Mandatory HPV Vaccination: Public Health vs Private Wealth

Abstract

By any measure, genital human papillomavirus (HPV) infection and HPV-associated cervical cancer are significant national and global public health concerns. An estimated 11 000 newly diagnosed cases of cervical cancer occur annually in the United States, resulting in 3700 deaths.1 Globally, an estimated 493 000 new cervical cancer cases occur each year, with 274 000 deaths; more than 80% of cervical cancer deaths worldwide occur in developing countries.2

Full text

EDITORIALS
Editorials represent the opinions
of the authors and JAMA and not those of
the American Medical Association.
Mandatory HPV V accination
Public Health vs Private W ealth
Lawrence O. Gostin, JD, LLD
Catherine D. DeAngelis, MD, MPH
B
Y ANY MEASURE, GENITAL HUMAN PAPILLOMAVIRUS
(HPV) infection and HPV-associated cervical can-
cer are significant national and global public health
concerns. An estimated 11 000 newly diagnosed
cases of cervical cancer occur annually in the United States,
resulting in 3700 deaths.
1
Globally, an estimated 493 000
new cervical cancer cases occur each year, with 274 000
deaths; more than 80% of cervical cancer deaths world-
wide occur in developing countries.
2
Human papillomavirus is the most common sexually trans-
mitted infection in the United States, with an estimated 6.2
million individuals newly infected annually.
3
Data from the
National Health and Nutrition Examination Survey re-
vealed a 26.8% overall HPV prevalence among US girls and
women, with increasing prevalence each year for ages 14
to 24 years (44.8% for ages 20-24 years) followed by a gradual
decline in prevalence through age 59 years (19.6% for ages
50-59 years).
4
Although infection with high-risk HPV types
is necessary for the development of cervical cancer (de-
tected in 99% of cervical cancers),
5
high-risk types 16 and
18 have a relatively low prevalence (3.4% of all HPV infec-
tions),
4
and not all women who are infected with high-risk
HPV types will develop cervical cancer. Approximately 90%
of women with new HPV infections clear the infection within
2 years.
6
In June 2006, the US Food and Drug Administration (FDA)
licensed a prophylactic quadrivalent HPV vaccine against
types 6, 11, 16, and 18 for use among girls and women aged
9 to 26 years.
7
The FDA approval is conditional on manu-
facturer assurances concerning ongoing safety and efficacy
studies.
8
The Centers for Disease Control and Prevention
Advisory Committee on Immunization Practices (ACIP) rec-
ommends routine vaccination of girls aged 11 to 12 years
with 3 doses of quadrivalent HPV vaccine; the vaccination
series can be started as young as age 9 years.
9
ACIP also rec-
ommends “catch-up” vaccination for unvaccinated girls and
women aged 13 to 26 years.
9
Clinical trials among 16- to 26-year-olds show that the
quadrivalent HPV vaccine is almost 100% effective in pre-
venting infection and disease associated with HPV types in-
cluded in the vaccine.
10
Studies show that the vaccine is safe
and immunogenic for girls aged 9 to 15 years for at least a
short term, but efficacy among this age group has not been
evaluated. For those older than 15 years, the vaccine pro-
vides protection for at least 5 years, and follow-up studies
are under way to determine the duration of protection.
9
A
bivalent vaccine against HPV types 16 and 18 also has been
shown to be highly immunogenic and safe for up to 4.5 years,
although it is not yet licensed.
11
Earlier this year, Texas (by executive order) and Vir-
ginia made quadrivalent HPV vaccine mandatory for girls
entering sixth grade. However, the Texas legislature re-
cently voted to overturn the governor’s order and Virginia
granted parents generous “opt-out” provisions.
12
Nearly 20
additional states are considering similar legislation,
13
and
some medical experts in Europe are calling for mandatory
HPV vaccination.
14
Routine use of the quadrivalent HPV vac-
cine undoubtedly is beneficial to the public’s health, as it is
likely to reduce the incidence of cervical cancers. How-
ever, the rush to make HPV vaccination mandatory in school-
aged girls presents ethical concerns and is likely to be coun-
terproductive.
The ACIP recommendation supports making quadriva-
lent vaccination the standard of clinical care. However, it is
important to emphasize that the vaccine is supported by lim-
ited efficacy and safety data. Clinical trials have thus far in-
volved a relatively small population (⬍12 000 partici-
pants) for a limited period of follow-up (5 years). The vaccine
has not been evaluated for efficacy among younger girls (aged
9 to 15 years). Yet, if the vaccine were required nation-
wide, it would be administered to some 2 million girls and
young women, most of them between 11 and 12 years old
and some as young as 9 years old. The longer-term effec-
tiveness and safety of the vaccine still need to be evaluated
among a large population, and particularly among younger
girls.
Given that the overall prevalence of HPV types associ-
ated with cervical cancer is relatively low (3.4%)
4
and that
the long-term effects are unknown, it is unwise to require a
young girl with a very low lifetime risk of cervical cancer to
be vaccinated without her assent and her parent’s consent.
Consider the information a clinician can honestly provide
Author Affiliations: Georgetown Law Center, Washington, DC (Dr Gostin). Dr DeAn-
gelis is Editor in Chief, JAMA.
Corresponding Author: Catherine D. DeAngelis, MD, MPH, JAMA, 515 N State
St, Chicago, IL 60610 (cathy.deangelis@jama-archives.org).
©2007 American Medical Association. All rights reserved. (Reprinted) JAMA, May 2, 2007—Vol 297, No. 17 1921
on August 20, 2007 www.jama.comDownloaded from

to a 12-year-old girl to obtain her assent: “The 3 injections
will probably protect you from an infection that you can only
get from sexual contact, but research has not shown how
long the protection will last or whether it might have
bad effects on your health.” Although many clinicians who
have spent most of their professional lives caring for chil-
dren and adolescents might recommend the vaccine, they
would be troubled if the patient and her family felt pres-
sured or coerced.
Making the HPV vaccine mandatory contributes to long-
standing parental concerns about the safety of school-
based vaccinations.
15
The use of compulsion, therefore, could
have the unintended consequence of heightening parental
and public apprehensions about childhood vaccinations. It
also does not help to offer generous religious and consci-
entious exemptions for HPV vaccination because legisla-
tors may extend these to other childhood vaccinations, which
would be detrimental to the public’s health.
16
Another important consideration is how vaccine recipi-
ents would be compensated if they incurred serious ad-
verse effects in the future as a result of a vaccine that the
state required. By making the vaccine mandatory, the state
would probably complicate tort claims, with some courts
holding that the manufacturer had no (or reduced) respon-
sibility for consumer harms. Ethically, if the state man-
dates an intervention, it should also provide a compensa-
tion system, for example, through the no-fault National
Vaccine Injury Compensation Program. As with other vac-
cines, issues of legal liability and fair compensation must
be considered carefully.
Public health authorities, pediatricians, and infectious dis-
ease specialists, rather than political bodies, should drive
mandatory vaccination decisions and policies. The Cen-
ters for Disease Control and Prevention recommend rou-
tine use of HPV vaccinations, but that is not equivalent to
mandatory use. Merck, the manufacturer of the HPV quadri-
valent vaccine, lobbied legislatures to make the vaccine man-
datory
17
before withdrawing its campaign when it became
controversial.
18
Since the manufacturer stands to profit from
widespread vaccine administration, it is inappropriate for
the company to finance efforts to persuade states and pub-
lic officials to make HPV vaccinations mandatory, particu-
larly so soon after the product was licensed. Private wealth
should never trump public health.
Human papillomavirus is not a highly infectious air-
borne disease, which is the paradigm for the exercise of com-
pulsory vaccination. There is no immediate risk of rapid
transmission of HPV in schools, as is the case, for example,
with measles. The HPV vaccine does not create herd im-
munity, although it would probably reduce the prevalence
of HPV infections. The primary justification for HPV vac-
cination is to protect women from long-term risks, rather
than to prevent immediate harm to others. This may not be
a definitive argument against universal use of HPV vaccine
because states already mandate vaccination against an-
other disease (hepatitis B) that can be transmitted sexually
(among other routes of exposure). But because the HPV vac-
cine is not immediately necessary to prevent harm to oth-
ers, it does suggest that compulsory measures need to be
more carefully thought through.
The ACIP probably recommended routine vaccination for
girls only because the data are limited to that sex. How-
ever, if compulsory powers were justified on classic public
health grounds, the same arguments could and should ap-
ply to vaccination of boys. While less is known about HPV
prevalence in men, some studies have shown that men can
have at least as high a prevalence of HPV infection as wom-
en,
19
and they are just as likely to transmit the infection to
their partners. Issues of fairness arise if young girls are com-
pelled to submit to a new vaccine as a condition of receiv-
ing publicly funded education, when boys are not.
There is also the question of cost—who will pay for the
mandated HPV vaccine and what other public health ser-
vices would society have to forgo because of the cost? The
estimated cost of quadrivalent HPV vaccine is $360 for a
3-course series, making it among the most expensive of all
vaccines.
17
Cost-effectiveness studies of HPV vaccination have
had variable results, depending on assumptions about ef-
fectiveness and safety.
20
Some pediatricians and other phy-
sicians are not offering the most costly vaccines because they
cannot afford to purchase them, and they cannot be certain
about full reimbursement.
21,22
Policy makers also have not
answered the question of who will pay: consumers, insur-
ers, or federal, state, or local government (ie, taxpayers). If
consumers or insurers were to pay, poor and uninsured per-
sons would be unable to afford the vaccine, which would
exacerbate health disparities. If the government were to pay,
it would have to find the funds from its general revenues,
perhaps reducing public health spending for other pro-
grams.
Years from now, when additional data and experience bet-
ter inform clinicians and policy makers about the risks and
benefits, states might consider requiring HPV vaccination
as a condition of school entry. But for now, it is preferable
to take a deliberative approach and view routine, volun-
tary HPV vaccination as part of a comprehensive package
for preventing sexually transmitted infections and cervical
cancer. A systematic approach to prevention would in-
clude promoting reduced sexual activity and safer forms of
sex, cervical cancer screening (eg, Papanicolaou tests and
HPV testing), and education about HPV and cervical can-
cer among schoolchildren, health care professionals, and the
general public. Interventions are particularly important
among African American and Hispanic women, who have
disproportionate burdens of cervical cancer.
23
These important concerns about mandatory HPV vacci-
nation are not motivated by morals, as there are no data to
suggest that an appropriately conducted public health pro-
gram encourages sexual activity. Rather, maintaining the pub-
lic’s trust is vital—both for HPV vaccination in particular
EDITORIALS
1922 JAMA, May 2, 2007—Vol 297, No. 17 (Reprinted) ©2007 American Medical Association. All rights reserved.
on August 20, 2007 www.jama.comDownloaded from

and for school-based vaccination programs more gener-
ally.
24
Legislation to make HPV vaccine mandatory has un-
dermined public confidence and created a backlash among
parents. There is nothing more important to the success of
public health policies than to ensure community accept-
ability. In the absence of an immediate risk of serious harm,
it is preferable to adopt voluntary measures, making state
compulsion a last resort.
25
Financial Disclosures: None reported.
REFERENCES
1. Saraiya M, Ahmed F, Krishnan S, et al. Cervical cancer incidence in a pre-
vaccine era in the United States, 1998-2002. Obstet Gynecol. 2007;109:360-370.
2. Parkin DM. The global health burden of infection-associated cancers in the year
2002. Int J Cancer. 2006;118:3030-3044.
3. Weinstock H, Berman S, Cates W Jr. Sexually transmitted diseases in American
youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health.
2004;36:6-10.
4. Dunne EF, Unger ER, Sternberg M, et al. Prevalence of HPV infection among
females in the United States. JAMA. 2007;297:813-819.
5. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a nec-
essary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12-19.
6. Ho GY, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papil-
lomavirus infection in young women. N Engl J Med. 1998;338:423-428.
7. US Food and Drug Administration. FDA licenses new vaccine for prevention of
cervical cancer and other diseases in females caused by human papillomavirus [press
release]. June 8, 2006. http://www.fda.gov/bbs/topics/NEWS/2006/NEW01385
.html. Accessed March 28, 2007.
8. US Food and Drug Administration. Product approval information: licensing action.
June 8, 2006. http://www.fda.gov/cber/approvltr/hpvmer060806L.htm. Ac-
cessed March 28, 2007.
9. Advisory Committee on Immunization Practices. Quadrivalent human papillo-
mavirus vaccine. MMWR Morb Mortal Wkly Rep. 2007;56:1-24.
10. US Food and Drug Administration. Gardasil. http://www.fda.gov/cber/label
/hpvmer060806LB.pdf. Accessed March 28, 2007.
11. Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years
of a bivalent L1 virus-like particle vaccine against human papillomavirus type 16
and 18: follow-up from a randomized control trial. Lancet. 2006;367:1247-
1255.
12. Saul S, Pollack A. Furor on rush to require cervical cancer vaccine. New York
Times. February 17, 2007:A1.
13. National Conference of State Legislatures. HPV Vaccine: Introduced Legislation.
2007. http://www.ncsl.org/programs/health/HPVvaccine.htm#hpvlegis. Ac-
cessed March 28, 2007.
14. Should HPV vaccination be mandatory for all adolescents? Lancet. 2006;368:
1212.
15. Colgrove J. State of Immunity: The Politics of Vaccination in Twentieth Cen-
tury America. Berkeley: University of California Press; 2006.
16. Salmon DA, Teret SP, MacIntyre CR, et al. Compulsory vaccination and con-
scientious or philosophical exemptions: past, present, and future. Lancet. 2006;367:
436-442.
17. Gardner A. Drugmaker assists in pushing for mandate for HPV vaccination.
Washington Post. February 11, 2007:C5.
18. Pollack A, Saul S. Lobbying for vaccine to be halted. New York Times. Feb-
ruary 21, 2007. http://query.nytimes.com/gst/fullpage.html?sec=health&res
=9403E6D6123EF932A15751C0A9619C8B63&n=Top%2fReference%2fTimes
%20Topics%2fPeople%2fS%2fSaul%2c%20Stephanie. Accessed April 10, 2007.
19. Dunne EF, Nielson CM, Stone KM, et al. Prevalence of HPV infection among
men: a systematic review of the literature. J Infect Dis. 2006;194:1044-1057.
20. Elbasha E, Dasbach EJ, Insinga RP. Model for assessing human papillomavi-
rus vaccination. Emerg Infect Dis. 2007;13:28-41.
21. Davis MM, Zimmerman JL, Wheeler JRC, et al. Childhood vaccine purchase
costs in the public sector: past trends, future expectations. Am J Public Health.
2002;92:1982-1987.
22. Pollack A. Rising costs make doctors balk at giving vaccines. New York Times.
March 24, 2007:C1.
23. Ries LAG, Eisner MP, Kosary CL, et al. SEER Cancer Statistics Review, 1973-
1999, National Cancer Institute. http://seer.cancer.gov/csr/1973_1999/cervix
.pdf. Accessed March 28, 2007.
24. Verweij M, Dawson A. Ethical principles for collective immunisation programmes.
Vaccine. 2004;22:3122-3126.
25. Association of Immunization Managers. Position Statement: School and
Child Care Immunization Requirements. http://72.14.209.104/search?q
=cache:mrNij2GA6fAJ:www.immunizationmanagers.org/pdfs/Schoolrequire-
mentsFINAL.pdf+AIM+Position+Statement.
Translating MicroRNA Discovery
Into Clinical Biomarkers in Cancer
Scott A. Waldman, MD, PhD
Andre Terzic, MD, PhD
I
N THE UNITED STATES, CANCER IS THE SECOND LEADING
cause of death, exceeded only by cardiovascular dis-
ease, and an estimated 500 000 patients with cancer will
die this year.
1,2
After cardiovascular and infectious dis-
eases, cancer is the third leading cause of mortality world-
wide.
3
However, the field of clinical oncology is poised for
unprecedented innovation, reflecting the confluence of break-
throughs in decoding disease pathobiology in the context
of high-throughput enabling technologies.
4
Harnessing the
full potential of transformative advances is predicated on
defining biomarkers that promote targeted cancer preven-
tion, diagnosis, and treatment of individual patients and
populations.
4,5
A new generation of molecular technolo-
gies, including genomic, proteomic, and metabolomic map-
ping, hold the promise of translating into practice the use
of biomarker panels for increased diagnostic and therapeu-
tic sensitivity and specificity.
2,4
Yet essential elements have
resisted definition in developing mechanism-based molecu-
lar markers for individualized management of cancer. In par-
ticular, the hierarchically organized integrated epigenetic,
genetic, and postgenetic circuitry that dictates developmen-
tal restriction of cell destiny and underlies tumorigenesis
when dysregulated has so far remained poorly understood.
Emerging science has revealed a layer of genetic program-
matic coordination by which cells determine their fate; this
layer involves posttranscriptional regulation of gene expres-
Seealsop1901.
Author Affiliations: Departments of Pharmacology and Experimental Therapeu-
tics and Medicine, Thomas Jefferson University, Philadelphia, Pa (Dr Waldman);
and Departments of Medicine, Molecular Pharmacology & Experimental Thera-
peutics, and Medical Genetics, Mayo Clinic, Rochester, Minn (Dr Terzic).
Corresponding Author: Scott A. Waldman, MD, PhD, 132 S 10th St, 1170 Main,
Philadelphia, PA 19107 (scott.waldman@jefferson.edu).
EDITORIALS
©2007 American Medical Association. All rights reserved. (Reprinted) JAMA, May 2, 2007—Vol 297, No. 17 1923
on August 20, 2007 www.jama.comDownloaded from

Table 4, the Reynolds Risk Score correctly results in an ab-
solute increase in the number who would be recom-
mended for treatment when thresholds are set at either 20%
10-year risk or at 10% 10-year risk, thus achieving a net clini-
cal benefit. As with any risk classification system, perfect
prediction will not be achieved, but an overall improve-
ment in the targeting of prescription drugs to those women
with the most appropriate levels of risk should help maxi-
mize benefits while minimizing cost and toxicity. Wang et
al are also concerned about the use of self-reported blood
pressure, weight, diabetes, and smoking. However, these vari-
ables show a similar magnitude of prediction in our data as
in other major studies.
With regard to comments from Dr Stevens and Ms Cole-
man, while Table 5 compares fit using the model most of-
ten used in clinical practice, Table 4 shows superiority of
the new models built using the same population and out-
come definition. We acknowledge that external validation,
using different cohorts, would be a useful next step. It is
true that the Hosmer-Lemeshow statistic can be consid-
ered a general measure of goodness of fit.
1
However, since
it directly compares observed with expected events, it is more
sensitive to recalibration than most other measures, par-
ticularly the c-statistic, and is often treated as a measure of
calibration.
2
We do not concur with Dr Daniels and colleagues that
epidemiologic data on natriuretic peptides support the
use of this biomarker in healthy populations. Of the
articles cited, most included prevalent myocardial infarc-
tion at baseline or evaluated elderly cohorts without
adequate exclusion of prior cardiovascular events. More
recent data suggest that B-type natriuretic peptide does
not predict cardiovascular events among those free of dis-
ease at baseline.
3
Paul M Ridker, MD
pridker@partners.org
Nancy R. Cook, ScD
Brigham and Women’s Hospital
Boston, Massachusetts
Financial Disclosures: Dr Ridker reports that he currently or in the past 5 years
has received research funding support from multiple not-for-profit entities includ-
ing the National Heart, Lung, and Blood Institute, the National Cancer Institute,
the American Heart Association, the Doris Duke Charitable Foundation, the Leducq
Foundation, the Donald W. Reynolds Foundation, and the James and Polly An-
nenberg La Vea Charitable Trusts. Dr Ridker also reports that currently or in the
past 5 years he has received investigator-initiated research support from multiple
for-profit entities including AstraZeneca, Bayer, Bristol-Myers Squibb, Dade-
Behring, Novartis, Pharmacia, Roche, Sanofi-Aventis, and Variagenics. Dr Ridker
reports being listed as a coinventor on patents held by the Brigham and Women’s
Hospital that relate to the use of inflammatory biomarkers in cardiovascular dis-
ease and has served as a consultant to Schering-Plough, Sanofi/Aventis, Astra-
Zeneca, Isis Pharmaceutical, Dade-Behring, and Vascular-Biogenics. Dr Cook re-
ports having received funding from the National Heart, Lung, and Blood Institute,
the National Cancer Institute, and Roche Diagnostics, and has served as a con-
sultant to Bayer Health Care.
1. Hosmer DW, Lemeshow S. Goodness of fit tests for the multiple logistic re-
gression model. Commun Stat Theor Methods. 1980;A9:1043-1069.
2. D’Agostino RB, Griffith JL, Schmidt CH, Terrin N. Measures for evaluating model
performance. In: American Statistical Association 1996 Proceedings of the Sec-
tion on Biometrics, Chicago, IL, August 1996. Alexandria, VA: American Statisti-
cal Association; 1997:253-258.
3. Salomaa V, Harold K, Sundvill J, Jousilahti P. Brain natriuretic peptide as a pre-
dictor of coronary and cardiovascular events and all-cause deaths in general popu-
lation [abstract]. Circulation. 2007;115(8):e269.
CORRECTIONS
Incorrect Wording and Data Error: In the Original Contribution entitled “Com-
parison of the Atkins, Zone, Ornish, and LEARN Diets for Change in Weight and
Related Risk Factors Among Overweight Premenopausal Women: The A TO Z
Weight Loss Study: A Randomized Trial” published in the March 7, 2007, issue of
JAMA (2007;297(9):969-977), a sentence was incorrectly worded in the ab-
stract, and data were reported incorrectly in the text. On page 969, in the “Con-
clusions” section of the abstract, the first sentence should have read “In this study,
premenopausal overweight and obese women assigned to follow the Atkins diet,
which had the lowest carbohydrate intake, had lost more weight at 12 months
than those assigned to the Zone diet, and had experienced comparable or more
favorable metabolic effects than those assigned to follow the Zone, Ornish, or LEARN
diets.” On page 972, in the last paragraph, the mean 12-month weight changes
for the LEARN and Ornish diets were reversed: for LEARN it should have been
−2.6 kg (95% CI, −3.8 to −1.3 kg) and for Ornish it should have been −2.2 kg
(95% CI, −3.6 to −0.8 kg).
Incorrect Prevalence: In the Editorial entitled “Mandatory HPV Vaccination: Pub-
lic Health vs Private Wealth” published in the May 2, 2007, issue of JAMA (2007;
297(17):1921-1923), 2 sentences regarding HPV prevalence were inaccurate. On
page 1921, in the second paragraph, the second to last sentence should read: “Al-
though infection with high-risk HPV types ...high-risk types 16 and 18 have a
relatively low prevalence (2.3% among screened females),
4
and not all wom-
en....”Also on page 1921, second column, the last paragraph on the page should
read: “Given that the overall prevalence of HPV vaccine types associated with cer-
vical cancer is relatively low (2.3%)....”
LETTERS
178 JAMA, July 11, 2007—Vol 298, No. 2 (Reprinted) ©2007 American Medical Association. All rights reserved.
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