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[Events]
Format: Layer, Start, End, Style, Name, MarginL, MarginR, MarginV, Effect, Text
Dialogue: 0,0:00:04.00,0:00:08.01,Default,,0000,0000,0000,,Hi, my name is Paul Offit. I'm from the Children's Hospital, Philadelphia and the
Dialogue: 0,0:00:08.01,0:00:12.00,Default,,0000,0000,0000,,Perelman School of Medicine of the University of Pennsylvania.
Dialogue: 0,0:00:12.00,0:00:16.00,Default,,0000,0000,0000,,What I thought I would talk about in this lecture is rotavirus vaccines.
Dialogue: 0,0:00:16.00,0:00:19.37,Default,,0000,0000,0000,,And it's the only, actually, what I'll talk just about one specific vaccine for the whole lecture.
Dialogue: 0,0:00:19.37,0:00:22.93,Default,,0000,0000,0000,,And it's not because I think rotaviruses are especially important among the vaccines,
Dialogue: 0,0:00:22.93,0:00:26.08,Default,,0000,0000,0000,,rather it's because I actually was fortunate enough to be part
Dialogue: 0,0:00:26.08,0:00:29.89,Default,,0000,0000,0000,,of the team at Children's Hospital, Philadelphia that developed this vaccine.
Dialogue: 0,0:00:29.89,0:00:35.04,Default,,0000,0000,0000,,So I really watched it go from, from early research through development and so
Dialogue: 0,0:00:35.04,0:00:38.76,Default,,0000,0000,0000,,basically from bench to bedside and it was an educational process for me.
Dialogue: 0,0:00:38.76,0:00:41.99,Default,,0000,0000,0000,,And so I thought it would be fun to kind of go through this story.
Dialogue: 0,0:00:41.99,0:00:51.00,Default,,0000,0000,0000,,So rotaviruses are a virus that infects the small intestine and it causes fever and vomiting
Dialogue: 0,0:00:51.00,0:00:54.06,Default,,0000,0000,0000,,and water loss or dehydration in young children.
Dialogue: 0,0:00:54.06,0:00:58.79,Default,,0000,0000,0000,,This is a study done by Bill Rodriguez at the Children's Hospital in DC.
Dialogue: 0,0:00:58.79,0:01:02.88,Default,,0000,0000,0000,,And he looked at rotavirus as compared to other viruses that cause the so-called stomach viruses,
Dialogue: 0,0:01:02.88,0:01:09.86,Default,,0000,0000,0000,,and found that rotaviruses were particularly capable of causing vomiting and dehydration.
Dialogue: 0,0:01:09.86,0:01:15.35,Default,,0000,0000,0000,,And that's why, when you have the stomach virus, you sort of lose water when you have dehydra-
Dialogue: 0,0:01:15.35,0:01:19.29,Default,,0000,0000,0000,,when you have diarrhea, you lose water when you have fever,
Dialogue: 0,0:01:19.29,0:01:22.09,Default,,0000,0000,0000,,and it's hard to rehydrate yourself when you're vomiting.
Dialogue: 0,0:01:22.09,0:01:26.00,Default,,0000,0000,0000,,So that's sort of those three things together can rapidly lead to dehydration,
Dialogue: 0,0:01:26.00,0:01:29.00,Default,,0000,0000,0000,,which can cause hospitalization, and death.
Dialogue: 0,0:01:30.54,0:01:40.15,Default,,0000,0000,0000,,This is just a stained section of the small intestine showing the virus infecting the intestine.
Dialogue: 0,0:01:40.15,0:01:43.10,Default,,0000,0000,0000,,And what you can see here is that,
Dialogue: 0,0:01:45.64,0:01:52.59,Default,,0000,0000,0000,,if you look here at this sort of, these kind of finger-like projections, so-called villi, into the small intestine,
Dialogue: 0,0:01:52.59,0:01:56.45,Default,,0000,0000,0000,,You can see that the virus is infecting these cells that are detected
Dialogue: 0,0:01:56.45,0:02:01.18,Default,,0000,0000,0000,,as so-called mature epithelial cells that line the intestine.
Dialogue: 0,0:02:01.18,0:02:05.12,Default,,0000,0000,0000,,That's what rotaviruses do. They infect those cells, and they damage those cells,
Dialogue: 0,0:02:05.14,0:02:09.97,Default,,0000,0000,0000,,and they make it very difficult to resorb water.
Dialogue: 0,0:02:09.97,0:02:14.68,Default,,0000,0000,0000,,And it causes diarrhea, and it causes vomiting, and it causes dehydration.
Dialogue: 0,0:02:15.03,0:02:20.27,Default,,0000,0000,0000,,So, every year, in the United States, prior to the vaccines are being licensed and used,
Dialogue: 0,0:02:20.28,0:02:27.45,Default,,0000,0000,0000,,which was around 2006, rotavirus accounts for about 2.7 million cases, about 500,000 doctor visits,
Dialogue: 0,0:02:27.45,0:02:34.53,Default,,0000,0000,0000,,about 270,000 emergency department visits, 70,000 hospitalizations, and 20-60 deaths each year.
Dialogue: 0,0:02:34.53,0:02:38.17,Default,,0000,0000,0000,,If you assume a broad cohort between 3.5 and 4 million children every year in the U.S.,
Dialogue: 0,0:02:38.17,0:02:42.48,Default,,0000,0000,0000,,that meant that about 1 out of every 50 children born in the United States would be hospitalized
Dialogue: 0,0:02:42.48,0:02:45.51,Default,,0000,0000,0000,,with dehydration secondary to rotavirus infection.
Dialogue: 0,0:02:45.51,0:02:50.13,Default,,0000,0000,0000,,Those numbers are dramatically decreased since the vaccine came. And then we'll talk about that.
Dialogue: 0,0:02:51.24,0:02:58.07,Default,,0000,0000,0000,,In the developing world, rotavirus is a killer. It accounts for about 500,000 deaths a year.
Dialogue: 0,0:02:58.07,0:03:04.31,Default,,0000,0000,0000,,That means about 2,000 children die every day from this virus, from the dehydration caused by this virus.
Dialogue: 0,0:03:04.31,0:03:08.87,Default,,0000,0000,0000,,Actually, it's the single agent. It's one of the most important killers of infants and young children in the world.
Dialogue: 0,0:03:08.87,0:03:11.01,Default,,0000,0000,0000,,And for that reason there was a tremendous amount of interest
Dialogue: 0,0:03:11.01,0:03:14.60,Default,,0000,0000,0000,,both publicly and privately to try develop a vaccine to prevent it.
Dialogue: 0,0:03:15.76,0:03:22.28,Default,,0000,0000,0000,,Now, the original idea on how to make a vaccine, and it's sort of Edward Jenner-like approach.
Dialogue: 0,0:03:22.34,0:03:26.00,Default,,0000,0000,0000,,And I talked about Edward Jenner in another lecture, in a history of vaccines lecture.
Dialogue: 0,0:03:26.00,0:03:30.41,Default,,0000,0000,0000,,But the initial idea was why - since all mammals that live
Dialogue: 0,0:03:30.41,0:03:33.56,Default,,0000,0000,0000,,on the face of the earth have their own rotavirus strain -
Dialogue: 0,0:03:33.56,0:03:35.99,Default,,0000,0000,0000,,why don't we actually do the same thing that Edward Jenner did?
Dialogue: 0,0:03:35.99,0:03:41.24,Default,,0000,0000,0000,,Remember, Edward Jenner used the cowpox virus to protect against human smallpox.
Dialogue: 0,0:03:41.24,0:03:47.27,Default,,0000,0000,0000,,He - we now know--he didn't know that, but we now know the cowpox is similar enough to,
Dialogue: 0,0:03:47.27,0:03:53.00,Default,,0000,0000,0000,,was similar enough to human smallpox, that infection with one could prevent disease caused by the other.
Dialogue: 0,0:03:53.00,0:03:55.84,Default,,0000,0000,0000,,So, really, that was the same thinking here was
Dialogue: 0,0:03:55.84,0:04:02.01,Default,,0000,0000,0000,,'why not use a non-human rotavirus strain to protect against human rotavirus?'
Dialogue: 0,0:04:02.01,0:04:07.54,Default,,0000,0000,0000,,This just shows you all the [inaudible] species that could be affected by rotavirus.
Dialogue: 0,0:04:08.16,0:04:13.33,Default,,0000,0000,0000,,But species barriers are high, meaning that as it was true, smallpox were,
Dialogue: 0,0:04:13.33,0:04:18.00,Default,,0000,0000,0000,,cowpox could cause significant disease in cows but not people,
Dialogue: 0,0:04:18.00,0:04:24.67,Default,,0000,0000,0000,,and human smallpox could cause significant disease in human but not cows. That's also true here.
Dialogue: 0,0:04:24.67,0:04:31.62,Default,,0000,0000,0000,,So for example, cow rotavirus could cause severe vomiting and diarrhea in cows,
Dialogue: 0,0:04:31.62,0:04:37.75,Default,,0000,0000,0000,,but really doesn't do that in people. And vice versa, human rotaviruses really don't cause disease in cows.
Dialogue: 0,0:04:37.75,0:04:43.16,Default,,0000,0000,0000,,So, it's the species barriers that are high, and that was the original idea.
Dialogue: 0,0:04:43.16,0:04:48.06,Default,,0000,0000,0000,,So what happened was, there was a group at the National Institute of Health,
Dialogue: 0,0:04:48.06,0:04:54.25,Default,,0000,0000,0000,,headed by Al Kapikian, Rob Chanock, Taka Hoshino, Harry Greenberg, Jorge Flores and others;
Dialogue: 0,0:04:54.25,0:05:01.25,Default,,0000,0000,0000,,who looked at a strain called RRV. Now that strain stands for Resist Rotavirus.
Dialogue: 0,0:05:01.25,0:05:07.08,Default,,0000,0000,0000,,This was a virus, a rotavirus strain that was isolated from a monkey in Northern California in the 1980's
Dialogue: 0,0:05:07.08,0:05:17.67,Default,,0000,0000,0000,,by H. Milerby. That virus was then purified by growing it in cell culture, and not so much weakened.
Dialogue: 0,0:05:17.67,0:05:21.05,Default,,0000,0000,0000,,The notion was that it would be weakened in humans because it wasn't a human virus.
Dialogue: 0,0:05:21.06,0:05:22.84,Default,,0000,0000,0000,,This is sort of the same idea Edward Jenner had.
Dialogue: 0,0:05:22.84,0:05:26.86,Default,,0000,0000,0000,,And when the vaccine was then given by mouth at 2, 4, and 6 months of age
Dialogue: 0,0:05:26.86,0:05:29.56,Default,,0000,0000,0000,,to children in Sweden, and in Finland, it worked.
Dialogue: 0,0:05:29.56,0:05:34.82,Default,,0000,0000,0000,,It seemed to protect against the moderate to severe dehydration
Dialogue: 0,0:05:34.82,0:05:39.00,Default,,0000,0000,0000,,as it's shown on the first two rows on the slide.
Dialogue: 0,0:05:39.00,0:05:43.71,Default,,0000,0000,0000,,But when the vaccine was then tested in Rochester, NY in a trial; it didn't seem to work.
Dialogue: 0,0:05:43.71,0:05:49.96,Default,,0000,0000,0000,,So, I think what people concluded after this series of trial was that a non-human virus - in this case, a monkey virus -
Dialogue: 0,0:05:49.96,0:05:55.71,Default,,0000,0000,0000,,was inconsistently capable of protecting against human rotavirus disease.
Dialogue: 0,0:05:56.52,0:06:02.02,Default,,0000,0000,0000,,Now we worked, and by we, I mean Stanley Plotkin and Fred Clark, who headed this program;
Dialogue: 0,0:06:02.02,0:06:07.59,Default,,0000,0000,0000,,worked at Children's Hospital, Philadelphia; with a strain called WC3.
Dialogue: 0,0:06:07.59,0:06:13.22,Default,,0000,0000,0000,,And that was actually isolated from a calf with diarrhea at the Kenneth Square facility
Dialogue: 0,0:06:13.22,0:06:16.78,Default,,0000,0000,0000,,which is the large animal facility, the , the veterinary school here at the University of Pennsylvania.
Dialogue: 0,0:06:16.88,0:06:20.68,Default,,0000,0000,0000,,And we took that virus and then we went back to the Wistar Institute
Dialogue: 0,0:06:20.68,0:06:23.66,Default,,0000,0000,0000,,and we purified it by passing it in a cell culture.
Dialogue: 0,0:06:23.66,0:06:29.67,Default,,0000,0000,0000,,And since it was from the third calf that we tested, it was called WC3 or Wistar Calf Three.
Dialogue: 0,0:06:29.67,0:06:35.59,Default,,0000,0000,0000,,We gave this virus by mouth to children at 2, 4 and 6 months of age in Philadelphia
Dialogue: 0,0:06:35.59,0:06:38.68,Default,,0000,0000,0000,,and found that it was excellent at protecting against moderate to severe disease
Dialogue: 0,0:06:38.68,0:06:42.79,Default,,0000,0000,0000,,and actually very good at protecting against even mild disease caused by rotavirus.
Dialogue: 0,0:06:42.79,0:06:47.01,Default,,0000,0000,0000,,But when we then tested the vaccine in\NCincinnati or in Bangui in the Central African Republic,
Dialogue: 0,0:06:47.01,0:06:52.00,Default,,0000,0000,0000,,we found that it didn't work well. So basically we've found
Dialogue: 0,0:06:52.00,0:06:56.00,Default,,0000,0000,0000,,with the calf strain exactly the same\Nthing that the NIH researchers had found
Dialogue: 0,0:06:56.00,0:07:00.00,Default,,0000,0000,0000,,with a simian strain, a monkey strain.\NThat the protection against rotavirus could occur
Dialogue: 0,0:07:00.00,0:07:04.00,Default,,0000,0000,0000,,with non-human strains, but it was inconsistent in it's ability to protect.
Dialogue: 0,0:07:04.00,0:07:08.01,Default,,0000,0000,0000,,So it was really back to the drawing board. And this slide shows what
Dialogue: 0,0:07:08.01,0:07:13.00,Default,,0000,0000,0000,,the drawing board was. We, we needed to\Ndetermine which rotavirus proteins were responsible
Dialogue: 0,0:07:13.00,0:07:17.00,Default,,0000,0000,0000,,for evoking virus specific neutralizing antibodies. In other words,
Dialogue: 0,0:07:17.00,0:07:21.01,Default,,0000,0000,0000,,what rotovirus proteins induce protective\Nimmunity and which rotovirus proteins
Dialogue: 0,0:07:21.01,0:07:26.00,Default,,0000,0000,0000,,were responsible for viral virulence. So it is\Nthe way that you make any vaccine.
Dialogue: 0,0:07:26.00,0:07:30.00,Default,,0000,0000,0000,,You're really trying, you're trying to separate\Nout the part of the, in this case, the virus
Dialogue: 0,0:07:30.00,0:07:34.00,Default,,0000,0000,0000,,that is pathogenic, that is disease causing from the part of the virus
Dialogue: 0,0:07:34.00,0:07:38.00,Default,,0000,0000,0000,,that induces an immune response which is\Nprotective. Hoping in this case
Dialogue: 0,0:07:38.00,0:07:42.00,Default,,0000,0000,0000,,that the genes that are responsible for making the proteins that cause disease are different
Dialogue: 0,0:07:42.00,0:07:46.01,Default,,0000,0000,0000,,from the genes that are required to make the proteins
Dialogue: 0,0:07:46.01,0:07:51.00,Default,,0000,0000,0000,,that induce a protective immune response. So\Njust a brief word about rotavirus structure,
Dialogue: 0,0:07:51.00,0:07:56.00,Default,,0000,0000,0000,,the cartoon of the rotavirus particle is shown on the right and there are two proteins
Dialogue: 0,0:07:56.00,0:08:00.01,Default,,0000,0000,0000,,to focus on. One is the protein called VP4 which stands for
Dialogue: 0,0:08:00.01,0:08:05.01,Default,,0000,0000,0000,,viral protein four. It's the viral protein that's responsible for
Dialogue: 0,0:08:05.01,0:08:10.00,Default,,0000,0000,0000,,binding to cells before it infects them.\NIt's also called a P protein,
Dialogue: 0,0:08:10.00,0:08:15.00,Default,,0000,0000,0000,,or a P serotype and you'll see what I mean by\Nthat in a second. P, just because it's sensitive to
Dialogue: 0,0:08:15.00,0:08:20.00,Default,,0000,0000,0000,,proteases. Proteases are proteins that cleave proteins.
Dialogue: 0,0:08:20.00,0:08:24.01,Default,,0000,0000,0000,,and this, in order for the virus actually\Nto enter the cell that VP4 needs to be
Dialogue: 0,0:08:24.01,0:08:29.00,Default,,0000,0000,0000,,cleaved to two smaller proteins called VP5\Nand VP8. The other protein defunct to
Dialogue: 0,0:08:29.00,0:08:33.00,Default,,0000,0000,0000,,focus on is called VP7, which just stands\Nfor Viral Protein seven. And that's kind
Dialogue: 0,0:08:33.00,0:08:37.00,Default,,0000,0000,0000,,of a coat protein. But again, on the\Nsurface of the virus. And it it's a
Dialogue: 0,0:08:37.00,0:08:41.01,Default,,0000,0000,0000,,glyco-protein, so it's also called a, a G\Nprotein. I'll talk about that also in a second;
Dialogue: 0,0:08:41.01,0:08:46.00,Default,,0000,0000,0000,,so, two surface proteins, VP4 and VP7.
Dialogue: 0,0:08:46.00,0:08:50.00,Default,,0000,0000,0000,,And as a general rule when you're trying to protect against viral infections, you want to try and make
Dialogue: 0,0:08:50.00,0:08:54.00,Default,,0000,0000,0000,,antibodies to the surface of a virus; so to this, surface of a bacteria.
Dialogue: 0,0:08:54.00,0:08:58.00,Default,,0000,0000,0000,,Because that would then prevent the virus or\Nbacteria from binding to a cell, entering a cell
Dialogue: 0,0:08:58.00,0:09:02.01,Default,,0000,0000,0000,,and causing disease. It's sort of a universal truth of vaccines. You're really,
Dialogue: 0,0:09:02.01,0:09:07.01,Default,,0000,0000,0000,,for the most part, trying to prevent\Nvirus-cell binding.
Dialogue: 0,0:09:07.01,0:09:14.00,Default,,0000,0000,0000,,Then, the rotavirus genome consists of eleven separate\Nsegments of double stranded RNA.
Dialogue: 0,0:09:14.00,0:09:20.01,Default,,0000,0000,0000,,And if you look at sort of, well, column A if\Nyou take the virus
Dialogue: 0,0:09:20.01,0:09:26.00,Default,,0000,0000,0000,,and you disrupt it with a, just a detergent and then you\Nput it on top of,
Dialogue: 0,0:09:26.00,0:09:31.00,Default,,0000,0000,0000,,so called, poly-acrylamide gel which is just a plastic\Nmesh and then you take the virus
Dialogue: 0,0:09:31.00,0:09:36.01,Default,,0000,0000,0000,,and you run it down with an electric current. You\Ncan actually separate those individual
Dialogue: 0,0:09:36.01,0:09:42.00,Default,,0000,0000,0000,,double strained RNA segments in.. by size.\NSo you can see the, the so called electropherotype of
Dialogue: 0,0:09:42.00,0:09:46.01,Default,,0000,0000,0000,,of virus A. And virus A and virus B are different.
Dialogue: 0,0:09:46.01,0:09:51.00,Default,,0000,0000,0000,,They're different strains therefore they\Nhave different ways in which their double-stranded RNA
Dialogue: 0,0:09:51.00,0:09:56.00,Default,,0000,0000,0000,,segments migrate in this gel.\NNow, if you take those two
Dialogue: 0,0:09:56.00,0:09:59.09,Default,,0000,0000,0000,,viruses and you co-infect cells at the\Nsame time,
Dialogue: 0,0:09:59.09,0:10:04.00,Default,,0000,0000,0000,,you find that about 20 percent of the time, the progeny viruses that are generated
Dialogue: 0,0:10:04.00,0:10:08.00,Default,,0000,0000,0000,,actually are reassorted viruses. Which is to say\Nthat they're a combination of the two viruses.
Dialogue: 0,0:10:08.00,0:10:12.01,Default,,0000,0000,0000,,So you can see at the virus strain on the right has all of its genes from
Dialogue: 0,0:10:12.01,0:10:17.01,Default,,0000,0000,0000,,virus A, and only one gene from virus B.
Dialogue: 0,0:10:17.01,0:10:22.01,Default,,0000,0000,0000,,Well, if virus A and virus B are different within their capacity to cause disease in experimental animals,
Dialogue: 0,0:10:22.01,0:10:27.00,Default,,0000,0000,0000,,in our case, we looked at mice, then you can\Nfigure out the genetics of virulence.
Dialogue: 0,0:10:27.00,0:10:31.00,Default,,0000,0000,0000,,If those two strains are different with\Nregard to their ability to induce
Dialogue: 0,0:10:31.00,0:10:36.00,Default,,0000,0000,0000,,neutralizing antibodies in the serum, then,\Nyou can say - - you can figure out the
Dialogue: 0,0:10:36.00,0:10:41.01,Default,,0000,0000,0000,,genetics of serotype which is to say that,\Nthat you can distinguish viruses based on
Dialogue: 0,0:10:41.01,0:10:46.00,Default,,0000,0000,0000,,their ability to evoke antibodies which\Nneutralize specific strains or specific serotypes.
Dialogue: 0,0:10:46.00,0:10:50.01,Default,,0000,0000,0000,,And so, again, by making these reassortant viruses as you see on the right,
Dialogue: 0,0:10:50.01,0:10:55.00,Default,,0000,0000,0000,,you can figure out the genetics of virulence.\NYou can figure out the genetics of
Dialogue: 0,0:10:55.00,0:11:00.00,Default,,0000,0000,0000,,serotype, or said another way,\Nneutralization phenotype, or said another way,
Dialogue: 0,0:11:00.00,0:11:04.00,Default,,0000,0000,0000,,just the genes responsible for evoking protective antibodies.
Dialogue: 0,0:11:04.00,0:11:09.00,Default,,0000,0000,0000,,So to make a long story short, to sort of summarize\Nten years worth of work in one slide,
Dialogue: 0,0:11:09.00,0:11:13.01,Default,,0000,0000,0000,,it's actually a little depressive. You can't do\Nthat, but to summarize ten years
Dialogue: 0,0:11:13.01,0:11:17.01,Default,,0000,0000,0000,,of work in one slide, what we found was\Nthat each of those two surface proteins
Dialogue: 0,0:11:17.01,0:11:22.00,Default,,0000,0000,0000,,evoked neutralizing antibodies or said\Nanother way, each of those two different proteins
Dialogue: 0,0:11:22.00,0:11:27.00,Default,,0000,0000,0000,,evoked or determined serotype.\NSo in a sense then, then rotaviruses actually
Dialogue: 0,0:11:27.00,0:11:31.01,Default,,0000,0000,0000,,are very similar to the influenza viruses,\Nwhich also are distinguished on the basis
Dialogue: 0,0:11:31.01,0:11:36.00,Default,,0000,0000,0000,,of two surface proteins.\NAnd that's the way that those viruses are characterized.
Dialogue: 0,0:11:36.00,0:11:40.00,Default,,0000,0000,0000,,H1N1, H5N1, the so-called bird flu.
Dialogue: 0,0:11:40.00,0:11:44.01,Default,,0000,0000,0000,,That's the way that the influenza viruses are characterized and that's the way the rotaviruses are characterized also.
Dialogue: 0,0:11:44.01,0:11:49.00,Default,,0000,0000,0000,,So, G1P1, for example.\NThe addition studies that were done
Dialogue: 0,0:11:49.00,0:11:53.00,Default,,0000,0000,0000,,by researchers at the National Institutes of Health specifically headed by
Dialogue: 0,0:11:53.00,0:11:57.01,Default,,0000,0000,0000,,Taka Hoshino as well as researchers in our lab \Ndetermined ultimately
Dialogue: 0,0:11:57.01,0:12:02.00,Default,,0000,0000,0000,,that there were four genes that were required for virulence. So by doing studies in mice, we showed that really
Dialogue: 0,0:12:02.00,0:12:06.01,Default,,0000,0000,0000,,there were four different genes, all of\Nwhich were required for virulence.
Dialogue: 0,0:12:06.01,0:12:11.00,Default,,0000,0000,0000,,Well, this was good news. It meant that you\Ncould include the genes, the human genes
Dialogue: 0,0:12:11.00,0:12:15.00,Default,,0000,0000,0000,,that were responsible for invoking\Nneutralizing antibodies, but as long as
Dialogue: 0,0:12:15.00,0:12:19.01,Default,,0000,0000,0000,,you didn't include all four that were\Nresponsible for virulence, then the virus wouldn't be virulent,
Dialogue: 0,0:12:19.01,0:12:24.00,Default,,0000,0000,0000,,or said another way, the virus shouldn't cause disease. \NAnd this was advanced beyond Max Tyler.
Dialogue: 0,0:12:24.00,0:12:29.00,Default,,0000,0000,0000,,Remember we talked about Max Tyler in another lecture.\NAnd Max Tyler was the one working at
Dialogue: 0,0:12:29.00,0:12:33.01,Default,,0000,0000,0000,,the Rockefeller Institute who showed\Nthat you could weaken viruses by
Dialogue: 0,0:12:33.01,0:12:38.00,Default,,0000,0000,0000,,serially passaging them in a cell culture.\NBut it was done really in a blind way, in a sense that
Dialogue: 0,0:12:38.00,0:12:42.01,Default,,0000,0000,0000,,you would pass it in non-human cells like in his case,
Dialogue: 0,0:12:42.01,0:12:47.00,Default,,0000,0000,0000,,you pass the Yellow Fever virus in mouse,\Nmouse embryo cells, or chicken embryo cells.
Dialogue: 0,0:12:47.00,0:12:52.00,Default,,0000,0000,0000,,And then he would take the virus out\Nto see whether it was weak enough by testing it in people.
Dialogue: 0,0:12:52.00,0:12:56.01,Default,,0000,0000,0000,,We, at Children's Hospital Philadelphia, at least had,
Dialogue: 0,0:12:56.01,0:13:00.01,Default,,0000,0000,0000,,we thought we had defined virulence genes,\Nby doing studies in mice.
Dialogue: 0,0:13:00.01,0:13:04.01,Default,,0000,0000,0000,,But again, you know, these were studies in\Nmice, you never really know
Dialogue: 0,0:13:04.01,0:13:09.00,Default,,0000,0000,0000,,until you test it in people.\NAnd so, you have to go very slowly, when you test in people,
Dialogue: 0,0:13:09.00,0:13:13.00,Default,,0000,0000,0000,,starting in adults, who you know have\Nalready been exposed to rotavirus and have antibodies
Dialogue: 0,0:13:13.00,0:13:17.00,Default,,0000,0000,0000,,And then working your way down, ultimately to children who hadn't been exposed to the virus.
Dialogue: 0,0:13:17.00,0:13:21.00,Default,,0000,0000,0000,,So this was reassuring, but, you really never know until
Dialogue: 0,0:13:21.00,0:13:25.01,Default,,0000,0000,0000,,you do the right kind of studies.\NSo the first rotavirus vaccine
Dialogue: 0,0:13:25.01,0:13:30.00,Default,,0000,0000,0000,,was, that was out there was called a Rota\Nshield. It was again the NIH reserchers
Dialogue: 0,0:13:30.00,0:13:35.01,Default,,0000,0000,0000,,had taken their simian strain, their so called research rotavirus or RRV strain.
Dialogue: 0,0:13:35.01,0:13:40.01,Default,,0000,0000,0000,,And they had it re-assorted it into that genes that determine
Dialogue: 0,0:13:40.01,0:13:45.00,Default,,0000,0000,0000,,human serotype, so called G1, G2, and G4.
Dialogue: 0,0:13:45.01,0:13:50.01,Default,,0000,0000,0000,,They assumed that the RRV strain was similar not\Nto the human G3, so there really there are
Dialogue: 0,0:13:50.01,0:13:55.01,Default,,0000,0000,0000,,sort of four major human G serotypes;\NG1, G2, G3, G4 and [inaudible] take this,
Dialogue: 0,0:13:55.01,0:14:00.00,Default,,0000,0000,0000,,this simian monkey strain.\NYou can then reassort into those human genes that
Dialogue: 0,0:14:00.00,0:14:05.00,Default,,0000,0000,0000,,determine those serotypes.\NAnd so that's what was done with this original vaccine.
Dialogue: 0,0:14:05.00,0:14:10.00,Default,,0000,0000,0000,,And, and the vaccine was on the,\Nwas actually brought onto the market in August 1998.
Dialogue: 0,0:14:10.00,0:14:15.00,Default,,0000,0000,0000,,It was on the market for about 10 months in the United States when this headline
Dialogue: 0,0:14:15.00,0:14:20.00,Default,,0000,0000,0000,,was published in a CDC journal called\NMorbidity and Mortality Weekly Report.
Dialogue: 0,0:14:20.00,0:14:24.01,Default,,0000,0000,0000,,It was called intussusception among recipients of rotavirus vaccine in the United States,
Dialogue: 0,0:14:24.01,0:14:29.01,Default,,0000,0000,0000,,1998 to 1999.\NAnd what had happened was, intussusception
Dialogue: 0,0:14:29.01,0:14:34.00,Default,,0000,0000,0000,,is caused when the small intestine sort of folds into itself, or invaginates into itself
Dialogue: 0,0:14:34.00,0:14:38.01,Default,,0000,0000,0000,,and gets stuck.\NAnd when that happens, there can be a critical loss
Dialogue: 0,0:14:38.01,0:14:43.00,Default,,0000,0000,0000,,of blood supply to the intestine mucosal surface,\Nwhich can cause intestinal mucosal surface damage
Dialogue: 0,0:14:43.00,0:14:48.00,Default,,0000,0000,0000,,and bleeding.\NIn addition, because the intestine has living on its surface,
Dialogue: 0,0:14:48.00,0:14:52.01,Default,,0000,0000,0000,,trillions, literally, of bacteria.\NThose bacteria can then enter
Dialogue: 0,0:14:52.01,0:14:57.00,Default,,0000,0000,0000,,the bloodstream and cause bloodstream\Ninfection, which can be overwhelming, even resulting
Dialogue: 0,0:14:57.00,0:15:01.01,Default,,0000,0000,0000,,in death. So intussusception is an important medical problem. It's a serious
Dialogue: 0,0:15:01.01,0:15:06.00,Default,,0000,0000,0000,,medical problem often requiring hospitalization.\NAnd so, the fact that,
Dialogue: 0,0:15:06.00,0:15:10.00,Default,,0000,0000,0000,,the, the that headline appeared in the\Nmorbidity mortality weekly report was
Dialogue: 0,0:15:10.00,0:15:14.01,Default,,0000,0000,0000,,really worrisome. And it was based on reports to VAERS, we've talked about in
Dialogue: 0,0:15:14.01,0:15:19.00,Default,,0000,0000,0000,,another talk, the so-called Vaccine\NAdverse Events Reporting System.
Dialogue: 0,0:15:19.00,0:15:23.01,Default,,0000,0000,0000,,This is a system that's passively, it's sort\Nof a passive reporting system
Dialogue: 0,0:15:23.01,0:15:27.01,Default,,0000,0000,0000,,to the FDA and the CDC.\NIf you're worried that, a vaccine
Dialogue: 0,0:15:27.01,0:15:33.01,Default,,0000,0000,0000,,could have caused a particular event, adverse event, then you can report it to this system. And then there
Dialogue: 0,0:15:33.01,0:15:35.00,Default,,0000,0000,0000,,were fifteen cases of intussusception were reported
Dialogue: 0,0:15:35.01,0:15:39.00,Default,,0000,0000,0000,,to various following Rotashield.\NWhat was worrying, worrisome, was that
Dialogue: 0,0:15:39.00,0:15:43.01,Default,,0000,0000,0000,,thirteen of those fifteen cases occurred after the first dose, which sort of lends to
Dialogue: 0,0:15:43.01,0:15:47.00,Default,,0000,0000,0000,,the biological plausibility of the fact that these two things were causally associated.
Dialogue: 0,0:15:47.00,0:15:51.00,Default,,0000,0000,0000,,Eleven of those thirteen cases, again, recur within seven days of vaccine administration,
Dialogue: 0,0:15:51.00,0:15:55.00,Default,,0000,0000,0000,,which is what you would expect if the vaccine was causing it. An eighth of those thirteen cases
Dialogue: 0,0:15:55.00,0:15:58.01,Default,,0000,0000,0000,,occurred in children 2-3 months of age.
Dialogue: 0,0:15:58.01,0:16:03.00,Default,,0000,0000,0000,,Now, intussusception occurs anyway. Intussusception occurs in children before there was a Rotavirus vaccine.
Dialogue: 0,0:16:03.00,0:16:07.00,Default,,0000,0000,0000,,But, it really occurred primarily in the 5-9 month-old.\NSo the thinking was that
Dialogue: 0,0:16:07.00,0:16:11.01,Default,,0000,0000,0000,,now that we were seeing it in 2-3 months of age,\Nwhen these kids were getting vaccinated,
Dialogue: 0,0:16:11.01,0:16:15.01,Default,,0000,0000,0000,,that again lent the fact at least the fact that this notion,
Dialogue: 0,0:16:15.01,0:16:20.00,Default,,0000,0000,0000,,that the, that the vaccine was causing\Nthe intussusception was biologically plausible.
Dialogue: 0,0:16:20.83,0:16:24.34,Default,,0000,0000,0000,,So the way that you answer this,\Nthe question, is to do the kinds of study
Dialogue: 0,0:16:24.42,0:16:26.89,Default,,0000,0000,0000,,that were done by Trudy Murphy and her co-workers,\Nand reported in
Dialogue: 0,0:16:26.92,0:16:29.72,Default,,0000,0000,0000,,the New England Journal of Medicine. The CDC\Nreally took the lead on this.
Dialogue: 0,0:16:29.75,0:16:33.48,Default,,0000,0000,0000,,Jeff Koplan, who was the head of the CDC at the time, stopped doing some other projects,
Dialogue: 0,0:16:35.25,0:16:38.01,Default,,0000,0000,0000,,lot of money into this, to see whether or\Nnot that association between
Dialogue: 0,0:16:38.01,0:16:42.00,Default,,0000,0000,0000,,intussusception and vaccination was\Ntemporal, or causal.
Dialogue: 0,0:16:42.00,0:16:46.00,Default,,0000,0000,0000,,And, and you gotta take your hat off to this group.\NThat the minute that they saw something
Dialogue: 0,0:16:46.00,0:16:50.00,Default,,0000,0000,0000,,that might have been problematic, they,\Nthey immediately addressed it, and found that
Dialogue: 0,0:16:50.00,0:16:54.00,Default,,0000,0000,0000,,if you received the rotavirus vaccine,\Nand your first dose was
Dialogue: 0,0:16:54.00,0:16:58.00,Default,,0000,0000,0000,,you received your first dose at 1-2 months of age,
Dialogue: 0,0:16:58.00,0:17:02.00,Default,,0000,0000,0000,,or 3-5 months of age, or 5-8 months of age,\Nthat within a week of getting that vaccine,
Dialogue: 0,0:17:02.00,0:17:06.00,Default,,0000,0000,0000,,you had a 25 to 30 fold increased risk\Nof getting the disease --
Dialogue: 0,0:17:06.00,0:17:09.01,Default,,0000,0000,0000,,getting the intussception\Nthan if you didn't get the vaccine.
Dialogue: 0,0:17:09.01,0:17:13.00,Default,,0000,0000,0000,,Similarly, there was a statistically signifigant increase,\Nif you, within 2 weeks of getting the vaccine,
Dialogue: 0,0:17:15.01,0:17:17.01,Default,,0000,0000,0000,,but not greater than 2 weeks after getting the vaccine.
Dialogue: 0,0:17:17.01,0:17:21.01,Default,,0000,0000,0000,,So this was supportive of the notion that, the\Nrot-, the intussusception following Rotashield vaccine
Dialogue: 0,0:17:21.01,0:17:26.00,Default,,0000,0000,0000,,was not a, just a temporal association,\Nbut was, in fact, a causal association
Dialogue: 0,0:17:26.00,0:17:30.00,Default,,0000,0000,0000,,that the vaccine actually was causing\Nthis intestinal blockage.
Dialogue: 0,0:17:30.00,0:17:34.01,Default,,0000,0000,0000,,For that reason, then the company had actually decided to
Dialogue: 0,0:17:34.01,0:17:40.00,Default,,0000,0000,0000,,withdraw the, the their vaccine from the\Nmarket and, and that, that was done after
Dialogue: 0,0:17:40.00,0:17:45.01,Default,,0000,0000,0000,,the vaccine had been on the market for\Nabout ten months. Now, you could argue
Dialogue: 0,0:17:45.01,0:17:51.00,Default,,0000,0000,0000,,that there is a difference between,\Nrelative risk and attributable risk.
Dialogue: 0,0:17:51.00,0:17:56.01,Default,,0000,0000,0000,,Relative risk, as we saw, was 25 to 30 to\None, following that vaccine.
Dialogue: 0,0:17:56.01,0:18:00.01,Default,,0000,0000,0000,,But the real risk or the attributed risk was\Nroughly 1 per 10,000. So let me try and
Dialogue: 0,0:18:00.01,0:18:04.01,Default,,0000,0000,0000,,give you an example of that. That if I am, if I\Nwalk across the street in front of my
Dialogue: 0,0:18:04.01,0:18:08.01,Default,,0000,0000,0000,,house, I have a certain risk of being hit\Nby a car. That would, no doubt, be much
Dialogue: 0,0:18:08.01,0:18:13.00,Default,,0000,0000,0000,,greater than the risk than if I was just\Nstanding. On the, the just in my doorstep
Dialogue: 0,0:18:13.00,0:18:17.00,Default,,0000,0000,0000,,in front of my house. And so the relative\Nrisk would be very high. It could be a
Dialogue: 0,0:18:17.00,0:18:20.01,Default,,0000,0000,0000,,1,000 to 1. But still the attributable\Nrisk is, is very low. I mean, I cross the
Dialogue: 0,0:18:20.01,0:18:24.00,Default,,0000,0000,0000,,street in front of my house all the time\Nand don't get hit by a car. That was true here.
Dialogue: 0,0:18:24.00,0:18:28.00,Default,,0000,0000,0000,,So while the, the relative risk was high,\Nthe attributable risk was pretty low.
Dialogue: 0,0:18:28.00,0:18:31.01,Default,,0000,0000,0000,,Still 1 in 10,000 recipients.\NAnd you could argue that if you took a
Dialogue: 0,0:18:31.01,0:18:35.00,Default,,0000,0000,0000,,theoretical million children who either\Ndid or didn't get the vaccine. Far more
Dialogue: 0,0:18:35.00,0:18:39.00,Default,,0000,0000,0000,,who didn't get the vaccine would have been\Nhospitalized. And, and then frankly, even
Dialogue: 0,0:18:39.00,0:18:43.00,Default,,0000,0000,0000,,five to ten fold more would have died from\Nnot getting the vaccine. Because Rotavirus
Dialogue: 0,0:18:43.00,0:18:47.00,Default,,0000,0000,0000,,kills children even in this, in the United\NStates. But I think at the time, the
Dialogue: 0,0:18:47.00,0:18:51.01,Default,,0000,0000,0000,,disease wasn't perceived to be terribly\Ndangerous. Certainly no one wanted to get
Dialogue: 0,0:18:51.01,0:18:57.00,Default,,0000,0000,0000,,something that you knew could have caused\Nintus susception and there was one child
Dialogue: 0,0:18:57.00,0:19:02.00,Default,,0000,0000,0000,,who died of intussusception following this\Nvaccine even though six to twelve will die
Dialogue: 0,0:19:02.00,0:19:07.00,Default,,0000,0000,0000,,from not having received the vaccine among\Na million children. So you could have made
Dialogue: 0,0:19:07.00,0:19:12.00,Default,,0000,0000,0000,,the argument that even with that adverse\Nevent that still the benefits outweigh the
Dialogue: 0,0:19:12.00,0:19:16.01,Default,,0000,0000,0000,,risk, but that's not the way that the\Nplayed out at the time and so the vaccine
Dialogue: 0,0:19:16.01,0:19:21.00,Default,,0000,0000,0000,,was taken off the market. Now, I think the\Nsaddest part of this, and the biggest
Dialogue: 0,0:19:21.00,0:19:25.00,Default,,0000,0000,0000,,tragedy, is that there was a World Health\NOrganization meeting held in February of
Dialogue: 0,0:19:25.00,0:19:29.00,Default,,0000,0000,0000,,2000. So it was about four months after\Nthe withdrawal of Rotashield from the
Dialogue: 0,0:19:29.00,0:19:32.01,Default,,0000,0000,0000,,United States, where the company was\Ngreat. I mean, wyeth made this vaccine,
Dialogue: 0,0:19:32.01,0:19:36.00,Default,,0000,0000,0000,,stood up and said, we, we, we'll give you\Nthe virus, the vaccine strains. We will
Dialogue: 0,0:19:36.00,0:19:40.01,Default,,0000,0000,0000,,give you, the you know, the technology on\Nhow to make it. We will give you the cell
Dialogue: 0,0:19:40.01,0:19:44.00,Default,,0000,0000,0000,,substrate on which we grew this,\Nthisvaccine. We'll help you build the
Dialogue: 0,0:19:44.00,0:19:48.00,Default,,0000,0000,0000,,buildings. Because the Wyeth knew that\Nthey had a technology that now they were
Dialogue: 0,0:19:48.00,0:19:52.00,Default,,0000,0000,0000,,not giving to American children. They\Ncould've saved. As many as 2000 lives a
Dialogue: 0,0:19:52.00,0:19:56.01,Default,,0000,0000,0000,,day in the developing world. But, But\Ncount-, country after country stood up and
Dialogue: 0,0:19:56.01,0:20:00.00,Default,,0000,0000,0000,,said, you know, if it's not safe for our\Nchildren, it not - if it's not safe for
Dialogue: 0,0:20:00.00,0:20:04.00,Default,,0000,0000,0000,,America's children, then it's not safe for\Nour children, therefore, we're not going
Dialogue: 0,0:20:04.00,0:20:07.01,Default,,0000,0000,0000,,to, to use it. Even though the risk\Nbenefit ratio was obviously very different
Dialogue: 0,0:20:07.01,0:20:11.00,Default,,0000,0000,0000,,in the developing world. So, I think the\Ntragedy was, if in this whole story, is
Dialogue: 0,0:20:11.00,0:20:14.01,Default,,0000,0000,0000,,that for seven years, a technology that\Ncould have saved a lot of lives in the
Dialogue: 0,0:20:14.01,0:20:18.01,Default,,0000,0000,0000,,developing world, and certainly even have\Nprevented a lot of suffering in the United
Dialogue: 0,0:20:18.01,0:20:22.01,Default,,0000,0000,0000,,States, sat on the shelf. And so, two\Nother, companies actually stepped forward
Dialogue: 0,0:20:22.01,0:20:27.00,Default,,0000,0000,0000,,to make vaccines. One of them was Merkin\NCompany, who, who, in collaboration with,
Dialogue: 0,0:20:27.00,0:20:31.00,Default,,0000,0000,0000,,researchers at Children's Hospital of\NPhiladelphia, developed this, this next
Dialogue: 0,0:20:31.00,0:20:35.00,Default,,0000,0000,0000,,vaccine. And again, it used that bovine\Nstrain that I talked to you about, that's,
Dialogue: 0,0:20:35.00,0:20:39.01,Default,,0000,0000,0000,,that's called iii.'Cause we certainly knew\Nthat, that virus was safe in children. It
Dialogue: 0,0:20:39.01,0:20:43.01,Default,,0000,0000,0000,,just didn't seem to be, consistently\Nprotective enough to make it a vaccine.
Dialogue: 0,0:20:43.01,0:20:48.01,Default,,0000,0000,0000,,And so what was done, was the same thing\Nreally that was done with the RotaShield
Dialogue: 0,0:20:48.01,0:20:53.00,Default,,0000,0000,0000,,vaccine, which was to make a series of\Nreassortant vaccines. And again, we talked
Dialogue: 0,0:20:53.00,0:20:58.00,Default,,0000,0000,0000,,about reassortants to some extent in the\Nin the history of vaccines talk. That
Dialogue: 0,0:20:58.00,0:21:03.00,Default,,0000,0000,0000,,included those human genes that, that\Nrepresented those, the, the proteins that
Dialogue: 0,0:21:03.00,0:21:08.00,Default,,0000,0000,0000,,were responsible for, for a serotypes G1,\NG2, G3 and G4, as well as one of the, the
Dialogue: 0,0:21:08.00,0:21:12.01,Default,,0000,0000,0000,,P serotypes, so called P1. So that's,\Nthat's what the RotaTeq vaccine was. It
Dialogue: 0,0:21:12.01,0:21:18.01,Default,,0000,0000,0000,,was given. As three doses by mouth at two,\Nfour and six months of age to, to
Dialogue: 0,0:21:18.01,0:21:24.00,Default,,0000,0000,0000,,children, It's This. Sorry, the, the, the\Ndose was 1.6 *ten^6 plaque forming units*
Dialogue: 0,0:21:24.00,0:21:28.01,Default,,0000,0000,0000,,per strain. A plaque form unit is, is just\Nwhen you test a virus. In cell culture,
Dialogue: 0,0:21:28.01,0:21:33.00,Default,,0000,0000,0000,,the virus can reproduce themselves, and\Ndestroy cells, as well as cells in the
Dialogue: 0,0:21:33.00,0:21:37.00,Default,,0000,0000,0000,,immediate area, which causes this sort of\Nplaque in the, in the or hole in the
Dialogue: 0,0:21:37.00,0:21:41.01,Default,,0000,0000,0000,,culture, and that's how you determine\Nthat. But the important to know here is
Dialogue: 0,0:21:41.01,0:21:46.00,Default,,0000,0000,0000,,that it was three doses given by mouth at\Ntwo, four, and six months of age. There
Dialogue: 0,0:21:46.00,0:21:50.00,Default,,0000,0000,0000,,were some advantages of the bovine strain,\Nbecause the cows are not as close
Dialogue: 0,0:21:50.01,0:21:55.00,Default,,0000,0000,0000,,phylogenetically to humans as primates\Nare. The there actually was a. To provide,
Dialogue: 0,0:21:55.00,0:21:59.00,Default,,0000,0000,0000,,less, for instance of sort of these common\Nless adverse events because of our
Dialogue: 0,0:21:59.00,0:22:03.01,Default,,0000,0000,0000,,assisted reproduced self as well. So I\Nthink the important thing here is, is that
Dialogue: 0,0:22:03.01,0:22:07.01,Default,,0000,0000,0000,,the vaccine was tested in, in more than\N70,000 children prospectively, in eleven
Dialogue: 0,0:22:07.01,0:22:12.00,Default,,0000,0000,0000,,countries It took four years to do this\Nstudy, it probably cost about 350 million
Dialogue: 0,0:22:12.00,0:22:16.00,Default,,0000,0000,0000,,dollars to do the definitive phase three\Ntrial of this vaccine. And what was found
Dialogue: 0,0:22:16.00,0:22:20.00,Default,,0000,0000,0000,,was that the vaccine was capable of\Npreventing any roto virus disease being
Dialogue: 0,0:22:20.00,0:22:24.01,Default,,0000,0000,0000,,mild, moderate or severe disease at about\N74%, which is roughly the equivalent of
Dialogue: 0,0:22:24.01,0:22:27.06,Default,,0000,0000,0000,,what natural infection capacity is to\Nprotect against roto virus disea se.
Dialogue: 0,0:22:27.06,0:22:33.00,Default,,0000,0000,0000,,Disease, Efficacy against severe disease\Nwas 98%, against rotavirus
Dialogue: 0,0:22:33.00,0:22:37.01,Default,,0000,0000,0000,,hospitalizations 94%, against rotavirus\Ndoctor visits 86%, and there was no
Dialogue: 0,0:22:37.01,0:22:42.00,Default,,0000,0000,0000,,clinically significant increase in fever.\NOr vomiting or diarrhea. Listlessness,
Dialogue: 0,0:22:42.00,0:22:46.01,Default,,0000,0000,0000,,lethargy, or poor feeding versus placebo.\NSo, the vaccine appeared to be safe and
Dialogue: 0,0:22:46.01,0:22:50.01,Default,,0000,0000,0000,,appeared to be effective. Importantly,\Nregarding [inaudible], within fourteen
Dialogue: 0,0:22:50.01,0:22:55.00,Default,,0000,0000,0000,,days of any dose, there was only one case\Nof in the vaccine group a one in the
Dialogue: 0,0:22:55.00,0:22:59.00,Default,,0000,0000,0000,,placebo group. Within 42 days of any dose,\N[inaudible] six, six weeks of any dose,
Dialogue: 0,0:22:59.00,0:23:03.00,Default,,0000,0000,0000,,there was six in the vaccine group, five\Nin the placebo group. And within one year
Dialogue: 0,0:23:03.00,0:23:07.00,Default,,0000,0000,0000,,again, twelve in the vaccine and fifteen\Nin the placebo group. So, again, the
Dialogue: 0,0:23:07.00,0:23:11.00,Default,,0000,0000,0000,,vaccine didn't appear to, to cause\N[inaudible] or prevent [inaudible]. And so
Dialogue: 0,0:23:11.00,0:23:15.01,Default,,0000,0000,0000,,those were, And, and we also have post\Nlicensure data that I'll talk about a
Dialogue: 0,0:23:15.01,0:23:19.01,Default,,0000,0000,0000,,little later. [inaudible] has been\Nintroduced, this vaccine has been
Dialogue: 0,0:23:19.01,0:23:24.00,Default,,0000,0000,0000,,introduced into the developing world.\NSpecifically in Nicaragua, Bangladesh,
Dialogue: 0,0:23:24.00,0:23:28.01,Default,,0000,0000,0000,,Vietnam, Ghana, Mali. And just within this\Npast week Rwanda. And that's a tribute to
Dialogue: 0,0:23:28.01,0:23:33.00,Default,,0000,0000,0000,,the Bill and Melinda Gates Foundation, who\Nhave made that possible. you know, the,
Dialogue: 0,0:23:33.00,0:23:37.01,Default,,0000,0000,0000,,although the World Health Organization\Ncertainly considers all the [inaudible].
Dialogue: 0,0:23:37.01,0:23:41.01,Default,,0000,0000,0000,,Caused by rotavirus important and, and\Nworthy of prevention. The World Health
Dialogue: 0,0:23:41.01,0:23:45.00,Default,,0000,0000,0000,,Organization doesn't really have the money\Nto introduce this vaccine in the
Dialogue: 0,0:23:45.00,0:23:49.00,Default,,0000,0000,0000,,developing world and, and frankly or the\Ncountries, the countries also don't have
Dialogue: 0,0:23:49.00,0:23:53.00,Default,,0000,0000,0000,,the money. So, that Bill and Melinda Gates\Nchoose to spend their money by preventing
Dialogue: 0,0:23:53.00,0:23:57.00,Default,,0000,0000,0000,,a disease which causes a lot of suffering\Nand death in the developing world is a
Dialogue: 0,0:23:57.00,0:24:00.01,Default,,0000,0000,0000,,tribute to them. Now there's, there's\Nanother rotavirus vaccine that, that's,
Dialogue: 0,0:24:00.01,0:24:05.00,Default,,0000,0000,0000,,that's developed, that was developed by\Nresearchers at Children's Hospital in
Dialogue: 0,0:24:05.00,0:24:09.00,Default,,0000,0000,0000,,Cincinnati specifically Dick Ward and\NDavid Bernstein, using the more classic
Dialogue: 0,0:24:09.00,0:24:13.00,Default,,0000,0000,0000,,way of making a vaccine, a live weakened.\NVaccine, which was to take the vi rus, and
Dialogue: 0,0:24:13.00,0:24:17.01,Default,,0000,0000,0000,,serially [inaudible] in non human cells as\Na way of attenuating it. This vaccine is
Dialogue: 0,0:24:17.01,0:24:21.00,Default,,0000,0000,0000,,given as two doses by mouth, which is an\Nadvantage. It's one fewer dose. At two,
Dialogue: 0,0:24:21.00,0:24:25.01,Default,,0000,0000,0000,,two to three, and then four to five months\Nof age. It's given at a somewhat lesser,
Dialogue: 0,0:24:26.00,0:24:29.01,Default,,0000,0000,0000,,dose. Because the virus is, is a human\Nvirus. So therefore, somewhat better at
Dialogue: 0,0:24:29.01,0:24:33.01,Default,,0000,0000,0000,,reproducing itself in the intestine than\Nthe bovine strain was. The, the
Dialogue: 0,0:24:33.01,0:24:37.00,Default,,0000,0000,0000,,researchers at children's hospital in\NCincinatti, in collaboration with
Dialogue: 0,0:24:37.00,0:24:41.00,Default,,0000,0000,0000,,GlaxoSmithKline, did a study of, 60, more\Nthan 63,000 infants who were given this
Dialogue: 0,0:24:41.00,0:24:45.00,Default,,0000,0000,0000,,vaccine at two to four months of age. And\Nthe studies were performed in Latin
Dialogue: 0,0:24:45.00,0:24:50.00,Default,,0000,0000,0000,,American countries as well as Finland and\Nthe vaccine worked very well, preventing a
Dialogue: 0,0:24:50.00,0:24:54.01,Default,,0000,0000,0000,,severe disease about a, [inaudible] an\Nefficacy rate of 85 percent and preventing
Dialogue: 0,0:24:54.05,0:24:59.00,Default,,0000,0000,0000,,80, hospitalizations at a rate of about\N85%. Rotateq. Was introduced in the United
Dialogue: 0,0:24:59.00,0:25:03.01,Default,,0000,0000,0000,,States in 2006. Rotarix in the United\NStates in 2008. Although Rotarix was
Dialogue: 0,0:25:03.01,0:25:08.00,Default,,0000,0000,0000,,introduced in the developing world also in\N2-, 2006. And, what we found was that.
Dialogue: 0,0:25:08.00,0:25:12.00,Default,,0000,0000,0000,,there was a 50, even in the US, 50 percent\Nimmunization rate causing 80 to 90 percent
Dialogue: 0,0:25:12.00,0:25:17.00,Default,,0000,0000,0000,,reduction in hospitalization. So it's a\Nthere is her immunity that is being
Dialogue: 0,0:25:17.00,0:25:21.06,Default,,0000,0000,0000,,induced by these two vaccines. So, so what\Nabout an [inaudible]. Why this, the Rota
Dialogue: 0,0:25:21.06,0:25:26.01,Default,,0000,0000,0000,,Virus vaccine, why did Rota shield cause\Nan [inaudible] interest. There were data
Dialogue: 0,0:25:26.01,0:25:31.00,Default,,0000,0000,0000,,presented from Brazil, Mexico, Australia\Nand the United States on October
Dialogue: 0,0:25:31.00,0:25:36.00,Default,,0000,0000,0000,,twenty-eighth, 2000 [inaudible] that show\Nthe [inaudible] was actually was a rare
Dialogue: 0,0:25:36.00,0:25:40.01,Default,,0000,0000,0000,,consequence Rota risk in Mexico and\NAustralia. Not at the one in 10,000 level
Dialogue: 0,0:25:40.01,0:25:46.00,Default,,0000,0000,0000,,that was seen for Rota, Rota Shield. But,\Nbut more an attributable risk of one per
Dialogue: 0,0:25:46.00,0:25:50.01,Default,,0000,0000,0000,,60,000 or 90,000 doses. And also, for\NRotaTeq as well, intussusception was a
Dialogue: 0,0:25:50.01,0:25:55.00,Default,,0000,0000,0000,,rare consequence in Australia, with an\Nattributable risk again between sort of,
Dialogue: 0,0:25:55.00,0:25:59.01,Default,,0000,0000,0000,,60,000 and 90,000 doses. So it now looks\Nlike all three Rotavirus vaccines,
Dialogue: 0,0:25:59.01,0:26:04.01,Default,,0000,0000,0000,,including Rotarix, which is simply an\Nattenuated human Rotavirus strain, causes
Dialogue: 0,0:26:04.01,0:26:09.00,Default,,0000,0000,0000,,intussusceptio N. So it sort of causes us\Nto re-evaluate why. Rotashield caused
Dialogue: 0,0:26:09.00,0:26:14.00,Default,,0000,0000,0000,,intussusception, I think the most likely\Nreason is that natural rotavirus infection
Dialogue: 0,0:26:14.00,0:26:19.00,Default,,0000,0000,0000,,is also a rare cause of intussusception.\NSo then the question becomes which is
Dialogue: 0,0:26:19.00,0:26:23.00,Default,,0000,0000,0000,,rarer, Intussusception caused by. By the\Nvaccine, or intussusception caused by the
Dialogue: 0,0:26:23.00,0:26:26.01,Default,,0000,0000,0000,,disease. Because remember the vaccine\Nprevents the disease. So if, if
Dialogue: 0,0:26:26.01,0:26:31.00,Default,,0000,0000,0000,,intussusception caused by the, the vaccine\Nis more common than intussusception caused
Dialogue: 0,0:26:31.00,0:26:35.01,Default,,0000,0000,0000,,by the. The, the natural virus, then, the\Nrates of interception should go up in
Dialogue: 0,0:26:35.01,0:26:40.00,Default,,0000,0000,0000,,countries that use the vaccine. Conversely\Nif, if interception caused by the. The
Dialogue: 0,0:26:40.00,0:26:44.00,Default,,0000,0000,0000,,natural virus is more common, then\N[inaudible] caused by the vaccine, given
Dialogue: 0,0:26:44.00,0:26:47.00,Default,,0000,0000,0000,,that the vaccine prevents natural\Ninfection. Then as you introduce the
Dialogue: 0,0:26:47.00,0:26:51.00,Default,,0000,0000,0000,,vaccine, rates of [inaudible] should,\Nshould go down. And sort of all of the
Dialogue: 0,0:26:51.00,0:26:55.00,Default,,0000,0000,0000,,evidence to date, is it certainly raises\Nthe [inaudible], the [inaudible] seem to
Dialogue: 0,0:26:55.00,0:26:59.00,Default,,0000,0000,0000,,be going up, and if anything they seem to\Nbe going down. A little. So I think that
Dialogue: 0,0:26:59.00,0:27:03.00,Default,,0000,0000,0000,,what we've learned is that in the long\Nrun, that [inaudible] is probably is a
Dialogue: 0,0:27:03.00,0:27:07.00,Default,,0000,0000,0000,,consequence of the natural infection. It's\Nprobably to some extent prevented by, by
Dialogue: 0,0:27:07.00,0:27:11.00,Default,,0000,0000,0000,,vaccination. I mean it's interesting to\Nknow what, what, what had happened if we
Dialogue: 0,0:27:11.00,0:27:15.00,Default,,0000,0000,0000,,had found out that [inaudible] shield had\Ncaused [inaudible]. This is after four
Dialogue: 0,0:27:15.00,0:27:18.00,Default,,0000,0000,0000,,years after it had already been\Nintroduced. Because now, we know that
Dialogue: 0,0:27:18.00,0:27:22.00,Default,,0000,0000,0000,,rotarix and rota, rotatech are two more\Nrecent vaccines for saving lives in the
Dialogue: 0,0:27:22.00,0:27:26.00,Default,,0000,0000,0000,,developing world are certainly preventing\Nhospitalizations and suffering in
Dialogue: 0,0:27:26.00,0:27:29.01,Default,,0000,0000,0000,,developed countries like the United\NStates. I wondered whether we would have
Dialogue: 0,0:27:29.01,0:27:34.00,Default,,0000,0000,0000,,still made the same decision rotashield\Nthat we found out that it was a rare cause
Dialogue: 0,0:27:34.00,0:27:37.06,Default,,0000,0000,0000,,of [inaudible] four years later. So I'll\Nstop right there and thank you for your atte