Combination Approaches

The ideal HPV vaccine would induce both humoral and cell-mediated immunity to prevent new infections as well as eliminating established infection or HPV-related disease. One such strategy has involved the fusion of HPV capsid proteins and HPV early proteins, for example the fusion of L1 with E7 to form chimeric VLPs. An early trial initiated by Medigene with chimeric L1-E7 VLPs demonstrated immunogenicity and safety, but insufficient clinical efficacy in CIN patients for further development by this company. Another potential chimeric/therapeutic vaccine is a fusion of HPV-16 L2 with E6 and E7 (called TA-CIN by Cantab/Xenova Pharmaceuticals). TA-CIN was also shown to be safe and immunogenic in several clinical trials. Vaccination with TA-CIN induces HPV16 and HPV18-specific neutralizing antibodies, even in the absence of adjuvant unpublished observations. Despite the absence of an adjuvant, specific antibody and T-cell proliferation responses were observed in the majority of patients receiving the highest dose (100). In order to further enhance vaccine potency, a "prime-boost" strategy, combining TA-CIN and TA-HPV (vaccinia virus encoding HPV 16/18 E6E7) vaccinations, was tested in 10 women with HPV 16-pos-itive high-grade vulvar intraepithelial neoplasia. They first received a TA-HPV vaccine and then were boosted three times with TA-CIN. HPV 16-specific proliferative T-cell and/or serological responses were observed in nine of the women, and three women showed lesion shrinkage or symptom relief. However, no direct correlation between clinical and immunological responses was observed. Importantly, all of these studies were performed using protein antigens without adjuvant and may therefore not be optimal.

Fig. 6 (Color Plate 6, following p. 50). Summary of strategies to prevent and treat cervical cancer.
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