*Early release publication at www.cmaj.ca on August 2 2007. Subject to revision
Human papillomavirus, vaccines and women’s health: questions and cautions
Abby Lippman PhD, Ryan Melnychuk PhD, Carolyn Shimmin BJ, Madeline Boscoe RN DU
Scroll down to also read: "McGill researchers caution that there are still too many unanswered questions about the vaccine" and "How politics pushed the HPV vaccine"
The federal government’s recently announced $300 million investment toward a program for vaccinating girls and women with the currently available human papillomavirus (HPV) vaccine Gardasil, framed by some as a way to prevent cervical cancer in Canada, has generally been welcomed by a wide range of commentators. However, although HPV infection is necessary for the development of cervical cancer and the vaccine may prevent primary infection with HPV types 16 and 18 (currently thought to be the cause of about 70% of cervical cancer cases1), we propose that these facts be assessed within a broad context before immunization policies are implemented. A careful review of the literature, including that submitted by the manufacturer with its application for approval of Gardasil, reveals a sufficient number of unanswered questions to lead us to conclude that a universal immunization program aimed at girls and women in Canada is, at this time, premature and could possibly have unintended negative consequences for individuals and for society as a whole.
In this article we summarize some of the main questions and concerns that need to be addressed before there is a fullscale rollout of an HPV vaccination program (for supplementary material go to www.cwhn.ca/resources/cwhn/hpv-brief.html. These closely reflect issues raised in the analytical framework created by Erickson and colleagues2 in the context of the development of the National Immunization Strategy and support efforts to ensure a comprehensive and systematic evaluation of all relevant factors before decisions regarding the implementation of a new immunization program are made.
As well, they echo some of the research questions identified as important in the final report from the Canadian Human Papillomavirus Vaccine Research Priorities Workshop, held in Quebec City in 2005.3 We hope raising these questions now will contribute to the deliberations necessary to ensure a responsible and transparent evidence-based decision-making process.
General questions and cautions
• There is no epidemic of cervical cancer in Canada to warrant the sense of urgency for a vaccination program initiated by the federal finance minister’s announcement. According to 2006 Canadian cancer statistics,4 cervical cancer is the 11th most frequent cancer affecting Canadian women and the 13th most common cause of cancer-related deaths, accounting for approximately 400 deaths per year. Both the incidence and mortality of cervical cancer have been declining in Canada, as in other resource-rich countries, although recently at a somewhat slower rate than has been observed in previous decades.5 However, the incidence and mortality still vary between different groups of women, being notably higher among Aboriginal women than among non-Aboriginal women.Figure 1: Avoidable mortality (age-standardized expected years of life lost per 100 000 people) due to cervical cancer in Canada from 1971 to 1996, by income quintile. Reproduced, with permission, from James et al.5 Copyright © 2007, BMJ Publishing Group Ltd.
• Invasive cervical cancer typically follows a slowly progressive course that can be halted at one of various stages. The dramatic decrease in deaths from cervical cancer in Canada, even before the development of any vaccine, represents a public health success (Figure 1).
Research attributes this to improved reproductive health practices and the widespread availability of publicly funded programs for Papanicolaou smear testing.6 In fact, the public funding of such programs has also significantly reduced health inequities among women.6 Consequently, deaths from cervical cancer — relatively rare in Canada but always unfortunate and not distributed evenly among women — must be considered as a failure in the adequate support of both the primary care and reproductive health services that would guarantee healthy living conditions for all women. Improvements here, as well as steps to ensure that all women receive appropriate Pap testing and follow-up, are needed.
• Most HPV infections are cleared spontaneously. Recent research using available molecular detection technologies has suggested that clearance occurs within 1 year for about 70% of infected women, and within 2 years for 90%.7 Thus, HPV infection and cervical cancer must not be conflated: cervical cancer will not develop in most women who are infected with even a high-risk strain of HPV.8 Unfortunately, there are no data on clearance rates among girls, nor even about the actual HPV prevalence rates among youth and children, yet this is critical information for developing, and subsequently evaluating, policy proposals.
• The nature of a vaccination program is necessarily dependent on the definition of clear and tangible goals. To date, such goals have not been made explicit with regard to a Canadian initiative. Is the aim of the zaccination program the eradication of high-risk HPV types from the population? Or is it to reduce the number of deaths from cervical cancer? These different goals require different strategies. For example, pathogen eradication would imply a herd-immunity goal, thus possibly necessitating the vaccination of boys and young men. In contrast, the reduction of deaths from cervical cancer would suggest the need for a vaccine directed against more than the 2 high-risk HPV types in Gardasil, which may account for only somewhat more than two-thirds of cervical cancer cases.
• Information about the efficacy of Gardasil remains uncertain. Its real-world effectiveness is even less clear. To date, only a handful of randomized controlled trials of sufficient quality to qualify for systematic review have been reported.9 Interestingly, all of the reported HPV vaccine trials, whether of Gardasil or its potential competitor Cervarix, were funded in whole or in part by the vaccine’s manufacturer. Although Rambout and colleagues,9 in their systematic review (available at www.cmaj.ca/cgi/rapidpdf/cmaj.070948v1), find that overall the vaccine is highly efficacious in the short term, particularly when all clinical outcomes are pooled, they also note that some methodologic weaknesses in the trial reports, combined with the limits in currently available data, continue to leave many information gaps. This situation is not unusual at this juncture in the development of new pharmaceutical products; however, it does caution against making overly optimistic descriptions of benefits and downplaying potential risks.
• We would add a number of questions to those raised by Rambout and colleagues. Specifically, what is the length of immunologic protection the vaccine confers against HPV types 16 and 18? Will boosters be needed to maintain this limited coverage, and if so, when? Other questions with regard to effectiveness centre on concerns about the possibility of short-term immunity altering the natural history of viral infection, as seems to be the situation with chicken pox: protection has been of shorter duration than expected, and viral infections in older people have been more severe than those in children.10 • Furthermore, we lack data on the effectiveness of the HPV vaccine when co-administered with other immunizations, as may occur in real practice. As well, will such factors as a person’s nourishment, smoking status and general health (e.g., comorbidities) influence the safety or usefulness of the HPV vaccine? Perhaps more importantly, might misunderstandings about what the vaccine does and does not do lead to reductions in safer sex practices and Pap screening rates? These are among the questions raised at the Research Priorities Workshop in Quebec City in November 2005, and they remain pertinent — and unanswered.
• Relatively few girls (about 1200 aged 9–15 years) were enrolled in the clinical trials of Gardasil, the youngest of whom were followed for only 18 months.11 Based on the assumption that they will not yet have been exposed to HPV viruses, girls in this age group represent the priority target population for mass vaccination. Clearly, this is a thin information base on which to construct a policy of mass vaccination for all girls aged 9–13, as per the National Advisory Committee on Immunization’s recommendations.12
• Gardasil is the most expensive childhood vaccine proposed for mass use; it currently costs $404 for the 3 required doses. Yet, the cost-effectiveness analyses of proposed vaccination programs needed to evaluate this expense are missing. The lack of effectiveness data makes it difficult to estimate what reduction in repeat testing or colposcopy can be anticipated to counter some of the vaccination costs and precludes determining whether vaccination will have any “added value.” Girls and women, even if vaccinated, will still need to practise safer sex and have access to existing care programs for Pap testing as well as for other reproductive health care. In similar need of analysis are possible lost opportunity costs and assessments of the impact on other health care priorities of devoting limited resources to HPV vaccination programs.
We propose a number of general recommendations that should be considered before a universal HPV vaccination program is developed and implemented (Box 1 - scroll down to read).Box 1: General recommendations for the development of a mass vaccination program against human papillomavirus (HPV) infection
To be clear, if and when evidence shows that an HPV vaccination program can be successfully implemented in Canada, it must be publicly funded. Lack of financial resources must not preclude any girl or woman from receiving what has been sanctioned by health officials. However, concern about how public funds are used to promote and protect the health of girls and women must consider broader issues, such as the needs of the marginalized and most vulnerable groups in society.
Government support for HPV vaccinations must not perpetuate existing health inequities. Instead, such programs ought to reduce health inequities through thoughtful, comprehensive, evidence-based approaches that permit those most at risk to benefit.
To promote and protect women’s health most effectively, and to work toward the prevention of deaths from cervical cancer in Canada, we should not focus only on a universal HPV vaccination program at this time when there is an urgent need for prompt and clear answers to the many questions outlined in this article.
Gardasil represents the first of what will likely be many vaccines targeting high-risk HPV strains, and how we proceed now will set a precedent for others. The foundation of a successful vaccination program must be solid, evidence-based research, and we now have the exciting opportunity to complete this work and develop a model for current and future HPV vaccination programs with clearly defined and measurable health outcomes. We must be certain that spending an estimated $2 billion to vaccinate a population of girls and women in Canada who are already mostly well protected by their own immune systems, safer sex practices and existing screening programs will not perpetuate the existing gaps in care and leave the actual rate of deaths from cervical cancer unchanged. Worse would be the emergence of iatrogenic effects, such as an increase in cervical cancer rates, if a false sense of security led girls and women to stop having regular Pap screening and to view vaccination as a simple fix.
In developing a model HPV vaccination program, governments should start by educating the public about the reality of cervical cancer, HPV infection and vaccinations, to quell anxieties about cervical cancer and HPV and to emphasize the importance of healthy personal practices, including use of barrier methods, good nutrition, smoking cessation and regular Pap smears and screening for sexually transmitted infections. As well, federal, provincial and territorial policies for reproductive health care should be reviewed, including an assessment of the place of any vaccination program within existing services for the prevention and management of cervical cancer.
The latter will require a definition of the goals of any potential mass vaccination program. If the aim is cervical cancer reduction, then the possibility of favouring safe and effective vaccines that cover a broad range of high-risk viral strains should be considered. If the objective is to eliminate HPV infections, then data on how to include boys and men as well as girls and women, and how to manage newly identified oncogenic HPV types within an immunization program, are essential. Head-to-head comparisons of different vaccines carried out in unbiased research programs free of conflict of interest will be most useful here to obtain data for evidence-based policy and health care decision-making.
Canada already has thoughtful and useful frameworks for developing vaccination and cancer prevention policies. Their use in amassing and evaluating the scientific (molecular, epidemiologic, immunologic) and social evidence related to HPV vaccines, and for assessing potential benefits and harms expected from widespread immunization with the HPV vaccine, is urgent before governments allocate huge sums of already limited health care dollars to such programs. It is time to take a breath and reflect on what we know and what we don’t know, and to develop a plan based on solid, reliable evidence that adds value for everyone.
Individual girls and women, as well as policy-makers, can make truly informed decisions about vaccinations only when they have all the evidence, and today, there are more questions than answers
• Governments should begin immediately to educate the public about the realities of cervical cancer, HPV infection and HPV vaccinations, emphasizing the importance of healthy personal and sexual behaviour practices, good nutrition, smoking cessation, and regular Papanicolaou tests and screening for sexually transmitted infections
• Federal, provincial and territorial policies on reproductive health care should be reviewed to assess the place of any
vaccination program within existing services for the prevention and management of cervical cancer
• The goals of any potential mass vaccination program need to be defined to ensure that the most effective and safest vaccine is used in the appropriate populations to meet these goals
• Governments must support unbiased research, free from any conflict of interest, to collect the data now missing but essential for evidence-based policy and health care decision-making. This research needs to include studies that assess the potential impact of vaccination on safer sex practices, on access to reproductive health services and on possible lost-opportunity costs.
Toronto ~~ Thursday August 2 2007
McGill researchers caution that there are still too many unanswered questions about the vaccine
SHERYL UBELACKER Canadian Press
The idea of vaccinating young Canadian females against the leading cause of cervical cancer has been embraced by a variety of public health advocates in Canada, but one group of researchers suggests the endorsement of widespread inoculation has been far too hasty.
The vaccine Gardasil protects against four strains of human papillomavirus (HPV), the primary cause of genital warts and the agent behind about 70 per cent of cervical cancer cases.
But researchers led by epidemiologist Abby Lippman of McGill University contend that federally backed provincial immunization programs against HPV are going ahead or are planned when there are still a large number of unanswered questions about the vaccine.
"What we're saying is what I used to tell my children when they had to cross the street: 'Stop, look and listen,' " Dr. Lippman said.
"Stop: We have no epidemic, no crisis, no major problem on our hands," said Dr. Lippman, noting that the number of Canadian deaths from cervical cancer is relatively low at 400 each year, and the vaccine doesn't protect against the cause of 30 per cent of cases.
"Let's look at the data we have, let's look for the answers that we don't have to some important questions that we have, then let's listen to those data and develop a really perfect program that may or may not include HPV vaccines for certain girls and women. ...
"But let's do it right."
Writing in the Canadian Medical Association Journal, in an article published online yesterday, Dr. Lippman and her co-authors say the incidence of cervical cancer deaths has been declining, primarily because of regular Pap smear programs to detect the condition.
"In many ways, the predicted 400 deaths per year are a failure of the health care system to address women's health needs, either because women aren't being seen, or they aren't being offered Pap testing when they are seen, or when they have the Pap test done there is not necessary follow-up and so on. ...
"There should not even be 400 women dying, but we don't know if we're going to change those numbers by having a vaccination program, because the vaccine that is available only deals with the virus [strains] that are associated with about 70 per cent of the cancers."
That means women still need to have regular Pap smears, but Dr. Lippman and others worry that many will mistake HPV vaccination as a carte blanche to have as many sexual partners as they want, with little thought for safe sex practices.
"So my question is what's the goal of the vaccine program? Has anybody defined it? How are you going to know when you got there?" asked Dr. Lippman, adding that the most vulnerable - among them the homeless and runaway teens - likely need protection the most but are the hardest for the system to reach.
Dr. Lippman said there are a number of unknowns about the vaccine - including how long the immunity it confers lasts and whether a booster is needed.
"How can responsible public health people not be curious about having these answers before they move ahead?"
Earlier this year, Ottawa pledged $300-million for provincial programs to vaccinate Canadian females aged 9 to 26. In June, Nova Scotia became the first province to announce a program, which will begin this fall with the immunization of about 6,000 Grade 7 girls, who will be offered the recommended three shots of Gardasil over six months. (Three injections cost about $400 for each person.)
Jean Riverin, a spokesman for the Public Health Agency of Canada, said the federal body stands by its endorsement of the vaccine.
"We have a vaccine now that's been tested, we have a vaccine that is available to protect young females that are aged from 9 to 26," he said from Ottawa. "Yes, we are aware that we still need to work and analyze the vaccine and its effectiveness, and ... we don't know if we'll need a booster shot or not."
But "we have a vaccine now. Let's fight cancer now. This gives us a period of time to continue forward."
Widespread HPV vaccination has also been backed by the National Advisory Committee on Immunization (NACI), the Society of Obstetricians and Gynaecologists of Canada and the Canadian Cancer Society.
"It sounds good to protect women, it's a wonderful political sound bite," Dr. Lippman said. "And it makes me look like I don't want to protect women. But I'm just saying if we want to advance and really promote women's health, we need to put it into the context of the lives women lead, how they're leading it and make sure they understand what they're getting into. ...
"All we're saying is we need some information before we allocate huge sums of already limited dollars to a vaccination program."
Toronto ~~ Saturday August 11 2007
How politics pushed the HPV vaccineANDRÉ PICARD
Not since the Salk vaccine was triumphantly unveiled in 1955 as the miracle drug that would end the scourge of polio has there been as much hoopla surrounding a vaccine as there is today about one that is being touted for having the potential to eradicate cervical cancer.
Nor has there been in the ensuing five decades a vaccine that has been such a lightning rod for social controversy and political grandstanding.
Unlike polio, where children were dying and crippled in large numbers and immunization stopped an epidemic in its tracks, cervical cancer develops slowly and the positive or negative effects of a vaccine for human papillomavirus (HPV), which can cause cancer of the cervix, will not be seen for decades.
There remain many unanswered questions about the vaccine: Will it actually prevent cervical cancer or just prevent infection with some strains of the virus? Will it confer long-term protection or will booster shots be required? Should boys be vaccinated?
How many doses are needed – three, or just two? And will the arrival of a competitor to the Gardasil vaccine, called Cervarix, bring down prices?
Scientists have hailed Gardasil as everything from the greatest advance in women's health since the pill to a monstrous experiment on a generation of young girls. Conservative politicians – despite claims from their core constituency that the vaccine will encourage licentious teen sex – have embraced the drug as a means of bolstering their street cred, and winning women's votes. The more liberal politicians – traditional supporters of public health measures like immunization – have railed about a Big Pharma conspiracy to ram Gardasil down our collective throats with sleazy lobbying and slick tug-at-the-heartstrings marketing.
Regardless of your take, the fact remains that since polio, no vaccine has gone from regulatory approval to mass use in government-funded programs with such dizzying speed.
Health Canada approved Gardasil on July 18, 2006. The National Advisory Committee on Immunization gave the vaccine a thumbs-up on Feb. 15, recommending that all girls between 9 and 13 receive the drug. Then the Canadian Immunization Committee, a federal-provincial-territorial body whose role is to determine that vaccines that are effective and cost-efficient are made available equitably to all Canadians, set to work to determine if the expensive new vaccine should be publicly funded and included in routine school-based immunization programs.
But on March 19, during his budget speech, Finance Minister Jim Flaherty short-circuited the scientific and economic discussions by announcing $300-million to kick-start an HPV vaccination program.
Ottawa's move stunned public health officials, as well as the provinces. They were thrilled by the money, particularly for a vaccine that the public was clamouring for, but alarmed by the manner in which the decision was made.
“Aside from the polio vaccine in the fifties, it was the first time that the federal government made a direct medical decision,” said Noni MacDonald, an infectious disease specialist and professor of pediatrics at Dalhousie University in Halifax.
“This has caused a lot of us in public health and medical circles to flinch,” she said.
The discomfort was made even greater when Ontario Premier Dalton McGuinty announced last week that the province will undertake mass HPV vaccination of Grade 8 girls at the beginning of the school year. Again, the breakneck speed of implementation is noteworthy.
Yet, in Toronto as in Ottawa, these scientific and pharmacoeconomic debates, not to mention the necessary public health logistical planning, appear to have been overtaken by the desire to score political points with soccer moms. (Ontario voters go to the polls in October.)
Sandra Pupatello, the Ontario Minister of Women's Issues, dismissed the criticism, saying her government was practising good public policy, not political opportunism.
“There has never been an issue around women's health that has had this level of unanimity. It wasn't a difficult decision.”
Dr. MacDonald said that while the vaccine that prevents the transmission of some strains of HPV may well prove to be a godsend and that public health officials are grateful for the money and attention afforded vaccination (usually the poor, neglected cousin of hi-tech medicine), the precedent is disturbing.
“Why are politicians making medical decisions? This is not how health-care delivery should be decided.”
Anne Rochon Ford, co-ordinator of Women and Health Protection, agrees. The lack of transparency in a program that could have a dramatic impact on women's health is troubling, she said, and doubly so because governments seem to have succumbed to backroom lobbying from the massive marketing campaign of Gardasil's maker, Merck Frosst Canada Ltd., and its international parent.
“It is staggering how quickly and secretly this has all happened and that points to some pretty active footwork behind the scenes,” she said.
Ms. Rochon Ford said the rhetoric about the vaccine with no long-term track record has been unbelievable, and the media has mindlessly and uncritically parroted outrageous claims, while ignoring the importance of proved measures of reducing cervical cancer like Pap testing.
The result of all the attention to Gardasil has been to drive public demand. A poll released earlier this week showed that 81 per cent of parents want their daughters to get the vaccine and 77 per cent favour a universal, school-based program.
And, even without a free vaccine program in place and despite its high price, the drug's maker has already sold 150,000 doses of Gardasil, an unprecedented amount.
“What has happened here is a milking of public sentiment around the fear of cancer and politicians, along with some other well-meaning people, have bought into it,” Ms. Rochon Ford said.
Many in the public health and medical fields share those views but are afraid to speak up, lest they be seen as kicking a gift horse in the mouth.
There is also a school of thought that all the machinations can be forgiven because, ultimately, the right decision was made.
“Yes, the process has been manipulated and politicized but let's not lose sight of the fact that this is a good vaccine and a great advance – immunization against a cancer,” said Joan Murphy, past president of the Society of Gynecologic Oncologists of Canada and a member of the cervical screening collaborative group at Cancer Care Ontario.
Provincial officials are similarly torn. Generally, they are enthusiastic about the vaccine but miffed at Ottawa's intrusion and dismayed at their inability to review and judge Gardasil like any other new drug vying for funding.
But, again, no one wants to raise seemingly bureaucratic arguments when discussing a vaccine that may prevent a nasty form of cancer.
Yet, there are real effects from the politicization of the process.
Nova Scotia, Prince Edward Island, Newfoundland and Labrador and Ontario will begin vaccinating girls against HPV this fall. British Columbia and Quebec will likely do so beginning in the fall of 2008, and other provinces and territories have not yet decided.
“There are troubling inequities,” said Karen Pielak, past chair of the Canadian Nursing Coalition for Immunization. And worse yet, the entire system designed to avert those inequities – children receiving vaccines in one province but not another – was circumvented.
Ms. Pielak, a member of the Canadian Immunization Committee, said all provinces and territories agreed to a come to a common position on introduction and funding of the HPV vaccine, but that fell apart.
“There was an opportunity for political gain and it looks like that took priority over everything else,” she said.
Now, in the place of scientific debate and planning, there is a rush to the gates to see who gets to vaccinate girls first.
B.C. has decided to wait a year, largely for logistical reasons. “The nurses said you can't do it this fall and, thankfully, their voice was heard loud and clear,” Ms. Pielak said.
Paradoxically, the jurisdictions that have opted to follow the rules to ensure they are implementing HPV vaccination for the right reasons are being viewed as laggards and cheapskates.
“Traditionally, Alberta has led the pack on immunization so people are wondering why we opted to wait on HPV,” said Karen Grimsrud, deputy provincial health officer for Alberta.
She said the priority is to review the vaccine thoroughly, like any other, and that it is important not to compromise other important public health programs.
Rushing to vaccinate girls in the fall could, for example, undermine influenza vaccination. The arrival of Cervarix could also bring down prices and make the HPV program more cost-effective, Dr. Grimsrud said.
Finally, and most important, she said that it is essential to prepare an education campaign to ensure that there is good uptake of the vaccine and that there are not negative spinoffs, like young women thinking that Pap tests are no longer necessary.
(HPV is so pervasive that virtually everyone will be infected at some point in their lifetime. In most cases, the body's immune system clears the virus, as it does a cold, but in a minority, the virus lingers and can cause cancer. The vaccine only prevents four strains of HPV, so infections and the risk of cancer will continue even with the vaccine. For all those reasons, women are being urged to continue routine Pap testing.)
“The last thing we want is a program that's not fully thought through,” Dr. Grimsrud said. “If you're going to do this, you should do it right.”
Yet, the momentum to vaccinate, to invest billions of dollars in the HPV vaccine, seems unstoppable.
The hope of supporters and detractors alike is that as girls start lining up for their needles in the fall, the discussion does not die, but moves to a higher level.
“I hope that the momentum for cervical cancer prevention won't die once we vaccinate,” Dr. Murphy said. “We can't allow the message that screening [Pap testing and newer technologies] is necessary and must continue to be forgotten.”
Ms. Rochon Ford has a similar wish.
“The vaccine may prove to be a smart thing in a few years but it's not a magic bullet,” she said. “We still need to teach girls, and boys, about preventive contraception, about Pap tests, and about health inequalities.
“I hope the moms of 12-year-olds who are worried about cervical cancer don't lose sight of that reality.”