A controlled trial of a human papillomavirus type 16 vaccine.

BACKGROUND: Approximately 20 percent of adults become infected with human papillomavirus type 16 (HPV-16). Although most infections are benign, some progress to anogenital cancer. A vaccine that reduces the incidence of HPV-16 infection may provide important public health benefits. METHODS: In this double-blind study, we randomly assigned 2392 young women (defined as females 16 to 23 years of age) to receive three doses of placebo or HPV-16 virus-like-particle vaccine (40 microg per dose), given at day 0, month 2, and month 6. Genital samples to test for HPV-16 DNA were obtained at enrollment, one month after the third vaccination, and every six months thereafter. Women were referred for colposcopy according to a protocol. Biopsy tissue was evaluated for cervical intraepithelial neoplasia and analyzed for HPV-16 DNA with use of the polymerase chain reaction. The primary end point was persistent HPV-16 infection, defined as the detection of HPV-16 DNA in samples obtained at two or more visits. The primary analysis was limited to women who were negative for HPV-16 DNA and HPV-16 antibodies at enrollment and HPV-16 DNA at month 7. RESULTS: The women were followed for a median of 17.4 months after completing the vaccination regimen. The incidence of persistent HPV-16 infection was 3.8 per 100 woman-years at risk in the placebo group and 0 per 100 woman-years at risk in the vaccine group (100 percent efficacy; 95 percent confidence interval, 90 to 100; P<0.001). All nine cases of HPV-16-related cervical intraepithelial neoplasia occurred among the placebo recipients. CONCLUSIONS: Administration of this HPV-16 vaccine reduced the incidence of both HPV-16 infection and HPV-16-related cervical intraepithelial neoplasia. Immunizing HPV-16-negative women may eventually reduce the incidence of cervical cancer.

Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial.

OBJECTIVE: Administration of a quadrivalent HPV-6/ 1/16/18 vaccine to 16- to 26-year-old women was highly effective in preventing HPV-6/ 1/16/18-related cervical/vulvar/vaginal precancerous lesions and genital warts. As the risk of acquiring HPV significantly rises after sexual debut, HPV vaccines should have the greatest benefit in sexually naive adolescents. We evaluated the tolerability and immunogenicity of quadrivalent vaccine in males and females 9 to 15 years of age through 18 months postenrollment. METHODS: In this randomized, double-blind trial, 1781 sexually naive children were assigned (2:1) to quadrivalent HPV-6/11/16/18 vaccine or saline placebo administered at day 1 and months 2 and 6. Serum neutralizing anti-HPV-6/11/16/18 responses were summarized as geometric mean titers (GMTs) and seroconversion rates. Primary analyses were done per-protocol (subjects received 3 doses, had no major protocol violations and were HPV type-specific seronegative at day 1). Adverse experiences were collected by diary card. RESULTS: At month 7, seroconversion rates were > or =99.5% for the 4 vaccine-HPV-types. GMTs and seroconversion rates in boys were noninferior to those in girls (P < 0.001). At month 18, > or =91.5% of vaccine recipients were seropositive, regardless of gender. A higher proportion of vaccine recipients (75.3%) than placebo recipients (50.0%) reported one or more injection-site adverse experiences following any vaccination. Rates of fever were similar between vaccination groups. No serious vaccine-related adverse experiences were reported. CONCLUSIONS: In 9- to 15-year-old adolescents, the quadrivalent vaccine was generally well tolerated and induced persistent anti-HPV serologic responses in the majority of subjects for at least 12 months following completion of a three-dose regimen. The vaccine durability supports universal HPV vaccination programs in adolescents to reduce the burden of clinical HPV disease, particularly cervical cancer and precancers.

Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial.

OBJECTIVE: Human papillomavirus (HPV) virus-like particle (VLP) vaccines have demonstrated effectiveness in preventing persistent HPV infections. Whether protection lasts longer than 18 months and, thus, impacts rates of cervical intraepithelial neoplasia (CIN) 2-3 has not yet been established. We present results from an HPV16 L1 VLP vaccine trial through 48 months. METHODS: A total of 2,391 women, aged 16-23 years, participated in a randomized, double-blind, placebo-controlled trial. Either 40 mug HPV16 L1 VLP vaccine or placebo was given intramuscularly at day 1, month 2, and month 6. Genital samples for HPV16 DNA and Pap tests were obtained at day 1, month 7, and then 6-monthly through month 48. Colposcopy and cervical biopsies were performed if clinically indicated and at study exit. Serum HPV16 antibody titer was measured by radioimmunoassay. RESULTS: Among 750 placebo recipients in the per protocol population, 12 women developed HPV16-related CIN2-3 (6 CIN2 and 6 CIN3). Among 755 vaccine recipients, there were no cases (vaccine efficacy 100%, 95% confidence interval [CI] 65-100%). There were 111 cases of persistent HPV16 infection in placebo recipients and 7 cases in vaccine recipients (vaccine efficacy 94%, 95% CI 88-98%). After immunization, HPV16 serum antibody geometric mean titers peaked at month 7 (1,519 milli-Merck units [mMU]/mL), declined through month 18 (202 mMU/mL), and remained relatively stable between month 30 and month 48 (128-150 mMU/mL). CONCLUSION: The vaccine HPV16 L1 VLP provides high-level protection against persistent HPV16 infection and HPV16-related CIN2-3 for at least 3.5 years after immunization. Administration of L1 VLP vaccines targeting HPV16 is likely to reduce risk for cervical cancer. LEVEL OF EVIDENCE: I.

Evidence of immune memory 8.5 years following administration of a prophylactic human papillomavirus type 16 vaccine.

BACKGROUND: The duration of protection conferred by prophylactic human papillomavirus (HPV) L1 virus-like particle vaccines is a critical determinant of their public health impact. A feature of vaccines that confer long-term immunity is their ability to induce immune memory. OBJECTIVES: We evaluated antibody responses against HPV types 6, 11, 16 and 18 following administration of the quadrivalent HPV-6/11/16/18 vaccine to women who had previously received a monovalent HPV-16 vaccine. STUDY DESIGN: As part of an extended follow-up study conducted between 2006 and 2009 in Seattle, Washington, we administered the quadrivalent HPV-6/11/16/18 vaccine to 52 women (19 vaccine and 33 placebo recipients) who had participated in a monovalent HPV-16 vaccine trial 8.5 years earlier. Serum samples were tested for anti-HPV antibodies using competitive Luminex immunoassay. RESULTS: Following administration of the first dose of the quadrivalent HPV-6/11/16/18 vaccine, the anti-HPV-16 geometric mean titer among monovalent HPV-16 vaccine recipients (GMT=5024.0 milli-Merck units per milliliter [mMU/mL]; 95% confidence interval [CI]: 2710.1, 9313.6 mMU/mL) substantially exceeded that among the placebo recipients (GMT=136.1; 95% CI: 78.5, 235.8 mMU/mL; p<0.01) and their own highest anti-HPV-16 response observed during the original trial (GMT at month 7 of the original trial=1552.7 mMU/mL; 95% CI: 1072.6, 2247.7 mMU/mL; p<0.01). CONCLUSIONS: The findings suggest that the administration of the three-dose regimen of the monovalent HPV-16 vaccine had produced memory lymphocytes, characterized by a heightened immune response following administration of the quadrivalent HPV-6/11/16/18 vaccine that effectively served as an antigen challenge.

Longer term efficacy of a prophylactic monovalent human papillomavirus type 16 vaccine.

We conducted an extended follow-up study (March 2006-May 2008) to assess the longer term efficacy of a prophylactic monovalent human papillomavirus (HPV) type 16 L1 virus-like particle vaccine in women (n=290) who had enrolled in a randomized controlled trial of this vaccine (October 1998-November 1999) in Seattle and remained HPV-16 DNA negative during the course of that trial. During the extended follow-up period, in the per-protocol susceptible population, none of the vaccine recipients was found to be infected with HPV-16 or developed HPV-16-related cervical lesions; among placebo recipients, 6 women were found to be infected with HPV-16 (vaccine efficacy [VE]=100%; 95% confidence interval [CI]: 29-100%) and 3 women developed HPV-16-related cervical lesions (VE=100%; 95% CI: <0-100%). Approximately 86% of vaccine recipients remained HPV-16 competitive Luminex immunoassay seropositive at an average of 8.5 years of follow-up. During the combined original trial and extended follow-up period, in the intention-to-treat population, 20 and 22 women developed any cervical lesion regardless of HPV type among the vaccine and placebo recipients, respectively (VE=15%; 95% CI: <0-56%). The results suggest that this monovalent HPV-16 vaccine remains efficacious through 8.5 years after its administration.