Prior human papillomavirus-16/18 AS04-adjuvanted vaccination prevents recurrent high grade cervical intraepithelial neoplasia after definitive surgical therapy: Post-hoc analysis from a randomized controlled trial.

We evaluated the efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in preventing HPV-related disease after surgery for cervical lesions in a post-hoc analysis of the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT00122681). Healthy women aged 15-25 years were randomized (1:1) to receive vaccine or control at months 0, 1 and 6 and followed for 4 years. Women were enrolled regardless of their baseline HPV DNA status, HPV-16/18 serostatus, or cytology, but excluded if they had previous or planned colposcopy. The primary and secondary endpoints of PATRICIA have been reported previously; the present post-hoc analysis evaluated efficacy in a subset of women who underwent an excisional procedure for cervical lesions after vaccination. The main outcome was the incidence of subsequent HPV-related cervical intraepithelial neoplasia grade 2 or greater (CIN2+) 60 days or more post-surgery. Other outcomes included the incidence of HPV-related CIN1+, and vulvar or vaginal intraepithelial neoplasia (VIN/VaIN) 60 days or more post-surgery. Of the total vaccinated cohort of 18,644 women (vaccine = 9,319; control = 9,325), 454 (vaccine = 190, control = 264) underwent an excisional procedure during the trial. Efficacy 60 days or more post-surgery for a first lesion, irrespective of HPV DNA results, was 88.2% (95% CI: 14.8, 99.7) against CIN2+ and 42.6% (-21.1, 74.1) against CIN1+. No VIN was reported and one woman in each group had VaIN2+ 60 days or more post-surgery. Women who undergo surgical therapy for cervical lesions after vaccination with the HPV-16/18 vaccine may continue to benefit from vaccination, with a reduced risk of developing subsequent CIN2+.

Long-term immunogenicity and safety of an investigational herpes zoster subunit vaccine in older adults.

BACKGROUND: An investigational subunit vaccine containing the varicella-zoster virus (VZV) glycoprotein E (gE) and the AS01B adjuvant system is being evaluated for the prevention of herpes zoster (HZ) in older adults. A phase II trial evaluating different formulations of this vaccine (containing 25µg, 50µg, or 100µg gE) was conducted in adults ≥60 years of age and showed that all formulations elicited robust cellular and humoral immune responses for up to 3 years after vaccination. In this follow-up study in subjects who received two doses of the 50µg gE/AS01B formulation (HZ/su), we assessed the persistence of the immune responses for up to 6 years after vaccination. METHODS: This phase II, open-label, multicenter, single-group trial conducted in the Czech Republic, Germany, Sweden, and the Netherlands followed 129 subjects who had received two doses (2 months apart) of HZ/su during the initial trial. Vaccine-induced immune responses (frequencies of gE-specific CD4(+) T cells expressing ≥2 activation markers and serum anti-gE antibody concentrations) were evaluated at 48, 60, and 72 months after the first HZ/su dose. RESULTS: Six years after vaccination with HZ/su, gE-specific cell-mediated immune responses and anti-gE antibody concentrations had decreased by 20-25% from month 36, but remained higher than the prevaccination values. At month 72, the gE-specific cell-mediated immune response was 3.8 times higher than the prevaccination value (477.3 vs. 119.4 activated gE-specific CD4(+) T cells per 10(6) cells), and the anti-gE antibody concentration was 7.3 times higher than the prevaccination value (8159.0 vs. 1121.3mIU/mL). No vaccine-related serious adverse events were reported between months 36 and 72. CONCLUSIONS: gE-specific cellular and humoral immune responses persisted for 6 years after two-dose vaccination with HZ/su in healthy older adults. No safety concerns were identified.

Comparative humoral and cellular immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine in healthy women aged 18-45 years: follow-up through Month 48 in a Phase III randomized study.

We previously reported higher anti-HPV-16 and -18 immune responses induced by HPV-16/18 vaccine compared with HPV-6/11/16/18 vaccine at Month 7 (one month after completion of full vaccination series) in women aged 18-45 y in an observer-blind study NCT00423046; the differences of immune response magnitudes were maintained up to Month 24. Here we report follow-up data through Month 48. At Month 48, in according-to-protocol cohort for immunogenicity (seronegative and DNA-negative for HPV type analyzed at baseline), geometric mean titers of serum neutralizing antibodies were 2.0- to 5.2-fold higher (HPV-16) and 8.6- to 12.8-fold higher (HPV-18) in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group. The majority of women in both vaccine groups remained seropositive for HPV-16. The same trend was observed for HPV-18 in HPV-16/18 vaccine group; however, seropositivity rates in HPV-6/11/16/18 vaccine group decreased considerably, particularly in the older age groups. In the total vaccinated cohort (regardless of baseline serological and HPV-DNA status), anti-HPV-16 and -18 neutralizing antibody levels induced by HPV-16/18 vaccine were higher than those induced by HPV-6/11/16/18 vaccine. CD4+ T-cell response for HPV-16 and HPV-18 was higher in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group. Memory B-cell responses appeared similar between vaccine groups. Both vaccines were generally well tolerated. Overall, the higher immune response observed with the HPV-16/18 vaccine was maintained up to Month 48. A head-to-head study incorporating clinical endpoints would be required to confirm whether the observed differences in immune response between the vaccines influence the duration of protection they provided.

Sustained efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine: final analysis of a long-term follow-up study up to 9.4 years post-vaccination.

HPV-023 (NCT00518336; ClinicalTrial.gov) is a long-term follow-up of an initial double-blind, randomized (1:1), placebo-controlled study (HPV-001, NCT00689741) evaluating the efficacy against human papillomavirus (HPV)-16/18 infection and associated cyto-histopathological abnormalities, persistence of immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine. Among the women, aged 15-25 years, enrolled in HPV-001 and who participated in the follow-up study HPV-007 (NCT00120848), a subset of 437 women from five Brazilian centers participated in this 36-month long-term follow-up (HPV-023) for a total of 113 months (9.4 years). During HPV-023, anti-HPV-16/18 antibodies were measured annually by enzyme-linked immunosorbent assay (ELISA) and pseudovirion-based neutralisation assay (PBNA). Cervical samples were tested for HPV DNA every 6 months, and cyto-pathological examinations were performed annually. During HPV-023, no new HPV-16/18-associated infections and cyto-histopathological abnormalities occurred in the vaccine group. Vaccine efficacy (VE) against HPV-16/18 incident infection was 100% (95%CI: 66.1, 100). Over the 113 months (9.4 years), VE was 95.6% (86.2, 99.1; 3/50 cases in vaccine and placebo groups, respectively) against incident infection, 100% (84·1, 100; 0/21) against 6-month persistent infection (PI); 100% (61·4, 100; 0/10) against 12-month PI; 97·1% (82.5, 99.9; 1/30) against ≥ ASC-US; 95·0% (68.0, 99.9; 1/18) against ≥ LSIL; 100% (45.2, 100; 0/8) against CIN1+; and 100% (-128.1, 100; 0/3) against CIN2+ associated with HPV-16/18. All vaccinees remained seropositive to HPV-16/18, with antibody titers remaining several folds above natural infection levels, as measured by ELISA and PBNA. There were no safety concerns. To date, these data represent the longest follow-up reported for a licensed HPV vaccine.

Efficacy of the HPV-16/18 vaccine: final according to protocol results from the blinded phase of the randomized Costa Rica HPV-16/18 vaccine trial.

BACKGROUND: A community-based randomized trial was conducted in Costa Rica to evaluate the HPV-16/18 AS04-adjuvanted vaccine (NCT00128661). The primary objective was to evaluate efficacy of the vaccine to prevent cervical intraepithelial neoplasia 2 or more severe disease (CIN2+) associated with incident HPV-16/18 cervical infections. Secondary objectives were to evaluate efficacy against CIN2+ associated with incident cervical infection by any oncogenic HPVs and to evaluate duration of protection against incident cervical infection with HPV-16/18. Vaccine safety and immunogenicity over the 4-year follow-up were also evaluated. METHODS: We randomized (3727 HPV arm; 3739 control arm), vaccinated (HPV-16/18 or Hepatitis A) and followed (median 53.8 months) 7466 healthy women aged 18-25 years. 5312 women (2635 HPV arm; 2677 control arm) were included in the according to protocol analysis for efficacy. The full cohort was evaluated for safety. Immunogenicity was considered on a subset of 354 (HPV-16) and 379 (HPV-18) women. HPV type was assessed by PCR on cervical specimens. Immunogenicity was assessed using ELISA and inhibition enzyme immunoassays. Disease outcomes were histologically confirmed. Vaccine efficacy and 95% confidence intervals (95%CI) were computed. RESULTS: Vaccine efficacy was 89.8% (95% CI: 39.5-99.5; N=11 events total) against HPV-16/18 associated CIN2+, 59.9% (95% CI: 20.7-80.8; N=39 events total) against CIN2+ associated with non-HPV-16/18 oncogenic HPVs and 61.4% (95% CI: 29.5-79.8; N=51 events total) against CIN2+ irrespective of HPV type. The vaccine had an acceptable safety profile and induced robust and long-lasting antibody responses. CONCLUSIONS: Our findings confirm the high efficacy and immunogenicity of the HPV-16/18 vaccine against incident HPV infections and cervical disease associated with HPV-16/18 and other oncogenic HPV types. These results will serve as a benchmark to which we can compare future findings from the ongoing extended follow-up of participants in the Costa Rica trial. TRIAL REGISTRATION: Registered with clinicaltrials.gov: NCT00128661.

Four-year follow-up of the immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine when administered to adolescent girls aged 10-14 years.

PURPOSE: Long-term immunogenicity and safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine when administered to adolescent girls was evaluated. METHODS: This open-label, follow-up study (NCT00316706) was conducted in 31 centers in Taiwan, Germany, Honduras, Panama, and Colombia. In the initial study (NCT00196924), 1,035 girls aged 10-14 years received the HPV-16/18 AS04-adjuvanted vaccine at 0, 1, and 6 months. Here, geometric mean titers (GMTs) of antibodies against HPV-16, HPV-18, and monophosphoryl lipid A (MPL), a component of the AS04 Adjuvant System, were reported up to month 48. RESULTS: In the according-to-protocol immunogenicity cohort (N = 563), GMTs at month 48 in initially seronegative participants were 2,374.9 (95% confidence interval: 2,205.7-2,557.0) EL.U/mL for anti-HPV-16 and 864.8 (796.9-938.4) EL.U/mL for anti-HPV-18, that is, six- and threefold higher than the plateau level in a reference study demonstrating vaccine efficacy in young women (age, 15-25 years). All participants remained seropositive for anti-HPV-16 and anti-HPV-18 at month 48. Most participants (81.8%) were seropositive for anti-MPL antibodies before vaccination. Anti-MPL antibody titers in initially seropositive participants increased initially, and then declined. Most initially seronegative participants for anti-MPL seroconverted; 69.6% remained seropositive at month 48, with anti-MPL antibody titers similar to the natural background level. The vaccine was generally well tolerated. No serious adverse events were considered related to vaccination. CONCLUSIONS: In adolescent girls, the HPV-16/18 AS04-adjuvanted vaccine produces anti-HPV-16 and anti-HPV-18 antibody titers that are maintained for up to 4 years at higher levels than those in young women in whom vaccine efficacy against cervical lesions was demonstrated.

Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule compared with the licensed 3-dose schedule: results from a randomized study.

The immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix®, GlaxoSmithKline Biologicals) administered according to its licensed vaccination schedule (3-dose, 3D) and formulation (20 µg of each HPV antigen; 20/20F) has previously been demonstrated. This partially-blind, controlled, randomized trial (NCT00541970) evaluated 2-dose (2D) schedules using the licensed 20/20F or an alternative formulation containing 40 µg of each antigen (40/40F), compared with the licensed 3D schedule. Healthy females stratified by age (9-14, 15-19, 20-25 y) were randomized to receive 2 doses of 20/20F at Months (M) 0,6 (n=240), 40/40F at M0,6 (n=241) or 40/40F at M0,2 (n=240), or 3 doses of 20/20F at M0,1,6 (licensed schedule/formulation, n=239). One month after the last dose, the 3D schedule was not immunologically superior to 2D schedules except in the 40/40F M0,2 group for HPV-16 (lower limit of 95% CI geometric mean antibody titer (GMT) ratio [2D/3D] < 0.5). For both HPV-16 and HPV-18, the 2D schedules in girls 9-14 y were immunologically non-inferior to the 3D schedule in women 15-25 y (the age group in which efficacy has been demonstrated) (upper limit of 95% CI for GMT ratio [3D/2D] < 2) one month after the last dose. At Month 24, non-inferiority was maintained for the 2D M0,6 schedules in girls 9-14 y versus the 3D schedule in women 15-25 y. All formulations had acceptable reactogenicity and safety profiles. These results indicate that the HPV-16/18 vaccine on a 2D M0,6 schedule is immunogenic and generally well tolerated in girls 9-14 y and that the 2D schedule is likely adequate for younger females.

Persistence of immune response to HPV-16/18 AS04-adjuvanted cervical cancer vaccine in women aged 15-55 years.

The HPV-16/18 AS04-adjuvanted vaccine (Cervarix®, GlaxoSmithKline Biologicals) has been shown to induce a robust immune response in women aged 15-55 years (103514/NCT00196937). This follow-up study is the first report of persistence of immune response and safety profile through 48 months after vaccination in women aged 15-55 years. In this open-label, age-stratified Phase III study in Germany and Poland (105882/NCT00196937), healthy women aged 15-55 years received 3 doses of HPV-16/18 AS04-adjuvanted vaccine at 0, 1, and 6 months. Anti-HPV-16/18 seropositivity rates and geometric mean antibody titers (GMTs) were assessed by enzyme-linked immunosorbent assay (ELISA) in women aged 15-25 (n=168), 26-45 (n=186) and 46-55 years (n=177) from the time of first vaccination through 48 months. At Month 48, all subjects were seropositive for anti-HPV-16 antibodies and 99.4% were seropositive for anti-HPV-18. Antibody kinetics were as previously reported, with peak response at Month 7 followed by a gradual decline tending towards a plateau in all age groups. Anti-HPV-16/18 GMTs were sustained at Month 48 in all age groups, including women aged 46-55 years in whom GMTs were respectively 11-fold and 5-fold higher than natural infection levels. The vaccine exhibited a clinically acceptable safety profile in all age groups. In summary, the HPV-16/18 AS04-adjuvanted vaccine induces high and sustained immune responses in women aged 15-55 years, with antibody levels remaining several-fold higher than natural infection levels for at least 4 years after the first vaccine dose.

Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted vaccine coadministered with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine and/or meningococcal conjugate vaccine to healthy girls 11 to 18 years of age: results from a randomized open trial.

BACKGROUND: A combined immunization strategy for administration of human papillomavirus (HPV) vaccine with other routine vaccines may lead to better compliance. Reactions and immunologic interference with concomitantly administered vaccines are unpredictable, necessitating clinical evaluation. METHODS: This was a randomized, open study conducted at 48 centers in the United States (NCT00369824). Healthy girls 11 to 18 years of age were randomized equally to 1 of 6 groups to receive 3 doses of HPV-16/18 AS04-adjuvanted vaccine administered at 0, 1, and 6 or 1, 2, and 7 months, with or without 1 dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) and/or 1 dose of meningococcal polysaccharide diphtheria toxoid conjugate vaccine (MCV4) in different coadministration regimens (1283 girls vaccinated). Coadministered vaccines were injected at separate sites. Antibodies were measured for all vaccine components. Reactogenicity and safety were monitored. RESULTS: The prespecified criteria for noninferiority were met for all primary and secondary immunogenicity end points, demonstrating similar immunogenicity of Tdap and MCV4 when given alone or coadministered with the HPV vaccine. Immunogenicity of the HPV vaccine (in terms of seroconversion rates and geometric mean antibody titers to HPV antigens) was similar, regardless of whether it was given alone or coadministered with Tdap and/or MCV4. No differences were observed in the reactogenicity profile of the HPV vaccine administered alone or coadministered with either Tdap and/or MCV4 in different regimens. CONCLUSIONS: Concomitant administration of HPV-16/18 AS04-adjuvanted vaccine with Tdap and/or MCV4 in different regimens did not interfere with the immune response to any of the vaccines and had an acceptable safety profile.

Long-term persistence of systemic and mucosal immune response to HPV-16/18 AS04-adjuvanted vaccine in preteen/adolescent girls and young women.

Vaccination against oncogenic human papillomavirus (HPV) types is one key intervention for cervical cancer prevention. This follow-up study assessed the persistence of the systemic and mucosal immune responses together with the safety profile of the HPV-16/18 AS04-adjuvanted vaccine administered to young women aged 10-25 years. Serum and cervicovaginal secretion (CVS) samples were collected at prespecified time-points during the 48-month follow-up period. Anti-HPV-16/18 antibody levels in serum and CVS were measured by enzyme-linked immunosorbent assay (ELISA). At Month 48, all subjects remained seropositive for serum anti-HPV-16 and -18 antibodies. As previously observed, anti-HPV-16 and -18 antibodies levels (ELISA Units/mL) were higher in subjects vaccinated at the age of 10-14 years (2862.2 and 940.8) compared to subjects vaccinated at the age of 15-25 years (1186.2 and 469.8). Moreover, anti-HPV-16 and -18 antibodies in CVS were still detectable for subjects aged 15-25 years (84.1% and 69.7%, respectively). There was a strong correlation between serum and CVS anti-HPV-16 and -18 antibodies levels (correlation coefficients = 0.84 and 0.90 at Month 48, respectively) supporting the hypothesis of transudation or exudation of serum immunoglobulin G antibodies through the cervical epithelium. The HPV-16/18 AS04-adjuvanted vaccine had a clinically acceptable safety profile. In conclusion, this follow-up study shows that the HPV-16/18 AS04-adjuvanted vaccine administered to preteen/adolescents girls and young women induces long-term systemic and mucosal immune response and has a clinically acceptable safety profile up to 4 years after the first vaccine dose.

Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine coadministered with combined diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine to girls and young women.

PURPOSE: Many countries recommend human papillomavirus (HPV) vaccination in female adolescents at an age when other vaccines are routinely administered. This open, randomized, multicenter study (108464/NCT00426361) evaluated coadministration of HPV-16/18 AS04-adjuvanted vaccine with diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine (dTpa-IPV). METHODS: Healthy females aged 10-18 years were randomized to receive HPV vaccine at months 0, 1, and 6 (n = 248), HPV vaccine coadministered with dTpa-IPV at month 0 and HPV vaccine at months 1 and 6 (n = 255), or dTpa-IPV at month 0 followed by HPV vaccine at months 1, 2, and 7 (n = 248). Immunogenicity was evaluated at months 0, 1, and 7 or 8 (depending on group). Vaccine reactogenicity and safety were also assessed. RESULTS: Coadministered dTpa-IPV and HPV vaccine was noninferior to dTpa-IPV alone in terms of seroprotection against diphtheria (99.2% and 100%), tetanus (100% and 100%) and poliovirus types 1, 2, and 3 (> or = 99.6%), and geometric mean antibody concentrations (ELISA Units/mL) for pertussis toxoid (84 vs. 75), filamentous hemagglutinin (612 and 615) and pertactin (426 and 360) at month 1. Coadministered dTpa-IPV and HPV vaccine was noninferior to HPV vaccine alone in terms of seroconversion rates for HPV-16 (99.5% and 100%) and HPV-18 (99.5% and 100%) and geometric mean antibody titers (ELISA Units/mL) for HPV-16 (15,608 and 18,965) and HPV-18 (6,597 and 6,902) at month 7. Coadministration was generally well tolerated. The reactogenicity of dTpa-IPV and the first dose of HPV vaccine was similar. CONCLUSIONS: Results from this study support coadministration of the HPV-16/18 AS04-adjuvanted vaccine with dTpa-IPV vaccine in females aged 10-18 years.