WEBVTT 00:00:04.000 --> 00:00:08.009 Hi, my name is Paul Offit. I'm from the Children's Hospital, Philadelphia and the 00:00:08.009 --> 00:00:12.005 Perelman School of Medicine of the University of Pennsylvania. 00:00:12.005 --> 00:00:16.001 What I thought I would talk about in this lecture is rotavirus vaccines. 00:00:16.001 --> 00:00:19.369 And it's the only, actually, what I'll talk just about one specific vaccine for the whole lecture. 00:00:19.369 --> 00:00:22.928 And it's not because I think rotaviruses are especially important among the vaccines, 00:00:22.928 --> 00:00:26.085 rather it's because I actually was fortunate enough to be part 00:00:26.085 --> 00:00:29.893 of the team at Children's Hospital, Philadelphia that developed this vaccine. 00:00:29.893 --> 00:00:35.038 So I really watched it go from, from early research through development and so 00:00:35.038 --> 00:00:38.757 basically from bench to bedside and it was an educational process for me. 00:00:38.757 --> 00:00:41.992 And so I thought it would be fun to kind of go through this story. 00:00:41.992 --> 00:00:51.002 So rotaviruses are a virus that infects the small intestine and it causes fever and vomiting 00:00:51.002 --> 00:00:54.065 and water loss or dehydration in young children. 00:00:54.065 --> 00:00:58.790 This is a study done by Bill Rodriguez at the Children's Hospital in DC. 00:00:58.790 --> 00:01:02.875 And he looked at rotavirus as compared to other viruses that cause the so-called stomach viruses, 00:01:02.875 --> 00:01:09.855 and found that rotaviruses were particularly capable of causing vomiting and dehydration. 00:01:09.855 --> 00:01:15.346 And that's why, when you have the stomach virus, you sort of lose water when you have dehydra- 00:01:15.346 --> 00:01:19.288 when you have diarrhea, you lose water when you have fever, 00:01:19.288 --> 00:01:22.086 and it's hard to rehydrate yourself when you're vomiting. 00:01:22.086 --> 00:01:26.005 So that's sort of those three things together can rapidly lead to dehydration, 00:01:26.005 --> 00:01:29.001 which can cause hospitalization, and death. 00:01:30.539 --> 00:01:40.154 This is just a stained section of the small intestine showing the virus infecting the intestine. 00:01:40.154 --> 00:01:43.099 And what you can see here is that, 00:01:45.638 --> 00:01:52.594 if you look here at this sort of, these kind of finger-like projections, so-called villi, into the small intestine, 00:01:52.594 --> 00:01:56.453 You can see that the virus is infecting these cells that are detected 00:01:56.453 --> 00:02:01.184 as so-called mature epithelial cells that line the intestine. 00:02:01.184 --> 00:02:05.124 That's what rotaviruses do. They infect those cells, and they damage those cells, 00:02:05.139 --> 00:02:09.971 and they make it very difficult to resorb water. 00:02:09.971 --> 00:02:14.677 And it causes diarrhea, and it causes vomiting, and it causes dehydration. 00:02:15.031 --> 00:02:20.270 So, every year, in the United States, prior to the vaccines are being licensed and used, 00:02:20.285 --> 00:02:27.447 which was around 2006, rotavirus accounts for about 2.7 million cases, about 500,000 doctor visits, 00:02:27.447 --> 00:02:34.528 about 270,000 emergency department visits, 70,000 hospitalizations, and 20-60 deaths each year. 00:02:34.528 --> 00:02:38.167 If you assume a broad cohort between 3.5 and 4 million children every year in the U.S., 00:02:38.167 --> 00:02:42.482 that meant that about 1 out of every 50 children born in the United States would be hospitalized 00:02:42.482 --> 00:02:45.509 with dehydration secondary to rotavirus infection. 00:02:45.509 --> 00:02:50.131 Those numbers are dramatically decreased since the vaccine came. And then we'll talk about that. 00:02:51.239 --> 00:02:58.071 In the developing world, rotavirus is a killer. It accounts for about 500,000 deaths a year. 00:02:58.071 --> 00:03:04.308 That means about 2,000 children die every day from this virus, from the dehydration caused by this virus. 00:03:04.308 --> 00:03:08.869 Actually, it's the single agent. It's one of the most important killers of infants and young children in the world. 00:03:08.869 --> 00:03:11.006 And for that reason there was a tremendous amount of interest 00:03:11.006 --> 00:03:14.603 both publicly and privately to try develop a vaccine to prevent it. 00:03:15.757 --> 00:03:22.282 Now, the original idea on how to make a vaccine, and it's sort of Edward Jenner-like approach. 00:03:22.340 --> 00:03:26.001 And I talked about Edward Jenner in another lecture, in a history of vaccines lecture. 00:03:26.001 --> 00:03:30.408 But the initial idea was why - since all mammals that live 00:03:30.408 --> 00:03:33.559 on the face of the earth have their own rotavirus strain - 00:03:33.559 --> 00:03:35.986 why don't we actually do the same thing that Edward Jenner did? 00:03:35.986 --> 00:03:41.235 Remember, Edward Jenner used the cowpox virus to protect against human smallpox. 00:03:41.235 --> 00:03:47.270 He - we now know--he didn't know that, but we now know the cowpox is similar enough to, 00:03:47.270 --> 00:03:53.003 was similar enough to human smallpox, that infection with one could prevent disease caused by the other. 00:03:53.003 --> 00:03:55.840 So, really, that was the same thinking here was 00:03:55.840 --> 00:04:02.006 'why not use a non-human rotavirus strain to protect against human rotavirus?' 00:04:02.006 --> 00:04:07.541 This just shows you all the [inaudible] species that could be affected by rotavirus. 00:04:08.157 --> 00:04:13.326 But species barriers are high, meaning that as it was true, smallpox were, 00:04:13.326 --> 00:04:18.003 cowpox could cause significant disease in cows but not people, 00:04:18.003 --> 00:04:24.667 and human smallpox could cause significant disease in human but not cows. That's also true here. 00:04:24.667 --> 00:04:31.615 So for example, cow rotavirus could cause severe vomiting and diarrhea in cows, 00:04:31.615 --> 00:04:37.754 but really doesn't do that in people. And vice versa, human rotaviruses really don't cause disease in cows. 00:04:37.754 --> 00:04:43.162 So, it's the species barriers that are high, and that was the original idea. 00:04:43.162 --> 00:04:48.058 So what happened was, there was a group at the National Institute of Health, 00:04:48.058 --> 00:04:54.253 headed by Al Kapikian, Rob Chanock, Taka Hoshino, Harry Greenberg, Jorge Flores and others; 00:04:54.253 --> 00:05:01.253 who looked at a strain called RRV. Now that strain stands for Resist Rotavirus. 00:05:01.253 --> 00:05:07.084 This was a virus, a rotavirus strain that was isolated from a monkey in Northern California in the 1980's 00:05:07.084 --> 00:05:17.670 by H. Milerby. That virus was then purified by growing it in cell culture, and not so much weakened. 00:05:17.670 --> 00:05:21.048 The notion was that it would be weakened in humans because it wasn't a human virus. 00:05:21.064 --> 00:05:22.838 This is sort of the same idea Edward Jenner had. 00:05:22.838 --> 00:05:26.862 And when the vaccine was then given by mouth at 2, 4, and 6 months of age 00:05:26.862 --> 00:05:29.559 to children in Sweden, and in Finland, it worked. 00:05:29.559 --> 00:05:34.823 It seemed to protect against the moderate to severe dehydration 00:05:34.823 --> 00:05:39.004 as it's shown on the first two rows on the slide. 00:05:39.004 --> 00:05:43.708 But when the vaccine was then tested in Rochester, NY in a trial; it didn't seem to work. 00:05:43.708 --> 00:05:49.959 So, I think what people concluded after this series of trial was that a non-human virus - in this case, a monkey virus - 00:05:49.959 --> 00:05:55.708 was inconsistently capable of protecting against human rotavirus disease. 00:05:56.523 --> 00:06:02.019 Now we worked, and by we, I mean Stanley Plotkin and Fred Clark, who headed this program; 00:06:02.019 --> 00:06:07.594 worked at Children's Hospital, Philadelphia; with a strain called WC3. 00:06:07.594 --> 00:06:13.223 And that was actually isolated from a calf with diarrhea at the Kenneth Square facility 00:06:13.223 --> 00:06:16.785 which is the large animal facility, the , the veterinary school here at the University of Pennsylvania. 00:06:16.881 --> 00:06:20.685 And we took that virus and then we went back to the Wistar Institute 00:06:20.685 --> 00:06:23.664 and we purified it by passing it in a cell culture. 00:06:23.664 --> 00:06:29.669 And since it was from the third calf that we tested, it was called WC3 or Wistar Calf Three. 00:06:29.669 --> 00:06:35.594 We gave this virus by mouth to children at 2, 4 and 6 months of age in Philadelphia 00:06:35.594 --> 00:06:38.685 and found that it was excellent at protecting against moderate to severe disease 00:06:38.685 --> 00:06:42.786 and actually very good at protecting against even mild disease caused by rotavirus. 00:06:42.786 --> 00:06:47.008 But when we then tested the vaccine in Cincinnati or in Bangui in the Central African Republic, 00:06:47.008 --> 00:06:52.002 we found that it didn't work well. So basically we've found 00:06:52.002 --> 00:06:56.003 with the calf strain exactly the same thing that the NIH researchers had found 00:06:56.003 --> 00:07:00.002 with a simian strain, a monkey strain. That the protection against rotavirus could occur 00:07:00.002 --> 00:07:04.003 with non-human strains, but it was inconsistent in it's ability to protect. 00:07:04.003 --> 00:07:08.006 So it was really back to the drawing board. And this slide shows what 00:07:08.006 --> 00:07:13.000 the drawing board was. We, we needed to determine which rotavirus proteins were responsible 00:07:13.000 --> 00:07:17.003 for evoking virus specific neutralizing antibodies. In other words, 00:07:17.003 --> 00:07:21.007 what rotovirus proteins induce protective immunity and which rotovirus proteins 00:07:21.007 --> 00:07:26.000 were responsible for viral virulence. So it is the way that you make any vaccine. 00:07:26.000 --> 00:07:30.000 You're really trying, you're trying to separate out the part of the, in this case, the virus 00:07:30.000 --> 00:07:34.002 that is pathogenic, that is disease causing from the part of the virus 00:07:34.002 --> 00:07:38.001 that induces an immune response which is protective. Hoping in this case 00:07:38.001 --> 00:07:42.004 that the genes that are responsible for making the proteins that cause disease are different 00:07:42.004 --> 00:07:46.008 from the genes that are required to make the proteins 00:07:46.008 --> 00:07:51.000 that induce a protective immune response. So just a brief word about rotavirus structure, 00:07:51.000 --> 00:07:56.000 the cartoon of the rotavirus particle is shown on the right and there are two proteins 00:07:56.000 --> 00:08:00.008 to focus on. One is the protein called VP4 which stands for 00:08:00.008 --> 00:08:05.006 viral protein four. It's the viral protein that's responsible for 00:08:05.006 --> 00:08:10.004 binding to cells before it infects them. It's also called a P protein, 00:08:10.004 --> 00:08:15.001 or a P serotype and you'll see what I mean by that in a second. P, just because it's sensitive to 00:08:15.001 --> 00:08:20.000 proteases. Proteases are proteins that cleave proteins. 00:08:20.002 --> 00:08:24.006 and this, in order for the virus actually to enter the cell that VP4 needs to be 00:08:24.006 --> 00:08:29.000 cleaved to two smaller proteins called VP5 and VP8. The other protein defunct to 00:08:29.000 --> 00:08:33.005 focus on is called VP7, which just stands for Viral Protein seven. And that's kind 00:08:33.005 --> 00:08:37.005 of a coat protein. But again, on the surface of the virus. And it it's a 00:08:37.005 --> 00:08:41.009 glyco-protein, so it's also called a, a G protein. I'll talk about that also in a second; 00:08:41.009 --> 00:08:46.003 so, two surface proteins, VP4 and VP7. 00:08:46.003 --> 00:08:50.001 And as a general rule when you're trying to protect against viral infections, you want to try and make 00:08:50.001 --> 00:08:54.003 antibodies to the surface of a virus; so to this, surface of a bacteria. 00:08:54.003 --> 00:08:58.003 Because that would then prevent the virus or bacteria from binding to a cell, entering a cell 00:08:58.003 --> 00:09:02.006 and causing disease. It's sort of a universal truth of vaccines. You're really, 00:09:02.006 --> 00:09:07.008 for the most part, trying to prevent virus-cell binding. 00:09:07.008 --> 00:09:14.002 Then, the rotavirus genome consists of eleven separate segments of double stranded RNA. 00:09:14.002 --> 00:09:20.009 And if you look at sort of, well, column A if you take the virus 00:09:20.009 --> 00:09:26.000 and you disrupt it with a, just a detergent and then you put it on top of, 00:09:26.000 --> 00:09:31.004 so called, poly-acrylamide gel which is just a plastic mesh and then you take the virus 00:09:31.004 --> 00:09:36.009 and you run it down with an electric current. You can actually separate those individual 00:09:36.009 --> 00:09:42.003 double strained RNA segments in.. by size. So you can see the, the so called electropherotype of 00:09:42.003 --> 00:09:46.007 of virus A. And virus A and virus B are different. 00:09:46.007 --> 00:09:51.003 They're different strains therefore they have different ways in which their double-stranded RNA 00:09:51.003 --> 00:09:56.000 segments migrate in this gel. Now, if you take those two 00:09:56.000 --> 00:09:59.093 viruses and you co-infect cells at the same time, 00:09:59.093 --> 00:10:04.002 you find that about 20 percent of the time, the progeny viruses that are generated 00:10:04.002 --> 00:10:08.005 actually are reassorted viruses. Which is to say that they're a combination of the two viruses. 00:10:08.005 --> 00:10:12.009 So you can see at the virus strain on the right has all of its genes from 00:10:12.009 --> 00:10:17.008 virus A, and only one gene from virus B. 00:10:17.008 --> 00:10:22.006 Well, if virus A and virus B are different within their capacity to cause disease in experimental animals, 00:10:22.006 --> 00:10:27.002 in our case, we looked at mice, then you can figure out the genetics of virulence. 00:10:27.002 --> 00:10:31.005 If those two strains are different with regard to their ability to induce 00:10:31.005 --> 00:10:36.005 neutralizing antibodies in the serum, then, you can say - - you can figure out the 00:10:36.005 --> 00:10:41.006 genetics of serotype which is to say that, that you can distinguish viruses based on 00:10:41.006 --> 00:10:46.004 their ability to evoke antibodies which neutralize specific strains or specific serotypes. 00:10:46.004 --> 00:10:50.008 And so, again, by making these reassortant viruses as you see on the right, 00:10:50.008 --> 00:10:55.003 you can figure out the genetics of virulence. You can figure out the genetics of 00:10:55.005 --> 00:11:00.001 serotype, or said another way, neutralization phenotype, or said another way, 00:11:00.001 --> 00:11:04.004 just the genes responsible for evoking protective antibodies. 00:11:04.004 --> 00:11:09.004 So to make a long story short, to sort of summarize ten years worth of work in one slide, 00:11:09.004 --> 00:11:13.007 it's actually a little depressive. You can't do that, but to summarize ten years 00:11:13.007 --> 00:11:17.009 of work in one slide, what we found was that each of those two surface proteins 00:11:17.009 --> 00:11:22.002 evoked neutralizing antibodies or said another way, each of those two different proteins 00:11:22.002 --> 00:11:27.001 evoked or determined serotype. So in a sense then, then rotaviruses actually 00:11:27.001 --> 00:11:31.006 are very similar to the influenza viruses, which also are distinguished on the basis 00:11:31.006 --> 00:11:36.000 of two surface proteins. And that's the way that those viruses are characterized. 00:11:36.000 --> 00:11:40.004 H1N1, H5N1, the so-called bird flu. 00:11:40.004 --> 00:11:44.007 That's the way that the influenza viruses are characterized and that's the way the rotaviruses are characterized also. 00:11:44.007 --> 00:11:49.000 So, G1P1, for example. The addition studies that were done 00:11:49.000 --> 00:11:53.003 by researchers at the National Institutes of Health specifically headed by 00:11:53.003 --> 00:11:57.007 Taka Hoshino as well as researchers in our lab determined ultimately 00:11:57.007 --> 00:12:02.001 that there were four genes that were required for virulence. So by doing studies in mice, we showed that really 00:12:02.001 --> 00:12:06.006 there were four different genes, all of which were required for virulence. 00:12:06.006 --> 00:12:11.000 Well, this was good news. It meant that you could include the genes, the human genes 00:12:11.000 --> 00:12:15.002 that were responsible for invoking neutralizing antibodies, but as long as 00:12:15.002 --> 00:12:19.006 you didn't include all four that were responsible for virulence, then the virus wouldn't be virulent, 00:12:19.006 --> 00:12:24.003 or said another way, the virus shouldn't cause disease. And this was advanced beyond Max Tyler. 00:12:24.003 --> 00:12:29.000 Remember we talked about Max Tyler in another lecture. And Max Tyler was the one working at 00:12:29.000 --> 00:12:33.007 the Rockefeller Institute who showed that you could weaken viruses by 00:12:33.007 --> 00:12:38.004 serially passaging them in a cell culture. But it was done really in a blind way, in a sense that 00:12:38.004 --> 00:12:42.009 you would pass it in non-human cells like in his case, 00:12:42.009 --> 00:12:47.004 you pass the Yellow Fever virus in mouse, mouse embryo cells, or chicken embryo cells. 00:12:47.004 --> 00:12:52.000 And then he would take the virus out to see whether it was weak enough by testing it in people. 00:12:52.000 --> 00:12:56.006 We, at Children's Hospital Philadelphia, at least had, 00:12:56.006 --> 00:13:00.009 we thought we had defined virulence genes, by doing studies in mice. 00:13:00.009 --> 00:13:04.008 But again, you know, these were studies in mice, you never really know 00:13:04.008 --> 00:13:09.000 until you test it in people. And so, you have to go very slowly, when you test in people, 00:13:09.000 --> 00:13:13.000 starting in adults, who you know have already been exposed to rotavirus and have antibodies 00:13:13.000 --> 00:13:17.001 And then working your way down, ultimately to children who hadn't been exposed to the virus. 00:13:17.001 --> 00:13:21.001 So this was reassuring, but, you really never know until 00:13:21.001 --> 00:13:25.006 you do the right kind of studies. So the first rotavirus vaccine 00:13:25.006 --> 00:13:30.004 was, that was out there was called a Rota shield. It was again the NIH reserchers 00:13:30.004 --> 00:13:35.007 had taken their simian strain, their so called research rotavirus or RRV strain. 00:13:35.007 --> 00:13:40.007 And they had it re-assorted it into that genes that determine 00:13:40.007 --> 00:13:45.005 human serotype, so called G1, G2, and G4. 00:13:45.007 --> 00:13:50.008 They assumed that the RRV strain was similar not to the human G3, so there really there are 00:13:50.008 --> 00:13:55.006 sort of four major human G serotypes; G1, G2, G3, G4 and [inaudible] take this, 00:13:55.006 --> 00:14:00.003 this simian monkey strain. You can then reassort into those human genes that 00:14:00.003 --> 00:14:05.002 determine those serotypes. And so that's what was done with this original vaccine. 00:14:05.002 --> 00:14:10.000 And, and the vaccine was on the, was actually brought onto the market in August 1998. 00:14:10.000 --> 00:14:15.000 It was on the market for about 10 months in the United States when this headline 00:14:15.000 --> 00:14:20.000 was published in a CDC journal called Morbidity and Mortality Weekly Report. 00:14:20.000 --> 00:14:24.009 It was called intussusception among recipients of rotavirus vaccine in the United States, 00:14:24.009 --> 00:14:29.006 1998 to 1999. And what had happened was, intussusception 00:14:29.006 --> 00:14:34.002 is caused when the small intestine sort of folds into itself, or invaginates into itself 00:14:34.002 --> 00:14:38.009 and gets stuck. And when that happens, there can be a critical loss 00:14:38.009 --> 00:14:43.005 of blood supply to the intestine mucosal surface, which can cause intestinal mucosal surface damage 00:14:43.005 --> 00:14:48.004 and bleeding. In addition, because the intestine has living on its surface, 00:14:48.004 --> 00:14:52.008 trillions, literally, of bacteria. Those bacteria can then enter 00:14:52.008 --> 00:14:57.004 the bloodstream and cause bloodstream infection, which can be overwhelming, even resulting 00:14:57.004 --> 00:15:01.006 in death. So intussusception is an important medical problem. It's a serious 00:15:01.006 --> 00:15:06.000 medical problem often requiring hospitalization. And so, the fact that, 00:15:06.000 --> 00:15:10.004 the, the that headline appeared in the morbidity mortality weekly report was 00:15:10.004 --> 00:15:14.006 really worrisome. And it was based on reports to VAERS, we've talked about in 00:15:14.006 --> 00:15:19.003 another talk, the so-called Vaccine Adverse Events Reporting System. 00:15:19.003 --> 00:15:23.007 This is a system that's passively, it's sort of a passive reporting system 00:15:23.007 --> 00:15:27.008 to the FDA and the CDC. If you're worried that, a vaccine 00:15:27.009 --> 00:15:33.006 could have caused a particular event, adverse event, then you can report it to this system. And then there 00:15:33.006 --> 00:15:35.005 were fifteen cases of intussusception were reported 00:15:35.006 --> 00:15:39.005 to various following Rotashield. What was worrying, worrisome, was that 00:15:39.005 --> 00:15:43.007 thirteen of those fifteen cases occurred after the first dose, which sort of lends to 00:15:43.007 --> 00:15:47.002 the biological plausibility of the fact that these two things were causally associated. 00:15:47.002 --> 00:15:51.002 Eleven of those thirteen cases, again, recur within seven days of vaccine administration, 00:15:51.002 --> 00:15:55.001 which is what you would expect if the vaccine was causing it. An eighth of those thirteen cases 00:15:55.001 --> 00:15:58.009 occurred in children 2-3 months of age. 00:15:58.009 --> 00:16:03.001 Now, intussusception occurs anyway. Intussusception occurs in children before there was a Rotavirus vaccine. 00:16:03.001 --> 00:16:07.004 But, it really occurred primarily in the 5-9 month-old. So the thinking was that 00:16:07.004 --> 00:16:11.006 now that we were seeing it in 2-3 months of age, when these kids were getting vaccinated, 00:16:11.006 --> 00:16:15.009 that again lent the fact at least the fact that this notion, 00:16:15.009 --> 00:16:20.003 that the, that the vaccine was causing the intussusception was biologically plausible. NOTE Paragraph 00:16:20.834 --> 00:16:24.342 So the way that you answer this, the question, is to do the kinds of study 00:16:24.419 --> 00:16:26.888 that were done by Trudy Murphy and her co-workers, and reported in 00:16:26.919 --> 00:16:29.719 the New England Journal of Medicine. The CDC really took the lead on this. 00:16:29.750 --> 00:16:33.481 Jeff Koplan, who was the head of the CDC at the time, stopped doing some other projects, 00:16:35.253 --> 00:16:38.007 lot of money into this, to see whether or not that association between 00:16:38.007 --> 00:16:42.003 intussusception and vaccination was temporal, or causal. 00:16:42.003 --> 00:16:46.002 And, and you gotta take your hat off to this group. That the minute that they saw something 00:16:46.002 --> 00:16:50.001 that might have been problematic, they, they immediately addressed it, and found that 00:16:50.001 --> 00:16:54.002 if you received the rotavirus vaccine, and your first dose was 00:16:54.002 --> 00:16:58.002 you received your first dose at 1-2 months of age, 00:16:58.002 --> 00:17:02.002 or 3-5 months of age, or 5-8 months of age, that within a week of getting that vaccine, 00:17:02.002 --> 00:17:06.003 you had a 25 to 30 fold increased risk of getting the disease -- 00:17:06.003 --> 00:17:09.007 getting the intussception than if you didn't get the vaccine. 00:17:09.007 --> 00:17:13.004 Similarly, there was a statistically signifigant increase, if you, within 2 weeks of getting the vaccine, 00:17:15.006 --> 00:17:17.007 but not greater than 2 weeks after getting the vaccine. 00:17:17.007 --> 00:17:21.008 So this was supportive of the notion that, the rot-, the intussusception following Rotashield vaccine 00:17:21.008 --> 00:17:26.001 was not a, just a temporal association, but was, in fact, a causal association 00:17:26.001 --> 00:17:30.002 that the vaccine actually was causing this intestinal blockage. 00:17:30.002 --> 00:17:34.007 For that reason, then the company had actually decided to 00:17:34.007 --> 00:17:40.004 withdraw the, the their vaccine from the market and, and that, that was done after 00:17:40.004 --> 00:17:45.007 the vaccine had been on the market for about ten months. Now, you could argue 00:17:45.007 --> 00:17:51.002 that there is a difference between, relative risk and attributable risk. 00:17:51.002 --> 00:17:56.007 Relative risk, as we saw, was 25 to 30 to one, following that vaccine. 00:17:56.007 --> 00:18:00.009 But the real risk or the attributed risk was roughly 1 per 10,000. So let me try and 00:18:00.009 --> 00:18:04.009 give you an example of that. That if I am, if I walk across the street in front of my 00:18:04.009 --> 00:18:08.008 house, I have a certain risk of being hit by a car. That would, no doubt, be much 00:18:08.008 --> 00:18:13.002 greater than the risk than if I was just standing. On the, the just in my doorstep 00:18:13.002 --> 00:18:17.000 in front of my house. And so the relative risk would be very high. It could be a 00:18:17.000 --> 00:18:20.006 1,000 to 1. But still the attributable risk is, is very low. I mean, I cross the 00:18:20.006 --> 00:18:24.004 street in front of my house all the time and don't get hit by a car. That was true here. 00:18:24.004 --> 00:18:28.001 So while the, the relative risk was high, the attributable risk was pretty low. 00:18:28.001 --> 00:18:31.006 Still 1 in 10,000 recipients. And you could argue that if you took a 00:18:31.006 --> 00:18:35.003 theoretical million children who either did or didn't get the vaccine. Far more 00:18:35.003 --> 00:18:39.001 who didn't get the vaccine would have been hospitalized. And, and then frankly, even 00:18:39.001 --> 00:18:43.001 five to ten fold more would have died from not getting the vaccine. Because Rotavirus 00:18:43.001 --> 00:18:47.000 kills children even in this, in the United States. But I think at the time, the 00:18:47.000 --> 00:18:51.009 disease wasn't perceived to be terribly dangerous. Certainly no one wanted to get 00:18:51.009 --> 00:18:57.000 something that you knew could have caused intus susception and there was one child 00:18:57.000 --> 00:19:02.001 who died of intussusception following this vaccine even though six to twelve will die 00:19:02.001 --> 00:19:07.002 from not having received the vaccine among a million children. So you could have made 00:19:07.002 --> 00:19:12.002 the argument that even with that adverse event that still the benefits outweigh the 00:19:12.002 --> 00:19:16.009 risk, but that's not the way that the played out at the time and so the vaccine 00:19:16.009 --> 00:19:21.000 was taken off the market. Now, I think the saddest part of this, and the biggest 00:19:21.000 --> 00:19:25.001 tragedy, is that there was a World Health Organization meeting held in February of 00:19:25.001 --> 00:19:29.000 2000. So it was about four months after the withdrawal of Rotashield from the 00:19:29.000 --> 00:19:32.006 United States, where the company was great. I mean, wyeth made this vaccine, 00:19:32.006 --> 00:19:36.005 stood up and said, we, we, we'll give you the virus, the vaccine strains. We will 00:19:36.005 --> 00:19:40.007 give you, the you know, the technology on how to make it. We will give you the cell 00:19:40.007 --> 00:19:44.001 substrate on which we grew this, thisvaccine. We'll help you build the 00:19:44.001 --> 00:19:48.001 buildings. Because the Wyeth knew that they had a technology that now they were 00:19:48.001 --> 00:19:52.003 not giving to American children. They could've saved. As many as 2000 lives a 00:19:52.003 --> 00:19:56.008 day in the developing world. But, But count-, country after country stood up and 00:19:56.008 --> 00:20:00.004 said, you know, if it's not safe for our children, it not - if it's not safe for 00:20:00.004 --> 00:20:04.001 America's children, then it's not safe for our children, therefore, we're not going 00:20:04.001 --> 00:20:07.007 to, to use it. Even though the risk benefit ratio was obviously very different 00:20:07.007 --> 00:20:11.003 in the developing world. So, I think the tragedy was, if in this whole story, is 00:20:11.003 --> 00:20:14.009 that for seven years, a technology that could have saved a lot of lives in the 00:20:14.009 --> 00:20:18.008 developing world, and certainly even have prevented a lot of suffering in the United 00:20:18.008 --> 00:20:22.009 States, sat on the shelf. And so, two other, companies actually stepped forward 00:20:22.009 --> 00:20:27.001 to make vaccines. One of them was Merkin Company, who, who, in collaboration with, 00:20:27.003 --> 00:20:31.004 researchers at Children's Hospital of Philadelphia, developed this, this next 00:20:31.004 --> 00:20:35.005 vaccine. And again, it used that bovine strain that I talked to you about, that's, 00:20:35.005 --> 00:20:39.008 that's called iii.'Cause we certainly knew that, that virus was safe in children. It 00:20:39.008 --> 00:20:43.009 just didn't seem to be, consistently protective enough to make it a vaccine. 00:20:43.009 --> 00:20:48.006 And so what was done, was the same thing really that was done with the RotaShield 00:20:48.006 --> 00:20:53.003 vaccine, which was to make a series of reassortant vaccines. And again, we talked 00:20:53.003 --> 00:20:58.003 about reassortants to some extent in the in the history of vaccines talk. That 00:20:58.003 --> 00:21:03.002 included those human genes that, that represented those, the, the proteins that 00:21:03.002 --> 00:21:08.001 were responsible for, for a serotypes G1, G2, G3 and G4, as well as one of the, the 00:21:08.001 --> 00:21:12.006 P serotypes, so called P1. So that's, that's what the RotaTeq vaccine was. It 00:21:12.006 --> 00:21:18.009 was given. As three doses by mouth at two, four and six months of age to, to 00:21:18.009 --> 00:21:24.002 children, It's This. Sorry, the, the, the dose was 1.6 *ten^6 plaque forming units* 00:21:24.002 --> 00:21:28.007 per strain. A plaque form unit is, is just when you test a virus. In cell culture, 00:21:28.007 --> 00:21:33.001 the virus can reproduce themselves, and destroy cells, as well as cells in the 00:21:33.001 --> 00:21:37.005 immediate area, which causes this sort of plaque in the, in the or hole in the 00:21:37.005 --> 00:21:41.007 culture, and that's how you determine that. But the important to know here is 00:21:41.007 --> 00:21:46.002 that it was three doses given by mouth at two, four, and six months of age. There 00:21:46.002 --> 00:21:50.005 were some advantages of the bovine strain, because the cows are not as close 00:21:50.007 --> 00:21:55.002 phylogenetically to humans as primates are. The there actually was a. To provide, 00:21:55.003 --> 00:21:59.005 less, for instance of sort of these common less adverse events because of our 00:21:59.005 --> 00:22:03.007 assisted reproduced self as well. So I think the important thing here is, is that 00:22:03.007 --> 00:22:07.009 the vaccine was tested in, in more than 70,000 children prospectively, in eleven 00:22:07.009 --> 00:22:12.002 countries It took four years to do this study, it probably cost about 350 million 00:22:12.002 --> 00:22:16.005 dollars to do the definitive phase three trial of this vaccine. And what was found 00:22:16.005 --> 00:22:20.005 was that the vaccine was capable of preventing any roto virus disease being 00:22:20.005 --> 00:22:24.007 mild, moderate or severe disease at about 74%, which is roughly the equivalent of 00:22:24.007 --> 00:22:27.063 what natural infection capacity is to protect against roto virus disea se. 00:22:27.063 --> 00:22:33.000 Disease, Efficacy against severe disease was 98%, against rotavirus 00:22:33.000 --> 00:22:37.007 hospitalizations 94%, against rotavirus doctor visits 86%, and there was no 00:22:37.007 --> 00:22:42.004 clinically significant increase in fever. Or vomiting or diarrhea. Listlessness, 00:22:42.004 --> 00:22:46.006 lethargy, or poor feeding versus placebo. So, the vaccine appeared to be safe and 00:22:46.006 --> 00:22:50.009 appeared to be effective. Importantly, regarding [inaudible], within fourteen 00:22:50.009 --> 00:22:55.000 days of any dose, there was only one case of in the vaccine group a one in the 00:22:55.000 --> 00:22:59.002 placebo group. Within 42 days of any dose, [inaudible] six, six weeks of any dose, 00:22:59.002 --> 00:23:03.005 there was six in the vaccine group, five in the placebo group. And within one year 00:23:03.005 --> 00:23:07.003 again, twelve in the vaccine and fifteen in the placebo group. So, again, the 00:23:07.003 --> 00:23:11.005 vaccine didn't appear to, to cause [inaudible] or prevent [inaudible]. And so 00:23:11.005 --> 00:23:15.009 those were, And, and we also have post licensure data that I'll talk about a 00:23:15.009 --> 00:23:19.008 little later. [inaudible] has been introduced, this vaccine has been 00:23:19.008 --> 00:23:24.002 introduced into the developing world. Specifically in Nicaragua, Bangladesh, 00:23:24.002 --> 00:23:28.009 Vietnam, Ghana, Mali. And just within this past week Rwanda. And that's a tribute to 00:23:28.009 --> 00:23:33.005 the Bill and Melinda Gates Foundation, who have made that possible. you know, the, 00:23:33.005 --> 00:23:37.008 although the World Health Organization certainly considers all the [inaudible]. 00:23:37.009 --> 00:23:41.006 Caused by rotavirus important and, and worthy of prevention. The World Health 00:23:41.006 --> 00:23:45.002 Organization doesn't really have the money to introduce this vaccine in the 00:23:45.002 --> 00:23:49.002 developing world and, and frankly or the countries, the countries also don't have 00:23:49.002 --> 00:23:53.002 the money. So, that Bill and Melinda Gates choose to spend their money by preventing 00:23:53.002 --> 00:23:57.001 a disease which causes a lot of suffering and death in the developing world is a 00:23:57.001 --> 00:24:00.007 tribute to them. Now there's, there's another rotavirus vaccine that, that's, 00:24:00.009 --> 00:24:05.000 that's developed, that was developed by researchers at Children's Hospital in 00:24:05.000 --> 00:24:09.000 Cincinnati specifically Dick Ward and David Bernstein, using the more classic 00:24:09.000 --> 00:24:13.001 way of making a vaccine, a live weakened. Vaccine, which was to take the vi rus, and 00:24:13.001 --> 00:24:17.006 serially [inaudible] in non human cells as a way of attenuating it. This vaccine is 00:24:17.006 --> 00:24:21.005 given as two doses by mouth, which is an advantage. It's one fewer dose. At two, 00:24:21.005 --> 00:24:25.008 two to three, and then four to five months of age. It's given at a somewhat lesser, 00:24:26.000 --> 00:24:29.008 dose. Because the virus is, is a human virus. So therefore, somewhat better at 00:24:29.008 --> 00:24:33.006 reproducing itself in the intestine than the bovine strain was. The, the 00:24:33.006 --> 00:24:37.002 researchers at children's hospital in Cincinatti, in collaboration with 00:24:37.002 --> 00:24:41.004 GlaxoSmithKline, did a study of, 60, more than 63,000 infants who were given this 00:24:41.004 --> 00:24:45.005 vaccine at two to four months of age. And the studies were performed in Latin 00:24:45.005 --> 00:24:50.005 American countries as well as Finland and the vaccine worked very well, preventing a 00:24:50.005 --> 00:24:54.008 severe disease about a, [inaudible] an efficacy rate of 85 percent and preventing 00:24:54.054 --> 00:24:59.005 80, hospitalizations at a rate of about 85%. Rotateq. Was introduced in the United 00:24:59.005 --> 00:25:03.006 States in 2006. Rotarix in the United States in 2008. Although Rotarix was 00:25:03.006 --> 00:25:08.001 introduced in the developing world also in 2-, 2006. And, what we found was that. 00:25:08.003 --> 00:25:12.004 there was a 50, even in the US, 50 percent immunization rate causing 80 to 90 percent 00:25:12.004 --> 00:25:17.000 reduction in hospitalization. So it's a there is her immunity that is being 00:25:17.000 --> 00:25:21.060 induced by these two vaccines. So, so what about an [inaudible]. Why this, the Rota 00:25:21.060 --> 00:25:26.009 Virus vaccine, why did Rota shield cause an [inaudible] interest. There were data 00:25:26.009 --> 00:25:31.003 presented from Brazil, Mexico, Australia and the United States on October 00:25:31.003 --> 00:25:36.002 twenty-eighth, 2000 [inaudible] that show the [inaudible] was actually was a rare 00:25:36.002 --> 00:25:40.009 consequence Rota risk in Mexico and Australia. Not at the one in 10,000 level 00:25:40.009 --> 00:25:46.001 that was seen for Rota, Rota Shield. But, but more an attributable risk of one per 00:25:46.001 --> 00:25:50.006 60,000 or 90,000 doses. And also, for RotaTeq as well, intussusception was a 00:25:50.006 --> 00:25:55.004 rare consequence in Australia, with an attributable risk again between sort of, 00:25:55.004 --> 00:25:59.009 60,000 and 90,000 doses. So it now looks like all three Rotavirus vaccines, 00:25:59.009 --> 00:26:04.006 including Rotarix, which is simply an attenuated human Rotavirus strain, causes 00:26:04.006 --> 00:26:09.003 intussusceptio N. So it sort of causes us to re-evaluate why. Rotashield caused 00:26:09.003 --> 00:26:14.003 intussusception, I think the most likely reason is that natural rotavirus infection 00:26:14.003 --> 00:26:19.000 is also a rare cause of intussusception. So then the question becomes which is 00:26:19.000 --> 00:26:23.004 rarer, Intussusception caused by. By the vaccine, or intussusception caused by the 00:26:23.004 --> 00:26:26.009 disease. Because remember the vaccine prevents the disease. So if, if 00:26:26.009 --> 00:26:31.004 intussusception caused by the, the vaccine is more common than intussusception caused 00:26:31.004 --> 00:26:35.008 by the. The, the natural virus, then, the rates of interception should go up in 00:26:35.008 --> 00:26:40.003 countries that use the vaccine. Conversely if, if interception caused by the. The 00:26:40.003 --> 00:26:44.000 natural virus is more common, then [inaudible] caused by the vaccine, given 00:26:44.000 --> 00:26:47.004 that the vaccine prevents natural infection. Then as you introduce the 00:26:47.004 --> 00:26:51.001 vaccine, rates of [inaudible] should, should go down. And sort of all of the 00:26:51.001 --> 00:26:55.000 evidence to date, is it certainly raises the [inaudible], the [inaudible] seem to 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 00:26:59.001 --> 00:27:03.002 what we've learned is that in the long run, that [inaudible] is probably is a 00:27:03.002 --> 00:27:07.003 consequence of the natural infection. It's probably to some extent prevented by, by 00:27:07.003 --> 00:27:11.001 vaccination. I mean it's interesting to know what, what, what had happened if we 00:27:11.001 --> 00:27:15.001 had found out that [inaudible] shield had caused [inaudible]. This is after four 00:27:15.001 --> 00:27:18.004 years after it had already been introduced. Because now, we know that 00:27:18.004 --> 00:27:22.004 rotarix and rota, rotatech are two more recent vaccines for saving lives in the 00:27:22.004 --> 00:27:26.001 developing world are certainly preventing hospitalizations and suffering in 00:27:26.001 --> 00:27:29.009 developed countries like the United States. I wondered whether we would have 00:27:29.009 --> 00:27:34.002 still made the same decision rotashield that we found out that it was a rare cause 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