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Hi, my name is Paul Offit. I'm from the Children's Hospital, Philadelphia and the

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Perelman School of Medicine of the University of Pennsylvania.

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What I thought I would talk about in this lecture is rotavirus vaccines.

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And it's the only, actually, what I'll talk just about one specific vaccine for the whole lecture.

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And it's not because I think rotaviruses are especially important among the vaccines,

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rather it's because I actually was fortunate enough to be part

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of the team at Children's Hospital, Philadelphia that developed this vaccine.

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So I really watched it go from, from early research through development and so

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basically from bench to bedside and it was an educational process for me.

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And so I thought it would be fun to kind of go through this story.

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So rotaviruses are a virus that infects the small intestine and it causes fever and vomiting

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and water loss or dehydration in young children.

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This is a study done by Bill Rodriguez at the Children's Hospital in DC.

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And he looked at rotavirus as compared to other viruses that cause the so-called stomach viruses,

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and found that rotaviruses were particularly capable of causing vomiting and dehydration.

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And that's why, when you have the stomach virus, you sort of lose water when you have dehydra-

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when you have diarrhea, you lose water when you have fever,

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and it's hard to rehydrate yourself when you're vomiting.

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So that's sort of those three things together can rapidly lead to dehydration,

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which can cause hospitalization, and death.

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This is just a stained section of the small intestine showing the virus infecting the intestine.

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And what you can see here is that,

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if you look here at this sort of, these kind of finger-like projections, so-called villi, into the small intestine,

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You can see that the virus is infecting these cells that are detected

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as so-called mature epithelial cells that line the intestine.

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That's what rotaviruses do. They infect those cells, and they damage those cells,

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and they make it very difficult to resorb water.

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And it causes diarrhea, and it causes vomiting, and it causes dehydration.

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So, every year, in the United States, prior to the vaccines are being licensed and used,

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which was around 2006, rotavirus accounts for about 2.7 million cases, about 500,000 doctor visits,

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about 270,000 emergency department visits, 70,000 hospitalizations, and 20-60 deaths each year.

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If you assume a broad cohort between 3.5 and 4 million children every year in the U.S.,

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that meant that about 1 out of every 50 children born in the United States would be hospitalized

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with dehydration secondary to rotavirus infection.

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Those numbers are dramatically decreased since the vaccine came. And then we'll talk about that.

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In the developing world, rotavirus is a killer. It accounts for about 500,000 deaths a year.

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That means about 2,000 children die every day from this virus, from the dehydration caused by this virus.

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Actually, it's the single agent. It's one of the most important killers of infants and young children in the world.

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And for that reason there was a tremendous amount of interest

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both publicly and privately to try develop a vaccine to prevent it.

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Now, the original idea on how to make a vaccine, and it's sort of Edward Jenner-like approach.

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And I talked about Edward Jenner in another lecture, in a history of vaccines lecture.

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But the initial idea was why - since all mammals that live

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on the face of the earth have their own rotavirus strain -

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why don't we actually do the same thing that Edward Jenner did?

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Remember, Edward Jenner used the cowpox virus to protect against human smallpox.

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He - we now know--he didn't know that, but we now know the cowpox is similar enough to,

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was similar enough to human smallpox, that infection with one could prevent disease caused by the other.

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So, really, that was the same thinking here was

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'why not use a non-human rotavirus strain to protect against human rotavirus?'

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This just shows you all the [inaudible] species that could be affected by rotavirus.

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But species barriers are high, meaning that as it was true, smallpox were,

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cowpox could cause significant disease in cows but not people,

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and human smallpox could cause significant disease in human but not cows. That's also true here.

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So for example, cow rotavirus could cause severe vomiting and diarrhea in cows,

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but really doesn't do that in people. And vice versa, human rotaviruses really don't cause disease in cows.

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So, it's the species barriers that are high, and that was the original idea.

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So what happened was, there was a group at the National Institute of Health,

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headed by Al Kapikian, Rob Chanock, Taka Hoshino, Harry Greenberg, Jorge Flores and others;

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who looked at a strain called RRV. Now that strain stands for Resist Rotavirus.

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This was a virus, a rotavirus strain that was isolated from a monkey in Northern California in the 1980's

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by H. Milerby. That virus was then purified by growing it in cell culture, and not so much weakened.

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The notion was that it would be weakened in humans because it wasn't a human virus.

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This is sort of the same idea Edward Jenner had.

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And when the vaccine was then given by mouth at 2, 4, and 6 months of age

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to children in Sweden, and in Finland, it worked.

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It seemed to protect against the moderate to severe dehydration

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as it's shown on the first two rows on the slide.

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But when the vaccine was then tested in Rochester, NY in a trial; it didn't seem to work.

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So, I think what people concluded after this series of trial was that a non-human virus - in this case, a monkey virus -

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was inconsistently capable of protecting against human rotavirus disease.

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Now we worked, and by we, I mean Stanley Plotkin and Fred Clark, who headed this program;

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worked at Children's Hospital, Philadelphia; with a strain called WC3.

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And that was actually isolated from a calf with diarrhea at the Kenneth Square facility

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which is the large animal facility, the , the veterinary school here at the University of Pennsylvania.

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And we took that virus and then we went back to the Wistar Institute

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and we purified it by passing it in a cell culture.

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And since it was from the third calf that we tested, it was called WC3 or Wistar Calf Three.

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We gave this virus by mouth to children at 2, 4 and 6 months of age in Philadelphia

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and found that it was excellent at protecting against moderate to severe disease

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and actually very good at protecting against even mild disease caused by rotavirus.

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But when we then tested the vaccine in
Cincinnati or in Bangui in the Central African Republic,

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we found that it didn't work well. So basically we've found

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with the calf strain exactly the same
thing that the NIH researchers had found

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with a simian strain, a monkey strain.
That the protection against rotavirus could occur

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with non-human strains, but it was inconsistent in it's ability to protect.

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So it was really back to the drawing board. And this slide shows what

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the drawing board was. We, we needed to
determine which rotavirus proteins were responsible

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for evoking virus specific neutralizing antibodies. In other words,

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what rotovirus proteins induce protective
immunity and which rotovirus proteins

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were responsible for viral virulence. So it is
the way that you make any vaccine.

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You're really trying, you're trying to separate
out the part of the, in this case, the virus

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that is pathogenic, that is disease causing from the part of the virus

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that induces an immune response which is
protective. Hoping in this case

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that the genes that are responsible for making the proteins that cause disease are different

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from the genes that are required to make the proteins

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that induce a protective immune response. So
just a brief word about rotavirus structure,

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the cartoon of the rotavirus particle is shown on the right and there are two proteins

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to focus on. One is the protein called VP4 which stands for

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viral protein four. It's the viral protein that's responsible for

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binding to cells before it infects them.
It's also called a P protein,

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or a P serotype and you'll see what I mean by
that in a second. P, just because it's sensitive to

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proteases. Proteases are proteins that cleave proteins.

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and this, in order for the virus actually
to enter the cell that VP4 needs to be

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cleaved to two smaller proteins called VP5
and VP8. The other protein defunct to

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focus on is called VP7, which just stands
for Viral Protein seven. And that's kind

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of a coat protein. But again, on the
surface of the virus. And it it's a

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glyco-protein, so it's also called a, a G
protein. I'll talk about that also in a second;

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so, two surface proteins, VP4 and VP7.

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And as a general rule when you're trying to protect against viral infections, you want to try and make

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antibodies to the surface of a virus; so to this, surface of a bacteria.

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Because that would then prevent the virus or
bacteria from binding to a cell, entering a cell

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and causing disease. It's sort of a universal truth of vaccines. You're really,

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for the most part, trying to prevent
virus-cell binding.

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Then, the rotavirus genome consists of eleven separate
segments of double stranded RNA.

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And if you look at sort of, well, column A if
you take the virus

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and you disrupt it with a, just a detergent and then you
put it on top of,

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so called, poly-acrylamide gel which is just a plastic
mesh and then you take the virus

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and you run it down with an electric current. You
can actually separate those individual

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double strained RNA segments in.. by size.
So you can see the, the so called electropherotype of

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of virus A. And virus A and virus B are different.

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They're different strains therefore they
have different ways in which their double-stranded RNA

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segments migrate in this gel.
Now, if you take those two

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viruses and you co-infect cells at the
same time,

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you find that about 20 percent of the time, the progeny viruses that are generated

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actually are reassorted viruses. Which is to say
that they're a combination of the two viruses.

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So you can see at the virus strain on the right has all of its genes from

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virus A, and only one gene from virus B.

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Well, if virus A and virus B are different within their capacity to cause disease in experimental animals,

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in our case, we looked at mice, then you can
figure out the genetics of virulence.

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If those two strains are different with
regard to their ability to induce

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neutralizing antibodies in the serum, then,
you can say - - you can figure out the

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genetics of serotype which is to say that,
that you can distinguish viruses based on

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their ability to evoke antibodies which
neutralize specific strains or specific serotypes.

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And so, again, by making these reassortant viruses as you see on the right,

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you can figure out the genetics of virulence.
You can figure out the genetics of

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serotype, or said another way,
neutralization phenotype, or said another way,

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just the genes responsible for evoking protective antibodies.

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So to make a long story short, to sort of summarize
ten years worth of work in one slide,

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it's actually a little depressive. You can't do
that, but to summarize ten years

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of work in one slide, what we found was
that each of those two surface proteins

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evoked neutralizing antibodies or said
another way, each of those two different proteins

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evoked or determined serotype.
So in a sense then, then rotaviruses actually

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are very similar to the influenza viruses,
which also are distinguished on the basis

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of two surface proteins.
And that's the way that those viruses are characterized.

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H1N1, H5N1, the so-called bird flu.

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That's the way that the influenza viruses are characterized and that's the way the rotaviruses are characterized also.

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So, G1P1, for example.
The addition studies that were done

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by researchers at the National Institutes of Health specifically headed by

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Taka Hoshino as well as researchers in our lab 
determined ultimately

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that there were four genes that were required for virulence. So by doing studies in mice, we showed that really

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there were four different genes, all of
which were required for virulence.

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Well, this was good news. It meant that you
could include the genes, the human genes

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that were responsible for invoking
neutralizing antibodies, but as long as

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you didn't include all four that were
responsible for virulence, then the virus wouldn't be virulent,

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or said another way, the virus shouldn't cause disease. 
And this was advanced beyond Max Tyler.

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Remember we talked about Max Tyler in another lecture.
And Max Tyler was the one working at

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the Rockefeller Institute who showed
that you could weaken viruses by

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serially passaging them in a cell culture.
But it was done really in a blind way, in a sense that

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you would pass it in non-human cells like in his case,

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you pass the Yellow Fever virus in mouse,
mouse embryo cells, or chicken embryo cells.

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And then he would take the virus out
to see whether it was weak enough by testing it in people.

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We, at Children's Hospital Philadelphia, at least had,

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we thought we had defined virulence genes,
by doing studies in mice.

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But again, you know, these were studies in
mice, you never really know

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until you test it in people.
And so, you have to go very slowly, when you test in people,

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starting in adults, who you know have
already been exposed to rotavirus and have antibodies

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And then working your way down, ultimately to children who hadn't been exposed to the virus.

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So this was reassuring, but, you really never know until

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you do the right kind of studies.
So the first rotavirus vaccine

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was, that was out there was called a Rota
shield. It was again the NIH reserchers

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had taken their simian strain, their so called research rotavirus or RRV strain.

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And they had it re-assorted it into that genes that determine

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human serotype, so called G1, G2, and G4.

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They assumed that the RRV strain was similar not
to the human G3, so there really there are

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sort of four major human G serotypes;
G1, G2, G3, G4 and [inaudible] take this,

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this simian monkey strain.
You can then reassort into those human genes that

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determine those serotypes.
And so that's what was done with this original vaccine.

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And, and the vaccine was on the,
was actually brought onto the market in August 1998.

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It was on the market for about 10 months in the United States when this headline

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was published in a CDC journal called
Morbidity and Mortality Weekly Report.

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It was called intussusception among recipients of rotavirus vaccine in the United States,

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1998 to 1999.
And what had happened was, intussusception

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is caused when the small intestine sort of folds into itself, or invaginates into itself

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and gets stuck.
And when that happens, there can be a critical loss

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of blood supply to the intestine mucosal surface,
which can cause intestinal mucosal surface damage

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and bleeding.
In addition, because the intestine has living on its surface,

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trillions, literally, of bacteria.
Those bacteria can then enter

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the bloodstream and cause bloodstream
infection, which can be overwhelming, even resulting

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in death. So intussusception is an important medical problem. It's a serious

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medical problem often requiring hospitalization.
And so, the fact that,

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the, the that headline appeared in the
morbidity mortality weekly report was

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really worrisome. And it was based on reports to VAERS, we've talked about in

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another talk, the so-called Vaccine
Adverse Events Reporting System.

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This is a system that's passively, it's sort
of a passive reporting system

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to the FDA and the CDC.
If you're worried that, a vaccine

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could have caused a particular event, adverse event, then you can report it to this system. And then there

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were fifteen cases of intussusception were reported

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to various following Rotashield.
What was worrying, worrisome, was that

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thirteen of those fifteen cases occurred after the first dose, which sort of lends to

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the biological plausibility of the fact that these two things were causally associated.

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Eleven of those thirteen cases, again, recur within seven days of vaccine administration,

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which is what you would expect if the vaccine was causing it. An eighth of those thirteen cases

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occurred in children 2-3 months of age.

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Now, intussusception occurs anyway. Intussusception occurs in children before there was a Rotavirus vaccine.

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But, it really occurred primarily in the 5-9 month-old.
So the thinking was that

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now that we were seeing it in 2-3 months of age,
when these kids were getting vaccinated,

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that again lent the fact at least the fact that this notion,

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that the, that the vaccine was causing
the intussusception was biologically plausible.

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So the way that you answer this,
the question, is to do the kinds of study

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that were done by Trudy Murphy and her co-workers,
and reported in

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the New England Journal of Medicine. The CDC
really took the lead on this.

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Jeff Koplan, who was the head of the CDC at the time, stopped doing some other projects,

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lot of money into this, to see whether or
not that association between

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intussusception and vaccination was
temporal, or causal.

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And, and you gotta take your hat off to this group.
That the minute that they saw something

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that might have been problematic, they,
they immediately addressed it, and found that

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if you received the rotavirus vaccine,
and your first dose was

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you received your first dose at 1-2 months of age,

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or 3-5 months of age, or 5-8 months of age,
that within a week of getting that vaccine,

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you had a 25 to 30 fold increased risk
of getting the disease --

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getting the intussception
than if you didn't get the vaccine.

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Similarly, there was a statistically signifigant increase,
if you, within 2 weeks of getting the vaccine,

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but not greater than 2 weeks after getting the vaccine.

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So this was supportive of the notion that, the
rot-, the intussusception following Rotashield vaccine

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was not a, just a temporal association,
but was, in fact, a causal association

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that the vaccine actually was causing
this intestinal blockage.

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For that reason, then the company had actually decided to

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withdraw the, the their vaccine from the
market and, and that, that was done after

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the vaccine had been on the market for
about ten months. Now, you could argue

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that there is a difference between,
relative risk and attributable risk.

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Relative risk, as we saw, was 25 to 30 to
one, following that vaccine.

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But the real risk or the attributed risk was
roughly 1 per 10,000. So let me try and

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give you an example of that. That if I am, if I
walk across the street in front of my

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house, I have a certain risk of being hit
by a car. That would, no doubt, be much

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greater than the risk than if I was just
standing. On the, the just in my doorstep

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in front of my house. And so the relative
risk would be very high. It could be a

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1,000 to 1. But still the attributable
risk is, is very low. I mean, I cross the

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street in front of my house all the time
and don't get hit by a car. That was true here.

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So while the, the relative risk was high,
the attributable risk was pretty low.

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Still 1 in 10,000 recipients.
And you could argue that if you took a

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theoretical million children who either
did or didn't get the vaccine. Far more

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who didn't get the vaccine would have been
hospitalized. And, and then frankly, even

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five to ten fold more would have died from
not getting the vaccine. Because Rotavirus

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kills children even in this, in the United
States. But I think at the time, the

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disease wasn't perceived to be terribly
dangerous. Certainly no one wanted to get

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something that you knew could have caused
intus susception and there was one child

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who died of intussusception following this
vaccine even though six to twelve will die

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from not having received the vaccine among
a million children. So you could have made

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the argument that even with that adverse
event that still the benefits outweigh the

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risk, but that's not the way that the
played out at the time and so the vaccine

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was taken off the market. Now, I think the
saddest part of this, and the biggest

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tragedy, is that there was a World Health
Organization meeting held in February of

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2000. So it was about four months after
the withdrawal of Rotashield from the

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United States, where the company was
great. I mean, wyeth made this vaccine,

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stood up and said, we, we, we'll give you
the virus, the vaccine strains. We will

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give you, the you know, the technology on
how to make it. We will give you the cell

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substrate on which we grew this,
thisvaccine. We'll help you build the

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buildings. Because the Wyeth knew that
they had a technology that now they were

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not giving to American children. They
could've saved. As many as 2000 lives a

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day in the developing world. But, But
count-, country after country stood up and

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said, you know, if it's not safe for our
children, it not - if it's not safe for

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America's children, then it's not safe for
our children, therefore, we're not going

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to, to use it. Even though the risk
benefit ratio was obviously very different

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in the developing world. So, I think the
tragedy was, if in this whole story, is

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that for seven years, a technology that
could have saved a lot of lives in the

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developing world, and certainly even have
prevented a lot of suffering in the United

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States, sat on the shelf. And so, two
other, companies actually stepped forward

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to make vaccines. One of them was Merkin
Company, who, who, in collaboration with,

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researchers at Children's Hospital of
Philadelphia, developed this, this next

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vaccine. And again, it used that bovine
strain that I talked to you about, that's,

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that's called iii.'Cause we certainly knew
that, that virus was safe in children. It

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just didn't seem to be, consistently
protective enough to make it a vaccine.

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And so what was done, was the same thing
really that was done with the RotaShield

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vaccine, which was to make a series of
reassortant vaccines. And again, we talked

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about reassortants to some extent in the
in the history of vaccines talk. That

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included those human genes that, that
represented those, the, the proteins that

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were responsible for, for a serotypes G1,
G2, G3 and G4, as well as one of the, the

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P serotypes, so called P1. So that's,
that's what the RotaTeq vaccine was. It

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was given. As three doses by mouth at two,
four and six months of age to, to

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children, It's This. Sorry, the, the, the
dose was 1.6 *ten^6 plaque forming units*

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per strain. A plaque form unit is, is just
when you test a virus. In cell culture,

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the virus can reproduce themselves, and
destroy cells, as well as cells in the

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immediate area, which causes this sort of
plaque in the, in the or hole in the

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culture, and that's how you determine
that. But the important to know here is

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that it was three doses given by mouth at
two, four, and six months of age. There

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were some advantages of the bovine strain,
because the cows are not as close

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phylogenetically to humans as primates
are. The there actually was a. To provide,

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less, for instance of sort of these common
less adverse events because of our

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assisted reproduced self as well. So I
think the important thing here is, is that

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the vaccine was tested in, in more than
70,000 children prospectively, in eleven

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countries It took four years to do this
study, it probably cost about 350 million

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dollars to do the definitive phase three
trial of this vaccine. And what was found

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was that the vaccine was capable of
preventing any roto virus disease being

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mild, moderate or severe disease at about
74%, which is roughly the equivalent of

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what natural infection capacity is to
protect against roto virus disea se.

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Disease, Efficacy against severe disease
was 98%, against rotavirus

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hospitalizations 94%, against rotavirus
doctor visits 86%, and there was no

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clinically significant increase in fever.
Or vomiting or diarrhea. Listlessness,

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lethargy, or poor feeding versus placebo.
So, the vaccine appeared to be safe and

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appeared to be effective. Importantly,
regarding [inaudible], within fourteen

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days of any dose, there was only one case
of in the vaccine group a one in the

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placebo group. Within 42 days of any dose,
[inaudible] six, six weeks of any dose,

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there was six in the vaccine group, five
in the placebo group. And within one year

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again, twelve in the vaccine and fifteen
in the placebo group. So, again, the

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vaccine didn't appear to, to cause
[inaudible] or prevent [inaudible]. And so

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those were, And, and we also have post
licensure data that I'll talk about a

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little later. [inaudible] has been
introduced, this vaccine has been

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introduced into the developing world.
Specifically in Nicaragua, Bangladesh,

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Vietnam, Ghana, Mali. And just within this
past week Rwanda. And that's a tribute to

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the Bill and Melinda Gates Foundation, who
have made that possible. you know, the,

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although the World Health Organization
certainly considers all the [inaudible].

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Caused by rotavirus important and, and
worthy of prevention. The World Health

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Organization doesn't really have the money
to introduce this vaccine in the

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developing world and, and frankly or the
countries, the countries also don't have

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the money. So, that Bill and Melinda Gates
choose to spend their money by preventing

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a disease which causes a lot of suffering
and death in the developing world is a

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tribute to them. Now there's, there's
another rotavirus vaccine that, that's,

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that's developed, that was developed by
researchers at Children's Hospital in

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Cincinnati specifically Dick Ward and
David Bernstein, using the more classic

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way of making a vaccine, a live weakened.
Vaccine, which was to take the vi rus, and

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serially [inaudible] in non human cells as
a way of attenuating it. This vaccine is

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given as two doses by mouth, which is an
advantage. It's one fewer dose. At two,

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two to three, and then four to five months
of age. It's given at a somewhat lesser,

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dose. Because the virus is, is a human
virus. So therefore, somewhat better at

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reproducing itself in the intestine than
the bovine strain was. The, the

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researchers at children's hospital in
Cincinatti, in collaboration with

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00:24:37,002 --> 00:24:41,004
GlaxoSmithKline, did a study of, 60, more
than 63,000 infants who were given this

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vaccine at two to four months of age. And
the studies were performed in Latin

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American countries as well as Finland and
the vaccine worked very well, preventing a

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00:24:50,005 --> 00:24:54,008
severe disease about a, [inaudible] an
efficacy rate of 85 percent and preventing

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00:24:54,054 --> 00:24:59,005
80, hospitalizations at a rate of about
85%. Rotateq. Was introduced in the United

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States in 2006. Rotarix in the United
States in 2008. Although Rotarix was

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introduced in the developing world also in
2-, 2006. And, what we found was that.

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there was a 50, even in the US, 50 percent
immunization rate causing 80 to 90 percent

336
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reduction in hospitalization. So it's a
there is her immunity that is being

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induced by these two vaccines. So, so what
about an [inaudible]. Why this, the Rota

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Virus vaccine, why did Rota shield cause
an [inaudible] interest. There were data

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00:25:26,009 --> 00:25:31,003
presented from Brazil, Mexico, Australia
and the United States on October

340
00:25:31,003 --> 00:25:36,002
twenty-eighth, 2000 [inaudible] that show
the [inaudible] was actually was a rare

341
00:25:36,002 --> 00:25:40,009
consequence Rota risk in Mexico and
Australia. Not at the one in 10,000 level

342
00:25:40,009 --> 00:25:46,001
that was seen for Rota, Rota Shield. But,
but more an attributable risk of one per

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00:25:46,001 --> 00:25:50,006
60,000 or 90,000 doses. And also, for
RotaTeq as well, intussusception was a

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rare consequence in Australia, with an
attributable risk again between sort of,

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00:25:55,004 --> 00:25:59,009
60,000 and 90,000 doses. So it now looks
like all three Rotavirus vaccines,

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00:25:59,009 --> 00:26:04,006
including Rotarix, which is simply an
attenuated human Rotavirus strain, causes

347
00:26:04,006 --> 00:26:09,003
intussusceptio N. So it sort of causes us
to re-evaluate why. Rotashield caused

348
00:26:09,003 --> 00:26:14,003
intussusception, I think the most likely
reason is that natural rotavirus infection

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is also a rare cause of intussusception.
So then the question becomes which is

350
00:26:19,000 --> 00:26:23,004
rarer, Intussusception caused by. By the
vaccine, or intussusception caused by the

351
00:26:23,004 --> 00:26:26,009
disease. Because remember the vaccine
prevents the disease. So if, if

352
00:26:26,009 --> 00:26:31,004
intussusception caused by the, the vaccine
is more common than intussusception caused

353
00:26:31,004 --> 00:26:35,008
by the. The, the natural virus, then, the
rates of interception should go up in

354
00:26:35,008 --> 00:26:40,003
countries that use the vaccine. Conversely
if, if interception caused by the. The

355
00:26:40,003 --> 00:26:44,000
natural virus is more common, then
[inaudible] caused by the vaccine, given

356
00:26:44,000 --> 00:26:47,004
that the vaccine prevents natural
infection. Then as you introduce the

357
00:26:47,004 --> 00:26:51,001
vaccine, rates of [inaudible] should,
should go down. And sort of all of the

358
00:26:51,001 --> 00:26:55,000
evidence to date, is it certainly raises
the [inaudible], the [inaudible] seem to

359
00:26:55,000 --> 00:26:59,000
be going up, and if anything they seem to
be going down. A little. So I think that

360
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what we've learned is that in the long
run, that [inaudible] is probably is a

361
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consequence of the natural infection. It's
probably to some extent prevented by, by

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vaccination. I mean it's interesting to
know what, what, what had happened if we

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had found out that [inaudible] shield had
caused [inaudible]. This is after four

364
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years after it had already been
introduced. Because now, we know that

365
00:27:18,004 --> 00:27:22,004
rotarix and rota, rotatech are two more
recent vaccines for saving lives in the

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developing world are certainly preventing
hospitalizations and suffering in

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developed countries like the United
States. I wondered whether we would have

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still made the same decision rotashield
that we found out that it was a rare cause

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00:27:34,002 --> 00:27:37,058
of [inaudible] four years later. So I'll
stop right there and thank you for your atte