Great progress has been made in the development of prophylactic vaccines against HPV, such that cervical cancer could very well be the second cancer to be prevented through mass vaccination (Fig. 6; see Color Plate 6, following p. 50). Important lessons can be learned from these successes and from the slower progress in the development of therapeutic HPV vaccines. Research into the etiology of cervical cancer and the biology of HPV provided critical insights regarding the relevant target antigens for effective vaccination. The importance of relevant and facile animal models is demonstrated both by the success of preventive vaccine development using animal papillomavirus challenge models, and the issues in using tumor transplant models in mice for therapeutic vaccine development. Similarly, the development of relevant immunological assays is also critical to the rational development of vaccines, as epitomized by the measurement of protective antibodies by VLP ELISA or in vitro neutralization assays. Unfortunately, the assays most relevant for therapeutic responses lag behind and correlate poorly thus far with clinical response. Nonetheless, each year sees remarkable advances in the field of immunology. With an improved understanding of the mechanisms governing tumor regression or tolerance, we are hopeful that these issues can be overcome.

The success of the VLP vaccine trials has catalyzed the development of second generation preventive vaccines. Clearly, additional HPV VLP types need to be included to provide broader protection and eventually render Pap and HPV screening programs unnecessary. The development of both broad HPV immunity and comprehensive vaccine programs are critical to the eventual elimination of cervical cancer. In addition to the highly multivalent HPV VLP vaccines, the potential for broad cross-protection by L2-based vaccines should be further explored. The second generation HPV preventive vaccines should build on the safety and efficacy of the L1 VLPs to provide broadly-protective, inexpensive, stable, and easily administered formulations. Such vaccine properties and support for comprehensive vaccine programs are critical to adequately address the global burden of HPV infection and cervical cancer.

The large existing burden of HPV disease and the ~20 year delayed impact of preventive vaccination on cervical cancer rates demonstrates the need for continued efforts to develop therapeutic HPV vaccines (Fig. 6; see Color Plate 6, following p. 50). The clearance of established infection or disease is clearly a more difficult problem than prevention of new infections. One of the major obstacles is an incomplete understanding of why most HPV-positive lesions naturally regress, whereas others do not. New research suggests the importance of tumor tolerance and immune suppression in the tumor environment. In addition, the virus and the cancer cells utilize multiple molecular tricks to escape immune surveillance. However, recent advances in the understanding of antigen processing, innate recognition (e.g., toll-like receptors), and tolerogenic mechanisms (e.g., NO, arginase) suggest several avenues to break tolerance and improve the effectiveness of virus-specific cytotoxic T-cell responses. Given these issues and ongoing screening programs, it may be appropriate to focus on early therapeutic vaccine efforts in patients with LSIL, for whom tolerance is less likely to be an issue (as suggested by high rates of spontaneous regression). Finally, technological improvements in vaccine delivery vehicles and immunologi-cal assays are important and should continue. Clearly, cervical cancer represents an important model system to develop immunotherapies for other cancers with less well-defined etiologies and rejection antigens. Research into HPV therapeutic vaccines shows great promise and is likely to have broad impact.

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