Era of Hope 2011 Plenary Sessions

Session Title: Morning Session – Success Models: What Can We Learn?

Title of Presentation: The Story of the HPV Vaccine

H. Kim Lyerly, MD, Duke University School of Medicine: Our next speaker is Larry Stanberry who as I mentioned will be talking about the remarkable progress made in the development of the vaccine against the cause of cervical cancer, the human papillomavirus; Larry.

Lawrence R. Stanberry, MD, PhD, Columbia University: Good morning. I’m really privileged to be here and I want to thank the organizers for this invitation. And I’m going to start by telling you that I hope you can read these slides. I’ve gone to putting everything on a white background because I got tired of people printing the blue ones and running out of ink. So hopefully they’re legible for you.

So I should just tell you by way of introduction because I think it’s important that—that I do consult for all—almost anybody who makes a vaccine because I think while we do some wonderful science, if you don’t translate it into products that benefit people, the science doesn’t serve people. And so I do consulting; I’m an Advisor for Nanobio and I get grants from the National Institutes of Health.

I am going to talk today about HPV vaccines, but in my lifetime, in our lifetime there have been enormous successes in eliminating diseases. I don’t know how many of you in this audience still carry a scar from the smallpox vaccine, but I’ll point out to you that most of our children do not. And so that is a disease that within our lifetime was completely eradicated. Polio is on the verge of eradication. We’ve introduced Hepatitis B vaccine universal immunization now. That’s actually the first vaccine to prevent cancer because Hepatitis B is one of the leading causes of hepatic cellular carcinoma in the world. So and there are other examples, Haemophilus Influenza B vaccine; you’ve heard I’m a pediatrician. When I was in training, the hospital always contained two or three children who had meningitis due to this really deadly pathogen. My son when he was an infant was a volunteer in clinical trials to develop a vaccine that’s all but eradicated this disease, and there are other examples on here. And now the most recent one that we’re very excited about is the HPV vaccine.

Just to show you smallpox and regrettably polio, which still does exist in parts of the world, we should have eradicated this disease by now but there are issues around implementation that you should also be thinking of as you think about any strategy to control or eliminate breast cancer.

So a little bit about cervical cancer. This disease was first described 2,500 years ago by Hippocrates and not only did he describe it, he was the ultimate consummate physician. He attempted to surgically treat it by removing the cervix and upper part of the vagina. And really not much improved on either the diagnosis or treatment for a very, very long period of time until 1928 when another Greek, George Papanicolaou, who had come to New York from Greece to Cornell University and who as a pathologist started exploring the notion of looking at the cells that could be found in the genital tract to see if they were useful in the diagnosis of cancer. And he published a paper in 1928 that described his findings that you could take a vaginal smear and—and were able to use that vaginal smear to make the diagnosis of in this case uterine cancer. That publication was really not appreciated. It by and large went unrecognized and it wasn’t until 1943 when he and one of his colleagues published a book entitled Uterine—the Diagnosis of Uterine Cancer by Vaginal Smear that really the importance of his work was recognized. And after that the use of the Pap smear really gained wide acceptance and resulted in without a question the—the early diagnosis of cervical disease and—and hence a cure for those people who the disease was diagnosed early.

And so I think the key point here around his work was that the importance of discoveries are not always immediately recognized. I think in terms of doing due diligence and paying attention to what’s out there and not always discounting things because they’re not immediately confirmed is an important lesson.

To say a couple of things about the epidemiology of cervical cancer, despite the use of the Pap smear and there are many parts of the world where these programs, Pap smear programs are not available, cervical death remains a leading cause of death. By some estimates within the last decade, it was estimated to be the second leading cause of death in women due to cancer globally with about over a quarter of a million women dying annually in the United States, 13,000 new cases, 4,100 deaths each year—really that’s a dramatic decrease and that’s because of the success of the Pap smear campaigns. But just as with breast cancer, each of those 4,100 people have a face. And I just want to introduce you to Michele “II-Juicy” Feaster, who was a blues musician in Cincinnati when I worked at the Children's Hospital. I knew her; she died a year ago at the age of 44 of cervical cancer. So despite having effective programs such as Pap smears, we still have people who fall through the cracks and—and succumb to these awful diseases.

One of the things that we learned in studying the epidemiology of any disease but certainly of cancers and cervical cancers is that some cancers seem to be linked or there was evidence to suggest that they could be caused by infectious agents. By some accounts it’s estimated that as many as 20% of cancers in the world can be due to an infectious ideology. And that’s sort of exciting in a way in that if one can find a cause that’s an infectious cause one can develop a vaccine the same way we have for smallpox or polio or anything else. And one of the key people who put the pieces together was Harald zur Hausen. Dr. zur Hausen is a German Scientist, Physician who following his medical training in Germany came to Philadelphia in the Children's Hospital to the Henle Lab—Gertrude and Lerner Henle. They had-were really pioneers in looking at viral oncogenesis. This is the notion that viruses can actually cause cancer. And—and Dr. zur Hausen started working on Epstein Barr virus, that’s the cause of infectious mononucleosis, because there was a link between that virus, EBV virus which most of us have had and the risk of developing one kind of lymphoma.

So he worked on that for a few years and then he returned to Germany and changed direction a little bit. He remained focused on the role of viruses in causing cancer, but he focused now on cervical cancer instead of on lymphoma. And one of the things that led him to explore this area—it was very strong epidemiologic data suggesting that cervical cancer might be associated with some sexually transmitted pathogens. And he got very interested in herpes simplex the cause of genital herpes and followed that for a few years. That turned out to be wrong. I think one of the lessons here is you don’t just continue down a path that’s not being fruitful. In his case he—he backed up and he really thought about it a good deal. And based on the number of other things going on in the field at the time, he postulated that the virus that was causing warts, and we knew it was a virus even though you couldn’t grow it—that the warts virus, HPV, human papillomavirus might be the causative agent of cervical cancer. And he started doing some studies using the limited techniques available at that time because you couldn’t grow the virus. And by and large the results were pretty unfavorable. And so he was convinced that this was the right approach and looked at his data and said well maybe the explanation for why I'm getting the negative results is because there’s more than one HPV type. Maybe there are multiple ones and I’m just not detecting the right one.

So he persisted in exploring that angle. And in 1983 and 1984 in rapid succession, he discovered HPV16 and HPV Type 18 which within 2 years were shown to be the leading cause of cervical cancer or certainly associated with cervical cancer. He then as any good scientist would do, you’ve got this—this—you find the virus present, you find the cancer; that doesn’t mean the two are linked, so he worked on the mechanism and was able to—to do some of the pioneering work around E6 and E7. Those are two of the genes that are encoded by the virus and showed that they were critical in developing cancer—cervical cancer.

In 2008 he was awarded the Nobel Prize for his discovery of papillomaviruses and their role in causing cervical cancer. What’s curious and—and it seems to be apropos with today’s two topics HPV and HIV, he shared the prize in 2008 with two French investigators who won the prize for discovering HIV. So 2008 was a particularly good year for virologists.

I just wanted to give you this quote because I thought he summarized it very nicely when he was awarded the prize. The early hypothesis that cervical cancer was caused by papillomavirus, the successful isolation and characterization of the two most frequent HPV types in this cancer and the understanding that the mechanism of HPV made it a carcinogenesis and eventually the development of preventive vaccines which he didn't work on were cited as the prime reason for awarding one-half of the Nobel Prize to him in 2008.

So in this case I think one of the things that was lovely was that the prize was not awarded earlier despite the importance of the discovery. It wasn’t awarded until we actually had an effective vaccine so I think the Nobel Prize Committee, my take on this—appreciated the importance of the discoveries but really felt that the prize was warranted not only based on the discoveries but the translation of the science to something that benefited people.

So 2,500 years, I think we can do a little better than that now. We finally know the cause of a major form of cancer.

One of the things that I think is so apparent from zur Hausen’s success is that he took advantage of discoveries in parallel fields; in this case Epstein Barr virus as a cause of lymphoma and utilized new research tools that were becoming available at that point, a number of technologies in molecular biology and bringing those together—it really allowed him to make the discoveries that resulted in the development of the vaccine.

I just wanted to mention a little bit about HPV epidemiology instead of cervical cancer epidemiology. HPV, genital HPV is the most common sexually transmitted disease in the world. It—in the United States, we estimate that there about 20,000,000 people infected currently and there are about 6,000,000 new cases each year. By and large it’s a self-limited infection; you get it—often you don’t know you have it, and you clear the infection all by yourself with no problem. But you can be re-infected over and over and over again. So you don’t get durable immunity from so-called natural infection.

Based on our best estimates, 80% of sexually active women will be infected by the time they’re 50 years of age. So this is one of those pathogens that’s very hard to escape. And not only is it associated with cervical cancer, we now know it can be the cause of some anal cancers, penile, and some oral and laryngeal cases. The little graph that you see down there I found to be—it was done by a friend of mine, Laura [Koutsky] at the University of Washington, I think is a great epidemiologic study. She was looking to see how quickly young virginal women acquired HPV once they became sexually experienced, so they recruited young women who were entering college at the University of Washington and they followed them every few months throughout their college careers. And what—the basic findings of the study—at the University of Washington when young women started becoming sexually experienced, within 4 years 50% of them will have become infected, so it’s an exceedingly—exceedingly common infection.

And I’m going to come back to this theme—re-infections don’t occur frequently and that really suggests that host response to this infection doesn’t result in a durable immunity. If you get measles you get durable immunity; you don’t get measles a second time. If you get most infections that are dramatic, you don’t have them. Now there are exceptions—influenza and a number of other things—papilloma falls in the influenza kind of category—no durable immunity from having become infected.

I don’t want to go into this in a lot of detail other than to tell you this is an extremely complex pathogenesis to this virus. And people like Lou [Lehman] at Northwestern and others have done some elegant work. But I’ll just give you the summary of it on this bullet point and that is that HPVs and there are over 100 HPV types now recognized are really stealth viruses. They get to the very basal layer of the skin. They replicate in there; they don’t get outside the cell. They stay within the cell the entire time. They don’t cause the cell to blow up and spread cell to cell. They don’t get into the bloodstream the way measles does or chicken pox virus. And so they’re really such a minimal pathogen that they don’t cause enough injury often for the immune system to even recognize they’re there. We’ve had patients who we can demonstrate are infected but never make an immune response that we can detect. So it’s one of the reasons that we think that just because you’ve been infected once doesn’t protect you against being re-infected.

So okay; we’ve got a virus; this is great. And we know it’s the cause of cervical cancer. The question really becomes can a vaccine then protect against HPV? And so there have been some studies going back a number of years as far as back as 37 and as recent as 1994 using animal systems and animal viruses whether they happen to the—a rabbit papillomavirus or a cattle papillomavirus or a dog papillomavirus where you can take material from the lesion itself, grind it up, and inject it in an animal and protect that animal against becoming infected. And so there was a lot of sort of experimental animal data that provided proof of principle that the likelihood was that one could develop a vaccine against HPV. So that was the good news.

There were challenges though with regard how you were going to take what approach you would take. Fundamentally there are three approaches one uses in making a viral vaccine. One is you—you grow the virus up, you manipulate it so as to minimize its pathogenicity and you put it back into people. Those are referred to as live attenuated viruses—the intranasal. And so you could do that; that would be one approach. The second approach is sort of the soft vaccine approach. You grow up very large amounts of the virus, and you chemically inactivate the virus and you inject the whole virus back into people. And the third approach is to take just a piece of the virus, surface component generally because that’s often quickly recognized by the immune system, and we call those sub-units and you use those to make a vaccine and Hepatitis B vaccine is an example of that.

Now my—my hope is that you’ve all had all three of these and later we’re going to actually check you all out to find out how many of you are up-to-date on your immunizations.

So there were problems with some of these approaches. The first one, two of the genes that are contained in HPV are the genes that cause the cancer so if you go with the whole live viral vaccine you may be giving people the genes that can cause the cancer. So the notion of going with a live attenuated vaccine was really problematic. Most—not most—many viruses like polio, like chicken pox, you can grow them in cell culture systems. You can grow huge amounts of them and then you can chemically inactivate them or you can grow them in chicken eggs which is how we do it for the flu vaccines. The problem with human papillomaviruses or animal papillomaviruses for that matter is they’re extremely difficult to grow in culture systems. And when you get them to grow they only grow very tiny amounts. So the standard approach of just growing very large amounts of virus was not going to—again was problematic. So the only really option—the only option that was available was to take the sub-unit approach. So then the question became how do you—what approach would make the most sense?

So there were a number of people who started working on trying to develop HPV vaccines. And so one of my questions for the audience here is by and large, people who do invent vaccines are sort of anonymous. Can you—anybody name anybody who is a vaccine inventor besides Stefan Johnson? Okay; I’ll give you a clue. Anybody know who these guys are? Yeah; these are probably the two last most-well-recognized people in terms of vaccine development and they’re Jonas Salk and Albert Sabin. And it was mentioned earlier about the O’Shinsky book, which is an incredible took on the development of the polio vaccine. These two men were remarkably driven, remarkably successful, and hated each other’s guts. They wouldn’t—no, I knew them both; they wouldn’t be on the same podium. They wouldn’t—the stage was not big enough for the two of them. But their impact on human health was incredible.

And so then the question becomes one of—so okay we know who invented the polio vaccine. You guys were really good at that. Who invented the HPV vaccine? Does anybody know the answer to that? Okay; so this speaks to collaborative science. So I won't make you vote. So some people would tell you that the HPV vaccine was invented by Dr. Schlegel from Georgetown University. There would be a reason to think that. Others would say no; it was an NIH invention—that it was John Schiller and Doug Lowy at the National Cancer Institute that had invented the HPV vaccine. Others especially from New York State would say no, no, no; it was University of Rochester scientists. It was Reichman, Rose, and—and Bill Bonnez who did it. And then if you’re not an American you would probably say it was Ian Frazer, a Scot, who has been in Australia for most of his career. And if you picked any one of those you’d be right because all four of the groups were instrumental in the development of the HPV vaccine.

And they all have competing and overlapping patents based on their science that were instrumental discoveries that were critical in the development of the HPV vaccine. So one point simply is that competing or parallel research programs can accelerate discovery; sharing is good and most of the time we benefit from that but races—trying to get somewhere first is something that really does drive people—some people.

So—so exactly what did they invent? That’s really the question; so what was so incredible, what was their discovery? Well this is—what they discovered was the virus-like particles. And the upper figure there is an electron-micrograph of a human papillomavirus varion and what you can see it’s got those interesting little shapes to them. These little pentamers here on this cartoon that form the capsid, and you can see then this is a real picture of the virus. Well, it turns out and this is—the cartoon represents the—the DNA structure and this is a double-stranded DNA virus. The genome of the virus and—and you can see it; it only encodes a very small number of gene products, so this virus doesn’t produce a lot of different proteins. The two in blue L1 and L2 encode proteins that end up in the capsid and form the outer shell of this virus and some of the bad actors over here are the ones that cause the development of cancer when they integrate into the human genome.

But what all of these guys did in one version or another was to take the gene encoding the L1 capsid protein and they put it into some sort of an expression vector. It could be yeast, it could be a baculovirus, an insect cell system, and then they got just the expression of the L1 protein. So just the sub-units that make up these little capsids, and what was really curious is that the individual pieces of protein self-assembled to form these pentamers these little clusters. And then the next thing that happened were these pentamers self-assembled. You didn't have to do anything to form this golf-ball-like structure that was hollow and empty in this case and that was referred to as a virus-like particle.

If you take these particles and you inject them into human beings you’re giving them absolutely purified protein that’s in this three-dimensional structure that looks like a virus, and so all four of those groups were key to—to discovering the fact that you could create this structure and demonstrated that these—when you put them into animals were highly immunogenic.

So two different companies bought the rights to their discoveries. Merck and—and GlaxoSmithKline, both licensed the technology and began work on trying to develop these—these virus-like particles into vaccines. Now the L1 component of the outer shell of the viruses are unique to the specific HPV type. So the capsid from the L—from the HPV type 16 doesn’t protect you against infection with HPV 18. They’re very specific. So if you’re going to make a vaccine against HPV 16 you’ve got to use the HPV 16 virus-like particle. So you get the idea, if there’s 30 different causes of cervical cancer theoretically, you need 30 different types of virus-like particles. But you’ve got to start somewhere and so they focused on the two most common causes of cervical cancer responsible for about 70% of the cases in the United States. And that’s HPV 16 and HPV 18.

HPV 6 and 11 are the most common causes of genital warts; Merck took the strategy that—they made the discovery that men don’t have a cervix [Laughs]. That was a landmark discovery. And so you’re not going to give a man 16 and 18 to protect them against cervical cancer. So if you want a vaccine that you’re going to use in both men and women then you’ve got to put something else in there as a rule. So they added 6 and 11 to protect men against genital warts and it also protects women against genital warts.

GlaxoSmithKline decided they just wanted to focus on women’s health and so they went with the same 16 and 18 and both of these vaccines were approved—Gardasil, the four-valent product by Merck was approved in June of 2006. And the GSK vaccine was approved in October of 2009. From the time GlaxoSmithKline started working on this, they acquired the rights to use the technology in 1998; it took them 11 years. It should have been a little quicker than that to get a licensed product. So the time frame was really quite dramatic and for Merck it was probably a little bit less time than that, so in less than a decade we went from intellectual property to vaccines on the market.

So this is—this is a little bit of a thought for the scientists and some for the advocates in the audience. And that is the question—what do you want a vaccine to do? Do you want it to prevent infection? Do you want it to prevent disease? Now that would seem to be a simple question, but in 2002 I wrote a review article; we were working on herpes simplex virus vaccines at that period and we said vaccines protect against disease and not infection. And one of the reviewers who read the article in review said—wrote back and said everybody knows that; you don’t have to say that. And the other reviewer wrote back and said that’s not true. So that—that was a little bit surprising.

And so we’ve spent a decade trying to figure out what do vaccines actually do? By and large they protect against disease. They—but they certainly can protect in some circumstances against infection. The other issue comes up is just how effective can a vaccine be? Can a vaccine be more effective than natural immunity? If you get measles, you won't get measles again, but getting measles the first time could be a deadly experience. So what you’d like to do is have a vaccine that’s better than what you get from natural infection but by and large that’s not what happens. So, one of the great success stories around the HPV vaccine in studies involving over 40,000 young girls and women were that the vaccines have been found to be remarkably safe, but very, very efficacious. These are probably some of the most effective vaccines ever developed. They protect against persistent infection, so what happens in the case of cervical cancer is you become infected and you don’t clear the virus. It stays within you for a very long period of time and that can lead to—to cancer. And in this case, what it does is this vaccine actually prevents the establishment of a persistent infection and if you don’t have persistent infection you don’t develop cancer.

The main downside to the vaccines at this point are the fact that they only contain a limited number of HPV types but Merck at the moment is working on a vaccine that would contain many, many more HPV types so that we—we will have coverage against hopefully all of the HPV types that cause genital and—and oral cancer.

Right now because we don’t have complete coverage against all the types that cause cervical cancer we’ve not been able to eliminate the need for Pap smears. But with much broader vaccines, the hope is that we will have elimination of Pap smears. So if one could imagine that they could have daughters or granddaughters who never have to go through the experience of—of a Pap smear. So I don’t want to get into this a great deal with you. We recommend that the vaccine be used in 11- or 12-year old females for prevention of cervical cancer, pre-cancers, and HPV—I’m sorry—genital warts. And that’s with the four-valent vaccine.

Why do we give it at such a young age? We give it at such a young age for two reasons. One is we found that young girls 11, 12, 13 make a much more robust immune response. I mean they’re really revved up to make a response that we think will last for decades, and the older you get, believe it or not, like so many other things, your immune system doesn’t behave quite as it did when you were younger. The—the other reason we do it is—is because you have to use this vaccine before people become sexually experienced and get exposed to the pathogens because once you’re infected the vaccine doesn’t work against clearing the virus. And there are plenty of data from the Centers for Disease Control about how quickly young women become sexually experienced in this country. But this is a good age. It also ties into an age where we’re immunizing young girls against meningococcal disease and we’re boosting them for other diseases, so it fits in nicely in that regard.

In 2009 the indications were expanded because there were good data that indicated that in boys the vaccine could also protect against genital warts so we started immunizing boys. But the difference and—and this is one for you to consider perhaps when you think about how policy impacts things; for girls, we make a universal immunization recommendation. All girls should get this vaccine. For boys, it’s a permissive recommendation. We almost never do that. But the Centers for Disease Control and the ACIP made the recommendation boys can get it or not get it; it’s really up to the boy. And it’s regrettable I think that—that was the recommendation. It’s really based on cost effectiveness, and we know it works. The question is—is it cost effective? And then last year at the end of the year, the FDA further expanded the indication of the vaccine for prevention of anal cancer and associated cancer lesions in boys and girls. And for those of you who may recall, anal cancer was the cause of death in Farah Fawcett. So it’s still a terrible disease that—because we don’t do something comparable to Pap smears for anal disease, it was missed.

So just to be aware if you come up with effective strategies the issue is always one of—are they cost effective and that’s critical in getting funding these days for implementation?

So what are the barriers to HPV uptake? A lot of people did a lot of work to create remarkable products that will save lives. There are barriers to having everybody use them. There’s cost; it’s an expensive vaccine. It’s probably in the range of about $400 for the three-dose series. We have infrastructure issues here and globally; it’s not always easy to move the vaccine around the globe. And certainly the cost is an impediment for it being used in places that don’t have Pap smear screening strategies. We have implementation strategies that are problematic. In this country, the reason that we get people immunized is because we mandate it for them to go to school. Whereas in other parts of the world, they have school-based immunization so while the children are right there at the school you immunize them. That’s not the U.S. approach.

Policy—universal versus permissive can influence uptake and then misinformation. Misinformation is an interesting one. There are people out there saying the vaccines are unsafe. My personal favorite one as a pediatrician is that the HPV vaccines cause people to be promiscuous. And if you can read the slide it—it—this young girl is being turned on by receiving the vaccine. So we laugh at it but the reality of it is—is that misinformation can really be deadly. There are—I could tell you a number of examples of people who are afraid of vaccines and didn't get their children immunized and their children ended up acquiring a deadly or a damaging disease. So counteracting misinformation is really important.

And I’m going to come back to Ian here and the notion that certainly with some cancers one catches them and one can prevent it. The other slide though, Ian didn't win a Nobel Prize. Ian was selected to be Australian Man of the Year and—and this was Ian—yeah. Yeah; Ian points out that they’re talking about the vaccine and not him. So but I think this speaks to the importance—the—the Australians appreciation for the importance of the—the public health impact of this product, and so I mean this is an incredibly important discovery.

So I just want to end with two slides. You know if you’re engaged in a war against a disease and—and this was mentioned earlier you know cross-fertilization enables new ideas and new approaches. And it’s meetings like this that are really critical to create that kind of fertile transfer of approaches and ideas. But advocacy and advocates are really important as well in this—in this battle. You—you heartened scientists and clinicians—and I got to tell you; it can be remarkably lonely in the laboratory—lab work is boringly redundant and tedious and goes on forever and so knowing that people appreciate the importance of the work that you’re doing makes those long hours and disappointments really bearable. So you really do hearten scientists and the clinicians in the trenches. But it also emboldens in the policy makers and politicians who have got to find the funding to continue to support this kind of effort.

Here you see the Cervical Cancer Awareness Group and I love this little slide with the Band-Aid on the injection site. So I’m just going to end with this one. There really has been in our lifetimes countless successes and breakthroughs and they’re really everywhere—polio, smallpox, Haemophilus Influenza B and these are the ones I know. When I started in my training there were seven vaccines for children and we now have 14. And so there are things that—diseases that our children will never experience or see I hope because of these discoveries and being translated, so I’ll just end with that. Thank you.