Prevention of Seasonal and Pandemic Influenza

Prevention of Seasonal and Pandemic Influenza


– Good afternoon, everybody. Thank you so much for coming
on a rainy Friday afternoon, I really appreciate you being here. And it’s really, in case
anybody doesn’t know me, I’m Ethel Kagan, I’m
the assistant director in the IDGI Pulmonary Group. And it’s my distinct pleasure
today to introduce you to Dr. Chip Walters. I’m sure most of you already know him since he’s been at Duke for a long time. He’s done a lot of work on vaccine and other types of research. He is associate professor of pediatrics, he’s also in the department
of pediatrics division of primary care peds
and infectious diseases and he’s also very involved in the Department of Epidemiology in the Gillings
School of Global Public Health. So without further ado, I’m
going to turn things over to Dr. Walter and he’s going to talk about a very I think topical
topic, and that is H1N1. – Thanks, Ethel. I’m just going to start,
how many people were here, I did a noon session
a couple of weeks ago. Mary was. (chuckles) Well, if you were here
a couple off weeks ago, I threw in a few different
things ’cause I knew like I’m coming back
and with the same people or they’re kind of walking out. I didn’t want to give
exactly the same talk. Many of the slides will look familiar but I figured some of the audience will be somewhat different. And I focused it a little bit differently. The talk I gave a couple
of weeks ago was entitled, Vaccine Unit Update and
also Influenza Update. Somehow maybe I’ll change
the title this time. So I was going to talk
more about prevention of seasonal flu and H1N1 influenza. As Ethel said, I am a
primary care pediatrician so I do mostly outpatient
pediatric, see sick kids and been seeing lots of H1N1 influenza. But the other part of my
time is spent doing research, so I work in the Duke Vaccine Unit. We actually have with us here, in your midst one of the very founders of the vaccine unit, Mary Maggio. When I first started working
with the vaccine unit, Mary was the study coordinator
with the vaccine unit before it was even called
a vaccine unit, right Mary? So she is one of the originals. Let’s see, is this gonna work? Let me go this way. Am I locked? Unlocked, okay, let me go forward. It’s not going forward. (man in black mumbles) I have to do my disclosures next, so maybe that did it, okay. So that’ll do it. – You go ahead and I’ll– – Okay, just quickly do my
potential conflicts of interest. I do get grant support from a number of different industry sponsors and I guess I probably should add the
federal government as well. That probably is a little
bit conflicted now. And I do some speaking for
Sanofi and Merck as well. And if I can, okay. – Right-click– – Right-click, okay, great. So before I start off talking about flu, I think it’s always important
to remember what the impact of influenza is. And you can see there,
everybody is so hyped about H1N1 Influenza. But I think we really need
to remember that on average, 36,000 deaths per year
occur in this country and 226,000 hospitalizations
due to influenza. So just because this is
H1N1 and has potential for potentially affecting more people, I don’t think we really
should ignore the implications of every day flu that we see each year. So before I start, I’m
gonna talk a little bit about the germ itself, influenza. This particular virus is an RNA virus and it has eight different genes, and there are really three
different genetic types. There’s an A, B or C influenza. And when we’re talking about H1N1, we’re really talking about type A. But if you’re talking about seasonal flu that occurs each year
you’re talking about really both types A and B. And type C is really ever
rarely reported in humans. When you think about the implications, clinically for influenza,
generally type A causes more moderate to even severe illness, can affect humans and other
animals whereas type B, generally only affects humans. And type B we usually a think
of affecting more children, so in my pediatric populations seem to be more disproportionately
affected from type B disease than type A. And the other thing that’s very important when we think about type A
is that it very frequently experiences that the virus undergoes a lot of genetic mutations or changes, and this is why we have
to vaccinate every year. Whereas type B is really a
lot more genetically stable so there are not a lot of changes. This is a cartoon of the virus here, and you can see the
different RNA segments. But really what’s important to notice are the surface proteins, viral proteins. And there are two that are
of particular importance. When you hear H1N1, what does that mean? Well, it’s really referring
to the type of hemagglutinin and there are a number of
different types of hemagglutinin, and the type of neuraminidase. If you’re talking H1N1, you’re talking the H1
type of hemagglutinin, the N1 or the number one
type for neuraminidase, you might hear H3N2 which
would be a different hemagglutinin type and a
different neuraminidase type. Now what are these viral proteins for? They’re important for attachment
of the virus to host cells in the respiratory tract and that’s particularly the hemagglutinin. And the neuraminidase is really important for viral release, yes? – [Man] I just have one question. What is, if you go back a slide. – [Ethel] Let me grab the mic. – [Man] Sorry, what is type C influenza? – It’s usually, more affects animals. So it’s not not really
important as a human pathogen so I’m going to kind of gloss over that. – Okay, thanks. – But good question and feel
free to stop and ask questions as we go along. It doesn’t really have a lot of importance for human disease so I’m not
gonna spend time on that, okay? And then there’s another
protein which is the M protein that I just want to point
out there, out here as well but the really important ones
in terms of pathogenicity are the hemagglutinin and
neuraminidase proteins. And these are the surface
proteins that give rise to what we know as protective antibody. Some of the data that
I’m gonna show you today, a lot of it’s really
more focused on immunity to the hemagglutinin protein, and we really think this
is the important marker for protection in influenza historically. But it may not be the only one. So how are these things named? Well, the World Health
Organization has come up with the nomenclature for naming influenza and if you look here, its first
name for the type of isolate so A or B or as you point out, maybe C. But in this case, since
we’re really only dealing with human isolates we’re
going to talk about A and B. The second letter here is Brisbane, that’s where it’s isolated. This is just really denoting
the number of isolate from the laboratory. This is the year in which
it was first isolated and then this last designation
here is the subtype of hemagglutinin and neuraminidase, so here we’re saying H1N1. Now this particular
isolate here is actually a seasonal influenza, this is not the H1N1 that we’re talking about. The H1N1 we’re talking about
is H1N1 California, okay, isolate so it’s not, and
it would be a 2009 isolate. So this is actually the isolate that’s in the current
seasonal influenza vaccine which has three different strains
in it and this is the H1N1 that’s in the seasonal flu vaccine. But I just wanted to point
out how these things are named in case you see all these things when you’re reading about it. Okay, so how is influenza transmitted? Well, it’s usually transmitted
by respiratory contact from person to person. So it’s transmitted by
when we call for sneeze, we aerosolize these particles
and then you come in contact with the aerosol and you potentially, you will get infected. The incubation periods
about one to four days, so after you contact somebody with disease that you come down with infection. You can also get infection
from direct contact with respiratory secretions. So if somebody sneezes or
rubs their eyes or whatever, touches here then you
go and you touch there and you rub your eye, which
I’m not gonna do right now, then you can potentially
transmit infection that way. So that’s why we talk about hand-washing is a good measure to prevent contagion. You can’t always protect
against this kind of thing that you’re seeing at
the top of the screen. So once somebody is infected, how long are they infectious for? Generally, we consider that
adults are probably infectious for about three to five days. Young children can shed
virus for some time, they can shed for up to 10 days. And if you’re immunocompromised
you might shed even a little bit longer. But that’s from the time that right before you become symptomatic
or right at symptoms or one day before until you stop shedding. Now, the general guidance
has been this flu season, is that somebody afebrile 24
hours can go back to work. Now that’s not afebrile on
Tylenol or motrin, okay? So we get parents that think that but… It’s afebrile without
Tylenol, without motrin, kid needs to be feeling pretty
good to go back to school. Now you could potentially transmit virus but there’s probably less
virus there at that point. But the young child still may
shed some virus at that point. Obviously if the kid is
still coughing a lot, a lot of runny nose you’re
probably not gonna want to send them right back to school. I think most of us know
the signs of influenza, fever, muscle aches,
headache, coughs, sore throat and runny nose. Children may get a lot more GI symptoms, so they may throw up. And it’s interesting, with the H1N1 virus, adults seem to be getting a
little bit more GI symptoms and that may be the, part
of that may be the fact that when children get
flu it’s novel to them, their bodies have never seen it before. Well, just like this
virus is novel in adults, so maybe one could think, maybe that’s why adults are
having some more GI symptoms with this particular infection. So usually though when I think
of flu or influenza illness, I think of fever and respiratory symptoms, so fever and cough are really
the hallmark symptoms for flu. Now how do we diagnose it? This has been really
problematic this year, particularly problematic, and why is that? Well, there are a number of
different ways to diagnose flu. Well, you can draw blood
and measure serologies but you have to do it at the
time that somebody comes in and then you have to do it
two to three weeks later. Well, that ain’t going to help you. So that really is only good
as a marker for infection and research and it’s a
good marker that we use in vaccine studies. And there are a number of
different assays that we use in research to look at responses, particularly the vaccination. So you’re left with trying
to isolate the virus. So you can actually grow the virus but that takes two, three, four days. So that ain’t gonna help you
if you’re sitting in the clinic with a bunch of sick people. You kind of want to know the answer now. So there have been a lot
of rapid detection tests that have been developed
over the years and approved that take less than 30 minutes. Anybody can run them pretty easily. The problem with a lot of those assays is that they have very low sensitivity. So if you go to the
clinic and you’re sick, it just may not test positive because they’re not very sensitive. And the other issue is
particularly with this H1N1, we found out that the
specificity was fairly low. So we had people testing
positive or kids in the spring testing positive on the assay,
and we’d send over a PCR test and they would be negative. So the specificity really
wasn’t very good as well particularly if you’re out of season. So these rapid tests aren’t very helpful. You can do fluorescent antibody
testing if you have a lab that can do that and they’re
fairly sensitive in good hands. Again you have to have the lab and what we really have
relied on is PCR testing which takes, here at Duke we send off a sample and we
get it back the next evening. So usually I get it back at 5:30 and then I’m calling
parents the next evening if I’ve done a test. So who are we testing? I don’t know that I put that in here. Really I’m only testing for
H1N1 certain populations and I will, I don’t know if
I come back to that later on but I’m really only testing
people who are hospitalized, although I don’t work
in the hospital too much would get tested or people if there’s a really high-risk condition. So if I have a child coming in sick and there’s a pregnant
mother, I think in that case it’s really important to try and document. Or if I have a young
child who’s at high risk that I’m going to treat
then I would go ahead and potentially test that child as well. Now I think when we’re talking, I’m still talking about
seasonal flu before I’m really, I’m kind of jumping back
and forth between H1N1 ’cause I’m going to try and show you how, we’ve learned from seasonal flu to kind of extrapolate to H1N1. But when we’re talking about seasonal flu, we always have to remember
that the peak for seasonal flu usually doesn’t come till February. And usually we start our
vaccination campaign, September, October, so in
fact, you have a long time. ‘Cause it only takes a couple weeks to get an immune response. You have through January a lot
of times to get your vaccine but I can tell you in
the clinic by December, we don’t want to see a flu shot. We are sick of flu shots. We’ve been given them so
long that we’re really tired. The enthusiasm starts to wane. But in fact it probably
shouldn’t and we really should be vaccinating
people up until flu season, which traditionally peaks in February. Now, right now I don’t know
if I have the curves for H1N1, we’re peaking and coming
down off that peak, I don’t have this week’s curve on there which I’ll show you later. But we don’t know what’s
going to happen in the spring. Some people have predicted that maybe H1N1 will come back in the spring. So it’ll die down and it’ll come back. Some people predict that
we’ll have seasonal flu, perhaps an H3N2 or a B in the springtime, we really don’t know. If we see it it probably
will occur around February which would be traditional. Now, as I mentioned,
this virus changes a lot, a lot of genetic changes
and there are two ways it can change. It can drift, so you
get really minor changes in the genetics, point
mutations in the genes. And it does this every year. It changes pretty much a little bit, the virus strains change almost, that’s why you have to
get a flu shot every year because the virus changes every year. It’s one of the few things
that you have to go in and it’s crazy we haven’t
figured out how to get a vaccine that cross protects against all these different
strains but we haven’t. So that is the reason why you
get a flu shot every year. But every once in a while
you get a major reassortant of the genes, for these viruses that leads
to a big shift in the virus and that’s what happened this year. We got a big shift in the virus, I’ll show you a cartoon
for the H1N1 down the road when I get more to H1N1. And the population hasn’t
been exposed to it before. The population isn’t immune. That means more people are susceptible and that’s why we expect more
people to get an infection, more people to be
hospitalized and potentially more people to die than what
you saw on the first slide. So the World Health Organization monitors this influenza activity
every year and they pick the vaccine candidates
based on what drifts and shifts they see. And usually for vaccine for
the northern hemisphere, they select that vaccine in February. But remember this epidemic
didn’t start until what? Like April, May of this year that we really first became aware of it. So the vaccine strains
have already been picked for this year’s vaccine, so that’s why the manufacturers were set and heading down that path
to make these vaccines. So it required to make an
H1N1 vaccine really retooling and thinking, making a
whole separate vaccine. And each year they select
two A type strains. So it’s one H1N1 strain and one
H3N2 strain and one B strain go in the vaccine. So this year’s vaccine
strains for H1N1 are here, the H3N2, you see everything
came from Australia this year. But these are the strains. So you can see there
was very little change between last year’s vaccine
and this year’s vaccine. There was no change in the A strains, it was only a change in
the B strain this year. So when you’re talking about
traditional flu vaccines, these are the current flu
vaccines that are on the market for seasonal influenza in this country. And they’re made by what? Five different manufacturers,
this is an Australian company that was recently licensed
a couple of years ago. After we had a lot of
shortages of vaccine, the US government funded
studies which we were part to bring additional
licenses to our vaccines to market here in the country
because manufacturing problems seem to be occurring every year with the current manufacturers
that were in the market. A recent change, the GSK product, so their inactivated
vaccine had an indication for over 18 and that now has an indication down to three years of age. If you’re looking in the
very youngest age group, from six to 35 months there’s
really only one vaccine that’s on the market. And then this last vaccine down here is a live attenuated vaccine
that’s a missed vaccine. You all have probably
heard of FluMist and it is, and I’ll tell you a little
bit more about that. It’s only approved for those
who are two to 49 years of age. So these two vaccines,
the inactivated vaccine is administered by injection. It’s killed, it’s not live,
it doesn’t cause the flu. As everybody always thinks,
flu vaccine causes the flu. This is killed, dead, does
not cause the flu, okay? Can be used for anyone six
months of age or older, and really the only contraindication
would be egg allergy. Potentially if somebody had a history of Guillain-Barre syndrome
which isn’t totally common. It’s fairly, fairly rare
would be another person that I wouldn’t give it to. The live attenuated vaccine
has more restricted use. As I mentioned it only
can be used in persons two to 49 years of age. And I’ll briefly mention that children under five with
possible reactive airways and people with asthma
should not get this vaccine because it can trigger asthma attacks, remember it’s a live attenuated vaccine. So you’re giving that
nasally and it can cause a little cold symptoms,
runny nose, stuffy nose. So we generally don’t give
it to people with asthma or anybody with a
high-risk medical condition or pregnant women. Do you have a question? – [Woman] Why 49? – 49, that was just the age to which it was initially studied so
that’s the indication it got. Why two? I can probably answer better, it was actually studied at younger ages and what came out from the
initial studies are two things. One is that if this
phenomenon of higher rates of wheezing particularly
if you had underlying or had had prior wheezing episodes. So that came out in the wash
when they did the study. And then the other thing,
young children seem to have higher hospitalization rates, not necessarily for wheezing but all types of hospitalization rates. So that didn’t seem to be
true if you were over two, but for those under two it did. So therefore it was decided
not to approve this vaccine for those under two. So these vaccines are both
effective for kids and adults. And what’s interesting
if you look at the data for both these vaccines, it’s different. Which one seems to work better? It depends on how old you are. So if you’re a young child
in fact, it seems as, it appears as if the live
attenuated actually works a little bit better. If you’re older, there have
been a series of studies done by one group over
many different seasons now that suggests that the inactivated is a little bit more effective. Why is that? Well, probably has to do with, these people have prior
experience with influenza and influenza vaccine,
they are not vaccine naive. Whereas these are very
naive hosts so therefore, the live attenuated
stimulates mucosal immunity and maybe that’s more important
in your primary infection. I don’t really know the
whole entire answer, I don’t think we quite understand
it but these are the data. So who do we immunize seasonally? This is a little bit
different than what we talked, are talking about with the H1N1 vaccine. So the priority groups
are a little different and I’ll explain why a little
more when we get to the H1N1. So anyone who really wants flu
vaccine can get flu vaccine, there’s no restriction on that except if you’re egg allergic,
we don’t have a vaccine if you’re egg allergic. Children six months to 18 years of age are a particular target group, particularly individuals at higher risk. So the higher risk kids
in Australia data suggest to emphasize that in just a few minutes. So if you’re six to 59 months
of age, if you’re over 50, if you’re on aspirin therapy, if you have underlying
pulmonary or cardiac conditions, if you’re immunocompromised
or if you’re pregnant, those are all considered high-risk. Another particular group
that we like to focus on if you’re a household contact, somebody who’s at high risk. So particularly children
or older individuals, and also healthcare personnel should get the vaccine as well. Now, how did these recommendations
for children come about? Well, they have evolved
over years in practice. So back in 2002 was the first year that we actually encouraged vaccine for the youngest age group of kids. And then the recommendation changed, it became more formal in 2004. This extended up to age five in 2006. 2008, it actually extended up between, to everybody up to 18 years of age so now we recommend vaccine
for the whole age cohort, six months to 18 years of age. So this has evolved and part
of the evolution of that has been supply of vaccine. If we had necessarily
said that five years ago there wouldn’t have
been a supply to provide to this whole entire age group. But the other indication if
you looked and reason why is risk and then also who spreads flu. And you can clearly show
that school-age children are the vectors for
influenza in the community. So if you have campaigns to
vaccinate school-age children, you can actually show reductions and there’s been studies done
of influenza in the community when you just vaccinate school-age kids. Particularly, they’re the vectors, those are the ones we
need to be immunizing. So the recommendation for kids
is a little bit complicated because if you’re under nine
for seasonal flu vaccine, you actually need two doses
of vaccine one month apart. So now, thinking about that, that is logistically very very difficult. Adults only need one dose. If you’re over nine,
you only need one dose. And if you had a prior
dose in a prior season and you’re a kid, you don’t really
necessarily need two doses. There are some limitations on that. But if this the first time
you’re getting vaccine and you’re a young child, you need to get two doses a month apart, well think about that. We see about a thousand
kids per birth cohort here in our practice. That means we have to get 2,000 kids, 1,000 kids in twice in
a short period of time in about a month period to
vaccinate them in our practice. Plus every other kid up to age 18. That’s a lot of kids that we
have to give flu shots to. So why do we have these
recommendations for kids? What proof do we have that it helps? Well, one of the very
first studies and I think, Mary you were here when
we did this with Tina. We actually, this is with Dr. Clements. Dennis Clements who was
one of the originators of the vaccine unit when I
very first joined the group. We actually went out to day
cares and we immunized young kids in the daycare with flu vaccine. We gave half of them flu
vaccine and the other half we gave actually hepatitis B vaccine because it was actually before
the recommendation came in to give hepatitis B vaccine. And what we showed is that we
could actually reduce the rate of otitis media in that
group during the flu season. And when you think about it, makes sense. You have some kid who gets influenza, they get a lot of runny snotty nose, everything gets congested up here, the eustachian tubes get
blocked and what happens? Bingo, they get an ear infection. So it really made sense. There are several studies
that have actually showed this and it showed a benefit
to immunizing young kids with flu vaccine. The other point I was trying to make is that flu for young
kids is not a good thing. And if you look at hospitalization
rates, you can see here that hospitalization rates
as you go down in age from five to 15 actually increase. If you look at the very
youngest group under six months, the hospitalization rates are really high and actually if you compare
they’re as high as they are in the elderly, it those over 65. Also if you look at mortality rates and this is just one particular
season, that bad flu year we had in 2003, 2004, you can see here, as you get down in age for kids, the mortality rate went up
in that particular season. Well, so these recommendations
came about to immunize kids and we were sitting around thinking, this is going to really be difficult to try and get all these kids in. So what happens, what would
happen if you gave flu vaccine in the spring with last year’s vaccine because it’s still sitting
around in the refrigerator, and you gave one dose in the spring and you gave the new one in the fall and it’d be a lot easier than
trying to get all these kids in at one time. And what would happen if you did that and compared it to just
the current recommendation of getting two doses in the fall. We thought that’s a pretty
practical study to do. So my colleague and I,
Janet England in Seattle kind of came up with this
study and presented it to one of the vaccine manufacturers. He said, it sounds like a good idea so they actually nicely funded this study. Well, so the study design
was we gave a dose of TIV in the prior season,
gave a dose in the fall and followed it up a
month later just to to be, give standard of care. And then we gave two doses,
compared it to a group who got two doses in the fall. We enrolled them all at the same time and randomized them to get to
either one of these two groups and then we measured Sera. These are kids so you can’t
draw blood every time you want because these are little kids, the parents won’t sign up for the study. They’re screaming so we
have to be a little bit nice so we’ve limited it to two blood draws. So we did one, for the spring
fall group we did one baseline and we did one after dose two. And for the fall group we
did a Sera after dose one and then one after dose two. So everybody had, this
group when we compared it, our main outcome was
comparing after two spring, a spring and a fall dose, excuse me, to two fall doses, okay? So the first year we did this
study, and what so happened that the vaccines didn’t change between the spring and the fall. It was like the only
year that I remembered the vaccine didn’t change. Well, it was actually to our
advantage that that happened because then the manufacturer
funded us for a second year. But, so we did this
study and lo and behold, we showed that if you got,
this is after two dose comparing after two doses,
this is the spring fall group and the fall fall group,
pretty comparable responses. And this is looking at anybody
to that hemagglutinin antigen which is considered to be the standard. So if you got above this level, it’s usually generally
considered protected. Depends on the assay you do, some say it’s greater than one to 32, some say greater than one to 40. So that was our result in the first year. Well, then we thought well
we got to restudy this when the antigens change. Well, we were hoping for
a little better result but we got actually some
interesting results. What they showed is for,
if you change the antigens, actually here for H1N1
they were pretty comparable when you change the antigen
and you’re comparing the spring fall versus the fall fall. However, for the H3N2, it was different, and for the B it was quite different. So we weren’t able to demonstrate, what we demonstrated by that is, it’s probably better to have
two fall doses than it is to have a spring and a fall dose. However, I want to point out
a couple of other things. And this is important when
we’re talking about H1N1. Look what happens if
you just give one dose. You get a very little response, and this is considered protective, very few kids get protected with one dose. That’s why we give two doses. And remember these are all kids who are probably disease,
pretty much disease naive because there their baseline
titers or their vaccine and they were all vaccine naive. So as you can see, this is current data, how are we doing at distributing
all these second doses of vaccine in real life. Because we’re stuck with this
policy to now give two doses and actually we thought
we were going to change the recommendation and the
recommendation then came forward from our study and some other studies, that if you only got two
doses, if you only got one dose and it was the year before then you need two doses that fall. So they made it even more strict. We thought maybe we would
get things liberalized a little bit. But anyway how are we at giving two doses to kids in the fall? Not so good, only about
30% of kids get both doses in the fall in that age group. About 50% are getting a
single dose of vaccine. Now, which brings me to the next point. If you looked, remember
I showed you that graph, which kids were at the highest risk for influenza hospitalization? Kids under six months, okay? They’re the age group
for which we don’t have any vaccine, all right? Well, why is that? Well, just recently,
we reanalyzed the data from those two studies over two years and looked at it by age. And you can see here
there’s a clear trend, and these are kids who were
seronegative at baseline. There’s a clear trend in
every analysis that we’ve done looking at this data, that
as the age group decreases your immune response decreases. So young kids tend not to
respond to vaccine as well. So besides the fact that
the data aren’t there from studying it in young kids. So several years ago,
we did undertake a study where we looked at giving
vaccine in children at between six and 12 weeks of age. We compared the responses to
kids who were six months of age and lo and behold you can see
they don’t respond as well. But there’s a caveat to that in that, a fair amount of these kids
because we did this study in the spring and the youngest group had antibody from their mothers. And this data here just
shows that if the mothers had had vaccine less than
180 days before birth, we collected that information, that in fact the baseline
titers were higher. So when you pull out those
kids who had baseline, Sera positivity, in
fact the immune response was pretty comparable. So that led us to do a
placebo control trial comparing vaccine versus
placebo in young kids. I don’t like to give placebo to young kids but we did in this, it
was a multi-site study. All the data from these
two studies are actually going to be published
in January and February. But here, these have been
presented and you can see here that responses to TIV
versus placebo are higher. About 50% of kids respond in
this, six to 12 age group month six to 12-week age group
with a protective level to H1N1 and about 80% respond to H3N2. Responses to B are abysmal
and that is not uncommon in many different age groups. The drug company went to the FDA to say, what about getting this
approved for young kids? They want to see efficacy data so that has yet to come. So until then what do we have left to do? We vaccinate caregivers. So this is called the cocoon strategy to protecting young kids, we vaccinate everybody around them. So this is the child care
provider, the health care worker, parents, siblings and grandparents. Now, you’d think this
would be for mothers, it would be pretty much a no-brainer. We have a recommendation
to vaccinate pregnant women yet if you look at the
national data, the latest, only about 24% of pregnant
women get flu shots during pregnancy so it’s pretty low. Health care workers aren’t
necessarily a lot better, but there are clearer data to show that as you go along in pregnancy, your rate of hospitalizations
actually increase. And I think we’re seeing a lot
of this information obviously emerge with the H1N1
epidemic that pregnant women are at high risk. So two seasons ago we
actually undertook a program at Durham Regional where we
offered vaccine to new mothers, fathers and made it available for siblings at Durham Regional in the hospital, and we were actually able to show that we could increase vaccination
rates at Durham Regional. About 40% of women actually had had it, reported having it prior
during the pregnancy. That was pretty good
compared to national data, but we were actually able
to increase that rate up to about 70% by offering
it in the hospitals. Likewise, dads we got up to about 50%. Okay, I’m going to switch over now and kind of move on to H1N1. And you can see here as I mentioned, pandemics occasionally do occur. This is when the virus changes a lot so there’s a big genetic change. To my way of thinking we always
have traditionally thought you can look down here of
thinking as the subtype changing, you can see here in every change, there’s been a change in
the type, the number type. So we went from an H3N2 to
an H1N1 to an H2N2 virus to an H3N2 virus to an H1N1. Well, what’s happened
since these pandemics, since these two, our last two pandemics since ’68 actually H3N2 an
H1N1 have kind of co-circulated in the population. So that’s why you see that the vaccine actually contains two different strains, it contains an H3N2 and H1N1. Some years we have more H1N1,
some years we have more H3N2, some years we have more B. But these were the past pandemics and as you all know the
1918 one was the big one of all big ones which caused
the most severe illness. Clearly we were overdue. So this is the bug, the
current bug, it’s H1N1. This right here was a
triple reassortant swine flu that actually had been around
for 10 or 15 years or so, and had been in the swine
population and occasionally had been transmitted to persons in the US, and there had been a
limited report of cases and it was really only
transmissible from animals. But you can see here,
what we have in California was actually something similar to this. But this particular
virus actually contained a Eurasian swine lineage,
so it actually has genes from a Eurasian influenza in there. Now, the other thing that I
think I want to point out here is that the hemagglutinin
in here actually comes from a swine strain. So it’s not like the
current seasonal H1N1. So remember I said there was
H1N1 in the current vaccine and this is H1N1, but
they’re very very different and that’s what makes this novel and is making it a pandemic. So unlike my classical thinking, where you switch over to an H5N something, this one stayed H1N1 but it
is very genetically distinct. So what’s happened with
this virus over time? You can see how the pandemic
has spread and this is activity over the past, I think by four week blocks starting here in August. And you can see it kind of started more in the southeast area probably
as kids went back to school, and has spread and really pretty
much has filled in the map. If you look here, I didn’t
update this slide this week, I’ve been pretty much updating them weekly but I didn’t change this one. You can see that I think
we’re past the peak and actually it’s really
kind of starting to come down here in North Carolina. So I think we hit the epidemic early and we’re kind of on the downward trend. So what about H1N1 vaccine? Well, this looks very
familiar to what I showed you on the earlier slide. So the different manufacturers
have come in with vaccines and got licenses for these
products and approvals really based on their current licenses for seasonal influenza vaccines. So they pretty much basically just said, it was a strain change difference and that’s how they got a quick approval. The last one to come in
and just got approval I believe two days ago and I heard this ’cause I was watching CNN at night. So I quickly edited
this to my slide was GSK just got approval this
week to bring more vaccine for their vaccine. Why did this take so long? They’ve been making an adjuvanted vaccines and the United States is very hesitant about adjuvanted vaccines. So they had put a lot
of their eggs literally into making the adjuvanted
vaccine, but they I think somehow eventually agreed to make some non-adjuvanted vaccine
to bring to US market. So now there will be four
inactivated vaccines. Again, only one for the youngest age group and there is also a live
attenuated vaccine as well. Now the target groups, as I mentioned, are a little bit different, why is that? So here we’re targeting
again pregnant women, people who care for young
kids, healthcare workers and young kids between
six months up to 24 years. And remember I said, the
reason this kind of extends is really it’s this young
school-age population and consider that kids up to
21, 22 are still in school, many of them that are
easily spreading virus. So that’s really why that recommendation is a little bit different,
up to 24 years of age. But the older age group
isn’t in this cohort. Well, why is that? And this was just in this week’s
New England Journal article and this differs from some
data that was published I think in Nature a few weeks ago that was presented at some meetings. The data from the Europe actually showed that the only people that
had protective antibody were really people that were
born back before like 1910, back in this earlier. So, it was really but
you had to be really old, or before 1910, 1920 I guess. But the data here from
the United States suggests that there may be some protective levels actually even if you extend
out to people born in 1940s, maybe even up to 1950. And there was some preliminary data that the CDC presented in their MMWR that suggested that as well. So it seems to be that older people have some protective level of antibody. Does this explain it all? Probably not, there may
be some cross-protection from other antigens, the
neuraminidase antigen, this is really only measuring
antibody to hemagglutinin. There may be some cell mediated immunity but clearly if you look at the
way the current epidemic is, older people seem to be more spared. It’s younger people, younger
adults and young children that are being
disproportionately affected. The other interesting
thing about this paper which isn’t shown here is if
you had the swine flu vaccine in 1976, how many people
had that, including myself? I was in college and we all
lined up and got our shot. If you had that vaccine
and you were older, you seemed to have
cross-protective antibodies to the H1N1 vaccine or to H1N1. A fair number of people did, a pretty high level of proportion. If you were younger when you got it, they went back and had Sera from that when they did those studies
since they reanalyzed it. If you were younger and
you got that vaccine and hadn’t seen prior influenza illness, probably it was novel at that time, you didn’t have
cross-protective antibodies. So older, how old was older? Probably if you were over 20. So if you were college-age
and got the vaccine, you probably had some protection. So maybe that’s why I didn’t
get sick in clinic this year, I don’t know. So this is kind of flu this
year and I just kind of, lots of questions and tough answers. So what happened when this, we had the vaccine, we knew it was coming, yet it really wasn’t very well studied. We didn’t have a lot of answers. We knew we were going to have vaccine but, who are we going to give it to? How many doses did you need? What kind of dose did you need? I’ve already shown you that young kids when it’s the first
time they’re seeing it, they don’t respond very well. We also knew from this data, from the experience with the H5 vaccine that people who were
getting really high levels, high amounts of antigen in the H5 vaccine, getting two doses of it,
only 50% of people responded with protective levels of antibody. So really made us
wonder, how much of this, where are we going to need two doses? So there were a lot of questions to ask, the amount of antigen, number of doses, how was this going to work
in special populations? Children, pregnant women,
HIV infected persons, persons with asthma. What was going to happen if
you gave it with other vaccines particularly the flu vaccine? And what if you gave it with an adjuvant? So we participated here in
these two studies at Duke. The first study was a
study, phase II study in adults and elderly, looking at giving two different dose levels of the vaccine. This is an unadjuvanted vaccine
and only one manufacturer. And also we did the
same study, same design in younger children in
three different age cohorts of younger children. So at Duke we enrolled 130 adults, we enrolled roughly 100
kids in a five-week period in the study, so it was
pretty intensive work. This was the scheme for following them. Day one they got vaccine and blood draw. We called them on day three,
they came back a week later. We called them again and they got… Then they came in again
at day 21, excuse me, got a second dose of vaccine. Came back, we called
again at day three after. They came back day eight
after the second dose, three weeks after their second dose and then we’re in this phase now where we’re actually doing
follow-up phone calls. So people got randomized
to one of two doses. You got one of two strengths,
15 or 30 micrograms and basically everybody
got two doses of vaccine. We did five blood draws in older people. Young kids we limited it to three ’cause we’re pediatricians and we’re kind. And these were the preliminary results that have been reported from this study. And you can see, day eight
after one single dose and this is really looking
at the 15 microgram dose. Young kids did, and this is the dose that’s in the vaccine now,
so that’s been approved. Young kids didn’t really
respond that well. As you got to over 10 the response was really the same as in
adults and you can see the older you are you tend not to respond as well. And this is really true of
seasonal flu vaccine as well. So in many ways, this
wasn’t acting so novel as we might have thought. So and follow-up for the
kids, what happens after they get a second dose. You can see here though they
didn’t respond very well after one dose, they look to be responding after a second dose. This is not the full dataset, this is only a partial
analysis of part of the study. So the recommendation is
that young kids get two doses and adults get a single dose. Pregnant women’s study,
this has been done too. Similar design, two different dosing. And why pregnant women? Disproportionately, a large
number have been hospitalized in ICUs, 28 pregnant women
so far have succumbed to swine flu. I believe two in this state here. One I know here at Duke. And you can see here, pregnant
women respond after one dose and Dr. Gita Swami actually here at Duke has participated in this particular study. Other studies at other centers looked at giving the specs, the H1N1
with seasonal flu vaccine and it appears as if you
can give both vaccines at the same time, regular
flu shot with the H1N1. You can space them,
you can give it before, you can give it after and it
doesn’t matter the time period. So just, the point is to give it. There are only one group
that we don’t know about, is if you want to take the mist vaccine, the FluMist from the seasonal and the FluMist from the H1N1, we don’t know what would
happen if you gave them at the same time. So it’s recommended to space
them by about four weeks. In most cases that hasn’t been an issue because availability has been limited, particularly for the H1N1. I’m going to leave it at that and not talk about treatment so much,
but I do want to acknowledge the collaborators here at Duke and all the staff that work with me, and I think that’s it. (audience applause) – [Ethel] Questions? – I’ll try, I don’t have
all the answers to flu. – [Man] Could you just
tell me a little bit about the difference between the 1918 H1N1 virus and today’s? – And the current H1N1. Genetically, I don’t know
all the differences, okay? So I can’t necessarily speak to that. I think it is fairly distinct from that, and this is the kind of,
these things reassort so much that it would be very unlikely that it would be very similar. There’s probably some cross reactivity and that maybe why these people, older people have some amount of immunity. But it is distinct because
there’s so much reassortant or reassorting of the
genes that it would be a different virus than the 1918. – So I’ll preface this by saying that I’m terrified of needles
and I was one of those people who lined up in the 1970s, because my parents dragged me
to the high school cafeteria and they used this little gun
where they gave us all a shot. – [Walter] I got the
gun too, it felt weird. – So all these years later,
I know they have FluMist but what progress are they making toward some other kind of
method of giving vaccines than those old syringes
and needles where the, I mean I feel sorry for those
poor health care workers who sit there and do a
thousand of those a day. I mean they must have some kind
of repetitive motion injury. (Walter chuckles) – Ask the nurses in my
clinic who are giving lots and lots of shots every day. There are different modes of delivery that are being investigated. Obviously we have the
intranasal vaccine now. For other immunizations we
have oral administration for example, they’re obviously for years there was oral polio but
we’ve made a switch back to inactivated for other
reasons I’m not gonna get into. We have oral rotavirus vaccine. There are other nasal delivery systems with different antigens
that people have looked at. People are exploring patch
delivery systems as well. We’ve looked at intradermal administration but I don’t know that that
is much more advantageous in terms of needles and ease of administration than intramuscular. Ultimately, hopefully,
oral may be the route we’re able to go and people
have looked at edible vaccines, getting vectors that you can… Feed to people in a banana. So down the road, but we’re just, we’re a lot of years away from that. – Chip, we hear about people
getting sick and dying, so what actually causes them to die? I mean you’ve described signs and symptoms that are pretty, don’t
sound all that severe. So what actually causes the breakdown? What do they die of? – There are a number of different ways people can die from influenza. A lot of them, well the virus
itself can cause pneumonia and it can cause a
myocarditis in some cases. It can cause just
overwhelming immune response, acute respiratory distress syndrome. A fair number of people
in reports that I’ve read have actually developed
secondary complications. So have developed streptococcal
pneumonia infections, so which brings the importance of, if you have a high-risk population, making sure that they’ve had
their immunovacses as well to potentially prevent that complication. Another needle, sorry. So there are a number of different, I didn’t describe the bad pictures but certainly overwhelming infection. A lot of these people have gotten acute respiratory distress syndrome, and I think there were reports,
you watch the news reports, you watch people on ECMO
and we’ve had several people on ECMO here. I deal in the outpatient clinic
so I don’t see them so much. I see the lighter end usually
of the disease spectrum. – Why do you think that it is
so hard to get the two doses? At the beginning, you mentioned supply, is it supply or is the
difficulty getting the parents to bring the kids back? Do you have the appointment
in the clinic, what? – I think there are a number
of different logistical reasons why we don’t get a second dose in. – [Woman] Or resistance from the parents? – I mean if they get the first dose, usually they’re willing to do it. I think a lot of them just get busy and don’t remember to come back, we don’t necessarily
give them appointments. Sometimes it is a supply
issue so we’ll have vaccine the day they get the first
dose and then we’ll run out and then they’ll call
back and we don’t have it, and then they don’t call back
again when we do have it. That supply issue every year is, is a crapshoot, I will tell you. It’s very difficult. So I think that plays into, there’s a lot of different
factors that play into why kids don’t– – [Automated Voice] Moderator
features, press zero. All participants have been unmuted. You will now rejoin the conference. – Am I muted? So it seems as though
daily in the mainline news, we’re seeing reports of
things like encephalitis and a little boy with flu. Do you think that the media
coverage has been appropriate? – Oh, that’s a loaded question. – [Bespectacled Woman] You
can say I’m a physician and I don’t… – If you watch The John Daly show ever, he did a thing about H1N1 coverage and it was actually pretty funny. I think the media gives a
lot of very mixed messages because on one, and they will… There are kids who have had
neurologic complications from flu so we do know that occurs. We do know that bad things occur, bad things occur every year. That’s why I tried to show
that first slide with flu but they’ll put that on and
then the very next segment will be don’t get your kid back vaccinated because they may get this. This too new. So you’ll have these two opposing things. We have a lot of parents
coming in the office. They’ll get the seasonal flu shot but they won’t get the H1N1 vaccine because they say it’s too new. What do I do? I try to reassure them that
this vaccine is being made the exact same way, we’ve
been making flu vaccine for many years now. It really is a strain
substitution with only one strain rather than three strains. If I had to pick today, which
vaccine I would get today, I would get the H1N1 because we don’t know what’s going to circulate in the spring. Yeah, we know H1N1 is out there. – That brings a good question segues into vaccine development. I know we’ve been using
the egg model for years. Are there currently any
platforms that are close to being approved to get away
from those egg syndromes? – Yeah, I’ve talked to
different manufacturers. Novartis is working on
cell culture-based vaccine. They actually have built a
plant here in North Carolina in Holly Springs, and I
think that’s the facility in which they plan to produce
a cell culture base vaccine. Then when you talk to one
of the other manufacturers who makes vaccine the
standard way, they say, well, they’re going to encounter
many of the same problems that we encounter. Is it gonna grow? They’ll have to go through
the same approval process. It’s not only always getting it to grow although this year it grew
slowly in eggs to start off with. Now the manufacturer when I talk to them they say that they’re
making it at regular rates so it’s actually growing fine. But just to start off with, it didn’t grow but once they adapted in
cell culture even more it starts to grow better. So they say well, probably the best answer and I tend to agree is
to have multiple ways we make this vaccine, not just to rely on one simple strategy or one strategy that it’s probably better. And over the years of having
done work in vaccines, I can tell you that if you rely
on one way, one manufacturer things happen in manufacturing processes and I’m not an expert but all of a sudden, that product is gone. And when that product is gone, and there may be one other
product or there may be no other product on the market
then you have shortages. And then you don’t have a product. I can’t count you the numbers
but we’ve just recently had a shortage of Hib product because one manufacturer couldn’t make, had problems with their Hib production. So we couldn’t boost kids. Not necessarily for that reason, but partially because of
that reason we started seeing some more haemophilus
disease-causing meningitis in young kids. And there have been several outbreaks now. So there are implications of relying on one manufacturing process,
I guess that’s my point. But I think you bring up a good point is that we need to look
at alternative platforms, they are being looked at. I think probably the closest
one may be that manufacturer, but I don’t know how, it’s probably several years off. – And also along those lines, as far as children under age of two, I know RSV is prevalent. I think it’s like 95%
of children under two but we do have an effective
treatment, the medamine product, has there been anything to look at? Maybe crossreactivity,
maybe is there prevention or comorbidity with the H1N1? – Well, I mean I think
it’s pretty different, they’re different viruses. So RSV is Respiratory Syncytial Virus which causes, is the most, as you say the most
frequent cause of pneumonia in young children and
respiratory infection. But it’s a completely different virus. You wouldn’t be expected to
get any cross-protection. The product we use for RSV
is a monoclonal antibody that actually will prevent infection so it’s not an active
immunogen like we’re giving with flu vaccine. So it’s just preformed
antibody, monoclonal antibody that we’re giving to kids
to prevent infection. It’s very expensive, it’s
about 1,000 bucks a pop. And so it’s really reserved
for very high-risk kids who were premature infants, cardiac disease and whatever. We can’t really afford
to give it to everybody at this juncture, but obviously a good point. Other questions? – Do you think from a physician standpoint that in this current season
that we’ll end up being able to vaccinate the number of children that physicians, pediatric
physicians would really want to be vaccinated? – Again, a very good question. The supplies have been very
short to coming to our office, so in fact we have to date received about, I think as of today we just
got 50 more doses of vaccines. We’ve received a total of 200
doses in our office for kids. Part of it is just where,
how fast it’s being made and how it’s getting distributed
to people in the community. And the distribution plan… This is different than any other vaccine. All the seasonal flu vaccines
are made by the drug companies and are either sold to the CDC at a, they negotiate a price
from the manufacturer or they’re sold privately
in the market and insurance or somebody else pays for it. H1N1 vaccine, our government
paid the manufacturer, our government owns that vaccine. As a matter of fact, the
manufacturer inadvertently shipped me some for another
trial and they called, they were on the phone
calling me at night, the vice president of the
company to get it back because they said the government
is counting every dose that is given, so it’s being very strictly
controlled by the government. But there’s a delay in getting it. It comes from the CDC then
the distribution is supposed to go to the state and
then it’s up to the state to distribute it. And then the state’s
distributing it here or there. It takes a while, and they
showed graphs on the lag in that and it’s a good lag in the
time it takes to get it out. But well, we have it, I’m sorry. To answer your question, I think we’re gradually getting there. But there are many factors at play. Some parents won’t want
it, we’ll be kind of past that initial hump in the epidemic. I would still recommend people get it because I think we’re
likely to see another peak in this, either in this
spring or next year. – So do you think masks work? Should we all be walking
around with masks? – [Walter] Should we all be
walking, there was a study– – I’ve seen a few people in the street that’s why I was saying it. – There is a study in JAMA this week looking at nursing staff. Actually it compared use of
the N95 to a surgical mask because they’re not enough N95s. And it showed that they
were equally as effective or non-effective I would guess, I think it’s still 25% of
nurses came down with flu, or medical staff came down with flu. I wear one in the clinic when
I’m going in to see a kid with respiratory infection now. Probably maybe we should
always be doing that ’cause kids, you go in
to look in their mouth and you’re getting the tongue depressor and they cough on you, you get it in your eyes. For me it’s worked but, I wouldn’t say we should
all be wearing masks. – [Ethel] I was actually kidding. – But there was a study, if
you look at JAMA this week. Okay, so any other questions? – [Ethel] Any other questions? – So how many people
have had their H1N1 shot? Any? No? (audience talk over each other) – You’re not patient care, right. So how many people would
get it if they could get it? Did I convince people to get it? Oh, pretty good, okay, good, thanks. – Thank you very much, Chip. That was really great and
appreciate your coming down on a rainy Friday afternoon.

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