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Perspective

T h e N EW ENGL A N D JOU R NA L o f M EDICI N E

december 7, 2006

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to propose that vaccination be compulsory for girls entering sixth grade. Parents who objected would be able to opt out of the requirement under the same pro- visions that apply to other vacci- nations. The bill passed the state senate by an overwhelming mar- gin a week later and awaits con- sideration by the house. Other states are likely to follow Michi- gan’s lead.

The development of Gardasil, Merck’s HPV vaccine, is of major public health importance. The vac- cine protects against four strains of HPV, the most common sexu- ally transmitted disease in the United States, including the two strains that cause most cases of cervical cancer. More than 6 mil-

lion people in this country become infected with HPV every year, and nearly 10,000 women are diag- nosed with cervical cancer. Be- cause the vaccine has the greatest benefit when it is given before a person becomes sexually active, the Advisory Committee on Im- munization Practices of the Cen- ters for Disease Control and Pre- vention recommended that it be given routinely to girls at 11 or 12 years of age; it is not yet approved for use in boys. The committee took no position on whether vac- cination should be required by law; such policy decisions are made by individual states.

Moves to make the vaccine compulsory are sure to ignite a new round of polarizing debates.

Controversy over the product be- gan before it was licensed, when some religious conservatives ex- pressed concern that the avail- ability of a vaccine against a sex- ually transmitted disease would undermine abstinence-based pre- vention messages. Advocacy groups such as Focus on the Family ulti- mately came to support availabil- ity of the vaccine, but they remain opposed to mandating its use. In their view, such a requirement constitutes an attempt by the sec- ular state to force a child to un- dergo an intervention that may be irreconcilable with her family’s religious values and beliefs.

It is a mistake, however, to view the contrasting stances on HPV-vaccine mandates as solely, or even primarily, evidence of a conf lict between science and re- ligion. A more complicated dy- namic will shape the ongoing dis- cussion.

On one side, support for legal

The Ethics and Politics of Compulsory HPV Vaccination James Colgrove, Ph.D., M.P.H.

On September 12, 2006, 3 months after the Food and Drug Administration licensed a vaccine against human papillomavirus (HPV), Michigan lawmakers became the first in the United States

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requirements is strongly inf lu- enced by the perception of HPV as a women’s health issue. The severe consequences that the disease may have for women lends urgency to the effort to maximize use of the vaccine through all policy means, including mandates. Women in Government, a Washington-based, bipartisan organization of female legislators, is leading a push to make HPV vaccination compulso- ry in every state. The group has issued recommendations for en- suring that the vaccine is acces- sible and affordable, including a recommendation that states add it to their Medicaid programs and encourage private health plans to cover it. The group follows in the tradition of breast-cancer activ- ists, who have mobilized through many political channels to com- bat an illness that disproportion- ately burdens women.

On the other side, opposition to mandates will come from a far wider range of constituencies than just religious conservatives wor- ried about threats to teenagers’ sexual abstinence. Vaccine require- ments — even generally well- accepted laws covering “classic” childhood diseases such as polio, measles, and pertussis — have been resisted in recent years on a wide range of philosophical, po- litical, scientific, and ideological grounds.

During the past two decades, in the face of a sharp increase in the number of recommended pe- diatric vaccines, unproven theo- ries alleging connections between vaccines and illnesses including autism, diabetes, and multiple sclerosis have been spreading. A social movement involving diverse participants has challenged the safety of vaccination and mount- ed attacks in courtrooms and leg- islatures on compulsory vaccina-

tion laws. Forty-eight states allow parents who object to vaccination on religious grounds to excuse their children from requirements, and 20 of those states also allow exemptions for parents who have secular philosophical concerns.1 Approximately 1 to 3% of U.S. children are excused by their par- ents from vaccine requirements, though the rate varies from state

to state; schools in a few commu- nities have exemption rates as high as 15 to 20%. Activists have sought to liberalize the circum- stances under which parents may opt out of vaccine requirements, a trend that ref lects the wide variation in people’s reasons for rejecting vaccines: devotion to “natural” or alternative healing, libertarian opposition to state power, mistrust of pharmaceuti- cal companies, belief that vaccines are not as safe as experts claim, and conviction that children re- ceive more shots than are good for them.2

Laws making vaccination com- pulsory raise unique ethical and policy issues. High levels of herd immunity protect all members of the community, including those who cannot receive vaccines be- cause of medical contraindica- tions. This protection provides a justification for compulsion. The availability of religious or philo- sophical exemptions mitigates

concern about governmental in- trusion on individual decision making. Opinions vary, however, about the permissible scope of ex- emptions. Data show that schools with exemption rates as low as 2 to 4% are at increased risk for disease outbreaks and that chil- dren who have been exempted from vaccine requirements have a much greater risk of acquiring infectious diseases than their vac- cinated peers.1 Minors have a right to be protected against vaccine- preventable illness, and society has an interest in safeguarding the welfare of children who may be harmed by the choices of their parents or guardians.

Bioethicists, who generally hold the values of patient autonomy and informed consent to be pre- eminent, tend to be skeptical about compulsory vaccination laws. Not surprisingly, some have expressed wariness about or opposition to mandating HPV vaccination.3,4 Be- cause HPV is not casually trans- missible, they argue, there is a less compelling rationale for re- quiring protection against it than against measles or pertussis, for instance; in the absence of poten- tial harm to a third party, such laws may be considered unaccept- ably paternalistic. Similar concerns have been raised about school- based requirements for vaccina- tion against hepatitis B: because the virus spreads primarily among sexually active people and injec- tion-drug users, some parents ar- gued that the vaccine should be given only to those groups rather than to all children. Such target- ing of the vaccine, however, proved to be less effective than universal vaccination in reducing the inci- dence of the disease.

A large body of evidence dem- onstrates that school-based laws are an effective and efficient way

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of boosting vaccine-coverage rates. Requiring HPV vaccination by law will almost certainly achieve more widespread protection against the disease than will policies that rely exclusively on persuasion and education. In the view of advo- cates, this effectiveness provides a clear justification. “The only way to ensure that as many girls as possible receive the HPV vac- cine is to require it before they enter middle school,” said Bev- erly Hammerstrom, the Michi- gan state senator who introduced the legislation. Whether such a mandate might extend to boys, should the product be approved for such use, remains uncertain.

A critical question is whether achieving a higher level of cov- erage justifies the infringement on parental autonomy that com- pulsory vaccination inevitably en-

tails. Different ethical frameworks that accord varying weights to communitarian and individualis- tic values will lead to contrasting answers to this question.

Ethical and epidemiologic analyses are essential to decisions about mandating the HPV vaccine; so are political calculations. Any new vaccine that a state adds to its list of requirements must be judged in the context of both the increasingly lengthy and complex regimen of vaccines that children now receive and the possibility that additional mandates may in- flame grassroots opposition, be it religious, philosophical, or ideo- logical.5 Although issues of reli- gion and adolescent sexuality have dominated the discussion, the move to require HPV vaccination raises broad questions about the acceptability of mandatory pub-

lic health measures, the scope of parental autonomy, and the role of political advocacy in determin- ing how preventive health mea- sures are implemented.

Dr. Colgrove is an associate research scien- tist at the Center for the History and Ethics of Public Health, Department of Sociomed- ical Sciences, Mailman School of Public Health, Columbia University, New York.

Salmon DA, Teret SP, MacIntyre RC, Salis- bury D, Burgess MA, Halsey NA. Compulso- ry vaccination and conscientious or philo- sophical exemptions: past, present, and future. Lancet 2006;367:436-42.

Colgrove JK. State of immunity: the poli- tics of vaccination in twentieth-century America. Berkeley: University of California Press, 2006.

Zimmerman RK. Ethical analysis of HPV vaccine policy options. Vaccine 2006;24: 4812-20.

Lo B. HPV vaccine and adolescents’ sexu- al activity. BMJ 2006;332:1106-7.

Temte JL. Should all children be immu- nised against hepatitis A? BMJ 2006;332: 715-8.

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The Ethics and Politics of Compulsory HPV Vaccination

Exploring the Uses of RNAi — Gene Knockdown and the Nobel Prize René Bernards, Ph.D.

The Nobel Prize in Physiology or Medicine was awarded this year to Andrew Fire (Stanford Uni- versity School of Medicine) and Craig Mello (University of Massa- chusetts Medical School) for their discovery of a new form of gene silencing. Nearly 9 years ago, Fire and Mello and their colleagues reported that exposing cells of the nematode Caenorhabditis elegans to double-stranded RNA resulted in specific and efficient gene silenc- ing.1 They also observed that double-stranded RNA is far more potent than sense or antisense RNA in silencing the gene that shares its sequence, and they dubbed the silencing process “RNA interference” (RNAi). Because RNAi rarely leads to the complete abrogation of gene expression,

its effect is often described as a “knockdown” of gene expression. At first glance, RNAi seems sim- ilar to the antisense approach to gene silencing, but it is far more effective and has a different mech- anism.

In plants and nematodes, the introduction of long double- stranded RNA into a cell leads to its cleavage into shorter frag- ments. These fragments are pow- erful silencers of gene expression and are therefore called “small interfering RNA” (siRNA). They are recruited into a protein com- plex that positions the antisense strand so that it acts as a snare for the RNA transcript to which it is complementary. Once bound to this snare, the RNA transcript is cleaved by the complex and is

degraded (see diagram). In lower organisms, RNAi is thought to function as a primitive immune system, protecting against viruses (which often generate double- stranded RNA as replication inter- mediates) and transposable ele- ments (also known as “jumping genes”).

In most mammalian cells, long double-stranded RNA provokes an interferon response as part of an antiviral defense. This interferon response induces a global shut- down of protein synthesis, thus precluding the use of long double- stranded RNA for specific gene silencing. This obstacle can be overcome by using short double- stranded RNA (less than 30 base pairs in length), which evades the radar of the mammalian interfer-