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The development of potential therapeutic and prophylactic vaccines for human papillomavirus (HPV) infection is a very exciting area of HPV research. There are a number of features of HPV biology that makes the development of a vaccine particularly difficult, although there are several examples of vaccines that have had spectacular success in the prevention of other viral diseases. Our poor understanding of the immune response to HPV infection is the first problem. We do not understand the mechanism by which spontaneous clearing of warts is generated and therefore cannot particularly target this pathway in the development of a vaccine. Furthermore, there is no in vitro culture system nor an animal model for HPV. Another problem is that there is no ready source of live virus that might be exploited for a live attenuated viral vaccine, such as was used with poliovirus. Although most other viruses spend a portion of their life cycle in the systemic circulation where they are vulnerable to neutralizing antibodies, HPV remain exclusively in the epithelium and thus antibodies must transverse the basement membrane and reach the other layers of the skin or mucosa to be effective in preventing infection. Significant progress is being made in the development of potential vaccine candidates despite these and other confounding factors.