Dr. John Modlin

John Modlin

TORGHELE: It is November 7, 2016. We are at the Bill and Melinda Gates Foundation to record an interview with Dr. John Modlin for the CDC [Centers for Disease Control and Prevention] Global Health Chronicles Polio Oral History Project. I am Karen Torghele, and I will be interviewing Dr. Modlin for this project. So I want to say welcome to Dr. Modlin, and thank you so much for agreeing to be interviewed for this. Just to get started, would you tell us a little bit about your background and how you became involved in public health in CDC?

MODLIN: Certainly. I went to medical school at Duke [University], and as a medical student was influenced in my career choices by [Dr. Samuel L.] Sam Katz, who had just arrived at Duke as the new chair of pediatrics, just coming from [Dr.] John Enders's lab in Boston. Sam is a charismatic figure, and he and [Dr. 00:01:00Catherine] Cathy Wilfert, his wife, were influential in my career choices. Sam suggested that I go to Boston, to Boston Children's [Harvard University], for internship. Those were the days of the draft, the Vietnam War, and I had some choices to make with respect to how I served my country. Joining the public health service turned out to be kind of a natural choice for me, because it fit my interest in infectious diseases and a growing interest in virology and vaccines at the time. So I signed up for the EIS [Epidemic Intelligence 00:02:00Service], and that's how I wound up at CDC.

This was 1973, and I was assigned to the Immunization Division, where [Dr.] John Witte was the chief of the Immunization Division. His chief sidekick was [Dr.] J. Lyle Conrad, who not only was responsible for the field officers in the EIS, but also participated in our activities within the immunization program. My senior EIS officers were [Dr.] Dave Brandling-Bennett and [Dr.] Joel Meyers. In 00:03:00my second year, I became the senior EIS officer to [Dr. Walter A.] Walt Orenstein and to [Dr.] Neal Halsey, who both have made both important contributions to vaccine-preventable diseases throughout their entire careers. It's been a joy for me to continue those relationships that developed very early on in the EIS.

This is 1973, and both polio vaccines had been introduced into the U.S. a decade before. The OPV [oral polio vaccine] vaccine was licensed in the early sixties and replaced IPV [inactivated polio vaccine] for routine immunization. By 1973 polio was pretty much--I won't say a forgotten story, but the numbers of cases 00:04:00had been reduced to such a small number that it wasn't a very high-profile problem for the CDC. As I recall, most of the polio activity consisted of surveillance and counting the small numbers of VAPP [vaccine-associated paralytic polio] cases, and writing a report once a year. And that was pretty much it. There was, as I recall, little interest in global polio. I'm not sure there was any interest in global polio issues anywhere in the early 1970s. It wasn't a high-profile problem at the time.

I spent most of my time on measles and rubella. Both of the vaccines had 00:05:00recently been licensed, measles in the mid-sixties and the rubella vaccine in 1969. There were a number of important issues, including the relationship between measles and subacute sclerosing panencephalitis, a rare but serious complication of measles. The question related to the influence of measles vaccine in causing SSPE [subacute sclerosing panencephalitis] or preventing it. We did a number of field studies trying to focus on that question. Similar with 00:06:00rubella vaccine, because [it was] also a live virus vaccine. And there was a major question--was whether it was safe for pregnant women, or if it were inadvertently given to a pregnant woman or a woman who didn't know she was pregnant, would there be some risk to herself and to her fetus? I spent most of my time at CDC focusing on those two problems for two years. And then I went back to Boston to complete my pediatric training at Boston Children's, stayed on there as an infectious disease fellow, stayed on for about three or four more years after my fellowship as a junior faculty member at Boston Children's, and 00:07:00then was recruited to go to Johns Hopkins, again, as a junior faculty member.

It was the early eighties, and when the HIV [human immunodeficiency virus]/AIDS [acquired immune deficiency syndrome] epidemic first surfaced. So my intended research path, which--I had intended to continue my enterovirus work at Hopkins, and was interested in the non-polio enteroviruses and neonatal disease caused by non-polio enteroviruses, and particularly how they were transmitted from mothers to babies. I had a grant to study that when I got to Hopkins, but my head was turned by HIV infection. With Hopkins located [in] inner-city Baltimore, some of 00:08:00the first pediatric cases were occurring right in our neighborhood. I wound up shifting a lot of my time to clinical care of these kids. And then I joined the Pediatric ACTG, the AIDS Clinical Trials Group that formed in the mid-1980s to develop antiviral drugs to treat HIV infection. We focused on the use of drug to not only treat kids, but also to prevent infection by treating pregnant women who were infected with HIV to see if we could reduce transmission to their newborn babies. That turned out to be perhaps the most successful projects that 00:09:00I was ever involved with, the so-called 076 study, including the studies leading up to the 076 study.

I was immersed in HIV infection throughout much of my time at Hopkins. I was there for eight years. And then in 1991--largely because I had a young family with young children, and where they grew up was important to me--I went to Dartmouth [College] with an opportunity to do enterovirus laboratory-based research. I arrived there in 1991 and worked as both a clinician and a laboratory scientist for several years. But what happens when you grow up in 00:10:00academic medicine and become one of the senior people, you wind up taking on more and more administrative responsibility. The last fourteen years I was at Dartmouth, I was the chair of the Department of Pediatrics, with a large administrative responsibility that included both the clinical program of the department and the academic mission as well. Three years ago, when I was approaching a certain age, thinking about what is next and giving up the administrative job, the opportunity to come to the foundation surfaced. With my interest in poliovirus infections and extensive background in enterovirus biology, this was an opportunity I just couldn't pass up.

I need to digress. When I was at Hopkins, we were doing a number of enterovirus assays in the laboratory for our research work. Marshall McBean, who was a faculty member at the School of Hygiene--now it's the Bloomberg School of Public Health--was running clinical trials of the new inactivated polio vaccines, which 00:12:00were more potent than the vaccines developed by Jonas Salk. And the new methods for literally growing the poliovirus to create IPV were developed in the Netherlands and in Belgium and led to the ability to make a more potent IPV economically. The U.S. wasn't using IPV at the time, but there was a need to study the new vaccines for their ability to induce an immune response. Marshall needed some help on the laboratory side, so I signed on to do the neutralization 00:13:00assays for some of the studies.

Marsh had already done one set of clinical trials comparing two different IPV formulations, one made by Pasteur-Merieux and the other made in human diploid cell, and he compared those with oral polio vaccine. We agreed to do the laboratory work, and one thing led to another. We began to think about the fact 00:14:00that, by the mid-1980s, we were seeing no cases of wild-type disease in the U.S., but we were still experiencing from six to ten cases of vaccine-associated polio. This raised the question of whether we should continue using OPV or whether, with a better inactivated polio vaccine, we should go back to using IPV in the U.S. The more we talked about it, the more we recognized [the] need to do 00:15:00additional clinical studies to see how much mucosal immunity might be induced by IPV compared to OPV. We also discovered that it was a very controversial idea and that it would be difficult to convince the ACIP [Advisory Committee on Immunization Practices] to make a switch.

By now, Walt Orenstein had been appointed director of the CDC immunization 00:16:00program. Together, we began talking about the concept of using both IPV and OPV in the immunization program, the idea being that one or two doses of IPV could be given initially to prevent VAPP, followed by one or two doses of OPV to confer the mucosal immunity benefits of OPV so, in some respects, the best of 00:17:00both vaccines. Neal Halsey, who had come to the School of Hygiene at Hopkins, joined in, and we did a large study evaluating several potential IPV/OPV schedules. Ultimately, the ACIP recommended a sequential schedule in the U.S. in 1997. We remained on the sequential schedule for about three years, which was 00:18:00long enough for people to get used to using IPV. At some point it became apparent that there was little reason to continue using OPV, and the ACIP voted to go to an entirely IPV schedule in the year 2000. We've been using IPV for the past sixteen years, and OPV is no longer licensed. Now it's interesting that we're beginning to transition from OPV to IPV globally.

T The chance to be involved at a global level just like I was at a domestic 00:19:00level twenty, twenty-five years ago was a chance I just couldn't pass up. So I came to the foundation about three years ago, and my work here at the foundation has been far more fun than I thought it would be. My position is deputy director for research, and I work closely with people at WHO [World Health Organization] and CDC and elsewhere, and my job is identify research gaps, information gaps, that are necessary to address to complete the job of eradication. This includes identifying ways to make inactivated polio vaccine less expensive for the global 00:20:00health community. We are working with a number of external partners, and we're making a lot of progress in that area. Oddly, just as we are considering stopping OPV altogether, we are also developing a new OPV vaccine. The idea is to make a live vaccine that has all the benefits of the current live vaccine, but is much safer, because it is less likely to cause VAPP and less likely to 00:21:00spread from one child to the next [or] revert to a more neurovirulent form. So long as you're using OPV, you will continue to generate VDPVs [vaccine-derived polioviruses] and therefore never truly eradicate polio. We're racing to assure 00:22:00that we have these new vaccines in place by the time they're needed. I've enjoyed this project immensely. Our team at the foundation works with the rest 00:23:00of the GPEI [Global Polio Eradication Initiative] on operations, with the objective of interrupting and ending transmission of polio in the endemic countries, including vaccine delivery through campaigns, surveillance, social mobilization, public advocacy programs, and working with donors.

TORGHELE: It's exactly what we wanted to hear, and it leads us into some--maybe more depth of some of the things you talked about. So I was interested, for instance, when you were in the Advisory Committee for Immunization Practices, what were the discussions like? And was there ever a time when Salk and Sabin were involved, in the earlier days when you started talking about changing vaccines?

MODLIN; Oh, they both were, and they were both very actively involved. However, I don't recall that they would show up to the ACIP meetings to state their case. Marshall McBean and I wrote an opinion piece that put forth the rationale for a 00:25:00sequential schedule using both vaccines in the U.S. We submitted the manuscript to one or two well-known journals, and at least in one case the editor turned it down for being too controversial. Can you imagine? That's true. So finally I called a colleague, [Dr.] George McCracken, who was the co-editor of the journal of pediatric infectious disease [The Pediatric Infectious Disease Journal], and George said, "Send it down and we'll take a look at it". He called back to tell 00:26:00us that he would like to publish the paper--but wanted [to] send it to both Jonas Salk and Albert Sabin for their opinions, which he did. The article was published alongside with a commentary by Jonas Salk and another commentary by Albert Sabin, and they each strongly disliked the article, but for exactly opposite reasons. Even back then, as a relatively young guy, I got kind of a chuckle out of it, rather than being too overly concerned about our opinion piece being taken apart by giants in the field. I guess it was somewhat predictable. But it was published, and I think that did help get some movement [from] the ACIP and the American Academy of Pediatrics, who were also thinking 00:27:00about the same thing at the same time, getting some movement in that direction.

Salk and Sabin weren't the only ones opposed to the sequential schedule. There were a number of very influential people, including [Dr.] D.A. Henderson. D.A. was dean at Hopkins at the time, my institution. I used to have fights in the 00:28:00hallway with him over the topic, and I remember D.A. coming to the ACIP and stating publicly that if we convert to a sequential schedule in this country, he would guarantee outbreaks of poliomyelitis in the United States within a decade. He was vehemently opposed to any change from the current policy. The practicing pediatric community, as represented by the academy, were also very conservative. They fell back on the position that, we have a vaccine that's cheap, it's easy to give, and is effective, so why should we switch to a more expensive vaccine that must be given by injection? These points were valid, but I don't think that they were particularly taking the public health point of view. Few pediatricians 00:29:00ever saw a case of vaccine-associated paralytic polio. So this was another constituency that we needed to move in order to make a change in policy. On the other side, the parents of the kids with vaccine-associated paralytic polio were 00:30:00very articulate and influential. I didn't join the ACIP until after much of this 00:32:0000:31:00discussion had taken place. I had been involved as an advocate and doing the research. I came to the committee to present our work, our data, but I was not on the committee at the time these decisions were made. I actually joined the ACIP shortly after at least the decision to move to a sequential schedule was made. By the time I joined the committee, it was a simple and straightforward step to transition to an all-IPV schedule. The last time OPV was given in the U.S. was in the year 2000. Still, my time on the committee, particularly my time as chair of the committee, was particularly eventful. We dealt with very different issues in polio, and it was a particularly eventful time.

TORGHELE: You're talking about the autism--

MODLIN: We were handed several thorny issues during my term as committee chair. One, thimerosal, became the target of the Autism Now crowd. After 9/11, the 00:33:00concerns were raised about smallpox as a weapon of mass destruction, and the decision on the part of the administration to encourage widespread immunization with vaccinia vaccine. The proposal came straight from the vice president's 00:34:00office. By now, D.A. was in the administration as--I forgot exactly what his title, his role was, but he was in the HHS [Department of Health and Human Services] structure as an advisor, and D.A. didn't consider this to be a good idea. The administration still wanted to push ahead and prepare for a potential 00:35:00bioterrorism attack with smallpox virus. The decision was made at some level that the ACIP should be the forum for the discussion on generalized use of smallpox vaccine. So we rapidly shifted into a very different rhythm. All of a sudden the schedule accelerated, and I was on the phone two or three times a week with Walt Orenstein, who was head of the Immunization Program at the time. 00:36:00We formed a subcommittee on smallpox immunization. The experience changed my life for a while because of the perceived urgency of the problem, and I scrambled to learn as much as I possibly could about smallpox and vaccinia.

It will be interesting when the historians go back and take a look at that era and what transpired at the CDC. On one hand, there was expert knowledge on the risks of vaccinia--would be on a population basis. What was unknown was what the 00:37:00bioterrorism risk--It was impossible to balance those risks, and this made for a very, very interesting time. I became an expert on smallpox in a short period of time. I had to. I immersed myself in the relevant literature. Then there was a long follow-up period after we immunized thirty, where we did immunize thirty or forty thousand persons, mostly health care workers and first responders. There 00:38:00was a follow-up program to assess the success of that program, particularly the risk of adverse outcomes, given that the vaccine had not been in the general population for more than thirty years. Within a two to three [year] period, we also encountered the vaccines and autism issues, first with MMR [measles, mumps, and rubella vaccine] and Andrew Wakefield's deceptions, and later the thimerosal 00:39:00proponents. There was a lot going on during the period I chaired the ACIP.

TORGHELE: It must have been stressful.

MODLIN: Well, stressful yes. But the process was fascinating. You're dealing with more than the usual public health immunization issues. These extra facets played a role in the decisions that needed to be made. In retrospect, even though we ran around in circles many, many times, I think with each of the important decisions that we ultimately made we landed in the right place. To me, that confirmed the power of conducting our work in the open with involvement of 00:40:00all the stakeholders. The process was often messy and contentious, but I think the ACIP almost always came down in the right place.

TORGHELE: From your experience with smallpox and the stockpiling that they did, have you thought about that ahead for polio when polio was eradicated?

MODLIN: Well, obviously, there are some issues that overlap with smallpox, and there are some that are very different. The big controversy with the smallpox 00:41:00virus itself was whether the virus should be preserved for future use for research purposes. We already have a vaccine for smallpox, more than one, so you don't need the smallpox virus to generate a new vaccine. But for polio, we need to contain polioviruses for the same reason. Once we stop using OPV on a global basis, population immunity will decline in those countries where transmission would likely occur the quickest and fastest. We'll be switching to IPV. Many 00:42:00countries won't be able to use IPV for long periods of time unless we can make it affordable. But it still means that immunity levels are likely to drop, and therefore any stocks of OPV that are around, or any source of OPV, represents a risk. We have the same containment issues as you had with smallpox. In some respects it's a more difficult task because the ubiquity of polioviruses, particularly vaccine polioviruses--not just vials of vaccine that may be lying 00:43:00around here and there for long periods of time, but also laboratory specimens that may contain OPV viruses taken for some other purpose that are frozen away someplace. WHO is beginning to tackle the issue of containment, and it's not an easy job. The laboratory team at the CDC are the real subject matter experts assisting the containment program. Polio doesn't represent the same potential 00:44:00for bioterrorism as smallpox virus.

You need to be prepared for a containment breach no matter what the cause of the breach may be. Since we need to continue to make polio vaccine, a breach could come from a manufacturing facility, as an example, and so you need to have some preparation for dealing with this as a possibility.

TORGHELE: You've had so many experiences dealing with different issues related to polio while you've been here at Gates and before. I'm wondering if there were any incidents that stand out in your mind that really made an impression on you 00:45:00or really changed your thinking about polio eradication and its possibilities.

MODLIN: Well, even though I was interested in polio vaccine back at Hopkins in the 1980s, we weren't thinking eradication at the time. I wasn't. It was during that time that Rotary [International] began this conversation. I was paying attention, but I'm not certain it made an impression on me at the time. When WHO 00:46:00announced the eradication initiative in 1988, there [were] very divergent responses, that either one, This would be easy to do because there is an effective vaccine that's cheap, and all we have to do is give it to kids and we'll eradicate the disease in a few years. And then there was the other camp that said, it's too complex a problem, we'll never do it. And in some respects they both turned out to be wrong. We have proven that it is possible to interrupt transmission in some of the worst settings within the world, but it's taken far longer than people had anticipated when these decisions were made.

What has interested me is that the project was set forth with a certain amount of naiveté, not recognizing the potential barriers to eradication that have since developed. And there are really two major ones with respect from a scientific standpoint. One, there was not a great appreciation for the fact that the oral polio vaccine was not as potent a tool in countries with poor 00:48:00sanitation and a high burden of gastrointestinal pathogens, where we have learned, at least during that time, that in those settings OPV efficacy is much less than one would've anticipated, certainly far less than using the same vaccine under conditions of good hygiene. Secondly, I don't think anybody anticipated the likelihood that the vaccine-derived polioviruses would represent a barrier to eradication. Some recognized a theoretical possibility, but it wasn't until we had the ability to sequence viruses that you could distinguish 00:49:00vaccine-derived polioviruses from wild-type polio. And that didn't occur until fifteen or twenty years ago. So none of that was knowledge that existed at the time GPEI was launched, and it's been these scientific issues that have added problems, on top of the unanticipated geopolitical issues that have developed. These are all issues that make this audacious program even more so, and it makes 00:50:00you realize that it's not just a public health problem challenge, but you've got all these other facets that must be addressed and overcome in order to eradicate polio. That's what's made this opportunity so interesting and rewarding.

TORGHELE: As much as I hate to end the interview, our hour is up. It's a wonderful way to end. You summarized it so well, and you talked about how you feel about the work and what it's meant to you. Wonderful, thank you.

MODLIN: I wish you well with this project. It's an important one.

7