Virus

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Prevention
Vaccines Against Human Papillomavirus and Cervical Cancer: Promises and Challenges
Ali Mahdavi, Bradley J. Monk Division of Gynecologic Oncology, Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, California,USA
Key Words. Human papillomavirus • Vaccine • Cervical cancer • Cervical dysplasia

Learning Objectives
After completing this course, the reader will be able to: 1. Discuss the epidemiology and pathogenesis of HPV and HPV-associated diseases. 2. Explain the immune mechanisms relevant to the control of HPV infection. 3. Describe vaccine strategies for the prevention and therapy of HPV infectionand cervical dysplasia and/or cancer.
CME

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Abstract
Cervical cancer and precancerous lesions of the genital tract are major threats to the health of women worldwide. The introduction of screening tests to detect cervical cancer precursor lesions has reduced cervical cancer rates inthe developed world, but not in developing countries. Human papillomavirus (HPV) is the primary etiologic agent of cervical cancer and dysplasia. Thus, cervical cancer and other HPV-associated malignancies might be prevented or treated by HPV vaccines. Two vaccine strategies have been developed. First, prevention of HPV infection through induction of capsid-specific neutralizing antibodies hasbeen studied in clinical trials. However, because the capsid proteins are not expressed at detectable levels by infected basal keratinocytes or in HPV-transformed cells, a second approach of developing therapeutic vaccines by targeting nonstructural early viral antigens has also been developed. Because two HPV oncogenic proteins, E6 and E7, are critical to the induction and maintenance of cellulartransformation and are coexpressed in the majority of HPV-containing carcinomas, most therapeutic vaccines target one or both of these gene products. A variety of approaches is being tested in therapeutic vaccine clinical trials, whereby E6 and/or E7 are administered in live vectors, as peptides or protein, in nucleic acid form, or in cell-based vaccines. The paradigm of preventing HPV infectionthrough vaccination has been tested, and two vaccines are currently in phase III clinical trials. However, current therapeutic vaccine trials are less mature with respect to disease clearance. A number of approaches have shown significant therapeutic benefit in preclinical papillomavirus models and await testing in patient populations to determine the most effective curative strategy. The Oncologist2005;10: 528–538

Correspondence: Bradley J. Monk, M.D., Division of Gynecologic Oncology, Chao Family Comprehensive Cancer Center, University of California, Irvine, 101 The City Drive, Building 56, Room 262, Orange, California 92868-3298, USA. Telephone: 714-456-7974; Fax: 714-456-6463; e-mail: bjmonk@uci.edu Received April 12, 2005; accepted for publication May 12, 2005. ©AlphaMed Press10837159/2005/$12.00/0

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Introduction
Cervical cancer and precancerous cervical lesions constitute a major problem in women’s health. Clinical, molecular, and epidemiological investigations have identified human papillomavirus (HPV) as the major cause of cervical cancer and cervical dysplasia [1]. Virtually all cervicalcancers (99%) contain the genes of high-risk HPVs, most commonly types 16,18, 31, and 45 [1]. Every year, 470,000 cases of cervical cancer are diagnosed worldwide, and about half of the women afflicted will die. In the U.S. alone, 50 million Pap tests are performed each year, and they discover close to 1.2 million cases of low-grade dysplasia (cervical intraepithelial neoplasia [CIN]1), 300,000...