Headlines around the globe recently proclaimed a new weapon in the war on cancer: a vaccine that may block most cervical cancers. The excitement was certainly justified; it's not every day an annual killer of 290,000 women worldwide is threatened with extinction. But few know the whole story of the vaccine's development. Its roots lie in the lab of Dr. Denise Galloway, as well as laboratories in Australia and NIH, where she and fellow investigators accomplished the groundbreaking step of getting a key viral gene to assemble into particles that look like the human papillomavirus (HPV).
Merck & Co. announced on Oct. 6 that their investigational vaccine, Gardasil, prevented 100 percent of high-grade cervical pre-cancers and non-invasive cervical cancers associated with infection by HPV types 16 and 18 in an ongoing clinical trial. More than 12,000 women from 13 countries participated in the study.
The vaccine was designed to target HPV types 16 and 18, which account for 70 percent of cervical cancers, and HPV types 6 and 11, which cause 90 percent of genital warts. These four types also cause benign cervical changes that result in "abnormal" Pap tests, the commonly used screening test for cervical cancer. Cervical cancer is a leading cause of cancer deaths for women worldwide.
Galloway, head of the Program in Cancer Biology in the Human Biology and Public Health Sciences Divisions, is thrilled about the scientific progress. "To think that in my career — not even my lifetime — we've gone from not knowing what causes cervical cancer to probably having a vaccine that will cure it. That's pretty impressive. There aren't many cancers you can say that about," she said.
That progress — while seemingly swift — has consumed much of Galloway's 26 years at the Hutchinson Center. She arrived at the Center in 1978 as a "young thing," she says, with her scientist-husband, the late Dr. Jim McDougall, a founding member of the Basic Sciences Division. Together, they made seminal discoveries that established a link between papillomaviruses and cancer.
Galloway's interest in HPV stemmed not so much from an overriding desire to halt cervical cancer, but from the virus' utility as a tool for understanding how normal cells turn abnormal. Viruses disrupt cellular pathways in much the same way as cancers do, so studying them illuminates parallel cellular processes.
The new HPV vaccine works like many vaccines. The virus has a protein coat, and if that coat is expressed — or multiplied — in cells, it reassembles itself and forms virus-like particles. The particles look just like the real virus, only there is no viral DNA inside of them. Without any DNA, they can't cause disease. But if you vaccinate people with these virus-like particles, the recipients make neutralizing antibodies. Like sponges ready to clean up an accident, those antibodies sit in the bloodstream, and if a person comes in contact with HPV, the antibodies sop up the virus before it infects cells.
A tool for antibody detection
In 1992, Galloway made a breakthrough discovery. She and her colleagues found that they could use one viral gene — L1 — from the type of HPV that causes plantar warts and get it to self-assemble and form virus-like particles. Another research group produced similar results using two genes, and a third set of researchers had comparable outcomes using L1 with bovine papillomavirus. Soon it was possible to make virus-like particles for the cancer-causing types of HPV, and that became the basis of the vaccine.
"We really developed these particles so we could detect HPV antibodies in people because we wanted to figure out who was infected," said Galloway of long-term research studies she did with Dr. Laura Koutsky in the University of Washington's Department of Epidemiology. Koutsky led the team of researchers conducting the new vaccine trials. "We wanted to find out who gets infected, when does the infection occur, how long does it persist and can you get infected with different types? The particles provided us with a tool to figure out who had antibodies already."
Galloway also collaborated for many years with Dr. Janet Daling, a PHS epidemiologist, doing case-control studies comparing people with cervical cancer and those without, to better understand why only some people who are infected with HPV get cancer.
Two pharmaceutical companies — Merck and GlaxoSmithKline — have HPV vaccines in Phase III trials with plans to license them. Galloway has worked with Merck to develop tests to measure the effectiveness of their vaccine and has provided input into statistical modeling of what the effects of the vaccine will be.
Galloway said the vaccine is an amazing breakthrough but it doesn't mean immediate eradication of HPV. "It's important to remember that this vaccine is only going to work on people who haven't been infected — basically, people who aren't yet sexually active," she said. "There are millions of people already infected with HPV that the vaccine will do nothing for. The creation of a vaccine doesn't shift my research focus. I've still got plenty of work to do."
Global delivery of the vaccine is likely to be a vexing issue due to lack of healthcare infrastructure and competing priorities for cash-strapped developing countries. The vaccine will likely be costly, as it uses a multi-shot regime like hepatitis B and because it's so new, plenty of research costs will be built into the price.
"The reason the Third World has so much cervical cancer now is because they can't afford existing, effective screening like Pap smears. Are they going to be able to afford a vaccine that prevents cancer when they need treatment for things that cause disease right now like malaria and tuberculosis? It's difficult to vaccinate somebody to protect them from something that might strike 20 or 30 years down the line," Galloway said.
The two vaccines currently being tested fight the two HPV strains responsible for causing most cases of cervical cancer in the United States and western Europe. However, there are at least 13 different types of HPV that cause cancer. In the United States, the vaccine will not protect against strains causing 23 percent of cervical-cancer cases. In other parts of the world, a higher percentage of HPV types are not blocked by the current vaccines.
"Theoretically, there's nothing to stop the companies from making virus-like particles against all of these other types. It's just really expensive," Galloway said. "So women are still going to need screenings, even in this country."
Though her professional pursuits continue, Galloway is immensely pleased to see the vaccine milestone reached. "It's been a rewarding pursuit," she said. "Being lucky enough to just make a small contribution to the process of discovery is very satisfying."
