U

P‑R‑O‑C‑E‑E‑D‑I‑N‑G‑S

(8:37 a.m.)

ADMINISTRATIVE MATTERS

MEMBER FREAS: Mr. Chairman, members of

the Committee, invited speakers, and members of the

public, I would like to welcome all of you to this,

our 97th meeting of the Vaccines and Related

Biological Products Advisory Committee meeting.

I am Bill Freas. I am the Acting

Executive Secretary for today. At this time, before

the meeting, begins, I would like to go around and

introduce to the public the members seated at the head

table.

We will start on the right side of the

table. That is the audience's right‑hand side. And

I will read the names of the people at the table.

Would the members please raise their hands as I call

their names?

David Markovitz, Professor, Division of

Infectious Diseases, University of Michigan Medical

Center.

Next is Dr. Walter Dowdle, Senior Public

Health Consultant, The Task Force for Child Survival

and Development.

Next is Dr. Judith Goldberg, Director,

Division of Biostatistics, New York University School

of Medicine.

Next is Dr. Ruth Karron, Associate

Professor, Johns Hopkins School of Hygiene and Public

Health.

Next is Dr. Walter Royal, Associate

Professor of Medicine, Morehouse School of Medicine.

Next is Dr. Monica Farley, Professor of

Medicine, Emory University School of Medicine.

Next is Dr. Pamela McInnes, Deputy

Director, Division of Microbiology and Infectious

Diseases, NIH.

Next is Ms. Cindy Lyn Province, Associate

Director, Bioethics Center of St. Louis.

Next is Dr. Bruce Gellin, Director,

National Vaccine Program.

In the empty chair, we will soon be joined

by Dr. Stephen Phillips, Director, Deployment Medicine

and Surveillance, Office of Assistant Secretary of

Defense.

Next I would like to introduce you to the

Chair of this Committee, Dr. Gary Overturf, Professor

of Medicine, University of New Mexico School of

Medicine.

Coming around the table, we have Dr.

Philip LaRussa, Professor of Clinical Pediatrics,

Columbia‑Presbyterian Hospital.

Next we have Dr. Martin Myers,

Co‑Director, Public Health Policy and Education,

University of Texas Medical Branch.

Next we have Dr. Bonnie Word, Assistant

Professor of Pediatrics, Baylor College of Medicine.

Next we have Dr. Peter Palese, Chairman

and Professor, Department of Microbiology, Mt. Sinai

School of Medicine.

Next we have Dr. Arnold Monto, Professor,

The University of Michigan.

Next we have Dr. Ted Eickhoff, Professor

of Medicine, University of Colorado Health Sciences

Center.

Next we have our nonvoting industry

representative, Dr. Michael Decker, Vice President,

Scientific and Medical Affairs of Aventis Pasteur.

Next we have a nonvoting participant, Dr.

Nancy Cox, Chief of the Influenza Branch, Centers for

Disease Control and Prevention.

Next we have Dr. Roland Levandowski from

the FDA.

Dr. Richard Whitley, University of

Alabama, member of this Committee, has recused himself

from today's participation.

I would like to thank the members for

attending. There is one other person I would like to

introduce at this time. Many people have asked me,

"When are you going to get a real executive secretary

for this Advisory Committee?" I would like to

introduce this morning Christine Walsh, who will be

the next Executive Secretary for this Committee at the

next meeting, which will be announced later. It will

be either in March or May. We have a teleconference

scheduled for March the 17th at this time.

I would now like to read the conflict of

interest statement into the record. Before I do that,

I would like to ask the members of the public if they

could put their cell phones on silence mode, it would

be appreciated.

"The following announcement addresses the

conflict of interest issues associated with the

Vaccines and Related Biological Products Advisory

Committee meeting on February 18th and 19th, 2004.

The Director of the Center of Biologics Evaluation and

Research has appointed Drs. Walter Dowdle, Ted

Eickhoff, Bruce Gellin, Judith Goldberg, Pamela

McInnes, Arnold Monto, Martin Myers, and Stephen

Phillips as temporary voting members for this meeting.

"Based on the agenda, it has been

determined that there are no specific products being

approved at this meeting. The Committee participants

have been screened for their financial interests. To

determine if any conflicts of interest existed, the

agency reviewed the agenda and all relevant financial

interests reported by the meeting participants.

"The Food and Drug Administration prepared

general matters waivers for participants who required

a waiver under 18 U.S. Code 208. Because general

topics impact on many entities, it is not prudent to

recite all potential conflicts of interest as they

apply to each member. FDA acknowledges that there may

be potential conflicts of interest, but because of the

general nature of the discussions before the

Committee, these potential conflicts of interest are

mitigated.

"We would like to note for the record that

Dr. Michael Decker is a nonvoting industry

representative for this Committee acting on behalf of

a regulated industry. Dr. Decker's appointment is not

subject to 18 U.S. Code 208. He is employed by

Aventis and, thus, has a financial interest in his

employer. In addition, in the interest of fairness,

FDA is disclosing that his employer, Aventis, is a

manufacturer of a product that could be affected by

today's discussions.

"With regards to FDA's invited guest

speakers, the agency has determined that the services

of these speakers are essential. The following

interests are being made public to allow meeting

participants to objectively evaluate any presentation

and/or comment made by the speakers.

"Dr. Antoine Flahault is employed by the

World Health Organization Collaborating Center for

Electronic Disease Surveillance in France. He has

associations with firms that could be affected by the

Committee discussion.

"Dr. Maria Zambon is employed by the

Respiratory Virus Unit, Health Protection Agency in

England. Her agency's laboratory conducts tests on

licensed influenza vaccines. Her employers

collaborates with firms that could be affected by the

Committee discussions.

"In addition, there are vaccine

manufacturers making industry presentations. These

speakers have financial interests associated with

their employer and with other regulated firms. They

were not screened for conflict of interest.

"Members and consultants are aware of the

need to exclude themselves from the discussions

involving specific products or firms for which they

have not been screened for conflict of interest.

Their exclusion will be noted in the public record.

"With respect to all other meeting

participants, we ask in the interest of fairness that

you address any current or previous financial

involvement with any firm or product you wish to

comment upon. Waivers are available by written

request under the Freedom of Information Act."

So ends the reading of the conflicts of

interest statement. Dr. Overturf, I turn the meeting

over to you.

CALL TO ORDER

CHAIRMAN OVERTURF: Good morning. I would

like to welcome everybody to this meeting of the

VRBPAC Advisory Committee February 18th and 19th.

Dr. Midthun, would you like to make

presentations to retiring members?

PRESENTATION OF PLAQUES TO RETIRING MEMBERS

DR. MIDTHUN: Good morning. I would like

to ask Dr. Judith Goldberg to please come up to the

podium. I would like to thank her for her many years

of service on this Advisory Committee. She has always

been here with great dedication, always has prepared

extremely well, and provided excellent input to us.

We are really going to miss her and really appreciate

all that she has given to us.

I think I am supposed to stand over here

so we can get with the picture of the plaque. Thank

you. And we also have a letter here for you from Mr.

Peter Pitts, who is our Associate Commissioner for

External Relations. So thank you so much.

(Applause.)

DR. GOLDBERG: I just want to thank all of

you because it has really been a privilege to serve on

this Committee. I have enjoyed every minute of it,

and I have learned a tremendous amount.

DR. MIDTHUN: Thank you so much.

CHAIRMAN OVERTURF: I think we will

proceed. As you know, there has been a great deal of

interest in influenza, for those of you who forgot

about last winter. So this year I think will be a

striking update of last year. So that I think we will

begin with the data that is going to be presented by

Dr. Roland Levandowski and his associates. Thank you.

DR. LEVANDOWSKI: Great. Thanks very

much, Dr. Overturf.

OPEN SESSION

STRAIN SELECTION FOR INFLUENZA VIRUS VACCINE

FOR THE 2004‑2005 SEASON

INTRODUCTION

DR. LEVANDOWSKI: I am going to try to

give a somewhat extended review of what has been

happening this last season. Generally I do give a

fairly brief review, but today I am going to be going

into a little bit more detail.

There is an awful lot that is going on.

What we would like to try to cover, just as a

reminder, the real business for today is what is first

on this list of topics for us to take a look at. We

are really here today to make the recommendations for

the strains that should be used in next year's

trivalent vaccine, for the 2004‑2005 trivalent vaccine

for the H1N1, H3N2, and Influenza B viruses.

We do also on this program, as you will

see from the agenda, have some other items that we

wanted to bring to the attention of the Committee. In

particular, there are some items that we have that we

would like to bring to the attention of the Committee

just mainly for information for things that are

happening.

There has been a lot of interest this year

about the effectiveness of vaccines. This has been a

discussion point at this Committee on many occasions

in the past. In fact, I can't remember one when it

hasn't been discussed in recent memory of mine.

So we have several speakers: Dr. Carolyn

Bridges from CDC, Col. James Neville from the

Department of Defense, and Dr. Antoine Flahault from

the Institut National de la Sante et de la Recherche

Medicale, who will be talking about some studies that

they have ongoing to look at vaccine effectiveness.

Some of these are still in progress, but we will at

least get to hear what is happening to try to look at

this in an ongoing manner.

I also wanted to bring to the attention of

the Committee what is happening with H5 avian

influenza in Asia. At this time last year, you might

remember we were talking about what is happening with

SARS. So we know that the Committee will be very

interested to hear this information. We also want to

bring it to the attention of the Committee because

there may need to be some activities that go on at a

later date. We just wanted to have them informed as

much as we can at this point.

Finally, on the agenda, we have something

that we would like to have some discussion with the

Committee. This relates to a point that was brought

up last year about use of tissue culture isolates from

field laboratories for preparation of influenza

vaccines.

You will see on the agenda that tomorrow

toward the conclusion of the meeting we have a couple

of presentations by one of my colleagues, Zhiping Ye,

Center for Biologics, and also Dr. Phil Minor from

NIBSC, to talk about our perspectives on what the

issues might be with issue of tissue culture isolates.

So this is the main business. Again, this

is the question that we are asking the Committee to

give us recommendations today. We are asking for a

vote on this. This is the abbreviated version of the

question, what strain should be recommended for the

antigenic composition of the 2004‑2005 influenza virus

vaccine for use in the United States?

Just by way of review, this was the

recommendation that was made by the Committee last

year at this time. It was for a trivalent vaccine

that would contain an A/New Caledonia/20/99 H1N1‑like

strain. Actually, it was A/New Caledonia/20/99.

It would also contain a B/Hong

Kong/330/01‑like strain. And in our case, the strains

that were used for vaccine preparation were the actual

strain, B/Hong Kong/330/2001 or B/Hong Kong/1434/2002.

The H3N2 component that was recommended based on all

of the information was for an A/Panama/2007/99‑like

strain.

Why do we change strains for influenza

vaccines? Well, we do it because the vaccine efficacy

is really related to two things. One is how much

antigen is present in the vaccine and then, very

importantly, what the match of the vaccine,

hemagglutinin and neuraminidase, are with the wild

type circulating strains. This has been very clear to

us since the earliest days of influenza vaccine use.

You might remember that influenza viruses

were first isolated in the mid '30s, human influenza

viruses, mid '30s to early '40s. And it was very

quickly that some vaccines were prepared as whole

virus vaccines.

The first vaccine was licensed in the

United States in 1945. And within two years, by 1947,

it was pretty clear that when there were antigenic

changes occurring by way of mutation in the viruses,

that there was reduced vaccine effectiveness. That

led to setting up the global surveillance system.

What we know from that period of time

onward is that there have been continuous antigenic

changes in the hemagglutinin and neuraminidase of both

influenza A and influenza B viruses.

These are the questions that are asked in

order to answer the question for recommendations. I

will just go over these a little bit with you. First

of all, we want to know, are there new either drifted

or shifted antigen influenza viruses present? Drift

is point mutation occurring in the viruses. And shift

would be exchange of an entire gene segment.

I guess I should remind you that influenza

viruses have a segmented genome. There are eight gene

segments for either influenza A or influenza B. These

can reassort in nature to put new hemagglutinin and

neuraminidases into human influenza viruses. That

usually results in a pandemic. But, anyway, the

question is, are there new influenza viruses present?

This is the purpose that surveillance

serves. It provides us with that information as to

whether there are new viruses that are occurring.

Mainly we are interested in, are they new in terms of

their antigenic properties, mainly for the

hemagglutinin but also for the neuraminidase?

It is also from surveillance that we get

the viruses that are used for vaccine preparation. So

without that underpinning, there really isn't anything

that we would be able to accomplish.

The question to be answered if there are

new viruses, ‑‑ and they almost always are new viruses

that are being identified because of the continuity of

evolution of the viruses ‑‑ are they spreading in

people?

It is not unusual to see that there are

influenza viruses that are really wildly different,

but it turns out they are one off. So that occurs

from time to time. And it takes a while, in fact, to

have an understanding as to whether these new viruses

really have any significance or a potential impact

that we need to take into consideration for vaccine

preparation.

If there are new viruses spreading, then

we also want to know whether our current vaccines are

going to have any likelihood of having effectiveness

against these new strains. And, for that purpose, we

look at responses from people who have been immunized

with the current vaccines. Often the case is that

although there are some new viruses that are

spreading, the current vaccines actually make

antibodies that cross‑react fairly well.

And while the differences you will see for

these two different activities are somewhat

complementary, there are thousands of influenza

viruses that are examined with a relatively small

number ‑‑ it is not entirely small, but it is a

relatively small number of sera that are used to

categorize them. With the human serologies, we are

looking at the reverse, where we have several hundred

different sera from people who have been infected or

immunized and looking at a relatively small, select

group of these viruses that have been identified in

surveillance.

And then, last but not least, if it is

true that there are new viruses, they are spreading,

the current vaccines don't look like they produce very

good antibody responses to those new strains, then we

still need to know, "Can we do something about it?

And are there any strains that are suitable for use in

vaccines?"

And so, to answer the questions, last

year, just to review what we did, were there new

influenza A, H1N1, viruses? No. The answer was no.

The HA of all of the strains was very similar to the

vaccine strain.

For H3N2, the answer, however, was yes.

There were quite a few strains that were identified.

Although most of these strains were originally very

much like the current vaccine strain, there were some

strains that were identified early in 2003 that were

antigenically distinguishable. And it was a

relatively small proportion to begin with, but that is

not unusual either that it starts out small and

quickly snowballs.

However, after collecting information and

analyzing, it wasn't really until February of last

year that it was clear that there was a cluster that

were antigenically and genetically related that seemed

to be the ones that were most likely to spread

further.

For influenza B viruses, again, the answer

was really no. There weren't really any new viruses

that were found. The majority of the strains were

very similar to what was in the vaccine, but there

were a small number of strains that are different.

There actually have been two hemagglutinin

lineages for influenza B viruses co‑circulating for at

least the past 15 years. One or the other of these

hemagglutinin lineages has tended to be the

predominant strain. We had just left a period of time

where for about ten years, the strains in the

so‑called B/Yamagata/16/88 lineage were the ones that

were predominant, particularly outside of Asia.

For the last two years, however, the

strains that have been predominating are on the other

HA lineage. They are in the B/Victoria/2/87

hemagglutinin lineage. And that is what we have

currently in our vaccine. But there was a small

proportion of viruses last year that were identified

that were in the B/Yamagata/16/88 lineage. That was

being paid attention to, but it was not sufficient to

think that there was something really happening there.

Were these viruses spreading? For the

H3N2, as I mentioned, the answer was yes. By the time

the Committee was meeting in February or March, it was

pretty clear that there were some of these viruses

found on several continents, including Asia, Europe,

and North America. Were these viruses inhibited by

the current vaccines? And the answer to that was

partially no.

There were a number of strains that were

very much like the Panama/2007/99 vaccine strain.

Those were very well‑inhibited. But for the group

that we are now calling A/Fujian‑like strains, some of

these were relatively well‑inhibited by current

vaccines and some were not. It was not a very

homogeneous situation.

Then, to answer the question, were strains

suitable for manufacturing available? The answer was

actually no. And it related to the fact that all of

this information was coming out just at the time that

decisions need to be made in order to prepare a

vaccine. I will give a little bit of explanation

shortly about why that is true, why the timing was

off.

Sort of in a nutshell here, the

manufacturing does depend on having an egg‑adapted

strain that will grow well. It could be either

wild‑type or a high growth reassortant for the

influenza A viruses. Generally it needs to be a high

growth reassortment.

The fact that these first Fujian‑like

strains were first identified in February made this

difficult. The first egg isolate of an A Fujian‑like

strain wasn't until April. The first high growth

reassortant wasn't prepared until toward the end of

June. That timing also is fairly typical for dealing

with new influenza viruses as they are appearing.

So the implications of the strain

selection from last year were that the preparation of

vaccines this current year was very much on schedule.

I will provide some information about that. And the

supply of vaccine matched the demand that was expected

by the previous year's experiences.

There were some other implications. One,

this year there was an early widespread appearance of

drift variant of A Fujian‑like viruses in the United

States. There were reports of mortality in children.

Now, that significantly increased vaccine demand.

And although there were several million

doses of vaccine, both of inactivated and live

vaccine, that were still available in mid November.

And it appeared that we were headed toward a situation

where a lot of vaccine would not be used again, which

has frequently been the case in the past, not just the

year before but for many years running. The amount of

vaccine that was available was not sufficient to avoid

some spot shortages that occurred after the

Thanksgiving holiday in the United States.

And then again, the effectiveness of the

vaccines against this drift variant has been

questioned. So there are some studies that are

ongoing. We are going to be hearing about those.

So for the United States, we have three

licensed influenza vaccine manufacturers. Two of them

produce inactivated vaccine: Aventis Pasteur and

Evans Vaccines. Evans is now part of Chiron. So I

have to be careful. It is hard for me to keep up with

the changes that occur business‑wise, but these two

companies have been licensed in the United States for

quite some time, as you can see here.

And last year, between the two companies,

there was production of about 83 million doses of

vaccine. Put that into a little bit of perspective.

Inactivated vaccines around 1990, there were

approximately 25 to 30 million doses produced per

year. So over the decade of the '90s, vaccine

production had increased substantially.

And our license manufacturer for live

attenuated vaccine is MedImmune. They were licensed,

as you might recall, in June of 2003. And they

produced about four million doses of vaccine for use.

The timelines for vaccine production are

shown here. And it is a little bit of a pyramid

scheme. What most everybody is interested in or what

gets the most visibility is vaccine use, which occurs

in the fall through the early winter. But supporting

that, underneath that, is all the work that the

manufacturers have to do to prepare the vaccine. And,

even before that, surveillance and other activities

are required. We are right here in February to March.

So we are right down here in this period of time. It

is early days for vaccine preparation, and it is

months away from vaccine use.

As I mentioned, without surveillance, we

would not have strains for use in vaccine production

in the first place. And there is a lot of work that

goes on between surveillance and trying to develop new

strains throughout the year, although there may be

periods of time when there is more activity than

others. But there is some activity going on pretty

much all the time.

Recommendations are generally made by the

WHO for the Northern Hemisphere and for the winter

months here and for the Southern Hemisphere and for

the winter months there. But these recommendations

are important so that the manufacturers know what they

should do.

Too, as there are reference strains that

are getting worked, the manufacturers throughout the

year are working on their seed viruses, which were

proprietary to them. They worked with the virus to

make sure that it is going to be appropriate for the

manufacturing conditions. And although there may be

some early seed viruses that are used in production,

there is some continuous work that goes on to try to

make that better so that manufacturing can be smoothed

out. I will show a little bit of information about

that, too.

Production of the monovalent components of

the vaccine takes many, many months. And, really, it

starts maybe earlier than January. Manufacturers may

be working at risk before recommendations are made to

produce monovalent components. They don't do this

without some education. They are paying close

attention to the surveillance that is being reported

throughout the year by WHO and our colleagues at CDC.

Once all three of the components are

present, trivalent vaccine can be produced, but you

will see that there is still overlap. There is still

for quite a long time, actually, many years, work

being done with the monovalent vaccines. And so there

is some vaccine that starts to come out, but it

doesn't all come out at one time. And that vaccine

uses the desired goal at the top again.

So to try to also give some understanding

about how long it takes, when there is a new strain

that is recommended, when there is a new reference

virus that is identified, for the point of time that

that new reference is identified to the time that that

is available for sending out to manufacturers to

develop their seed viruses, for the period of several

weeks, part of this is trying to understand, is this

the best strain that is available or are these the

best strains that are available for producing the

vaccine? It takes some analysis. It takes some

collaboration between the WHO centers to come to that

understanding.

Part of the time for influenza A viruses

and probably for influenza B viruses in the future is

preparing the high growth reassortants that make it

more expeditious for producing the vaccine. At the

same time that that is happening, reference reagents

for standardization of the vaccine need to be

prepared. And this is true not only for inactivated

vaccines, but it may be necessary for the live

vaccines also.

Potency testing for these is dependent

upon having antisera that can be used for the tests

that are done to try to standardize in terms of

potency.

Once the manufacturer has a seed virus

prepared, then they can start to manufacture. As I

mentioned, there may be manufacturing at risk when the

strains are not changed. Those strains can be

prepared in advance of this meeting if the

manufacturers so desire, but they really can't do

anything until they have in their hand something that

is appropriate for making a seed virus. And they

can't manufacture all the strains without having those

available.

So this just shows manufacturing three

different strains. And I am showing down here vaccine

release. There are activities that go on between the

manufacturer and regulatory authorities to try to make

sure that these seed viruses: first, are appropriate

for use, that they maintain their antigenic

characteristics; and, second, that other kinds of

qualities are maintained.

Now, this bar is about three weeks long

for each of the monovalents. That is an

approximation. Most of that time I think you will

hear from our colleagues from industry relates to

quality control, not necessarily interaction with

regulatory authorities but just needing to meet their

own good manufacturing practices and be sure that the

vaccines are going to meet all of the specifications

that are set for them.

Once the three strains are produced, then

it is possible to go ahead and formulate vaccine and

to fill it and to send it out. You see, each of these

points have bars that are about three weeks long as

well. And there are some release activities that go

on for the trivalent vaccines.

This duration of time here again is not so

much the actual physical manipulation of the vaccine.

It has to do with the quality control measures that

need to be met and some very important ones, like

sterility for inactivated vaccines, for example.

So once that has all happened, then, of

course, the vaccine can be distributed. But, you see,

this time line up here, for a new strain, I am

indicating about 20 weeks. I think that is a

reasonable estimate. If you put that in months, that

is about five months from the time of the first

appearance of the new strain until there is really the

possibility of having a product in hand that can be

used.

That is just the first. Once the first

comes out, then, of course, it just keeps rolling.

Again, to try to put this into some more perspective,

it seems to be cut off a little bit on the boundaries.

That is okay.

I went back and reviewed monovalent

vaccines that were produced for inactivated vaccine

over the last several years. What I am trying to show

you here is that when strains are changed and those

are shown across the bottom, the relative proportion

‑‑ this should add up to 100 percent for all 3 strains

‑‑ of the strains that are produced really tends to

favor the new strains that are added. So you can see

between 1998 and 1999, there was a new influenza B

virus. And although 38 percent of all of the

monovalent concentrates produced in 1998 were

influenza B, over half of them, about 55 percent, were

influenza B.

You see that with other changes. In 2000,

we added a new H1N1 and H3N2. And you can see in both

instances, the amount of effort, the relative amount

of effort, in terms of the number of monovalent

concentrates that had to be produced was mostly

devoted toward the new strains. You can see that all

the way across here, that when new strains were added,

that there needs to be an adjustment that it is the

early work that has to be done by the manufacturers to

figure out how best to get things growing.

Once they get it organized, you can see

that it is possible that things may even out a little

bit more between the three strains, but the strain

that has changed, the strains that are changed are the

ones that are the most difficult in terms of overall

production, at least for the first year.

In terms of timing of these things, this

is what we see in terms of submission to the Center

for Biologics for Release. I am showing the number of

lots here against the month for both the monovalent

vaccine and the trivalent.

What I really want to point out to you on

this slide, the numbers aren't so important. It is

the overall pattern. You see that there is kind of

this buildup of more and more monovalent concentrates

coming in up until about August‑September. And then

it starts to wane.

And this relates to the point at which

manufacturers when they are trying to meet the need

for vaccine in October and November have already

planned out how they are going to be putting together

how they are going to be manufacturing the vaccine

components, when they need to have them on tap and so

on. And so they come to a decision point about August

or September where they have to decide whether it is

worthwhile for them to continue manufacturing or not.

There is a lot of effort and money that

goes into that continuation. And it is possible for

them to do so. They could keep going if they knew

that there would be demand, for example, within our

current system. It is possible to make more vaccine.

It doesn't have to stop right here, but it does

because there is a target that has been developed from

sales and demand. And it is really kind of a

practical decision.

You see that there still is overlap

between the preparation of the trivalent vaccine and

preparation of the monovalent right on out to the end

of the overall campaign for the year.

For this year, because the strains were

the same as the previous year and the demand was

fairly well‑understood at the beginning of the year,

it was possible to get everything ready.

This curve shows cumulative percent of all

the lots that are submitted to us for release from

June to December. Two thousand was the year that we

had the shortages or delays that were concerning. And

this was an atypical year in that the point at which

50 percent of the vaccine that was available was

shifted out substantially from where it normally is.

These curves over here are more typical of

what we would be seeing. And generally 100 percent of

the vaccine in the past has been out by about October.

And that is where we are here. This is the red color

here, the diamonds. The red diamonds are this year,

2003.

So you can see that vaccine was being

produced fairly consistently throughout this period of

time and very expeditiously met the overall goal for

this production campaign without any delays.

So why are influenza vaccines important?

Well, they are important because influenza has a lot

of economic consequences, the lost work, school time,

and so on. We know that morbidity is high,

particularly in the very young.

Pneumonia and Influenza, that is the only

category that is in the top ten causes of death in the

United States, the only infectious diseases category

that is in the top ten causes of death in the United

States. And this is for ages overall. It is not for

a specific age group but for the ages overall.

We know from other statistics that we can

expect somewhere between 20,000 and 40,000 deaths in

a typical year related to influenza. That is

generally in the elderly. And we know that pandemics

cause even more.

I just wanted to read a couple of things

that were from some publications that sort of put this

into perspective. So I am quoting here. It says,

"Early apprehension was increased by the fact that

when the first indications of the outbreak were

observed in the country, the influenza had already

attained epidemic proportions in England.

The sharp rise in influenza deaths,

however, was found not to be due to virulence of the

causative organism but to a high case incidence. The

term "lightening influenza" was used in newspaper

reports.

Also, the epidemic caused by influenza A

viruses was unusually severe for the inner pandemic

period. The attack rate in children was much higher

than for adults. At least 30 percent of children

under 5 years of age were ill. And most were taken to

medical care facilities.

Over 320 children per day crowded into the

pediatric outpatient clinic at Ben Taub Hospital. So

you might think that was this year, but the first one

is from 1943 and the second one is from 1975.

I just wanted to try to remind everybody

that what we are dealing with here is something that

maybe has been a little bit forgotten but that we

should remember that influenza is a very serious

disease.

And to try to highlight that more, I have

got some other slides here that I have taken from some

of the older literature. This is data from

door‑to‑door surveillance activities in Baltimore that

were undertaken during and after the pandemic of 1918

to try to get some information about what was

happening. Unfortunately, my legend is cut off over

here. The red one is 1918. The purplish one down

here is 1919. The green one is 1928 to '29. And the

black one down here is '40 to '41. This is 1943 to

1944.

That quote that I was reading partly

related to this. There was what was seen as a

relatively large incidence of case attack rate in

children predominantly during that period of time.

There was a large fear that this was the return of the

1918 pandemic strain. So you can see, by comparison,

it wasn't quite as high an attack rate, but it was

much higher than what had been seen in some of these

intervening years. So there was a lot of concern

about that.

I think what it indicates to us is that

attack rates can be higher or lower. It is sort of

interesting that in the case of both of these years,

there is sort of a relative disproportionality in

terms of younger children and then sort of young

adults. It caught my attention because I think that

may relate a little bit to what we are seeing this

year as well. I think we are seeing more activity,

and I think we will hear more about that.

So in terms of pneumonia ‑‑ and these were

cases per 10,000 shown on the other slide, and it is

the same scale here, but the numbers are drastically

different. So this is the pneumonia cases in those

same surveys.

You can see from 1918 to 1919, this very

much parallels the mortality curve, where there was a

kind of instead of a U‑shape, where it is very high at

both ends in the very young and the very old, there

was this extra peak occurring in young otherwise

healthy adults. And there is a small echo of that in

the year following 1918, during 1919 and 1920.

What I am showing here is that this blue

down here again is 1943, where there is a huge number

of cases occurring, but the amount of pneumonia that

was being identified in Baltimore was relatively low,

particularly in young healthy adults. There was a

little bit of an increase more in elderly than in

children, but the young children were affected as

well.

These are some data from 1975‑1976 in

Houston during an A/Victoria/3/75 epidemic of

influenza. I am showing this. Again, I am trying to

use that same scale. This is hospitalizations per

10,000. These are the ages of the individuals.

I guess what I should have said in my

previous two slides is that a lot of this, of course,

1918, some of this could have been something other

than flu. We didn't really have virologic

capabilities until later, but it is based on the

sharpness of the peak of the epidemic. And it is

probably true a little bit here for these data as

well.

These are not all virus isolates. These

are clinical studies that were done to try to define

what was happening in the epidemic. But this is

during an epidemic in Houston. Again, you see this

U‑shaped curve, where the hospitalizations are most

marked for the very young and the very old. In fact,

the number of hospitalizations in this particular

instance appear to be probably more than in the

elderly. But you see some level of hospitalization

during this relatively severe influenza season in all

age groups.

Different from that, however, is what has

been seen for mortality in some of these epidemics.

This is a different age 3 and 2 epidemic in Houston,

encompassing Harris County, Texas, the statistics,

health statistics, from there. Again, these are

deaths per 10,000 at different ages.

Here you can see that, really, it is the

elderly who are most markedly affected. They are the

ones who die when they become ill and develop

pneumonia. But there are deaths that are reported in

all ages. It is kind of a small number here in the

young adults. And there are quite a few more seen in

young children but not nearly what we see in the

elderly.

So from this information, the effects

here, we know that influenza attack rates are often

highest in children who are less than ten years ago.

There is serious illness in all of the age brackets,

with the young and the old most affected. And the

mortality is generally highest in the elderly,

although it is also seen in young children. And in

some instances, it seems to parallel the incidence of

pneumonia during the period of time that the influenza

epidemic is occurring.

So a brief history of influenza vaccine

efficacy. In 1941, there was a request to license the

first inactivated vaccine in the United States, but

the regulatory authorities at the time, who were part

of NIH under the Public Health Service Act, thought

that it was best to get efficacy. That wasn't really

required, I believe. It was mainly safety data that

were needed. But there was a request to show that the

vaccine would actually be efficacious.

They were set to do the study. They had

all of the materials in place and the desire to do the

study in 1942, but this often happens to those people

who are trying to study influenza. There was no

epidemic that year. So it was not possible to do the

studies. Instead, there were some challenge studies

that were done at the time, which demonstrated that

these vaccines were effective against influenza A and

Those studies were published as well as

the information from the studies that were done later

from large‑scale field studies. Those were done in

1943 through 1945. And they were done with bivalent

vaccine using influenza A and B viruses.

The first vaccine was licensed in the

United States in 1945. And, as I mentioned before, it

was very shortly after that that it was recognized

that antigenic drift could reduce the effectiveness of

vaccines and the Global Surveillance System was

inaugurated to try to identify changes that were

occurring and to be able to make alterations in

influenza vaccine as necessary.

So the first studies that were done by

Tommy Francis and Jonas Salk and others with the armed

forces and a special commission that was set up to

investigate influenza, the studies that I am going to

be talking about were done as randomized

placebo‑controlled field efficacy studies between 1943

and 1945. The vaccines that were used at that time

were whole virus, formal and inactivated. They were

highly formalin‑inactivated reactogenic.

A large percentage of the people who got

the vaccines felt ill for a couple of days. Some of

them went to infirmary. The antigens that were

contained in the vaccine, it was actually trivalent

vaccine. It had two H1N1 components: A/Puerto

Rico/8/34 and A/Weiss/43. There was an influenza B

component. It was B/Lee/40.

The studies were done at the Army

specialized training program centers around the

country at the time. These were located in a number

of universities and medical schools. In these

particular studies, there were more than 10,000

participants.

What they were looking at, mainly they

were looking at the clinical endpoint. It was

influenza illness. It was most important. They did

have the capability. And they were using it during

the studies to identify infection by culture. They

also could look for serologies. But, really, the

endpoint here was the illness.

Illness was supposed to be characterized

by symptoms that included abrupt onset fever,

myalgias, cough, sore throat, and nasal symptoms. And

the cases were further categorized by illness

severity. Those who had a temperature over 100 by

whatever the going criteria were, they were sent to

the infirmary for hospitalization to get them away

from the rest of the men in the barracks where they

were staying. They also, of course, did X‑rays when

they wanted to look for pneumonia.

There were some differences between the

multiple centers in terms of the way the actual study

was run. So that in some instances, hospitalization

could have been for lesser fever, but generally this

is what was followed.

I am showing the two different studies

that were done here looking at influenza A and

influenza B. Again, this was a clinical measurement.

It was clinical influenza that resulted in febrile

illness that needed hospitalization. There were

approximately 12,000 individuals who were randomized

to get either the vaccine, the trivalent vaccine, or

somewhat identical placebo.

The number of cases that occurred was

substantially higher in those who got the placebo than

those who got the vaccine. If you calculate

protective effectiveness from that, it works out to be

about 69 percent protective effectiveness against the

clinical febrile illness requiring hospitalization.

A similar study was done for influenza B.

The numbers here are approximations because the people

involved in these programs at the time were sort of

going in and out. There was a lot of personnel

transfer in motion. So they did the best they could

to try to determine what the denominators were here,

but it really is kind of an estimate.

The number of cases, it is firmer. Again,

you can see that for the vaccine, there were

substantially fewer cases than in the placebo group.

Translated, it would be a protective effectiveness,

around 88 percent.

There were some subanalyses that were done

in this set of studies that have been published also.

In one subset at the University of Michigan, they

tried to look at the effect on illness, different

levels of severity. They looked at people who had any

kind of respiratory illness. This included the common

cold or what they called the common cold. It was

illness that was obvious, but it wasn't severe enough

to result in hospitalization. And it didn't have

other symptoms that they thought would be more typical

of the syndrome that we call influenza with all of

those symptoms that I listed early on.

We know very clearly that influenza

infection can cause what seems to be a common cold in

some people, and we know just as well that other viral

infections can cause what seems to be influenza by its

clinical manifestations with fever, myalgias, and so

on. So it is a very nonspecific indicator.

For those that they thought were more

likely to have influenza based on the symptomatology,

again, that is based on the clinical symptoms but

being more typical for influenza syndrome. These

inpatients had fever. Then, of course, they were also

looking at pneumonia.

What you see across the bottom here if you

try to figure out a protective effectiveness, you can

see that there is increasing effectiveness of the

vaccine against the more severe forms of illness.

It is very difficult to show vaccine

effectiveness when it is diluted by many different

types of respiratory viruses, none of which were known

at the time. They were identified specifically at the

time these studies were being done, but they were, the

giants whose shoulders we stand on were, very much

aware of the fact that there were other etiologic

agents out there that needed to be categorized. You

can see that it is very difficult to show that.

If you go to the most severe forms of

illness, it is a lot easier to try to show that there

is some effect. They commented that throughout the

study, there were no cases of pneumonia in anybody who

got the vaccine. There were ‑‑ this is a relatively

small number ‑‑ only four cases of pneumonia in the

recruits who got the placebo. That does fit, however.

These studies were done in 1943 and 1944, when I

showed that there was very low incidence of pneumonia,

even though there was a high attack rate for

influenza.

So there were some other observations they

made from this. One of them was that in these kinds

of studies, the placebo group was actually diluted by

having an immunized cohort that may have been able to

reduce transmission in the placebo group. This was in

one of the first thoughts about herd immunity.

The differences in the attack rates

between vaccine and placebo were really greatest at

the peak of the epidemic. And as the epidemic

receded, it was harder and harder to be able to show

anything.

One corollary to this part was that there

was at least one center where there was an attempt to

immunize in the face of what seemed to be the

developing epidemic. And they noted that it was very

clear‑cut that during the first week, they couldn't

really show any difference in the attack rate in the

placebo or the vaccinated individuals, but after one

week, it was very clear who had been immunized. There

seemed to be a big difference, even after that

one‑week period of time.

I mention this just because we often talk

about needing two weeks after immunization, somebody

who is immunologically primed. Of course, these

individuals all were immunologically prime by previous

exposures. But there may be protective effects that

are kicking in, even in an earlier period of time.

So, to add a little bit of information

about some of the other studies that had been done, I

wanted to concentrate on a few studies. These are

selected by me to make some points about the effect of

vaccine when there is antigenic drift that is

occurring.

This first study that I want to talk a

little bit about was done in Texas in 1976. It was

the Houston family study for this particular

publication. There were 37 families who had 155

members of different ages, ranging from infants up to

about mid '40s.

The A/Port Chalmers/1/73‑like viruses had

caused an epidemic in 1975. And so these individuals

who were not immunized specifically had antibodies

that were directed against or should have had some

possibility of having antibodies directed against Port

Chalmers, but then the following year, A

Victoria/3/75‑like viruses caused an epidemic. These

viruses, the A Victoria/3/75 viruses, are really drift

variants of the previous strains.

At the time, it was noted that this was a

very dramatic difference in terms of antigenic

characteristics between these two viruses. I don't

know whether it is fair to say so, but it probably was

at least as different as what we are seeing this past

year with the Panama‑like strains and the Fujian‑like

strains and possibly more because, actually, it was

remarkable and there was a lot of comment about how

different those strains were.

They were able to use virus isolation and

serologies to try to document infection. As I

mentioned, there was no vaccine used. Now, what I am

showing here are the preexposure hemagglutination

inhibition titers from the people who were in the

study. They were able to get blood from 154. They

tested them for antibodies to both Port Chalmers 73

and Victoria 75 strains.

What you can see here, I think, is that

there was some proportion who had, really, very low

antibodies in both of these groups. These are the

same people, of course. So you see that some higher

frequency of those who they tested for antibodies to

Victoria were more likely. They were more likely not

to have antibodies is what I am trying to say.

If you look at the distribution from low

antibody to high antibody, you can see that in

comparison to Port Chalmers, there is a shift toward

lower antibody titers for Victoria strains. And that

is what we are usually dealing with when we are

looking at our serology. So this is very similar.

They were able to do some other things to

look at infection and illness. I think that what you

can see is that there is a relation between antibody

presence and protection. As you get higher antibody

titers, there are fewer and fewer people who are

infected. The same thing is true if you look at

clinical illness. Those who have higher antibody

titers are less likely to be clinically ill.

What this also says is that the number of

people who are infected who are relatively

asymptomatic is fairly high compared to the numbers

that we would recognize as having had influenza. So

it is something else to keep in mind in terms of

trying to make sense out of what is there.

So another study done by the same group in

1986. Again, it was the family study, Houston family

study. They had 98 families enrolled with 192

children who are between 3 and 18 years old.

These children were randomized. I am not

sure that is quite the right word. They were groups

that got either placebo or inactivated trivalent

vaccine or a live attenuated bivalent vaccine.

Each of those vaccines contained an

A/Chile/1/83‑like H1N1 virus. These children all got

a single dose of vaccine. That particular year, the

H1N1 virus was a new one that had appeared only in

March, was first identified in March.

And you might remember that that was the

year that there was a supplemental vaccine that was

produced for A/Taiwan/1/86. It was not used in this

study, but it was recognized that the Taiwan/1/86

virus was substantially different from Chile so much

so that it was thought that for younger people, that

an A/Taiwan vaccine would be a good idea.

Again, they had virus isolation and

serology to try to document infection. What they

showed was both of these vaccines had protective

effect against infection with A/Taiwan/1/86. And this

is infection and not illness that we are looking at

now. So it is the measurement that would pick up more

individuals.

Anyway, you see this is fairly similar.

It was about 52 percent protective effect on this

drift variant from the live attenuated vaccine in use

at that time and about 61 percent for the inactivated

vaccine.

The authors commented that they thought,

actually, in the younger age group, the live

attenuated vaccine performed better than the

inactivated vaccine and vice versa for the inactivated

vaccine, which you can see here. Nevertheless, both

of these vaccines were substantially better than no

vaccine in terms of what happened to the placebo

group.

So, finally, one more drift variant story,

a nursing home in Colorado in 1987 during an outbreak.

There was an outbreak that was caused by an H3N2 drift

variant.

The vaccine strain at the time was

A/Leningrad/6/86. The viruses that were being

isolated have names. They are Colorado, of course.

They were all similar to this reference strain, the

Sichuan/2/87 strain. And that strain was different

enough that the following year, it was included in the

vaccine for use. So that there was some difference.

I am not sure that the difference between

Sichuan/2/87 and Leningrad/6/86 is the same as the

Victoria/Port Chalmers difference, but there was still

enough that it was thought a good idea to change the

vaccine after those had appeared.

Not everybody in this nursing home was

immunized, but they immunized a very high percentage

of them after the outbreak started. The outbreak

itself had a peak that occurred about two weeks after

the immunization campaign.

This analysis was done retrospectively,

but they were able to get pretty good documentation

from the nursing home records about who had fever; as

measured by thermometer, who had illnesses, what kind

of illnesses they were. Of course, pneumonia and

death were pretty obvious because the residents needed

for the treatments. In a subset, they were able to

confirm that infection had occurred because of H3N2.

But generally this again was a clinical observation.

This just shows the epidemic, how it

occurred. When it was first recognized, it was a

fairly sharp epidemic. There were about five of the

residents of the nursing home who were infected. The

following week, vaccine was given to all who wanted it

or could receive it. There were a number of

individuals who refused the vaccine, and there were a

number of individuals who had other ongoing illnesses

that were thought to be contraindications to getting

the vaccine.

So the numbers peaked around week four

here on the epidemic. And then it kind of quickly

tapered off afterward. What you can see is that

although there are quite a few cases in both the

immunized and the unimmunized populations, looking at

vaccine effectiveness, as calculated by the authors,

they mainly were looking at febrile upper respiratory

illness.

They excluded a number of individuals who

had been immunized in that two‑week interval. From

the time they immunized until two weeks, they excluded

those from their true analysis. And that was true for

both vaccinees and non‑vaccinees. There were some

other exclusions as well.

Looking at the incidence, these are

numbers and not percents here. Looking at the number

of febrile upper respiratory illnesses that occurred,

the proportion was significantly less in those who

received vaccine. And protective effectiveness

against febrile upper respiratory illness in that

group was calculated to be about 65 percent.

There were no pneumonias in those who got

vaccine and there were no deaths in those who got

vaccine; whereas, there were pneumonias and deaths in

those who did not. This isn't really randomized

prospectively. So there may be some other reasons for

that. But if you look at all of the residents all

together, you can see that all together, the residents

who got vaccine, there were no pneumonias and no

deaths; whereas, there was a substantial number of

both incidence of pneumonia and death in the residents

who were not immunized.

Some facts that I guess we could take from

those studies are that the vaccine protective effect

is a lot more obvious for severe forms of illness and

for complications that are related to influenza and

infection.

The vaccine shifts the spectrum of disease

toward the less severe consequences and milder

illness. Whatever you are looking at, they have to

keep that in mind. And higher antibody titers are

more likely to result in protection from clinical

illness.

Also, for infection, this is not an

absolute. There is in my own mind not an absolute

number to use for this, but it is pretty clear that

the more antibody you have, the better.

The vaccine administered in an ongoing

epidemic still may reduce illness, pneumonia, and

death, even when there is antigenic drift that has

occurred.

Turning away from that at the moment,

these are the recommendations that were made by the

World Health Organization for influenza vaccine

composition for the Northern Hemisphere for 2004‑2005.

The recommendations from there that are

based on the information that was available to WHO

last week were to continue to use an A/New

Caledonia/20/99 H1N1‑like virus, to use an

A/Fujian/411/2002 H3N2‑like virus, and to use a

B/Shanghai/361/2002‑like virus for the B strain.

Again, the question for the Committee,

"What strain should be recommended for the antigenic

composition of the 2004‑2005 influenza virus vaccine?

Should it be based on the epidemiology and antigenic

characteristics of the viruses, the serologic

responses, and availability of candidate strains?"

All the information that we are going to

be presenting apart from the vaccine effectiveness

studies this morning will relate directly to answering

this set of questions by the Committee. And I think

I can stop there and ask if there are any questions.

CHAIRMAN OVERTURF: Were there any

questions for Dr. Levandowski? Yes? Please identify

yourself.

DR. MARKOVITZ: David Markovitz. I am

speaking from the somewhat claustrophobic right

corridor of the table, where it is difficult to see or

breathe. So if you will excuse me, I am not

articulate.

My question is this. You showed a graph

that implied that the vaccine manufacturing process

was quite effective this year but, yet, also alluded

to some early gaps, early in the season, which we all

noticed just in our hospitals or reading the

newspaper. What is your overall assessment of how the

manufacturing process kicked in this year?

DR. LEVANDOWSKI: Well, I am not sure what

gaps you are referring to, but from the point of view

of production and vaccine release this year, it went

about as smoothly as it ever goes, which means that

manufacturers were busy producing monovalent vaccines

and busy producing trivalent vaccines and having those

released and being able to get them into distribution.

I don't know that I have any other

information. From our perspective, things went

extremely well.

DR. MARKOVITZ: I guess at our hospital,

in the fall, for example, people were not able to get

vaccine. I don't know what the cause of that was.

Was that just too early in the year? Did they strike

too soon or what? Is that just an anecdotal

observation from what I have seen? I believe I read

about that nationally, too, I thought.

DR. LEVANDOWSKI: Again, from our

perspective, I don't understand it. I don't have any

information that relates directly to distribution. We

don't get involved with distribution per se at FDA.

It is more understanding that the vaccines meet their

specifications and that they are okay to go out.

What we saw was a steady stream of vaccine

preparation release. And maybe this is a question for

the manufacturers and not for me because I don't know

what issues there might have been for them in terms of

distribution.

DR. MARKOVITZ: I wasn't really thinking

of distribution. I was thinking more of manufacture.

DR. LEVANDOWSKI: Well, that is an

important part of manufacturing: getting the vaccine

out to where it is supposed to be used. But, again,

that is not a part that FDA really interacts with

directly as the vaccine is being prepared. It is more

of the release specifications being met for the

vaccine and that all of the good manufacturing

practices have been met to make sure that the vaccine

is ready to go.

Again, I would have to say that this year

‑‑ and the graph I showed I think is an indication of

that ‑‑ all the vaccine that came through FDA came

through at a very early time point.

CHAIRMAN OVERTURF: Dr. Myers?

DR. MYERS: Roland, the data sometimes is

presented for children less than five and sometimes

broken down by a year or less than five. The data you

showed is striking for the morbidity being for

children less than a year of age. Is there any

protective effectiveness data for that population?

DR. LEVANDOWSKI: There is relatively

little direct information. Again, I would have to ask

some of our other colleagues out there what they know.

I don't know that there has been a specific study to

look at vaccine effectiveness in children who are less

than one year of age.

I think we do have some understanding that

immunogenicity may be decreased in the very young

children as well. I think that is partly reflected in

the setting, the cutoff at six months for use of

vaccines, if there is an understanding that maybe the

vaccines won't be so immunogenic in those children and

maybe the reactogenicity is a bigger concern than any

clinical benefit that they might get.

There is, however, relatively little for

inactivated vaccines. There is more recently for live

attenuated vaccines. In children 15 to 72 months of

age, the studies that were done by MedImmune show a

very high level of vaccine effectiveness, efficacy

actually, in those children.

CHAIRMAN OVERTURF: Dr. Gellin?

DR. GELLIN: Well, two questions. The

first is you made a comment in 1986 that there was a

supplemental vaccine produced. Could you give us a

little more insight into what that was?

DR. LEVANDOWSKI: Right. The vaccine was

made for the A/Taiwan/1/86 strain. That virus was

first identified, I believe, in March of that year.

It was at a very late point in time. There was a

recommendation that a supplemental vaccine be

prepared. And the manufacturers did that, but the

timing for it was not available until late November

anyplace.

And because of the way it came out, there

was a lot of confusion, part of the confusion because

I was in clinical practice at the time trying to

figure out what to do with the vaccine late November

and early December. There was a lot of confusion on

the part of practitioners about what to do with it.

Not much of it got used. Most of it was subsequently

discarded. It had to be thrown away, basically. That

strain was what was used in the vaccine, then, the

following year for the trivalent vaccine.

DR. GELLIN: So it was a monovalent

product?

DR. LEVANDOWSKI: Yes. Sorry. It was a

monovalent supplemental vaccine, right, that one year.

DR. GELLIN: The second question was, in

your chart about the efforts, intensive efforts, that

go into when they are changed each year and then the

subsequent graph about the delay in production.

In 1992 to 2000, there were two changes.

And that was the year that there was a delay in the

release of the vaccine that was used. I was wondering

if they were related.

DR. LEVANDOWSKI: It is partly related.

Some manufacturers had some difficulty with

replication of the H3 strain early on, but that was

worked out, as it usually is. Manufacturers are

actually quite resourceful at making things work.

If you will look at that chart that you

are talking about ‑‑ I am not sure I can get to it

because of the touch pad here on the computer. It is

not that friendly. If you look at that graph that you

are referring to, you can see that most of the effort

actually goes into producing the H1 strain. And

although the H3 is the one that got all the notoriety

for being difficult to work with, at least initially,

the H1 strain took up more manufacturing time in terms

of number of monovalents.

The way I presented that information, you

can't directly equate that with the overall amount of

vaccine that is being produced because their

variability, lot sizes are variable from manufacturer

to manufacturer and even within a manufacturer. So it

is not like you have one box that has 100 units in it.

You have a box that might have ten units. You have a

box that might have 150 units. It is not that direct.

But I just tried to give some impression

as to the overall effort. It is actually the H1

strains that have been more difficult the last few

years in terms of overall manufacturing effort.

CHAIRMAN OVERTURF: Dr. Monto?

DR. MONTO: I would comment about the

nursing home and how to interpret drift in terms of

nursing home outbreaks. We have had a surveillance

going on in a number of Michigan nursing homes for a

number of years now. Two years ago, with a rather

wimpy A/H3N2 outbreak with a non‑drifted variant, we

had confirmed transmission in 26 percent of our homes.

This year it is going to be higher. And

we had an outbreak in December. It is going to be in

the 30 percent range, we think, once we finish the

analysis.

What I am saying is that you really have

to look at what happens in nursing homes, even in a

non‑drifted year, in terms of putting things into

context because the vaccine really does not protect

all that well against just influenza‑like illness,

even laboratory‑confirmed, even in a non‑drifted year,

in this population. Our nursing homes were typically

80 percent and many of them 90 percent vaccinated.

CHAIRMAN OVERTURF: Dr. Farley?

MEMBER FARLEY: To me, one of the most

striking features of this year's influenza profile was

the early onset of disease. Given the manufacturing

timetable that you presented, if there were any

indication to attempt to begin immunizations earlier

in the fall or late summer even, is it even possible

within the constraints of the timetable?

DR. LEVANDOWSKI: I think the answer, is

it possible, yes, I think it is. I mean, I think that

this year the vaccine was prepared at a very early

point. If you have that graph? Again, I am not sure

I can get to it easily here because of the computer

system.

There was a substantial amount of vaccine

in trivalent form. That graph that I was showing was

for trivalent vaccine. There was a substantial amount

that had been released for distribution, even in the

summer months. So it is possible that it could have

been.

This year, although there was an early

epidemic of influenza, although it started early,

there was a substantial amount of vaccine that could

have been available around the country at that point

based on the manufacturing timelines for this past

year.

If we had made a strain change this last

year, I don't know that that would have been true. I

am not sure that there would have been further delays.

Given the timelines for preparation of seed viruses

and so on this past year, I would assume that we would

not have been seeing vaccine early in the summer but

probably the first vaccines might have been available

September, rather than in July.

So, again, from my perspective, I think

manufacturing went very efficiently and was early and

on time with a total amount that was intended for

production for this year based on what the demand

parameters were that the manufacturers understood for

all of the vaccines.

CHAIRMAN OVERTURF: Dr. LaRussa?

MEMBER LaRUSSA: Just to carry that a

little further, can you just sort of estimate?

According to one of your slides, the high growth

reassortants were available in June for the Fujian

strain. If you had decided to go ahead and make a

monovalent vaccine, what would be the earliest that

would have been available?

DR. LEVANDOWSKI: Well, that is what I was

trying to get to with that other slide that I had

about manufacturing timelines, the 20 weeks. If you

take about six weeks for development of the reference

virus at that point, what would that be? That is

about three and a half months.

So from June until sometime late September

probably by the time we would be seeing any vaccine

produced that was trivalent; whereas, with the

manufacturing system as it was, the first trivalent

vaccines were actually coming in end of June,

beginning of July.

CHAIRMAN OVERTURF: We have time for about

one more question. Any other questions?

(No response.)

CHAIRMAN OVERTURF: I think we will go

ahead and proceed, then, with the discussion regarding

vaccine effectiveness. I guess Dr. Carolyn Bridges is

going to make that presentation.

VACCINE EFFECTIVENESS

DR. BRIDGES: Good morning. Today I am

going to be discussing some studies that have been

done on vaccine effectiveness of the inactivated

influenza vaccine this year that CDC collaborated on.

I will be discussing a little bit of

background about the flu season, most of which Roland

has already covered. Then I will be describing two of

those studies, where we have preliminary results; and

then listing some other studies that are currently in

progress; and then end with some final remarks.

As Roland stated, influenza activity

started earlier than usual this year. And children

appeared to be disproportionately affected compared

with recent years. There were widely publicized

reports of pediatric deaths that received quite a bit

of attention.

There is also unprecedented demand for

vaccine more than in some recent years. And there was

discussion at the HHS level about additional vaccine

purchase. Although, as Roland says, the amount of

vaccine that was purchased or was manufactured was

equal to the demand from the previous year.

In addition to these pediatric deaths,

there is also a drifted variant of influenza H3N2,

which predominated, which was different from the

vaccine strain. And influenza vaccine effectiveness

was questioned.

In order to assess the effectiveness of

this year's inactivated vaccine, several studies were

initiated simultaneously using various age groups and

looking at different outcomes.

Preliminary results are available from two

of those studies, which were conducted in the State of

Colorado. One of those studies was a retrospective

cohort study among health care workers. The principal

investigator for that study is Dr. Nidhi Jain.

The other one is a case cohort and

subsequent case control study among persons aged 50 to

64 years who have laboratory‑confirmed influenza. And

the co‑PIs for that study are Drs. Marika Iwane and

Guillermo Herrera.

This is some surveillance data from the

Children's Hospital in Denver, Colorado. And, as you

will look at the left scale, it goes from zero to 400.

This is a scale for influenza A viruses. On the

right‑hand of the graph, it is a scale for RSV and

influenza B, which goes from zero to 40. So there is

a tenfold difference in the scales.

As you can see, influenza A activity began

early in November. It peaked towards the end of

November and then started on this decline. There were

very few influenza B viruses and very few cases of RSV

that were identified at the Children's Hospital among

hospitalized as well as outpatients.

This is the remainder of their

surveillance data. Again notice the scale, zero to

20. So there also was very little in the way of

paraflu, adeno, rhinovirus, or pertussis that was

identified.

Incidentally, of the respiratory specimens

that were tested in the hospital laboratory, the

percent of specimens that tested positive for

influenza at the peak was around 60 to 70 percent. So

this is a very high percent positive rate from

respiratory specimens.

We decided to conduct a study among health

care workers at the Children's Hospital because the

staff provided a large cohort for rapid analysis. And

we knew that a large number was needed if we were

going to look at nonspecific outcome.

Also, this cohort has substantial

opportunities for exposure to influenza as they had

many hospitalized patients who were influenza‑positive

and they had conducted the bulk of their inactivated

influenza vaccine campaign in the month of October.

Influenza‑like illness was the outcome.

This has been used, as Roland has described, in many

prior studies, although we clearly understand that

this underestimates the vaccine effectiveness that

could be seen looking at more specific outcomes, such

as laboratory‑confirmed influenza.

We thought that this may provide us with

a reasonable estimate or reasonable chance of finding

vaccine effectiveness because influenza was so

predominant as the cause of flu‑like illness in the

population based on the Children's Hospital

surveillance data. Preliminary results of this study

were published in the January 16th MMWR.

The objective of this study was to

estimate the effectiveness of the 2003‑04 inactivated

influenza vaccine in preventing influenza‑like

illness, or ILI, among adults working at the

Children's Hospital in Denver, Colorado.

This is a retrospective cohort study. A

questionnaire was distributed via e‑mail and also

paper surveys to approximately 3,100 employees. This

is an anonymous survey, and very limited demographic

information could be collected. Information was

collected on age group, sex, whether they had patient

contact, whether they had one or more high‑risk

conditions, whether they are vaccinated, and the

timing of their vaccination, illness onset and

symptoms, and whether they had physician visits or

were influenza‑tested. We also asked about missed

workdays from flu‑like illness. The questionnaire was

distributed from December 11th through December 17th.

The ILI definition used was self‑reported

fever plus either cough or sore throat, which is

similar to the CDC surveillance case definition.

Illnesses were counted if they began on or after

November 1st or through the date of survey completion.

We conducted two different types of

analysis, one a categorical analysis and the other a

person‑time analysis. For the categorical analysis,

we estimated vaccine effectiveness against ILI only

among persons who were vaccinated before November 1st

and compared those with those who were never

vaccinated.

We looked at two different vaccination

definitions for persons who became ill less than two

weeks after being vaccinated. In one instance, we

categorized those persons as being unvaccinated. In

the second analysis, we excluded them from the

analysis.

For the person‑time analysis, again, the

person‑time began November 1st and ended on the date

of survey completion. We did not exclude persons who

were vaccinated during the illness period for this

analysis, but an individual could contribute both

vaccinated and unvaccinated time if they got

vaccinated during the period of interest of November

1 through survey completion date.

The outcome for this study was ILI

incidence density rate. And, similar to the first

study for those who became ill one to 13 days after

vaccination, we either counted that time as being

unvaccinated time in one analysis or we excluded those

person‑days from the analysis.

This graph shows the number of

influenza‑like illness cases among staff. Those are

in the short light blue bars; the number of

laboratory‑confirmed influenza cases among patients at

the Children's Hospital, which are the tall purple

bars; and the line graph shows the percentage of the

cohort that was included in the study, the percent of

the cohort that was vaccinated by time.

So as of November 1st, 54 percent of the

persons who answered the questionnaire were

vaccinated. An additional 24 percent were vaccinated

during the outbreak period of November 1 and later.

So of 3,100 persons to whom the

questionnaire was distributed, 1,886, or 61 percent,

completed the survey. Half of those completed it

online and half of those completed it by paper.

Persons were excluded if they did not

report their vaccination status as being yes or no or

if they did not report date of vaccination. We also

excluded persons who did not report whether or not

they had an illness or if they did not report date of

illness onset.

This is the demographic information from

the persons who completed the questionnaire. It