00:23
MARCIA DAY CHILDRESS: Good afternoon.
00:26
Welcome to today's Medical Center Hour.
00:29
I'm Marcia Day Childress.
00:31
I'm from the Center for Biomedical Ethics
00:33
and Humanities, which is happy to bring
00:36
you these weekly Medical Center Hour programs often
00:40
in partnership with other programs
00:43
here at the medical center, or medical school and health
00:47
system.
00:48
Today's program on the centenary of the 1918 flu,
00:53
"Remember the Past and Planning for the Future,"
00:56
is a combined Medical Center Hour and medical grand rounds
01:01
for the express and excellent purpose of the Department
01:04
of Medicine's annual Hayden Farr lecture in epidemiology
01:09
and virology.
01:11
This endowed lectureship highlights achievements
01:14
in epidemiology and virology by esteemed physicians
01:17
and scientists.
01:19
The lectureship UVA professor emeritus Fred Hayden
01:24
and the late professor and hospital epidemiologist Barry
01:27
Farr.
01:28
What a pleasure it is to welcome Dr. Haydon here today
01:32
and to remember fondly our longtime colleague Dr. Farr.
01:38
This year's Hayden Farr lecturer is the distinguished
01:40
pathologist Jeffrey Taubenberger.
01:44
Taubenberger is chief of the viral pathogenesis
01:47
and evolution section in the laboratory
01:50
of infectious diseases and deputy chief of said laboratory
01:54
of infectious diseases at the National Institute of Allergy
01:58
and Infectious Diseases of the National Institutes of Health.
02:02
He has done landmark work with the 1918 influenza virus
02:07
and so is quite uniquely qualified to discuss with us
02:11
past, present, and future concerns
02:14
related to pandemic influenza.
02:17
As you know, 2018 marks the centennial of the Spanish flu
02:21
pandemic, the world's deadliest event, which killed at least 50
02:26
million persons worldwide.
02:28
The pandemic's sudden emergence and high fatality
02:32
are stark reminders of the threat that influenza
02:35
has posed to human health and human society
02:38
for more than a millennium.
02:40
There's quite a lot we still don't understand
02:43
about that pandemic, but the recent sequencing
02:47
and reconstruction of the 1918 virus work accomplished
02:51
by Dr. Taubenberger and colleagues
02:54
represent a significant breakthrough.
02:57
So how does this scientific advance
02:59
help us better to know the past and prepare for the future?
03:06
This fall, as you may know, Medical Center Hour
03:08
has partnered with the School of Nursing Bjoring
03:10
Center for nursing historical inquiry
03:13
and historical collections in the Claude Moore Health
03:15
Sciences Library and now with the Department of Medicine
03:19
to observe the centennial of the 1918 flu.
03:23
We're marking this somber anniversary
03:25
with three programs, one examining
03:27
the pandemic in the historical context of World War I--
03:31
that happened in September-- one focused
03:34
on science, which is today's presentation,
03:37
and one addressing the human toll of the epidemic, program
03:41
on the 14th of November.
03:43
Information about it is in your handout.
03:47
So please see your handout, not only
03:49
for a bio sketch of Dr. Taubenberger,
03:52
but also information about that final program two weeks
03:55
from today.
03:57
Also please do visit the exhibit in the library lobby
04:01
on the impact of the 1918 flu right
04:03
here in Charlottesville, Albemarle and at UVA.
04:07
And if you've not already done so, get a flu shot.
04:12
We'd like to thank the Department of Medicine
04:14
and the Division of Infectious Disease
04:16
for partnering with us today and also
04:18
all those involved in the Hayden Farr lecture.
04:21
We also thank historical collections and the library
04:24
sponsor of the history of the health sciences lecture
04:26
series, of which this program is a part,
04:29
and our influenza 1918 2018 joint commemorative
04:34
project with the university's historians
04:36
of nursing and medicine.
04:38
And now Dr. Jeffrey Taubenberger and on the centenary
04:43
of the 1918 flu.
04:44
Welcome.
04:47
Thank you very much.
04:49
Thank you, Marcia.
04:49
It's an honor to be here and to give
04:51
this talk on the 100th anniversary of the 1918 flu.
04:55
So I will start with the important thing.
04:57
I work for the US government, and I can only
04:59
dream of having something financially to disclose.
05:03
So unfortunately I do not.
05:06
It's an honor to give this combined talk, in which I
05:09
see that I'm supposed to talk about epidemiology,
05:11
virology, medicine, and history, and I will do my best
05:14
and show lots of slides and talk really fast and cover
05:16
all those things.
05:18
I didn't have the opportunity to meet Dr. Farr, unfortunately,
05:21
but I have known and been friends and colleagues
05:23
with Fred Hayden for over 20 years
05:26
and can conclude that 20 years is a really long time, even
05:29
for a good bottle of wine.
05:31
So it's going to start with talking about the 1918 flu
05:37
by thinking about last year's flu season, which
05:39
was less than a year ago.
05:40
I think you probably all recall what a really bad flu year we
05:43
had.
05:44
There were reports all over the nation
05:46
about how bad the flu was, including here in Virginia.
05:50
And the numbers of those impacted are just coming in
05:55
and are looking to be very serious.
05:57
It could be that as many as a million people were
05:59
hospitalized in the United States
06:01
for flu in the last flu season and upwards of 70,000
06:04
or 80,000 people may have died.
06:07
Of course, influenza comes in different forms--
06:10
not only seasonal flu, but occasional pandemics in which
06:13
a new strain gets into people.
06:14
And it's here especially on this day
06:16
that we think about the specter of pandemic flu,
06:19
and the worst one that we've ever
06:21
seen which happened exactly 100 years ago in October 1918.
06:26
So if we cast back 100 years and just picked
06:30
one random example of what could be a description of what
06:34
happened almost anywhere in the world in the fall of 1918,
06:37
he at Camp Devens at the end of World War I,
06:39
the United States was really gearing up
06:41
to put men in the field on the Western Front.
06:44
And Camp Devens was one of a couple dozen training
06:47
camps in the United States for the army.
06:49
This was about 50 miles west of Boston.
06:51
So here at the beginning of September,
06:53
a single soldier presents with an influenza-like illness
06:55
to the hospital.
06:57
The next day there were a dozen.
06:59
A week later there were three dozen,
07:01
and a week after that there were 12,000 US soldiers
07:05
in this one little training camp hospitalized
07:08
for severe influenza.
07:09
At the end of this outbreak, a third of the camp became ill
07:12
and nearly 800 men died.
07:14
These were extremely healthy 18 to 25-year-old men
07:17
who dropped dead of influenza.
07:20
Here's some pictures of Camp Devens
07:23
and their supportive care only for flu virus infections.
07:28
They had no antivirals, no antibiotics, no vaccines,
07:33
no intensive care.
07:34
So all they could do was just generalized nursing care.
07:39
A letter from one of the physicians treating patients
07:42
that he sent to another one of his physician
07:44
colleagues was not known at the time,
07:46
but in the last couple of decades was found.
07:49
And this letter talks about how these patients developed
07:53
the most vicious type of pneumonia that's
07:55
ever been seen, and then you get these patients rapidly develop
07:58
cyanosis and then struggle for air until they suffocate.
08:03
It is horrible.
08:04
We've been averaging about 100 deaths per day
08:06
and keeping it up.
08:08
William Henry Welch-- he was probably the most famous
08:10
physician in the United States at the time--
08:14
was keenly involved in military medicine in World War I
08:20
and came to tour this camp and, after visiting the camp,
08:23
was quoted to say that this must be some new kind of infection
08:26
or plague.
08:27
And yet it wasn't plague, and it wasn't new.
08:29
It was just influenza, a disease that
08:31
had been recognized for at least 500 years before that.
08:35
Here's some pictures of US troops
08:39
being treated for influenza in a very primitive camp hospital
08:42
on the Western Front in October 1918.
08:47
So if we talk about some of the numbers, they're astounding.
08:50
And I think that we will never know the full impact
08:52
of the 1918 flu.
08:54
The numbers keep rising as the developing world is
08:58
looked at more closely.
09:00
So currently, I think a reasonable number of deaths
09:03
would be 50 million people in about a nine
09:05
or 10 month period in 1918, 1919, but 100 million
09:08
is not unreasonable and is it possible to be
09:13
closer to the truth.
09:14
In the US, there were little under 700,000 people that died.
09:18
So to try to put that in perspective,
09:20
in a city like Philadelphia, 16,000 people
09:22
died, 11,000 just in the month of October.
09:25
So at its peak, 4,500 people died in Philadelphia
09:28
in a seven day period.
09:31
The US military entered World War I late
09:33
compared to the European countries,
09:34
but of 100,000 troops that died to all causes in World War I,
09:38
40% of them died of flu.
09:42
There were about 17,000 deaths in Virginia, which is about 1%
09:47
of the population at the time.
09:50
Here's some work from colleague Michigan State,
09:54
Dr. Chandra, who's been doing work as a demographer,
09:57
trying to understand and model the influenza pandemics
10:01
mortality in countries where no mortality statistics were
10:06
collected at the time by looking at the divit that
10:09
occurred in the growth of the population.
10:11
And from these work, he suggests that at least 14 million people
10:14
died in India of the 1918 flu.
10:17
Other estimates have gone as high as 17 million people.
10:21
Here's a temporary camp hospital in Fort Riley, Kansas,
10:25
again where they recognized that it was a respiratory disease.
10:28
They had patients wear masks and try to separate them.
10:31
But other than supportive care, there
10:32
was nothing that could be done.
10:35
The pandemic blew up and was recognizable
10:38
everywhere in the world in September through November
10:41
in 1918 in a major wave.
10:43
There seems to be some flu activity that
10:46
occurred earlier in the late spring and early summer.
10:49
Certainly in northern Europe there
10:50
was clear evidence of the pandemic in June and July.
10:54
But where the virus started and where it began to be circulated
10:59
is not known and possibly will never
11:01
be known because it's under the radar of what happened.
11:03
And then there were subsequent waves.
11:05
Some places had outbreaks again in the early months of 1919.
11:10
A very sad and easy way to look at the impact of the 1918 virus
11:16
is just to take a look at pictures of death records
11:20
where each death record is a single page bound by month
11:22
from the state of Oregon sitting on the shelf of the National
11:25
Library of Medicine.
11:26
And here you see the emergence of the flu in October,
11:28
November, December, January, and then
11:30
going back to a normal amount of monthly deaths for the state.
11:35
You can find pictures, not just in military camps,
11:39
but in civilian life.
11:39
Here's a picture of ill students in Dartmouth College, people
11:44
at training camps, people at Walter Reed Army Hospital.
11:48
You see Americans being Americans.
11:50
They played baseball during the pandemic.
11:53
They went to the theater.
11:55
They had to have volunteers dig mass graves.
11:59
This one gravestone, which is in central Pennsylvania,
12:01
says in remembrance of the children buried in this area
12:03
who died in the flu epidemic of 1918
12:05
and whose names are known only to God.
12:08
This is not a sight that you would
12:10
expect to see in cities of the United States,
12:12
but were relatively common sights in the fall of 1918.
12:17
Its impact on World War I was tremendous.
12:19
I think that the combatent countries could
12:21
think of no good way to end the war,
12:23
and I think the flu ended it for them.
12:27
The leaders of the United States, Britain, and Germany
12:30
all got the flu.
12:32
Prime minister Lloyd George almost died of flu.
12:35
Woodrow Wilson became extremely ill with flu,
12:38
and his slow recovery prevented him from participating fully
12:41
in the peace conference.
12:42
And that probably affected the way
12:44
that the peace treaty was negotiated.
12:47
General Pershing got the flu.
12:49
Kaiser Wilhelm got the flu.
12:53
Thinking about its impact on society,
12:55
I can't emphasize again the enormous impact of the 1918
12:58
virus in terms of the personal tragedy of how many people
13:01
died.
13:04
Some of the most famous artists were affected.
13:07
Edvard Munch in Norway got the flu
13:10
but recovered but almost died.
13:12
Egon Schiele, the expressionist artist who was 28 at the time,
13:15
died and this is actually a picture of his deathbed.
13:18
He died in the same bed with his wife
13:19
who was six months pregnant.
13:21
They also all died within a couple days of each other
13:24
in that same bed.
13:25
Gustav Klimt also died of pneumonia in 1918.
13:31
The impact of the virus was so great
13:33
that it caused a life expectancy the United States to drop
13:35
by about a dozen years.
13:37
And this is due predominantly to one very remarkable feature,
13:42
which is still really unexplained,
13:45
which is that usually influenza virus has its highest
13:47
impact in the extremes of life-- that
13:49
is, in neonates and in the elderly,
13:51
two populations that are thought to be immunocompromised
13:55
in some extent with a little mortality in between.
13:59
So you get this roughly u shape mortality curve for typical flu
14:04
before and after.
14:05
But in 1918, what you see was a new hump in the middle,
14:09
peaking at about age 28.
14:13
And this is the one cardinal feature epidemiologically
14:17
of the 1918 virus that's seen everywhere in the world,
14:21
that young healthy adults had very
14:24
high and unexpected mortality.
14:26
And there are many hypotheses about them, but none of them
14:28
adequately explain the data.
14:30
And it still remains a big mystery.
14:33
So let's talk very briefly about the biology
14:35
of the virus itself.
14:37
The 1918 virus was an influenza A virus.
14:40
It's an orthomyxovirus, and it's a single stranded RNA
14:42
virus with a segmented genome.
14:44
Not to talk about the biology of the virus too much, but just
14:47
to know that it's an envelope virus
14:49
and expresses a couple of surface proteins, which play
14:52
key roles in viral lifecycle.
14:54
One of them, hemagglutinin, or HA, is involved in viral entry.
14:59
It binds to the receptors on the cells, which
15:01
are glyocoprotein-- the sugars on the tips of glycoproteins
15:05
on epithelial cells.
15:06
And it comes in a variety of subtypes or flavors.
15:10
And the neuraminidase has the opposite effect.
15:12
It helps newly formed viruses be released from the cell
15:16
by cleaving off those same cleavages.
15:18
The virus is a single stranded RNA virus,
15:21
and its polymerase lacks proofreading.
15:24
So it has a lot of errors.
15:25
So the virus lives in its kind of error prone lifestyle
15:29
where every single virion that's replicated has between 1
15:32
and 10 or more mutations.
15:35
Many of these are deleterious, but the virus can rapidly
15:38
select positively for mutations, for example,
15:41
that help it escape from pre-existing immunity,
15:43
from antiviral drug treatment.
15:46
Or if for example of a virus from one animal
15:48
finds itself in a non-native host,
15:53
there might be some mutations that help select for adaptation
15:56
to a new host.
15:57
The kind of continual change in flu that we see,
16:00
especially of the surface protein
16:01
genes to escape pre-existing immunity,
16:03
has been called antigenic drift.
16:05
And because it's a segmented genome,
16:07
if one host and specifically one cell
16:10
is infected with two flu strains at the same time,
16:13
you can mix and match the gene segments
16:15
to create a completely novel virus that
16:17
can have very different phenotypic properties.
16:19
And that's been called antigenic shift.
16:25
So you probably are all familiar with flu,
16:28
but this is a helpful algorithm, as we start in flu season,
16:31
to figure out if you have the flu.
16:34
It's based on a lot of data.
16:35
So it says, do you feel like you've
16:37
been hit by a train, yes or no.
16:38
No, you do not have the flu.
16:40
Yes, have you been hit by a train.
16:42
Then yes, you've been hit by a train.
16:44
And if no, then you have the flu.
16:48
You can look at how rapidly influenza viruses change
16:51
by doing sequence analysis and phylogenetic trees,
16:54
and what you can see is that the influenza viruses that
16:57
circulate in winter outbreaks every single year
16:59
form distinct clades, which can be dated,
17:02
so that is, if you look up a sequence in GenBank,
17:05
you could say, this human H3N2 virus is from 1998 or one
17:09
in 1984, so on.
17:11
It's that rapid.
17:12
You can actually look at molecular evolution in one
17:15
host, and you can look at molecular evolution
17:17
during one flu season.
17:18
And most of that change is driven
17:21
by changing the protein of the hemagglutinin on the top
17:25
where the antibody's recognized and where actually
17:28
the hemagglutinin binds to the receptors
17:30
that it's going to recognize.
17:33
The result of this is that the flu vaccine has
17:35
to keep up with this rapid evolution,
17:38
and you can see the H3N2 viruses that have been the dominant flu
17:41
strains in the last 50 years.
17:43
The strain has to be changed almost every single year
17:46
to keep up with this mutation rate, H1 slower.
17:50
So we clearly need to do a better job
17:52
at coming up with ways to make vaccines that are not
17:55
so sensitive to the kinds of mutations of flu viruses
17:59
to make more broadly protective vaccines.
18:00
And I'll touch on that briefly at the end.
18:03
So just to mention again.
18:05
Last year's flu season was particularly bad.
18:11
The numbers are not in yet, but it's possible
18:13
that 80,000 people died of influenza pneumonia
18:16
in the US last season and almost 200 children were
18:20
documented to have died.
18:22
Influenza in our world is a human disease
18:26
and is obviously a hugely important medical
18:29
and public health problem.
18:31
But influenza infections of humans
18:33
is really kind of an accident.
18:34
It's really a wild bird virus.
18:36
It's a gastrointestinal virus in over 100 species of birds,
18:41
but commonly in waterfowl, like ducks and geese, shorebirds,
18:45
terns, seagulls, et cetera.
18:47
But many other species of birds have flu.
18:49
So it's a GI virus.
18:50
It's spread by fecal spread in the water.
18:56
But influenza viruses have this ability
18:58
to adapt to many other warm blooded animal
19:02
species, including other domestic poultry,
19:04
like chickens and turkeys, but also mammals, including
19:08
wild mammals as divergent as whales and seals and bats,
19:11
but important agricultural and economically important
19:14
animals like horses, dogs, pigs, and of course to humans.
19:18
And the complicated ecobiology of how influenza viruses move
19:21
and adapt between these species is still
19:23
only poorly understood, but means
19:25
that eradication of the virus from humans
19:27
is never going to be possible, like was possible for smallpox
19:30
and could be possible for polio and measles.
19:34
Flu is the poster child for Darwinian evolution
19:37
and natural selection with its rapid ability
19:41
to respond to negative and positive selection.
19:44
Here is a phylogenetic tree of the different subtypes
19:48
of hemagglutinin, looking like a sketch that came out
19:51
of Darwin's notebook, looking at the evolution
19:55
of these different subtypes that occurred in birds.
19:58
So if you were to read a textbook of influenza
20:00
as to how pandemics form, you would see something
20:03
like this paradigm-- that birds like this duck
20:07
are the natural host for flu, and that bird viruses adapt
20:10
to pigs to become swine flu, and that swine
20:14
viruses become human pandemics.
20:17
So outside of Washington D.C., there's very little evidence
20:20
for this actually occurring, and it's
20:23
just a much more complicated problem.
20:26
It turns out that humans give viruses
20:29
to pigs much more commonly than swine give viruses to us.
20:34
In looking at this picture, I don't know which of the two
20:36
is enjoying their kiss more, but they both
20:38
seem to be enjoying it and sharing viruses probably
20:40
in both directions.
20:43
So if we go back and look at pandemics in history,
20:46
we know of what's happened in the last 100 years.
20:50
So we're talking about the 1918 flu, which
20:53
was an H1N1 subtype-- so that hemagglutinin subtype
20:56
1 and neuraminidase subtype 1.
20:58
In 1957, there was a pandemic that was H2N2--
21:02
in 1968, the Hong Kong flu, which
21:05
is H3N2, which is still circulating.
21:07
In 1977, the old lineage of H1 came back.
21:11
And in 2009, there was a new H1N1 that emerged,
21:15
and now this new H1N1 and this H3 virus
21:18
continue to circulate as the influenza A viruses.
21:21
We do not know what happened before 1918.
21:24
If you look at mortality as just one measure of a pandemic,
21:28
you find that pandemics are defined
21:30
as having a novel virus, presumably an animal derived
21:33
influenza virus completely or in parts,
21:37
that has emerged in humans.
21:39
But just because it's a novel virus
21:41
does not mean that it's equally pathogenic
21:44
or has equal public health impact.
21:46
The 1918 flu had a huge impact, and the 2009 virus
21:50
was a particularly mild pandemic.
21:51
And yet it was a novel virus for humans.
21:54
If you look at pandemics in history,
21:57
certainly they have gone back at least since about 1510.
22:01
There have been 14 pandemics in the last 500 years,
22:04
but there is some evidence of pandemics going back earlier
22:07
than that, although it's very hard to look
22:08
at the medical literature from the Middle Ages.
22:13
So there were no virus isolates made in 1918.
22:17
The concept of viruses was still rather new.
22:19
While flu was recognized clinically,
22:21
its causative agent was not.
22:23
Spurred by the 1918 pandemic, researchers
22:26
isolated the first influenza A viruses from pigs in 1930
22:29
and from humans in 1933.
22:31
But by that point, there was no way
22:33
to actually study the 1918 virus itself.
22:35
So about 25 years ago at the Armed Forces Institute
22:39
of Pathology, I had this crazy idea
22:42
that we could perhaps use PCR based approaches
22:45
to find gene segments of the virus that caused the 1918
22:49
flu in autopsy tissues of people who died in the pandemic that
22:52
were preserved in the national tissue repository.
22:55
And this project worked unfortunately or fortunately.
22:59
Here are autopsy tissue sections cut and stained in 1918
23:03
that had been sitting on the shelf at that point for 80
23:06
something years and are still in good shape.
23:08
And the tissues are a little bit of lung
23:10
like this fixed in formaldehyde and embedded in candle wax
23:13
about the size of your fingernail.
23:15
So using that, we had a small group
23:18
of people that took nine or 10 years to sequence
23:20
the genome of the 1918 virus, using
23:23
what were for us pushing the technology as far as it could
23:26
go back in the '90s.
23:29
Then we expanded our collection of tissues
23:32
going from other locations, including
23:34
from a person who died of influenza whose body was buried
23:40
in the permafrost in northern Alaska, exhumed by my colleague
23:43
you Johan Hultin in Brevig Mission, Alaska.
23:47
He did an exhumation in 1951 from the same site
23:50
with the attempt to try to culture the 1918 flu virus,
23:53
and that failed.
23:55
There was no lab containment.
23:56
They didn't even have biological safety cabinets in 1951.
23:59
So I'm not sure what they would have done with the virus
24:01
had they recovered it, but they did not.
24:04
They looked at a place where, in a local outbreak
24:07
in a small Inuit village 85% percent of the adult population
24:11
died in five days and were buried in permafrost,
24:15
leaving dozens and dozens of orphans
24:16
with the same mortality pattern that young adults died
24:19
and children did not.
24:21
And it was extremely devastating to these communities.
24:26
This is right on the tip of the Seward peninsula of Alaska
24:29
where Brevig Mission is.
24:31
This is flying in about 10 years ago with the frozen Bering
24:36
Sea here.
24:37
And with apologies to Tina Fey, this
24:38
is one of the very few places in Alaska you can see Russia
24:41
from your house.
24:44
This is where the bodies are buried
24:46
on a bluff right on the beach in between these two
24:49
wooden crosses.
24:50
So if you look online, you see all sorts of weird things
24:52
about how the 1918 virus was sequenced
24:55
and here this thing says that we use these complex computer
24:59
program and supercomputers to perfectly match the structure.
25:02
So I just wanted to show you our supercomputer,
25:05
which was that there were between femtogram and attogram
25:09
amounts of viral RNA in the tissue.
25:11
Most of it were single nucleotides.
25:13
There was a tiny fraction of stuff up to about 80 bases
25:16
or so.
25:17
You had to retroactively label the heck out of it
25:20
to see anything, even with 40 cycles of PCR,
25:23
and then do Sanger sequencing.
25:24
So it took a couple of weeks to get 20 to 40 bases of sequence
25:28
of the virus using this approach and so a 10 year effort
25:32
to put the virus together.
25:33
So here's the supercomputer where we recorded
25:36
the sequence of the 1918 flu.
25:39
And then rebuilding the virus after the sequences were done
25:43
was a multicentered collaboration funded by the NIH
25:46
that involved a bunch of different collaborators
25:48
in a very exciting program project.
25:51
And the 1918 virus could be resurrected
25:53
to be studied in high containment labs
25:55
to model pathogenesis.
25:59
Recently, we've been able to develop
26:01
high throughput sequencing approaches that
26:04
are much more efficient.
26:05
And so now in about a week or two I can sequence in my lab
26:10
the complete genome of the 1918 virus instead of a 10 year
26:13
effort, which is good, because I'm old and impatient now.
26:16
And we can do this more efficiently.
26:18
So that means that we can look backward in time from 1918.
26:22
Let me briefly show you some pathology
26:24
from people who died in 1918.
26:26
This is the histology of normal lung, which
26:28
is mostly just blank airspace.
26:30
And here what you see in 1918 deaths
26:33
are features of the primary viral pneumonia
26:35
with a diffuse alveolar damage with fulminant pulmonary edema
26:39
and/or hemorrhage, sometimes alveolitis
26:41
with a necrosis of alveolar cells--
26:45
again, DAD, abundant thrombi.
26:48
But the predominant pathology that you see was of secondary,
26:51
untreated bacterial pneumonias, massive bronchi pneumonias with
26:56
"C"s of neutrophil destruction of the bronchial tree but with
26:59
evidence of repair going on probably from the primary viral
27:03
cause and then death from the secondary bacterial pneumonia.
27:07
You can see abundant bacteria by tissue gram stain,
27:10
the nasopharyngeal common causes of bacterial pneumonia--
27:16
pneumococcus, group A strep, Staph.
27:19
But they were gram negatives, and a variety
27:22
of bacteria that cause secondary pneumonias in 1918.
27:26
The influenza virus is present throughout the bronchial tree
27:29
from nose to alveolus.
27:31
It replicates in the tips of the cells lining
27:34
the respiratory epithelium, not the full thickness epithelium,
27:38
which is of interest.
27:39
And we have cases going back to as early as May 11th, 1918,
27:45
the earliest sequence of a soldier that died of the 1918
27:48
virus and a partial sequence.
27:50
And those sequences are identical with fall wave cases.
27:54
So the most important lesson initially
27:56
from sequencing the 1918 flu is that the 1918 virus is truly
28:00
the mother of all pandemics in the sense
28:03
that every single human influenza
28:05
infection, whether every year a seasonal flu for the last 100
28:08
years or the subsequent pandemics
28:10
we've had in 1957, '68, and 2009,
28:13
are all genetically descended from this one founder virus.
28:16
So if 50 or 100 million people died of influenza in 1918,
28:20
tens of millions of people have died of influenza
28:23
in the last 100 years, all of them
28:25
due by the successful introduction of a single virus
28:27
into the human population.
28:29
So we're 100 years into a pandemic era
28:32
that has no signs of stopping.
28:36
And so just to make this point-- if you take the last 50
28:39
years of mortality, and including the pandemics
28:42
that have occurred in the last three pandemics,
28:44
75% of the mortality has been to seasonal flu.
28:47
So while there's a huge concern to prepare for and prevent
28:51
pandemic flu, it's the annual flu
28:53
that is causing most morbidity and mortality in the United
28:56
States and the rest of the world and something
28:58
that we should think about very seriously.
29:00
So now let me very briefly talk about what
29:02
we've learned about why the 1918 virus had such an impact,
29:05
and I'm going to talk about a variety of factors that
29:09
come together to provide more serious illness in 1918
29:13
than in other influenza virus infections.
29:15
So let's start with the virus--
29:17
you can work with the virus.
29:18
It's a select agent once you have approval
29:21
under very high containment conditions.
29:24
And the 1918 virus is very pathogenic.
29:26
Unlike most human viruses, without adaptation
29:29
in mice, in ferrets, in non-human primates,
29:32
the virus basically causes severe disease and death
29:36
very rapidly.
29:37
And it's very different than what
29:39
happens with normal seasonal viruses or other avian viruses.
29:43
To make a long story short, of all the genes encoded
29:47
by the virus, the hemagglutinin surface protein gene
29:50
is probably the major virulence factor of the virus
29:53
that just putting this gene on the backbone
29:55
of a non-pathogenic modern human virus
29:57
is enough to kill mice and ferrets.
30:00
And this is not shared with the HA genes
30:03
of other pandemic viruses.
30:06
And so again, to make a lot of data very compressed,
30:11
we think that the 1918 virus is a very avian-like virus
30:14
and that there was likely an avian ancestor to the pandemic
30:17
shortly before the pandemic emerged
30:19
and that the 1918 hemagglutinin is
30:21
a very avians-like hemagglutinin with just small adaptations
30:26
to receptor binding.
30:29
And we know that interestingly now
30:32
and scarily that the H1s of wild bird, duck hemagglutinins
30:37
that you can find in a pond just outside of Charlottesville,
30:41
if put in the context of a mammalian replicating virus,
30:45
share the same pathogenic features of the 1918 virus
30:48
so that the mutations that are not
30:51
pandemic-specific but in a sense are just
30:53
inherited from a bird H1.
30:56
And since we know that H1 viruses share
30:58
this pathogenicity, we wondered about the other subtypes
31:00
that circulated in birds.
31:01
So we made a series of viruses that
31:03
were identical, but just different
31:05
in their hemagglutinin.
31:06
All of these are hemagglutinins right out
31:07
of wild birds with no adaptation, and all of them
31:10
replicated in mouse lung.
31:12
But most of them did not cause any appreciable disease,
31:15
no weight loss, but some of them were very pathogenic like 1918
31:19
with death in about a week.
31:20
And it did not correlate with their ability
31:22
to replicate in the lung.
31:24
Some that were very pathogenic had lower titers,
31:26
and some that were not pathogenic at all
31:28
had higher titers.
31:29
But the subtypes that were pathogenic
31:31
were H1, 6, 7, 10, and 15, and they
31:35
share a number of features in that they induce a very marked
31:39
proinflammatory response.
31:42
But they're very divergent on the family tree,
31:44
and so it's not clear that they share
31:46
structural features that account for this high pathogenecity.
31:51
And that's something that we're still investigating.
31:54
It's not just an animal artifact.
31:57
If you take normal human bronchial epithelial airway
32:00
cells, you can culture them in vitro,
32:03
and you see that the viruses that
32:05
are pathogenic in mice and ferrets
32:06
are cytopathogenic in human cells, like H1 and H7.
32:13
This is scary to me and others because some of these viruses
32:16
have caused outbreaks in humans and, currently in the last five
32:20
years in China, there has been an H7 outbreak of an avian
32:23
virus that has currently infected about 1,600 people
32:26
and caused about 800 deaths.
32:31
So let's talk briefly about host inflammatory factors.
32:35
One thing that characterizes the 1918
32:37
and these other pathogenic bird viral infections
32:40
is this very profound proinflammatory response
32:42
that you see with an abundance of CD45 cells coming
32:47
into the lung early on in infection.
32:48
But especially crucial here is that 1918 viruses
32:53
induce this huge neutrophilic infiltrate, which
32:55
is very unusual for a viral infection,
32:58
that they induce a lot of proinflammatory responses
33:01
and cell death.
33:03
So taking advantage of this, John Cash in the lab
33:06
took a series of experiments in which he infected mice
33:10
with a lethal dose of the 1918 virus,
33:12
waited for them to be ill by day 3,
33:14
and then treated them with a drug that is a super oxide
33:18
dismutase catalase mimetic that reduces the production
33:22
of free radical oxygens.
33:23
It has no antiviral properties, and yet
33:25
mice that were injected with this drug for a week
33:30
during the infection could actually
33:31
clear virus and recover and have minimal damage in their lungs
33:36
and little evidence of free radical oxygen damage,
33:38
whereas untreated mice had this very profound death, suggesting
33:42
that, while the virus itself is a very virulent virus,
33:45
it's not just the virus infection itself that's lethal
33:48
but the inflammatory response is contributing
33:50
to an immunopathology.
33:53
We'll talk briefly about bacterial factors.
33:55
As I said, secondary bacterial pneumonias
33:57
were a crucial feature in 1918.
34:00
And as you'll recall, along the respiratory epithelium down
34:05
through the bronchial tree into the lungs,
34:07
the influence of virus replicates
34:08
in the superficial cells but not the basal cells, which
34:11
also turn out to be the local respiratory epithelial
34:14
stem cells and rapidly reproliferate and recover
34:17
and repair after a typical flu infection.
34:21
But in the case of damage caused by a very pathogenic virus
34:25
like 1918 and then secondary bacterial pneumonia,
34:29
you get a complete loss of these basal epithelial cells,
34:34
and you actually lose the ability
34:36
to reproliferate and repair.
34:38
And I think this lack of repair is
34:40
one of the reasons for severe disease
34:42
and the progression of 1918 copathogenic pneumonias.
34:47
Another interesting and still evolving
34:50
story is that the inflammatory response generated by the 1918
34:55
virus with high levels of neutrophils
34:58
actually ended up changing the behavior and gene expression
35:02
patterns of secondary bacteria like pneumococcus strains here
35:07
and actually make them more virulent.
35:09
And in the case of the 1918 virus, what we think
35:12
is that this co activation of neutrophils by the 1918 virus
35:16
and then subsequently by secondary bacterial infections
35:20
induces a widespread vascular tree thrombotic picture.
35:26
And if you back to 1918 autopsies,
35:29
you see very frequent small venule thrombo.
35:33
And here you see a massive factor three deposition
35:38
in 1918 autopsies that you do not
35:40
see in autopsies of people dying of the 2009 pandemic,
35:43
even those with secondary strep infections.
35:46
So this seems to be a 1918 unique thing that
35:50
is inducing this thrombosis, and this may have certainly have
35:53
contributed again to the extreme pathogenecity of the 1918
35:56
virus.
35:59
Just as a quick aside, one of the cases showing
36:02
a widespread thrombi had sickled red cells,
36:06
and we ended up just doing PCR across the globin gene.
36:10
And this was an African-American soldier
36:12
who died in October 1918 who had the Glu6Val sickle cell
36:16
mutation and so, in a sense, is the world's oldest diagnosed
36:20
case of sickle cell anemia four years before the term was
36:23
described in 1922.
36:26
So studying influenza in animals is clearly very important,
36:32
and it allows us to understand basic biology and pathogenesis
36:35
of viruses like 1918 and certainly are crucial,
36:39
but ultimately as a physician, our goal
36:43
is to understand influenza in humans
36:45
and to control influenza in humans.
36:47
And so we have been studying naturally infected patients
36:52
with influenza in the last dozen years
36:54
or so at the NIH hospital, concentrating
36:57
on people who are in high risk groups,
36:59
people who are immunocompromised, pregnant
37:02
women, et cetera.
37:04
But in the last five or so years,
37:06
we have started doing studies that Dr. Hayden has
37:10
done for many years in the past and other groups had
37:14
successfully done.
37:15
But then people stopped doing them,
37:16
which were volunteer challenge studies, in which healthy, very
37:20
carefully screened volunteers are brought into the hospital
37:23
and intentionally infected with circulating wild type influenza
37:26
viruses to study basic pathogenesis
37:29
and immunocorrelates but using this as a basis for phase two
37:33
studies that are very efficient in terms of ability to look
37:37
at efficacy of novel drugs or therapeutics
37:40
and vaccines in small numbers of patients.
37:42
So this has been something that's
37:44
been done very successfully and safely
37:47
with no adverse consequences for the last five or six years.
37:51
Here's my colleague Matt Memoli, who runs
37:54
all of our clinical studies.
37:55
He's an infectious disease physician in my group,
37:58
inoculating a patient with influenza using
38:03
a little atomizer spray here.
38:06
This is done in a high containment suite
38:10
at the NIH Clinical Center hospital, the same suite where
38:14
Ebola patients were treated.
38:16
And we are actively recruiting for various studies all
38:19
of the time, and get a number of recruits
38:24
to help us with these studies.
38:25
And that's extremely crucial.
38:27
We've done over 400 patients so far with H1 and H3 viruses.
38:31
We have additional H1 and 3 viruses
38:33
and influenza B viruses in production,
38:35
and we've done a number of phase two studies
38:37
with novel vaccines and novel therapeutics that
38:41
are helping us try to understand how to better prevent and treat
38:44
influenza in humans.
38:48
So if one looks at antibodies in the blood,
38:54
in the serum as correlates of protection for flu, something
38:57
that's been studied for decades and decades,
39:01
most of the decision making that occurs
39:03
in terms of looking at people's protection against influenza
39:06
as well as vaccine efficacy has been
39:08
based on antibodies against the head of the hemagglutinin
39:11
protein.
39:12
So the antibodies that inhibit hemagglutinin
39:15
from binding to its receptor, in this case a surrogate
39:18
assay binding to red blood cells and aglutinating them
39:22
in culture.
39:24
And so this assay hemoglutination inhibition test
39:27
to HAI titers are the marker that
39:30
has been used for vaccine efficacy and their idea
39:33
that a dilution of this antibody to 1 to 40 or so
39:36
is a protective titer.
39:38
So what we've done in our challenge studies is--
39:41
that it's difficult to do in a natural infected system--
39:45
is that we know when time zero is for the infection.
39:48
We know what their preexisting titers are.
39:50
We know the sequence of the virus.
39:53
We can follow the development of their infection,
39:55
their inflammatory response and their subsequent immune
39:58
response during the course of infection.
40:00
And we also have been looking at other antibody titers
40:03
as correlates.
40:04
And interestingly the hemagglutinin inhibition titer
40:06
is clearly a correlative protection,
40:09
but it is not the best correlative protection
40:12
that we found.
40:13
It turns out that the other surface protein, neuraminidase,
40:15
is actually a better and an independent correlative
40:19
protection against prediction of shedding
40:22
duration, symptom duration, the number of symptoms,
40:24
and symptom severity.
40:26
More recently, there's been a lot of emphasis
40:27
in looking at antibodies against the stock of the hemagglutinin,
40:31
that I'll talk about briefly, the part
40:33
of the hemagglutinin that drifts less, that is
40:36
under less mutation.
40:37
And so the idea is that, if you can make antibodies
40:40
against this conserved part, you might
40:42
be able to make a more universal vaccine.
40:45
And stock titers are also correlates of protection,
40:47
but again not as good an independent predictor
40:50
of prevention of illness than neuraminidase antibodies.
40:56
Here are some data from stock antibodies.
40:59
You find that, rather than what some people have suggested,
41:04
that stock antibodies are actually rare,
41:07
that we find that every patient that we've looked at
41:10
has some detectable stock antibodies
41:12
in the serum to the 2009 virus, of course, over a wide range.
41:15
But if you look, for example, at those who develop flu infection
41:19
and develop illness after infection or inoculation
41:22
in the challenge system versus those that do not,
41:24
there is a difference in the mean tire in the stock
41:27
antibody.
41:28
But importantly that, if you look at the highest
41:31
quartile of stock antibody, you find
41:34
that about half the patients at this highest level of stock
41:37
antibody were in the group that was protected from developing
41:41
infection and disease, and yet that the people with stock
41:45
anybody titers at the same level still developed infection
41:49
and disease, suggesting that it's not a perfect correlative
41:52
protection and that, while it certainly
41:54
plays a role in protection, it might not
41:55
be the magic bullet that some people would like it to be.
42:01
If you look at influenza shedding and symptom
42:05
development, you find that influenza viruses replicate
42:09
often to a titer of as high as 10 to the 3 or 10
42:12
to the 4 in nasal wash fluid before the actual development
42:16
of clinical symptoms, which is why influenza
42:18
is so hard to control, because you can be shedding
42:21
virus and transmitting virus to others
42:24
before you really know that you're ill or very ill.
42:27
So in this little window of the first couple of days,
42:30
you have the possibility of trying
42:33
to make some predictive biomarker
42:35
assessments of who will develop more
42:37
severe disease than others.
42:38
And this is really important because at the moment,
42:40
if someone presents with an influenza like illness
42:43
in the hospital and even if a rapid diagnosis is made
42:45
of influenza, it's not clear if this person is going
42:47
to have a self limited course, is this person going to develop
42:50
a severe infection, is going to need to be hospitalized
42:53
and given supportive care.
42:55
And so if there were a way to assess this,
42:57
this would be very useful.
42:59
So using our challenge system, since we
43:02
know what time zero is and we have a nasal wash
43:07
and peripheral blood serum, peripheral blood
43:10
white cell sampling everyday during infection,
43:13
we can begin to examine this.
43:14
And by day two, in studies of looking at over 100 patients,
43:19
you can begin to look at gene expression in peripheral blood
43:23
mononuclear cells on day one or day two,
43:26
that would predict duration of shedding so you can make
43:29
an annotated gene set that's very predictive of who
43:33
will shed virus the longest.
43:35
And you can do the same thing for symptom severity
43:38
and how severe the illness is going to be.
43:42
And so if these markers can be further validated
43:44
in additional studies that might be
43:46
possible to provide some prognostic information
43:52
to help guide whether patients might need
43:54
more intensive therapy earlier on to try
43:57
to prevent the development of severe illness, pneumonia,
44:00
and death.
44:02
So in the last couple of minutes,
44:05
I will just go back to the problem
44:07
that the current vaccine is based on an idea
44:11
that we have to perfectly match the virus that
44:14
is in the vaccine antigen to the virus that's circulating.
44:17
Since flu viruses continually evolve and mutate in ways
44:21
that are unpredictable and that it takes at least nine or 10
44:24
months from selection to making vaccine and filling
44:27
vials and distributing it for vaccination,
44:29
that we're always behind the eight ball,
44:32
that we're always trying to catch up with flu evolution.
44:35
And of course, as you know, sometimes the vaccine
44:37
is a good match and sometimes it's a poor match.
44:40
And last year was an example of a less than optimal match,
44:44
and we had a very bad outbreak.
44:45
Of course, we have no ability to predict
44:47
when a pandemic will occur or what subtype it would be.
44:50
And so at the moment, there's really no way
44:51
to make a pre-pandemic vaccine.
44:54
We can only make a vaccine against a virus
44:57
after a pandemic starts, in which case
44:59
it's really too late.
45:00
In this day and age of interconnected travel,
45:04
it didn't take the SARS virus very long
45:06
to be on three continents and the same
45:08
would happen with a transmissible novel flu virus.
45:12
So there has been a huge push by my institute and others
45:15
to try to make so-called universal vaccines,
45:17
and the word universal vaccine could
45:19
mean lots of different things to lots of different people.
45:21
This could be perhaps a vaccine that
45:23
would give you a better breadth of protection
45:24
from seasonal viruses so that maybe you
45:26
don't need to be vaccinated every year.
45:28
Maybe you only have to be vaccinated every five
45:30
years or every 10 years.
45:31
A broader one would be a vaccine that could actually
45:34
be a pre-pandemic vaccine that, no matter what bird or horse
45:38
or swine flu could get into people of any subtype,
45:41
that you would have immunity.
45:43
This is a pretty high bar given how
45:45
diverse flu is and how much it mutates Personally,
45:48
I don't think it's possible to make a sterilizing vaccine that
45:51
would prevent infection from any and all subtypes of flu,
45:55
but I do think it might be possible to make vaccines that
45:57
would at least help mitigate disease,
46:00
reduce transmission, and reduce severe illness.
46:03
And if you could actually prevent severe illness
46:05
and death, that would be a huge public health improvement.
46:09
So a number of groups have very interesting ideas
46:13
out there, many of them based on stock antibody epitopes.
46:17
But we've taken a more generian, general approach,
46:21
and we have been making a series of vaccines
46:23
that are non-infectious, that present
46:25
a mixture of avian influenza virus hemagglutinins.
46:27
These are the donor source for all human pandemic
46:30
and seasonal viruses.
46:32
And so as a proof of concept set of experiments
46:34
that I'll show you, we make an inactivated--
46:37
I mean, a non-infectious vaccine cocktail
46:39
that expresses avian H1, 3, 5, and 7
46:41
in a variety of platforms.
46:43
And we've been able to show in animals
46:45
that it provides extremely broad protection against most
46:48
or all influenza subtypes.
46:50
So as an example, the avian virus
46:54
could protect mice against lethal challenge
46:56
against the 1918 virus.
46:58
So this is within the same subtype that's in the vaccine,
47:01
but not a matched vaccine to the 1918 virus.
47:05
And yet you get 100% protection.
47:08
But more importantly and interestingly
47:11
and intriguingly, we get protection against subtypes
47:14
that are not in the vaccine.
47:15
So the vaccine only contains H1, 3, 5, 7 hemagglutinins.
47:18
And yet any other subtype that we can use to infect animals
47:22
provides protection-- for example, the 1957 H2 pandemic,
47:26
or an avian H10 virus, for example.
47:29
So these are very encouraging results.
47:32
So in summary, in mice, what we have is that, between 10 and 50
47:36
times lethal dose challenges with any subtype that
47:39
causes disease in mice, we get 100% protection.
47:44
You make antibodies against the vaccine antigens,
47:47
but that does not explain the heterosubtipic protection
47:49
because you do not make antibodies
47:50
against the head of novel HAs you haven't seen.
47:53
So there is a huge T cell component to this
47:55
as well, which we're investigating.
47:57
And you can see that you get big rises in memory CD8
48:00
and effector CD4 cells in the lungs.
48:03
You get tetramer staining.
48:05
You get a lot of flu specific CD8 cells
48:08
to various T-cell epitopes on the hemagglutinin
48:11
in the head and the stock.
48:14
One of the features of that induces
48:16
severe pneumonias like in 1918 is this influx
48:19
of neutrophils in the part of the acute viral infection.
48:22
And you completely abrogate and eliminate
48:25
the influx of neutrophils in the lungs of mice and ferrets
48:29
that receive vaccines, and here in ferret experiments
48:33
you eliminate the development of primary viral pneumonia.
48:36
And you're just left with a very mild sort
48:38
of focal bronchialitis.
48:39
You reduce lung titers in ferrets by four to five logs.
48:45
So these data are looking good, and we are a GMP manufacturer
48:50
of some candidates now, and we hope
48:52
to be doing phase 1 studies in humans next year to be followed
48:55
with small phase 2 studies in our challenge model
48:58
in the future.
49:00
So in summary, influenza is an incredibly
49:03
complicated and protean problem.
49:06
It has been with us for hundreds of years,
49:09
and it likely will continue to be a huge problem.
49:11
There is ultimately no way to eliminate
49:13
influenza A viruses from human circulation
49:15
unless we were to eliminate all warm blooded animals
49:18
from the planet, which I think would be bad.
49:22
And so we have to cope with the fact
49:24
that flu is here and continues to evolve and outwit us,
49:28
how a virus with the eight genes and 13,000 bases
49:31
does a lot better than human beings.
49:35
And we still actually don't understand
49:37
very simple questions of how flu viruses move around
49:40
between species, adapt between species,
49:42
and vary in their pathogenicity.
49:44
1918 is an example of a virus that
49:46
is helping us understand some of those questions,
49:48
but is simply one virus out of thousands and tens of thousands
49:52
and millions of flu viruses that have circulated and will
49:55
circulate in the future.
49:57
I think that it's crucially important to study influenza
50:00
in humans.
50:00
We need to do a better job of understanding
50:03
how humans are protected from influenza,
50:06
and what we see is the incredible varied response--
50:08
I didn't have time to talk about.
50:10
But that some people who are challenged develop big rises
50:14
their antibody titers after they clear their virus,
50:16
and some people develop protection against the virus
50:19
and their antibody titers never go up.
50:20
So they're doing other things.
50:22
Are they only doing a T cell response?
50:24
Are they developing stock antibodies but not
50:26
head antibodies?
50:27
And we're beginning to tease some of this out,
50:29
and it's possible that there might not
50:32
be a one size fits all idea for new generations of vaccines.
50:36
It might be that, if you could work out
50:38
the different kinds of responses that you have,
50:40
there might be in a sense multiple vaccine
50:43
choices available in kind of a personalized medicine
50:45
approach in a very Star Treky kind of future look.
50:49
So with that, I will stop and try to take some questions,
50:54
but I want to acknowledge all the people in the group who've
50:58
contributed to all the studies I've described,
51:00
both in the group and our collaborators
51:02
and then particularly our funders, of course the NIH
51:05
and the NIAID funding us.
51:07
But we've also received extramural funding
51:09
from DARPA, from BARDA, and from the Bill and Melinda Gates
51:12
Foundation.
51:13
So thank you for your attention, and I'd
51:14
be happy to take any questions.
51:23
MARCIA DAY CHILDRESS: Wow, thank you very much.
51:25
JEFFREY TAUBENBERGER: You're welcome.
51:25
MARCIA DAY CHILDRESS: You've taken us
51:27
through much territory, and we have quite a nice amount
51:30
of time in which to talk with members
51:34
of the audience about what you think of this presentation
51:38
and what questions you have.
51:40
And Dr. Anthony Peters and I will
51:41
have mics available to bring to you to ask your question
51:46
or offer your comment.
51:47
Please do identify yourself when you ask your question
51:51
or offer your comment.
51:53
So the floor is now yours.
51:55
JEFFREY TAUBENBERGER: Question, right?
52:03
AUDIENCE: Jack Waltney with a little bit
52:06
of laryngitis, if you'll excuse me,
52:08
but not a rhinovirus infection.
52:13
You said what we think of the presentation.
52:15
I thought it was wonderful, number one.
52:18
When you challenge with the volunteers with the spray,
52:22
is that a small particle aerosol?
52:23
JEFFREY TAUBENBERGER: It is a large particle aerosol
52:25
specifically designed so that we do not
52:28
get lower respiratory tract involvement.
52:31
So it's greater than 10 micron spray.
52:34
AUDIENCE: What about a challenge with drops in the nose?
52:36
Is the infection rate in the illness similar?
52:40
JEFFREY TAUBENBERGER: Most of previous challenges
52:42
have been used with drops, and we
52:45
thought that perhaps a spray like this with a large particle
52:47
aerosol would give better distribution,
52:50
that there would be less chance of the inoculum running out
52:54
of the nostril.
52:56
We have not done a comparison of the technology.
53:01
In our H1N1 series, if you have people
53:04
who have low HAI titers before challenge, we see 75% or 80%
53:09
of them shed virus and develop symptoms.
53:11
So it's a very efficient system.
53:14
In our recent H3 viruses, we're seeing a little less
53:16
than that--
53:17
about 60%.
53:18
But still this system seems to be a pretty good one.
53:21
Of course we want to prevent serious illness.
53:23
Obviously, we do not want to induce
53:25
a pneumonia in our volunteers.
53:27
AUDIENCE: There's some old rhinovirus studies
53:29
that suggest drops give you a better infection
53:31
rate that of course--
53:32
JEFFREY TAUBENBERGER: That's interesting.
53:32
AUDIENCE: --aerosol.
53:34
But did it appear that the deaths in the 1918
53:42
were mainly due to a secondary bacterial pneumonia?
53:46
Is that what you said?
53:46
Because you hear of these patients getting sick and dying
53:51
so rapidly it didn't seem like there
53:53
was time for them to get a secondary bacterial pneumonia
53:57
that would be severe enough to kill them.
53:59
And I was an intern when they had the H2N2,
54:02
and we did see patients that would come in
54:04
and died very rapidly.
54:06
And so I wondered what you thought about that.
54:09
JEFFREY TAUBENBERGER: No, those are great questions.
54:13
I think that certainly that there
54:14
were people who had very rapid courses,
54:16
and there must have been some people who had,
54:18
in a sense, fatal primary viral infections.
54:21
But if you look at the aggregate data,
54:22
I think it's overwhelming that the vast majority of people
54:25
died with secondary bacterial pneumonias.
54:27
If you look at tens of thousands of published autopsy studies,
54:31
including careful post-mortem microbiology, 95% of them
54:35
had culture positive secondary bacterial pneumonias at death.
54:39
The average course to death in 1918 from onset of illness
54:43
to death was 11 days, exactly like the 2009 pandemic.
54:46
So certainly there were a tiny number
54:49
of people who probably had very rapid deaths
54:51
or cardiovascular deaths or other things.
54:54
I think the clinical course of severe illness and death
54:56
was one of a viral infection, partial recovery,
55:00
the secondary bacterial pneumonia, and then death
55:04
10 or 11 days later.
55:05
AUDIENCE: Your colleague--
55:08
Bob Chadwick used to talk a lot about nasal antibody.
55:11
Is that still part of the picture?
55:13
Do you think there's anything to that?
55:14
JEFFREY TAUBENBERGER: That's a great--
55:15
I could have paid you to ask that question.
55:17
That's fantastic.
55:19
As I said, I think that serum antibody correlates are clearly
55:23
some marker of infection.
55:24
But flu doesn't have viremic phase, as of course you know.
55:28
It's not a systemic infection.
55:30
And you're looking at antibody at the wrong place.
55:32
It's a localized, mucosal infection.
55:34
And I think the key to understanding
55:36
why flu is such a problem maybe be
55:38
why other mucosal only infections are hard to develop
55:42
vaccines against--
55:43
GI viruses, or other respiratory virus,
55:46
be it RSV or peri flu or flu--
55:48
is that there's something about the memory
55:52
response in the mucosal system that's
55:54
different from a virus like measles
55:55
that has a systemic phase.
55:57
So I think we think that in our group
55:59
that looking at what's happening in the mucosal level
56:01
is going to be really important.
56:02
In all of our new challenge studies,
56:04
we're going to be doing mucosal antibody, mucosal cytokine,
56:06
mucosal brushings, looking at cellular responses,
56:10
as part of that.
56:10
And we hope that this will help us guide vaccine development.
56:15
AUDIENCE: Jeff, thanks.
56:16
That was a tour de force.
56:18
Much appreciated.
56:19
Fred Hayden-- two pathogenesis questions,
56:24
if I may, in your autopsy work from 1918,
56:29
did you look for extra-pulmonary dissemination of virus?
56:33
I know you've done some publication on whether there
56:36
was virus in the central nervous system as an explanation
56:39
for some of those syndromes, but I
56:41
didn't know more broadly if you'd look--
56:43
and I have a second after that.
56:44
JEFFREY TAUBENBERGER: We have not
56:46
found any evidence of extrapulmonary replication
56:49
of the virus by PCR.
56:51
And I think the pathology-- the really good autopsies that
56:54
were done at the time would really
56:56
support that it was a respiratory only thing.
56:58
Of course, if you have a really bad fatal pneumonia
57:02
and you're getting hypoxic and cyanotic,
57:04
you have secondary hypoxic changes
57:07
so that you would typically see in the kidneys and the brain
57:11
and others due to hypoxic damage, but not
57:13
a primary viral thing.
57:14
We do not think the virus was systemic.
57:18
AUDIENCE: That's helpful.
57:19
There've been no reports, even with seasonal influenza
57:23
B with myocarditis and things like that,
57:25
leading to fairly rapid mortality
57:28
in some unfortunate individuals.
57:31
And then getting back to this issue
57:33
of the importance of the host responses,
57:36
these immunopathologic responses,
57:39
and you showed data mostly on the reactive oxygen species.
57:44
And have you examined any interventions
57:47
that might influence the influx of polys or their activation?
57:52
Have you had a chance to examine that in the animal models
57:54
or in the challenge model?
57:56
I mean, really what should we be testing?
57:59
JEFFREY TAUBENBERGER: Yeah, I think those are really
58:01
excellent things, and the neutrophilic influx is really
58:06
characteristic and cardenal feature of the 1918
58:09
pathogenicity that seems to be shared with, say, H7 virus
58:12
infections, not with H5 as an example.
58:15
So it could be that that, for certain viruses with those
58:18
subtypes that we model, that pharmacotherapy that
58:24
could, in a sense, influence neutrophils influx
58:27
into the lung or activation might be important.
58:30
But there's a knife's edge because, if those people
58:33
with severe flu infections develop
58:35
secondary bacterial pneumonias, it's
58:38
hard to know how you would do that in a clinical setting.
58:42
So mostly we were trying to show that the inflammatory response
58:45
itself was contributing to the pathology,
58:47
but there is the possibility that you could intervene
58:50
in a very careful way in a very severe viral infection
58:53
in a way that could modulate immune responses.
58:55
But we have not further investigated.
58:58
AUDIENCE: I'm Costi Sifri, infectious diseases-- so I also
59:01
want to thank you for providing just a fantastic lecture.
59:05
I just was really curious specifically
59:07
about your observation about neuraminidase
59:10
and its marker as a correlative immunity in comparison
59:15
to hemagglutinin and a two part question that
59:17
may be settled science.
59:18
But is there any implication in terms
59:22
of that finding with recombinant hemagglutinin vaccination,
59:25
which is now on the market?
59:27
And also-- and this may be settled science--
59:30
but is neuraminidase an alternative target
59:33
for vaccine development?
59:34
JEFFREY TAUBENBERGER: I think that neuraminidase should
59:36
be an important target for vaccine development,
59:39
not necessarily by itself, although you can imagine,
59:42
for example, that you could supplement neuraminidase
59:44
in the vaccine.
59:45
So a couple of points--
59:47
the current vaccines, inactivated
59:49
vaccines are inactivated virus vaccines
59:52
but that then tend to-- the hemagglutinin and neuraminidase
59:54
are split of the virus and purified.
59:57
The process is such that, while neuraminidase
59:59
is present in the vaccine, it's less likely to be immunogenic
60:03
than the HA, probably because it's just less--
60:05
the tetramer of neuraminidase is less stable.
60:08
So often, even though neuraminidase is in the vaccine
60:10
and it's not quantitated like HA,
60:14
you variably get an immune response.
60:17
Some vaccines do, some perhaps don't.
60:20
I think that making NA more immunogenic
60:23
and quantitating NA would be a big improvement.
60:25
So one possibility would be to have a supplement NA vaccine.
60:29
We've done vaccine studies where we just
60:31
make NA expressed on a viral like particle--
60:34
so no hemagglutinin.
60:35
And we can vaccinate animals and provide
60:39
really excellent protection against nasty viruses like H5.
60:43
So clearly neuraminidase immunity is really important.
60:47
These data are very old.
60:48
I mean, neuraminidase data go back to the '50s and '60s
60:51
that it's a really important correlative protection.
60:53
But for whatever reason, the sort
60:56
of whole government vaccine industrial complex for flu
61:02
has just focused on hemagglutinin titers
61:06
in the absence of really good data.
61:07
So I would strongly encourage that new vaccine candidates
61:13
focus on adding at least an immonogenic neuraminidase.
61:18
AUDIENCE: Erick Hewlett over here.
61:21
You showed that virus shedding occurs before symptoms begin,
61:26
but with the course of illness as a relatively brief period
61:30
of time, how do you envision transmission
61:32
occurring long distances to India
61:35
and places like that in 1918 when they didn't have
61:38
travel the same way that we do?
61:44
JEFFREY TAUBENBERGER: Flu viruses are not
61:46
nearly as transmissible as many other viruses
61:49
like measles for example, but they're clearly
61:50
transmissible enough.
61:52
So the R0 for flu is somewhere around 1.51, 1.7.
61:57
So one person can give it to 1 and 1/2 people or so.
62:00
But that's clearly enough-- and there's probably
62:03
contact transmission.
62:04
There's large particle and small particle aerosol transmission.
62:09
I think one of the reasons that flu viruses transmit more
62:12
in the winter months is that people are more likely to be
62:15
closer together and indoors.
62:16
Kids are back in school, these features.
62:18
But the spread of virus in 1918 or even before that
62:22
was the same way.
62:22
It was just person to person.
62:23
And in 1918, the world was still relatively interconnected
62:26
that the exact same week that the flu peaked in Philadelphia
62:30
it was peaking in Auckland, New Zealand and Town, South Africa.
62:34
I think the virus had been seeded everywhere in the world
62:37
during the wrong time of the year.
62:40
It was in the spring and the summer
62:42
when it was the wrong time of the year for flu
62:43
to circulate because temperature, humidity,
62:45
and other things and that, when the appropriate time came up,
62:48
it just exploded.
62:49
So it really was everywhere.
62:51
If you go back to the first pandemics of the 1500s that
62:54
were seen and recorded in North America,
62:59
they follow in less than a year from a pandemic in Europe
63:02
and being brought by the tiny number of people coming
63:06
on the tiny number of ships coming
63:07
to the New World in the 1500s.
63:09
So clearly flu spreads really well.
63:13
There's a paper in the 1700s of a British physician who
63:15
talked about how outbreaks can occur in towns in England
63:20
faster than you can get there by coach.
63:22
So obviously that can't be true, but with this idea
63:26
that they're seeded everywhere and then, when the right time
63:30
comes, they kind of explode.
63:31
That's I think the best explanation.
63:33
MARCIA DAY CHILDRESS: So we're out of time,
63:35
but I'd like to thank Jeffrey Taubenberger
63:38
for an amazing hour.
63:40
Thank you.
63:41
JEFFREY TAUBENBERGER: Thank you.
63:42
[APPLAUSE]