HPV Vaccination Program Raises Concerns

The morning after Emily Cunningham got a shot of Gardasil, the new vaccine that protects against four strains of the human papilloma virus (HPV) that can cause cervical cancer and genital warts, she woke up with a headache, and neck and back pain. By 9 p.m.

HPV Vaccination Program Raises Concerns

The morning after Emily Cunningham got a shot of Gardasil, the new vaccine that protects against four strains of the human papilloma virus (HPV) that can cause cervical cancer and genital warts, she woke up with a headache, and neck and back pain. By 9 p.m. that evening in April, she had a fever so high "you could feel the heat rising from her a foot away," according to her mother, Laurie. She was delirious during the night, and the following day couldn't walk without assistance. Bedridden for nearly a week, the 18-year-old from Wyoming missed school, and took Tylenol every four hours. "If Emily had been the only one to get sick we would have said she must have had something else [like the flu]," explained Laurie, "but we know of three other students to have reactions, that is why we are concerned."

Emily's story is only one of 1,637 complaints involving Gardasil, filed as of May to the Vaccine Adverse Event Reporting System (VAERS), a national surveillance database sponsored by the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) in the United States. One could discount what happened to Emily because she had a flu shot that same day, but other really bad reactions have been reported, including seizures, paralysis - and worst of all, three deaths, including one girl who "died of a blood clot three hours after getting the Gardasil vaccine," reads one complaint. Elsewhere in the world there have been reports of similar reactions. In Melbourne, Australia, where a national HPV vaccination program started in April, 26 girls reportedly fainted and were mildly paralyzed after getting one shot each.

In almost every instance, the response of medical authorities and government officials is the same: bad reactions are rare. When they do occur, there's no evidence that Gardasil was the cause. Arguably, both points could be true. Some say the problem, however, is that no one really knows, medically speaking, just how dangerous this vaccine could be. "Usually at this stage in the life span of a vaccine we would not have this kind of action," Maclean's has heard from Abby Lippman, an epidemiologist at McGill University who recently aired her concerns about the speed with which Gardasil has been adopted in the Canadian Medical Association Journal. "We're making guesses that it's going to last long, that [we're immunizing] the right age [of girls], and that it's effective. We don't have a solid basis for this thought."

And yet, nearly every province in Canada has, in recent weeks, put forth some plan to implement an HPV vaccination program that will see the mass inoculation of an entire generation of girls - some as soon as this September - with no serious acknowledgement of the potential health risks they might face. While everyone debates the moral and political consequences of endorsing Gardasil, the fundamental, essential medical and scientific debate remains untouched. So, in a few weeks, when thousands of girls concerned about Facebook and who will be in their class this year - not HPV - go back to school, many will become part of the biggest Canadian science experiment in decades. They will be the guinea pigs.

To find out the worst case scenario when it comes to Gardasil, one need only hear the stories of parents whose children have become ill or died after receiving the vaccine. Recently, one angry father from Chicago phoned up John Driscoll, an attorney at the law firm Brown & Crouppen in St. Louis, Mo. Shortly after receiving Gardasil, his daughter was diagnosed with Guillain-Barré syndrome, an autoimmune disease. It starts with tingling sensations in the legs, which then travel to the upper body, and finally become so intense in the muscles they paralyze, though often they diminish over time. "He believes it was linked," says Driscoll, and wants to sue Merck & Co., Inc., the U.S. pharmaceutical company that manufactures Gardasil. This will be the first such lawsuit, but Driscoll, who believes the vaccine was rushed to market, predicts that, "unfortunately, we'll get more and more calls about this in the future."

In fact, Guillain-Barré syndrome is one of the more serious adverse reactions noted in the hundreds of complaints filed to VAERS. "When you go to your doctor's office, the list of symptoms is very short: dizziness, fainting. But there's a whole laundry list of potentially serious side effects," says Dee Grothe, an investigator at the Washington-based watchdog organization Judicial Watch, which filed freedom of information requests to access details about negative reactions relating to Gardasil. "This is information that everybody receiving the shot should know," she says.

Merck Frosst Canada Ltd., which is the Canadian manufacturer of the vaccine, sees no proof that Gardasil is responsible for the illnesses or deaths. "There is a relationship between Gardasil and these events, but there's no cause and effect," says Sheila Murphy, manager of public affairs for Merck Frosst. Similarly, the FDA and CDC have said there's no likely connection (they claim the two deaths from blood clots were caused by birth control pills taken at the time of immunization, and the third death was due to heart inflammation brought on by the flu). But some skeptics find these explanations ambiguous and suspicious. "I'm not a doctor, but when I read this information, to me, that is a clear indication that there may have been a problem," says Grothe.

It's obvious that even in the best-case scenario, many believe there is still not enough known about the HPV vaccine to warrant mass inoculation programs. For starters, there are concerns that not enough nine- to 15-year-old girls were studied during clinical trials for Gardasil. Approximately 1,200 were enrolled, and according to a June report by the Canadian Women's Health Network, only 100 of them were age nine, and that limited group was only followed for 18 months. "Clearly, this is a very weak information base on which to construct a policy of mass vaccinations for all girls aged nine to 13, as per the National Advisory Committee on Immunization's recommendations," the CWHN report summarized.

The CWHN also worries about the long-term effectiveness of Gardasil, given the longest that clinical trial participants who received the vaccine were tracked was for five years. "If we're talking about vaccinating nine-year-old girls we want protection for 20 or 30 years," concedes Laura Koutsky, an epidemiologist at the University of Washington who helped Merck design the clinical trials and oversaw them for Gardasil. "Can we infer protection out to that period? We don't know. But we have evidence that suggests it's likely."

Inference, though, is not the scientific evidence some expect. Analysis beyond clinical trials is critical to ensuring public safety, warns Lippman. "What happens in the real world can be very different from what happens in the clinical research world," where girls are in a controlled environment, and get health examinations frequently to gauge any problems. "The real world is where we find out what really happens when you let a vaccine loose on a population."

A study in the May issue of the New England Journal of Medicine speaks to how real world situations such as "imperfect compliance" (such as not receiving all three doses of Gardasil), and a girl's previous exposure to HPV, could take Gardasil's 70 per cent protection against precancerous lesions (which lead to cervical cancer) down to a staggering 17 per cent. "That's one more reason we should be slowing down," says Hans Krueger, a health care consultant who has advised the B.C. Cancer Agency, among other organizations, on Gardasil. "This suggests to me we just don't know enough."

What's more, there is some debate over just how many shots girls aged nine to 13 actually need - either the recommended three doses, or just two - which would cut costs (a triple shot costs $404). A collaborative research project, which will involve about 800 girls, to look into this is getting under way next week in B.C., Quebec and Nova Scotia. The latter province, for now at least, is going ahead with its three-dose plan for Grade 7 girls this September.

Nova Scotia is not the only province to put forth plans for mass immunization in recent weeks. Ontario announced it will give Gardasil to Grade 8 girls beginning in September. Newfoundland will administer the shot to Grade 6 girls, as will Prince Edward Island. Meanwhile, British Columbia and Quebec are expected to launch their programs at some point next year.

All this comes just as Merck's competitor GlaxoSmithKline (GSK) is seeking Health Canada's approval to market another HPV vaccine called Cervarix (already available in Australia, and heading towards approval in Europe). GSK claims that Cervarix's edge is an adjuvant that, it claims, creates a stronger and longer-lasting immune response compared to the conventional aluminum-based adjuvants. And while Gardasil focuses on two strains (16 and 18) that account for 70 per cent of cervical cancer cases and two others that cause genital warts, Cervarix protects against four HPV strains responsible for 80 per cent of cervical cancers (types 16, 18, 31 and 45).

Canada's widespread adoption of the HPV vaccine in some ways makes the country a guinea pig for Gardasil on an international scale, says Diane M. Harper, a lead researcher in the development of the HPV vaccine, and a professor at Dartmouth Medical School in New Hampshire who has worked with Merck and GSK. While developing nations where cervical cancer rates are high could stand to benefit the most from Gardasil, they aren't "going to readily adopt a vaccine unless they feel comfortable that other countries have adopted the vaccine and done well and seen success with it. That's the history of how the world has gone in health care."

Merck has explicitly stated that Gardasil does not offer total protection against cervical cancer. And so the question remains, in the absence of HPV 16 and 18, what's to stop other resistant strains of the virus from evolving into something more aggressive? "We're making educated guesses of what we think will happen to the virus in the future based on what we know of the virus right now," says Koutsky. A super-strain of HPV is unlikely to occur, she continues, because the papilloma genome does not evolve at a rapid pace. "But it's true we don't know," she says.

One possibility is that other strains, which cause the remaining 30 per cent of cervical cancers, may become more prevalent. "If you knock off two big tough drug dealers who control 70 per cent of the market and take them to jail, the other guys will quickly fill the void," says Andrew Lynk, a Sydney, N.S.-based pediatrician. "We've seen that also in the vaccination world."

In the June report published by the Canadian Women's Health Network, medical experts point to a cautionary tale in Alaska, where native children were inoculated en masse against a strain of pneumococcal pneumonia. A follow-up study found that, since the vaccinations in 2004, "the invasive pneumococcal disease rate caused by non-vaccine serotypes [had] increased 140 per cent compared with the pre-vaccine period." Studies like this one, the CWHN warns, demand that the medical community, the government and the public consider "how Gardasil, or any other HPV vaccine, might alter the natural history of HPV infections - and whether other HPV strains might move in to occupy the vacated niche - before engaging in a massive vaccination program."

Knowing about the potential dangers of Gardasil, one wonders if the recommendation for mass inoculation in so many provinces is even necessary. The HPV vaccine has been sold by Merck and its proponents as a tool for ending cervical cancer. But a quick look at statistics shows that the risk of developing this disease, let alone dying from it, is very low - in Canada, 1,350 women were diagnosed and 390 died last year, making cervical cancer the 11th-most common cancer in women here, and the 13th-most common cause of cancer-related death.

In fact, Canada has among the lowest incidences of cervical cancer in the world. But hype around Gardasil has created a false sense of urgency about the need for the vaccine, according to cautious observers such as Lippman. "If there was an epidemic and people were dropping dead on the street corner, you'd want to do something," she says. But "we have the luxury to reflect, think and act wisely. Then we can put our foot into the street and cross. [Right now] I'm the yellow light mode."

When HPV strains, of which there are up to 200, do cause infections, they are usually slow to grow, which makes identifying them through Pap smears relatively easy. In a statement published in the February issue of the Canada Communicable Disease Report, the National Advisory Committee on Immunization explained that "In general ... the vast majority of precancerous lesions, which progress slowly, can easily be detected and treated." Even when the HPV infection is caused by one of the cervical-cancer-causing strains, reports the Canadian Women's Health Network, it takes about a decade for the disease to develop - long enough for women to get their Pap test done (annually, and then every three years after smears come back clear twice in a row).

Despite these promising outcomes, cervical cancer is being turned into a new millennium polio, according to Dr. Sharon Moalem, author of Survival of the Sickest, and a neurogeneticist and evolutionary biologist at New York's Mount Sinai School of Medicine. "The problem that I've seen is many of the advocates for [Gardasil] say everyone should be vaccinated, but this is not polio and a lot of people can have HPV and not every variant of HPV causes cancer as far as we know."

In fact, most people will wind up with HPV at some point in their lives and fight it off without ever even knowing they were exposed to the virus, which is primarily transmitted through skin contact with genitalia. According to the Canadian Women's Health Network, most women who don't smoke, eat well and have a healthy immune system will clear the virus without any treatment. And the Public Health Agency of Canada has said that more than 80 per cent of HPV infections acquired at an early age were gone within a year and a half. Even better, after a woman has fought off a strain, she has almost no chance of contracting it again.

HPV is so common that even infants and children have been found with infections, suggesting that the virus isn't just transmitted sexually, says Krueger. While there is no conclusive literature explaining how else it might be contracted, some have suggested that newborns could acquire HPV while in their mother's vaginal tract. However it happens, Gardasil critics point to these puzzling cases as another reason why the vaccine - which is only preventive, and won't have any effect on those who already have HPV - shouldn't be given to all girls. "These data do warn against assuming too quickly the lack of exposure to HPV in even young girls in developing vaccination programs and policies," states the CWHN.

Even for the limited number of women who do wind up contracting the HPV strains that could lead to cervical cancer, some say current screening methods - Pap smears - are effective and safe ways of preventing the disease. About 79 per cent of Canadian women between the ages of 18 and 69 have had a Pap in the last three years, and according to the the immunization advisory committee, this has "led to dramatic reductions in invasive cancer in the developed world."

Further proof of the test's effectiveness is found in the fact that the majority of women who do wind up with cervical cancer - 60 per cent - were either unscreened or underscreened, meaning they didn't get their Pap at all, or didn't get it on schedule, according to the advisory committee. As such, the current push for young girls to be immunized largely ignores the group of women most affected: immigrants, refugees, Aboriginals, the disabled, poor and those living in remote regions (the rate of infection among Inuit women in Nunavut is 86 per cent). Realizing this, some have called on the federal government to reallocate the $300 million it put up for HPV vaccination programs in March toward targeting high-risk populations. "Maybe the money would be better spent hiring nurses who would set up mobile clinics and go out to the First Nations or immigrant neighbourhoods," says Nova Scotia pediatrician Lynk.

Even if HPV vaccination programs continue to expand, the public needs to understand that young women can still develop HPV infection and cervical cancer after being immunized, say experts. Paps will be a critical complement to Gardasil, insists the immunization advisory committee. "Women who have been vaccinated will still be susceptible to other [high-risk] HPV types. Even if those types are less prevalent than HPV 16 or 18, these women should still expect to take part in the currently recommended cervical cancer screening programs."

Harper, the HPV researcher at Dartmouth, tells of a yet unpublished study showing that, even if every female aged 12 to 26 is vaccinated, if they don't go for Pap tests thereafter the rate of cervical cancer will actually go up compared to pre-immunization rates. "So there is significant danger in people feeling this vaccine offers them a force field protection," says Harper, "and that could actually rebound back to us because there are other HPV types out there and they're not going to stop causing cancer just because we've given a vaccine."

All these questions and caveats highlight just how little medical and scientific evidence exists to make the case against mass inoculation a no-brainer. "The medical, scientific community has to sit down and say, what are really the costs and benefits here?" says Moalem. "It's been turned into a public health issue and everyone's trying to spin it their own way and most cancer doctors will tell parents, why would you risk having your child get cervical cancer if I can give you a vaccine to prevent it? But they don't know what the long-term costs are."

Her strong recommendation is for parents to talk to their children about HPV as a sexually transmitted virus, and its link to cervical cancer, among other illnesses. "It's much easier as a parent to get your child to have a vaccine than to sit down and have a conversation and say, using condoms can reduce HPV exposure, therefore that reduces cervical cancer. I'll just give you a shot, then we don't have to talk about it," she says. Moalem believes the original marketing of Gardasil as the vaccine against cervical cancer has been misleading. "That's not what this is. This is a vaccine against a sexually transmitted disease. I think that's what people should be very clear on. That really would change the frame of the debate."

Until more medical and scientific analysis illuminates just what Gardasil will do to young girls, Krueger is wary. "We have a virus here that has so many different types and affects so many body systems that it's just very complex. The fact that we have a vaccine against HPV types that cause cervical cancer is a medical breakthrough," he says, but then adds, "My girls will not be vaccinated. That's not just because of deaths or adverse effects, it's because of all these unknowns."

Maclean's August 27, 2007