CURRENT ISSUES AND FUTURE FOR PROPHYLACTIC AND THERAPEUTIC HPV VACCINES

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Abstract

Cervical cancer is the leading cause of cancer mortality among women in worldwide and caused by oncogenic human papillomavirus (HPV). Vaccines against HPV infections hold promise to reduce incidence of cervical cancer cost-effectively. Current prophylactic HPV vaccines, L1-VLP vaccines, are HPV type-specific and are not thought to be ultimate strategy and study on HPV vaccines remains necessary. We are developing two novel HPV vaccines; (i) broad-spectrum prophylactic vaccines against all oncogenic HPV types, and (ii) therapeutic vaccines for treatment of precursor lesions of cervical cancer, CIN3. (i) We focused on L2, the other structural protein of virus particles, which contains many conserved regions among all HPV types. We have demonstrated that highly conserved regions of L2, 59-81aa and 108-120aa of HPV16 L2, contain neutralization epitopes. Recently, 56-75aa of L2 is demonstrated to be most reliable candidate for the broad-spectrum prophylactic vaccine. (ii) In immunotherapy for CIN3, induction of anti-HPV cytotoxic T lymphocytes (CTL) in cervical mucosa is critical. We here attempted for the induction of mucosal E7-specific type 1 T-cell responses by stimulating gut-associated lymphoid tissues (GALT) through oral immunization. We developed a novel lactobacillus-based HPV therapeutic vaccine using the Lactobaccilus casei strain expressing HPV16E7 (GLBL101c). Marked induction of mucosal T cells possessing CTL activity to E7 was observed at intestinal mucosa after oral immunization of mice with GLBL101c. We have also revealed that gut-derived integrin αEβ7+ T cells are homing to CIN lesions. Taken together, oral immunization with GLBL101c can induce mucosal E7-specific CTL, which home to cervical epithelium and attack CIN3 lesions. Then, phase I/IIa clinical trial of GLBL101c for CIN3 immunotherapy is on-going under the approval of IRB. Because of limitations of the current HPV vaccine, next generation vaccines are necessary for prevention of cervical cancer. In this term, our developing novel HPV vaccines are very attractive.

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