Dr. Walter Orenstein

 Walter Orenstein

TORGHELE: It is August 31, 2016. I am Karen Torghele, and I'm at the Centers for Disease Control and Prevention with Dr. Walter Orenstein today to talk about CDC's history and polio for the Global Health Chronicles Oral History Project. Dr. Walter A. Orenstein is currently associate director for the Emory Vaccine Center and professor of medicine, pediatrics and global health at Emory University. Dr. Orenstein has had a long and distinguished career at the Centers for Disease Control and Prevention, Emory University, and the Bill & Melinda Gates Foundation. Between 1988 and 2004, he was director of the United States Immunization Program, rising to become an Assistant Surgeon General of the United States Public Health Service. Welcome, Dr. Orenstein.

ORENSTEIN: Thank you very much, Karen.

TORGHELE: To start, would you tell us a little bit about your background before you came to CDC, and how you came to work here in the first place?

ORENSTEIN: I went to medical school and was interested in pediatrics. I was specifically interested in pediatric nephrology. I had been interested in chemistry. But I had a cousin who—his name was [Dr.] Harry Rubin—was an EIS officer in 1956, and he was the doctor in the family, and I wanted to get some advice. And he strongly recommended that I do a two-year rotation at CDC [Centers for Disease Control and Prevention] in the EIS [Epidemic Intelligence Service], and I said okay. My intent was to go back into pediatric nephrology and live my whole life in San Francisco. And what happened was I volunteered to work in India on smallpox eradication, and I saw this terrible disease with a 30% death-to-case ratio disappear before my eyes, and I decided vaccines were a powerful tool and therefore made a career in vaccinology and trained in infectious diseases and then came back to CDC in the immunization program. So, overall, I worked for 26 years at CDC.

TORGHELE: So you had personal experience—you knew about CDC before you applied for EIS?

ORENSTEIN: Correct. I knew about CDC through my cousin, who just described what he did. Now, to be honest with you, what really intrigued me—I had grown up in the Bronx, I lived at home at college, and I went to City College of New York, went to medical school about a mile from where I grew up, at Albert Einstein [College of Medicine]—what really intrigued me is he said you really got to travel. And that really played a big role in saying, Wow, I want to travel. And that's why I volunteered for the Smallpox Eradication Program in India, was also just to see the world. And at the time, you could go around the world with a Pan Am flight, and so I arranged an around-the-world trip that at the time I went over to India, because I just wanted to see the world.

TORGHELE: So you got interested in immunization with your very first experience at CDC.

ORENSTEIN: Yes. What happened was, I wanted to live on the West Coast. I lived in San Francisco before I came, and that's where I thought I wanted to live my life. At that time, you ranked your choices once you got into the EIS in a matching program, although it wasn't a strict match, and they had a rule that you couldn't have an assignment within thirty miles or something like that, so I couldn't go to the vacant spot in Berkeley, but Los Angeles was my first choice. My second choice—I'm trying to remember—one was Phoenix Labs and one was Denver, but one was two and one was three. And then I said, Well, I guess I ought to put an Atlanta choice in, and as a pediatrician, I said, What is really relevant to pediatrics? And that was immunization. So that's how I chose. Immunization was my fourth choice. So I was disappointed I got my fourth choice, but obviously it changed my career and my life.

TORGHELE: So, talk a little bit about your experience in India. That must have been an amazing time.

ORENSTEIN: It was miraculous. I mean, I got there toward the very end of smallpox eradication, and I got to work in two different areas, which were quite different. One was a rural area in the villages. And what we would do is look for cases, and then I would gather the village around me and I would vaccinate myself to show I wasn't afraid, and then we would get the village vaccinated. Then we went to a place called Aligarh, which was the second two months of the four-month assignment. And Aligarh was a city not too far from Agra, where the Taj Mahal is, and not too far from Delhi, and that was a much more difficult area, that's where we had cases in the slums.

But what I had in Aligarh is the last case of smallpox in Uttar Pradesh. She was a seven-month-old girl. Her name was Shanti, daughter of Pyari Lal. And what's really sad is she died from a late complication of smallpox, late hemorrhagic, where they hemorrhage into the skin lesions. It was just really sad. But it turned out to be the last case in Uttar Pradesh, which is India's largest state in population, in north central India. So it was invigorating. And, in a sense, eradication is an achievement of immortality, because it's basically a gift from the generation that achieves it to every future generation, and we don't have to be worried about the disease. And that really changed my whole life.

TORGHELE: Must have been an amazing experience.

ORENSTEIN: Yeah, it was an amazing experience. And the people I got to work with were just outstanding, very dedicated, very hardworking, having to deal with difficult situations—distrust, conspiracy theories, and the like—and having to overcome them. So it was just a wonderful experience, to help bring people together and accomplish something as great as we did.

TORGHELE: So that's how you got started with immunization.

ORENSTEIN: Yes.

TORGHELE: How, specifically, did you get involved with polio?

ORENSTEIN: Polio came a little bit later. Initially, in my career, mumps and then measles was my focus. And then I left CDC for three years and focused on my training. I finished my pediatrics training in pediatric infectious diseases. I came back to the Division of Immunization, and in the early 1980s we were given responsibility for polio. So initially my focus was completely on domestic polio, achieving high immunization rates and making sure we didn't have an outbreak. And then as the polio eradication effort started going forward, I got involved with the polio eradication effort. But a big focus initially was the domestic immunization, and immunization policymaking with regard to which of the two polio vaccines—inactivated polio vaccine or the live attenuated oral polio vaccine, the Salk versus the Sabin—and how we changed, and I was intimately involved with that.

TORGHELE: Going back to your EIS years for just a minute—you had the EIS course, and do you remember much about the course and how it prepared you for the work that you later did?

ORENSTEIN: The course, I remember, was really good, because it was very problem-oriented, and I remember getting very involved. It was not just lectures. You really had to think through problems. And I later taught one of the EIS courses, which was even more helpful in terms of preparing for it. But trying to understand what epidemiology is, what surveillance is, how to do an outbreak investigation—all of that was extremely helpful to me in gearing me up for my career.

TORGHELE: Do you remember some of your teachers?

ORENSTEIN: Well, [Dr. Philip] Phil Brachman was the head of the EIS at that time. I think that there were various people who played a role in it. My initial supervisor, who was one year ahead of me in the EIS, was [Dr.] John Modlin, who is now at the Bill & Melinda Gates Foundation and a former chair of the Advisory Committee on Immunization Practices or ACIP. He was extremely helpful. The other teachers—[Dr. J.] Lyle Conrad, who was involved in state services. And then, probably my major mentor who really focused me was [Dr. Donald P.] Don Francis. Don was my supervisor in India, and he was just superlative. And he focused me on measles, which, again, was my initial area of focus, and played a role—I would continue to consult with him. And the other one that really was a good mentor was [Dr. William H.] Bill Foege, so I got to talk with him and work with him. And this was really on measles, not polio, which was because, I think, both Don and Bill had worked in Africa on smallpox. And in Africa, a major draw was measles more than smallpox, and measles was a big killer. And so their hope was eventually that maybe we could get into a measles eradication program. So measles played a big role in my early career, and then polio subsequently.

TORGHELE: You had some exceptional mentoring.

ORENSTEIN: Yes.

TORGHELE: So when you began your work with polio, a lot of the history of polio with CDC had happened earlier. And I wondered if you had been told this history or if you knew about the—

ORENSTEIN: I knew vaguely about the history. I knew the importance of the Cutter incident, and what I remember being told by [Dr. Alexander D.] Alex Langmuir is that that played a big role in CDC getting surveillance responsibilities. I knew polio was important to the overall immunization program. And one of the more important parts with the whole issue is informed consent. There was a lawsuit, a very famous lawsuit, Reyes v. Wyeth, in which a family of an individual who was paralyzed after receiving oral polio vaccine sued the manufacturer, Wyeth, and won the suit. The basis of the suit was failure to inform in a public health program that one of the risks of getting the oral vaccine was developing vaccine-associated paralytic polio. And this led to a contract with the manufacturer where in public health clinics we had to develop something called Vaccine Information Statements, or Important Information Statements, to be given to people to give informed consent. There was less of a concern in a private practice setting where there was an individual physician, but there was concern in a public health setting. So I was well aware of the importance and the precedent that polio set, in terms of informed consent and just providing information, which later became a legal requirement when the National Vaccine Injury Compensation Program law was passed.

TORGHELE: Can you talk a little bit about how you think polio changed the direction CDC took, or maybe how polio affected CDC and CDC affected polio?

ORENSTEIN: I think polio played a major role in CDC. I've already mentioned the whole issue of providing information to people. This became, then, a cornerstone of the program for all vaccines when the National Vaccine Injury Compensation Program began in the late 1980s. Polio was such a motivating force because it was such a fearful disease, and I think it helped build the structure and was a major focus of the funding we provided through our 317 Immunization Grant funding to states for polio.

And I think another major issue with polio was the discovery of vaccine-associated paralytic polio, which preceded me. It was actually discovered not too long after the oral polio vaccine was licensed and used. And there were major debates, over a prolonged period, of what was the appropriate vaccine to use in the United States—the oral polio vaccine, which can rarely cause associated paralytic polio, or the inactivated polio vaccine, which did not. And CDC got involved first in the 1950s with the inactivated vaccine, and then, when the oral vaccine became available in the early 1960s, gave a preference to the oral vaccine, and in fact was a major champion for the oral polio vaccine despite the cases of vaccine-associated paralytic polio.

I think CDC also became involved in eliminating polio before there was a global polio eradication goal. The Pan American Health Organization in 1985 embarked on an effort to eliminate polio in the Western Hemisphere, and CDC was heavily involved in that. So, I think, from a policy point of view, CDC was very involved in polio. It was a fundamental part of our immunization program. We were involved in surveillance, and particularly one of the things that CDC did that was extremely important is the development of the field of molecular epidemiology. This became important in trying to track and relate viruses, and it is still playing a major role today in the Global Polio Eradication Program. What it does is it basically fingerprints viruses and allows you to determine, if you find a virus in location A and a virus in location B, how closely related those viruses are, which would suggest one might have been transported from one place to another. On the other hand, if they were very different, it would suggest their sources were different. So the whole field of molecular virology was another major contribution CDC has made to—particularly—the Global Polio Eradication Program.

TORGHELE: And those techniques in molecular biology were developed here within CDC?

ORENSTEIN: Correct, they were developed here. [Dr. Olen M.] Kew, in particular, played a major role, and [Dr.] Mark Pallansch, and there were others who were involved in developing molecular epidemiology. What it is, as it turns out, that the poliovirus—there are certain parts of it that can change. And what was found is in the VP1 capsid protein—which is a little less than 1,000 nucleotides—that you can get about 1% change per year, and that's how you could look at the relatedness. And most of them were synonymous changes—that is, they didn't change the amino acid structure and they weren't involved in immunity induction. Immunity induction by the vaccines was against a different area that was constant, and so it didn't affect that. But you could, in a sense, fingerprint the virus by looking at how many genetic changes in the nucleotides there were from virus to virus, which could let you know how much silent circulation there was and where it came from.

TORGHELE: So you could tell the difference from a vaccine-introduced virus, from a wild virus, and from somewhere else?

ORENSTEIN: First of all, you could look at vaccine virus versus wild virus, but you could do even more than that. You could look, among the wild viruses, how closely they were related to one another. So you could geographically pinpoint where a source may have come from, or whether this was similar to a prior virus, suggesting prolonged local circulation. And you could, again, if you had a virus that was more than 3% difference, for example, an orphan virus that would suggest up to three years of undetected circulation. So you could also evaluate the quality of your surveillance program. I may be not absolutely correct on the definition of orphan, but you could look at orphan viruses as a way of looking at the quality of surveillance. And that's been a very, very important tool in the Global Eradication Program.

TORGHELE: It must have been like breaking a secret code.

ORENSTEIN: Exactly. And so the other thing that the molecular epidemiology helped with is the issue of vaccines, and helping to identify, when you had a virus, if it was vaccine-like or wild, but also something called circulating vaccine-derived polioviruses, which are Sabin viruses—the oral vaccine virus—that gets passed from person to person and then mutates and reacquires the phenotypic properties of the wild virus, both transmissibility and neurovirulence. And that's been another major benefit of the tool of molecular virology, or of molecular epidemiology, I should say.

TORGHELE: When the discovery related to molecular biology and polio was introduced, how was that done within the scientific community? And was there trouble with scientists accepting it?

ORENSTEIN: I am not aware of any problems with acceptance. And it was published in the medical literature. CDC was one of the few places doing it at the time, and I think it played just a major role in trying to understand where polio outbreaks came from. And what's become very important is seeing that chains of virus are extinguished as we move to eradication. And it helps us in trying to understand, when we get a new outbreak somewhere, whether it's been undetected domestic virus that has been there for quite a while, or whether it's a new introduction from somewhere else. So, for example, we've recently detected virus from Nigeria, a wild poliovirus type 1. And molecular epidemiology or molecular virology has basically shown us that this was virus from Nigeria that had been potentially circulating for several years undetected, raising concerns about the quality of surveillance. So it helps us focus on, we need to do better in terms of surveillance in that particular area.

TORGHELE: So it helps you crosscheck for accuracy in surveillance?

ORENSTEIN: Yeah. The purpose of surveillance, particularly in eradication, is to detect every infection and to ensure, when you don't detect it, that the virus is gone. When you do detect one when you haven't for a while, if it's closely related to a virus from somewhere else, that would suggest a new introduction, and your surveillance is working well. However, if it's distantly related to any viruses currently circulating, and is most closely related to something found several years ago in your own area, it raises serious concerns that there has been prolonged silent transmission and that your surveillance system missed it. So that's where molecular virology or molecular epidemiology can play a big role in trying to strengthen the overall eradication program.

TORGHELE: That must have been a very helpful tool.

ORENSTEIN: It was and is a very, very helpful tool.

TORGHELE: Talking about where polio is, before your time there were polio outbreaks in this country; there were outbreaks other places still after you came. Were you ever a participant in any of those outbreaks?

ORENSTEIN: The first outbreak that I was involved with was an outbreak in 1988 in Israel. Israel had some problems in certain parts of it where there was a substantial rate of oral polio vaccine failure and they, in these selected populations, switched to the inactivated polio vaccine—the Salk vaccine—because they thought it would be more effective. And then they had an outbreak in these same areas. The kids who got the Salk vaccine didn't come down with polio, but older individuals who had been vaccinated years earlier with the oral vaccine were coming down with polio.

And so there was a great debate as to whether the older individuals were transmitting to each other, or whether the children who got the inactivated polio vaccine were protected from paralysis—in other words, that their central nervous systems were protected, but they were still getting infected, shedding the virus and infecting others whose central nervous systems were unprotected, the oral vaccine failures. And in fact, we had an interesting article that appeared in the Lancet that had a single agreement about what the facts were, and two discussions. I was involved in the discussion that the thinking was the inactivated polio vaccine was protecting against paralysis but not against transmission, and the other group said the problem was the oral vaccine in the older people and it was older people transmitting. Neither of us had data to support the hypothesis, but it played a big role in my thinking that the U.S. should use oral vaccine, and made me somewhat negative about the inactivated polio vaccine at the time.

And that changed dramatically in '95 or 1996. What happened was, we were seeing somewhere between eight and ten people a year paralyzed in the U.S. with what was called vaccine-associated paralytic polio, which was caused by the oral Sabin vaccine. It was controversial because Albert Sabin, I think until the day he died, didn't believe that these were vaccine-associated polio. And it was [Dr. Lawrence] Larry Schonberger who suggested an analysis which played a very important role. And his argument was, if this was coincidence, then the distribution of these cases should be independent of dose number—it could be dose one, dose two, dose three, dose four. On the other hand, if the oral vaccine was playing a role, then we ought to see more of the cases with dose one, because that's when the individuals vaccinated or their contacts are susceptible. And lo and behold, we saw the great majority of cases followed dose one, so it helped support the role.

Nevertheless, we felt that it was better to use the oral vaccine for the following reasons: One, it was easy to give, and so if there was any reticence to get injections, we could point to it was oral. Two, it induced better intestinal immunity. And poliovirus, when ingested, gets shed in the stool, and there was—particularly in developing countries, but even in industrialized countries, there were concerns about fecal-oral spread. And third is that people can shed the virus in their stool—the vaccine virus—and passively immunize people we weren't reaching in our immunization program. And in fact, we had data, particularly from inner-city Detroit and Houston, showing a substantial proportion of unvaccinated kids had polio antibodies through this passive spread. So for those reasons, we really supported the oral vaccine. At that time, we didn't know about these circulating vaccine-derived polioviruses, these vaccine viruses that acquired both the transmissibility and neurovirulence of wild viruses and caused the outbreaks. We didn't know that. But for those other reasons we preferred the oral vaccine virus.

And then in 1995 or '96, someone got many of these VAPP [vaccine-associated paralytic polio] cases to come to the ACIP [Advisory Committee on Immunization Practices], and we had a room full of these horribly crippled people as a result of the oral vaccine, and so what I had trivialized through the small numbers became real people with real illness. And I, in a sense, went over almost overnight from being an oral polio vaccine—an OPV [oral polio vaccine] hawk to an IPV [inactivated polio vaccine] hawk, because here were these people who were paralyzed, some horribly paralyzed, who had a perfectly safe alternative. And what we did in 1997 is we adopted, initially, a sequential schedule, hoping to get the benefits of both vaccines. And that included starting with inactivated vaccine—two doses of the Salk IPV—followed by two doses of the oral vaccine, to prevent VAPP but also to get the benefits of the oral vaccine. But what we found is that a number of physicians were still using the oral vaccine first, so even though VAPP had come down, we were still seeing cases of VAPP. And that's why, in 2000, we went to an all-IPV schedule to completely avoid the occurrence of vaccine-associated paralytic polio, or VAPP.

TORGHELE: Can you talk a little bit about how that process happens—how the decisions are made, which version of the vaccine to use—and then how that's adopted within the medical community?

ORENSTEIN: The decision is made by the Advisory Committee on Immunization Practices, or ACIP. Now, the CDC can reject an ACIP decision, but in my experience, I only remember that once. And it wasn't really a rejection, it was an issue of smallpox preparedness in the run-up to the Iraq War, and the need to vaccinate. And the ACIP gave a narrower population to target for vaccination, and the Department of Health and Human Services wanted to vaccinate more, so what they said is, they accepted the ACIP recommendation and added to it. But the ACIP is a process, and what you balance is several things—you balance risks and benefits, cost-effectiveness is figured in, and moral values.

For the polio decision, the moral value issue really took precedence, because the cost of the inactivated polio vaccine, or the Salk vaccine, was substantially more than the oral vaccine. And we calculated that the cost per case prevented by the switch—the case of VAPP prevented by the switch—was roughly $3 million per case prevented. But we felt that, morally and ethically, to deny the inactivated vaccine to people who had this choice—that appeared to be as close to perfectly safe as possible—was wrong. So the ACIP recommended—again, initially—the sequential schedule, to try and get the benefits of both, and then, eventually, the IPV. It also was thought that we also strengthened people's faith in the immunization system, to know that we are willing—because of moral and ethical issues—to pay that much per case prevented, because that, for our overall population, was the best.

Now, the big fear and the big unknown was, Would we get everybody vaccinated with the OPV? In other words, since it was later in the schedule, would we miss out, would we have some just IPV-vaccinated kids? And did we really need that OPV-induced immunity, and were we going to get outbreaks? I always like to say it's so much easier to be a historian than to have to make history. It's so much easier to know in retrospect what it is, but that's the gamble we took. And if we certainly had outbreaks, we would have been really blasted for that. But it turned out we didn't have outbreaks, and we've done very well with an IPV-only schedule. I just couldn't look those people in the eye, when they had a perfectly safe alternative, and cause anybody else to be crippled. So I was a strong proponent of the change in schedule.

TORGHELE: I'm trying to envision what those meetings would be like. I assume there were camps of people who were for one or the other. Can you talk about how that works?

ORENSTEIN: Exactly. First of all, the ACIP meetings are completely open. Press can be there, as well as others. And yes, there were people who felt very strongly that this was a mistake, that here we had basically our last outbreak of polio in the U.S.—was in 1979 in the Amish population, which was unvaccinated—and even before that we really didn't have much polio. And they felt that the oral vaccine properties, the ones I mentioned—the passive spread, so we were immunizing people we weren't reaching in the Immunization Program, the better intestinal immunity, and, potentially, the better vaccine acceptance, because it was oral and not requiring an injection—is what led us to this great record in preventing wild virus polio outbreaks in the United States. And so there was real fear that we would get outbreaks, and people felt very, very strongly about that, and they would speak up at the ACIP. And then you had the other group of people, who were saying that, here was this vaccine that we were acknowledging was causing damage to people, and hence we ought to get rid of it.

Now, the pro-OPV group—at that time we had a Vaccine Injury Compensation Program, so at least those who were injured by the oral vaccine could receive compensation, and that was—the pro-OPVers say, we do have something to compensate people who were injured. And the pro-IPVers said, we don't want to injure them and then compensate them, we want to prevent the injuries, and that's what IPV will do. And certainly no one argued for the individual that IPV was better. The big question is, for society, was IPV better? And that's why we went to the sequential schedule first, to get benefits of both vaccines.

TORGHELE: There must have been some pretty heated discussions.

ORENSTEIN: Yeah, there was some heated discussions, and very emotional discussions, because data can take you only so far, and nobody really knew, on either side, whether we would get outbreaks or not. I mean, it's not something you know for sure. You can make some predictions. And with the pro-sequential schedule, the feeling is we would avoid outbreaks. And the pro-OPV only, feeling we would get outbreaks. But those are things you don't know. And had the sequential schedule or pro-IPV group been wrong, as I said, there would have been a lot of blame cast, and cast aspersions to, and saying, See, you had these properties of the oral vaccine that you gave up on—the intestinal immunity, the passive spread, perhaps better uptake because it was an oral vaccine. We would have clearly been blamed if, in fact, we had outbreaks. And no one knew for sure. We just had to gamble on it. I think that's probably like a lot of decision-making—you don't always get all the data and information you want at the time you make your decision. You have to do your best decision with what you have. And we could have been wrong.

TORGHELE: So it turned out to be the right decision.

ORENSTEIN: It turned out to be the right decision. And we went all-IPV, and we haven't had any outbreaks of polio since we've been on an all-IPV schedule, which has been now—starting in the beginning of 2000, so we're almost sixteen full years, or almost seventeen—say we've done sixteen full years.

TORGHELE: You talked about Dr. Sabin not ever accepting that there were vaccine-associated cases. Did you know Dr. Salk and Dr. Sabin?

ORENSTEIN: I got to meet both of them. They were both brilliant. I must say that Jonas was gentler than Albert, and tried to make the case multiple times of the importance of IPV. This was before the change in policy—this was in the 1980s—and we rejected his recommendations because at the time we thought OPV was the way to go. But I think he made good arguments for his case. We just didn't want to switch when we had been so successful in preventing outbreaks of polio. Albert was much more boisterous and bombastic, in a sense, than Jonas. I will never forget, we had one meeting at the Pan American Health Organization in the 1980s where both of them were, and the issue at that time for the whole Western Hemisphere is, Should we go OPV, IPV or some combination of both? And the last session had both Jonas and Albert in there with some others. And I will never forget Jonas saying, There's one thing upon which I believe Albert and I can agree: there is only need for one vaccine. And the whole place just cracked up. So I think Jonas had a better sense of humor.

Albert, though, was absolutely brilliant, and from an academic perspective, he was the most respected one. And I remember his work on measles—which is where I spent most of my career—where he looked at the experience with the oral vaccine and played a pioneering role in trying to develop a measles vaccine that could be given mucosally instead of by injection, and could be given while children still had maternal antibody, which interfered with the response to measles vaccine. The example with the oral polio vaccine is that even though babies had from their mother's antibody that had been transferred that could protect them from polio disease, that you could still infect them and induce an immune response with the oral polio vaccine. And he tried to apply that to measles. Measles was an injectable vaccine at the time, and the greatest risk factor for vaccine failure was the presence of maternal antibody, so you had to wait until maternal antibody waned before you could vaccinate. But with Albert's technique, there was the theoretical potential of being able to vaccinate children even earlier, while they still had maternal antibody, and protect them when measles is most serious. Now it turned out that it hasn't worked out, but there were some studies that suggested that that would be very helpful.

All I'm trying to make the point is that Albert was a real thinker, and from a scientific perspective was probably super respected. But to me, Jonas Salk did remarkable work and was, in my opinion, an outstanding scientist and an outstanding public health person. But it took those cases at the ACIP meeting to really change our policy.

TORGHELE: Now, there's been another change, too, since then.

ORENSTEIN: There's been a change—not domestically in the U.S., but a change globally. Most of the developing world uses oral polio vaccine for several reasons. One, it's much cheaper. The inactivated vaccine is at least five times—and generally more—expensive than the oral vaccine. Number two is that it is oral and it's easier to give. Number three, the virus—the wild poliovirus—particularly in developing countries, where one is concerned about poor hygiene and sanitation, is thought to spread particularly through the fecal-oral route, which the oral vaccine virus is better at preventing.

What has changed with policy is the recognition that the oral vaccine not only can cause VAPP, but in 2000 in an outbreak of Hispaniola, can cause what's called circulating vaccine-derived polioviruses, or cVDPVs, and these can cause outbreaks. We've recognized that the type 2 virus—there are three types, 1, 2 and 3—that the last natural outbreak of wild type 2 virus was in 1999, interestingly, in Aligarh, India, where I worked on smallpox and had the last case of smallpox in Uttar Pradesh. So the last case of wild type 2 was 1999, and then we were getting cases of VAPP from type 2, and we were getting loads—not loads, but outbreaks—of type 2 and cVDPVs, circulating vaccine-derived polioviruses. More than 90% of the outbreaks in recent years were type 2. So what has been accomplished very recently is the introduction of IPV into developing country immunization programs, to both boost immunity for types 1 and 3, which are not yet eradicated—wild virus polio—as well as to provide an insurance policy of some immunity to type 2 virus. And removing the type 2 component from the oral vaccine, so that we now give only bivalent type 1, 3 oral vaccine, and we no longer use the trivalent oral polio vaccine.

TORGHELE: When a change like that happens, how does it get coordinated? It's hard to imagine.

ORENSTEIN: Well, a change like that has never happened before, so this is the first time. And this is just an amazing effort that was led by the World Health Organization and the Global Polio Eradication Initiative partners, which includes CDC, it includes Rotary International, includes UNICEF [United Nations Children's Fund] and it also includes groups like the Bill & Melinda Gates Foundation, who played a major role, and others, I'm probably blanking on a couple of them. But what was done is, one, getting the recommendation from the global advisory groups, which is the Strategic Advisory Group of Experts on immunization, or SAGE, for the World Health Organization. It was making a recommendation of how the IPV should be used. It was working with the World Health Assembly to get a resolution. It was working with regional WHO [World Health Organization] and UNICEF offices to get their technical people on board. It was training them—then, in turn, them training the national people, and the national people training the local people. It was working with the manufacturers to get them to stop producing the trivalent oral vaccine. It was working with groups to collect and destroy the trivalent oral vaccine. And it was sending independent monitors in to verify that the oral vaccine—the trivalent oral vaccine—was no longer there and no longer being used, and that they were using IPV according to the schedule.

I cannot think of anything in the annals of immunization that can match this change. I believe this is over 100 countries. Much of the industrialized world was already—such as the U.S.—on an all-IPV schedule, but for the developing world it was a big, big change. And it required all this independent monitoring and taking action when there are problems, things like, also, how to incinerate or destroy the trivalent oral polio vaccine that was collected. So it is a remarkable achievement. And the reason you had to destroy it is, the major risk factor for emergence of the cVDPV is low immunity in the population. If you're no longer using the trivalent vaccine, your immunity to type 2 is reduced. The IPV provides some insurance, but not 100% insurance. And if somebody is using the type 2 oral vaccine, they can then seed your population and facilitate this chain of transmission and mutation to regain the neurovirulence and transmissibility properties that lead to outbreaks of polio. So that's why it needed to be simultaneously, synchronously coordinated. And that's what was done over a two-week period, is the tOPV [trivalent oral polio vaccine] to bOPV [bivalent oral polio vaccine] switch. Two weeks.

TORGHELE: So you have public agencies, you have private agencies, you have 100 different countries, and this change that had to be coordinated perfectly, and the procedures had to be done according to a certain schedule and specification. And it's been successful.

ORENSTEIN: Correct. Correct. It is remarkable that the world can work together to achieve it. I think the big issues clearly were at the national level, where the big stores of the trivalent vaccine had to be destroyed. And then there were monitors who went out to the periphery. Now, they didn't necessarily inspect every clinic, but they inspected a lot of them, but the major reservoirs were all inspected. And they needed to be independent monitors. And again, in so many countries in a two-week period, I mean—It sets a precedent, I think, hopefully, for other kinds of areas where the world can unite against the common enemy like the poliovirus.

TORGHELE: So now that you know that it can be done, you can use it in other situations?

ORENSTEIN: Right, that's the hope. And we'll have to do it again when we eradicate type 1 and 3, because the goal is to stop all use of the oral polio vaccine. And that's because if you look at it, that would be a risk of the cVDPVs for type 1 and type 3. And so we'll have to do the same thing all over again when type 1 and 3 are declared eradicated.

TORGHELE: So does the infrastructure to do what you've already done stay in place?

ORENSTEIN: Well, that's one of the big issues, is—there has been a lot of support from external donors, for example, for the polio program. I think at the moment, I think we're in good shape through eradication of wild virus, but we clearly need the donors to stay in through that.

The question then that comes up is, What is the insurance policy that we don't have a return of polio? Because there are some things that are going on now—for example, there is a global effort to contain the type 2 polioviruses. This includes the wild and the vaccine viruses. And so we don't want any laboratories other than what has been called essential polio laboratories, which have to meet criteria to have these viruses, because—to give you an example, everybody talks about the last case of smallpox being in 1977 in Merca, Somalia, Ali Maow Maalin. Well, the actual last cases of smallpox were two cases in the United Kingdom in 1978 as a result of a laboratory break in containment. So, with polio, it's critical to assure we don't get the virus reintroduced over time. And, in fact, I say that the last wild type 2 was in Aligarh in 1999. That's true if you say the last naturally occurring. There was actually a wild type 2 introduced in 2002 or 2003 in northern India from a laboratory strain of wild virus. They got rid of it, but we need to make sure we don't get a reintroduction from laboratories. So laboratory containment is one issue.

Another risk to eradication is that it turns out some people with severe immune deficiencies can be chronically infected and shed [virus]. And so there is an effort to, one, identify them, and two, to develop antiviral drugs to stop their shedding. And then there is the potential of bioterrorism in terms of synthesizing the viruses, although that's probably very unlikely in the sense that there are a lot of other agents that would probably be better bioterrorist tools than the poliovirus. And so the other thing that needs to be maintained, though, is the response capacity if—in fact, at some point, for whatever reason—viruses are introduced. So that needs to be built. So we need to have a stockpile of vaccine to use just in case there is a reintroduction, and we need to train people in how to respond, just in case. So, a very, very unlikely event, but a potential high-consequence event. And so that will be, as we move forward, trying to develop those capacities.

TORGHELE: So you anticipate issues.

ORENSTEIN: Yes.

TORGHELE: And come up with solutions before they happen?

ORENSTEIN: Correct. Exactly. Exactly, because for example, even now we have a type 2 stockpile of oral vaccine to potentially be used if a type 2 virus emerges. Because if we didn't have any vaccine, we'd be in big, big trouble. So while we don't think that will happen, we have to be prepared just in case it does. And again, eradication is the permanent absence. And that's what we hope will be achieved, and certainly has been achieved for smallpox. But with polio, we have to be prepared just in case there is a leak, even years later. I mean, the chances are slim, very slim. And we need to make them as slim as possible, and that's why we need to do the containment. We need to develop the antiviral drugs and treat people who may be shedding and the like, just so that we can come close to a guarantee that it's permanently gone.

TORGHELE: I'm wondering if, when you were Assistant Surgeon General, if those issues had to be addressed by you with Congress. For instance, I know that you had to testify before Congress at one point. It would have been after the World Trade Center attack, and I know that, at that time, people were thinking of all different ways that the country might be attacked.

ORENSTEIN: Right.

TORGHELE: What was it like for you to testify before Congress, and what things did you have to talk about?

ORENSTEIN: I didn't testify so much after the World Trade Center issue, but I've testified a number of times before Congress. And it depended. We had some real allies in Congress for the Immunization Program. One of our greatest champions, who just recently died, was Dale Bumpers. Betty Bumpers, Dale's wife, when she was First Lady of Arkansas, became interested in immunization, and I think she got him interested. And he was just amazing. You could talk with him like a colleague. I mean, he loved to get into the technical stuff, but he was on the Appropriations Subcommittee in the Senate and was just a champion. He just looked after us, and helping so we would meet with him. We had other people, Tom Harkin, in the Senate, Jack Reed, and there were others. And in the House [of Representatives] we had—Henry Waxman was a big supporter; we had a number of others.

And I think one of the issues is—for the success of the public health program is—you need to have political will. That's the number one issue. And we had, over the course of time, two presidential initiatives, which made a big, big difference in our Immunization Program. The first one was in the 1970s. As I mentioned, Betty Bumpers was our heroine in terms of immunization. And she was First Lady of Arkansas and was a governor's spouse with Rosalynn Carter, who was First Lady of Georgia, and she convinced Rosalynn, and when the Carter administration came in, we got a presidential initiative on immunization. And this was just a miracle, getting all the attention. And the focus at that time was particularly on enacting and enforcing school laws. And we achieved super high immunization coverage, and we set the precedent during that period of school laws.

Then, in the 1980s, the Children's Defense Fund, an advocacy group for poor children, was looking for a way of measuring access of poor children to healthcare. And what is the one medical intervention recommended repeatedly for all children? Injections, immunization. And they looked at a survey called the United States Immunization Survey, the USIS—which we abandoned in 1985 because of budget cuts, but we also weren't exactly clear of its accuracy, because a lot of was based on parental recall of immunizations. But they looked at it and saw a big susceptibility gap, and raised a big issue in the press of concerns about that we were at risk for outbreaks of vaccine-preventable diseases.

At the time, my gut reaction was to say—was to blow them out of the water—They are using faulty data, and our disease incidence was relatively low. And the best advice I got, maybe the best advice in my career, was from my chief administrator, [Philip R.] Phil Horne, who said, You don't tick off the Children's Defense Fund. And we invited them down to our National Immunization Conference. They were represented by a woman named Kay Johnson, and we became instant allies. And then we had a big measles outbreak, a resurgence. Turned out they were right and I was wrong. We had a big measles problem, but nothing was done because low immunization coverage is a theoretical problem. But we had a big measles resurgence between 1988 and 1991, over three years. Before that, in the '80s we had about 3,000 cases of measles reportedly annually. During this period, we had—over this three-year period—over 55,000 cases, over 11,000 hospitalizations, 123 deaths.

And little did I know that Hillary Clinton was on the board of the Children's Defense Fund, and so when the Clinton administration came in, we got a presidential initiative on immunization. And getting a presidential initiative is unbelievable. I remember going to a meeting at the Department of Health and Human Services, and basically it was like being in a candy store. I was getting millions and millions of dollars for this and that, et cetera, although I did leave the meeting depressed, wondering if I'd asked for enough. It was a miracle.

We got a new measurement system of immunization coverage called the National Immunization Survey, which measured immunization in all fifty states, the District of Columbia, and a number of our larger cities with a refined methodology. And we got something called the Vaccines for Children Program, which was an entitlement program that, if the ACIP voted a vaccine into it, automatically purchased that vaccine for kids. And this covers, I think, around 40% to 50% of the birth cohort. And it put in the hands, basically, of an advisory committee of experts the ability to de facto make appropriations—not really, but it just took it out of the usual budget process. These are miracles that came and helped us. And I remember, for example, I could call the head of the Medicaid Bureau, who was a very nice woman, but I doubt whether—this is my surmising, I doubt whether she would've taken my calls, she's a very busy woman—but when the White House is tracking, she would take my call immediately, and we would work very collaboratively together. Same with the Department of Agriculture and the Women, Infants and Children—the WIC—Program, nutrition. Because those were kids at risk of getting a vaccine-preventable disease, and a number of them had higher rates of measles.

So all of this came out of the surveillance effort, and polio was also important in that effort. But primarily what we did in the first initiative is get the schoolkids, and what we did in the second is we got the preschool kids. So it really complemented our effort and played a major role.

TORGHELE: So the surveillance program that you mentioned—can you talk a little bit more about what was included, and how you used it?

ORENSTEIN: The surveillance program was key. I mean, that was one of CDC's strengths, and it's always been one of CDC's strengths. For polio, that's how we picked up the vaccine-associated cases, is through surveillance. And it allowed us to point out it was predominantly first dose. We were able to define quantitatively what the risks were for polio in the U.S. What played a big role in the U.S. was measles, and there—as opposed to polio, which we had gotten rid of in terms of wild virus—we had substantial measles. And we would then collect information on measles cases and investigate them, and we would classify the cases as preventable or nonpreventable.

A preventable case is a case in a child who should have been vaccinated but was not—in other words, a program implementation failure. A nonpreventable case was either a vaccine failure—someone who had been vaccinated and still came down with disease, was one of the few people not protected—or someone for whom vaccine was not indicated, so that was, in a sense, a strategy failure. And we used that information when we found with measles that we had two patterns of outbreaks. We had a pattern of preschool children where preventable cases were predominant, and program failure was the problem. And that played a role in the Clinton Immunization Initiative, what was called the Childhood Immunization Initiative, or CII. And a lot of the cases in the school-aged population were nonpreventable—were vaccine failures—and that's how we came to a two-dose schedule. So, domestically, we used surveillance more for policymaking of measles than polio.

Globally, on the other hand, surveillance was absolutely critical in finding areas at risk for polio and then setting up efforts to get rid of polio there. And so what we were able to do with polio is set up a global laboratory network, for example, which plays—and continues to play—a major role in the eradication initiative. Because in contrast to smallpox—smallpox you didn't need a laboratory, it was so clinically distinctive you could make a clinical diagnosis. With polio, the paralysis—there's a textbook kind of paralysis, but there are other causes of similar illnesses. So you require confirming the diagnosis is polio by detecting the virus, in the stool, usually. And so you would collect stool specimens and then send them to laboratories, and the laboratories would work on detecting the virus, and then on sequencing it to determine if it was vaccine virus or wild virus, and then genetically characterizing it within those groups as to how related they were. So polio has played a leading role—and that laboratory capacity, I should say, has played a leading role—in developing this way of trying to understand what's going on, and then taking actions based on what's coming out of the laboratory results.

TORGHELE: And coordinating the efforts, it sounds like.

ORENSTEIN: And coordinating the efforts. It's a laboratory network, and so one needs to assure competency, needs to assure it's working well, that they should be detecting virus if it's there, not falsely detecting it when it's not there, and being able to characterize it. All of that is done, and the CDC laboratory plays a major role in the quality assurance parts of this, as well as many other things.

TORGHELE: So a lot of what you're describing, it sounds like, came from CDC over the years.

ORENSTEIN: Yes. Much of it is CDC. The molecular epidemiology, as I mentioned earlier, was the CDC technique, and CDC is a major reference laboratory. There are others, but CDC is a major reference laboratory in the network, and helping with the quality assurance aspects as well.

TORGHELE: Now, speaking of the collaborative efforts, you've talked about some of the collaborative efforts that you had related to polio eradication and other programs. Can you talk a little bit more about how the World Health Organization and PAHO and NIH [National Institutes of Health] and the private groups like Gates and Rotary all work together, and what roles they have come to take?

ORENSTEIN: The major leader of the Global Polio Eradication Initiative is the World Health Organization, but the partners meet frequently and are in constant communication. CDC provides laboratory resources, it provides training resources for investigations, it helps people in doing the investigations, it trains people, much as I was trained to do smallpox in 1974-'75. There's something called STOP, which is Stop Transmission of Polio Teams, where people are trained for about five-month-or-so assignments where they go into places and help people with their polio eradication efforts. So CDC provides leadership on some of the epidemiology, some of the policymaking, and works very closely particularly with WHO.

UNICEF focuses particularly on communications, vaccine ordering, vaccine delivery, achieving high coverage—although CDC and WHO and others are involved. Rotary International is an advocator; they get resources, they give resources, they develop political will within countries, they participate in coalitions. The Gates Foundation is a major funder, and they fund research, developing better tools than we have now, helping with policy, helping to support independent monitoring groups. And I'm sure I'm leaving out groups, but each has roles. But there are—there's an independent monitoring board that independently monitors and recommends what else needs to be done. I'm on a working group for SAGE, the SAGE polio working group, which—SAGE is the major policy group, and the SAGE polio working group reports to SAGE and makes recommendations for them to consider, about policy changes such as the switch from the trivalent oral polio vaccine to the bivalent oral polio vaccine. And there's much, much more taking place.

When the polio eradication effort began in 1988, there were an estimated 350,000 persons paralyzed and 125 countries that had ongoing transmission of polio. And now we're down to two or three. I don't know if Nigeria has been reclassified as endemic, but Afghanistan, Pakistan, and potentially Nigeria. And last year we had less than 100 cases.

TORGHELE: In the world.

ORENSTEIN: In the world, exactly. So, our goal is to get to zero cases. Eradication is a very unforgiving goal, but we are doing better than we ever have, and so we're hoping to just coordinate everybody to finish the job in these last few places. I think one of the things we have to be very careful of is a number of people have said, Well, if we have less than 100 cases, can we stop now? Isn't this good enough? We have other problems.

And the problem is that if you completely stop, it's likely we will have a massive resurgence of polio. So that's one of the hard things to sell, is—until people understand that if we're low today doesn't mean we'll be low tomorrow, if we don't continue efforts. Every day babies are born, and they become susceptible. If we don't vaccinate them, they are going to remain susceptible. And we saw this in the United States on measles. When it started, we had a big federal infusion of funding for measles, and it really dropped measles down. And people said, Oh, we don't need measles anymore. So in 1969, they switched it to rubella and took all the money away from measles, and then we had another big outbreak after several years and so federal resources went back up. And then that went down, and resources went down again, and it allowed another outbreak to occur. So one of the messages that's difficult for people to understand is, for many of our vaccine-preventable diseases, it's not constant, it's episodic. You need to accumulate susceptibles, and then you have an outbreak. And we need to get people to understand, you've got to continue your investment in immunization, that you just can't stop when you get down to a low in diseases.

Now, if you get down to eradication, that's a different story. So, for smallpox, when we eradicated smallpox, we stopped all vaccination. Whether we would do that for polio will be discussed, or whether we want to keep vaccinating as an insurance policy against return. That will be discussed, but the goal is clearly to remove that risk, and get the savings from having removed that risk.

TORGHELE: That's a very good explanation. What would you say to people who choose not to vaccinate their children?

ORENSTEIN: I think, in a sense, vaccines have become victims of their own success. What's amazing to me, for example, is when I trained in pediatrics and pediatric infectious diseases in the 1970s, we almost always had kids on the ward with meningitis due to Haemophilus influenzae type b, or Hib. Many parents have never even heard of Hib. And I remember in 1972 being taken through, doing a tap. At that time—people don't do it anymore—one of the complications of Hib meningitis is what's called subdural effusions, which is liquid collecting on top of the brain. And being taken through by a neurosurgery resident, when I was an intern, of a tap through the infant's soft spot to drain that fluid. Horrible. Now there are people today who are calling themselves pediatricians, never having taken care of a case of Hib meningitis. It's just mindboggling. But the problem is that these organisms are there around the world, and if you don't vaccinate your kid, your kid is susceptible. And because there's not disease today, doesn't mean there won't be disease tomorrow. People travel. People for example, bring back measles. They go and they leave and they bring it back. They have the potential to bring back polio, potential to bring back Hib and what have you. If you don't vaccinate, you're taking that risk.

The second issue is there's not an understanding in a lot of the public of what a vaccine is. We need to say that we all have immune systems, and the immune system functions as an army or a police force to detect the pathogen—the harmful, for example, bacteria or virus—and destroy it before it can cause disease. What a vaccine does is it gives the immune system practice. In a sense, it trains the immune system so that it doesn't have to learn, it's ready. You wouldn't send an army into battle without training. What the vaccine does is it helps train the immune system to get it early, before the germ—the virus or the bacteria—can cause the disease.

And it is not easy to develop a vaccine. Many take ten or more years to develop. And for some, we haven't been able to develop them—such as AIDS [acquired immune deficiency syndrome]—yet. We're hopeful, but not yet. And there is an extensive process of testing the vaccine. First you start with pre-clinical work, trying to determine what is a protective immune response. Then you try and generate that in animals, then you have several phases of trials in humans—phase I, II, and III, where you look for safety and effectiveness. And it's not until after the phase III trials—which, as I said, can take ten or more years before the initial start—that you can get a license, and you have to prove your vaccine is both safe and effective.

And the people who make recommendations for those vaccines, many of them have children themselves. And this is how I got my own children vaccinated and my own grandchildren vaccinated. These vaccines are very carefully processed and monitored, and we even monitor them on a continuing basis for safety and for effectiveness. And so I think the problem is people don't understand what a vaccine is, and they are not seeing the diseases. And our hope is that we don't need to see the preventable diseases to get them to recommend vaccine. That would be a tragedy, is to have some children die or be brain damaged or be hospitalized because the parent doesn't think that disease is a threat. And hopefully it will never be a threat. But these vaccines are safe and effective, and before a vaccine is licensed, there's a tremendous process to assure they are safe and effective.

TORGHELE: I think you could make a very good public service announcement and say it just like that. It would be very effective.

So, I'm wondering too—I'm remembering that you and [Dr.] Paul Offit and [Dr.] Stanley Plotkin have a book called Vaccines that's been called the bible for vaccinologists, and I know that it's relied on around the country and the world as the resource about vaccines. And I'm wondering if you ever foresee a day when you wouldn't have to have a section in there about polio and smallpox.

ORENSTEIN: Probably, for historical reasons, we would keep the sections on polio and smallpox, but my hope would be that they would be less important. The smallpox issue is primarily now the potential of terrorism, although I think it's more historical than anything else. My hope is polio will become a historical part of that. We have chapters on both the inactivated vaccine—the Salk vaccine—and the Sabin oral polio vaccine, and we deal with issues of telling about the disease, the characteristics, the risk factors, the epidemiology, vaccine, the production, the effectiveness, the safety, and then policies for that.

And I think my hope, however, is that it gets larger as we have vaccines against more diseases. There are still a number of infectious diseases that we don't have super-effective vaccines, and my hope is that we will have those someday. Tuberculosis, we have a vaccine, but it's not optimal. We are developing malaria vaccines, HIV [human immunodeficiency virus] vaccines. I mean, my hope is that we can take more advantage of vaccines as a tool, and in fact, that the tool be used even for noninfectious diseases. Because if we can use a vaccine to stimulate the immune system, then perhaps it could be even helpful in dealing with things like cancer. I should say that we have two vaccines that we recommend routinely in the United States to prevent forms of cancer. We have hepatitis B vaccine, that is one of the causes of liver cancer, and we have human papillomavirus vaccine, which is a major cause of cervical cancer as well as a number of oral and throat cancers, anal cancers and others as well, and they are there.

And one thing that perhaps I didn't mention earlier is, I said the vaccine gives the immune system practice. What a vaccine is, is either a killed whole organism—so it basically gives the immune system the shapes that it needs to be looking at—or it's a part of the organism, which, again, tells the immune system this is the shape you ought to be looking for. Or it's a live weakened version of the organism that has genetically changed to take away its virulence, but still has the right shapes to get the immune system looking for it. Or, in the case of tetanus and diphtheria, it is poisons that those bacteria produce that are detoxified chemically and then have the right shapes so the immune system reacts against them. The immune system acts in two ways. One is called humoral immune system, where it produces proteins called antibodies, which bind to the viruses or bacteria and either neutralize them or don't let them to interact with host cells or whatever. So that's the humoral system. And the other is the cellular system, which helps in destroying infected cells before other cells get infected.

TORGHELE: Those are really good explanations.

ORENSTEIN: Thank you.

TORGHELE: It brings it to a level I think that people could mostly understand. So now I'm aware that we've been talking for a while, and I wondered if there were things that you wanted to address that we haven't covered yet, before we finish up.

ORENSTEIN: I think the big issue, I think, is on the polio side. We are so close that it's very important that we continue our investment. That means that the U.S. government needs to continue to support polio eradication, and that people potentially advocate with their legislators to continue to support the polio eradication effort. Because as long as polio is anywhere, there's a risk of it coming back here. So, both for humanitarian reasons and our own health security, supporting immunization abroad, particularly polio, is helpful.

The second issue deals with that, is—people think about building a wall of immunization, and that's good to protect us, but there will always be defects in the wall, and we are much better off if there isn't an organism to breach the wall. And that's a complicated way of saying that it's important for us to help global immunization programs vaccinate their children, because that not only protects them, for humanitarian benefits of their population, but it helps our global security because we're not exposed. For example, last year we had an outbreak centered in Disneyland that came from a foreign virus. If there are no viruses, if there's no measles virus circulating elsewhere, it's not going to be brought back here. And so, we're one world, one population. And helping to support immunization programs in developing countries is important for them and for us, and it's a way of collaborating and working together.

TORGHELE: That's a very important message for us to take with us today. And I think the way you delivered it, because of your expertise and all the various positions you've held and the experiences you've had around the world, it makes it so much more interesting.

ORENSTEIN: Thank you.

TORGHELE: I want to thank you for your contribution to this oral history and the Global Health Chronicles, and we'll look forward to watching it again. Thank you so much for participating.

ORENSTEIN: Thank you so much, Karen. I appreciate it. Thank you.

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