Experimental Vaccine Appears to Prevent Cervical Cancer

By DENISE GRADY

cientists have created the first vaccine that appears able to prevent cervical cancer. The vaccine works by making people immune to a sexually transmitted virus that causes many cases of the disease.

The vaccine is still experimental and is not available to the public.

A successful vaccine could sharply reduce rates of cervical cancer, which affects 470,000 women a year worldwide and kills 225,000. In the United States, there are 13,000 cases a year and 4,100 deaths.

In a study of 2,392 young women, half of them vaccinated and half given placebo shots, the vaccine was 100 percent effective: followed for 17 to 27 months, no vaccinated woman developed infections or precancerous growths from the virus, whereas 41 non-vaccinated women did become infected, including 9 with precancerous cervical growths. A report on the study is being published Thursday in The New England Journal of Medicine.

"These are tremendous results," said Dr. Laura A. Koutsky of the University of Washington in Seattle, director of the study, which was carried out by researchers from 16 universities and Merck Research Laboratories. Merck made the vaccine and paid for the research.

"It's very encouraging that there will be a vaccine to prevent invasive cervical cancer," Dr. Koutsky said.

An expert not connected with the study, Dr. Carol L. Brown, a gynecologic cancer surgeon at Memorial Sloan Kettering Cancer Center in New York, called the study "highly, highly significant and very exciting."

"This has the potential if it pans out to be a really effective way of preventing cervical cancer," she said.

By preventing the virus from persisting in the genital area, the vaccine can also help prevent people from spreading it to sexual partners.

The vaccine described in The New England Journal of Medicine was made only to test whether people could be made immune to one type of the cancer-causing virus, and it is not the vaccine that Merck hopes to market, company officials said. Merck is already testing a new version that will work against multiple virus types, but that one will not be ready for several years, a company scientist said. The vaccine will be used to prevent cervical cancer, but will not be able to treat it. As a preventive, the vaccine will have to be given to girls and young women before they become sexually active, to make sure they have not already been infected.

But researchers cautioned that the vaccine would not do away with the need for Pap tests to screen for cervical cancer, because not every virus that can cause the disease will be prevented by the vaccine.

Dr. Allan Hildesheim, a senior investigator at the National Cancer Institute, called Merck's results extremely promising, but, he said, larger and longer-term trials were needed to make sure the vaccine is safe and effective, especially since it is intended for large numbers of young, healthy people. He said researchers at the cancer institute were also developing a cervical cancer vaccine. So is GlaxoSmithKline, a spokeswoman for the company said.

Most deaths from cervical cancer occur in developing countries where women do not have regular Pap tests, which can prevent the disease by detecting abnormal growths early so that they can be removed before they turn cancerous. Vaccination is less complicated than cancer screening programs, and may be a more practical option in many parts of the world.

"For individuals in countries with no screening, vaccination is a lifesaver," said Dr. Kathrin U. Jansen, senior director of microbial vaccine research at Merck.

In the United States, where 50 to 60 million Pap tests are done every year, a great benefit of a vaccine would be a drop in the number of women who, because of the virus, have abnormal Pap tests and then need repeated examinations and tests to look for cancer. Most of the abnormalities will not turn cancerous, but it is hard to predict which ones will, so all must be monitored. Some women have surgery they may not truly need. By preventing the infections and abnormal growths, a vaccine could spare close to a million women a year the worry, expense and unpleasant procedures. Cost savings could be in the billions.

In an editorial in the medical journal, titled "The Beginning of the End for Cervical Cancer?" Dr. Christopher P. Crum wrote that if an effective vaccine becomes available, "The captives of our current system — both patients and their caregivers — may be set free." Dr. Crum is director of women's and perinatal pathology at Brigham and Women's Hospital in Boston.

There is now only one widely used vaccine that prevents cancer: the vaccination against the hepatitis B virus. In parts of Africa and Asia, chronic infection with that virus is a major cause of liver cancer, and, Dr. Crum noted, rates of both the infection and the cancer have dropped markedly in areas with vaccination programs. Like the cervical cancer vaccine, the one for hepatitis B prevents cancer in an indirect way, by blocking infection with the virus that causes the cancer.

A few other types of cancer, including certain types of leukemia and lymphoma, have been linked to viruses, but vaccines for them do not exist. Common cancers like those of the lung, breast, prostate and colon are not known to be associated with viruses.

Dr. Koutsky said that when she lectures about her research, people often suggest that many parents, loath to acknowledge that their teenage daughters could be sexually active, may refuse the vaccine.

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But Dr. Koutsky said she disagreed, noting that parents today grew up in a era when sexually transmitted diseases became rampant, and that many women had suffered the anxiety of abnormal Pap tests and would want to spare their daughters that experience.

"I think a generational shift has occurred, where most parents recognize that their children will make decisions about sexual activity that they have no control over, and they want them to be protected," Dr. Koutsky said.

More research is needed to find out how long the vaccine protection lasts, she added.

Almost every case of cervical cancer is caused by viruses belonging to a group called human papillomaviruses, which are sexually transmitted, very common and hard to avoid. Condoms may help prevent transmission, but not as well as in other sexually transmitted diseases, probably because the papillomaviruses are spread by skin contact, and inhabit more territory than a condom covers.

More than 30 types of the virus infect the genital area in people, and more than half the adults in the United States have been infected with one or more types at some time, Dr. Koutsky said. Not every type causes cancer. Even with those that do cause cancer, the infection is harmless in the vast majority of people, and their immune systems either eliminate the virus or suppress it to levels too low to detect. They then become immune to further infection.

But in some women the virus persists and causes lesions on the cervix. Most of the lesions go away, but some turn cancerous. On average the cancers take about 20 years to develop, but some can emerge much faster. Teenage girls and young women in their early 20's are more prone to develop lesions than older women, possibly because normal cellular changes in the cervix during those years make it more vulnerable to the virus, Dr. Brown said.

One type of human papillomavirus, HPV-16, is most commonly linked with cancer; it is found in 50 percent of cervical cancers. Another type, HPV-18, causes 20 percent. Others cause the rest. Still other types of human papillomavirus cause genital and anal warts in both men and women, which are not cancerous but can be extensive, ugly and difficult to treat.

In trying to develop a vaccine, the researchers chose as their target HPV-16, the leading cause of cervical cancer. They made the vaccine by splicing a viral gene into yeast so that the yeast would produce a protein normally found in the outer shell of the virus. The protein, also called a virus-like particle, is the vaccine. It cannot cause infection, but it so resembles the whole virus that it sparks the patient's immune system to make antibodies that fight off HPV-16.

The vaccine that Merck is now testing, and hopes to market, will immunize patients against both HPV-16 and HPV-18, which together cause 70 percent of all cases of cervical cancer. The vaccine will also protect against two other HPV types, 6 and 11, which cause about 90 percent of genital warts.

The wart protection was included to "give incentive to young men to also take the vaccine," Dr. Jansen said.

She explained: "Men don't get cervical cancer. I always strongly felt that if we only go for cervical cancer types, there would be no reason for men to accept the vaccine. Even though they are vectors for transmitting the virus, they don't usually have effects."

But men do get genital warts, and many young men are eager to avoid them since they are ugly and may repel potential sex partners, Dr. Jansen said.

People who want information about entering the study can call Merck at (484) 344-4804 or (404) 344-7337.

She and Dr. Koutsky said that future vaccines may also act against more of the virus types that cause cervical cancer. Dr. Hildesheim said that would be an important improvement. Best of all, he said, would be a vaccine that would prevent infection in unexposed women and also treat it in those who were already infected. He said researchers were trying to develop vaccines that could treat the infection.

The subjects in the HPV-16 study were 2,392 young women, ages 16 to 23, who were picked at random to receive three doses of either the vaccine or a placebo during six months. But the results were based on only 1,533 women; 859 were excluded from the final data analysis, some for various technical reasons and 510 because they were found to have been infected with HPV-16 before being vaccinated, and the vaccine does not work in people who are already infected.

The only women who became infected were 41 members of the placebo group, 9 of whom also developed precancerous lesions. The lesions were treated; it would have been unethical to leave them alone to see whether cancer developed. But the researchers say that persistent infection with HPV-16 is so strongly associated with cervical cancer that it can reasonably be used as a surrogate for cancer. The study will continue until all the women have been tracked for four years, and in the meantime, researchers have also begun studying the newer version of the vaccine, which protects against two cervical cancer virus types and two types that cause warts.