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for use in women aged 9 to 26 years in the United States and several other countries. The second vaccine (Cer- varix) is a bivalent HPV-16/18 cervical cancer candidate vaccine that contains VLPs only from the 2 oncogenic HPV types, HPV-16 and HPV-18. This vac- cine has been approved for use in Aus- tralia. Application for approval in the United States and other countries is under review by the US Food and Drug Administration and other regula- tory bodies.

Viruslike particle–based vaccines have been shown to provide near com- plete type-specific protection against infection with HPV types included in the vaccine in the initial years follow- ing vaccination.2,3,6 Preliminary evi- dence suggests that at least 1 of the vaccines (the bivalent HPV-16/18 cer- vical cancer candidate vaccine) might provide partial protection against oncogenic HPV types phylogenetically related to HPV-16/18 (ie, HPV types 31 and 45).3 The protection against initial infection afforded by vaccina- tion with either of the vaccines under evaluation is believed to be mediated primarily by neutralizing antibodies generated through vaccination.7,8 Con- sistent with this concept, high levels of antibodies are observed systemically and in the genital tract after vaccina- tion in humans.9-11

Antibodies are not typically involved in treating intracellular infections after their establishment; however, HPV vaccination has also been shown to induce cell-mediated immune responses traditionally involved in the eradication of infections.10,12-15 If directed against the appropriate antigenic targets, these cell-mediated responses could provide some benefit of vaccination among individuals already infected. Given that HPV infection depends on the viral genome being present in the epi- thelial basal cells that give rise to the cells in the higher layers of the epithe- lium and that the L1 protein is only expressed in these higher cell layers, it is not clear whether the vaccine- induced immune response directed

against L1 would have curative poten- tial among infected individuals.8 Ani- mal studies have not supported such therapeutic effects of HPV VLP-based vaccination, but no published data on humans exist that directly address this possibility.16

Most HPV infections, regardless of type, clear spontaneously, typically within 6 months to 2 years.17 Risk of progression to in situ disease and invasive cancer is highest among the small subset of women with persistent infections beyond this period.1 Under- standing whether vaccination pro- vides any therapeutic benefit to infected women is of importance in countries where HPV DNA testing has been incorporated into cervical cancer screening programs.18,19 Women in such programs who test positive for HPV might want to avail themselves of the vaccine instead of waiting sev- eral months to determine whether their infections clear or opting for treatments based on excision or abla- tion of the cervical transformation zone where cancers arise.

Because current management pro- tocols often involve retesting HPV- positive women within months of an initial HPV-positive result before treat- ment decisions are made, understand- ing the impact of vaccination on viral clearance in the first 6 to 12 months fol- lowing an initial HPV-positive result would be informative. If effective at clearing established infections, it is rea- sonable to expect that vaccination would work within this time frame, given the near complete rate of sero- conversion and high levels of immune response observed after 1 or 2 doses of vaccine.10-12

To directly address the question of whether women positive for HPV DNA should be encouraged to receive HPV- 16/18 vaccination as a useful strategy to induce or accelerate clearance of their infections, we evaluated whether the rates of resolution of prevalent HPV in- fections are affected by vaccination in an ongoing community-based random- ized clinical trial conducted in Costa Rica.

METHODS Recruitment and Eligibility Women included in the present evalu- ation are participants in a larger, ongo- ing randomized clinical trial of 7466 women designed to evaluate the effi- cacy of an HPV-16/18 VLP vaccine formulated with the AS04 adjuvant system (Cervarix, GlaxoSmithKline [GSK] Biologicals, Rixensart, Belgium) against persistent type-specific infec- tion with HPV and HPV-associated precancerous lesions. Participants in our clinical trial were women aged 18 to 25 years residing in the provinces of Guanacaste and Puntarenas in Costa Rica who were identified via a new population census. Women identified through this census were invited to participate via a letter delivered to their home by study staff members. Women who attended 1 of the 7 study clinics were screened for eligibility between June 28, 2004, and December 21, 2005.

To be eligible for study, women had to fulfill the following require- ments at the time of entry: age 18 to 25 years (inclusive), planned resi- dence in the study area for the 6 months following enrollment, ability to speak/understand Spanish, good general health as determined by history and a physical examination, and willingness to provide written informed consent.

Specific exclusion criteria at enroll- ment included history of chronic or immunodeficient conditions requiring treatment; history of allergic reaction to any vaccine or of significant allergic conditions, suspected allergy, or reac- tions to components of the vaccine or to latex; history of vaccination against hepatitis A or a known history of hepatitis A infection; history of recent (6 months) long-term administra- tion of immunosuppressants or immune-modulating drugs; and unwillingness to use an effective method of birth control for a period covering the vaccination phase of the trial (among sexually active individu- als). Enrollment of pregnant women was deferred until they were at least 3


JAMA, August 15, 2007—Vol 298, No. 7 (Reprinted)

©2007 American Medical Association. All rights reserved.

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