Because certain subtypes of human papillomavirus (HPV) are associated with the development of cervical cancer, the search for a prophylactic or therapeutic HPV vaccine has been an important endeavor. Although more than 30 types of HPV are known to be sexually transmittable, the major types associ- ated with malignancy (HPV-16, -18, -31, -33, -45, -52, and -58) and condylomata (HPV-6 and -11) are relatively few in num- ber, allowing for more focused strategies for immunization against these speciﬁc subtypes. Vaccine development has been hampered in the past because of the inability to culture HPV. However, an in vitro culture system for HPV has more recently been developed, furthering the prospect for advancements in this ﬁeld (269). Virus-like particle (VLP) vaccines are pro- duced by recombinant DNA technology and are designed to self-assemble into conformations that resemble natural HPV. These vaccines contain no viral DNA and carry no risk of infection or oncogenic exposure. VLP vaccines have been designed for all of the major HPV subtypes and clinical trials are currently underway for HPV-11 L1 VLP (270), HPV-6 L1 VLP (271), and HPV-16 L1 VLP (272).
Fusion protein vaccines are currently under evaluation for the immunotherapy of cervical cancer and genital warts. TA- HPV is a live recombinant vaccinia virus which has been engi- neered to express the E6 and E7 protein genes for HPV-16 and -18 as a treatment for cervical cancer (212). This method also utilizes the viral vector approach, using vaccinia as a vehicle. Viral vector vaccines can be polyvalent and have the potential to produce immunity similar to that induced by live attenuated vaccines. A phase I/II clinical trial of TA-HPV (273) has shown encouraging results, and further studies are underway. TA-GW is a recombinant fusion protein vaccine consisting of HPV-6 L2 and E7 proteins, which is under investigation for the treatment of genital warts. A phase IIa clinical trial showed the vaccine to be immunogenic, with encouraging clinical responses (274). A third protein vaccine, TA-CIN, is in preclinical development for the treatment of cervical dysplasia (212).
Peptide-based vaccines have been shown to be protective against HPV-induced tumors in mice, although the T-cell rep- ertoires in mice and humans differ. Two early-stage human clinical trials are underway, one involving HLA A*0201 bind- ing HPV-16 E7 peptides, to assess the possible therapeutic implications these vaccines may offer (275). Other investiga- tional approaches to HPV immunization include DNA vac- cines (275), bacterial vectors (276–278), and dendritic cells pulsed with HPV epitopes (279). Koutsky reported in a study of 2392 young women that a HPV-16 VLP vaccine was 100% effective in preventing HPV-16 infection. In addition, the vac- cine was safe, with no serious side effects reported. Therefore, immunization of HPV-16–negative women may eventually reduce the incidence of cervical cancer (280).