Page
201
1 know, every
two years we put out a new edition
2 of the Yellow
Book. And so we do a
3 comprehensive
look country by country of what
4 the malaria
situation is. And so we were
5 laughing as we
were going from Mexico all the
6 way down to
South America because every single
7 country says
we have our malaria program under
8 control. It is
the Guatemalans next door.
9 Guatemalans
say it is the Belizeans. Then it
10 is the Nicaraguans.
Then it is the -- and so
11 everyone cites that
same issue as a concern
12 that it is the
cross-border traffic that is
13 the real concern.
So I think it is there in
14 every country, to
some degree.
15 DR. CABLE: Richard
Cable from the
16 Red Cross. I am
wondering if you had
17 considered adding
to the one-page sheet that
18 they fill out, the
doctors, or when you talk
19 to the doctors,
asking whether these travelers
20 with malaria have
donated blood since their
21 return.
22 DR. ARGUIN: Well,
I guess, to
Page 202
1 address that
question about donation practices
2 and
international travel, we are taking a look
3 at that. We actually, I mentioned a Health
4 Style survey before where investigators can
5 add questions to a population-based sampling
6 of the U.S. to determine risk behaviors,
7 etcetera. And we have added those questions
8 to that survey.
9 So, we will
get some survey data
10 to help answer that
question. I am not sure
11 we can add that to
the surveillance form,
12 however. It asks an
awful lot of questions.
13 There is actually a
fairly involved process to
14 add more variables
to a surveillance form to
15 determine the
burden on the U.S. public,
16 etcetera.
17 DR. CABLE: But if
there were a
18 public health
problem with this, wouldn't it
19 be up to the public
health authorities to find
20 out about another
case occurring in the United
21 States from blood
donation? I would think it
22 would be in your
purview.
Page 203
1 DR. ARGUIN:
It certain is within
2 the purview.
If we wanted to add a question,
3 if we thought
there was a compelling need to
4 do that, we
could certainly try and do it. I
5 would say at
this point with the current
6 prevention
mechanisms in place, we are not
7 having an
awful lot of transfusion transmitted
8 malaria.
9 DR. CABLE: So
you don't think
10 there is sufficient
risk to add the question.
11 Is that what you
are saying?
12 DR. ARGUIN: We'd
see what the
13 survey shows and
see to what degree this is
14 happening. If there
is a suggestion that it
15 is data worth
gathering, we could certainly
16 try and gather
it.
17 CHAIR SIEGAL:
Another question.
18 DR. KULKARNI: I
wanted to know if
19 the patterns of
donor deferral in Mexican
20 blood banks for
Malaria, do we know anything
21 about that? Does
that go with your pattern of
22 distribution of
malaria?
Page 204
1 DR. ARGUIN: I
don't know that. I
2 am not aware
of a source of information on
3 that.
4 CHAIR SIEGAL:
Okay. Thank you
5 very much, Dr.
Arguin. Let's move on. We are
6 next going to
hear from Dr. David Leiby from
7 the American
Red Cross on Serologic Testing of
8 Malaria
Deferred Blood Donors: Ferreting Out
9 the At-Risk
Donors.
10 Dr.
Leiby.
11 DR. LEIBY: Good
morning. Thanks
12 to Sanjai for the
opportunity to address the
13 committee on this
issue. And he has asked me
14 to present some of
our data of our studies at
15 the American Red
Cross looking at the at-risk
16 donors and the
potential that they may be
17 infected with
malaria.
18 I think it is
important though to
19 review again,
although I know that Bryan, as
20 well as Sanjai
discussed this, the U.S.
21 deferrals for
malaria. And briefly, as you
22 already saw, both
the deferral for residence
Page 205
1 and history
malaria is a three-year deferral.
2 The travel
deferral is a one-year deferral.
3 And on first
glance, these look to
4 be rather
simplified versions of what really
5 occurs. They
look like they are easily
6 defined,
easily approached and easily
7 addressed in
the blood centers. In fact,
8 travel is more
or is less defined past three
9 years traveled
out side U.S. to an endemic
10 area for less than
five years and are symptom
11 free results simply
in a one-year deferral.
12 Well, in practice,
it is not really that
13 simple.
14 And if you look at
the system that
15 we use at the
American Red Cross and for
16 instance, this is
question 29 from the UDHQ.
17 And this is what we
ask our donors when they
18 come in. So this is
what our donor, as well
19 as our donor health
historians are confronted
20 with each time a
donor comes in. And it asks
21 if in the past
three years have you been
22 outside the United
States or Canada. And if
Page 206
1 they say no,
they are accepted for donation.
2 If they say
yes, then we have to
3 figure out
what country they traveled to. Is
4 the country
malarial, have they been to Iraq
5 because it
also included in this portion a
6 separate
deferral for Leishmania. A donor
7 health
historian then has to determine if the
8 country they
went to is in fact malarious.
9 And if it is
malarious, as we just heard, what
10 parts of that
country might be malarious as
11 well.
12 Then it asks as
well if they have
13 been an immigrant,
refugee, citizen or
14 resident, lived
more than five years in
15 another country,
just adding another level of
16 complexity. And we
all go on down here to
17 yes, which country
was that and so forth.
18 Eventually, you
might end up over
19 in this oval box,
which I quite like. It
20 says, defer three
years after departure from
21 malaria country of
birth or residency, or 12
22 months after
departure from Iraq, or from
Page 207
1 recent travel
to malaria area, whichever is
2 later. This
just gives you an example of the
3 complexity of
the questions that we are
4 confronted
with each and every time when a
5 donor comes to
donate.
6 Thankfully
for question 40 on
7 malaria risk,
if they have had malaria in the
8 past, it is
much shorter. But one of the
9 problems with
the questioning strategy as it
10 exists now, if they
are deferred for question
11 29, we never get to
question 40. So, we never
12 really know if they
have had malaria in the
13 past. So the system
certainly has its issues.
14 Now, Bryan Spencer
referred to
15 some of this data
before and this is actually
16 going to be
published next month in
17 Transfusion. It is
already out in preview
18 issues. You can
find it online. And this was
19 a study that we did
looking at unique donors,
20 the numbers of
percentage of donors lost
21 between 2000 and
2006 for each of the three
22 deferral criteria.
The numbers deferred for
Page 208
1 malaria, a
history of malaria, are relatively
2 low and have
been flat for seven years,
3 probably
longer than that. The rate of
4 deferrals for
residents since 2000 has
5 decreased.
That is a significant decrease
6 over time,
over that seven year period. In
7 part, that is
probably due to restrictions on
8 immigration
since 2001.
9 When one
looks at travel though,
10 it is quite obvious
that since 2000 we have
11 increased from 0.8
to approximately 1.2
12 percent of donors
lost to travel deferrals.
13 This is the Red
Cross system alone I should
14 mention, not other
blood systems.
15 So as Bryan, I
think, alluded to,
16 that is
approximately a 50 percent increase
17 over that seven
year period. And again, that
18 is a fairly highly
significant increase and
19 the regression
coefficients are included for
20 your
benefit.
21 Now when we look
at the number of
22 donors lost due to
that same period, we can
Page 209
1 make some
calculations about potential
2 donations lost
as well. Over that seven year
3 period, we
determined that we lost 316,000
4 donors due to
these three deferrals. During
5 that period in
the Red Cross System, there is
6 approximately
let's say 29 million donations
7 as a
percentage then, and we have seen this
8 figure before,
one percent was due to travel,
9 0.09 due to
residence, 0.002 due to malaria,
10 with our overall
deferral rate for malaria at
11 0.17. If you want
to round it up to 1.1, I
12 think it is very
close to what Celso showed
13 earlier for
America's Blood Centers.
14 Using a multiplier
of 1.7, the
15 number of donations
a donor usually makes per
16 year times the
number of deferrals, we can
17 make some kind of
estimate about the number of
18 donations lost
during this period. And so the
19 number we get is
538,000 donations lost, of
20 which as you can
see, almost 500,000 of those
21 are due to
travel.
22 I must stress that
this is an
Page 210
1 extremely
conservative estimate of the number
2 of donations
lost. It does not address the
3 issue of the
number of donors who never
4 present at the
blood center. Some estimates
5 suggest that
the number of donors who do not
6 present at the
blood center is larger than the
7 number
deferred. Donors who do not present
8 think in their
mind that they will not be
9 accepted for
blood donation because they have
10 traveled somewhere.
And they be right and
11 they may be wrong
but nevertheless, they do
12 not present for
donation.
13 This also does not
take into
14 account future
donations. It only addresses
15 donations within a
given year. So, potential
16 future donations
lost are not factored into
17 this as well. So,
by any measure, the number
18 of donations lost
is extremely large.
19 And this got us to
move forward
20 and try to address
the issue of who among
21 these donors who
are deferred are really at
22 risk? Is it those
with malaria? Is it those
Page 211
1 with residence
or the travel donors? Or is it
2 more than one
of the groups?
3 So, for the
past two and a half
4 years at the
American Red Cross, we have been
5 conducting a
study looking at this factor in
6 deferred and
non-deferred donors in the
7 Greater
Chesapeake Potomac Region, which is
8 largely in the
Washington-Baltimore area. The
9 test we have
been using, and I think we are
10 going to hear about
this after the break more
11 is a serologic
test. It is an EIA developed
12 by Lab21
Healthcare, which was actually
13 formerly NewMarket.
So if you have heard
14 about the NewMarket
test, this is the same
15 test, just a
different company.
16 Initially, we
tested over 3,000
17 non-deferred
donors, because we were
18 interested in
trying to determine what the EIA
19 background because
we initially assumed that
20 there would be a
relatively rare event that we
21 would find positive
donors. We were actually
22 mistaken, so this
became even more important.
Page 212
1 Then we tested
malaria deferred donors and
2 have been
doing so in Greater Chesapeake and
3 Potomac for
the last 25 months.
4 We have also
included supplemental
5 testing of any
donors who found repeat
6 reactive or
seropositive. By PCR and real-
7 time PCR, I
will state right here, we have
8 only found one
donor that was actually PCR
9 positive that
was parasitemic. In many ways,
10 that is not
surprising. I know Sanjai showed
11 some data at the
workshop two years ago that
12 the likelihood of
finding a donor parasitemic
13 is very low. In
part, it doesn't deal with
14 the fact that PCR
is not sensitive. It is
15 often because of
the volumes which we test are
16 extremely small, as
opposed to the large
17 volume which you
transfuse.
18 We did the PCR in
part to identify
19 species. But as I
said, that has really not
20 become a major part
of the study. We have
21 also asked donors
who are a part of the
22 deferred donor
study, we gave them a risk
Page 213
1 factor
questionnaire. Because the data that
2 you acquire
through the UDHQ and other BDR
3 mechanisms is
really rather brief and we don't
4 have a
complete history on the donors. We may
5 know why they
were deferred but we don't know
6 the rest of
their history. And so we gave
7 them a rather
extensive questionnaire to learn
8 more and, as
you will see, that proved to be
9 invaluable.
10 This is the data
set to date.
11 Initially, we
tested slightly over 3200 non-
12 deferred owners.
Twenty-one were initially
13 reactive and 11 of
them were repeat reactive
14 to 0.34 percent.
Initially you might say that
15 that is not such a
great, a lot of false-
16 positives but I
will come back and address
17 that in a
second.
18 We have tested
over 2100 deferred
19 donors at this
point, 36 were initially
20 reactive and 31
were repeat reactive. If one
21 wishes to compare
the repeat reactive rate
22 between
non-deferred and deferred, they are
Page 214
1 significantly
different and perhaps this is
2 not
surprising.
3 It shows that
we are picking out
4 those donors
who are at risk. It is an
5 enriched
population as opposed to the random,
6 non-deferred
population.
7 But let's go
back and talk about
8 these
non-deferred donors, in particular,
9 these 11 who
we identified as being positive
10 by this EIA. Two of
those donors had
11 absolutely no
travel at all. No travel to
12 malaria endemic
areas, no travel any place.
13 So, we consider
those probably to be false-
14 positives.
15 Two had European
travel only and
16 the European travel
was to areas where we
17 consider them not
to be at risk for
18 contracting
malaria. Then it gets
19 interesting. One of
them actually traveled to
20 endemic areas of
India. And as I will relate
21 later, most of our
-- not most. Many of our
22 positive
individuals who are donors who have
Page 215
1 had malaria
before actually contracted it in
2 India. Two
were born and lived in Africa.
3 Four were
previously diagnosed and treated for
4 malaria
greater than three years. And at
5 least three
were born and lived in Africa.
6 These are
non-deferred donors, keep in mind.
7 So, four of
them had it and they
8 qualified for
donors because they had it
9 greater than
three years ago. They are
10 acceptable donors
based on all of our existing
11 criteria but they
have some sense that there
12 is antibodies still
in their system and we
13 will talk about
that a little bit later.
14 So, when you look
at these 11,
15 four of them are
probably false-positives but
16 one can make the
argument that the other seven
17 perhaps are at risk
and this may represent
18 past infections or
perhaps underlying
19 infections.
20 When we looked at
our deferred
21 donors, during the
last 25 months, there has
22 been almost 7500
donors in Greater Chesapeake
Page 216
1 that have been
deferred. You can look down at
2 the breakdown.
You have seen these
3 comparisons
before but by and large, the large
4 number is due
to travel deferrals.
5 And our goal
is really to look at
6 as many donors
as possible so we invited all
7 resident
deferrals and all malaria deferrals
8 by letter to
join the study and approximately
9 every third
donor who was a travel deferral to
10 enter our study.
They came in, gave a tube of
11 blood. Then they
were tested by PCR and
12 serology.
13 And what is
interesting, when you
14 invite the donors,
who actually comes in the
15 end. And out of the
49 who had been deferred
16 for malaria, only
one was willing to
17 participate in the
study. Slightly more
18 donors who deferred
for residence, 12.4
19 percent entered the
studies, while 70 percent
20 of the donors who
had been deferred for travel
21 came back and
entered the study. By and large
22 these are donors
who are, at times, somewhat
Page 217
1 angry about
being deferred for simple travel.
2 They want to
take part in the study and they
3 are looking
for a way that they can help
4 improve and
better understand this issue. So
5 they are
really actively involved.
6 Now, if we
look at that same
7 population
which I just showed you, those who
8 enroll in the
study and find out what they
9 were deferred,
where did they travel to or
10 what was the issue,
first of all, for the one
11 malaria donor, the
person who had malaria
12 before, that is
very easy, he acquired malaria
13 in Africa. If we
look at the residents, the
14 largest percentage
of them, 63 percent, 63
15 percent of the 55
are actually in Asia or the
16 Western Pacific,
only four in Africa. About
17 a quarter of them
were from South America and
18 then just one each
from Central America and
19 Mexico.
20 The interesting
thing is when you
21 look at the over
2,000 travel deferrals and
22 over 80 percent of
those are for travel to
Page 218
1 Latin America,
Central America, the Caribbean,
2 Mexico and
South America. And I think this
3 mimics what
Bryan Spencer spoke about and what
4 we heard from
the CDC data was well. A
5 relatively
small number of the travelers are
6 actually going
to the Asia Western Pacific and
7 even a smaller
number are going to Africa.
8 When one
looks at the malaria
9 positives and
where they traveled, what is the
10 relationship? A
couple of things are
11 immediately pretty
clear. Again, the one with
12 Africa who had
malaria went to Africa. If we
13 look at all of the
Latin American donors,
14 remember all the
individuals who were deferred
15 because of visiting
residence in Latin
16 America.
17 Throughout the
studies so far, we
18 have only
identified one positive individual.
19 It turns out this
was a 27-year-old woman who
20 was on her
honeymoon for nine days in Costa
21 Rico. She denied
any potential exposure, did
22 not have any
symptoms or anything else. At
Page 219
1 first, we
thought that was perhaps a false
2 positive
result. Then interestingly enough,
3 when we shared
some of these samples with
4 Abbott and
they are going to, I think, speak
5 about this
after lunch, on a prototype assay
6 they have been
working with on a prism assay
7 using
completely different antigens and in a
8 blind assay,
they detected this individual as
9 being positive
for vivax. So we have some
10 questions about
that.
11 What is important
now then is you
12 see these other
ones are residents in Asia and
13 Africa and the
others have traveled to Africa
14 and Asia as well.
We spent a lot of time
15 today talking about
travel, how big a role
16 does travel really
play? Is this really the
17 biggest concern?
And you might look at me and
18 say, well you are
showing 20 people have
19 traveled to Africa
and Asia who are at risk.
20 Well, when we
really looked at those 20
21 people, based on
our results from our
22 questionnaire, it
becomes much more interest
Page 220
1 and perhaps in
some ways, much more complex.
2 These are the
31 positive donors
3 we have. And
if you use the results from the
4 questionnaire,
those who have actually
5 traveled to
endemic areas, those who have had
6 residence
prior, and those who previously had
7 malaria, you
see in many cases, these people
8 have multiple
factors. They may only be
9 deferred
because of travel but they have also
10 been a resident in
a malarious area and they
11 have had malaria
once, twice, sometimes
12 multiple
times.
13 In fact, there are
only three
14 individuals on this
chart here who have had
15 only travel, no
residence, and no malaria.
16 The first one is
number five and is the young
17 lady on her
honeymoon in Costa Rica, which we
18 related. The next
one, I believe is number
19 eight. It turns out
that was a U.S. born
20 citizen but he
traveled routinely back to see
21 family in India and
spend extensive time in
22 India. And number
17, the third one, was a
Page 221
1 gentleman who
had spent time, he was deferred
2 for travel to
Punta Cana in the Dominican
3 Republic but
more interestingly, he was with
4 the U.S.
military and had spent over a year in
5 Somalia.
6 So, we can
look at all of those
7 and say well
those perhaps have other risk
8 factors
besides travel to get beyond the Costa
9 Rican donor.
But the important thing is these
10 donors often,
people at risk, people who were
11 pulling up
positive, have multiple risk
12 factors,
particularly residence and having had
13 malaria
before.
14 So, in conclusion,
there is a past
15 history of malaria
among deferred and non-
16 deferred donors.
This is based on their
17 verbal telling us
they have had malaria
18 multiple times.
Also antibody tests picking
19 up some level of
antibody.
20 Latin American
travelers seem to
21 be targeted
unnecessarily. We have large
22 numbers that we are
deferring. We don't see
Page 222
1 the levels of
infection among the Latin
2 American
donors. Similarly, we have seen
3 similar data
by prior speakers as well.
4 We have the
issue of long-term
5 antibody
titers. And what does that really
6 mean? And
there has always been a question
7 about
long-term antibody titers by Dr. Goodman
8 and what that means. There is actually a
9 picture, a graph. It is not mine. I didn't
10 use it. It is by Mariana Wilson of the CDC
11 several years ago, which I think the CDC did
12 a
study looking at long-term antibody titers
13 and those perhaps who are exposed only once,
14 the titers dissipate and disappear rather
15 rapidly. Vietnam vets maintain their titers
16 much longer than someone who lives in endemic
17 areas of Africa and is repeatedly exposed may
18 maintain their antibody titers for years. But
19 it is something that is not really well
20 understood.
21 But what it may
indicate is
22 actually the
semi-immune donors, those
Page 223
1 individuals
who are at greatest risk for
2 transmitting
infection, transmitting a
3 malaria. And
by and large, transfusion
4 transmitted
malaria cases fall among these
5 individuals
who appear to be asymptomatic but
6 still carry
the parasite.
7 As I said,
there is already a
8 relationship
to transfusion-transmission.
9 Wherever their
infection status looks unclear,
10 they cannot readily
be determined to be
11 parasitemic by any
tests. It is relatively
12 hard to understand
but they do have the
13 parasite present in
their blood.
14 And lastly, this
leaves us with
15 the concept that
perhaps it is time for a new
16 malaria paradigm.
And I would suggest perhaps
17 the elimination of
the travel-related
18 questions. They
have become cumbersome, as
19 you saw earlier on,
very complex, difficult to
20 administer. They
are difficult from the
21 standpoint of what
collection agencies for
22 what they need to
follow through as far as
Page 224
1 regulatory
requirements, call-backs at the
2 donor centers.
That is the most frequent
3 thing I hear
from our donor health historian.
4 And these
malaria questions are really the
5 bane of their
existence is the issues of not
6 only
administering the question but he call-
7 backs and the
time and effort that goes with
8 them.
9 I think it
would not be
10 unreasonable to
defer donors with a history of
11 malaria since most
cases of transfusion
12 transmission
malaria involve donors who
13 previously have had
malaria. And as you saw
14 previously, the
numbers of those individuals
15 who have had
malaria are relatively small.
16 Keep in mind we
already defer donors who have
17 had lobesia and
that is a topic, I guess, for
18 tomorrow's
discussion.
19 And lastly, I
think the focus has
20 to be on those
donors with a history of
21 residence in
malarious areas because those,
22 coupled with the
individuals who have had
Page 225
1 malaria
before, are at the greatest risk.
2 And I just
want to thank three
3 people because
they are the ones who do all of
4 the work.
First, Megan Nguyen, who is here
5 and in my lab.
She manages the study for me
6 and then the
staff in Greater Chesapeake and
7 Potomac, Joan
Gibble and Tami Goff. Thank
8 you.
9 CHAIR SIEGAL:
Thank you very
10 much, Dr. Leiby.
Questions for this speaker?
11 DR. BRACEY: Okay,
I have a
12 question.
13 CHAIR SIEGAL: Dr.
Bracey.
14 DR. BRACEY: We
have had
15 restrictions on
blood donors from Sub-Sahara
16 and Africa for some
time related to the O
17 strain. That has
been lifted in many centers.
18 And that
potentially might pose more risk. I
19 would be interested
in your comments on would
20 you project that
the risk of malaria might be
21 increased using our
current screening
22 questions, by
virtue of reintroducing that
Page 226
1 group? I don't
know how many immigrants there
2 are, but I
would be interested in your
3 comments.
4 DR. LEIBY:
There might be others
5 who can speak
better to that. I am not sure
6 of the number
we would lose because of what we
7 used to lose
because of the O deferral. And
8 I am not sure
what those seven countries
9 necessarily
the overlap with malaria endemic
10 regions. I think it
is probably pretty
11 significant. We
would probably defer them
12 anyway. But I am
not positive about that.
13 DR. EPSTEIN: Now
David, in the
14 samples that you
tested and where the Petrie
15 reacted, did you
confront them with any assay?
16 Is there any assay,
you know, supplemental
17 assay which you
would confront just by saying,
18 you know, looking
at their history, that some
19 of them were
non-residents, some were
20 residents.
21 DR. LEIBY: That is
the difficult
22 part, is finding a
suitable confirmatory
Page 227
1 asset. We have
looked at IFA and had some
2 issues with
that as well, found some
3 underlying
reactivity with most of the samples
4 but below what
one we consider the normal
5 cutoff. Now,
the cutoff was established for
6 clinical
cases, not for cases who had long-
7 term exposure.
So we are getting, I think we
8 are all
getting into an area that is not well-
9 characterized
and we don't understand quite
10 very well. And I
think those are some of the
11 issues we are going
to have to address today.
12 DR. KATZ: David, I
was just
13 sitting here and my
BlackBerry started to
14 vibrate. And from
my quality department back
15 at the center,
hello, I am sending you a blood
16 product deviation
report regarding a donor who
17 traveled to Roatan,
Honduras and has donated
18 three times since.
So we now have to notify
19 three hospitals,
actually probably more than
20 three hospitals,
about this donor's history
21 and that we
shouldn't have collected the
22 donor. And we file,
you know, I would guess,
Page 228
1 100 a year.
And if you look at the FDA's
2 database
post-donation information for this
3 kind of
travel, tens of thousands, do you know
4 the burden in
the red cross system?
5 DR. LEIBY:
You are asking the
6 wrong person
but Sue is here and she might
7 know.
8 The only
thing I can add is that
9 as I got
deeper into the study and I started
10 getting out from
behind my desk and actually
11 speaking to the
staff in the regions and I
12 found out what
really goes on. I mean, I
13 always thought it
was just a simple question
14 on the BDR, they
checked it yes or no and it
15 was fine. Then I
realized all the
16 complications with
the question. And that is
17 why, quite frankly,
I put up the first slide
18 with a flowchart to
show the complexity.
19 But then I was
actually astounded
20 when I actually
talked to the regions as I
21 alluded to and
found out the call-backs, the
22 mistakes that are
made, the complexity of just
Page 229
1 following up
with all the regulatory paperwork
2 they are
required to do as well and now you
3 will be doing
as well, too. Of course, you
4 have already
notified the FDA so you should be
5 in good
shape.
6 So, I'll turn
it to Sue. She
7 might know
better.
8 DR. STRAMER:
I'm Susan Stramer,
9 American Red
Cross, for 2004 and 2005, those
10 are the two years
that I have collated data,
11 we have had each
year about 1200 BPDs.
12 DR. RENTAS: Are
there any
13 exceptions made for
platelet donors and donors
14 of plasma as why as
not deferring them? I
15 mean, I am assuming
out of these 96
16 transfusions that
we have had since 1963, most
17 of them probably
involved the transfusion of
18 red
cells.
19 DR. KATZ: It is
interesting
20 because Jed Gorland
all these many years ago
21 applied for a
variance from FDA to make fresh
22 frozen plasma from
donors deferred for malaria
Page 230
1 and that was
not granted. It is very
2 interesting
that, I don't think there is
3 anybody from
Australia to talk today, is
4 there? When
they defer their donors, they
5 don't lose
contact with them. They make a
6 unit of plasma
for further manufacture from
7 the donor but
don't use red cells. So they
8 have a very
interesting way of never losing
9 contact with
that donor, which I think is kind
10 of
slick.
11 CHAIR SIEGAL: Any
other questions
12 or commentary? All
right. Thank you very
13 much. Let's move on
to the last discussion by
14 Hong Yang Ph.D. and
Mark Walderhaug, Ph.D.
15 from FDA. Risk
Analysis for Malaria Exposure
16 in Blood Donors and
Its Effect on Blood Safety
17 and
Availability.
18 DR. YANG: Good
morning. My name
19 is Hong Yang. I
come from Office of
20 Biostatistics and
Epidemiology, CBER, FDA.
21 Today I am
presenting a risk analysis for
22 malaria exposure in
the blood donor and its
Page 231
1 effect on the
blood safety and availability.
2 This
presentation will be split
3 into two
parts. In the first part of the
4 presentation,
I am going to give an overview
5 of the
analysis, include analysis approach,
6 the input data
and the assumption of the
7 analysis. In
the second part of the
8 presentation,
my colleague Mark Walderhaug, he
9 will present a
finding of the analysis.
10 As we all heard
from previous
11 FDA's presentation,
currently, FDA recommends
12 deferral of the
donors who have potential
13 malaria risk.
Current donor deferral greatly
14 reduces the risk of
transfusion-transmitted
15 malaria in the
United States. However, it
16 also costs
significant donor loss.
17 Balance between
blood safety and
18 blood availability
is always major
19 consideration in
the FDA's risk management
20 associated with the
blood supply. Currently,
21 malaria antibody
testing has been used by some
22 other countries as
blood screening tests to
Page 232
1 identify the
donor who has had prior exposure
2 to malaria.
FDA is seeking advice from BPAC
3 on the
possible management option that would
4 allow to
reduce the donor deferral period
5 based on the
result of antibody testing.
6 Some risk
management questions
7 have been
raised by FDA. What other risks are
8 associated
with the possible management
9 options? What
are the benefits? How many
10 number of the
donors need to be tested and
11 what are the
requirements for the antibody
12 testing?
13 Modeling approach
can be used to
14 integrate variable
information, including the
15 uncertainty of
information. It can be used to
16 evaluate risk
management option, using "what
17 if" scenarios. FDA
developed a computer
18 simulation model.
It simulates the process of
19 donor deferral,
blood testing and the blood
20 donation. And the
model includes a key factor
21 in this process
that contribute to the risk
22 and benefit of all
kinds. The output of the
Page 233
1 model
evaluates the impact of malaria antibody
2 testing in the blood safety, and the
3 availability.
4 FDA's model
used current donor
5 deferral as
baseline to evaluate the risk and
6 benefit of
possible management options. FDA's
7 model uses
three model scenarios to evaluate
8 the testing
strategy on the selection of
9 target
population. Model scenario one we also
10 called universal
testing with questionnaire.
11 In this scenario,
all the presenting donors
12 would take donor
questionnaire as we have now.
13 And for the donors
that are deferred were
14 allowed to be
tested after four months'
15 deferral. And this
allowed early reentry of
16 this at-risk donor
if they come back and test
17 negative in
antibody test.
18 In this scenario,
we also tested
19 all other
non-deferred donors. Only those
20 donors who test
negative would be allowed to
21 donate.
22 Model scenario
three, we also call
Page 234
1 it testing the
at-risk donor. In this
2 scenario, we
only test deferred donor after
3 four months'
deferral. It allows early
4 reentry of
at-risk donor if they come back and
5 test negative
in antibody. And all other non-
6 deferred
donors in this scenario will be
7 allowed to
donate without antibody testing.
8 The model
scenario four we call
9 testing
travelers to Mexico. In this model
10 scenario, we only
test a subgroup of deferred
11 donors. They are
deferred because of travel
12 to endemic parts of
Mexico. And this group of
13 at-risk donors
would be tested for antibody
14 after four months'
deferral. It allows the
15 early reentry of
this group of at-risk donors
16 if they test
negative after the deferral.
17 And for all other
deferred donors
18 would be still
deferred for the same period of
19 time as the current
donor deferral.
20 This slide shows
the over-
21 structure of the
FDA module. It consists of
22 four conceptive
modules and each module has
Page 235
1 input and
output. The output of the previous
2 module will
feed into the next module as a
3 part of input.
In the next few slides, I am
4 going to
discuss in more detail for the input
5 assumption and
the output of each module.
6 Module one,
potential donor at
7 risk. FDA
model used projected any number of
8 donor
deferrals for malaria risk in the United
9 States as input to estimate the potential
10 number of donors in the United States as a
11 malaria risk. These data have been presented
12 by Mr. Bryan Spencer in his previous
13 presentation. Here, I want to draw your
14 attention to the donor deferral associated
15 with potential exposure in Mexico. It
16 accounts for 41 percent of the total measure
17 of deferrals.
18 The input of
Module 1, we also use
19 CDC reported any
malaria cases in the United
20 States to estimate
the malaria prevalence
21 among U.S. at-risk
population. These data
22 include information
on the risk group about
Page 236
1 travel of
immigrants and also include the
2 region of
exposure and the distribution of
3 Plasmodium
species.
4 FDA's model
also uses CDC-reported
5 interval
between arrival and the onset of the
6 disease to
calculate the probability of
7 asymptomatic
malaria amount at-risk
8 population.
The data indicates more than 90
9 percent of the
cases displayed these very
10 symptoms within the
90 days of exposure.
11 However, the
immigrant from a malaria endemic
12 country may carry
malaria asymptomatically for
13 a longer period of
time due to the semi-
14 immunity. And some
Plasmodium species may
15 have a longer
incubation period then the other
16 species.
17 This slide shows a
true pie chart.
18 On the left side is
a pie chart that
19 represents the
malaria risk among U.S.
20 population. And the
pie chart on the right
21 side represents
CDC-reported malaria cases in
22 the United States.
I want to point out for
Page 237
1 this pie
chart, the scale of the pie chart
2 shall be much
smaller than they appear on this
3 slide. I
enlarged it because I tried to show
4 all of the
slide more clearly.
5 Based on our
estimate, there is
6 about four
million population in the United
7 States as a
malaria risk. They attribute to
8 about 1500
malaria cases reported in the
9 United States.
More at-risk population
10 traveling to
endemic parts of Mexico account
11 for 33 percent and
they only attribute to less
12 than one percent of
malaria cases.
13 Using this data,
we calculate the
14 probability of
infection. On average, there
15 is about 300
infections for every one million
16 exposure. However,
among travel to Mexico,
17 there is only five
infections in every one
18 million exposure.
And this number indicates
19 the travel to
endemic parts of Mexico has
20 relatively low risk
of infection by malaria.
21 The output of the
Module 1 is
22 estimated number of
potential donors who are
Page 238
1 at malaria
risk. And the prevalence of
2 asymptomatic
malaria in the at-risk donor
3 population.
4 Module 2,
questionnaire screening.
5 In this
module, FDA's model assumed all the
6 donor
deferrals occurred on the side of blood
7 collection
facility. However, it has been
8 reported that
some potential donors-- they
9 self-deferred
for perceived risk by not
10 presenting to
donate. However, there is no
11 data for the rate
of self-deferral.
12 Therefore, FDA's
model simply assumed there
13 are no
self-deferrals.
14 FDA's model
assumed there is a
15 four-month deferral
period prior to antibody
16 testing for the
reentry of at-risk donors.
17 The purpose of four
months' deferral is to try
18 to reduce or
eliminate the window risk that
19 may not be detected
by malaria antibody tests.
20 FDA's model
assumes sensitivity of
21 donor questionnaire
ranges from 85 to 99
22 percent. This
assumption is based on the
Page 239
1 donor deferral
for HIV and CJD. There is no
2 data for donor
deferral for malaria risk.
3 The output of
the module is the
4 estimated
number of the donors deferred and
5 not deferred,
including infected donors and
6 non-infected
donors.
7 Module 3,
Antibody Testing. In
8 this module,
FDA model assumes currently
9 available
antibody testing can only detect
10 Plasmodium
falciparum, Plasmodium vivax after
11 four months' window
period. And the testing
12 sensitivity for
both species is 99 percent and
13 the testing
specificity is 99.8 percent.
14 The output of the
module is
15 estimated number of
donors who are qualified
16 for antibody
testing and the number of donors
17 who are testing
negative. These represent the
18 donor availability.
And the number of false
19 negative, these
represent the residual risk
20 and the number of
false positive, this
21 represents the
donor loss due to testing
22 errors.
Page 240
1 Module 4,
blood donation. In this
2 module, FDA's
model converts the estimated
3 number of the
donor to the estimated number of
4 blood
donation, based on average of 1.75
5 donation rates
per donor per year. The output
6 of the module
is also the final output of the
7 model. There
is an estimated number of the
8 unit from
infected donors. It represents the
9 risk of
possible policy options.
10 Another output is
the number of
11 donors gained over
current donor deferral. It
12 represents the
benefit of the management
13 options.
14 Next, I am going
to turn over the
15 presentation to Dr.
Mark Walderhaug. He is
16 going to continue
to present the result of the
17 analysis.
18 DR. WALDERHAUG:
Thank you, Dr.
19 Yang. If this were
a meal, Dr. Yang has
20 presented you with
the entree and the
21 appetizers and I
get to present the dessert.
22 And the desserts
are the results.
Page 241
1 So let me
start at the bottom.
2 This is
scenario one, the current deferral
3 simulation
that we did, which indicates that
4 the basic risk
is around 1.4 units per year as
5 the result of
current deferral policies. And
6 we are showing
a range of around a zero to six
7 units
appearing. And this might seem high to
8 you because of
the fact that we have already
9 been shown
data based on epidemiology that the
10 rate is actually
much lower than that.
11 But there are
several reasons for
12 this rate. It could
be because of the fact
13 that not all units
from infected donors have
14 the potential to
cause transfusion-transmitted
15 malaria, and
perhaps the greatest utility is
16 that it provides a
relative baseline to
17 compare the other
scenarios with the current
18 deferral
policies.
19 So, looking at the
universal
20 testing, we would
have to test around eight
21 and a half million
donors. We would gain
22 about 87,000 and
the reason why we would gain
Page 242
1 not as many as
we would like is because we
2 would have a
very substantial rate of false
3 positives with
the specificity that we have
4 modeled in our
particular simulation. The
5 rate would be
slightly higher. And I will
6 show you a
reason why it would be higher than
7 the current
deferral policies.
8 Looking at
scenario three where we
9 are just
testing the at-risk donors, we gain
10 around 100,000
donors, about two-thirds of the
11 amount that are
currently being deferred
12 according to our
assumptions. It looks like
13 we haven't lost any
but we have lost some to
14 false positives and
also detections, true
15 positives. We have
a little bit higher rate
16 as a result of just
testing at-risk donors as
17 well.
18 And looking at
testing travelers
19 to endemic parts of
Mexico, we gain around
20 37,000 donors.
These, we have a certain
21 number of false
positives that we lose as
22 well, as well as
some detects. And the rate
Page 243
1 is slightly
higher but at the resolution that
2 we felt
comfortable sharing with you, it is
3 about the same
as current deferral policies.
4 This explains
some of the reasons
5 why the units
are the way they are. If you
6 look here, the
reason why it is relatively
7 higher risk
associated with universal testing
8 and testing
at-risk donors is because of the
9 fact that we
are not catching the malaria P.
10 malariae and P.
ovales. So these are coming
11 through to the
total risk. Because of the
12 fact that P.
malariae and ovale are very rare
13 in Mexico, it does
not contribute much to the
14 risk for those
particular simulations.
15 You will see that
testing everyone
16 does cut down the
risk of falciparum and vivax
17 because we are
catching those donors who are
18 answering the
questionnaire improperly and are
19 winding up donating
anyway, with some evidence
20 of that from
presentation by David Leiby. And
21 you can see the
risks for the current scenario
22 and testing
travelers to Mexico after a four-
Page 244
1 month deferral
have basically the same rates.
2 Some goes up.
Some goes down. Part of the
3 reasons for
the differences have to do
4 independent
draws in our simulations. But we
5 are pretty
confident the rates are about the
6 same.
7 Now, this is
a complicated slide
8 and let me
take you through this slowly so you
9 can understand
it better. I am just showing
10 testing at-risk
donors. I am not talking
11 about testing
everyone but certainly, those
12 results are
important as well.
13 So, when we look
at the identified
14 at-risk donors,
they make up these sets of
15 donors. These are
the ones that we are going
16 to lose because of
the fact that they have had
17 exposures of less
than four months from the
18 time they traveled
to an endemic area. And
19 these are the ones
with the potential to gain.
20 These donors right
here are those
21 donors that are
donating now, even though they
22 shouldn't be. These
are the ones that were
Page 245
1 the baseline
risk for all of our scenarios
2 because of the
fact that our questionnaires
3 are not
perfect and our ability to keep these
4 people from
donating.
5 So these are
the donors tested for
6 universal. We
also have all the other donors
7 as well. So
that is a substantial number of
8 tests that
have to be done. These are the
9 tests of the
at-risk people. Again, we don't
10 catch the people
who should not be donating in
11 this particular
scenario. And these are the
12 donors that we are
testing who are traveling
13 to at-risk areas of
Mexico. And you can see
14 the summary of the
residual risk right here.
15 We reduced this
risk with
16 universal testing
but we have residual risk
17 primarily from
Plasmodium malariae and
18 Plasmodium ovale
for both the Mexico and non-
19 Mexico travelers.
We have this baseline risk
20 present for the
residual risk as well. And
21 the difference for
the Mexico travelers to
22 endemic areas is we
have a very slight
Page 246
1 increase in
risk from our baseline but it is
2 very
small.
3 So, I want to
reemphasize the
4 major
limitations of our analysis here and
5 that is that
we have uncertainties with
6 respect to the
behavior of the test and window
7 periods, the
sensitivity and the specificity
8 are uncertain.
We have set them for our
9 particular
model, but real-life models may
10 differ from these
sensitivities and
11 specificities. It
is also nice though that
12 our model can be
run as new data come in for
13 the sensitivity and
specificity. We can
14 incorporate that in
the model and run it
15 again.
16 The issue of
self-deferral is an
17 important one. We
have assumed no self-
18 deferral and, as a
result, we may be
19 overestimating the
risk and that has indicated
20 perhaps that our
estimated risk is higher than
21 our observed risk
from an epidemiological
22 point of view. And
we may again, also, be
Page 247
1 underestimating the donor gain because of
2 self-deferral. So those are two important
3 things-- limitations to keep in mind when you
4 look at this data.
5 We also
acknowledge our internal
6 collaborators
who have contributed mightily to
7 our analysis.
And it is always a pleasure to
8 work with Paul
Arguin and CDC, and with our
9 fellow members
over at the American Red Cross.
10 We thank Bryan
Spencer for his data as well.
11 So, I have
completed that meal.
12 If there are any
questions I can answer to
13 help you digest it
better, please let Dr. Yang
14 and I know what
they are.
15 CHAIR SIEGAL: So,
are there
16 questions from the
committee?
17 DR. KLEIN: Did you
calculate the
18 risk and donors
gained if you just kept the
19 current system but
eliminated travelers to
20 Mexico?
21 DR. WALDERHAUG:
Eliminated
22 travelers to
Mexico?
Page 248
1 DR. KLEIN:
Yes.
2 DR.
WALDERHAUG: We haven't done
3 that analysis
but you can see here that the
4 donors gained
under those analysis, if I
5 understand you
correctly, would be this number
6 minus 37,000
but I may be misunderstanding.
7 So we will
gain donors using at-risk with this
8 increased
number of units, according to the
9 simulation.
10 This is roughly
two-thirds of the
11 number of total
people being deferred from
12 travel to Mexico at
the present time. So this
13 is our benefit and
with relatively small
14 increase in
risk.
15 CHAIR SIEGAL:
Tom.
16 DR. FLEMING: I've
got a series of
17 questions here,
just to make sure. This key
18 table-- to make
sure I am understanding it.
19 So with this key
table, the number
20 1.4 is if we had
the current system with 8.4
21 million donors, we
would have an expected 1.4
22 infected
donors?
Page 249
1 DR.
WALDERHAUG: Right.
2 DR. FLEMING:
Okay.
3 DR.
WALDERHAUG: This is our
4 current
risk.
5 DR. FLEMING:
Right.
6 DR.
WALDERHAUG: And this is not
7 including the
number of donors that are
8 donating but
this would be the number of
9 donors tested,
which is present here.
10 DR. FLEMING:
Right. Now, what we
11 stand to gain,
possibly 100,000 donors.
12 DR. WALDERHAUG:
Right.
13 DR. FLEMING: First
of all, this
14 number was 1.7 in
what was handed out. Now it
15 is
2.6.
16 DR. WALDERHAUG:
Right. And part
17 of that problem was
the fact that we had
18 double counting
errors or deletions for the
19 baseline risk here.
And so we made that
20 correction on this
particular set of data.
21 DR. FLEMING: So
just to be sure I
22 am interpreting the
2.6 correctly, with the
Page 250
1 current
system, with eight million donors, we
2 would have 1.4
cases.
3 DR.
WALDERHAUG: Those are
4 infected
units. We are not necessarily saying
5 because we
don't have dose response whether or
6 not they would
be wind up being transfusion --
7 DR. FLEMING:
All right. So I will
8 call them
infected units.
9 DR.
WALDERHAUG: Right.
10 DR. FLEMING: If we
add the
11 103,000, that 2.6
doesn't come from the 103.
12 That 2.6 is over
the total. Is that correct?
13 DR. WALDERHAUG:
That is correct.
14 DR. FLEMING: Okay.
So that leads
15 me to basically the
essence. This is
16 extremely helpful
and what I would find most
17 helpful then is to
say, you have got the
18 current system
where we get basically eight
19 million donors and
there is 1.4 infected
20 units. We could add
Mexico, which is adding
21 37,000, basically
the Mexico travelers --
22 DR. WALDERHAUG:
Right.
Page 251
1 DR. FLEMING:
-- and then we would
2 add the other
non-Mexican travelers, which is
3 an added
66,000.
4 DR.
WALDERHAUG: These would be
5 both with
Mexico and --
6 DR. FLEMING:
I understand. That
7 is why I am
trying to break it out.
8 DR.
WALDERHAUG: Right.
9 DR. FLEMING:
So, basically, you
10 have got your
current eight million. You have
11 got 37,000 Mexican
travelers that we are
12 trying to add back
in. Then you have another
13 66,000 outside of
the 37 --
14 DR. WALDERHAUG:
Right.
15 DR. FLEMING: --
who are others.
16 DR. WALDERHAUG:
Yes.
17 DR. FLEMING: Okay.
In essence,
18 what we are seeing
here is that when you add
19 in the 37,000,
there is essentially no
20 incremental gain
over the 8.4 million. Now,
21 it would be nice to
see this to more
22 significant digits
to know in essence "what is
Page 252
1 the number per
unit here?" Per unit. And I
2 get 1.665 per
ten to the seventh. This is 1.4
3 to just under
ten to the seventh. That is
4 1.665 per ten
to the seventh.
5 It would be
interesting to know
6 how this
breaks out there, but it seems
7 similar and
that is based on everything that
8 we are seeing
today.
9 DR.
WALDERHAUG: Right.
10 DR. FLEMING: That
the overall
11 prevalence is going
down and when we can test
12 for specifically
falciparum and vivax, that is
13 exactly what exists
in Mexico. So, everything
14 seems quite
safe.
15 Here, what would
be interesting is
16 to see the other
travelers, basically the ones
17 who are not Mexico.
The 66,000 that are left
18 over. With this,
you are almost doubling the
19 over total number
of infected units. You get,
20 incrementally, 1.2
infected units out of
21 66,000, which by my
count is 182 per ten to
22 the seventh, 182.
So whereas here you are
Page 253
1 getting 1.67
and you are getting essentially
2 the same here,
meaning Mexican travelers are
3 safe, the
non-Mexican are giving 182, which is
4 a relative
100-fold increase. Am I
5 interpreting
that correctly?
6 DR.
WALDERHAUG: Well, a 100-fold
7 increase
in...
8 DR. FLEMING:
So, if you take a
9 look at
basically you are almost doubling the
10 number of infected
units by adding in a one-
11 one hundredth the
number of added donations.
12 DR. WALDERHAUG:
Right.
13 DR. FLEMING: Here,
these numbers
14 of donations are
100-fold what those numbers
15 of donations are
and you are doubling the
16 total number of
infected units.
17 DR. KLEIN: Those
aren't just
18 travelers in that
next to last.
19 DR. FLEMING: I
know. In fact,
20 that is my fourth
question. You are right.
21 I shouldn't call
them travelers. It is
22 excluded or
deferred donors. Thank you.
Page 254
1 DR. YANG: So
--
2 DR. NAKHASI:
Hita Nakhasi. Maybe
3 I can simplify
a little bit clearer. The
4 difference
between the risk which you see at
5 the scenario
number three and the scenario
6 number four is
because you're using the two
7 species
test.
8 See, in the
case of scenario four,
9 you heard that
there are only two species, the
10 falciparum and the
vivax. Whereas in the all
11 at-risk, there are
four species. And the risk
12 which is coming,
increasing risk, comes from
13 the other malariae
and ovale.
14 DR. FLEMING: But
and I thought I
15 addressed this
earlier, this group of 37,000
16 is a subgroup of
the 103,000. Correct?
17 DR. NAKHASI:
Yes.
18 DR. FLEMING: These
are the
19 Mexicans, subgroup
of the 103,000.
20 DR. NAKHASI:
Absolutely.
21 DR. FLEMING: So,
what would be
22 more informative or
particularly helpful
Page 255
1 would be to
take these 103,000 and subdivide
2 them into the
66 that aren't Mexico and the 37
3 that are. And
what you see by doing that is,
4 you already
see this, the 37,000 that are
5 Mexico are
very safe. But the added 66,000
6 here are
contributing an additional 1.2 units.
7 That is a rate
of units per donation that is
8 100-fold
larger than what you have in current
9 testing and
what you would get in Mexico. Am
10 I interpreting that
correctly?
11 DR. YANG:
Actually, the total
12 number of the
donors -- this is donor gain.
13 So, total number of
donors should be this
14 number and this
number when you calculate.
15 DR. FLEMING:
Understood.
16 The main point I
am trying to get
17 at is I am trying
to subdivide the 103 in to
18 the 37 Mexico and
the 66 who aren't. And the
19 point is, when you
have got the 66,000
20 donations that
aren't from Mexico, you are
21 getting 1.2
additional infected units from
22 those 66,000. That
rate of infected units per
Page 256
1 donation is
100-fold what you are getting
2 under the
current system and 100-fold what you
3 would be
getting under the Mexicans.
4 DR. YANG:
Yes, because the
5 assumption is
counting of antibody testing
6 only to tell
two...
7 DR. FLEMING:
And that is part of
8 the reason.
You are right. Part of the
9 reason is you
are only detecting two and that
10 is perfectly fine
in Mexico because that
11 covers the species.
It doesn't cover it
12 elsewhere. But it
is more than that. From
13 everything we are
seeing today, the overall
14 engine driving
these transmissions and these
15 infections are
outside of Mexico, Central
16 America, Africa, et
cetera. All those things
17 go
together.
18 The one last thing
that I can't
19 discern from this
is that if we had column
20 that had only the
66,000-- and this is coming
21 to your point-- the
66,000 who are non-Mexican
22 deferrals, it would
be interesting to break
Page 257
1 that into
travelers and non-travelers. So,
2 those 66,000
non-Mexican deferrals are a very
3 problematic
group. They have 100-fold the
4 rate of units
that would be infected. But
5 could that be
found-- is that in fact entirely
6 because of
residence and infected individuals
7 and not
travelers?
8 DR. KLEIN: We
already know the
9 really high
risk of the people who were born
10 in Africa and India
and those who have resided
11 for five years or
more. We know that for a
12 fact. You could
quantify it but that is a
13 fact.
14 DR. FLEMING:
Right. So we know,
15 we surely know that
the subset of that 67,000
16 or 66,000, the
subset that are residents or
17 infected are
problematic. What I can't tell
18 from this is the
subset of the 66,000 who are
19 simply travelers,
what would their rate be?
20 So what seems to
be the case from
21 all of this is Dr.
Katz is saying "give us
22 Mexico." These data
seem to strongly advocate
Page 258
1 yes, give him
Mexico. The question is, in the
2 other 66,000
where there is a problem, is the
3 problem all of
them or are the travelers in
4 that group
acceptable? And I can't tell from
5 your
models.
6 DR. KUMAR: So
maybe, so there are
7 some things we
can tell probably even without
8 having that
sort of breakdown. I mean, in the
9 beginning I
said only 0.6 percent of travel is
10 to Sub-Sahara in
Africa. But we get about 60
11 percent of clinical
malaria in this country.
12 And similarly, if
you look at the
13 more recent cases
of donors we implicated
14 directly to the
cause of malaria, most of that
15 is coming from
Africa now and some to Asia.
16 So, you are right
on the money
17 there, those 66,000
cases for that higher risk
18 group there-- and
Paul Arguin showed it very
19 nicely-- the risk
factor of malaria exposure
20 is significantly
lower in Mexico compared to
21 many -- and again,
those 66,000 donors are
22 those differences
you see there. There are
Page 259
1 types that are
different, and many are who are
2 lower risk
even than Mexico, actually.
3 But the big
significant part of
4 the intense
malaria transmission area is where
5 malaria is
transmitted year round where the
6 risk is coming
from actually. And we can do
7 those things
and we will sort of look for
8 those donor
populations, once a better test
9 that detects
all four species becomes
10 available. And that
is the next thing we will
11 look
into.
12 DR. SIMONE: I
think the other
13 thing that is
missing is a scenario number
14 five, where you
haven't used any antibody
15 testing for travel
to Mexico in terms of
16 deferral at four
months. Have you, by any
17 chance, run
those?
18 DR. WALDERHAUG:
I'm sorry. Can
19 you ask that
question again?
20 DR. SIMONE: If you
did scenario
21 number four as a
scenario number five but you
22 are assuming there
will not be an additional
Page 260
1 antibody
testing.
2 DR.
WALDERHAUG: Oh, yes. We have
3 looked at that
and as you know from the
4 previous
presentations, the risk from Mexico
5 is very low.
At least in terms of our
6 assumptions,
it stays low even without the
7 antibody
testing. The antibody testing
8 provides a
level of extra security that would
9 not be present
otherwise. But again, it would
10 be very, very low
as well.
11 DR. SIMONE: Well,
then I would
12 encourage you to
show this committee those
13 data. That would be
very useful, I think.
14 DR. YANG: Actually
we did that
15 modeling. With all
the antibody testing, it
16 doesn't take the
traveler to Mexico back. We
17 were at an actual
0.02 donor, infected donor
18 every year into the
donor pool. So, the risk
19 is very
small.
20 DR. KULKARNI: You
said 0.02?
21 DR. YANG:
0.02.
22 DR. FLEMING: So
let me modify my
Page 261
1 request and
give me Mexico except Oaxaca and
2 Chiapas. I
mean --
3
(Laughter.)
4 DR. SIMONE:
So I would strongly
5 encourage you
to again show us those
6 additional
data. And also, I don't see
7 anywhere where
we have discussed costs, which
8 would be, you
know, what do you gain from the
9 donors and
then of course, what is the cost
10 involved in adding
an additional testing?
11 DR. WALDERHAUG: We
haven't
12 discussed cost
because we don't have the cost
13 data. It would be
possible to do analysis if
14 we had -- again, it
starts to get tenuous
15 because we have to
go get a dose response
16 function for the
infected units. And then do
17 a quality impact
for the problems of
18 transfusion
transmitted malaria. So it would
19 be complicated and
difficult to do and we
20 haven't done
it.
21 CHAIR SIEGAL: Dr.
Kuehnert.
22 DR. KUEHNERT: I
just, since we
Page 262
1 are talking
about very small numbers here with
2 Mexico, there
was one other slide that broke
3 down the
additional risk by species. There,
4 yes.
5 And I was
just wondering why this
6 is that there
are under Mexico, there is a
7 risk for
species that don't seem to presently
8 exist in
Mexico.
9 DR.
WALDERHAUG: Right. And that
10 is not
risk-associated with Mexico. That is
11 the baseline risk
that carries through with
12 the Mexico protocol
as well. So, that
13 represents
--
14 DR. KUEHNERT: Oh,
okay. I
15 understand.
16 DR. WALDERHAUG:
Okay.
17 DR. KUEHNERT:
Okay, so that is
18 the scenario of
Mexico but includes all the
19 other donors as
well.
20 DR. WALDERHAUG:
Right.
21 DR. KUEHNERT:
Okay, thank you.
22 DR. WALDERHAUG:
Sure.
Page 263
1 CHAIR SIEGAL:
Dr. Epstein.
2 DR. EPSTEIN:
Yes, well, actually
3 Dr. Spencer's
presentation did contain an
4 estimate for
non-deferral and non-testing, if
5 I understood
it correctly. And that estimate
6 was 0.066
infectious donations per year. But
7 I did notice
that some of the underlying
8 assumptions
were not identical to the
9 assumptions
that FDA had used. So, there is
10 an effort needed to
reconcile the models.
11 But I think
another point that
12 needs to be
reiterated is that the addition of
13 an antibody test,
if we think we need it, is
14 an added safeguard
and that we could go that
15 way for a period of
time and find out if we
16 ever see true
positives. If you don't, you
17 sort of confirmed
you didn't need to do the
18 test.
19 If you do, then
you realize that
20 well, you really
didn't need to do the test.
21 And I think one
point also to bear in mind is
22 that Dr. Arguin's
data showed that there have
Page 264
1 been some
resurgences in malaria and so the
2 antibody test
is a safeguard against a lag in
3 recognition of
resurgence. And then lastly,
4 to point out
that there is flexibility, that
5 deferral for
Mexican travel is not all of
6 Mexico. It is
based on regions identified as
7 malarious by
the CDC. And that there is a
8 whole other
strategy here, which is a more
9 precise
delineation of which regions do and do
10 not require
deferral.
11 And one of the hot
topics has
12 always been whether
you need to be deferred if
13 you go to a Mexican
resort which lies within
14 a larger region
that is designated as
15 malarious. And that
has always been the
16 question about
effectiveness of malaria
17 control at
Western-type resorts.
18 So, I am just
pointing out here
19 that many of the
donors we now defer could be
20 recaptured simply
by more precise strategies
21 of deferral and
that the role of antibodies,
22 although it may not
be apparent up-front, has
Page 265
1 a safeguard
value. And part of the issue
2 whether we are
willing to waive that, based on
3 the estimates
of low risk.
4 Nobody would
take the position
5 that Mexico is
anywhere near the risk of
6 Africa or
Asia. You know, we understand that
7 there is a lot
less malaria. It is just that
8 there is a lot
more travel. And where we are
9 hung up is the
specificity of the deferral in
10 relation to that
large volume of travel.
11 CHAIR SIEGAL:
Harvey.
12 DR. KLEIN: Yes,
Jay but knowing
13 the sensitivity and
specificity of the assay
14 and the risk of the
travelers to Mexico and
15 knowing that
antibody presence does not
16 correlate with
infectivity, I guess, wouldn't
17 you have to spend a
number of years knowing
18 that we only see a
case every couple of years
19 in the United
States, until you have figured
20 out that you are
actually doing anything?
21 Now, that would
certainly be beyond my
22 professional
lifetime and, I suspect, beyond
Page 266
1 my
lifetime.
2 DR. EPSTEIN:
Well, it depends if
3 the model is
right or wrong is one way to look
4 at that. But
no, I take your point, Harvey.
5 CHAIR SIEGAL:
Tom.
6 DR. FLEMING:
I agree. It would
7 take a long
time. If the model is correct and
8 by using
scenario four without the antibody
9 testing, it
adds 0.02. That sounds reassuring.
10 But when you work
the numbers here, that means
11 then, without
antibody testing, those
12 contributions have
three-fold the risk of
13 yielding an
infected unit than the current.
14 Now, three-fold,
it is three-fold
15 over an incredibly
low. It is a lot better
16 than the 100-fold
that you are getting from
17 the non-Mexican.
But it is three-fold. But
18 to discern whether
it is true or not, 0.02, it
19 would take our
collective lifetimes to be able
20 to discern
that.
21 To me, the more
critical issue is,
22 it seems quite
clear from all of what we are
Page 267
1 hearing and
from these analyses that doing
2 this
four-month deferral, re-testing with
3 antibodies in
the Mexican travelers appears to
4 be a very safe
approach. It appears to be
5 giving Dr.
Katz's Mexican donations.
6 The issue
though is, I keep coming
7 back to it,
trying to understand the other
8 66,000 because
that is very problematic.
9 Collectively,
they have 100-fold the rate of
10 infected units that
you currently are getting.
11 But is that heavily
driven? It is obviously
12 substantially
driven by the residents and by
13 the
infected.
14 I have heard two
pieces of
15 information that
tear me in different
16 directions.
Listening to Dr. Leiby's
17 presentation, it
would seem to say that the
18 travelers aren't
where the problem would be.
19 And yet when we
looked at the data that was
20 just presented, the
data that you have just
21 presented, you
showed that the probability for
22 travelers of
infection per one million
Page 268
1 exposures is
five in Mexico and 300 outside of
2 Mexico. So, it
is about a 60-fold. Did I get
3 that number
correct?
4 DR.
WALDERHAUG: Yes.
5 DR. FLEMING:
Which gives me
6 concern about
the travelers outside of Mexico.
7 But I still
can't sort all of that out to
8 understand
clearly if you take these 66,000,
9 they are
problematic, in my view. Unless you
10 can give me data to
reassure us that the
11 reason they are
problematic is entirely the
12 non-travelers
versus the travelers. And how
13 do we get an
insight into that?
14 DR. BALLOW: Yes,
but that may be
15 a moot point
because there is two species they
16 are not able to
test for.
17 DR. FLEMING:
Right.
18 DR. BALLOW: So
therefore, that
19 throws a different
algorithm in the whole
20 scenario.
So--
21 DR. FLEMING: It in
fact --
22 DR. BALLOW: Now,
if I would argue
Page 269
1 that even
though you are right, travelers
2 versus
non-travelers. But if they can't test,
3 you know for
all four species, then all bets
4 are
off.
5 DR. FLEMING:
I hear you. And so
6 there is very
good reason to anticipate that
7 the subset of
these 66,000 that are travelers,
8 which is
probably 60,000 of the 66,000, aren't
9 going to be as
low as everybody else. But are
10 they going to be
two, three, four-fold-- the
11 entire group of
66,000 is 100-fold. But is
12 that because it is
1,000 fold in the six and
13 the 60,000 are
two-fold because of the reasons
14 of not having the
full antibody coverage? Or
15 is it 1,000-fold in
10 or 20-fold? And I
16 guess in the
absence of that insight, it would
17 seem problematic to
allow any of those 66,000
18 through.
19 DR. KUEHNERT: I
think if you saw
20 that other table
also broken down by species,
21 you would be able
to get that estimate.
22 CHAIR SIEGAL:
Okay. I think,
Page 270
1 Louis. But
Louis is going to be the last, I
2 think because
it is so late. We will talk
3 about the
other stuff later.
4 DR. KATZ: We
nag Paul and his
5 colleagues for
more precision, even before I
6 was a blood
banker we were nagging. And I
7 think they
give the right answers. Well, this
8 is the best we
know right now. In point of
9 fact, kind of
the data on imported malaria and
10 travelers speaks
for itself. There are
11 occasional cases
but it is pretty small. And
12 the question is,
whether it is 0.02 or 0.06
13 additional infected
red cells in the supply,
14 are we willing to
take that risk to recover
15 some tens of
thousands of donors.
16 I would point out
that malaria
17 transmission is
unstable. And there is a
18 couple of great
examples, three great examples
19 very recently:
Great Exuma repeatedly, Jamaica
20 recently, and Punta
Cana in the Dominican
21 Republic. In fact,
the blood community
22 responds virtually
in real time to re-
Page 271
1 implement
deferrals, when there is an apparent
2 change in
malaria epidemiology in a place
3 where
travelers go.
4 CHAIR SIEGAL:
At this point, I am
5 going to ask
that we close for lunch and
6 reconvene in
45 minutes. Thank you.
7 (Whereupon, a
lunch recess was
8
taken.)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Page 272
1
A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N
2 (1:50
p.m.)
3 CHAIR SIEGAL:
All right. We
4 would like to
reconvene because we have
5 committee
members who will need to leave for
6 planes and
things of that sort.
7 We are now at
the point of our
8 open public
hearing. Don, you want to read
9 the -- I have
to read this? Okay.
10 I am obligated to
read the
11 following material,
if I could have the
12 attention of those
who are participating,
13 please.
14 Open public
hearing announcement
15 for particular
matters meeting. For example,
16 product-specific.
Both the Food and Drug
17 Administration and
the public believe in a
18 transparent process
for information-gathering
19 and
decision-making. To ensure such
20 transparency, at
the open public hearing
21 session of the
Advisory Committee meeting, the
22 FDA believes that
it is important to
Page 273
1 understand the
context of an individual's
2 presentation.
3 For this
reason, the FDA
4 encourages
you, the open public hearing
5 speaker, at
the beginning of your written or
6 oral
statement, to advise the Committee of any
7 financial relationship that you may have with
8 the sponsor, its products and, if known, its
9 direct competitors.
10 For example, this
financial
11 information may
include the sponsor's payment
12 of your travel,
lodging or other expenses in
13 connection with
your attendance at the
14 meeting. Likewise,
the FDA encourages you, at
15 the beginning of
your statement, to advise the
16 Committee if you do
not have any such
17 financial
relationships.
18 Should you choose
not to address
19 this issue of
financial relationships at the
20 beginning of your
statement, it will not
21 preclude you from
speaking.
22 And that having
been said, we have
Page 274
1 a cast of
characters here for this afternoon.
2 Dr. Dawson
from Abbott will be the first
3 speaker.
4 DR. DAWSON:
Okay. Can you hear
5 me? Yes, okay.
Thank you very much. I work
6 for Abbott
Laboratories so I am a full-time
7 employee of
Abbott, so I am representing
8 Abbott today.
Thank you very much to the
9 organizing
committee for allowing Abbott to
10 present today. We
have been working on
11 malaria the last
couple of years. I am just
12 going to show you
kind of a snippet of some of
13 the information
data that we generated the
14 last couple of
years.
15 But to give you
some background,
16 as we have been
hearing today, we know that
17 the current
deferral practices prevent about
18 150,000 donations
from being made. This is
19 done at the blood
bank site. It has been
20 estimated at one of
the FDA meetings that an
21 additional 730,000
donors self-defer and
22 choose not to
donate blood.
Page 275
1 And it has
been discussed this
2 morning and at
other times that an in vitro
3 test could
possibly be used to identify donors
4 who are
infected with any of the Plasmodium
5 species. This
could be used as an alternative
6 to the
questionnaire, as an adjunct to the
7 questionnaire,
or as a method to reinstate
8 donors who
have traveled to malaria-endemic
9 areas.
10 What are the
options for a test?
11 Blood smears is
insensitive. In the
12 transfusion
transmitted cases that have been
13 identified in the
United States, only about
14 one-third of those
would have been diagnosed
15 with a blood smear
test.
16 PCR is also
insensitive. We know
17 that one organism
of Plasmodium species can
18 cause an infection
and, therefore, just from
19 a sampling error,
even if a single red blood
20 cell were infected
and you didn't test it by
21 PCR, you
potentially have a false negative.
22 So, it has been
kind of agreed that antibody
Page 276
1 infection
would be a very nice way to screen
2 donors for
potential exposure to the
3 Plasmodium
species. In a look back study, it
4 was found that
58 of 59 donors implicated in
5 transfusion
transmitted malaria were antibody
6 positive with
an amino fluorescence test. The
7 antibody test
would detect both acute and
8 convalescent
patients. And in general, many
9 of the studies
have indicated that within two
10 to four weeks after
infection, antibody
11 seroconversion
would be detected, both in
12 animal model
studies and in human studies.
13 In the United
States, four
14 plasmodium species,
falciparum, vivax,
15 malariae, and ovale
have been implicated in
16 transfusion-transmitted malaria. And every
17 year, each of these are found among U.S.
18 travelers returning from malaria-endemic
19 areas.
20 Currently, there
are no licensed
21 tests for screening
or reinstating blood
22 donors that
reliably detect antibodies to all
Page 277
1 four species
that commonly cause human
2 malaria.
Current assays only use P.
3 falciparum and
P. vivax antigens, that we are
4 aware of, at
least.
5 So we started
out with our goal is
6 to develop an
assay that detects antibodies to
7 four
Plasmodium species. We would develop
8 this assay
using recombinant proteins. The
9 assay could be
utilized to screen blood donors
10 in universal
screening or could be used to
11 reinstate blood
donors who have traveled to
12 malaria endemic
areas.
13 So we decided in
order to achieve
14 this that we
searched the databases. There
15 were no genes
available, no sequences
16 available for
MSP1-19 from Plasmodium ovale or
17 malariae. So, we
initiated some antigen
18 discovery studies
that would lead to the
19 development of
antigens that would be useful
20 for identifying
infection with malariae ovale.
21 We started out by
targeting the
22 MSP1 genes, which
we know there is a lot of
Page 278
1 literature
indicating that MSP1 is a very good
2 antigenic
target for antibody response in
3 humans in an
animal studies.
4 As part of
the HIV viral
5 surveillance
program, we have collected
6 samples from
various places in Africa. We
7 have some very
extensive collections made by
8 Gerry
Schochetman and his group working on
9 HIV. And we
started looking at prevalence of
10 antibodies, the
Plasmodium in these various
11 species using
falicparum and vivax proteins
12 and we found very
high prevalence rates in
13 some of these
African samples, up to about 90
14 percent were
antibody positive. And we had
15 the good fortune as
part of this viral
16 surveillance
program to have whole blood
17 available. So, we
had been reading literature
18 and looking at
various ways to detect
19 plasmodium DNA in
samples. And we came across
20 a paper that
targeted ribosomal RNA. So we
21 decided we would do
a PCR and look in these
22 red blood cells, in
the whole blood, for
Page 279
1 evidence of
whether we can find any of the
2 plasmodium
species. And we did melting curves
3 and this
identifies the various species. But
4 we were lucky
enough to find some of these
5 blood samples
had either plasmodium ovale only
6 or plasmodium
malariae only. So these became
7 a source by
which we could try to sort out and
8 see if we
could find the MSP1 genes in these
9 samples.
10 So, we looked at
the sequences of
11 all of the
plasmodium species that affect
12 mammals. And we
generated consensus PCR
13 primers and took
and extracted the whole blood
14 from these samples
that were plasmodium ovale
15 or plasmodium
malariae positive and we found
16 some fragments of
the MSP1 gene. Remember the
17 MSP1 gene is about
5,000 base pair. So we
18 found some small
fragments.
19 And then by virtue
of generating
20 newer and newer
primers for doing PCR, some of
21 them using actually
ovale or malaria-specific
22 sequence, we are
able to identify the entire
Page 280
1 MSP1 gene from
the start code on to the stop
2 code on for
both Plasmodium ovale and
3 Plasmodium
malariae.
4 Then we
decided that we know that
5 the MSP1-19
gene is an excellent antigenic
6 target of
immune response, we decided that we
7 would clone
out and express the MSP1 gene. We
8 did that and
you can see here in the protein
9 gel that we
have a pretty good purification of
10 the MSP1-19 gene
protein. And so we decided
11 we could now embark
on some serologic studies
12 to find out how
useful these new antigens
13 might
be.
14 Before I do that,
I wanted to look
15 at the percent of
amino acid identity when we
16 can compare
falciparum to vivax, malariae and
17 ovale. We see that
across the board that
18 these two new
Plasmodium species-- at least
19 the sequences are
new-- is quite distinct from
20 falciparum and
vivax and quite distinct from
21 each other. In
general, between about 43 and
22 52 percent amino
acid identity between these
Page 281
1 various
antigens. This tells you they are
2 quite distinct
and one might expect that
3 probably not a
high probability of seeing
4 cross
reactivity of antibody response when
5 about half of
the amino acids comprising an
6 epitope is
going to be different from species
7 to
species.
8 So this kind
of was something that
9 we thought of
right away that you are probably
10 going to see some
species-specific antibody
11 detection.
12 So, we developed
individualized
13 markers and
individualized enzyme immunoassays
14 using our
quarter-inch polystyrene beads that
15 we have been
working on for 30 some years and
16 have been very
worthy of our work. We did a
17 lot of good work
with these. And so we coded
18 these and did some
studies. We wanted to look
19 at, in a volunteer
donor population with no
20 risk factors, how
often do you find antibodies
21 to falciparum,
vivax, malariae, or ovale? And
22 we can see zero
percent in three of the four
Page 282
1 species. We
found a few reactives in the
2 vivax group.
We also did some very initial
3 work on PRISM.
And you will see the word
4 PRISM come up
here a few times. It does not
5 indicate we
are developing a test for that
6 platform. We
simply have this, we wanted to
7 do it both on
polystyrene beads and on an
8 automated
platform. So, we chose PRISM at
9 this time to
look at.
10 So you will note a
low prevalence.
11 And we want to
compare that with some of the
12 other
seroprevalence data that we have gotten
13 from other panels.
As I mentioned, we have a
14 panel from Africa
from HIV negative donors.
15 That is from an
area that is very hyper-
16 endemic for
malaria. And we also had the good
17 fortune to get some
panels from the CDC. We
18 got some samples
from experimentally infected
19 non-human primates
from Dr. John Barnwell. And
20 Dr. Marianna
Wilson, formerly of the CDC,
21 provided us with
some human malaria samples
22 from blood smear
confirmed cases. And for
Page 283
1 reference, we
had in many cases blood smear,
2 IFA,
commercial EIA data and PCR.
3 So the first
thing I will draw you
4 to is this
African Panel. There were 230
5 samples that
we had access to test. And you
6 probably can't
read this here. I can't read
7 it from back
there. But I know that there are
8 various-- we
have done probably, we do not
9 even have it
all depicted here. We probably
10 have had at least
30 distinct proteins from
11 Plasmodium species
that we have looked at,
12 proteins and/or
peptides.
13 And we have here
several of them
14 shown. And we have
had a few from vivax but
15 most of them from
falciparum. And you will
16 see that we have
the red arrows here
17 indicating where
the MSP1 genes were. The
18 MSP1 genes work
very well. And we found for
19 each of the MSP1
genes-- we found antibody
20 detection in this
group, suggesting that
21 infection with
three or more of these
22 plasmodium species
probably is occurring in
Page 284
1 this
area.
2 With vivax,
we are not so sure
3 what the
serologic data indicates because in
4 general, these
people in this area lack the
5 Duffy antigen
that is needed for infection
6 with
Plasmodium vivax. But you can see here
7 the
seroprevalence numbers are pretty high, 87
8 percent in falciparum, ovale 45 percent, 71
9 percent for malariae.
10 Next I will turn
your attention to
11 studies with
experimentally-infected monkeys.
12 These were New
World monkeys and the samples
13 were provided to us
by John Barnwell. There
14 were six animals
shown in this study. And you
15 will the
infections. There is a pre-infection
16 bleed that is
labeled as none and then a post-
17 infection bleed.
And you will see here the
18 four colored boxes
indicate ELISAs that we
19 have developed for
falciparum, vivax, malaria,
20 and ovale. And you
will see the colored one
21 with a 26.6, 47.6
indicates what we call a
22 reactive result. So
in this case, all six
Page 285
1 animals in
their post-infection bleed, at
2 about three
weeks after infection, developed
3 antibodies to
P. falciparum proteins that did
4 not develop a
detectible response to vivax,
5 malaria, or
ovale proteins. So we didn't see
6 any
cross-reactivity.
7 The next
slide shows the antibody
8 response again
with four separate EIAs:
9 falciparum,
vivax, malariae, and ovale. For
10 animals infected
with vivax, malariae, or
11 ovale, in this case
they were experimentally
12 infected chimps,
again, provided by Dr. John
13 Barnwell. And we
see again the same type of
14 trending, that if
you use vivax proteins, you
15 do a very good job
detecting vivax infections.
16 Seven of nine of
the animals infected with
17 vivax made an IgG
response. Two of these were
18 also positive for
IgM but we did not include
19 that in this table
at this time.
20 So you can see,
when you use the
21 right protein that
matches the infecting
22 species, you do a
much better job of detecting
Page 286
1 infection. For
the malariae, the falciparum,
2 vivax, and
ovale proteins did not work very
3 well. For
ovale, we see one was reactive with
4 all three
species but ovale did the best job.
5 So again we
see, you know, that
6 having the
malariae and ovale proteins allow
7 you to detect
exposure in these animals that
8 would have
gone undetected with falciparum and
9 vivax
proteins.
10 We have done a
similar study with
11 a panel provided by
Dr. Marianna Wilson from
12 CDC, wherein there
were human samples that
13 were obtained from
individuals with smear,
14 blood-smear proven
infection with falciparum,
15 vivax, malariae, or
ovale. And we compared
16 our data to a
commercial EIA. Here is our
17 EIA, which includes
all four species of MSP1s.
18 And we can see here
that all of the assays do
19 very well with
falciparum and vivax. With
20 malariae, the
commercial assay does not detect
21 it but our assay
that uses the malariae-
22 specific protein
detects it. Here for the
Page 287
1 ovale, five of
eight were positive with a
2 commercial
test. Seven of eight were
3 positive. And
these additional reactives were
4 specifically
due to detection of antibodies
5 either to
malariae or ovale. We did the
6 individual
EIAs on these as well.
7 We have also
done some work with
8 Dr. Leiby. And
we looked at a panel just to
9 start looking
at some U.S. donors. And we
10 had here two
categories of deferred donations
11 and we can see we
do very well in detecting
12 antibodies in
these, detecting 11 of 11 or
13 five of
six.
14 For the
non-deferred donors, it
15 had a risk of
having had a past history of
16 malaria or travel
to a malaria-endemic area.
17 We detect all of
those. For the individuals
18 with no risk, the
non-deferred donors with no
19 travel background,
we did not detect any of
20 these three. What
we don't know at this time:
21 is this, you know,
our failure to detect
22 antibodies in these
or are these false
Page 288
1 positives in a
commercial test? And like I
2 said, we are
in an early stage of assay
3 development.
4 So to
summarize, we think that
5 preferred
antibody tests should include
6 antigens from
all four Plasmodium species. We
7 have looked
very heavily at the literature,
8 which many
studies have shown that using
9 falciparum and
vivax proteins you can detect
10 individuals who are
smear positive for ovale
11 or malariae. But
the question is, it is
12 usually from areas
that is highly endemic, and
13 they could very
easily have been exposed to
14 falciparum or vivax
previously to having an
15 acute infection
with ovale or malariae.
16 So for the first
time, the MSP1
17 genes have been
identified for both ovale and
18 malariae. We have
sequenced the entire genes
19 from the start code
on through the stop code
20 on. We have
expressed the proteins and we
21 have shown their
utility. These recombinant
22 antigens brought
additional detection and
Page 289
1 samples both
from nonhuman primates and humans
2 that would
have gone negative with falicparum
3 and vivax
proteins only. And our assay
4 development
studies will be ongoing. We will
5 be looking at
additional studies with deferred
6 and
non-deferred donors and hopefully some
7 additional
studies on non-human primates to
8 really map out
the human response a little
9 more finely to
find out how long after
10 infection does it
take to mount an immune
11 response, et
cetera.
12 These are some of
the people that
13 worked on this.
Gerry Schochetman is here
14 today and he
actually got the invitation to
15 give this
presentation today and he gave me
16 the opportunity to
address this group. And
17 here are the
individuals that were involved in
18 generating the MSP1
genes and developing the
19 serology for
this.
20 Thank
you.
21 CHAIR SIEGAL:
Thank you, Dr.
22 Dawson. Are there
any questions from the
Page 290
1 floor for Dr.
Dawson?
2 DR. DI
BISCEGLIE: The assay that
3 you described
measures IgG. Can you comment
4 on IgM? I am
concerned in the commercial
5 assay and also
in what data you have about the
6 detection of
antibody in those first three
7 months. So the
technical question but then
8 also maybe the
abilities of the assay in acute
9 disease.
10 DR. DAWSON: We did
find IgM in
11 many of the animals
and in a couple human
12 samples that were
IgG negative. And I didn't
13 report on the IgM
data at this time because we
14 are really, IgM
assays are a lot trickier than
15 IgG assays. You get
a lot more sticky type of
16 reactions with
solid phases with IgM sticking.
17 So it takes a lot
more work to identify a
18 suitable cutoff for
these.
19 And secondly, what
we would want
20 to do-- most likely
what you would have to do
21 to make a viable
test is to include either a
22 direct assay that
will detect IgM, IgA, and
Page 291
1 IgG antibodies
or to really make a combined
2 anti-IgG/IgM
test and that takes quite a bit
3 more
work.
4 So, we are
well aware that IgM
5 detection, I
think, will be important to be
6 able to catch
the earlier window period. You
7 do see earlier
detection. There is an early
8 IgM response
followed by IgG. And like I
9 said, we want
to do some studies where we more
10 finely look at the
immune response, where you
11 could really
control the date of infection.
12 You know, in
non-human primates you can
13 control the date of
infection and map out
14 every few days what
is the IgG response, what
15 is the IgM
response, et cetera. So, we want
16 to do more studies
in that area.
17 DR. KUMAR: In your
oldest
18 monkeys, were these
oldest monkeys single
19 infection or
multiple infection? Had they
20 seen multiple
parasite infections? Say there
21 were nine monkeys
they were given one
22 infection?
Page 292
1 DR. DAWSON:
They were singly
2 infected.
3 DR. KUMAR:
Singly.
4 DR. DAWSON:
We had baseline data
5 on
those.
6 DR. KUMAR:
And the data that you
7 showed us,
that is how many days post-
8 infection, the
blood was drawn?
9 DR. DAWSON:
It was around 21 days
10 post-infection. It
was about three weeks,
11 plus or minus a
couple of days.
12 DR. KUMAR: So the
infections were
13 treated by then, I
guess. The monkey were
14 already treated for
parasitemias. The monkeys
15 were already
treated for infections. Correct?
16 DR. DAWSON: They
were treated for
17 infections? I'm not
sure about that.
18 DR. KUMAR: Well
usually, I mean--
19 if probably they
used the oldest strains.
20 DR. BARNWELL: Yes.
Sanjai, yes.
21 They were, most of
them had been treated
22 approximately one
week before the serum was
Page 293
1 collected but
some of them were still
2 positive.
3 DR. KUMAR: So
they were allowed
4 to reach, I
guess, the two or three person
5 parasitemias.
6 DR. BARNWELL:
Right.
7 DR. KUMAR: I
am just trying to
8 see, I mean
--
9 DR. BARNWELL:
Right.
10 DR. KUMAR: -- what
you will
11 achieve with
current parasitemias in humans.
12 DR. BARNWELL: Yes
and I might
13 point out in one of
your slides, you know, the
14 studies on the
human challenge studies at
15 Walter Reed, those
individuals are usually
16 treated at very low
parasitemias.
17 DR. KUMAR: At the
first sight of
18 parasite, yes.
Absolutely.
19 DR. BARNWELL:
Right.
20 DR. KUMAR: So the
parasite burden
21 that we see is
--
22 DR. BARNWELL: Is
much.
Page 294
1 DR. KUMAR: --
much lower.
2 DR. BARNWELL:
Very different.
3 DR. KUMAR:
Yes, that is what I
4 was getting
at. Thanks.
5 CHAIR SIEGAL:
Okay. Thank you
6 very much. Oh,
there is another question.
7 Sorry.
8 DR.
McCUTCHAN: Yes. Since the
9 central issue
here is, or seems to be,
10 travelers donating
and whether to defer them
11 or not, how often
with any of these four
12 malarias do
travelers come back asymptomatic
13 after four months
or five months and have the
14 antibody, the
combination?
15 DR. DAWSON: You
are asking me
16 that question? I
really don't know the answer
17 to
that.
18 DR. McCUTCHAN: I
don't know how
19 often somebody has
-- I mean, you would have
20 to have an
asymptomatic case or a misdiagnosed
21 case of malaria for
this to be of too much
22 value for
travelers, it seems to me.
Page 295
1 DR. NAKHASI:
Tom, maybe we can
2 ask, direct
the same question to David because
3 I think I had
the same question for the table
4 for George
here. The data that you presented
5 on Table 14,
which is from the ARC studies, do
6 you know how
often, you know, that is Jay's
7 question
earlier, then how long after they
8 return from
these places were these tested?
9 DR. DAWSON:
We do know that.
10 David Leiby has
provided a lot of that. We
11 know what year some
of the people had malaria
12 that we detected,
but I didn't have, you
13 know, bring that
data or I didn't have enough
14 time to present all
of that. But a lot of
15 that is known.
David, I don't know if you
16 have anything to
add to that but there is a
17 lot of
information.
18 DR. LEIBY: Of
course I don't know
19 off the top of my
head what they were but I
20 mean, they were
all, in most cases they had
21 malaria many years
ago. So we were not
22 picking up anybody
with a clinically acute
Page 296
1 infection. I
think you are just, you are not
2 going to see
those, I don't think.
3 DR. NAKHASI:
But there are
4 travelers also
in there, no? And how long --
5 when was the
travel, three months? Four
6 months?
Because the question Tom is asking is
7 how long the
antibody comes up after that and
8 how long can
it stay there.
9 DR. LEIBY:
Right. And the
10 travel, obviously
the honeymooner was within
11 the year period but
they are all relatively--
12 but if they are a
travel deferral, they are
13 within less than a
year from the return from
14 their travel and
potential exposure. Is that
15 what you are
asking?
16 CHAIR SIEGAL:
Okay, the next
17 speaker.
18 DR. WYNN: I
actually-- I am Megan
19 Wynn, I am the one
who does the study.
20 Basically, the
people that were tested, they
21 were deferred for
traveling to-- depending
22 under what deferral
category they were
Page 297
1 recruited
under the study for. With the
2 travel
deferral people, they were deferred for
3 travel
purposes but they came up positive,
4 repeat
reactive, because of past malaria
5 infections,
whether it was 20, 30, ten years
6 ago, that is
where the reactivity was coming
7 from, except
for the honeymooner.
8 CHAIR SIEGAL:
Okay, there is
9 another
question. No. Dr. Knox now. Dr.
10 Knox from
Lab21.
11 DR. LEIBY: Can I
just pose one
12 question? And I
haven't seen it addressed yet
13 today. I mean,
there is now described as a
14 fifth species of
malaria that infects humans
15 and I haven't heard
anybody say a word about
16 it.
17 CHAIR SIEGAL:
Could you repeat
18 the
question?
19 DR. BARNWELL: He
is talking about
20 Plasmodium
knowlesi, which is a monkey
21 parasite that
occurs in Southeast Asian
22 macaques. And that
is their natural hosts.
Page 298
1 And for many
number of years we have actually
2 wondered if
humans living in these areas could
3 be infected
because we knew that they could
4 infect humans.
And recent studies coming out
5 of Sarawak and
other regions of Malaysia have
6 shown that a
good number of individuals in the
7 hundreds have
been infected with knowlesi or
8 are currently
getting infected with Plasmodium
9 knowlesi. It
is a zoonosis at this point. We
10 have not seen any
evidence of human to human
11 transmission at
this point, but it is
12 something you might
want to consider at this
13 point.
14 DR. KLEIN: Do we
know anything
15 about the severity
of the disease outside of
16 monkeys?
17 DR. BARNWELL: It
ranges from mild
18 to death. Okay?
There have been a few deaths
19 from it, and we
have known this every since
20 the 1930s that it
can very virulent in humans
21 when there was
neurosyphilitic studies done
22 with this parasite
in Romania.
Page 299
1 DR. KUMAR:
Knowlesi is known to
2 be more
permanent and fatal probably than
3 falciparum,
actually. So that is why John
4 said
neurosyphilitic they just use knowlesi to
5 key syphilitic patients and then they stop.
6 They started to use vivax now. But the
7 question is, there are ten primary malaria
8 that we know of, and each are capable to
9 infect humans, given their parsinity. So
10 whether we consider this as established human
11 parasite disease is debatable still. So, I
12 guess we can wait and watch.
13 CHAIR SIEGAL:
Thank you for that
14 interlude. Now Dr.
Knox, please.
15 DR. KNOX: Good
afternoon, or for
16 anybody still on
European time, good evening.
17 My name is Colin
Knox. I am a full-time
18 employee of Lab21
Limited. I am going to tell
19 a little bit about
our experience with the
20 strategy of
reducing the deferral period and
21 combining it with
antibody testing. As Dr.
22 Leiby kindly eluded
to earlier, some of you
Page 300
1 may be
familiar with Newmarket Laboratories
2 but probably
not with Lab21 Limited.
3 Newmarket
Laboratories has been purchased by
4 Lab21. So, it
is fairly simple. We are in
5 the process of
re-branding at the moment.
6 Okay so the
strategy which is
7 present in
many non-endemic areas is the
8 deferral of
donors for a period of time and
9 that may vary.
Whatever the period of time
10 is, there are two
factors which are the same.
11 One is that there
may be a loss of too many
12 donors. In the UK,
they found that they were
13 losing 30,000
donors and multiplying that up,
14 potentially, to
60,000 donations per year. We
15 have various
figures for the U.S. I have got
16 down there 100,000
donors per year, possibly.
17 And it is worth
pointing out that these losses
18 are cumulative
because you will lose a certain
19 portion of these
donors who are deferred for
20 a long period of
time.
21 Secondly the
deferral system is
22 not 100 percent
effective. You will still get
++