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Dr. Hibberd>> And as Dr. Killen mentioned,
our research is also highly related to the FDA.
Our research is under investigator-initiated IND
because, clearly, the goal of our research is to prevent,
treat, mitigate or cure
relating to the prevention and treatment of infectious diseases
at the extremes of age or in immunocompromise.
So we are very much under regulation from the FDA,
which has changed dramatically the way we move forward.
So in 2006, it was all so simple.
I was very, very fortunate to get this NIH grant funded,
and the concept here was simple.
Elderly people do not respond well to the flu vaccine.
They need some help.
Probiotics may have some immunomodulatory properties—
but the idea that probiotics would actually benefit a flu shot was
a little far fetched.
However, what about that mucosally administered flu
vaccine that clearly has a site of action in the mucosa where
the probiotics have a site of action?
Is it possible we could boost the immune response of the flu
vaccine for elderly subjects?
So we were very, very excited to talk to the FDA,
and they said no.
Their argument was,
you've got to show that this product is safe,
and also how the heck do you know it's safe in the elderly?
Have you really thought about that?
And the answer was, probably not as much as we should.
So what the FDA asked us to do,
and I'm going to report a little bit of data on today,
is first do something just very, very simple.
Can elderly people safely tolerate a probiotic over a
short period of time?
And if they can, then what I'm going to do is move ahead to see
whether or not administering the probiotic
with the flu shot helps.
Honestly didn't really expect it would.
But then, and unfortunately at the end of the flu season,
because the flu mist is not approved for people over the
ripe old age of—49
The bottom line is, we then wanted to move ahead with this
to evaluate safety and preliminary immunogenicity,
and to potentially study the mechanism of action of the
probiotics in this particular circumstance.
Then—and this is where we are right now—
we can go back and talk to the FDA and see what they think
about proceeding with the original study.
So that open label study in elderly people,
we found 15 of them aged 65 to 80.
It really is amazing how many people truly think they're
healthy, yet have a large number of conditions.
We have people who came in, we asked if you had—
if they had diabetes. "No."
What meds are you taking?
Well, don't you have diabetes?
No, the insulin cures the diabetes.
I don't have diabetes anymore!
So you clearly have got to really do these studies properly
in order to make sure you have healthy people.
But I was also amazed to find individuals 80 years old
who aren't on a single medication.
We had these subjects consume Lactobacillus GG,
a fairly high dose, for 28 days,
and then we followed them for another 28 days.
We followed their safety on a daily basis,
prompting them if they had abdominal complaints
or any other issues.
We then called them up, we had study visits,
and in this circumstance, along with Dr. Fraser,
we were able to do some of the microbiome and omics studies,
and with Dr. Gloria, we were able to do
a whole blood cell transcriptor studies.
Our safety data honestly moderately boring
but that's good.
I will tell you one of the things we are very good at is we
really like to follow up these subjects,
and we actually have great track records.
The types of subjects who participate in these studies
often love these studies.
They love filling out their daily diaries.
Oh, my goodness.
When we stopped asking them for the daily diaries,
many of them were crushed.
What were they going to do?
But clearly, when we're asking people all the time if we have
any side effects, we are going to get them,
and yes, 15 people, 47 side effects sounds like a lot,
but they were all mild, meaning they did nothing.
They didn't take any meds, they didn't go to the doc,
nothing else was going on.
And we did have just one severe unrelated adverse event and
somebody who passed a kidney stone,
but other than that, totally trivial side effects.
What this slide shows in collaboration with Dr. Gloria is
that if we actually look at the LGG in the stool that we get
from these subjects, and this was at day 28 and they were
moderately compliant, it was only one subject who was not
compliant at all, there's a lot of variability in the number of
counts of LGG using PCR, which does pick up dead and alive
organisms, but also if you do routine culture,
you'll also see there's a lot of variability.
Does this matter?
I don't know.
But with this is one of the things we are delving into right
now and has not been well addressed in the literature.
So the recovery of LGG is variable by subject,
and it also is not the same by method because the methods are
doing different things.
This work done with Dr. Fraser at Maryland
basically is the 16S ribosomal RNA information.
So it's not that whole set of gene information,
it's a more limited set.
And what this shows is these are the three days,
baseline, day 28, and day 56, and that's repeated
for each of the subjects.
And I think you can see overall, this looks incredibly boring.
Like there's not much going on at all.
And if you focus on the phylogenetic diversity over here
which is ranging from 20 to 40 percent,
you'll see it mostly bounces around and stays flat.
So at the 16S level, give people LGG for 28 days,
not much happens.
This guy is mildly interesting, he was prescribed Cipro,
and his diversity dropped dramatically
about six weeks into therapy.
So that was a most exciting thing that we found as far as
that was concerned.
This, again, is a representation of that 16S data,
but then what Dr. Fraser did was the whole gene data.
And can you see the patterns in general are similar,
but the data are different, again telling us we've got to be
awfully careful what we're looking at,
and we really need to understand
the questions that we are asking.
The thing that was very interesting here is we're
picking up all this yellow stuff.
This yellow stuff are the archaea.
Not in everybody.
In seven of the individuals, but it doesn't look like it's
changing in any particular way.
What are these archaea doing?
Again, something pretty interesting.
And then this is really cool.
What Dr. Fraser did was look at the LGG itself.
Is there anything going on with LGG at baseline?
On day 28, all these yellow indicate that the probiotic is
actually making copies or there's in vitro expression of
the genes involved in LGG.
The only person that we didn't find any expression in was
somebody who wasn't taking it.
That's a relief.
And on day 56, gone.
So three different ways of looking at the data telling us
But what this probably tells us, the idea of lobbing in LGG,
changing what's going on in the gut,
in terms of the bugs that are there,
probably not going to happen.
But it doesn't mean that there aren't subtle effects.
And these data from Dr. Gloria's lab are also very interesting.
These are PAXgene RNA from the host—
so we're now looking at the host immune response.
Remember these were healthy elderly people
who just took LGG.
There was nothing going on.
We weren't treating anything at all.
But there was differential expression
at day 28 versus day zero.
And the gene that struck out the most in this circumstance
happened to be a gene that was down-regulated related to the
regulation of IgE.
The consequences of this, again, we're investigating further.