Dr. Paul Offit



Dr. Paul Offit

TORGHELE: It's May 20, 2016, and I am at Children's Hospital of Philadelphia with Dr. Paul Offit. I will let Dr. Offit introduce himself in a minute. I will just say that he is a co-inventor of the rotavirus RotaTeq vaccine, along with Fred Clark and Stanley Plotkin. The rotavirus vaccine is credited with saving hundreds, if not thousands, of children's lives worldwide every day. He's the author of a number of books that contribute enormously to public health education, especially related to vaccines. Today we're focusing on polio and CDC's [Centers for Disease Control and Prevention's] role overall with polio, how polio affected CDC, the Centers for Disease Control and Prevention, and how CDC affected polio. So we'll focus on those years related to how both evolved over the years, and since Dr. Offit wrote The Cutter Incident in 2005, we'll 00:01:00talk mostly with him about that book. Now, I'll let you introduce yourself and tell your title, Dr. Offit. Thank you for being here, by the way.

OFFIT: Sure, my pleasure. I'm Paul Offit. I'm a member of the Division of Infectious Diseases here at the Children's Hospital of Philadelphia, and the director of its Vaccine Education Center. I'm also a professor of pediatrics, and Maurice R. Hilleman professor of vaccinology, at the Perelman School of Medicine at the University of Pennsylvania.

TORGHELE: Thank you. Now, what I'd like to find out is how you got interested in medicine, and what led you to specialize especially in vaccines. What was your interest, and how did that happen?

OFFIT: I think my interest in medicine came from probably a series of events that occurred when I was a little boy. When I was five years old, I had a couple things that happened. One is that I ruptured my spleen after falling from a 00:02:00height, and that put me in the hospital for a few days. And all this bigness and, at some level, glamour of being in the hospital and seeing all these physicians who saved my life. Secondly, but probably more importantly, was that I was in the polio ward for a couple of months when I was five years old. I wasn't there because I had polio. I was there because I had been born with clubbed feet, and one of my two feet never really corrected, and so there was a surgery that was done that was apparently a difficult surgery. So I ended up having a fairly lengthy post-op course that was in a polio ward, as it turns out. The other 19 people who were in that ward all had polio, and I just saw them as sort of vulnerable and helpless and alone. I think that drew me to trying to work with children, and especially the draw, I guess, to infectious diseases.

TORGHELE: That's interesting. You were interested in infectious diseases, specifically in vaccines. How did that come about?

OFFIT: I think it was, I was of a time, because I was a child of the '50s, where my pediatrician came to our office. I'm sorry, I was of a time, as a child in the 1950s, where the pediatrician that I had, who was Milton Markowitz, came to our home when we were ill. When we had to get vaccines, we actually went to his home. He sort of pulled the vaccines out of the refrigerator and gave it to us actually in his home. It was kind of like a family affair. Dr. Markowitz became probably the world's expert on rheumatic fever. He published a monograph on rheumatic fever with Leon Gordis that still stands as the seminal work. He eventually became dean of the University of Connecticut's Medical School. I grew up in Baltimore, so he was a private pediatrician, then and I just happened to 00:04:00have a guy as a private pediatrician who was an enormous role model for me.

TORGHELE: Did you talk to him then about the possibility of you becoming a physician as well?

OFFIT: Yes, definitely. He made it glamorous and fun.

TORGHELE: So he was sort of a mentor.

OFFIT: Yes. To the degree that one can have a mentor as a five, or six-year-old, yes.

TORGHELE: Do you remember getting the polio vaccine?

OFFIT: Yes. I certainly remember getting vaccines. I can't remember whether it was that vaccine. I was born in 1951, so the vaccine came out in 1955. I can tell you for a fact that our physician, Dr. Markowitz, specifically told my parents to wait. The Cutter incident had happened before I was going to be getting that vaccine, and so he said, let's wait. Then what ended up happening is after a couple of years he felt then that the inactivated vaccine was safe enough, and so I got the inactivated vaccine. Then when the live attenuated vaccine came out, the Sabin vaccine came out, I got that also. I guess I was of 00:05:00an age where we actually got the sequential schedule, what became known as the sequential schedule. The inactivated vaccine followed by the oral vaccine.

TORGHELE: I wonder now how you got interested in writing books, along with all that you were doing. What was the drive that made you write The Cutter Incident about the…

OFFIT: So here was a vaccine that was made badly. You had this tremendous interest in a polio vaccine. When Jonas Salk announced that, when the trial of Jonas Salk's vaccine was performed at the University of Michigan and the announcement was made that it was safe, potent and effective, it was dramatic, as dramatic as D-Day.

So five companies stepped forward to make it, and at least one company made it badly, and as a consequence about 120,000 were inoculated with live, fully 00:06:00virulent polio virus. About forty thousand developed abortive or short-lived polio. About two hundred were permanently paralyzed and ten were killed. I think you could argue that was, if not the worst, one of the worst biological disasters in our country's history. I just wanted to understand how it could happen.

I think what drove me to that was that I talked to Neal Nathanson, who at the time was a young Epidemiology Intelligence Service Officer at the CDC, and Maurice Hilleman, both of whom told me that there was basically a bad actor at Cutter Laboratories. His name was Walter Ward. He was head of that program, and he was a bad actor. He essentially knew that the vaccine had a problem, and yet he let it be released anyway. I found that very hard to believe. Even though these two senior scientists told me that that was true, I found it very hard to believe that at that time, in the 1950s, given what was at stake with that vaccine, that anybody would knowingly let a bad vaccine out there. So that set me on what really ended up being about an eight-year course of digging through 00:07:00archives trying to figure out what happened at Cutter Laboratories.

Actually, that one chapter in my book called "What Went Wrong at Cutter Laboratories" is my favorite chapter, because it was that much work to get there. It obviously wasn't that simple. All five companies had a problem inactivating virus, as did Wyeth, who not only had a problem inactivating it, but also made a vaccine that paralyzed and killed children. That I was able to dig out at the National Archives and Record Administration with a CDC archivist who really pointed to me where that particular monograph, what was called "The Wyeth Problem." It was never published. Neal told me it existed. Neal Nathanson told me it existed, but he didn't tell me where it was. He didn't know where it was. Then you saw that actually it shouldn't have been called the Cutter incident. It should have been called the scale-up incident because that was really what the problem was. We just had trouble scaling up that vaccine.

Cutter was blamed, but I think Cutter was sacrificed really so that everybody could feel they were the problem, they were the bogeyman. It wasn't anything other than them, and once they stopped making the polio vaccine we could all feel safe again.

In truth, we could all feel safe again because we developed better safety 00:08:00testing methods, both in animals and in tissue cultures. So we could feel better, but I think it was Alexander Langmuir actually at the CDC who gave this the name "the Cutter incident," I think for that reason. But it was much more complicated than that and much greater than that, I think, of any of the books I've written. I think The Cutter Incident was the most satisfying because it was a process of discovery, just like science is a process of discovery. When, I think, I realized what went wrong at Cutter Laboratories, it was just satisfying to see that there wasn't a bad actor at one company, which just didn't make any sense.

TORGHELE: The Wyeth information was suppressed for a long time. Were you the first to discover that?

OFFIT: I think, well, Neal Nathanson certainly knew it existed. He wrote the paper, he knew that it was suppressed, that it wasn't going to be put out there, because I think that would have scared people that we just didn't know what we were doing. So we blamed it all on Cutter, but it was odd that, the archivist 00:09:00who helped me at CDC was named Love, was his last name. I can't remember his first name. But he took me to the National Archives and Record Administration, the southeastern branch which was in Atlanta, Georgia, and we went through this huge warehouse. There was this big cardboard box which was way up on a skid that had to be, we had to elevate ourselves to pull this box down using one of those sort of forklifts. And in that unmarked box, buried in this big unmarked box, was that document, "The Wyeth Problem," which I think really helped explain things. I think it was fortunate that he was kind enough and smart enough to show me where it was. And Neal certainly never hid the fact that that existed.

TORGHELE: It must have been like finding treasure!

OFFIT: Yeah, it was remarkable. It was just fun putting the whole thing together. Also the other thing that was really hard, and it was revelatory, were the court cases. You couldn't really find the court cases. These were not criminal suits. They were civil suits, so the court records weren't kept for 00:10:00very long. So even though there were a number of trials, I couldn't really find those early trials because everybody sort of settled after the first couple trials. So I called Melvin Belli's wife, who eventually directed me to a guy who lived on a houseboat off of the beach in Southern California who told me, for $1,500 he could find these records for me because I couldn't find them in law libraries, I couldn't find them in the lawyers' offices because they had thrown all those records away. I agreed to pay him half initially and then another half for when I had it in hand. He was ultimately able to find that for me. Those court records and all the documents associated with those court records were also very informative.

TORGHELE: Yes, because you include conversations in the court between lawyer and judge and the plaintiff. You describe it very well. It feels like you're sitting right there with them as you read the book. The outcome was interesting. Do you want to tell what happened and how that was unique?

OFFIT: It was a directed verdict. At the time, it was the birth of liability without fault. Which is to say, at the time, you would have had to have proven before that that when somebody in this case, for example, made a vaccine badly, that they knew that they had made it badly and that therefore they were culpable. Obviously, these companies didn't know that they'd made it badly. The safety tests just weren't good enough to pick up the fact that there were still live, virulent polio viruses in these batches of vaccines. They didn't think, they thought they were making safe vaccines. In fact, they gave these vaccines to their own children. The people who did the safety testing gave the vaccines to their own children. I think that tells you everything you need to know about whether there was an evil player at any of these companies. With that, let's pause for one second because I just lost my train of thought. The original question was --

TORGHELE: The outcomes and what changed in law.

OFFIT: Law case, got it. What the judge basically said was, if you are to find this company guilty, if they made a vaccine that caused polio, in other words, if a vial says polio vaccine, it is understood that it prevents polio and doesn't cause it. Therefore, for that reason, you have to find these companies guilty, in this case, Cutter Laboratories. It was a directed verdict, and it was the birth of liability without fault. You could be liable for something that was made badly, even if you didn't know that you were making it badly, even if you were making it according to all the prescriptive guidelines that were in place at the time both by the government and others, regulatory agencies.

TORGHELE: Just to step back a little bit, these pharmaceutical companies got their information about how to make the vaccine directly from Dr. Salk's labs. Is that correct?

OFFIT: When the vaccine was made for the field trial, for the big 1954 field trial, the one that was run by Thomas Francis, that was made according to a 00:13:00fifty-five-page document that was produced by Jonas Salk in collaboration with the people that were making the vaccine for the field trial, which were only two of the companies, Parke-Davis and Eli Lilly, who were veteran vaccine makers. When it then became a matter of federal regulation, and this was really before we were very good at federally regulating vaccines. It was the Division of Biological Standards within the National Institutes of Health, but it was really only a handful of people. They did it part-time. Really, their main interest was their own research lab. The federal regulation of vaccines was weak. So that fifty-five-page document really became a five-page document. You didn't even have to use formaldehyde to inactivate the vaccine. You could use UV light, as one of the companies had asked to do. It was a much thinner, weaker regulatory guideline. Because there was so much wiggle room in it, I think that was part of the problem.

TORGHELE: You mentioned NIH [National Institutes of Health], National Institutes 00:14:00of Health. They were the ones who went first to Cutter Labs when there was an inkling that there may be some trouble there. Can you tell what happened when they went to see Cutter Labs?

OFFIT: People from the NIH, representatives from the NIH, went to Cutter Laboratories to see if they could figure out what went wrong. They did see some things that were wrong. So for example, a live virus was stored, for example, as in the same area as, in theory, the vaccine was, and there was worry about cross-contamination. But I don't think it was ever really clear that the problem was largely a filtration problem. Which is to say when Salk did his filtration, he used a Seitz filter. This filter, which was much slower, but much more thorough at pulling out the cells and cellular debris. When it went to the 00:15:00commercial laboratories, the filtration process was much faster, but also much less thorough. I think that was the problem, but I think that only was revealed much later. I don't think that the NIH researchers really figured that out.

TORGHELE: So they passed Cutter, essentially.

OFFIT: Yes, that's right.

TORGHELE: What happened next?

OFFIT: Cutter Laboratories made vaccines for primarily people in the West and Southwest, and there were, they made lots of vaccines, two of which were the so-called high-risk lots that contained, that had live, virulent polio virus in it.

TORGHELE: What I'm wondering here is when CDC got involved and how, and also, 00:17:00there were other people who were concerned about Cutter. One of them I'm thinking of is Julius Youngner. I wonder if you could tell the story. I know it's public now and it's been published already, but I wonder if you could add that as part of the story.

OFFIT: I actually had done that interview with Dr. Youngner, and, interestingly, when David Oshinsky wrote his book Polio: An American Story, and he interviewed me for that book, I had told him I thought he should talk to Julius Youngner because I think Julius had some interesting things to say. For which he, David Oshinsky ultimately won the Pulitzer Prize for his book, which is just a wonderful historical book written by a great historian. In any case, what Youngner believed was that when he went to Cutter Labs, because he also went there on behalf of Dr. Salk to look at the way that they were producing this vaccine, he saw the same thing the NIH researchers had seen which was that there was a storage of live virus in the same place as inactivated vaccine. He told 00:18:00Dr. Salk that and regretted that he only told Dr. Salk that, and then Dr. Salk never really said it to anybody else. He felt that Dr. Salk had buried that information and that that is what led to the Cutter tragedy. But that wasn't it. It was a filtration problem.

When they grew polio virus in cell culture and then inactivated it with formaldehyde, if you didn't filter out the cells and cell debris, then the formaldehyde couldn't get to some of those virus particles. It was essentially, the virus particles would be hidden in the cells and cell debris. You needed to filter out that cell and cellular debris. I don't think anybody realized that until later. It really took time to realize. Also, you had to develop better safety methods, which is to say, you did animal inoculation studies where you actually immunosuppressed the animals with steroids before you inoculated. You did direct inoculation into the animal's spinal column or spinal cord. You also had in vitro studies, which is to say, studies in the laboratory where you kept 00:19:00those cells around for much longer to pick up what would be much smaller inoculum virus. That took time to realize. I don't think, I know Dr. Youngner feels that he had, by not going directly to authorities, somehow led to the Cutter incident. I think he's wrong. I don't think that would have mattered. That wasn't the problem.

TORGHELE: In any case, Wyeth had the same problem.

OFFIT: And Wyeth had the same problem.

TORGHELE: And he didn't know about that one.

OFFIT: Yes, just at a lesser scale. They didn't produce as much vaccine, there weren't as many deaths. But when Cutter released its vaccine, very quickly in April of that year you started to see children coming down with polio at a time before you would have expected to see children develop polio, number one, because typically it's more of a summer virus. Secondly, you saw them coming down with polio in the limbs, in which they were inoculated. Those two things, I think, led CDC to immediately send people like Neal Nathanson into the field to see what was happening. And you saw that it wasn't, this wasn't natural polio. This was polio that was being caused by the polio vaccine, and it shut down the 00:20:00program for a few weeks.

TORGHELE: Speaking of Neal Nathanson, and being an Epidemic Intelligence Officer, can you tell how CDC became involved first and what that was like, what was done and what you know about the process of how they handled that emergency?

OFFIT: Well, Neal would be the best person to talk to. He's still around. He's here at Penn, head of our Global Health Program. I think they very quickly, with a series of phone calls, which fortunately there were transcripts for, got involved in this incident to see just what had happened, what had gone wrong. And when then they did realize that there was a problem caused by the vaccines, and they took a very dramatic step, which was to shut down the whole program. Nobody was vaccinated anymore until they could figure out what went wrong. If that had happened today, I think you would have seen a much different response than what happened at that time. At that time, people still trusted the government, they still trusted pharmaceutical companies, they still trusted what 00:21:00we non-euphemistically call the medical establishment today, and so they waited. People waited, trusting that people would figure out what had happened.

Think about it, this was a vaccine that paralyzed and killed children, and yet people waited to see what the problem was. And when the problem was figured out, people embraced, for the most part, embraced the vaccine again. I mean, the American Academy of Pediatrics was probably the slowest to embrace it, but ultimately people did embrace it. If you listen to the exit interviews, even with these court cases, when Cutter was taken to court, people trusted the pharmaceutical industry. They believed that they weren't evil-doers trying to hurt children so that they could make money. That's not true today. I think I'd be curious what would have happened to the CEO of Cutter Laboratories today. Probably would have been hung.

TORGHELE: Yes, things have changed quite a bit. When Alex Langmuir was involved with this, do you remember hearing about how he handled it and how he maximized 00:22:00that experience to establish EIS in CDC in their role of surveillance and being the disease detectives that they are today?

OFFIT: Yes, I think this launched the CDC in many ways as the amazing detective agency that it is. It gave it enormous credibility. They were able to isolate the problem, figure out what the problem was, ultimately then to move forward so that we can continue to protect children against polio using a polio vaccine. They were facing, I think, what is an enormous amount of distrust from the public, and also they need to maintain the trust of the pharmaceutical industry. Those were the only groups, the pharmaceutical industry were the only ones to have the expertise and resources to make vaccines, so you don't want to alienate them by being too burdensome or restrictive, but I think they walked that line well. As detectives figuring out what happened, I think this launched the CDC. You can see exactly how quickly they could act and how effectively they could act.

TORGHELE: These were guys, mostly guys, who had had a little bit of training right after medical school and went right out into the field. I did talk to Dr. Nathanson on Wednesday, and he said he's the only EIS Officer who didn't have the course because he was sent right out into the field to do that work. It was quite a story. No computers, no handheld calculators or anything.

OFFIT: It's just sort of shoe-leather detective work, and that was done. It was at a time when, remember, polio was still a common disease in the United States. They needed to figure it out and needed to figure it out quickly. They were under the gun to figure it out because we were about to enter polio season. They shut down the program for three weeks and when it was reestablished again, it was reestablished again as a safe, effective vaccine. It was very quickly done, and it had to be done quickly because polio season was about to start.

TORGHELE: And people were scared.

OFFIT: Yes. I was born in 1951 so my mother didn't let us go to public swimming pools. I was able to swim with me and my two cousins in the backyard in one of those little plastic pools because they didn't want us, because they were scared to death of polio. Actually, the birth of summer camps in the Northeast was to get away from the city in the hopes of avoiding polio. One thing I talk about in the book is, my father went to a camp called Camp Idlewild where there was a polio outbreak in the camp that paralyzed the children, and I think even killed a child or two. He wakes up the next morning, comes out to revelry or whatever, and sees that the head of the camp had actually hung himself.

TORGHELE: Oh, gosh.

OFFIT: I think the best description, just in terms of a novelist, is Philip Roth's book Nemesis, which describes the polio outbreak in New Jersey, and it's 00:25:00really well done.

TORGHELE: It is well done. It's a very well-done book. I'm trying to do this sequentially. CDC then took the information that they had and it resulted in the report called "The Cutter Incident." This is coauthored by Alex Langmuir and Neal Nathanson. What happened as a result of that paper?

OFFIT: I think as a result of that paper, we put in place for the first time, I guess, post-licensure surveillance systems. Now you had in place a system to very quickly determine whether there was a problem. I think it's funny, people will ask me the question all the time, why should I trust the pharmaceutical industry, and it's a for-profit industry. Why should I trust them when I know that this is all for the purpose of making money?

The answer is you don't have to trust them. There is in place now something even 00:26:00larger, the so-called Vaccine Safety Data Link that will very quickly see who's gotten a vaccine and who hasn't, and if there's a problem that comes up, they'll see it quickly. With the RotaShield vaccine that was released in this country in 1998, it was on the market for ten months, was found to be a very rare cause of intussusception very quickly. If Vioxx, frankly, were a vaccine, its being a rare cause of heart attacks would have been picked up much quicker than it was because there is no drug safety link. I think if there was a drug safety link similar to what we have for vaccines, you would see that more quickly.

TORGHELE: I'm wondering now, what was the reaction of Jonas Salk during the Cutter incident goings-on?

OFFIT: When I wrote this book, I didn't interview Jonas Salk since he had passed away, but I talked to his wife and she said he was utterly heartbroken, just heartbroken that this had happened. This thing he had worked so hard on now had 00:27:00come crashing down. At some level, he was always upset that this fifty-five-page document for producing vaccine, as was done in the Francis Field trial, had suddenly become a five- or five-and-a-half-page document that was much looser and he knew, feared would be too loose.

TORGHELE: By contrast, what was the reaction of Albert Sabin?

OFFIT: I think Sabin, who frankly was a bastard, was probably gleeful that this had happened. He always had felt that his vaccine was the better vaccine. Although I think he was wrong because he was still under the false notion, as everybody was at the time, that the only way you could induce, i.e., confer immunity, which is to say, long-term immunity, would be with either getting naturally infected or being inoculated with a live weakened virus. He never believed that you could develop a memory response, a so-called anamnestic response, by giving a whole killed virus. He believed, as everybody did at the 00:28:00time, that you would need to give frequent boosters throughout your lifetime if you were to be protected.

Jonas Salk, if you look at his original data from the 1950s, he had proven that you can induce a memory response. For that observation, which was groundbreaking at the time, I honestly think he should have won the Nobel Prize, because it was an enormous technological advancement at the time. But Jonas Salk wasn't embraced. He was seen as a self-promoting scientist, a scientist who was willing to go on the airwaves, and scientists didn't like that.

TORGHELE: You make a point of, he wasn't in any of the organizations that you would expect him to be elected to, like the Institute of Medicine or --

OFFIT: That's right. Never a member of the National Academy of Sciences, the Institute of Medicine, the National Academy of Sciences.

TORGHELE: But never stopped working.

OFFIT: No, he was dogged.

TORGHELE: When you wrote your book Vaccinated about Maurice Hilleman, he was 00:29:00also involved with the polio vaccine. Can you talk a little bit about him and what he did?

OFFIT: Maurice trained at the University of Chicago, where he got his PhD. He then actually went to work in industry, initially at E. R. Squibb, to make what was at the time a Japanese encephalitis virus vaccine. Then he left Squibb to work at Merck. His flagship product at Merck was a polio vaccine. What he found in the manufacture of that vaccine was that, he found a contaminating virus. What we now know as the 40th Monkey Virus, identified the 40th Monkey Virus, identified, it's called Simian Virus 40, or SV40, and he stood up in 1960 in front of a group of stunned virologists and explained that these vaccines, both the Sabin vaccine and the Salk vaccine, were contaminated with this virus.

Now, the Salk vaccine was inactivated with formaldehyde, therefore that 00:30:00inactivation method reduced infectivity of SV40 by about ten thousand fold, essentially eliminating it. But not Sabin's vaccine. Sabin's vaccine was not treated with an inactivating agent at all, and it contained live SV40 virus, which was known to cause cancer in experimental animals. We didn't know whether or not it was a cause of cancer of people, and Hilleman just wouldn't take that chance, so he refused to put out that vaccine, because he didn't know. Now we know that SV40 doesn't cause cancer in people, but he didn't know it then.

TORGHELE: So he was extra cautious.

OFFIT: Yes.

TORGHELE: You mentioned how many vaccines he worked on and how little credit he got.

OFFIT: Yes, Maurice really either did the primary research or primary development of nine of the fourteen vaccines that we give to infants and young children today. We actually made a movie about Maurice, which NOVA's now considering. It's finished. It's called Hilleman. Hilleman is the title of it. It's The perilous quest to save the world's children. We have a little segment 00:31:00on polio and I'll show it to you. I have it on my computer.

TORGHELE: Okay, yes. That sounds great. I know about him from a number of people and how self-effacing, what a good scientist he was.

OFFIT: In October 2004 he was diagnosed with disseminated, what was thought to be pancreatic cancer, and felt he would only have about six months to live. With that in mind, I went to interview him because I thought, he was this amazing guy and all these stories are going to die with him. That was, of all the books I've written, I think that was a true labor of love. I just really wanted to save all that information for posterity, and he was very, very generous with his time when he was quite sick.

TORGHELE: That's very apparent in your book, how you felt. It really was a service for everyone to document that.

Just to change up a little bit, I know that you have been a member of the 00:32:00Advisory Committee for Immunization Practices with CDC. Can you talk about that organization and how CDC and ACIP [Advisory Committee for Immunization Practices] work together and what they do?

OFFIT: I came on in 1998. I was there until 2003, and in my first year made head of the Polio Vaccine Working Group, actually. Becky Prevots was our liaison to the CDC. I knew nothing about the ACIP or the CDC. I didn't have any idea how any of this worked. I'd been sort of buried in a lab for years and didn't know anything about public health or public health agencies. I was just a lab researcher. But I was really impressed. Really impressed by Becky Prevots and everybody who I met there, their dedication to trying to get it right, protecting the public's health. I hadn't seen anything like it. I was just amazed. Becky, I think, eventually went to work in Southeast Asia, I think to try and do what she could to save lives there.

So as the head of the working group, I felt it was time to move to a fully inactivated polio vaccine program. Although we'd eliminated polio from this country by the '70s, we hadn't eliminated the polio that was caused by the old polio vaccines, for twenty years, every year, about six to eight children would be permanently harmed by that vaccine. I thought, given that we have another choice, the inactivated vaccine, given that Scandinavian countries had essentially eliminated polio by only using the inactivated vaccine, although it was going to be more expensive, it was just not fair, I thought, when you had a safer vaccine, to not use it. So it was sort of the trying to herd everybody into that sort of feeling.

What was interesting was that, and I can't tell you how much respect I have for D. A. Henderson, who has been on the shortlist for the Nobel Prize forever and certainly should have gotten it. But he was reluctant. I think one of the reasons he was reluctant to move away from the oral polio vaccine was because of 00:34:00the Cutter incident. There was still sort of a lingering fear that we couldn't really fully inactivate that vaccine. That Jonas Salk's so-called straight line theory of inactivation was at best a theory and maybe not a good one, and that we couldn't really prove that there weren't some live viral particles at least in some batches. It's interesting how fifty years later we still were feeling the reverberations of that. I guess forty years later, forty-five years later, we're still feeling the reverberations of that incident.

TORGHELE: It had a big impact. Since you described the sequence, the straight line of, can you describe that? When you say straight line that Salk developed, can you describe that process?

OFFIT: Sure. What Salk's reasoning was the following. Let's suppose we have a million infectious particles per milliliter, or roughly one-fifth of a teaspoon of vaccine, of polio that we've grown in a culture. If I treat that at a certain 00:35:00pH with a certain quantity of formaldehyde for, let's say, three days, and that I get a thousandfold reduction. So instead of getting a million, I just have a thousand infectious particles. You can test that. You can see whether you have a million infectious particles. You can see whether you have a thousand infectious particles. Then if you treat for three more days, then you get another thousandfold reduction, you would essentially have one infection particle per milliliter, which you also can test.

But he then reasoned that it would continue to be that way. That if you continued to treat for another three days, you would get another thousandfold reduction. Another three days, another thousandfold reduction. So that in theory by, let's say, nine more days, you would have for all practical purposes a completely inactivated product. Which is to say you would have, say, only one infectious particle theoretically, say, per trillion milliliters.

Once you get to a certain point below that line, you can't test. You can't really test to see whether you have, say, one infectious particle per million 00:36:00milliliters. That's too hard to do. So you just, that becomes a matter of faith. The area sort of above the x-axis is a matter of fact because you can test for it, but you get to a certain level of dilution where you just have to believe that it's true, have faith that it's true. And as we learned from the Cutter incident, that didn't happen. That straight line inactivation curve didn't happen. It started to level off.

TORGHELE: Thank you for that explanation. It really makes it clear.

When you mentioned the side effects and the people who got vaccine-associated paralysis, can you talk about that a little bit and how it was related to the Sabin vaccine?

OFFIT: I guess what was striking for me was the ability to go interview some people who had been paralyzed by this Cutter's vaccine, because it really made it come alive for me. Anne Gottsdanker, specifically, was crying when she was 00:37:00telling me what had happened to her. I asked her if she could have any wish, what would it be. She said, I wish that I could meet with the CEO of Cutter Laboratories and he could see what it is that I have to live with, what I've gone through.

It was a tough time. Medicine, when you try and challenge the evils of this world, in this case polio virus, it's a war. At some level when there's a war, there are invariably casualties. The casualty was that we had to learn how to make this vaccine and mass produce it well. There were casualties with that. I think if you look at the early days of bone marrow transplants or heart transplants or liver transplants or kidney transplants, they're brutal. We learn as we go. So that's one. It's just the human face that was put on this tragedy by people like Anne Gottsdanker who, again, were really generous about their time, to live through this terrible event of the past.

TORGHELE: She, of course, was the one in the court case.

OFFIT: That's right. She was the lead court case.

TORGHELE: And she was awarded some money for it even though Cutter was not found liable?

OFFIT: Well, they were found liable without fault.

TORGHELE: Liable without fault.

OFFIT: Right. It was the birth of liability, which the jurors didn't want. They wanted to find Cutter not guilty. They felt that this was a bigger problem, that it wasn't really, Cutter was doing what they were asked to do, that we learn as we go. The jury got it, actually. It was the judge who directed the verdict. So you see the tragedy of paralysis caused by a vaccine, and we fixed that. The straight-line theory of inactivation was correct, we just had to do a better job at filtering out the cells and cell debris.

Then we go to Sabin's vaccine, which is unique among vaccines, and it's the only live attenuated viral vaccine that actually has the capacity to revert back to neurovirulent type or essentially wild type. In other words, the type III virus that he had only had two mutations that attenuated neurovirulence, and that's 00:39:00number one. So it really wasn't highly attenuated. It was attenuated for growth in the nervous system, but it wasn't attenuated for growth in the intestine. It could grow fine in the intestine. So here you have a virus that grows well in the intestine, that's a single-stranded RNA virus so its replication is only so faithful, that only has two mutations that attenuate neurovirulence. Therefore, there were occasionally times when it could revert back to wild type and cause polio not only in the person who received it, but in a person who came in contact with a person who received it, because the virus could be shed in the stools for weeks, sometimes months. I think Albert Sabin went to his grave never believing that was true. He never believed that that was the case, but it was the case.

So his vaccine, which came onto the market in the 1960s, ultimately was replaced with the inactivated vaccine by the year 2000 because the Salk idea was the right one, which was that we can eliminate this disease using an inactivated vaccine that provides long-term immunity and anamnestic response, and we don't 00:40:00need to take the risk of a live attenuated viral vaccine.

TORGHELE: Again, that decision was made by ACIP with the support of CDC?

OFFIT: Right, so the ACIP is an advisory committee. We give advice and the CDC invariably follows that advice. Not always, but they did here and so we moved to the inactivated vaccine.

The person who I think was the key person, that was a guy named John Salamone, who was a true vaccine safety activist. You hear all these days about people like Barbara Lowe Fisher or Lynn Redwood or J. B. Handley or Jenny McCarthy call themselves vaccine safety activists, but they're not vaccine safety activists because they're asking for vaccines to do something that they already don't do. Vaccines don't cause autism, therefore you can't make a vaccine that is safer in that it doesn't cause autism, and the current vaccines don't cause autism. But Salamone's son had developed polio from the oral polio vaccine, and he never knew that was the possible problem. He never knew that there was another vaccine 00:41:00that one theoretically could have used. So in a very respectful manner, and he was good at it. He had been a lobbyist for the Italian-American Association, so I think he understood how to apply political pressure in a manner to get things done without putting people off.

I brought him onto that committee, on to our polio working group, because I thought his voice should be on there. It kept us all straight about what was at risk here. It therefore became much harder to have the conversation about how much money we were spending to prevent a case of paralytic polio, vaccine-associated paralytic polio, which ended up being about four million dollars. We spent about four million dollars per case of preventing vaccine-associated paralytic polio by moving from the live attenuated vaccine to the inactivated vaccine. But he put a human face on that, John Salamone.

TORGHELE: That makes all the difference for people.

Now, I know you have a time limitation. I wondered if you could just touch on 00:42:00your thoughts about global eradication of polio.

OFFIT: I think there will be global eradication of polio. We've already eliminated type II. That's a good start, so there's only two strains, two serotypes left. I think it's a challenge, but I do think we're getting there. We now have just two countries in which the virus is endemic, and although it involves countries that surround those countries I think this will happen because there's such an enormous effort to make it happen. Obviously the difficulties with the infrastructure in some of these countries, difficulties with war in these countries, has made this more difficult than it should be, but we'll get there. We will. I say that because we've been able to eliminate one of the serotypes. Smallpox was the first human virus that was eliminated by vaccines. Polio type II is the second. We've also eliminated one animal strain, an animal virus called rinderpest has now been eliminated by vaccination. I 00:43:00think vaccinations are the most powerful thing we do in medicine, and I have no doubt we're going to be able to eliminate this disease just like we eliminated smallpox. It's not as quickly as we had hoped, but it will happen.

TORGHELE: Do you have any last thoughts before we wind up?

OFFIT: I would say this. I think that the Cutter incident taught us a lot of things, but one thing it taught us is how quickly and effectively the CDC could act at preventing what was a terrible tragedy, which could have been a much worse tragedy if we had withheld that vaccine for much longer. If we had withheld all those vaccines instead of for weeks but held it for months, we would have entered another polio season and there would have been thousands of children who were paralyzed and hundreds to a few thousand who would have died. That's all because of the CDC, their ability to act quickly and effectively, identify the problem and hold manufacturers to safety standards that made for a better vaccine. I think it was an example of real heroism by public health 00:44:00agency, but unfortunately we don't like our heroes to come from public health agencies, but they're there.

TORGHELE: Thank you so much. This has been a real joy to interview you, and it's been very informative. You've clarified a lot of issues that no one else could as well. Thank you very much.

OFFIT: Thank you.