caused approximately 10 percent morbidity.

The virus behaved differently in different countries. It reached England with some sailors
in early June, but few secondary cases developed. In Holland, several schools had attack
rates above 50 percent but, again, there were only sporadic adult cases and no community
spread. In Iran, though it was first reported June 24 and one month later the country had
an attack rate of 30 to 35 percent. Through July in most northern hemisphere countries,
only sporadic cases occurred in community settings, despite intense outbreaks in closed
populations (some schools and military bases). In August, however, widespread
outbreaks began.

The United States was typical. In 10 days in June, 10,000 cases occurred on military
bases in California alone. Few civilian outbreaks occurred, however, except in special
situations of close contact. For example, there was an 80-percent attack rate at a
conference attended by 300 schoolgirls. Several similar eruptions occurred over the
summer, but no community-wide outbreaks developed. Of 2,000 college students
attending a national conference in Iowa on June 26, 10 percent fell ill. State health
officials in numerous states tracked them upon their return home, but no community
outbreaks developed. A similar, but more limited, H2N2 spread occurred at a Boy Scout
jamboree of 53,000 young boys July 10-24, but again no community spread was seen
after the boys returned home. Additional outbreaks occurred through August, but “the
influenza-related mortality rate was extremely low.”21

These first exposures are not generally considered the first wave of the 1957 pandemic,
but that is largely a question of definition. Obviously, Iran and a few other countries
suffered significant epidemics in this period. But this early spread did seed the virus
around the country as it was seeded around the world.

The first U.S. and European wave is generally considered to have commenced in August
in Louisiana, when children returned to school, got sick, and quickly spread disease to the
community. Schools are also suggested as involved in transmission by the fact that in
11 of 14 U.S. cities studied, peak school absenteeism preceded peak industrial
absenteeism by from 1 to 4 weeks; in 2 cities, school and industrial absenteeism peaked
the same week; and in 1 city, industrial absenteeism peaked 1 week before schools.
By September 28, 50 percent or more counties reported at least 20 cases in Louisiana,
California, Arizona, New Mexico, Mississippi, the Gulf Coast of Alabama, and Florida.
By October 26, 45 states reported the same. This wave peaked the preceding week, and
20 Dunn, FL, Pandemic Influenza in 1957. Review of International Spread of new Asian strain, JAMA,
1958, 166:1140-1148
21 Trotter, Yates, et al, Asian Influenza in the United States, 1957-58, Am. Jour. Hygiene, 1959, vol 70, 34-
50.
13
decline continued into December. Excess U.S. deaths were about 40,000.22 Morbidity
was estimated at 30 percent of the population in October and November alone.

First wave activity never declined to near zero, but contemporary observers still defined
increased activity from January to March 1958 as a second wave. This second wave had a
much flatter peak and lower intensity, and during it excess U.S. deaths were about
20,000. This second wave is particularly interesting because deaths occurred without
significant widespread illness. One study observed “an absence of community-wide
outbreaks of influenza, but … continued sporadic occurrence of small outbreaks. These
were not considered sufficient to cause the high level of mortality unless the disease had
increased in virulence. Several large influenza diagnostic laboratories reported a marked
decrease in the number of influenza specimens submitted, and a lower yield of
positives.”23

The third wave from January to March 1960 actually had a much sharper peak – higher
than either the first or second wave – but a quick falloff, causing 26,000 excess U.S.
deaths. Approximately 20 to 25 percent of the deaths were attributed directly to viral
pneumonia; secondary bacterial pneumonias accounted for most of the remaining deaths,
but other factors also are reflected in these excess mortality numbers.

There were almost no net excess deaths in those younger than age14; 2,000 excess deaths
among those ages 15-24; 6,000 among those ages 25-44; 22,900 among those ages 45-64;
and 57,000 among those 65 and older. It should be pointed out that mortality among
those <65 is substantially higher than in seasonal flu. Today, in a population almost
double that of 1957, annual influenza-associated deaths in those younger than 65 is only
7,000.

Exposure did generate immune protection. Mountain and Pacific regions had little excess
mortality in the fall wave and virtually no second wave, but the third wave in early 1960
was most severe there, while the Mid-Atlantic region, hit hard in 1957-58, largely
escaped the third wave.24 (The mortality expressed here, a total of 86,000, comes from a
1961 study in JAMA25; today, the death toll is usually reported as 70,000, but I have been
unable to locate the source for this number or an explanation for the discrepancy.)

1968

The 1968 virus, H3N2, was first isolated in Hong Kong in July 1968, and reached the
United States and Japan in August and England and Wales in September. In all these
countries, there was sporadic influenza activity for 2.5 to 4 months before the disease
22 Eickhoff TC, et al, Observations on Excess Mortality Associated with Epidemic Influenza, JAMA, June
3, 1961,
23 Ibid.
24 Eickhoof, TC, Sherman, IL, Serfling, RE, “Observations on Excess Mortality Associated with Epidemic
Influenza,” JAMA, June 3, 1961, 776-782.
25 Ibid
14
erupted in November. In Canada, the virus was not isolated until immediately before it
reached epidemic status, also in November.

No civilian outbreaks in the continental United States occurred until the third week of
October, with no outbreaks on the East Coast until the week of November 16. One week
later, 21 states showed epidemic activity, and by December 28 all 50 states had epidemic
activity.

In all the countries above, a first wave peaked in January 1969. U.S. morbidity was
around 20 percent overall and much higher in schoolchildren. A second wave peaked a
year later, in January 1970, in Canada, Japan, and England and Wales, and in February in
the United States.

Yet, there are significant unexplained differences. In the United States, 70 percent and in
Canada 54 percent of all mortality occurred in the first wave, with the rest of the deaths
coming a year later. Japan, however, suffered only 32 percent mortality. In England and
Wales, 23 percent of total deaths came in the first wave; the second wave was more
deadly. In those countries, the second wave was 2 to 3 times more severe than the first.26
Mortality in the United States was an estimated 34,000 people, compared to a then annual
influenza-attributed mortality of 20,000. There were few cases of viral pneumonia, in
contrast to 1957. This was by far the mildest of the four pandemics discussed.

7. The Future of Novel H1N1

Three of the preceding four pandemics, 1889, 1918, and 1957, show clear evidence of
some fairly intense but sporadic initial local outbreaks scattered around the world.
The novel H1N1 virus seems thus far to be following the pattern of those three
pandemics, and it seems highly likely that it will return in full flower. If the virus is fully
adapted to and efficient at infecting humans, this would occur soon, possibly during the
influenza season in the southern hemisphere or possibly a few months later in the
northern hemisphere. The 1918 and 1957 viruses both exploded in September and
October in the northern hemisphere, even though this is not the influenza season.
If the virus needs further adaptation to become fully efficient in infecting humans, that
could be delayed, quite possibly a year or two later. It seems very unlikely that this virus
will peter out.

The most disturbing information molecular biology has provided is that, according to
scientists at CDC and elsewhere, “genetic markers predictive of adaptation to humans are
not currently present in the [H1N1] viruses, suggesting previously unrecognized
26 Viboud, et al, Multinational Impact of the 1968 Influenza Pandemic: Evidence for a Smoldering
Pandemic, Jour. Inf. Dis., 2005:192 (15 July), 233-248
15
determinants could be responsible for transmission.”27 This suggests two things: first, this
virus may have other things to teach us; second, we do not know the whole story of how
influenza becomes transmissible from human to human, so our monitoring of H5N1 for
these markers is incomplete.

Novel H1N1 also lacks genetic markers for virulence identified in the 1918 virus and is
expected to remain a mild virus, but this information about transmissibility has unsettling
implications.

H5N1 continues to infect and kill people, and Robert Webster, one of the most respected
virologists in the world, has expressed concern about a further reassortment of novel
H1N1 with H5N128. This is not so far-fetched. A recent laboratory study in which ferrets
(the usual animal model for influenza studies) were coinfected with H5N1 and the
seasonal H3N2 virus found that a new reassortant virus with genes from both was
produced 9 percent of the time.29 This reassortant was likely much milder than H5N1
itself. (H5N1 is virulent because it binds only to receptors deep inside the lung; other
influenza viruses bind to receptors, usually in the upper respiratory tract; the reassortants
all were found in the upper respiratory tract.) But given the lethality of H5N1, a
reassortant that includes it is frightening. Assuming H1N1 matures to full pandemic
status and begins to infect 20 to 40 percent of the population, reassortment with H5N1 is
a threat.

There are no certainties about influenza, but the most likely scenario and also the
consensus view at the moment is that novel H1N1 will surge in the next influenza season
in the northern hemisphere. Like the 1918 and 1957 pandemics, it will infect 15 to
40 percent of the population.

The key question is how much immune protection the middle-aged and elderly will have,
that is, how vulnerable they will be. This is a major variable. Another is how many
people will have been exposed to the wave currently moving through the country; this
will probably be an insignificant percentage of the population, but these people will likely
have considerable protection against a second wave.

The key questions relating to drugs are the obvious. Will the virus develop resistance to
anti-virals and will drugs be available? More important, how long will it take to produce
and distribute a vaccine?

In 1999, CDC modeled a moderate pandemic, factored in vaccine availability, and
concluded that deaths would most likely range between 89,000 and 207,000.30 But CDC
27 Garten, RJ, et al, Antigenic and Genetic Characteristics of Swine-Origin 2009 A (H1N1) Viruses
Circulating in Humans, Science DOI: 10.1126/science.1176225
28 Associated Press, May 8, 2009
29 Jackson, Van Hoeven, Chen, Maines, Cox, Katz, and Donis, “Reassortment between avian H5N1 and
human H3N2 influenza viruses in ferrets: a public health risk assessment,” Journal of Virology, online
6/5/09
30 Meltzer, M, Cox, N, Fukuda, K, “The Economic Impact of Pandemic Influenza in the United States,”

http://www.cdc.gov/ncidod/eid/vol5no5/meltzer.htm

16
assumed deaths would occur primarily in the elderly, as happened in 1957 and 1968
(although in both pandemics, a higher number of young adults also died than in seasonal
flu). H1N1 is hitting a different target. If the young are the chief susceptibles and the
virus does not increase in virulence, deaths would probably be less than CDC’s projected
best case.

The world could also benefit from its experience this spring. Numerous studies have
examined the economic impact of a pandemic, with most estimating a 1918-like outbreak
would cut world GDP by about 4 to 6 percent, while a mild pandemic would cut GDP by
1 percent.31 Some experts think these estimates, especially for a mild pandemic,
understate economic impact because of supply chain vulnerabilities, which have greatly
increased with just-in-time inventory systems. Just-in-time, of course, discourages
stockpiling supplies, not only for health care – and not just antibiotics but also syringes,
gowns, gloves, and so on – but also for businesses. A mild pandemic could well infect the
same proportion of the population as a severe one, and some workers would stay home to
care for sick family members; this could easily cause peak absenteeism in the 20 percent
or higher range for a week or more. This could ripple through the economy and create
major bottlenecks. However, the current H1N1 wave could cause businesses to anticipate
supply chain problems in the next 6-10 months and adjust stockpiles accordingly, which
could improve resilience and lessen economic impact, assuming a full-bore pandemic
does strike.

If the current outbreak intensifies or another wave builds, it will be interesting to watch
international reaction. Will nations again try to screen airport passengers, close borders,
and so on? The problem is that almost any leakage completely destroys the entire edifice.
And, for example, models predicting that airport screening could delay the arrival of a
pandemic by several weeks focus only on passengers. Even in the extraordinarily
unlikely event that screening caught all infected passengers, keeping influenza out also
requires keeping freight, mail, express packages, and so on out, as well as quarantining
baggage handlers, workers who clean planes, and others. Shutting down all air travel –
and not just with infected nations – has a theoretical chance of success, but a virus would
have to be extraordinarily dangerous to take such steps simply to delay its arrival by a
few weeks. However, 90 years ago Australia did delay the arrival of the second lethal
wave until January 1919 by instituting a stringent quarantine of all vessels. By then the
virus had weakened, and Australia’s per-capita mortality was only half that of most other
developed countries.

This author supports most proposed NPIs except for quarantine, which historical
evidence strongly suggests is ineffective, and possibly school closing, pending analysis of
recent events. But some things clearly do work. Having the ill stay home, and once at
home minimizing contact with other family members, should have an impact. Data
strongly suggest an important role for hand transmission, hence handwashing matters.
Isolating the sick as much as possible is protective, and historical data clearly correlate
the amount of space per person and morbidity. Masks on the sick protect the healthy,
31 See Warwick McKibbin and Alexandra Sidorenko, Global Consequences of Pandemic
Influenza,(Washington, D.C.: Brookings Institution, Lowy Institute for International Policy, February 2006
17
although only in very narrow circumstances does it make sense for healthy people to
wear them – and they can be dangerous when removed. (Evidence from the SARS
outbreak suggests that most health care workers infected themselves while removing
protective equipment.) Social distancing is useful, but telecommuting will collide with
capacity limits.

NPI strategy does involve “layering” interventions, with the idea that reasonable
compliance with a number of interventions would have a cumulative effect. Nonetheless,
although this layering could improve upon the impact of individual NPI measures to
mitigate outbreaks, this author is less optimistic than most who recommend them. This is
partly because some assessments are based on models that use deficient 1918 data and
partly because in 1918 most U.S. cities took dramatic actions and their statistics already
reflect the impact of these measures. Improving upon that may be possible, but advocates
underappreciate the difficulties in changing behavior and sustaining compliance. Even in
1918, under horrific circumstances, compliance with essentially the same measures as
proposed today quickly declined, and public health leaders expressed disappointment
with their “education” efforts. The rapid decline in mask usage in Mexico during the
current outbreak suggests that such dynamics remain true today, and is not conducive to
optimism.

The long-term answer to influenza is a vaccine that works against all influenza viruses,
which does seem to be possible. Meantime, sustained investment in vaccine production
technologies is essential. Cell-based production, while faster than current egg-based
methods, still take many months. Only newer technologies, such as but not limited to
“virus-like-particles,” have the potential to produce tens of millions of dosages rapidly.
The second most important resource is communication. Getting and sustaining
compliance – changing behavior and keeping it changed – requires winning public trust.
Gaining trust requires explaining in detail why each recommendation was made and why
others were not. It also requires, when decisions are made, taking the offense through a
massive campaign to dominate all media, including the internet. And if the situation
becomes severe, experience from 1918 to SARS demonstrates that only full and candid
disclosure of the truth will contain panic. This author is wary of the term “risk
communication.” It implies management of information. You do not manage the truth.
You tell the truth.

8. Acknowledgements

Work on this paper was supported under a cooperative agreement with the U.S. Centers
for Disease Control and Prevention (CDC), grant number 1 PO1 TP000307-01, "LAMPS
(Linking Assessment and Measurement to Performance in PHEP Systems), awarded to
the Harvard School of Public Health Center for Public Health Preparedness (HSPHCPHP)
and the Massachusetts Institute of Technology (MIT), Center for Engineering
Systems Fundamentals (CESF). This paper represents part of the MIT team's LAMPS
research, "Linking Assessment and Measurement to PHEP through Engineering
18
Systems Analysis." The author serves as senior research consultant on the MIT team
and gratefully acknowledges support of the LAMPS grant. The discussion and
conclusions in this paper are those of the author and do not necessarily represent the
views of CDC, the U.S. Department of Health and Human Services, Harvard or MIT.

[Zac]

Re: White paper on novel h1n1

As of this writing, H3N2 has shown some resistance to the neuraminadase inhibitors
oseltamivir and zanamivir (tamiflu and relenza), while previously circulating H1N1 has
shown nearly universal resistance to those drugs.

Have there been any reports of relenza resistance in seasonal or swine H1N1? The reports I've seen said seasonal H1N1 has nearly 100&#37; tamiflu resistance, but not to relenza.

Because the 1918 virus came directly from
birds, no one had been previously exposed to it, and by 1920 everyone old enough for
school had been exposed. In seasonal flu, 1957, 1968, and today’s H1N1, a reassortant
virus caused illness. Adults therefore had some protection, while children had little or
none, making school transmission much more important.

I thought it had been established the 1918 virus was from swine...

A third wave struck intermittently around the world from January-April 1919, and caused
about one-third of the total deaths. Exposure to the first wave did generate immune
protection to the second wave, but strangely evidence suggests neither first nor second
wave exposure protected against the third wave.

Have the viruses from each of 3 waves in 1918/1919 been sequenced? Were they all substantially different?

Only 31 percent of the vaccine needed is produced in the United States. This raises the
question of whether foreign governments would block the export of vaccine until their
own populations are fully protected.

Is this correct? I read elsewhere that US facilities could only produce about 15 million flu vaccine doses per year.

[wotan]

Re: White paper on novel h1n1

As far as 1918 coming from bird, I believe the ideas have gone from: to humans from birds through pigs, then directly from birds to humans and humans to pigs, and just recently (like in the last couple of weeks) coming to humans from pigs.

None of what I have seen from Dr. Niman, however, indicates he ever supported the straight from birds contention.

[Thornton]

Re: White paper by John Barry on novel H1N1

From my perspective in behavioral health this is the resource I will promote:

The second most important resource is communication. Getting and sustaining
compliance ? changing behavior and keeping it changed ? requires winning public trust.
Gaining trust requires explaining in detail why each recommendation was made and why
others were not. It also requires, when decisions are made, taking the offense through a
massive campaign to dominate all media, including the internet. And if the situation
becomes severe, experience from 1918 to SARS demonstrates that only full and candid
disclosure of the truth will contain panic. This author is wary of the term ?risk
communication.? It implies management of information. You do not manage the truth.You tell the truth.

The most significant deficiency I have seen in the communications arena is using one message for all circumstances eg "the person died with pre-exisitng medical conditions," and "prevent getting flu by staying home when sick."

The authorities clearly are trying to get people to remain calm, wash their hands and to stay home when sick. However, giving the same message to all people in all circumstances does not acheive a unform behavioral response. People will behave according to their own risk assessment with the information they have. Some people prepare for a storm 3 days in advance, others when the storm is 3 hours away. Thus a general storm warning is insufficient for the public to prepare for the pandemic. People in affected communities need more details in order to make their own risk assessment and to adjust their behaviors.
Joe Thornton MD, psychiatrist

[tropical]

Re: White paper by John Barry on novel H1N1

#1:...
"However, 90 years ago Australia did delay the arrival of the second lethal wave until January 1919 by instituting a stringent quarantine of all vessels. By then the virus had weakened, and Australia’s per-capita mortality was only half that of most other developed countries."

[AlaskaDenise]

Re: White paper by John Barry on novel H1N1

Australia did delay the arrival of the second lethal
wave .......by instituting a stringent quarantine ........ By then the virus had weakened, and Australia?s per-capita mortality was only half that of most other developed countries

Impressive.

Being an island & presumably a self-contained economy, has it's advantages.

.

[ARR_309]

Re: White paper on novel h1n1

Have there been any reports of relenza resistance in seasonal or swine H1N1? The reports I've seen said seasonal H1N1 has nearly 100% tamiflu resistance, but not to relenza.



I thought it had been established the 1918 virus was from swine...



Have the viruses from each of 3 waves in 1918/1919 been sequenced? Were they all substantially different?



Is this correct? I read elsewhere that US facilities could only produce about 15 million flu vaccine doses per year.

That is CORRECT. There have been NO reports of resistance to Relenza in human (or for that matter swine) H1N1. For both human and swine H1N1 viruses, resistance has only ever been observed for Tamiflu (nearing 100% in human H1N1). Quite a surprising oversight for such a report - don't you think?

[AlaskaDenise]

Re: White paper by John Barry on novel H1N1

H3N2 is often resistant to amantadine.

.

[AlaskaDenise]

Re: White paper by John Barry on novel H1N1

Results

A total of 209 influenza A(H3N2) viruses isolated from patients in 26 states were screened, of which 193 (92.3%) contained a change at amino acid 31 (serine to asparagine [S31N]) in the M2 gene known to be correlated with adamantane resistance. Two of 8 influenza A(H1N1) viruses contained the same mutation. Drug-resistant viruses were distributed across the United States.

http://jama.ama-assn.org/cgi/content/abstract/295/8/891

.

[marcovth]

Re: White paper by John Barry on novel H1N1

Impressive.

Being an island & presumably a self-contained economy, has it's advantages.

.

Isn't Australia a continent?

[AlaskaDenise]

Re: White paper by John Barry on novel H1N1



Either way, they didn't need to worry about the ill sneaking across a border.

.

[Blue]

Re: White paper by John Barry on novel H1N1

Either way, they didn't need to worry about the ill sneaking across a border.

.

I seem to remember reports of fishermen from Indonesia being found on their shores.

Just a thought...

[tropical]

Re: White paper by John Barry on novel H1N1

I seem to remember reports of fishermen from Indonesia being found on their shores.

Just a thought...

Things that can be resolved by enaugh patroling the side waters.
The important thing is drasticaly cutting off the numbers until it vanish, or more vacc. came.

Perfection is not a goal now ...