Vaccination of Healthy Volunteers with Human Papillomavirus Type 16 L2E7E6 Fusion Protein Induces Serum Antibody that Neutralizes across Papillomavirus Species (original) (raw)

Oncogenic human papillomavirus (HPV) infection is a necessary cause of cervical cancer. Therefore, vaccination to prevent or eliminate HPV infection could reduce the incidence of cervical cancer. A fusion protein comprising HPV16 L2, E6, and E7 is a candidate combination preventive and therapeutic HPV vaccine. The L1-and L2-specific and neutralizing serum antibody titers and peripheral blood mononucleocyte antigen-specific proliferative responses generated by vaccination thrice at monthly intervals with HPV16 L2E7E6 were compared in two studies: a phase I randomized double-blind placebo controlled dose escalation trial in 40 healthy volunteers and a phase II trial of HPV16 L2E7E6 at the maximum dose in 29 women with highgrade anogenital intraepithelial neoplasia (AGIN). Vaccination of healthy volunteers induced L2-specific serum antibodies that were detected 1 month after the final vaccination (P binomial < 0.001). There was a significant trend to seroconversion for HPV16 and HPV18 neutralizing antibodies with increasing vaccine dose (P = 0.006 and P = 0.03, respectively). Seroconversion for HPV18 neutralizing antibodies showed a significant positive trend with increasing dose (P = 0.03) and was associated with seroconversion for HPV16 neutralizing antibodies (P exact = 0.04). The antigen-specific proliferative response of vaccinated healthy volunteers also showed a significant trend with increasing vaccine dose (P = 0.04). However, AGIN patients responded less effectively to vaccination than healthy patients for induction of HPV16 L2-specific antibody (P < 0.001) and proliferative responses (P < 0.001). Vaccination of healthy volunteers thrice with 533-Mg HPV16 L2E7E6 at monthly intervals induced L2specific serum antibodies that neutralized across papillomavirus species. Responses in AGIN patients were infrequent. (Cancer Res 2006; 66(23): 11120-4) Materials and Methods Human sera. Studies were done with the permission of the Johns Hopkins University Internal Review Board. The study sera were obtained in two HPV16 L2E7E6 vaccination trials from 40 healthy volunteers (30 men, ages 19-55 years, and 10 postmenopausal women, ages 43-55 years, with a negative Pap smear at entry) at weeks 0 and 12 in a phase I trial (12) and from 27 women, ages 22 to 61 years, all with noncervical high-grade AGIN (2 of 27 with VAIN3 and 25 of 27 with VIN3, all but two being HPV16+) in a phase II trial (14, 15). Sufficient sera from 23 of 27 AGIN patients were available for evaluation. Proliferation assays. The proliferation assays are described in refs. 12, 14.