U. S. Department of health & human services

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the panel felt that careful consideration needed to be

given to what might go wrong, and then once the

immortalized cells are developed they may pose issues

like other types of neoplastic cells, for example, the

creation of a PrP gene as a result of some abnormal

mutation in the genome.

Finally, in summarizing the meeting, the

panel considered that the defined risk approach that

I showed you earlier was a useful way to organize

thinking about the process, however, I think the

committee was a bit skeptical of our ability to

generate useful numbers to address these levels of

risk, and they thought that the outcome of this type

of analysis would, at this stage of our knowledge,

probably be suspect in some circumstances. However, I

thought that they did think that when sufficient data

were available to allow the application of this

technique that useful information could be obtained.

And finally, that there was considerable

discussion toward the end of the session on the risk

posed by residual DNA and the fact that they are

insufficient data, even though this question has been

around now for probably 25 years, to dismiss it as a

concern. And, I think the meeting ended on the note

that it would be extremely useful for regulatory

agencies, and CBER in the United States, and NIBSC,

and, perhaps, the Paul Ehrlich Institute and other

institutes, regulatory institutes, to try to get

together and develop a game plan, or a series of

experimental approaches to answer this question, which

most people think could be answered relatively simply

once and for all.

I think thats sort of where we are. Id

be happy to try to answer any questions. As I say,

this was an extensive meeting, there was a huge amount

of information presented. I think what we did

accomplish, and we accomplished several things, at

least from my superficial perspective, and the first

thing was that as asked by the committee be got this

information out before the scientific public. I think

from the comments I heard the issues were favorably

received by our colleagues, and I think they were

quite enthusiastically discussed. And, I think that

we also, at least from the folks that talked to me,

there was considerable sympathy to the types of

problems that we are trying to address here, and a

number of people expressed a willingness to help us

out in any way they possibly could.

CHAIR GREENBERG: Well, thank you, Andy,

for reviewing what must have been an incredibly

complicated meeting. Im sure that many of you on the

panel will look forward to receiving the documents

which will be chock full of good science, actually.

We have time for some questions. We are,

obviously, panel members, not going to be able to

explore each one of those areas, despite many of your

interests, but we do have time for some questions. So,

if there are any for Andy.


DOCTOR FAGGETT: Doctor Lewis, again, Walt

Faggett. Thanks for a very clear, this is strictly

very complex subject.

On the topic of genomic instability, you

mentioned that there is a possibility of replication

of some endogenous agents. Whats the worst case

scenario in that instance? What could that result in?

DOCTOR LEWIS: I think that, again, it

would depend on the substrate itself, from my

perspective, and Doctor Peden and a number of folks

who were at the meeting are here, so I would ask a

little help in this situation if I dont cover it


In a human cell, I think that at least

from my own personal perspective, the thing that I

worry about the most would be the induction of a

latent virus, and Ill give two for example. The

first for example would be theres an increasing

amount of data now accumulating on the presence of

human polyoma viruses in various types of human

tumors. I wont bother to mention them, but these

viruses occur latently, and they are not too difficult

to induce, and they are in most of us, and they are

present in many of our tissues. So, I think the

possibility exists that this particular genome could,

in fact, be induced to expressed as an infectious

virus as a result of a mutational event within the

cell itself.

Now, with this particular series of

viruses we have some comfort, because we have the

capacity to detect these agents with quantitative PCR

assays at an extremely efficient level. So, I think

it would be possible with this particular example to

be sure that the genome was either there or not there

before we ever developed the substrate. So, thats

just one type of example.

Endogenous retro viruses in tissues other

than man would, I think, present a possible problem,

especially rodent and non human primate tissues might

be the source of endogenous retro viruses that could

be activated by this type of technique.

And finally, the example of the PrP gene

I think is the thing that gives us the most pause,

because technology is not very good at detecting

infectious PrP or prion activity at this point in

time, and so, in fact, the suggestion was made by

Doctor Cashman at the meeting that one way to deal

with this would be the possibility of engineering a

cell line in which the PrP gene was, in fact, ablated,

so that you could get rid of this problem once and for


CHAIR GREENBERG: Any other questions from

panel members? No?

Well, if not, thank you, Andy, for moving

ahead with this. I guess  can I just ask one thing?

When will this circle back?

DOCTOR LEWIS: I was afraid you might ask

that. Unfortunately, at this point in time, you know,

we just havent had a chance to digest this

information, and, in fact, I was confronted just this

morning when I was trying to put these slides together

that the planning meeting for the next VRBPAC session

meeting in November is tomorrow. And, I just think

that its not going to be possible for us to get this

together for a week or two anyway.

Now, I would certainly hope that by the

end of the month we should have a pretty good handle

on what transpired at the meeting and what we gleaned

from it and what we didnt glean from it, how it is

going to impact on our immediate problems with dealing

with some of the issues that are already before us,

and maybe we can, in that period of time, we ought to

have some idea of where we need to go in the future.

I would think realistically we should be

back before the committee in January. That would be

my feeling. Doctor Egan may choose  and Doctor

Patriarca may choose to set another agenda.

CHAIR GREENBERG: Well, thats always the


Thank you, Andy.

Id like to move on now to our third

update session, an update on RotaShield by Doctor


Oh, and I am recused from conducting this

session, so Doctor Daum?

For this one Im allowed to stay in the

room, for the next one Ive got to leave.

DOCTOR DAUM: For the transcript record, I

am Robert Daum, and Im temporarily chairing this

meeting for the Rotavirus item.

Doctor Carbone?


Today Id like to review the chronology of

the events prior to licensure and post licensure of

Rotavirus vaccines.

Just as background information, why are we

interested in Rotavirus as an agent of illness in the

United States? Its the single most important

etiological agent of severe diarrhea in infants and

young children worldwide. Virtually all children are

infected by age three to five years, thats four out

of five children, and notice that this is true of

developed and undeveloped countries. Severe diarrheal

disease is caused in children of three to 35 months,

and in the U.S. it regularly causes seasonal diseases

from November to May, depending on what part of the

country you live in.

Specifically in the United States, the

impact of the disease that causes half a million

physician visits a year, that is one out of seven

children, 50,000 of those children are hospitalized,

thats one out of 78, and there are 20 deaths per year

of children under five years of age, one out of


Just as a little background about the

agent itself, Rotavirus is an RNA virus and contains

11 segments of double stranded RNA as its genome.

Because the genes are in individual segments of

RNAase, you can actually end up with a chimeric or

hybrid virus when two different viruses infect the

same cell and the genes reassort. Therefore, progeny

may have genes from two or more parent viruses.

There are many strains in multiple

species, and there are multiple serotypes, and that

one single serotype, one single virus, is unlikely to

be made into a vaccine, vaccines are likely to require

multiple viruses. All of these issues with Rotavirus

play a role in development of the vaccine itself.

RotaShield vaccine is the first licensed

Rotavirus vaccine in the United States. It is a live

attenuated reassortant of a rhesus Rotavirus, RRV

strain, that contains a single human gene, the VP7

gene, for issues of immunogenicity. The vaccine

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