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In this study, the authors investigated the ability of a human papillomavirus-16 (HPV-16) virus-like particle vaccine to protect against cervical intraepithelial neoplasia (CIN) over a 48-month period. The study population consisted of young women (age 16–23 years) recruited from 16 different centers via college campuses and surrounding areas across the United States. At enrollment, participants underwent a thorough gynecologic examination during which swabs were taken from the cervix and external genitalia and lavage specimens were obtained from the upper vagina. Blood serum samples were also tested for HPV-16 antibody titers. The women were randomized to receive 40 μg HPV-16 L1 virus particle-like vaccine or placebo on day 1 of enrollment, month 2, and month 6. They were seen for follow up 1 month after the third injection (7 months), 12 months after enrollment, and at 6-month intervals for the next 3 years. Cervical smears for Pap cytology and HPV DNA testing were taken at each visit, and blood serum antibodies against HPV-16 were tested.A total of 2391 women received at least one vaccination. Fifteen percent (n = 360) of these women did not complete the 3 doses of vaccine, including 9 who dropped out because of clinical adverse events, 189 lost to follow up, 33 who became pregnant, 35 with other protocol deviations, and 94 who withdrew their consent.Different subsets of the study population were used for analysis. The per-protocol population included women seronegative for HPV-16 at enrollment, HPV-16 DNA-negative from enrollment to month 7, who received all 3 doses of vaccine or placebo, and met all protocol criteria (vaccine group, n = 755; placebo group, n = 750). The modified intention-to-treat (MITT-1) group included women who were HPV-16-seronegative and HPV-16 DNA-negative at enrollment and who received at least one vaccination dose as well as all protocol violators (vaccine group, n = 834; placebo group, n = 843). A second modified intention-to-treat group included all the MITT-1 patients plus those who tested positive for HPV-16 at study enrollment (vaccine group, n = 1017. control group; n = 1050).There were no diagnoses of persistent HPV-16 infection (defined as HPV-16 DNA positivity for 2 consecutive visits more than 4 months apart) among women who received all 3 doses of vaccine and completed 48 months of follow up (100% effective). When women who were lost to follow up but were HPV-16 DNA-positive at their last visit were also included in the analysis, persistent HPV-16 infection was counted in 7 of 755 women who received the HPV-16 vaccine compared with 111 of 750 women who received placebo. This represents a 94% reduction in the incidence of persistent HPV-16 infection among HPV-16-vaccinated women.There were no cases of HPV-16-related CIN diagnosed among the per-protocol vaccinated women compared with 14 cases of HPV-16-related CIN 1 and 12 of CIN 2 or worse among women in the placebo group. In the 834 MITT-1 patients who received at least one dose of the vaccine, none developed HPV-16-related CIN compared with 20 women with HPV-16-related CIN 1 and 17 with CIN 2 in the placebo-treated women. Although not statistically significant, a 52% reduction in cases of any type HPV-related CIN 2 or 3 and a 30% reduction of cases of CIN 1 were observed among per-protocol women who received the HPV-16 vaccine.The level of anti-HPV-16 titers rose after each dose of vaccine. A decline was observed after the high point after the third dose but leveled off at 30 months and remained elevated through the 48-month visit. At this time, anti-HPV-16 titers were higher among vaccinated women than in women who received placebo or who were seropositive at enrollment. Among women who tested positive for HPV-16 DNA but who were seronegative at the first visit, there were 4 cases of CIN 2–3 in the placebo group but none in the vaccinated group. No benefit to vaccination was observed in women who were seropositive at enrollment.