HPV Vaccine, 6 Editorials/Perspectives/ Letter To The Editor
NEJM, May 10, 2007
Human Papillomavirus Vaccine - Opportunity and Challenge
Lindsey R. Baden, M.D., Gregory D. Curfman, M.D., Stephen Morrissey, Ph.D., and Jeffrey M. Drazen, M.D.
In this issue of the Journal, we publish three Original Articles,1,2,3 two Perspective articles,4,5 two editorials,6,7 a letter to the editor,8 and an audio interview9 on the subject of human papillomavirus (HPV). We bring together this unique body of information in response to the enormity of the health problems that stem from HPV and the broad interest that has been kindled by the possibility of preventing HPV-related cervical cancer and other anogenital conditions through vaccination.
The HPV vaccine is the first vaccine explicitly designed to prevent cancer induced by a virus. (The hepatitis B vaccine was not primarily designed to prevent cancer.) As noted in the Perspective article by Agosti and Goldie,5 the consequences of HPV infection are a global health concern that disproportionately affects those in developing countries. The potential ability to reduce the burden of HPV-related disease by vaccination against certain disease-inducing strains of the virus has created a volatile intersection between the community's interest in limiting the transmission of infectious diseases and promoting health on the one hand and social mores on the other, as discussed by Charo in her Perspective article4 and related audio interview (podcast available at www.nejm.org).9 However, this volatility should not keep us from recognizing the enormous potential for medical progress and from addressing the numerous unanswered questions that remain.
The finding that infection with HPV is a critical factor in the majority of cases of cervical cancer allowed the development of strategies to prevent this form of oncogenesis. It is important to note that several other cancers are also associated with HPV infection, including head and neck cancers, as demonstrated by D'Souza and colleagues.3 Although there are many HPV serotypes, two of them - 16 and 18 - account for the lion's share of the oncogenesis. The data that are presented in reports on the vaccine efficacy trials in this issue of the Journal1,2 confirm the success in reducing the incidence of precancerous cervical lesions with vaccine directed against the HPV-16 and HPV-18 serotypes.
Although this is a remarkable achievement, the efficacy of the vaccine is limited by at least these two factors. First, not all cervical cancer is caused by HPV-16 or HPV-18, and second, it appears necessary to vaccinate young women before they are infected with these two serotypes. Also, whether this approach will extend the paradigm of vaccination to the prevention of death and disability from cervical cancer is an unanswered question.
It is difficult to show that an intervention prevents cancer, given the relatively long induction phase between exposure to an inducing agent and development of disease. Thus, key surrogate markers, in this case cervical intraepithelial neoplasia grades 2 and 3, were used so that data could be gathered in a timely fashion. However, correlation with the ultimate outcome - cancer prevention - will require the long-term observation of a large number of treated women. We must also carefully monitor for unintended adverse consequences of vaccination. For example, when selective immunologic pressure is applied with vaccination, the potential exists for nonvaccine-related strains to emerge as important oncogenic serotypes. These critical points are clarified in the editorial by Sawaya and Smith-McCune.6
Many other questions are raised by these remarkable data. Should young men be vaccinated? What is the durability of immune protection? Could fewer than three vaccinations provide adequate protection? Will future HPV vaccines extend protection to cover additional pathogenic serotypes? Will the economics allow this therapy to reach all who may benefit, such as those in the developing world? Might HPV vaccination be beneficial in preventing other, noncervical HPV-induced cancers (such as HPV-related oropharyngeal cancer3)?
There is no doubt that the findings reported in this issue of the Journal open a new field at the interface of basic science, clinical medicine, public health, and public policy. It is important to keep in mind that these new treatments raise many scientific, medical, economic, and sociological questions. We have begun an exciting journey; we need to continue in the right direction.
HPV Vaccination - More Answers, More Questions
George F. Sawaya, M.D., and Karen Smith-McCune, M.D., Ph.D.
Departments of Obstetrics, Gynecology and Reproductive Sciences (G.F.S., K.S.-M.), Epidemiology and Biostatistics (G.F.S.), and the Comprehensive Cancer Center (G.F.S., K.S.-M.), University of California, San Francisco, San Francisco.
The availability of a "cancer vaccine" has elicited enormous enthusiasm from the medical community and the public, culminating in advocacy for mandatory vaccination against human papillomavirus (HPV) and a recommendation from the Centers for Disease Control and Prevention (CDC) that 30 million girls and women between the ages of 11 and 26 years in the United States be vaccinated.1 Previous reports2,3 showed a remarkable 100% efficacy of a quadrivalent vaccine targeting HPV types 6, 11, 16, and 18 on outcomes related to vaccine HPV types in women with no evidence of previous exposure to those types. Since HPV types 16 and 18 are implicated in 70% of cervical cancers,4 these types are ideal targets for a new vaccine.
In this issue of the Journal, reports on two large, ongoing, randomized, placebo-controlled trials show the effect of this vaccine on important clinical outcomes, including rates of adenocarcinoma in situ and cervical intraepithelial neoplasia after an average of 3 years of follow-up.5,6 Investigators in these trials have hit their mark soundly: the vaccine showed significant efficacy against anogenital and cervical lesions related to vaccine type in women with no evidence of previous exposure to vaccine-specific types; the vaccine also appeared to be safe. In addition, the studies report outcomes in all subjects regardless of HPV status at baseline and regardless of whether outcomes were related to HPV types targeted by the vaccine. Policymakers now have more evidence to assess the benefits and risks of widespread vaccination.
Given the rarity of incident cervical cancer, preinvasive cervical lesions with high invasive potential are used in contemporary studies as surrogate outcomes for cervical cancer. Adenocarcinoma in situ is a rare lesion widely considered to be a precursor of cancer. Cervical intraepithelial neoplasia is graded from 1 to 3 on the basis of histopathological criteria. Grade 1 cervical intraepithelial neoplasia indicates the presence of active HPV infection and is not considered to be precancerous; current guidelines discourage treatment of this condition.7,8 Grade 2 cervical intraepithelial neoplasia is treated in most women but is not an irrefutable cancer surrogate, since up to 40% of such lesions regress spontaneously9; current guidelines suggest that some young women with such lesions do not need to be treated.7,8 Grade 3 cervical intraepithelial neoplasia, on the other hand, has the lowest likelihood of regression and the strongest potential to be invasive. The Food and Drug Administration (FDA) considers grade 2 and 3 cervical intraepithelial neoplasia and adenocarcinoma in situ to be acceptable surrogate outcomes for cervical cancer; other observers consider grade 3 cervical intraepithelial neoplasia and adenocarcinoma in situ to be more appropriate surrogates.9
In these trials, called Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I and II, what is the efficacy of vaccination among all subjects, regardless of causal HPV types? In the FUTURE I trial,5 rates of grades 1 to 3 cervical intraepithelial neoplasia or adenocarcinoma in situ per 100 person-years were 4.7 in vaccinated women and 5.9 in unvaccinated women, an efficacy of 20%. Analyses by lesion type indicate that this reduction was largely attributable to a lower rate of grade 1 cervical intraepithelial neoplasia in vaccinated women; no efficacy was demonstrable for higher-grade disease, but the trial may have lacked adequate power to detect a difference. Vaccinated women also had lower rates of external anogenital and vaginal lesions (1.3 vs. 2.1). In the larger FUTURE II trial,6 rates of grade 2 or 3 cervical intraepithelial neoplasia or adenocarcinoma in situ were 1.3 in vaccinated women and 1.5 in unvaccinated women, an efficacy of 17%. In analyses by lesion type, the efficacy appears to be significant only for grade 2 cervical intraepithelial neoplasia; no efficacy was demonstrable for grade 3 cervical intraepithelial neoplasia or adenocarcinoma in situ.
What can be inferred from these data about the potential effect of vaccination on populations that include sexually active women? In the FUTURE II trial, 93% of subjects were nonvirgins. With grade 2 or 3 cervical intraepithelial neoplasia or adenocarcinoma in situ as the outcome, the difference in risk so far appears to be modest: 219 of 6087 vaccinated women (3.6%) received this diagnosis over an average of 3 years, as compared with 266 of 6080 unvaccinated women (4.4%). The absolute risk difference of 0.8% indicates that 129 women would need to be vaccinated in order to prevent one case of grade 2 or 3 cervical intraepithelial neoplasia or adenocarcinoma in situ occurring during this period. If grade 3 cervical intraepithelial neoplasia or adenocarcinoma in situ were the most relevant outcome, evidence was insufficient to infer the effectiveness of vaccination.
Why is vaccine efficacy modest in the entire cohort? One factor is the apparent lack of efficacy among subjects with evidence of previous exposure to HPV types included in the vaccine. The FUTURE II trial showed no effect of vaccination up to month 12, perhaps owing either to preinvasive lesions or to vaccine-type HPV infections that were present at enrollment. Therefore, vaccination before the onset of sexual activity seems to be preferable. In contrast to the CDC's guidelines, the American Cancer Society does not recommend universal vaccination among women between 18 and 26 years of age, citing probable diminished vaccine efficacy as the number of lifetime sexual partners increases.10 Trial outcomes stratified by risk factors that are strong surrogates for HPV exposure and are readily obtained clinically (e.g., the number of lifetime sexual partners) may prove to be useful in the future development of guidelines.
Another factor explaining the modest efficacy of the vaccine is the role of oncogenic HPV types not included in the vaccine. At least 15 oncogenic HPV types have been identified,4 so targeting only 2 types may not have had a great effect on overall rates of preinvasive lesions. Findings from the FUTURE II trial showed that the contribution of nonvaccine HPV types to overall grade 2 or 3 cervical intraepithelial neoplasia or adenocarcinoma in situ was sizable. In contrast to a plateau in the incidence of disease related to HPV types 16 and 18 among vaccinated women, the overall disease incidence regardless of HPV type continued to increase, raising the possibility that other oncogenic HPV types eventually filled the biologic niche left behind after the elimination of HPV types 16 and 18. An interim analysis of vaccine trial data submitted to the FDA11 showed a disproportionate, but not statistically significant, number of cases of grade 2 or 3 cervical intraepithelial neoplasia related to nonvaccine HPV types among vaccinated women. Updated analyses of data from these ongoing trials will be important to determine the effect of vaccination on rates of preinvasive lesions caused by nonvaccine HPV types.
What can be inferred from these data about the potential effect of vaccination among girls 11 and 12 years of age? The FUTURE trials did not enroll subjects in this age group. Within both trials, subgroups of subjects with no evidence of previous exposure to relevant vaccine HPV types were evaluated separately for vaccine efficacy. In these subgroups, efficacy of nearly 100% against all grades of cervical intraepithelial neoplasia and adenocarcinoma in situ related to vaccine HPV types was reported in both trials. However, it would be important to know the overall rates of grade 2 or 3 cervical intraepithelial neoplasia or adenocarcinoma in situ regardless of HPV types. Without these data, it is difficult to infer both the effectiveness of vaccination and the role of nonvaccine HPV types in overall rates of preinvasive lesions.
What do these results mean for cervical-cancer screening? Screening should continue in all vaccinated women, given the cumulative lifetime risk of exposure to other oncogenic HPV types and the unknown duration of anti-HPV immunity. The effect of vaccination on cervical cytologic findings was not reported in either trial, but if vaccination reduces the rates of abnormal findings, this benefit would be important. Of note, a trial of a monovalent HPV-16 vaccine reported no effect on cytologic abnormalities.12
Policymakers, clinicians, and parents have a keen sense of urgency about HPV vaccination. On one hand, the vaccine has high efficacy against certain HPV types that cause life-threatening disease, and it appears to be safe; delaying vaccination may mean that many women will miss an opportunity for long-lasting protection. On the other hand, a cautious approach may be warranted in light of important unanswered questions about overall vaccine effectiveness, duration of protection, and adverse effects that may emerge over time. HPV vaccination has the potential for profound public health benefit if the most optimistic scenario of effectiveness is realized.
No potential conflict of interest relevant to this article was reported.
Human Papillomaviruses in Head and Neck Carcinomas
Stina Syrjanen, D.D.S., Ph.D.
Department of Oral Pathology, Institute of Dentistry, Faculty of Medicine, University of Turku, Turku, Finland.
Each year, almost 650,000 patients worldwide receive the diagnosis of head and neck cancer and some 350,000 die from this disease.1 Nearly 90% of these cancers are squamous-cell carcinomas. The two main causative factors in approximately 80% of oral, oropharyngeal, and laryngeal carcinomas are smoking and alcohol use. Consumption of vegetables and fruit may modulate the carcinogenic effects of tobacco and alcohol, whereas low body-mass index increases the risk of oral cancer.2 The idea that human papillomavirus (HPV) plays a role in these cancers has been under investigation for at least 20 years.
It is widely accepted that HPV causes cervical cancer.3 HPV has also been associated with several other types of squamous-cell carcinoma and their precursors at different sites - skin, vulva, vagina, penis, esophagus, conjunctiva, paranasal sinuses, and bronchus - but the role of HPV in the pathogenesis of the lesions is less clear than it is in cervical cancer.4 The similarity of the morphologic features of genital and oral HPV-associated lesions was one of the early findings that raised the possibility that HPV might be involved in oral and laryngeal squamous-cell carcinomas.5,6 Until recently, however, the role of HPV in the pathogenesis of head and neck squamous-cell carcinoma has been uncertain, mainly because detection of HPV DNA has been highly variable, with rates ranging from 0 to 100%.4
New data from case-control studies suggest that HPV is an independent risk factor for oral and oropharyngeal squamous-cell carcinomas.7,8,9 Moreover, a systematic review showed an overall prevalence of HPV infection of 25.9% in specimens obtained from 5046 patients with head and neck squamous-cell carcinoma that had been analyzed in 60 separate studies.10 This review found that the prevalence of HPV infection was significantly higher among patients with oropharyngeal squamous-cell carcinoma (35.6%) than among those with oral (23.5%) or laryngeal (24.0%) squamous-cell carcinoma. A review of more than 5000 cases of head and neck squamous-cell cancers showed that, as in cases of anogenital squamous-cell carcinoma, HPV type 16 (HPV-16) was the most prevalent genotype, accounting for 86.7% of cases of oropharyngeal squamous-cell carcinoma, 68.2% of oral squamous-cell carcinoma, and 69.2% of laryngeal squamous-cell carcinoma.10 Key unresolved questions concern where latent HPV resides in the head and neck region and whether HPV is transmitted through sexual contact into these regions.
In this issue of the Journal, D'Souza and colleagues report further evidence of the association between HPV and oropharyngeal cancer.11 Their study involved 100 patients with newly diagnosed oropharyngeal cancer and 200 control subjects who did not have cancer. Sampling for HPV testing was performed with the use of a saline oral rinse and 5 to 10 strokes of a cytology brush on the posterior oropharyngeal wall. Serum antibodies against the HPV-16 proteins L1, E6, and E7 were also studied. Both a prevalent oral infection with HPV-16 and an oral infection with any of 37 other HPV types were significantly associated with oropharyngeal cancer. Moreover, on pathological examination of paraffin-embedded specimens with the use of in situ hybridization, HPV-16 was found in 72% of 60 oropharyngeal cancers sampled.11
One of the shortcomings of the study is the use of rinsing of the oral cavity as the sampling method. Where HPV resides in the oropharynx is not known - whether in the oral mucosa, in the tonsils, or in the anterior or posterior part of the tongue or both. There is evidence that tonsillar carcinomas have a stronger association with HPV than does any other HPV-associated extragenital tumor. It is unclear, however, whether HPV-associated cancer of the tonsils originates from crypt or surface epithelium, although data suggest that HPV inhabits the normal crypt epithelia.12,13 The possibility that tonsillar tissue in Waldayer's ring, which surrounds the oropharynx and is important as an antigen-presenting site, is the reservoir of HPV cannot be excluded.
Data presented by D'Souza and colleagues11 suggest that sexual behavior is associated with oropharyngeal cancer, as has been suggested previously.7,9 In their study, a high lifetime number of vaginal- or oral-sex partners was associated with the presence of oropharyngeal cancer, and the degree of association increased with an increasing number of vaginal- or oral-sex partners. Transmission of the virus by direct oral contact or by other means could not be excluded, however. In a study that my colleagues and I performed, involving married couples with healthy oral mucosa (sampling at baseline and at months 2, 6, 12, 24, and 36), the results suggested that the oral route is an important means of HPV transmission between partners: one spouse had a 10-fold risk of acquiring persistent oral HPV infection if the other spouse had persistent oral HPV infection.14 Oral sex was not associated with oral or genital HPV infection in these studies, and oral HPV infection in one spouse was unrelated to genital HPV infection in the other spouse.14 In our study and in the study by D'Souza and colleagues, however, the patients were different: the couples we studied were younger and had no evidence of clinical lesions in the oropharynx, whereas those in the study by D'Souza and colleagues were older patients who had oropharyngeal cancer.11
Mork and colleagues found a 14-fold increase in the risk of oropharyngeal cancer among patients seropositive for HPV-16 L1 protein and suggested that exposure to HPV can precede the appearance of oropharyngeal cancer by 10 or more years.15 Their observation is supported by the results of D'Souza and colleagues,11 who found a significant association between head and neck squamous-cell carcinoma (odds ratio, 32; 95% confidence interval, 15 to 71) and seropositivity for the HPV-16 L1 capsid protein, which is a measure of lifetime exposure to HPV-16. Nevertheless, whether persistent HPV infection in the head and neck region is a risk factor for oropharyngeal cancer has not been rigorously demonstrated.
It is possible that HPV-associated head and neck squamous-cell carcinoma arises by a different mechanism from that involved in the pathogenesis of HPV-associated cervical carcinoma. D'Souza and colleagues present data suggesting that smoking and alcohol use, which are important risk factors for oropharyngeal cancer, may not act as cofactors in HPV-mediated carcinogenesis in the oropharynx. Whether smoking is an independent or synergistic component of the mechanism of HPV-associated squamous-cell carcinoma in the oral and oropharyngeal region requires further study.
Now that the association between some cases of oropharyngeal cancer and HPV infection appears to be firmly established, the question that arises is whether there is any need for screening for persistent oral or oropharyngeal HPV infection in high-risk groups (smokers and drinkers). Moreover, we need to examine how to treat HPV-positive intraepithelial neoplastic lesions, which are cancer precursor lesions, in the head and neck region. Should HPV-associated oral and oropharyngeal carcinomas be treated in the same way that their HPV-negative counterparts associated with heavy smoking and drinking are treated? And finally, it is worth considering the possibility that some oral, oropharyngeal, and laryngeal cancers might be prevented by HPV vaccination.
Dr. Syrjanen reports receiving consulting fees from Merck. No other potential conflict of interest relevant to this article was reported.
Politics, Parents, and Prophylaxis - Mandating HPV Vaccination in the United States
R. Alta Charo, J.D.
professor of law and bioethics at the University of Wisconsin, Madison.
Cancer prevention has fallen victim to the culture wars. Throughout the United States, state legislatures are scrambling to respond to the availability of Merck's human papillomavirus (HPV) vaccine, Gardasil, and to the likely introduction of GlaxoSmithKline's not-yet-approved HPV vaccine, Cervarix, which have been shown to be effective in preventing infection with HPV strains that cause about 70% of cases of cervical cancer. At the Centers for Disease Control and Prevention (CDC), the Advisory Committee on Immunization Practices (ACIP) has voted unanimously to recommend that girls 11 and 12 years of age receive the vaccine, and the CDC has added Gardasil to its Vaccines for Children Program, which provides free immunizations to impoverished or underserved children.
Yet despite this federal imprimatur, access to these vaccines has already become more a political than a public health question. Though the more important focus might be on the high cost of the vaccines - a cost that poses a genuine obstacle to patients, physicians, and insurers - concern has focused instead on a purported interference in family life and sexual mores. This concern has resulted in a variety of political efforts to forestall the creation of a mandated vaccination program. In Florida and Georgia, for example, efforts to increase adoption of the vaccine have been stalled by legislative maneuvering. The Democratic governor of New Mexico has announced that he will veto a bill that mandates vaccinations. And the Republican governor of Texas came under fire (and under legal attack from his own attorney general) when he issued an executive order to the same effect, mandating that all girls entering the sixth grade receive the vaccine; the policy was attacked as an intrusion on parental discretion and an invitation to teenage promiscuity. But all these measures included a parental right to opt out, whether on religious or secular grounds. The opposition seemed more about acknowledging the realities of teenage sexuality than about the privacy and autonomy of the nuclear family.
For more than a century, it has been settled law that states may require people to be vaccinated, and both federal and state court decisions have consistently upheld vaccination mandates for children, even to the extent of denying unvaccinated children access to the public schools. State requirements vary as to the range of communicable diseases but are often based on ACIP recommendations. School-based immunization requirements represent a key impetus for widespread vaccination of children and adolescents1 and are enforceable even when they allegedly conflict with personal or religious beliefs.2 In practice, however, these requirements usually feature exceptions that include individual medical, religious, and philosophical objections.
All legislation mandating HPV vaccination includes some form of parental opt-out. The Texas mandate is the result of an executive order from the governor, and its legality is being challenged by the attorney general of Texas. There is also legislation under consideration in Texas that would prohibit a mandate. If passed, it would override the executive order. The Virginia law was passed by the legislature and signed by the governor. The New Mexico legislation was passed by the House and Senate and was then vetoed by the governor. Bills in California and Maryland have been withdrawn for consideration, and the bill in South Carolina has been tabled. Neither Alaska nor Hawaii has considered a mandate. Legislation that makes provisions for funding is under consideration in many states but is not shown here. The various bills would require insurance companies to cover vaccination, allocate state funds, direct agencies to apply for federal funds, or some combination. Information is from the National Conference of State Legislatures and is accurate as of April 27, 2007.
HPV-vaccination mandates, which are aimed more at protecting the vaccinee than at achieving herd immunity, have been attacked as an unwarranted intrusion on individual and parental rights. The constitutionality of vaccination mandates is premised on the reasonableness of the risk-benefit balance, the degree of intrusion on personal autonomy, and, most crucial, the presence of a public health necessity. On the one hand, to the extent that required HPV vaccination is an example of state paternalism rather than community protection, mandatory programs lose some of their justification. On the other hand, the parental option to refuse vaccination without interfering in the child's right to attend school alters this balance. Here the mandates act less as state imperatives and more as subtle tools to encourage vaccination. Whereas an opt-in program requires an affirmative effort by a parent, and thus misses many children whose parents forget to opt in, an opt-out approach increases vaccination rates among children whose parents have no real objection to the program while perfectly preserving parental autonomy.
Opposition to HPV vaccination represents another chapter in the history of resistance to vaccination and, on some levels, reflects a growing trend toward parental refusal of a variety of vaccines based on the (erroneous) perception that many vaccines are more risky than the diseases they prevent. In most cases, pediatricians have largely restricted themselves to educating and counseling objecting families, since it is rare that the risks posed by going unvaccinated are so substantial that refusal is tantamount to medical neglect. In the case of HPV vaccine, parents' beliefs that their children will remain abstinent (and therefore uninfected) until marriage render it even more difficult to make the case for mandating a medical form of prevention. Even with an opt-out program, critics may argue that the availability of a simple and safe alternative - that is, abstinence - undermines the argument for a state initiative that encourages vaccination through mandates coupled with an option for parental refusal.
But experience shows that abstinence-only approaches to sex education do not delay the age of sexual initiation, nor do they decrease the number of sexual encounters.3 According to the CDC, though only 13% of American girls are sexually experienced by 15 years of age, by 17 the proportion grows to 43%, and by 19 to 70%.4 School-based programs are crucial for reaching those at highest risk of contracting sexually transmitted diseases, and despite the relatively low rate of sexual activity before age 15, the programs need to begin with children as young as 12 years: the rates at which adolescents drop out of school begin to increase at 13 years of age,1 and younger dropouts have been shown to be especially likely to engage in earlier or riskier sexual activity.
Another fear among those who oppose mandatory HPV vaccination is that it will have a disinhibiting effect and thus encourage sexual activity among teens who might otherwise have remained abstinent. This outcome, however, seems quite unlikely. The threat of pregnancy or even AIDS is far more immediate than the threat of cancer, but sex education and distribution of condoms have not been shown to increase sexual activity. Indeed, according to a study conducted by researchers at the University of Pennsylvania, it is the comprehensive sex-education approaches that include contraceptive training that "delay initiation of sexual intercourse, reduce frequency of sex, reduce frequency of unprotected sex, and reduce the number of sexual partners."5 Opposition to the HPV-vaccination mandates, then, would seem to be based more on an inchoate concern: that to recognize the reality of teenage sexual activity is implicitly to endorse it.
Public health officials may have legitimate questions about the merits of HPV vaccine mandates, in light of the financial and logistic burdens these may impose on families and schools, and also may be uncertain about adverse-event rates in mass-scale programs. But given that the moral objections to requiring HPV vaccination are largely emotional, this source of resistance to mandates is difficult to justify. Since, without exception, the proposed laws permit parents to refuse to have their daughters vaccinated, the only valid objection is that parents must actively manifest such refusal. Such a slight burden on parents can hardly justify backing away from the most effective means of protecting a generation of women, and in particular, poor and disadvantaged women, from the scourge of cervical cancer. To lighten that burden even further, the governor of Virginia has proposed that refusals need not even be put in writing. Perhaps it is time for parents who object to HPV vaccinations to take a lesson from their children and heed the words of Nancy Reagan: Just say no.
Introducing HPV Vaccine in Developing Countries - Key Challenges and Issues
Jan M. Agosti, M.D., and Sue J. Goldie, M.D., M.P.H.
Dr. Agosti is a senior program officer for infectious diseases in the Global Health Program, Bill and Melinda Gates Foundation, Seattle. Dr. Goldie is a professor of health decision science in the Department of Health Policy and Management, Harvard School of Public Health, Boston.
More than any other cancer, cervical cancer reflects striking global health inequity. It is the second most common cancer among women worldwide, with about 493,000 new cases diagnosed annually (see map). Of 274,000 deaths due to cervical cancer each year, more than 80% occur in developing countries, and this proportion is expected to increase to 90% by 2020.1 Affecting relatively young women, it is the largest single cause of years of life lost to cancer in the developing world. The deaths of women who are in their most productive years have a devastating effect on the well-being of their families, resulting, for example, in decreases in school attendance and nutritional status among their children.
A new quadrivalent human papillomavirus (HPV) vaccine has now been proved to be effective in preventing cervical intraepithelial neoplasia grade 2 and grade 3 caused by HPV types 16 and 18 (see reports by the FUTURE II Study Group on pages 1915-1927 and by Garland and colleagues on pages 1928-1943). According to meta-analyses, these two types of HPV account for an estimated 70% of all cervical cancers worldwide, representing a slightly higher fraction in developed regions (72 to 77%) than in less developed regions (65 to 72%).2 Longer follow-up will be required to establish the degree of protection against other oncogenic strains (including HPV types 31, 33, 35, 45, 52, and 58), but the preliminary data are encouraging. Long-term monitoring will determine the durability of protection and the need for booster immunization. This vaccine has been studied in 27,000 women in 33 countries and is licensed in more than 60 countries. Results from the bivalent HPV-16/HPV-18 vaccine demonstrate similar efficacy. These data constitute sufficient evidence to support global policy recommendations for the introduction of either HPV vaccine.
Considerations for policymakers debating the use of HPV vaccine in any particular country will include that country's disease burden, its health care infrastructure, and its capacity for initiating and sustaining an immunization program for adolescents. Other considerations include the affordability and cost-effectiveness of vaccination relative to other programs competing for resources and the likelihood of cultural acceptability, political will, and public support.
Ultimately, the field effectiveness of HPV vaccine will require improved systems for providing health care to adolescents. Sociocultural sensitivities in this area abound, although concern about vaccinating adolescents against a sexually transmitted infection have been tempered by an emphasis on the vaccine's role in cancer prevention. Yet in environments characterized by mistrust of governmental health care initiatives, vaccination programs targeted toward young women may be misunderstood as attempts to control fertility - misapprehensions that have held sway in some countries even with regard to immunization campaigns against poliovirus and tetanus. If such fears can be allayed, an adolescent immunization program, possibly school-based, could be designed to deliver other adolescent health services and immunizations against tetanus, measles, rubella, meningococcus, typhoid, or even, ultimately, the human immunodeficiency virus, as well as HPV. In areas where the rate of school enrollment among girls is low, community-based efforts to reach girls outside school must be evaluated.
The factors with the greatest influence on the cost-effectiveness of vaccination will be the price of the vaccine and the costs of a program to reach adolescents. An analysis of options for cervical-cancer control in Brazil found that at a cost of $5 per dose (excluding wastage, administration, and costs of programs), the cost-effectiveness ratio associated with adolescent vaccination would be less than $150 per year of life saved, and vaccination combined with screening women three times during their lifetime would meet the criteria for a very cost-effective intervention.3 At a price of $100 per dose, vaccination would not be cost-effective, as compared with screening three times per lifetime. For countries with a gross domestic product of less than $1,000 per capita, the per-dose cost may need to be as low as $1 to $2 to make vaccination both cost-effective and affordable.
Without a doubt, one of the greatest barriers to the introduction of this vaccine is price. The three-dose series of the Merck quadrivalent vaccine will cost an estimated $360 in the United States; dramatic price tiering will be required to facilitate its timely use in developing countries. The GAVI Alliance (formerly known as the Global Alliance for Vaccines and Immunization) - a partnership of national governments, the World Health Organization, the World Bank, the Bill and Melinda Gates Foundation, the vaccine industry, public health institutions, and nongovernmental organizations - provides technical assistance and financial support for vaccines in countries with a gross national income of less than $1,000 per capita, as well as in China, India, and Indonesia. With subsidies from GAVI, HPV vaccine can be brought to the poorest parts of the world. Over the course of the next year, GAVI will review its new-vaccine policies to determine whether HPV vaccine should be among the vaccines prioritized for support.
The high probability of acquiring HPV infection once one has become sexually active raises the question of whether the vaccine will be effective if given to girls who have already been infected with HPV type 16 or 18. According to data from the FUTURE II study, vaccination did not alter the course of existing HPV infection but did protect against infection by a strain to which subjects had not yet been exposed. This observation highlights the need for immunization before the onset of sexual activity. Though the question of immunization of older girls and women deserves attention, from a public health perspective, the first priority in resource-poor settings would be to vaccinate young adolescent girls.
Fortunately, for older women in developing countries there are new options for cervical-cancer screening that are likely to provide cost-effective strategies for reducing the risk of cancer.4,5 The resources, infrastructure, and technological expertise required, together with the need for repeated screening at frequent intervals, have made conventional cytology-based screening prohibitively difficult in most poor countries. Promising newer approaches include HPV DNA testing and visual-inspection methods, focusing screening efforts on women between 30 and 45 years of age, and minimizing loss to follow-up by delivering screening and treatment in as few visits as possible. Employing a single-visit "screen-and-treat" strategy is now possible if cryotherapy is used in women in whom lesions have been detected on visual inspection of the cervix with acetic acid; it will soon also be possible to pursue such a strategy with the use of low-cost, rapid HPV DNA testing. It is imperative that the momentum behind the past decade's efforts to develop feasible options for cervical-cancer screening in low-resource settings continue to build, since screening will still be required - not only for nonvaccinated women but also to prevent cancers caused by HPV types other than 16 or 18 that are not included in any HPV vaccine. Even in resource-poor settings, the ideal program for cervical-cancer prevention would include vaccination of adolescent girls and screening of women between 30 and 45 years of age.
Too many women living in poverty have died of invasive cervical cancer. With the availability of an effective, safe vaccine, there is real hope for reducing the global burden of cervical cancer. Although achieving broad coverage of young adolescents, negotiating tiered pricing, and securing financing will be challenging, it is sobering to realize that with every 5-year delay in bringing vaccination to developing countries, 1.5 million to 2 million more women will die. Vaccination has the potential to save many lives. Let us hope that a committed global effort makes fulfillment of the promise of the new vaccine possible.
Mandating HPV Vaccination - Private Rights, Public Good
To the Editor: Those who oppose mandating vaccination against human papillomavirus (HPV) as a condition for school entry generally open the debate with two fundamental questions. First, how can the government interfere in the medical decisions parents make for their children by compelling immunizations for school entry? Second, how can the HPV vaccine be a good candidate for school mandates when HPV infection is transmitted only through intimate contact, not through casual encounters, as with other diseases that are preventable with vaccines? In fact, requiring vaccination against HPV for school entry is firmly rooted in American jurisprudence.
The Supreme Court, when first adjudicating compelled vaccination, recognized that the "police power" granted to states under the Constitution's 10th Amendment permits all jurisdictions to legislate to "protect the public health and the public safety."1 Thus, the Court said, Massachusetts was acting within its appropriate authority when requiring persons to submit to vaccination against smallpox and when imposing sanctions for noncompliance. Seventeen years later, the Court affirmed a Texas mandate that required documentation of the receipt of certain vaccinations before children could enter school.2
Today, all states and the District of Columbia have instituted immunization requirements for school entry and all jurisdictions provide a procedure for parents to opt out of the requirements. These mandates have proved to be the most effective tool ever devised for increasing access to recommended vaccines for our children. Indeed, the national coverage rate for most childhood vaccines is 95%.3
Another argument against compulsory HPV vaccination contends that because the infection is not casually communicable, the traditional justifications outlined in previous judicial decisions do not apply. However, the mode of transmission is a distinction without meaningful difference, and the result is the same. Twenty million persons are currently infected with HPV; 6 million more become infected each year. The threat to the public's health, at least with respect to vaccine-related strains, is preventable with the vaccine.
Legal precedent, although established before the introduction of the new vaccine against a virus that is transmitted through intimate contact, will nevertheless serve as the nexus for decisions about the future. If courts are ever called on to review the appropriateness of mandating vaccination against HPV, the traditional underlying principles set forth to justify vaccine mandates could easily outweigh concerns about the mode of transmission. Courts must rely on and respect the established precedent on which immunization mandates have been built.
Alexandra M. Stewart, J.D.
George Washington University Medical Center
Washington, DC 20006
Dr. Stewart reports working under a contract from Merck (with the Department of Health Policy at George Washington University Medical Center, which has conducted research on access to vaccines among the underserved) to study Medicaid coverage of the HPV vaccine. No other potential conflict of interest relevant to this letter was reported.