Source: www.scientificamerican.com
Author: Dina Fine Maron

A winner of this year’s Lasker Awards talks about his work with HPV

Imagine a vaccine that protects against more than a half-dozen types of cancer—and has a decade of data and experience behind it.

We have one. It’s the human papillomavirus (HPV) vaccine, and it was approved for the U.S. market back in June 2006. It can prevent almost all cervical cancers and protect against cancers of the mouth, throat and anus. It also combats the sexually transmitted genital warts that some forms of the virus can cause.

On Wednesday, two researchers who completed fundamental work on these vaccines received one of this year’s prestigious Lasker Awards, a group of medical prizes sometimes called the “American Nobels.” Douglas Lowy and John Schiller, whose research provided the basis for the HPV vaccine, were selected alongside a researcher who separately unraveled key aspects of metabolic control of cell growth. Planned Parenthood was also given an award, for its public service. Lowy and Schiller, who both work at the U.S. National Cancer Institute (NCI), received the Lasker for their research on animal and human papillomaviruses—work that enabled the development of a vaccine against HPV-16 type, a form of the virus that fuels many HPV malignancies. The duo’s experiments proved that the vaccine is effective in animals, and they also conducted the first clinical trial of an HPV-16 vaccine in humans. That gave pharmaceutical companies the evidence they needed to invest in their own vaccines designed to protect against multiple kinds of HPV, and ultimately led to the versions administered around the world today.

Yet HPV shots have had a difficult run. Despite overwhelming evidence of their safety and effectiveness, in some developed countries—including the U.S.—HPV inoculations face opposition from individuals and groups that fear the shots are still too new and unproved to use on their children. The HPV vaccine also faces another hurdle beyond other routine pediatric shots: the virus is transmitted via sexual contact—which some parents and communities believe teens should not or will not have, and thus that the shots should not be mandatory. (The U.S. Centers for Disease Control and Prevention [CDC] currently recommends administering two doses of the vaccines to children 11 to 12 years old, administered at least six months apart.)

Scientific American spoke with Schiller, a virologist, about his and Lowy’s award-winning HPV research, their future plans and how to combat anti-vaccine attitudes.

[An edited transcript of the interview follows.]

What’s the biggest hurdle to getting more coverage with the HPV vaccine?
The biggest problem is actually not in the West or most developed countries; it is in the lower- and middle-income countries because of availability there and vaccine prices that limit availability. In those settings vaccine acceptance is actually very high. But those settings present the biggest problem, since some 85 percent of cervical cancers occur in low-resource settings. In the more developed countries there are many different factors involved [in vaccine hesitancy], and they differ by country. In the U.S. it is more about fear of vaccines in general. And there are some issues with HPV vaccines specifically related to this being about a sexually transmitted disease.

So far, more than 270 million doses of HPV vaccines have been distributed worldwide. But in the United States, by 2015 only 28 percent of teen males and 42 percent of teen girls had received the full course of three shots then recommended by the CDC. How can the science community help combat HPV vaccine hesitancy?
There are quite a few studies that show one of the biggest issues is that the vaccine is not being promoted sufficiently by pediatricians and general practitioners. If you look at other vaccines like for meningitis and hepatitis B—which are also administered to adolescents and could be given in the same visit as HPV—they are given at greater rates than HPV. So, there is some disconnect in communication between pediatricians and parents there. Part of the problem here is that the HPV vaccine is a prophylactic vaccine to prevent a disease—cervical cancer—that those providers never see. Obstetrician-gynecologists see it, but pediatricians don’t, which is the opposite of most other childhood or pediatric vaccines. Right now it’s being singled out as something special instead of treated as a routine childhood or adolescent vaccine. But we’ve had this vaccine for 10 years now and it’s not the new kid on the block anymore.

Mounting evidence suggests that among people who feel vaccines are unsafe, any new data showing that they arereally safe does not move the needle to convince them. So, what can be done?
My feeling is that there is a certain percentage of people who, no matter what facts you present to them, they are just not going to be convinced. Quite frankly it doesn’t pay to spend a lot of resources trying to convince that relatively small fraction. What we need to focus on is a much larger fraction of the population who aren’t having their kids vaccinated for reasons like convenience—like it’s a hassle—or they just need a bit more information to make them comfortable. People against all vaccines, those people would not be convinced to get an HPV vaccine so it’s not worth spending a lot of resources on them. I think one of the things that would increase HPV vaccine coverage would be allowing people to get them at their local CVS. I’m not an expert on this, but I have a daughter who as a teen spent much more time at the local CVS than at her local Kaiser clinic. Different states have different laws about which vaccines can and can’t be delivered at pharmacies—but if someone could go get an HPV vaccine at the same place they get their flu vaccine, presumably it would lead to an uptick.

I see you studied molecular biology as an undergrad at the University of Wisconsin–Madison. Did you always want to work on vaccines?
No, absolutely not. When I first started out I was an academic purist and thought you should study knowledge for its own sake. I was fascinated by molecular biology. When I first heard about the way metabolism works in bacteria, plants and humans, that just wowed me because that was a common feature of all life. I just wanted to study that. I thought people who did translational work were sort of selling out to the man—this was in the 1970s. I didn’t get interested in vaccines until much later. Now, I’m very fascinated with translational research.

So, what changed?
It was a very gradual thing. To this day we still do basic research, and it’s still intrinsically valuable to do basic research because you don’t know when it will lead to a transformational breakthrough.

What led you to work on HPV?
When I had just joined the field, suddenly there was this discovery that made papilloma viruses important for human health as opposed to just an understanding of how cells become cancerous. I had joined Doug Lowy’s lab at the National Cancer Institute as a postdoc back in 1983, and the second lecture I went to there was by Harald zur Hausen—who later won the Nobel Prize—and his lecture was saying “eureka! We found a virus that seems to cause 50 percent of cervical cancers”—and that virus turned out to be a human papilloma virus strain, HPV-16. So basically we went from looking at a model about how a normal cell transforms to become carcinogenic to something probably involved in causing human cancer. It was somewhat serendipitous.

What are you working on now?
One thing we are doing at the NCI, and cosponsored by the Bill & Melinda Gates Foundation, is testing if one dose of HPV vaccine is enough to provide long-term protection. It would be transformative, especially in the developing country setting, if you could just have one dose at a younger age. This new trial is going to be done in Costa Rica in collaboration with the Costa Rican government. That’s the site where we had done a prior pilot trial that suggested one dose may be enough.

We are also looking into cancer immunotherapy work. It turns out that these virus-like particles that we work with for the HPV vaccine—these are typically the outer shell of a virus, like from the HPV-16 strain or other animal, or human papilloma virus particles—have a unique ability to infect tumor cells and bind to them specifically. So we are using that knowledge to develop cancer therapies that are broad-spectrum. It turns out these cancers, like melanoma, do bind these particles, specifically.

One other thing we are doing is trying to develop vaccines that would treat herpes simplex infections and HPV infections in the female genital tract. Again, this would take advantage of these virus-like particles’ structures.

Last year I interviewed Michael Sofia, who won a Lasker Award for his hepatitis C vaccine work. The name of that vaccine, sofosbuvir—brand name Sovaldi—is a nod to his last name. But the National Institutes of Health (NIH) do a lot of early-stage research, and then it’s passed off to private companies that develop it further. Your name isn’t part of the HPV vaccines Gardasil or Cervarix, for example. Is it frustrating doing a lot of that behind-the-scenes work?
It’s funny because I would never have thought of that. It would have never entered my mind to name a vaccine after ourselves. We are so used to doing this translational work. My job is to move a project along so it’s interesting enough for a company to invest hundreds of millions of dollars for the benefit of large numbers of people. NIH doesn’t have the money to do phase III trials for lots of drugs, and even if they did it wouldn’t lead to all the drugs we need—because NIH wouldn’t have the money to develop them. This translational and basic research is what NIH does best. That work is way too fraught with failure for companies to do it all. It has to be done in the public sector, and then when things look more promising companies can take it over.

What advice would you offer someone considering becoming a scientist now?
It’s got to be a passion because being a scientist—especially early in your career—is more a lifestyle than occupation. You have to really want to do it, because there is a lot of uncertainty—especially about running your own lab and getting funding. Success and failure can be on a knife’s edge sometimes. The other thing is that you need to be strategic about thinking of what you want to go into, and that’s hard for young people because they don’t have the perspective: There are some fields just opening up ripe for discoveries. And there are some areas that are very mature, that we have been working on for a long time, where there are a lot of scientists working already—so the chances of making a big impact are lower. From my own life, this is like when we started with human papilloma viruses. When I went into this field, we had just been given the tools to study them and so it seemed like a great opportunity to get involved. In some ways it’s best if you can pick an emerging field with new tools to answer big questions. But you have to pick something you are really interested in and go with it.

The other thing I’d say is read a lot. Now with PubMed and access to all these journals there is no excuse for not knowing the background in something that basically has already been done. Young people tend to want to get out and do experiments, but a few days searching PubMed may save someone years of work trying to reinvent the wheel.

Right now, what would you say is the biggest challenge—or one of the biggest challenges—that needs to be solved?
That’s a really tough one. I think as scientists we are all sort of locked into the things we study. I could say cancer, obviously. But Alzheimer’s is something we obviously need to solve. HIV infection. All these different things. One of the things that really needs to be solved in terms of the whole scientific enterprise now is stable funding. Right now we are in a situation where there are too many good scientists—especially young scientists—competing for a limited pot of money. So you lose some good people because there’s not enough money to go around. Also, people are forced to do relatively mundane things that are really a methodological extension of something they’ve done before instead of something truly transformative that would have a large chance of failure. Grant reviewers are looking at something likely to succeed and move the field incrementally, or something transformative that may have a high chance of failure, and have to make those decisions. This is an issue across the sciences. The obvious solution would be to have more funding, but then that raises the question about how to do that. And I’m not a politician.

What, if anything, does this Lasker Award do for your work?
Quite honestly, probably nothing, because one of the nice things about being part of intramural research [at NIH] is that I have stable funding. I’ve had six people in my lab for the last 25 years, so this won’t lead to more grants or me doubling the size of my lab, or anything like that. I’m happy with my moderate-sized lab and collaborations with a lot of great people. That’s why I’m here. Every four years we have a site visit, which is a retrospective review of “what have you done for us lately,” and if it’s reasonable I will continue to get funding. So the award won’t affect my research career much at all.

Right now, some in the scientific community fear amid this political climate that facts matter less than they once did and thus science matters less. What’s your take on that?
Obviously, my perspective is science matters a lot. I really can’t comment on what’s happening in the country overall—and whether this is something that is pervasive where science is really held in less esteem, or it’s that there is a vocal minority being heard a lot now. I would hope it’s the latter.