HPV 疫苗, 机会和挑战

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.

Interview with R. Alta Charo. (Available at http://content.nejm.org/cgi/content/full/356/19/1905/DC1.)