Reported by Nancy Nelson
March 21, 2003
While vaccines to prevent infectious diseases such as measles, mumps, and polio have been
available for decades, prevention vaccines for cancer have been much slower to reach the commercial
market. To date, the only cancer vaccine licensed by the Food and Drug Administration is a prophylactic
vaccine against hepatitis B virus, an infectious agent associated with liver cancer.
However, it seems very likely that a second prophylactic vaccine will reach the market in the next
few years. The promising contender is a vaccine against human papillomavirus (HPV), the primary cause
of cervical cancer. Early results from a trial conducted by Merck & Co., Inc. in 1,500 young women
showed that the vaccine was 100 percent effective in preventing persistent HPV infection and low-grade
cervical cytological abnormalities attributable to a strain of the virus known as HPV-16.
(N Engl J Med 2002;347:1645). This type of HPV accounts for about half of the cervical cancer cases
world-wide. (For more information on HPV types, see BenchMarks April 2002.)
Douglas Lowy, M.D., a National Cancer Institute (NCI) scientist since 1975, has conducted research on the
molecular biology and growth regulation of tumor viruses as well as early phase human trials of a vaccine
against HPV-16 (J Natl Cancer Inst 2001;93:284). He and his NCI colleagues developed the technology that
underlies the candidate prophylactic HPV vaccine. He is chief of the Basic Research Laboratory and the
Laboratory of Cellular Oncology at the Center for Cancer Research, where he also serves as deputy director.
He was interviewed by Nancy Nelson.
It seems as though the HPV vaccine would be most useful in developing countries, not only because 80
percent of the cases of cervical cancer occur in those countries, but because of the high cost of Pap smear
screening and follow-up. Is that true? (In the United States, these costs are estimated to be $5 billion
every year.)
Dr. Lowy: It depends. We have enough money for routine Pap smears. If everyone had routine Pap smears, we could prevent
almost all cervical cancers today. However, the developing world doesn't have the same financial resources,
and the preponderance of cervical cancers occur in the developing world. There is really no alternative in the
developing world, so the opportunity to save lives and reduce the incidence of cervical cancer is greater there.
Having said that, the vaccine could have a tremendous impact on women in the developed world. In the short term,
it would reduce the incidence of serious abnormal Pap smears. There's a lot of anxiety as well as morbidity that goes
with those. It would also reduce the number of follow-ups needed for abnormal Pap smears and the number of surgeries
needed for high-grade dysplasia.
One of the ironies is that the impact of the vaccine will be felt sooner in the developed countries than in the
developing world. That's because changes in the cervix occur relatively soon after infection. Let's say that today
you could implement world-wide vaccination. What would happen five years from now? In the developed world, there
would be a reduction in abnormal Pap smears and a reduction in need for surgeries to treat high-grade dysplasia.
In the developing world, the impact will be zero. That's because cervical cancers don't occur until 15 to 25 years
after you get infected. So actually, you will see no benefit until you get out to that time. It's one of the
"deficiencies" of a purely preventive vaccine.
One more point is that you won't be able to eliminate cervical cancer screening because the vaccine will only
target a subset of the viruses that are implicated in cervical cancer.
Is HPV infection required for cervical cancer to develop?
Dr. Lowy: Yes. If you don't have HPV infection, you don't get cervical cancer. The latest study, published about three
years ago, showed that over 99.5 percent of cervical cancers contained HPV. Because the types of HPV linked
to cervical cancer are sexually transmitted, behaviors such as beginning sexual intercourse at an early age
(especially age 16 or younger) and having many sexual partners increase the chance that a woman will develop
an HPV infection in the cervix.
Is HPV infection alone enough to cause cervical cancer?
Dr. Lowy: Most people don't develop cervical cancer after infection. Even an infection with high risk HPV-16 is usually
a self-limiting infection. You get it and it goes away. Probably at least 80 percent of HPV-16 infections end
up going away -- maybe 90 percent. Somewhere between 10 to 20 percent of HPV-16 infections will be associated
with some cytological abnormality. A smaller proportion will persist and go on to become cervical cancer.
Besides exposure to HPV, what are other risk factors for cervical cancer?
Dr. Lowy: The biggest clearly identified risk factor is immuno-suppression. Survivors of renal transplant, AIDS patients,
and people with impaired cell-mediated immunity are at high risk of persistent HPV infection, high-grade dysplasia,
and cervical cancer. Beyond that, there is epidemiologic evidence implicating smoking. It makes some sense because
there are carcinogens in cigarette smoke that can be found in the vaginal tract.
You published a paper in February 2001 in the Journal of the National Cancer Institute showing proof-of-principle
for your HPV vaccine. Could you briefly describe how the vaccine was made and the results?
Dr. Lowy: The vaccine we used consists of several copies of an HPV-16 protein, L1. By way of some background, our breakthrough
observation in 1992 (Proc Natl Acad. Sci USA 1992;89:12180-12184) showed that multiple copies of the L1 protein alone
can join together to form a 3- dimensional structure that resembles the virus - it has the shell of the virus but without
the viral genetic information inside. When assembled, the L1 proteins are called virus-like particles, or VLPs. Besides
this ability to self-assemble, our further work showed that vaccinating animals with the VLPs of animal papillomaviruses
protected them from subsequent viral challenge (J Virol 1995;69:3959-3963 and Virology 1996;219:37-44). All of this
earlier work led us to believe that the L1 protein of HPV-16 would be a good candidate for a human vaccine.
Using insect cells, we made a relatively pure preparation of VLPs that we used to immunize normal volunteers, looking
for safety and immunogenicity.
There were four bottom line results. The vaccine was very well tolerated. There were almost no side effects due to
the vaccine itself. The second point was that everybody sero-converted and developed high levels of neutralizing
antibodies. No one was resistant. The third finding was that at the high dose, you didn't need adjuvant. The last
point is that the levels of antibody that people developed were similar to levels that protected animals against
infection with animal papillomavirus. So, while you couldn't say the level of antibodies in humans was protective,
you could say that people behaved the same way as rabbits and mice, in terms of making robust immunological responses.
Are you continuing to use the vaccine in future trials?
Dr. Lowy: We've tested the vaccine in a larger group of women to confirm the results. In phase II trials involving about 100
women, we found that the vaccine induces a durable antibody response. When we measured the antibody level six months
after the last vaccination, there was a three-fold drop in level compared to one month after the last vaccination, and
that's considered a small drop in level. So, the response is durable.
The other thing we did was to measure antibody at the cervix. We found antibody at the cervix.
There is one wrinkle, however. The level of the antibody is different for women who are on oral contraceptives compared
with those who are menstruating. For women on contraceptives, the levels are constant, whereas for menstruating women,
the antibody levels vary by a factor of 10, depending on where you are in your ovulatory cycle. Whether this has any
implications for protection, we don't know, but we're going to look into it.
What other HPV vaccine trials are taking place?
Dr. Lowy: Merck has embarked on a large phase III trial with a vaccine against HPV types 16, 18, 6, 11. (Types 6 and 11 cause
genital warts.) Tens of thousands of women in the United States, Latin America, Europe, Asia, and Australia are
involved. GlaxoSmithKline is testing a vaccine against types 16 and 18.
The question now is, can you make a commercial vaccine that has multiple components that will be highly protective.
Merck already has immunological data that they reported in October at the HPV international conference. They found that
the immunological response to HPV-16 in the four-component vaccine is as good as the response to HPV-16 alone. In other
words, there's no suggestion of attenuation of the response as a consequence of giving multiple HPV types.
It seems like everything looks extremely hopeful for these vaccine trials. Dogs, rabbits, and calves were
protected against papillomavirus infection with similar vaccines, and the early results from human trials seem to be
very favorable. Is there any reason to believe that things won't go fabulously well?
Dr. Lowy: It's as good as you could hope for. It's an immunogen that people see normally. You're just giving them more of it.
On the other hand, it's possible that out of 20,000 people, two might have a terrible side effect. We certainly hope
that's not true, but we really don't know that now, because the vaccine hasn't been given to 20,000 people. However,
barring that, it's hard to imagine that if there's as much protection as you see in the Merck trial, that you won't also
get protection with a multivalent vaccine. At this point, if you didn't see protection, you might say, "Well, somebody
made the vaccine wrong."
Is immunizing men just as important as immunizing women?
Dr. Lowy: It is assumed in the developed world that it will be recommended that men be immunized, but it is not such a straight
forward issue. There are several points. The first is that at the moment there is no evidence that immunizing men is
beneficial. It might be useful to do studies that indeed show that the vaccine would have some protection -- not so
much to protect men against HPV-16, but to have a rationale for immunizing men as a way to protect women.
The second issue is that the more protective the vaccine is for women, the better off you would be in immunizing all
women, rather than immunizing two-thirds of men and two-thirds of women. You would get more protection if you immunize
100 percent of women, rather than immunizing two-thirds men or two-thirds women. To make the vaccine more relevant to
men, Merck is incorporating HPV-6 and HPV-11, which are the main causes of genital warts, which are as big a problem
for men as women. If there is a reduction in infection with those HPV types, then men would get a direct benefit.
But, on a population-wide basis and from a public health point-of-view, the most important thing is to immunize
women. If you have enough money, you may want to immunize both men and women. But the rationale for immunizing men
is not as strong as women.
### |