publication date: Sep. 6, 2017
Conversation with The Cancer Letter
Lowy: NCI’s intramural program made development of the HPV vaccine possible
NCI Acting Director
After getting the news that he and collaborator John Schiller have won the 2017 Lasker-DeBakey Clinical Medical Research Award, Douglas Lowy said that part of the credit belongs to the NCI intramural research program.
Lowy and Schiller got the award for their role in developing the human papillomavirus vaccine, likely preventing millions of deaths worldwide from cervical cancer and HPV-induced malignancies.
Lowy, the NCI acting director, said the institute’s intramural program offered him and Schiller the opportunity to continue a three-decade collaboration, giving them access to expertise, and freedom from grant writing and the publish-or-perish rules of extramural academic medicine.
Lowy spoke with Paul Goldberg, editor and publisher of The Cancer Letter.
Congratulations. Wow! This is huge.
I guess we should probably first talk about the NCI intramural program. What does the story of the HPV vaccine say to critics of the program?
I think that the intramural program at NIH has many special aspects to it. One of them is that it is quite straightforward for people to have long-term collaborations and work together; such as I have had with John Schiller. And, our working together has really made it far easier for us to make progress in this area than might have been the case, certainly, if I had been working alone.
As you probably are aware, the Discovery Channel had a three-part series about the [NIH] Clinical Center. And, there were many breakthrough discoveries that have been made there over the years, and are continuing to be made there. As a matter of fact, when members of Congress, or people from the administration, come to NIH, they are really impressed by seeing the cutting-edge research that is being performed, and meeting some of the patients who are benefiting from this research.
How long have you been working with Dr. Schiller?
We have been working together for more than 30 years.
Which is uncommon, really, in the extramural world?
Yes, intramurally, it is far easier to do that, because the issues of first authorship, last authorship, et cetera, are less important than what the content is of the research.
Plus, of course, you’re trained in dermatology, and Dr. Schiller’s expertise is immunology?
Well, actually, when we started working on the vaccine, neither of us had any training in immunology. John’s PhD was in bacterial genetics, and his work in animal viruses, as with mine, had mainly been on their molecular biology, transforming genes, etc.
Another dermatologic connection with the vaccine is that Reinhard Kirnbauer is the person who did most of the early work. Reinhard is a dermatologist who now is a professor at the University of Vienna in Austria.
The impact, of course, is gigantic. Could we do the numbers?
Well, HPV infection is responsible for more than a half million cases of invasive cancer throughout the world each year. Cervical cancer is by far the most important of these, globally, because, about 85 percent of the cancers attributable to HPV infection occur in the developing world, and about 90 percent of the deaths occur in the developing world. And, in the developing world, cervical cancer accounts for about 90 percent of the HPV-associated cancers.
HPV-associated cancer accounts for about 10 percent of female cancers worldwide. The vast majority of the cancers occurring in the developing world, because it is cervical cancer dominated, arises in women.
In the United States, the spectrum of cancer is quite different. There are a total of about 30,000 HPV-associated cancers each year in the United States. About half of them are cervical cancer. But, the other half are what often are referred to as non-cervical cancers, which include anal cancer, vulvar or vaginal cancer, penile cancer, and head and neck cancers.
About a third of these cancers arise in males. And, therefore, in the United States and other industrialized countries, HPV-associated cancer arises in a fair proportion of men, as well as in women.
What role did chance play in this discovery? Now, it looks like engineering, as things always do in retrospect. But, how much of this was clear in the beginning? How did you get interested?
I would say that none of it was clear. We clearly were performing very high-risk research. We were fortunate that Reinhard was willing to take a chance. And, it actually was the first foray that John and I made into studying the genes that give rise to the structural proteins, or the particles, of the papillomavirus.
Prior to that time, we had been studying the genes that either are involved in cell transformation, or the genes that regulate the expression of the viral genes that are in the papillomavirus. So, we were extremely fortunate that the first set of experiments that we tried actually led to the expression of virus-like particles, which form with very high efficiencies, and were able to induce very high levels of neutralizing antibodies.
It was not at all preordained that this would be the case.
In fact, other investigators had started doing analogous research before we did, using HPV 16, which is the most important oncogenic HPV type. But, those experiments led to either the failure to produce virus-like particles, or when particles were produced, they were aberrant.
John and I actually were fortunate that we started our research in this area, with the bovine papillomavirus. Because, we had infectious virus available, and my lab had developed a neutralization assay for BPV, so that we knew that we had the reagents in hand, so that if we were able to get particles and induce high levels of neutralizing antibodies, they could be measured in a straightforward way. This was not feasible with HPV 16.
Therefore, after having done this initially with BPV, we were looking at HPV 16 and seeing that it self-assembled about 1,000 times less efficiently. And, this led us to hypothesize that the strain that we were working with, which was the reference strain that virtually everyone in the world was using at that time, might encode a mutant of the gene that gave rise to the particles. And, indeed, when we received genes of HPV 16 from lesions that were dysplastic rather than having progressed to cancer, we were able to determine that they self-assembled with an efficiency very similar to that of the bovine papillomavirus. And, I guess you could say, the rest is history.
After you got the initial hypothesis and the initial results, was it difficult to get the support that this project needed?
Actually, no. One thing that happened was that Rick Klausner, who was the director of the NCI, actually asked if I would develop a clinical-grade HPV vaccine for use in people, so that early-phase studies could be carried out. And, that is indeed what we did. So, there actually was substantial support for vaccine development from the first. I will also say that my division director, Alan Rabson, as soon as he heard about the results, was equally enthusiastic, and also supported our research in this area, although, I should point out that John and I had no track record in the study of the structural papillomavirus protein, in immunology, or in vaccine development.
This is really a story about publicly funded research. But, the NCI needed the industry to make and test the vaccine. In this case study, what did NCI bring to the table and what did the industry bring to the table? What’s NCI good at, in other words, and what’s the industry good at?
Well, we brought the intellectual property and, in addition, the technological approach for making the virus-like particles. MedImmune, which was the first company to make the virus-like particles according to the way that we did it in our lab in insect cells with recombinant baculovirus, really used our process directly. They subsequently sub-licensed the license to GlaxoSmithKline, which made a commercial version of the vaccine. Merck had experience making vaccines in yeast, and so they transferred the technology to express the particles in yeast. Both companies actually took a substantial risk, because the track record of making vaccines against local sexually transmitted infections had been quite poor.
For example, there had been disappointing results with herpes simplex virus type 2 vaccines, although they worked well in animals. And so, both of the companies brought their capabilities of doing development and scale up to make commercial versions of the vaccine, whose effectiveness actually has vastly exceeded our even optimistic expectations.
What are your thoughts about the uptake of this technology? Is this where you expected it to be?
Since I didn’t have any specific experience in vaccinology, it was difficult to predict. The uptake of the vaccine, in some countries, has been very high. And, in those countries there has been the development of herd immunity, and a dramatic reduction in the short-term effects that one sees from the vaccine. For example, a dramatic reduction in the incidence of cervical dysplasia, and for the Merck vaccines, a substantial reduction in genital warts.
In the United States, although the uptake has been lower, herd immunity has also been seen here.
My expectation going forward is that, because the vaccine was approved now more than ten years ago, and there had been no showstoppers during that time, that we will continue to see a gradual increase in the uptake of the HPV vaccine in the United States.
The big question is whether the vaccine will be taken up on a worldwide basis. Although there is tiered pricing, it is relatively expensive, and a real investment on the part of developing-world countries, because the benefits, in terms of the reduction of the incidence of cervical cancer and mortality from cervical cancer won’t be seen until more than 20 years after initiating vaccination.
So, the very large number of people who haven’t died, haven’t died. How do you make the uptake better?
What we are trying to do at the NCI is to make a rigorous test of the hypothesis that a single dose of one of the FDA-approved HPV vaccines, or all of them, will be able to induce long-term protection. If this is the case, it will become much less expensive for administering the vaccine, but in addition, especially in low-resource settings, the logistics of administering one dose is far easier than that of administering more than one dose.
We are doing a clinical trial in Costa Rica, with partial support from the Bill and Melinda Gates Foundation. And, we look forward to the data, which will become available probably in five or six years, to determine whether one dose is able to do this.
The clinical trial is based on post hoc analyses that we have carried out with an initial clinical trial that was conducted in Costa Rica of the GlaxoSmithKline vaccine, that’s the vaccine made by GlaxoSmithKline, which strongly suggests that a single dose of the vaccine might be sufficient to confer long-term protection.
The post hoc analysis, however, is not sufficient to change standard of care, whereas the rigorous trial that is about to start should be able to do that, if indeed our hypothesis turns out to be correct.
What does this technology mean for future cancer prevention strategies? What do you know now that you didn’t know before?
I would say that the first part, for future vaccines against other infectious agents that the high immunogenicity of the repetitive structure of the virus-like particle, I think is something that people have really paid attention to. As a matter of fact, there have now been several international conferences on virus-like particles, largely because of the success of the HPV vaccine.
The second part, which is trying to develop immunological approaches to reduce the risk of developing cancer that’s not attributable to infectious agents, that is more speculative, but certainly worthy of research support.
Ned Sharpless, your successor at the NCI, is about to be sworn in. Based on your experience now, as acting NCI director, what would be your advice to Ned?
I would say to him, first, that being the NCI director is an extraordinary opportunity to have an impact on cancer research. And, second, to try to take maximum advantage of that opportunity.
Is there anything we’ve missed? Anything you’d like to add?
I would say that the freedom of the research in the intramural program made the research that John and I did quite straightforward.