Merck’s Gardasil not cleared for older women
U.S. regulators have told Merck & Co they cannot yet approve Merck’s application to expand marketing of its cervical cancer vaccine Gardasil to an older group of women, the drugmaker said on Wednesday.
Merck had applied for the use of Gardasil in women ages 27 through 45. The U.S. Food and Drug Administration said in a letter regarding the application that it has completed its review and there are “issues” that preclude approval within the expected review time frame, Merck said.
“It’s hard to get a feel for if this is a dead issue or if this is delayed,” said Linda Bannister, an analyst for Edward Jones. “At the minimum, it’s going to be delayed.”
Merck said it also failed to win FDA approval to expand Gardasil to protect against more strains of the Human Papillomavirus that causes cervical cancer. The company for now is dropping plans to pursue that expansion, a spokeswoman said.
Shares of the New Jersey-based drug maker, which also reiterated its long-term revenue and earnings targets, fell 0.8 percent.
Gardasil, approved in June 2006 for preventing cervical cancer and genital warts in females ages 9-26, has been one of Merck’s most successful newer products and has helped the company recover after the 2004 withdrawal of its Vioxx arthritis treatment.
The Gardasil setbacks could raise concerns about the degree of growth that Merck can hope to achieve with the product, which is the world’s first vaccine to prevent cervical cancer.
A Merck spokeswoman said the agency has specific questions regarding Gardasil’s effectiveness in this older age group.
The company said it had already discussed the questions with the FDA and expects to respond to the agency in July.
“Once we go back to the FDA, we’ll have a better sense of what the review timing looks like,” spokeswoman Amy Rose said.
The agency’s response on the application for the older group does not affect Gardasil’s current approval for females ages 9 to 26, Merck said.
Global sales of Gardasil rose 7 percent in the first quarter to $390 million. Cowen and Co has predicted annual sales of the vaccine would reach $1.9 billion in 2008 and jump to $3 billion by 2012.
Edward Jones’ Bannister said she had expected Gardasil sales to reach $2.6 billion by 2012, with about one-third to come from that older age group.
Deutsche Bank analyst Barbara Ryan said failure to win approval for the older age group could reduce her $3.8 billion estimate for 2012 sales by about $300 million.
Ryan said the most important new opportunity for the vaccine will be for its use in males. The vaccine could help prevent males from contracting Human Papillomavirus and spreading it to females through sexual contact. Merck is on track to seek approval for use in males by the end of the year, Rose said.
Gardasil has benefited from lengthy delays in approval of GlaxoSmithKline’s rival Cervarix vaccine. The FDA in December issued a complete response letter for Cervarix, meaning it had completed its review of the product but had further questions about it.
Bannister said the Gardasil delay reflects broader challenges facing drug makers within the U.S. regulatory environment.
“It’s not specific to Merck,” Bannister said. “This is an industry-wide issue.”
Merck shares fell 29 cents to $36.74 in afternoon trading on the New York Stock Exchange. The shares have fallen some 37 percent this year, hurt by setbacks to its cholesterol franchise.
Cervical Cancer Vaccines May Start Soon
A cervical cancer vaccine programme is likely to be introduced in the Republic in the near future, on foot of today’s publication of a Health Information and Quality Authority (Hiqa) report.
The HIQA value-for-money report should pave the way for the early announcement of a formal immunisation programme aimed at 12-year-old girls. The report also recommends a once-off vaccination programme for 13 to 15 year-olds.
Cervical cancer is caused by certain types of the human papillomavirus (HPV), with evidence of infection found in 99 per cent of women with cervical cancer.
The Minister for Health, Mary Harney has said she would introduce a HPV/cervical cancer vaccine programme if advised to do so.
Although there are in excess of 200 HPV strains, just a small number are associated with the development of cancer of the cervix. HPV types 16 and 18 are found in almost 70 per cent of cervical cancers, while another five sub types are responsible of a further 20 per cent of cases. Some HPV types are non cancerous but are linked to the presence of warts in the genital area.
Cancer of the neck of the womb (cervix) is diagnosed in almost 200 women here every year; some 70 women die from the disease annually.
Cervical cancer usually develops quite slowly, passing through a number of pre invasive stages (carcinoma in situ - CIN) before progressing to full blown disease. If caught in the early stages, it has a five-year survival rate of 80 per cent or greater.
HPV is a sexually transmitted infection; it is estimated that almost 80 per cent of sexually active people have been infected with at least one virus type by the age of 50. It is usually symptomless and in 90 per cent of cases, the body clears itself of the virus within two years of infection. But it is when the virus persists that the risk of cervical cancer increases.
Gardasil and Cervarix are the approved vaccines against HPV. Both aim to prevent cervical cancer; in addition Gardasil is active against those HPV subtypes known to cause genital warts. Both products involve a three-vaccine course, given over a six-month period. And clinical trials involving a five-year follow-up, have shown that vaccination is 100 per cent effective in preventing HPV infection and non-invasive cancer .
HPV vaccines must be given before infection with the virus occurs. This means administering the course prior to the person becoming sexually active so that a comprehensive vaccination program would need to be administered to girls in the 11- to 13-year age bracket.
Vaccination Against Human Papillomavirus Decreases Related Tests and Treatment for Cervical Cancer
Researchers affiliated with the Quadrivalent HPV Vaccine Merck Study Group have reported that vaccination against human papillomavirus (HPV) is associated with a reduction in Pap tests, colposcopy, cervical biopsy, and definitive treatment among women who were uninfected at the time of vaccination. The details of this study were presented at the 39th annual meeting of the Society of Gynecologic Oncologists (SGO) in Tampa, Florida, from March 9 to 12, 2008.
Pap smears have decreased the incidence and death rate of cervical cancer among women in developed countries such as the United States. Cervical cancer is caused by specific high-risk strains of HPV, which can be detected by a special test called Hybrid Capture II (made by Digene).
Now that an HPV vaccine (Gardasil®, manufactured by Merck) has been approved by the U.S. FDA, further reductions in cervical cancer incidence and death may be anticipated. Gardasil is a quadrivalent vaccine because it confers protection against four subtypes of HPV (HPV 6 and HPV 11, which cause 90 percent of genital warts, and HPV 16 and HPV 18, which cause 70 percent of cervical cancers).
Despite the success of Pap smear programs and the ability to detect HPV, over 2 billion dollars in healthcare expenditure occurs annually as a result of abnormal Pap tests and their subsequent evaluation, which often requires cervical biopsies and other surgical procedures on the cervix. This is because, although Pap smears and HPV detection allow a pre-cancerous or dysplastic state of the cervix to be detected and treated before it can turn into cancer, neither of these two methods eliminate the original problem, which is infection with HPV.
The end-of-study data from three pivotal Phase II/III clinical trials of the quadrivalent HPV vaccine were reported at the SGO meeting. A total of 18,150 16 to 26-year-old women were enrolled in one of three randomized, placebo-controlled trials. Vaccine or placebo was given at Day 1, Month 2, and Month 6. Subjects underwent Pap testing on Day 1 and every six to 12 months for up to 48 months. Patients with specific abnormalities on the Pap smear were referred for colposcopy and, depending on the findings, definitive treatment was carried out.
After an average follow-up period of four years, the investigators noted a reduction in Pap tests, colposcopy, cervical biopsy, and definitive treatment among women who were uninfected with HPV at the time of vaccination. Interestingly, these reductions were seen irrespective of the specific type of HPV involved.
Comments: Vaccination with the quadrivalent vaccine appears to be able to decrease the number of Pap tests, colposcopies, cervical biopsies, and treatment women require. This occurs presumably because the vaccine protects against infection with HPV, which is the inciting event in the development of pre-cancerous cervical disease. Long-term studies are required to determine the duration of protection that is achieved by the three-dose vaccination series.
HPV Vaccine & Fainting
by Amy Fleming
Allentown, PA - Recently the Centers for Disease Control & Prevention reported that in the last two years, more than 450 youngsters fainted after getting a vaccination.
That may explain why some teenagers are taking a new position on the HPV vaccine.
Gardasil protects against a virus that cervical cancer and genital warts.
Researchers aren’t sure why, but about 10% of girls in studies for the HPV vaccine got dizzy or passed out after the shot.
The Gardasil website lists fainting as a possible side effect.
To be safe rather than sorry, doctors are proposing an easy solution.
“The recommendation as a result of this, is pretty simple. Just that you give them a vaccine either sitting sown or lying down and you watch them for 15 to 20 minutes just to make sure that they don’t have any significant reaction,” said Dr. Larry Glazerman.
The vaccine is given in a series of three shots.
For more information on the vaccine go to www.gardasil.com.
More links found between cancer in men and HPV, but men aren’t approved for vaccination
by Brian Boyer
Men are neither vaccinated nor screened for human papillomavirus, but two university studies suggested last week that it may be the cause of cancer for many men, and that those cancers could have been prevented.
The virus, better known as HPV, is the primary cause of cervical cancer in women. Recent research, at the University of Michigan and University of Louisville, suggests that it is also the cause of a disease that disproportionately affects men, cancers of the head and neck.
“You should be testing everybody,” said Payal Desai, leader of a pilot study at the Louisville’s James Graham Brown Cancer Center. Both men and women carry HPV, the virus that will affect at least 50 percent of sexually active people, according to the Food and Drug Administration, though only a fraction of those will develop cancer.
More than 35,000 new cases of head and neck cancer are expected to be diagnosed in the United States in 2008, according to the American Cancer Society. Twice as many men as women will develop the disease, which the society estimates will kill 7,590 Americans this year.
Currently a screening test only exists for women. Similarly, a vaccine for HPV exists, but is only approved for use in women ages 9 to 26. Studies are under way to test the efficacy of the HPV vaccine in men, according to the FDA.
If the vaccine were successful in preventing HPV infections in men, the studies suggest it is possible that a significant number of cancer cases in men could be avoided.
In one study, tissue samples from 43 head and neck cancer patients were tested by the Louisville team. They found that almost one-third of the samples tested positive for HPV, specifically the strain of the virus known as HPV 16.
In the other study, at Michigan’s Comprehensive Cancer Center, had similar findings. More than one-third of the 66 head and neck cancer cases they examined tested positive for HPV 16. This study’s primary finding was encouraging: The HPV-associated tumors responded significantly better to treatment than those not associated with HPV.
In women, HPV types 16 and 18 are responsible for 70 percent of cervical cancer cases. The American Cancer Society estimates that 11,070 cases will be diagnosed, and that the disease will kill 3,870 women in the United States in 2008.
Infection by strains 16 and 18 can be prevented through vaccination, with almost 100 percent effectiveness. The drug Gardasil, first made available to young women in 2006, also vaccinates against types 6 and 11, which are responsible for 90 percent genital warts cases.
Desai presented the findings of their study May 15 at the American College of Physicians Internal Medicine Conference. The results have not yet been published. The University of Michigan study was published online May 12 in the Journal of Clinical Oncology. In February, another study, at the National Cancer Institute and Johns Hopkins Medical Insitutions, suggested a link in men between HPV and oral cancer.
Boys should also get HPV protection
Kelly Sinoski, Vancouver Sun
Published: Saturday, May 17, 2008
B.C. I Boys as well as girls should be offered the free HPV vaccine to stop the spread of the cervical cancer-causing disease, former deputy health minister Dr. Penny Ballem says.
The vaccine, which will be offered by the provincial government to girls entering Grade 6 and 9 on a voluntary basis next year and women up to age 26, is not even licensed for use on males in Canada.
But Ballem insists that should change if the province is intent on controlling the spread of the human papillomavirus, which can lead to cervical cancer in women and genital warts and other cancers in both sexes.
“If you really want to wipe out a scourge, you have to go after the people who carry the virus and pass it on,” Ballem said. “There needs to be more of a burden on men in our society in protecting women.”
The virus is among the most common sexually transmitted infections in Canada. The vaccine, Gardisil, targets the two strains of the infection responsible for 70 per cent of cervical cancer.
Boys and men can only access the vaccine “off label” from their doctors if they want it but will have to pay the full cost, which is about $300 to $400 for treatment, said provincial health officer Dr. Perry Kendall.
Kendall said although there are calls to offer the vaccine to men, he doubts doctors are recommending it to males because of the high cost. Nor does he think it will be offered to the male population in the next year because it hasn’t been tested or licenced for use on males in Canada.
If it was to spend $100 million, he said, the government would likely to find other areas where the money could be better spent.
He noted it would about $8 million to vaccinate the Grade 6 girls, but said if you calculated over a lifetime how many deaths the vaccine would prevent and the quality of life for survivors, it works out to “$25,000 per quality of life adjusted year.”
For males, it would be about $35,000.
“The question is the return worth the investment?” he said.
“If the price comes down substantially it might be something you offered to both sexes.”
Kendall noted that while HPV can cause genital warts and a few hundred cases of penile and other cancers in males, it carries a higher risk for women, who can get cervical cancer and be possibly rendered sterile if they require invasive surgery to their cervix.
Cervical cancer is the second most common cancer for Canadian women aged 20 to 44, with 150 women contracting the disease each year, he said. Of those about 50 die annually.
“Far fewer boys die from cancer associated with HPV and no one dies from genital warts,” Kendall said. “We’re doing it for cancer.”
But Ballem said she doesn’t believe the decision to offer the vaccine to only girls and women was well thought out, noting there are “gaps in the coverage.”
The vaccination, which requires three shots over six months, will not prevent all cervical cancers, meaning women will still have to have annual pap smears, she said.
She added girls may even get false sense of security that sex is safer than it is because they’ve had the vaccine.
Apart from passing on the disease, she maintains that by vaccinating boys it would help boost immunity across the sexually active population.
She added women are more vulnerable to disease because they have more mucus membranes exposed to bodily fluids than men.
“The focus was never on where do they get the virus from? They get it from men,” Ballem said. “Frankly, maybe we should go after the source of HPV and the people who are spreading it around.”
University Health Services nears 1,000th course of HPV vaccine
The first cancer vaccine was supposed to be unequivocally a good thing.
The Gardasil vaccine, touted as a triumph of modern medicine, protects against four strains of human papilloma virus (HPV) that commonly cause genital warts and cervical cancer.
In the two years since obtaining FDA approval and being released by Merck, however, the vaccine has faced tremendous opposition from critics who believe that it encourages sexual activity in young women.
Adel Mahmoud, a senior policy analyst at the Wilson School and a molecular biology professor, is eagerly watching the controversy and anticipating the day when Gardasil will be routinely administered to all Americans as children.
But Mahmoud is not just a casual observer. Before coming to the University, he oversaw the development of the Gardasil vaccine during his tenure as president of Merck Vaccines from 1998 to 2006.
Mahmoud said that the search for the HPV vaccine “was very high on [Merck’s] development program” since a “discovery in the ’80s and ’90s [showed] that HPV was directly related to cervical, anal, penile, head and neck cancers.”
By age 50, 80 percent of women in the United States are infected with HPV. Cervical cancer kills 233,000 women every year, including about 3,700 in the United States.
The Gardasil vaccine protects against the two strains of the disease that cause more than 70 percent of HPV-related cancers as well as against the two other strains that cause more than 90 percent of genital warts, Mahmoud said.
About 20 million Americans and at least 50 percent of sexually active people in the world have genital warts, according to a 2005 study by the Centers for Disease Control and Prevention (CDC).
The vaccine was also widely hailed as a great success of scientific innovation because the HPV genome was particularly challenging to study and sequence. To develop an effective vaccine, the researchers first needed to understand what proteins were coded for by the genome.
Scientists are unable to culture HPV in vitro, a process needed to develop most vaccines. Nonetheless, “the HPV genome was sequenced, its proteins characterized, and their functions defined,” Mahmoud wrote in a May 2007 letter to Science magazine.
Distributing the vaccine
In June 2006, the vaccine was approved for distribution in the United States in a three-dose series over the course of six months.
Merck, like many healthcare practitioners, had originally hoped that states would mandate the vaccine for school-age girls to systematically combat the most common sexually transmitted infection (STI) in the world, HPV.
Not everyone, however, thought preventing the spread of genital warts was a good enough reason to mandate vaccination.
An ongoing controversy
Texas seemed poised to lead the charge against HPV, but heated controversy greeted Gov. Rick Perry’s executive order in February 2007 requiring that 11- and 12-year-old girls receive the vaccine. Three other states — New Jersey, Massachusetts and Virginia — mandated in 2007 that girls entering sixth grade receive the Gardasil vaccine.
“Vaccines work best when they are given before exposure to the infective agent,” Mahmoud said. “So the 11-to-12 age group was targeted for the vaccine because the idea was that this was definitely before exposure and sexual activity.”
Abstinence advocates believed the vaccine encouraged sexual activity in young girls who should instead be protecting themselves against the disease by avoiding sexual activity entirely. Legislators, on the other hand, were concerned that not enough was known about the relatively new vaccine to assure them of its safety.
The backlash against mandating the vaccine was successful.
Merck announced that same month that it would stop lobbying state legislatures to mandate the vaccine, fearing that campaigns instigated protests that actually hindered widespread adoption of the vaccine.
Following this decision, the Texas House of Representatives passed a law in April 2007 that barred the state from mandating Gardasil immunizations until at least 2011.
“We did not want to be the first in offering young girls for the experiment to see if this vaccine is effective or not,’’ State Representative Dennis Bonnen told The New York Times at the time.
Mahmoud, however, disagrees, citing the six years of vaccine testing, “which is probably more than most vaccines that come to market have. It would never have been approved by the FDA or the Europeans or the Australians if it had not been rigorously tested. They absolutely know the consequences.”
In these studies, the vaccine was found to be almost 100 percent effective in preventing HPV infection and absolutely 100 percent effective in preventing the pre-cancerous changes in the lining of the cervix that signal the beginnings of cancer.
The vaccine was initially tested on more than 25,000 women up to the age of 25, and thus, the vaccine is only approved for females ages 9 to 25, Mahmoud said.
Women who have already been infected with HPV should still consider getting the shots, Mahmoud explained, because the vaccine is effective against four strains of the virus and can protect women infected with one strain against the other three.
The FDA has not approved the vaccine for males, but Merck is currently conducting a clinical trial of the vaccine with a test group of 4,000 men. Some scientists, however, believe that waiting years for the final results of this trial could mean failing to protect an entire generation of American men and their sexual partners.
Australia and countries in Europe have already decided to give the vaccine to young men, a decision that was based on preliminary data showing that Gardasil produces an immune response in boys.
What about college students?
While legislators continue to debate mandating the vaccine for girls before they enter their teenage years and become sexually active, many healthcare practitioners are advocating that high school and college students get the shots before they get any older.
This campaign has met with only limited success, Mahmoud said, because of the difficulties associated with adolescent vaccination.
In fall 2006, University Health Services (UHS) began offering the shots to members of the University community at a cost of $402. UHS has since administered almost 1,000 doses of the vaccine, UHS coordinator for women’s and men’s health Olga Hernandez said.
Mahmoud explained that one of the biggest problems is that vaccination is widely regarded as “a childhood phenomenon.” This is coupled with the additional issue that adolescents interact with the healthcare system less frequently than other age groups. “And this [HPV is] an STI, which gives it a little bit more of a twist,” he said.
A CDC study announced in March showed that one in four females aged 14 to 19 is infected with at least one of the four most common STIs: HPV, chlamydia, trichomoniasis or genital herpes. HPV was by far the most common, affecting 18 percent of the girls who took part in the study.
Mahmoud said he thinks it’s likely that the current college-aged generation won’t be as thoroughly protected as it could be against HPV. Still, he has hope for the future.
“This was exactly what happened with the hepatitis B vaccine. When it first came out, it was also recommended for adolescents, and that was problematic, but now the first dose is given at birth, and it’s done; it protects us for the rest of our lives,” he said. “I think that’s what will happen with Gardasil, and I look forward to that day.”
Cancer Vaccine For Girls At Private Hospital
A cervical cancer vaccine for young girls, that has yet to be made available under the NHS, can be accessed at Spire Gatwick Park Hospital – part of independent hospital provider Spire Healthcare.
The vaccine is administered in three doses and protects against the human papilloma virus (HPV). It is believed to reduce the incidence of genital warts by 90%, cervical cancer by 75%, other cancers of the genital tract and also of the oesophagus and some oropharyngeal cancers, the hospital claims.
Every year 3,000 new cases of cervical cancer are diagnosed in Britain and three women under 44 die every day from the disease.
Dr Tina Peers, consultant in contraception and sexual health, has set up a new clinic at Spire Gatwick Park Hospital to administer the vaccine and provide advice to women and the parents of girls aged 12 and over.
“The benefits of this vaccine will be felt by women and their families for a long time,” she said. “Although the government has recommended that the vaccine is available on the NHS for 11-12 year olds from next September there has been no announcement of a catch up programme so those girls aged between 13 and 24, who are most at risk will not receive treatment on the NHS.”
Spire Gatwick Park Hospital
0845 6035511
From Virus To Vaccine
The back story of the new cervical-cancer vaccine includes, among its many twists: Warts, Italian nuns, a virus old as humanity, a German scientist who shared DNA samples even with those who’d spurned him, numerous naysayers and red herrings, thousands of University of Washington student volunteers, a mended friendship — and a Peace Corps returnee who launched her pivotal career in sexually transmitted diseases (STD) through a chance encounter at the Northgate Mall.
“It didn’t seem to be a linear pathway to how I got here,” laughs UW epidemiology professor Laura Koutsky. She’s credited with developing the world’s first human papillomavirus (HPV) vaccine along with Dr. Kathrin Jansen, a yeast expert then at Merck Research Laboratories.
Human papillomaviruses are responsible for virtually all cervical cancers. Cervical cancer strikes 493,000 women every year and kills 274,000 of them, usually in their most productive years. After breast cancer, it is the second most common cancer among women. In poor countries, it is the leading cause of cancer-related death because Pap tests to screen for pre-malignant cells are not routine.
Talk about contagious! Within a year of first intercourse, a young woman has a 30 percent chance of becoming infected with HPV even if she has only one partner. Within three years, 60 percent of women are infected. By the time women are in their 40s, the infection rate is 70 to 80 percent.
Koutsky calls HPV “an equal-opportunity infection,” unlike other sexually transmitted diseases that tend to hover around people who have many sexual partners. You can get HPV your first time. You can even get it through genital contact without having intercourse.
Those were the startling results of Koutsky’s ground-breaking research that enlisted 900 women volunteers on the UW campus starting in the late-1980s for three years of pelvic exams, shots and detailed questions about their sex lives.
The dogma, back then, was that to learn about any sexually transmitted disease, you had to study high-risk populations at STD clinics. But Koutsky suspected that by the time people sought help at an STD clinic, they’d have already been long infected. It would be too late to figure out how and when they got the virus and how long it would take for the bug to damage cells.
So Koutsky also recruited at UW’s Hall Health outpatient clinic and focused on women who’d had fewer than four sexual partners in their lives. Her important early studies, published in the New England Journal of Medicine and the American Journal of Epidemiology, examined the disease’s natural history — what causes cervical cancer and HPV, who gets it and when.
Without knowing those basics, it would have been impossible to make a vaccine.
FLASH ON VACCINES, and most people think of scientists tinkering with slides and serums. (That was Jansen’s realm.) Koutsky’s role, as an epidemiologist, was to design studies that demonstrated the vaccines’ safety and effectiveness, an endeavor considered so significant that Koutsky is first author on the scientific papers announcing the vaccine breakthroughs.
Two of Koutsky’s key studies, published in 2002 and 2007 in the New England Journal, proved HPV vaccines were effective. “You can have a million vaccines out there,” Koutsky says, “but do they work? Can you point to data that say this product is safe, this product is effective, it does what we think it should do in a group of people”?
In a May 10 editorial in the New England Journal, Dr. Christopher Crum writes: If the promise implicit in the study by Koutsky et al. is realized, we could, in our lifetime, see the gradual but progressive dismantling of the barriers to preventing cervical cancer. The captives of our current system — both patients and their caregivers — may be set free.
For most people, the immune system tackles and virtually clears HPV infections in one to three years. But about 15 percent of the time, the virus lingers. This can lead to warts or cancer in men, women and youths. That’s why our health system promotes frequent Pap smears and removal of suspicious pre-cancerous lesions. Such intensive monitoring and treatment carries a hefty price tag, never mind the stress.
“The HPV vaccine ranks with the hepatitis B vaccine as the two most important vaccines to be given to prevent cancer,” says Dr. King Holmes, chairman of the UW’s Department of Global Health and director of the Center for AIDS and STD. “Laura brought the HPV vaccine trials forward in the most efficient manner possible. There were no missteps. As a result, this is a vaccine that got out to women more quickly and with all of the right considerations.”
Creating a vaccine and getting it to the public was a monumental task involving hundreds of scientists, thousands of volunteers, layers of logistics on everything from syringe length to inadvertent pregnancy.
Koutsky’s team had to figure out how many volunteers to recruit, how many shots to give and when, how long it takes to become infected (or not), when you have enough information to stop. They enrolled 12,167 young women in a randomized, double-blind, placebo-controlled trial at 90 sites in 15 countries and followed them for three years.
In all, it took more than two decades to create Gardasil, the new Merck vaccine that protects against four types of HPV (two cancer viruses and two wart viruses) using Koutsky’s 1980s natural-history study as a starting point.
In the world of vaccines, that’s fast.
LAURA KOUTSKY was born in Seattle in 1953 and grew up in the Montlake and Laurelhurst neighborhoods, the middle of five children of a surgeon dad and stay-at-home mom.
Her mother, Ruth, says Laura always knew how to make her laugh, and even as a young child would befriend underdogs. Her sister describes Laura as an artistic, happy-go-lucky kid, a cheerleader and athlete who loved swimming, water skiing, doodling and exploring around their Whidbey Island cabin. Even though their father was a doctor, Koutsky says her parents never pressured the kids to go into medicine or the sciences, though they did emphasize a responsibility to give back to society.
“I was not driven at the age of 5 to become an epidemiologist,” Koutsky says. “I wasn’t even driven at the age of 20!”
In retrospect, however, she recalls vaccinations were a big deal. The family’s home movies chronicle childhood birthdays, Christmas morning — and the day they all got the polio vaccine.
At Roosevelt High School, a teacher sparked Koutsky’s interest in biology, which became her major at the University of Oregon. One summer, she studied invertebrate zoology at the Oregon Institute of Marine Biology outside Coos Bay. Every day, she wandered the tide flats for hours in hip waders. “It was fascinating. It had to do with patterns and relationships and evolution. Worms. Insects, mammals.”
Yet she soon realized careers in marine biology begin by washing a lot of glassware on research vessels. A friend suggested the Peace Corps.
Koutsky landed in the South Pacific kingdom of Tonga with an array of colorful homemade dresses and her usual enthusiasm. She credits the Peace Corps with directing her talent, strengthening her internal resolve.
“I learned there’s a lot in life that isn’t going to turn out the way you think it will, and you have to find solutions for problems you’d never thought you’d confront; and in the end, you will feel good if you solve these problems.”
She was charged with teaching high-school biology but had no textbooks, no paper, no writing utensils. There was a chalkboard. But no chalk. “So you get to be friends with the other teachers,” Koutsky says, “and arrange to use their chalk when they’re not using it.”
Luckily, Koutsky could draw. Cells, granules, organ systems. A natural teacher, she was also a great listener, recalls fellow Peace Corps volunteer Julianne Hickey. Students would go to her for additional help. They could tell if she was home by whether her black bike was parked out front. After the Peace Corps, Koutsky applied to the UW’s School of Public Health with an eye toward international health. She was rejected. “They were underwhelmed by my undergraduate transcript. B-minus.”
Around that time, while shopping at Northgate, she ran into a former junior-high classmate who was headed to medical school and leaving behind her job as research assistant in the lab of King Holmes, a world expert on sexually transmitted diseases.
“I wouldn’t recommend just anybody for my job,” Julie Adam says. “But I had always believed in Laura. She’s very intelligent, she has ethics, a big heart. She was able to bridge many groups of people. And she’s a hard worker.”
Over the next year, while gathering data about chlamydia in pregnancy, Koutsky fell in love with epidemiological research. “The idea of being able to ask questions about what was causing a disease!” She was immersed in patterns and relationships, just like during her beloved summer on the tide flats, only this time in a landscape of diseases and populations. It was like being a detective investigating the links between humans, environment, behaviors, organisms and disease.
Koutsky also realized she loved the dynamics of working with scientists who hypothesized, challenged each other’s ideas and contributed different bits to solve a problem: Collaboration. The UW School of Public Health accepted her the following year, and she eventually pursued a doctorate in epidemiology, all the while continuing to work in Holmes’ lab.
“She came in here with her eyes wide open ready to take on anything,” Holmes recalls. “My initial impression was that she was incredibly enthusiastic and at the same time very level-headed. It became apparent as we worked on many different projects that everything she put her hand to came out successfully.”
Come time for her dissertation project, Koutsky proposed studying the link between sexually transmitted diseases and spontaneous miscarriages. Holmes thought the project would be problematic and costly.
Besides, HPV was rising on the horizon as the next big sexually transmitted disease. He wanted Koutsky to tackle it. “She’d worked on 14 different STDs and was unique in having so much experience . . . Of all the young people we had coming along, she was the best prepared to handle it.”
HUMAN PAPILLOMAVIRUSES evolved with humans a million years ago. Ancient Greeks and Romans described genital warts thousands of years ago. But for most of human history, no one understood how sex, HPV and cancer were linked.
People had long suspected a relationship between cervical cancer and sex. In 1842, Italian physician D. Rigoni-Stern reported that nuns had virtually no cases of the disease; cervical cancer was rare among married women; the rate among prostitutes was unusually high. By the 1900s, it became clear. Women with more sex partners were more likely to get cervical cancer.
By the 1960s, researchers surmised that one or more sexually transmitted diseases caused cervical cancer — perhaps herpes or chlamydia, they thought. Then, in the 1970s, Harald zur Hausen, a German cancer researcher training at the University of Pennsylvania, bucked conventional wisdom, demonstrating that HPV was a family of viruses that caused everything from common warts to malicious cancers of the cervix, and more rarely, of the anus, penis, mouth and neck. Until then, nobody realized certain viruses could cause cancer.
Zur Hausen freely shared with labs worldwide the viral-DNA fragments he’d painstakingly isolated, an act credited with speeding up vaccine research. (And unlikely to happen now, Koutsky says, in an age when everyone wants to patent everything.)
Your skin, right now, is probably covered in human papillomavirus; there are more than 200 types. Two, HPV-16 and HPV-18, cause 70 percent of all cervical cancers.
Koutsky’s natural-history studies proved a strong temporal relationship between cervical cancer and those two. Soon after becoming infected with those virus types, women developed abnormal cells; sometimes these progressed to lesions, including the sort that typically turn into cancer. (In the study, lesions were removed before becoming cancerous.)
The fact that it took only months to go from infection to bad Pap — instead of 10 to 20 years as previously thought — meant it would be realistic to test a vaccine.
“No one believed it,” says Dr. Nancy Kiviat, who collaborated with Koutsky on the natural-history study and now directs pathology/cytopathology at Harborview Medical Center. It was Kiviat who developed the assays to test whether women in Koutsky’s early study had HPV and which type. Not an easy task.
“Now, everybody gets the same answer and tests are more standardized,” says Denise Galloway, a microbiologist and collaborator on the natural-history study. “In the late ’80s, early ’90s, everybody was using different techniques, and the results were a mess. HPV was everywhere or was nowhere.”
To double-check lab results, dual samples from each woman were sent to different labs. The results should’ve matched. Not even close. Kiviat worried her lab was wrong. Koutsky pored over the data and recognized consistent patterns in Kiviat’s results. These are right, she reassured her colleague.
Koutsky credits Kiviat with teaching her the power of collaboration. Early in their careers, the two were icy competitors, each recalls. After about a year, Kiviat approached Koutsky:
You know, as a pathologist, I’m going to develop lab expertise and clinical expertise and you’ll have the epidemiologic, analytic, biostatistical expertise. If we work together, we could have the world!
The rivalry melted. They became lifelong friends and collaborators, Kiviat’s lab central to the success of Koutsky’s studies.
Around the same time, DNA technology was moving forward. Until then, the problem with HPV was that you couldn’t grow it in a lab, ruling out a vaccine based on live or attenuated HPV virus. New molecular technology made it (theoretically) possible to snip fragments of viral DNA and insert them into a vehicle that could infect the cell systems of insects or yeast. That would produce a capsid protein, or viral shell, that could stimulate an immune response without transmitting disease.
Enter Kathrin Jansen, a scientist at Merck with expertise in yeast. She was a newcomer to the HPV field when she met Koutsky at a conference.
Jansen believed she could use yeast to make an HPV vaccine; Merck had already made a hepatitis B vaccine using a similar concept. She needed Koutsky’s HPV expertise to design a vaccine trial. Jansen: “If you design a study wrong, involve too few people, you can have a trial that will not reach statistical significance.”
Koutsky’s team enrolled 2,392 young women in a double-blind trial to test the HPV-16 vaccine Jansen had created (an arduous years-of-late-nights-in-lab process using a dozen different yeast strains).
The volunteers received three doses of either placebo or vaccine and underwent Pap tests about every six months. Koutsky’s team figured that by the time 31 women had persistent HPV-16 infection they’d know whether the vaccine had any impact. After 17 months, the 31st woman tested positive for persistent HPV-16. The study was unblinded to a biostatistician. All of the persistent HPV-16 infections were in women who’d received the placebo. None of the vaccinated women had the virus.
“We were clapping and jumping through the hallways” at Merck, Jansen recalls. Immediately, they phoned Koutsky with the good news. Was it by chance that a vaccine for women was developed by women? Coincidence, Jansen says. “But then, it was a lot of fun to have it go that way.”
Next decision: Which strains of HPV to include in the vaccine that would go to the public? Everyone agreed two of the four spots should go to HPV-16 and HPV-18, the virus types causing most cervical cancer. Koutsky wanted to fill the other two slots with two more cancer types. Jansen argued for a couple of genital wart virus types to make the vaccine appealing to men.
Because men don’t have cervixes, they can’t get cervical cancer. But like mosquitoes that transmit malaria to humans, men carry and transmit HPV to women. (Men who have sex with men are also at risk for anal cancer.) If both men and women were vaccinated, HPV rates might decrease faster in the general population, an effect known as herd immunity.
“Look, Laura,” Jansen said. “So what makes it palatable for a young man to get immunized if he doesn’t get a benefit for himself? You count on the goodwill of that person? You know, I imagine it must be quite devastating to have one of those big, ugly things growing on his penis, right? Certainly not very attractive, and the treatment is not particularly pleasant . . .”
Koutsky was convinced.
Licensed last summer, the Merck vaccine protects against two cancer viruses and two genital wart viruses. It’s targeted at girls around age 12, before they become sexually active. That makes it controversial among parents who worry the vaccine could encourage sexual relationships.
Parents have to look at facts, the epidemiologist says: 40 percent of 16-year-old girls are sexually active; 70 percent of 18-year-old girls are. Washington state fully covers the vaccine for girls 18 and younger. At $360 for the three-dose series, that’s a significant savings.
Now that Koutsky’s developed the vaccine, she’s on to the next challenge: Getting it to the public. “It would be a travesty if we have this highly safe and effective vaccine and it doesn’t get used.”
HPV vaccine recommended for women through age 26
Human papillomavirus, a disease that causes 70 percent of cervical cancer cases and 90 percent of genital warts cases, is most common for people in their late teens and early twenties, according to the Centers for Disease Control and Prevention Web site.
HPV was publicized widely earlier this year when Texas Governor Rick Perry tried to make the vaccine, called Gardasil, mandatory for all girls entering the sixth grade. The vaccine, generally thought of in regard to pre-teenage girls, actually is recommended for women through the age of 26 years old.
“If I were a 26-year-old who had never had intercourse or had never been exposed to the virus, I’d get the vaccine,” said Dr. Roger Yandell in the Department of Obstetrics and Gynecology at the Texas Tech Health Sciences Center. “It definitely has more impact on younger girls, though. The cervix changes during menarche, a girl’s first period. That’s when it’s most susceptible to the virus, so we try to start the vaccine just before that takes place.”
The Advisory Committee on Immunization Practices consists of 15 experts - selected by the Secretary of the U.S. Department of Health and Human Services - who provide advice and guidance to the CDC. The committee recommends women through age 26 years old receive catch-up vaccinations, according to the CDC Web site.
“You have to look at what we’re trying to treat,” Yandell said. “Cervical cancer is really what we’re talking about here, and on a lesser scale, genital warts. This is the most common disease for causing either of those.”
Unlike many vaccines, Gardasil is a recombinant vaccine, which means it does not contain any live forms of the virus. According to the CDC Web site, the vaccine is comprised of proteins from the outer coat of the virus.
“There are a lot of different ways to make a vaccine,” Yandell said. “In this case, it works extremely well.”
The Food and Drug Administration first licensed Gardasil in June, 2006, according to the FDA Web site.
The vaccine protects against four different strains of HPV - types 6, 11, 16 and 18, according to the CDC Web site. At least 50 percent of all sexually active people will get HPV at some time in their lives. Approximately 6.2 million Americans get HPV each year.
Yandell said the reason college students need to be aware of this is that the risks increase with higher rates of sexual activity.
“For years - and I mean centuries - we’ve known that women with higher numbers of sexual partners have a greater risk for cancer,” he said. “It’s a sexually transmitted disease, and we’ve known that for a long time.”
There are approximately 100 types of HPV, Yandell said. The virus usually infects a woman’s cervix, altering the cells there. Most strains cause no symptoms and go away on their own, after which the cervical cells return to normal. Some types, however, do not go away. Instead, they continue to change the cells, which eventually can lead to cervical cancer.
“The virus invades the cells,” he said. “It changes them into something half-virus, half-human.”
According to the American Cancer Society Web site, www.cancer.org, approximately 11,150 women will be diagnosed with cervical cancer in 2007. About 3,670 women will die of it this year. According to the Web site, women can prevent most precancers of the cervix by avoiding exposure to HPV.
“We have a vaccine with the potential to eliminate one type of cancer,” Yandell said. “The sooner you get the vaccine, the higher your chance of being protected for the rest of your life.”
There is no treatment or cure for HPV, according to the CDC Web site. It is recommended that all women get the vaccine before contracting any form of HPV.
However, women who already have contracted one form still can benefit from the vaccine because it prevents four strains of HPV.
“The key is to get the immune system to recognize the virus,” Yandell said. “This could be a cure for a very nasty type of cancer. This has the potential to eliminate maybe 90 percent of that.”