Gary Dubin

Universitair Ziekenhuis Ghent, Gent, VLG, Belgium

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Publications (44)507.17 Total impact

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    ABSTRACT: A prophylactic human papillomavirus (HPV) vaccine targeting oncogenic HPV types in addition to HPV-16 and -18 may broaden protection against cervical cancer. Two Phase I/II, randomized, controlled studies were conducted to compare the immunogenicity and safety of investigational tetravalent HPV L1 virus-like particle (VLP) vaccines, containing VLPs from two additional oncogenic genotypes, with the licensed HPV-16/18 AS04-adjuvanted vaccine (control) in healthy 18-25 year-old women. In one trial (NCT00231413), subjects received control or one of 6 tetravalent HPV-16/18/31/45 AS04 vaccine formulations at months (M) 0,1,6. In a second trial (NCT00478621), subjects received control or one of 5 tetravalent HPV-16/18/33/58 vaccines formulated with different adjuvant systems (AS04, AS01 or AS02), administered on different schedules (M0,1,6 or M0,3 or M0,6). One month after the third injection (Month 7), there was a consistent trend for lower anti-HPV-16 and -18 geometric mean antibody titers (GMTs) for tetravalent AS04-adjuvanted vaccines compared with control. GMTs were statistically significantly lower for an HPV-16/18/31/45 AS04 vaccine containing 20/20/10/10μg VLPs for both anti-HPV-16 and anti-HPV-18 antibodies, and for an HPV-16/18/33/58 AS04 vaccine containing 20/20/20/20μg VLPs for anti-HPV-16 antibodies. There was also a trend for lower HPV-16 and -18-specific memory B-cell responses for tetravalent AS04 vaccines versus control. No such trends were observed for CD4(+) T-cell responses. Immune interference could not always be overcome by increasing the dose of HPV-16/18 L1 VLPs or by using a different adjuvant system. All formulations had acceptable reactogenicity and safety profiles. Reactogenicity in the 7-day post-vaccination period tended to increase with the introduction of additional VLPs, especially for formulations containing AS01. HPV-16 and -18 antibody responses were lower when additional HPV L1 VLPs were added to the HPV-16/18 AS04-adjuvanted vaccine. Immune interference is a complex phenomenon that cannot always be overcome by changing the antigen dose or adjuvant system.
    Vaccine 03/2014; · 3.77 Impact Factor
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    ABSTRACT: Background. We examined risk of newly detected HPV infection and cervical abnormalities in relation to HPV-16/18 antibody levels at enrollment in PATRICIA (PApilloma TRIal against Cancer In young Adults; NCT00122681).Methods. Using Poisson regression, we compared risk of newly detected infection and cervical abnormalities associated with HPV-16/18 between seronegative versus seropositive women (15-25 years) in the control arm (DNA-negative at baseline for the corresponding HPV type [HPV-16: n=8193; HPV-18: n=8463]).Results. High titers of naturally-acquired HPV-16 antibodies and/or linear trend for increasing antibody levels were significantly associated with lower risk of incident and persistent infection, atypical squamous cells of undetermined significance or greater (ASC-US+), and cervical intraepithelial neoplasia grade 1, 2 or greater (CIN1+, CIN2+). For HPV-18, while seropositivity was associated with lower risk of ASC-US+ and CIN1+, no association between naturally-acquired antibodies and infection was demonstrated. Naturally-acquired HPV-16 antibody levels of 371 (95% confidence interval: 42-794), 204 (129-480) and 480 (250-5756) EU/mL were associated with 90% reduction of incident infection, 6-month persistent infection, and ASC-US+, respectively.Conclusions. Naturally-acquired antibodies to HPV-16, and to a lesser extent HPV-18, are associated with some reduced risk of subsequent infection and cervical abnormalities associated with the same HPV type.
    The Journal of Infectious Diseases 03/2014; · 5.85 Impact Factor
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    ABSTRACT: The purpose of this study is to further evaluate the safety of the human papillomavirus (HPV)-16/18-AS04-adjuvanted vaccine (HPV-16/18-vaccine Cervarix®, GlaxoSmithKline, Belgium) through a pooled analysis of data from 42 completed/ongoing clinical studies. Unsolicited adverse events (AEs) were reported for 30 days after each dose. Medically significant conditions, serious AEs (SAEs), potential immune-mediated diseases (pIMDs) and pregnancy outcomes were captured until study completion. Events leading to subject withdrawal were reviewed. Relative risks compared incidences of spontaneous abortion and pIMDs in controlled studies. Thirty one thousand one hundred seventy-three adolescent girls/women received HPV-16/18-vaccine alone (HPV group), 2166 received HPV-16/18-vaccine coadministered with another vaccine and 24 241 were controls. Mean follow-up was 39 months (range 0-113.3). Incidences of unsolicited AEs reported within 30 days after any dose were similar between HPV and Control groups (30.8%/29.7%). During the entire study period, reports of medically significant conditions (25.0%/28.3%) and SAEs (7.9%/9.3%) were also similarly distributed between groups. Deaths were rare: HPV (alone/coadministered) n = 25, controls n = 20 (n = 18 in blinded groups). pIMDs within 1 year were reported by 0.2% of HPV-16/18 vaccinees and controls. For each pIMD event category, no increased relative risks were reported for HPV-16/18 vaccinees versus controls. Coadministration did not change the overall safety profile. Pregnancy outcomes and withdrawal rates were similar between groups. Analysis of safety data arising from 57 580 subjects and 96 704 HPV-16/18-vaccine doses shows that the incidences and distribution of AEs were similar among HPV-16/18-vaccine recipients and controls. No new safety signals were identified. The data confirm previous findings that HPV-16/18-vaccine has an acceptable benefit-risk profile in adolescent girls and adult women. © 2014 GlaxoSmithKline. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.
    Pharmacoepidemiology and Drug Safety 02/2014; · 2.90 Impact Factor
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    ABSTRACT: 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 cytology 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 ongoing extended follow-up of participants in the Costa Rica trial. Trial registration : Registered with NCT00128661.
    Vaccine. 01/2014;
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    ABSTRACT: Background. Public Health England has reported a decrease of up to 20.8% in new diagnoses of external genital warts (GWs) among women aged <19 years since the national vaccination program with the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine began in 2008. A post hoc analysis of the phase III PATRICIA (PApilloma TRIal against Cancer In young Adults) trial (NCT00122681) was performed to ascertain whether protection against low-risk HPV types was apparent. Methods. Vaccine efficacy (VE) at 48 months was assessed against 6-month persistent infection (6MPI) with low-risk HPV types in the total vaccinated cohort (TVC) and in the TVC naive (for 25 HPV types tested) populations. Results. In the TVC naive cohort, VE against 6MPI (95% confidence interval) was 34.5% (11.3 to 51.8) for HPV-6/11, 34.9% (9.1 to 53.7) for HPV-6, 30.3% (-45.0 to 67.5) for HPV-11, and 49.5% (21.0 to 68.3) for HPV-74. Conclusions. The HPV-16/18 AS04-adjuvanted vaccine appears to have moderate efficacy against persistent infections with a number of low-risk HPV types (HPV-6/11/74), which are responsible for the majority of external GWs, and recently, antibody and cell-mediated immune response to HPV-6/11 have been observed. These findings may help to explain the decrease in external GW diagnoses seen in England.
    The Journal of Infectious Diseases 11/2013; 208(9):1391-1396. · 5.85 Impact Factor
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    ABSTRACT: In January 2010, porcine circovirus type 1 (PCV1) DNA was unexpectedly detected in the oral live-attenuated human rotavirus vaccine, Rotarix™ (GlaxoSmithKline [GSK] Vaccines) by an academic research team investigating a novel, highly sensitive analysis not routinely used for adventitious agent screening. GSK rapidly initiated an investigation to confirm the source, nature and amount of PCV1 in the vaccine manufacturing process and to assess potential clinical implications of this finding. The investigation also considered the manufacturer's inactivated poliovirus (IPV)-containing vaccines, since poliovirus vaccine strains are propagated using the same cell line as the rotavirus vaccine strain. Results confirmed the presence of PCV1 DNA and low levels of PCV1 viral particles at all stages of the Rotarix™ manufacturing process. PCV type 2 DNA was not detected at any stage. When tested in human cell lines, productive PCV1 infection was not observed. There was no immunological or clinical evidence of PCV1 infection in infants who had received Rotarix™ in clinical trials. PCV1 DNA was not detected in the IPV-containing vaccine manufacturing process beyond the purification stage. Retrospective testing confirmed the presence of PCV1 DNA in Rotarix™ since the initial stages of its development and in vaccine lots used in clinical studies conducted pre- and post-licensure. The acceptable safety profile observed in clinical trials of Rotarix™ therefore reflects exposure to PCV1 DNA. The investigation into the presence of PCV1 in Rotarix™ could serve as a model for risk assessment in the event of new technologies identifying adventitious agents in the manufacturing of other vaccines and biological products.
    Human vaccines & immunotherapeutics. 08/2013; 9(11).
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    ABSTRACT: Herpes simplex virus (HSV) type 2 (HSV-2) is the main cause of genital and neonatal herpes and is highly prevalent worldwide. Previous phase I and II studies showed the immunogenicity and safety of the candidate prophylactic HSV-2 glycoprotein D-based subunit vaccine (gD2-AS04), containing aluminum hydroxide and 3-O-deacylated monophosphoryl lipid A (MPL) as adjuvant (AS04), in healthy adults. The primary objective of the study presented here was to compare the immunogenicity and safety of five different vaccine formulations: 3 different antigen doses [20, 40 or 80 μg of truncated glycoprotein D from HSV-2 strain (gD-2t)], different aluminum salts [AlPO 4 or Al(OH) 3], different preservatives or different volumes of vaccine (0.5 or 1 ml). 150 healthy men and women aged 18-45 y, with negative serological markers for HSV-1 and HSV-2 infection, were vaccinated with one of 5 formulations of the gD2-AS04 candidate vaccine according to a 0-, 1-, 6-mo schedule. No statistically significant difference was observed in humoral or cellular immune responses between different antigen doses or the different aluminum salts, preservatives or volumes of vaccine. The gD2-AS04 vaccine was well tolerated by study participants for the duration of the study period. Local symptoms were more frequently reported than general symptoms, with muscle stiffness and/or injection site redness being the most frequently reported. Overall, the incidence of adverse events was comparable in all groups. Based on these results the gD2-AS04 formulation, containing 20 μg of gD-2t, was selected for evaluation of prophylactic efficacy in further clinical trials.
    Human vaccines & immunotherapeutics. 02/2013; 9(6).
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    ABSTRACT: The primary objective of this investigation was to assess whether the AS04-adjuvanted herpes simplex virus (HSV) glycoprotein D candidate prophylactic vaccine against genital herpes disease increases the risk of spontaneous abortion associated with pregnancy conceived within the vaccination exposure window (vaccine dose received within the period starting 60 days before and ending 20 weeks post-conception day). We performed a meta-analysis of studies designed as part of the clinical development program for this vaccine, to examine the relative risk of abortion (spontaneous or elective) associated with unintended vaccination exposure during pregnancy. Nineteen studies, completed before September 2010, were eligible; 5 matched the inclusion criteria for this analysis (presence of a control arm and at least one adverse pregnancy outcome reported). All vaccinated women (N=19,727) were included, of whom 660 reported a pregnancy during the study period. Overall, 13.3% of pregnancies in the HSV vaccine group and 11.0% in the control group resulted in spontaneous abortion; 24.2% and 20.0% resulted in elective abortion. Among 180 women with a first pregnancy conceived in the vaccination exposure window, 16.7% (HSV vaccine) and 9.5% (control) had a spontaneous abortion and 38.5% and 33.3%, elective abortion. The relative risk for spontaneous abortion associated with vaccine exposure during the risk period for abortion in the course of pregnancy was 1.7 (95% CI: 0.7-4.6). For all women receiving HSV vaccine, this relative risk was 1.3 (95% CI: 0.8-2.1). The corresponding relative risks for elective abortion were 1.2 (95% CI: 0.7-2.0) and 1.3 (95% CI: 0.9-1.8). There was no apparent relationship to dosing and no difference between groups in gestational age at the time of spontaneous or elective abortion. In conclusion there is no statistical evidence that the investigational HSV vaccine increased the risk of spontaneous or elective abortion.
    Vaccine 01/2013; · 3.77 Impact Factor
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    ABSTRACT: In this large prospective study of primary HSV infections in young HSV seronegative women we found the rate of HSV-1 infections was over twice that for HSV-2 but there were important age and race differences.
    Clinical Infectious Diseases 10/2012; · 9.37 Impact Factor
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    ABSTRACT: OBJECTIVE: We evaluated baseline data from the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT00122681) on the association between behavioral risk factors and HPV infection and cervical abnormalities. METHODS: Women completed behavioral questionnaires at baseline. Prevalence of HPV infection and cervical abnormalities (detected by cytological or histological procedures) and association with behavioral risk factors were analyzed by univariate and stepwise multivariable logistic regressions. RESULTS: 16782 women completed questionnaires. Among 16748 women with data for HPV infection, 4059 (24.2%) were infected with any HPV type. Among 16757 women with data for cytological abnormalities, 1626 (9.7%) had a cytological abnormality, of whom 1170 (72.0%) were infected with at least one oncogenic HPV type including HPV-16 (22.7%) and HPV-18 (9.3%). Multivariable analysis (adjusted for age and region, N=14404) showed a significant association between infection with any HPV type and not living with a partner, smoking, age <15years at first sexual intercourse, higher number of sexual partners during the past 12months, longer duration of hormonal contraception and history of sexually transmitted infection (STI). For cervical abnormalities, only history of STI (excluding Chlamydia trachomatis) remained significant in the multivariable analysis after adjusting for HPV infection. CONCLUSIONS: Women reporting 3+ sexual partners in the past 12months had the highest risk of HPV infection at baseline. HPV infection was the main risk factor for cervical abnormalities, and history of STIs excluding Chlamydia trachomatis increased risk to a lesser extent. Although behavioral factors can influence risk, all sexually active women are susceptible to HPV infection.
    Gynecologic Oncology 08/2012; · 3.93 Impact Factor
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    ABSTRACT: Control of human papillomavirus (HPV)-related cancers by inclusion of HPV vaccination into national vaccination programmes is likely. One open question is replacement of the vaccine types with other high-risk (hr) HPV types in the vaccination era. We studied occurrence of HPV types in adolescent females participating in a population-based vaccination trial. A total of 4,808 16- to 17-year-old females from Finland were enrolled in the 1:1 randomized phase III (PATRICIA) trial of the efficacy of vaccination with the AS04-adjuvanted HPV-16/18 virus-like particle vaccine as compared to hepatitis A virus (HAV) vaccine. HPV infection was assessed from cervical samples taken every 6 months for 4 years post-vaccination by polymerase chain reaction (PCR) for genital oncogenic HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 58, 59, 66, 68, and 73 as well as low-risk types HPV-6 and HPV-11. The HPV-16/18 vaccine coverage ranged between 1 and 22% by age-cohort and study community. Odds ratios (ORs) for infections with different HPV types in baseline PCR negative HPV-16/18 vs. HAV vaccinated women, and Poisson regression derived HPV incidence rate ratios (IRRs) in baseline positive vs. negative women were calculated. The OR and IRR estimates for acquisition of any genital HPV types showed no excess risk neither in baseline HPV DNA-negative HPV-16/18-vaccinated women compared to baseline HPV DNA-negative HAV vaccinated women nor in HPV-16/18-vaccinated baseline HPV-16/18-positive women compared to baseline HPV-16/18-negative women. In the HAV-vaccinated, baseline HPV-18-positive women showed an increased risk of acquiring other clade A7 HPV types (39, 45, 59, 68) (IRR 1.8, 95% confidence interval = 1.01.-3.1). We found no increased occurrence of non-vaccine HPV types suggestive of type-replacement 1-4 years post-vaccination among HPV-16/18-vaccinated Finnish adolescents.
    International Journal of Cancer 04/2012; 131(12):2832-8. · 6.20 Impact Factor
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    ABSTRACT: Two previous studies of a herpes simplex virus type 2 (HSV-2) subunit vaccine containing glycoprotein D in HSV-discordant couples revealed 73% and 74% efficacy against genital disease in women who were negative for both HSV type 1 (HSV-1) and HSV-2 antibodies. Efficacy was not observed in men or HSV-1 seropositive women. We conducted a randomized, double-blind efficacy field trial involving 8323 women 18 to 30 years of age who were negative for antibodies to HSV-1 and HSV-2. At months 0, 1, and 6, some subjects received the investigational vaccine, consisting of 20 μg of glycoprotein D from HSV-2 with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant; control subjects received the hepatitis A vaccine, at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units. The primary end point was occurrence of genital herpes disease due to either HSV-1 or HSV-2 from month 2 (1 month after dose 2) through month 20. The HSV vaccine was associated with an increased risk of local reactions as compared with the control vaccine, and it elicited ELISA and neutralizing antibodies to HSV-2. Overall, the vaccine was not efficacious; vaccine efficacy was 20% (95% confidence interval [CI], -29 to 50) against genital herpes disease. However, efficacy against HSV-1 genital disease was 58% (95% CI, 12 to 80). Vaccine efficacy against HSV-1 infection (with or without disease) was 35% (95% CI, 13 to 52), but efficacy against HSV-2 infection was not observed (-8%; 95% CI, -59 to 26). In a study population that was representative of the general population of HSV-1- and HSV-2-seronegative women, the investigational vaccine was effective in preventing HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection. (Funded by the National Institute of Allergy and Infectious Diseases and GlaxoSmithKline; number, NCT00057330.).
    New England Journal of Medicine 01/2012; 366(1):34-43. · 51.66 Impact Factor
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    ABSTRACT: This randomized, open, controlled, multicenter study (110886/NCT00578227) evaluated human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (HPV-16/18 vaccine) coadministered with inactivated hepatitis A and B (HAB) vaccine. Coprimary objectives were to demonstrate noninferiority of hepatitis A, hepatitis B, and HPV-16/18 immune responses at month 7 when vaccines were coadministered, compared with the same vaccines administered alone. Healthy girls (9-15 years) were age-stratified (9, 10-12, and 13-15 years) and randomized to receive HPV (n = 270), HAB (n = 271), or HPV + HAB (n = 272). Vaccines were administered at months 0, 1, and 6. Immunogenicity was evaluated at months 0 and 7. The hepatitis A immune response was noninferior for HPV + HAB, versus HAB, for seroconversion rates (100% in each group) and geometric mean antibody titers (GMTs) (95% CI) (4,504.2 [3,993.0-5,080.8] and 5,288.4 [4,713.3-5,933.7] mIU/mL, respectively). The hepatitis B immune response was noninferior for HPV + HAB, versus HAB, for anti-HBs seroprotection rates (98.3% and 100%); GMTs were 3,136.5 [2,436.0-4,038.4] and 5,646.5 [4,481.3-7,114.6] mIU/mL, respectively. The HPV-16/18 immune response was noninferior for HPV + HAB, versus HPV, for seroconversion rates (99.6% and 100% for both antigens) and GMTs (22,993.5 [20,093.4-26,312.0] and 26,981.9 [23,909.5-30,449.1] EL.U/mL for HPV-16; 8,671.2 [7,651.7-9,826.6] and 11,182.7 [9,924.8-12,600.1] EL.U/mL for HPV-18, respectively). No subject withdrew because of adverse events. No vaccine-related serious adverse events were reported. Immune responses and reactogenicity were similar in girls aged 9 years compared with the entire study population. Results support coadministration of HPV-16/18 vaccine with HAB vaccine in girls aged 9-15 years. The HPV-16/18 vaccine was immunogenic and generally well tolerated in 9-year-old girls.
    Journal of Adolescent Health 01/2012; 50(1):38-46. · 2.97 Impact Factor
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    ABSTRACT: In this observer-blind study (NCT00423046), women (N=1,106), stratified by age (18-26, 27-35, 36-45 y), were randomized (1:1) to receive the HPV-16/18 vaccine (Cervarix®, GlaxoSmithKline Biologicals, Months 0, 1, 6) or the HPV-6/11/16/18 vaccine (Gardasil® Merck & Co., Inc., Months 0, 2, 6). Month 7 results were previously reported; we now report Month 24 results. In the according-to-protocol cohort for immunogenicity (seronegative and DNA-negative at baseline for HPV type analyzed), seropositivity rates of neutralizing antibodies (nAbs) [pseudovirion-based neutralization assay] were, across all age strata, 100% (HPV-16/18 vaccine) and 97.5-100% (HPV-6/11/16/18 vaccine) for HPV-16, and 99.0-100% (HPV-16/18 vaccine) and 72.3-84.4% (HPV-6/11/16/18 vaccine) for HPV-18. Corresponding geometric mean titers (GMTs) were 2.4-5.8-fold higher for HPV-16 and 7.7-9.4-fold higher for HPV-18 with the HPV-16/18 vaccine versus the HPV-6/11/16/18 vaccine; HPV-16 and HPV-18 GMTs were significantly higher with the HPV-16/18 vaccine than the HPV-6/11/16/18 vaccine (p< 0.0001) in the total vaccinated cohort (received ≥1 vaccine dose, irrespective of baseline sero/DNA-status). Similar results were obtained using enzyme-linked immunosorbent assay (ELISA). Positivity rates and GMTs of antigen-specific IgG antibodies in cervicovaginal secretions (ELISA) were not significantly different between vaccines. At Month 24, CD4⁺ T-cell responses for HPV-16 and HPV-18 were higher with the HPV-16/18 vaccine; memory B-cell response was higher for HPV-18 with the HPV-16/18 vaccine and similar between vaccines for HPV-16. Both vaccines were generally well tolerated. Although an immunological correlate of protection has not been defined, differences in the magnitude of immune response between vaccines may represent determinants of duration of protection.
    Human vaccines 12/2011; 7(12):1343-58. · 3.14 Impact Factor
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    ABSTRACT: We evaluated the efficacy of the human papillomavirus HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types in the end-of-study analysis after 4 years of follow-up in PATRICIA (PApilloma TRIal against Cancer In young Adults). Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to HPV-16/18 vaccine or a control hepatitis A vaccine, via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The study was double-blind. The primary endpoint of PATRICIA has been reported previously; the present analysis evaluates cross-protective vaccine efficacy against non-vaccine oncogenic HPV types in the end-of-study analysis. Analyses were done for three cohorts: the according-to-protocol cohort for efficacy (ATP-E; vaccine n=8067, control n=8047), total vaccinated HPV-naive cohort (TVC-naive; no evidence of infection with 14 oncogenic HPV types at baseline, approximating young adolescents before sexual debut; vaccine n=5824, control n=5820), and the total vaccinated cohort (TVC; all women who received at least one vaccine dose, approximating catch-up populations that include sexually active women; vaccine n=9319, control=9325). Vaccine efficacy was evaluated against 6-month persistent infection, cervical intraepithelial neoplasia grade 2 or greater (CIN2+) associated with 12 non-vaccine HPV types (individually or as composite endpoints), and CIN3+ associated with the composite of 12 non-vaccine HPV types. This study is registered with, number NCT00122681. Consistent vaccine efficacy against persistent infection and CIN2+ (with or without HPV-16/18 co-infection) was seen across cohorts for HPV-33, HPV-31, HPV-45, and HPV-51. In the most conservative analysis of vaccine efficacy against CIN2+, where all cases co-infected with HPV-16/18 were removed, vaccine efficacy was noted for HPV-33 in all cohorts, and for HPV-31 in the ATP-E and TVC-naive. Vaccine efficacy against CIN2+ associated with the composite of 12 non-vaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), with or without HPV-16/18 co-infection, was 46·8% (95% CI 30·7-59·4) in the ATP-E, 56·2% (37·2-69·9) in the TVC-naive, and 34·2% (20·4-45·8) in the TVC. Corresponding values for CIN3+ were 73·8% (48·3-87·9), 91·4% (65·0-99·0), and 47·5% (22·8-64·8). Data from the end-of-study analysis of PATRICIA show cross-protective efficacy of the HPV-16/18 vaccine against four oncogenic non-vaccine HPV types-HPV-33, HPV-31, HPV-45, and HPV-51-in different trial cohorts representing diverse groups of women. GlaxoSmithKline Biologicals.
    The Lancet Oncology 11/2011; 13(1):100-10. · 25.12 Impact Factor
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    ABSTRACT: Cervical intraepithelial neoplasia grade 2 or greater (CIN2+) is the surrogate endpoint used in licensure trials of human papillomavirus (HPV) vaccines. Vaccine efficacy against CIN3+, the immediate precursor to invasive cervical cancer, is more difficult to measure because of its lower incidence, but provides the most stringent evidence of potential cancer prevention. We report vaccine efficacy against CIN3+ and adenocarcinoma in situ (AIS) in the end-of-study analysis of PATRICIA (PApilloma TRIal against Cancer In young Adults). Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA, irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to receive an HPV-16/18 AS04-adjuvanted vaccine or a control hepatitis A vaccine via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The patients and study investigators were masked to allocated vaccine. The primary endpoint of PATRICIA has been reported previously. In the present end-of-study analysis, we focus on CIN3+ and AIS in the populations of most clinical interest, the total vaccinated cohort (TVC) and the TVC-naive. The TVC comprised all women who received at least one vaccine dose, approximating catch-up populations and including sexually active women (vaccine n=9319; control=9325). The TVC-naive comprised women with no evidence of oncogenic HPV infection at baseline, approximating early adolescent HPV exposure (vaccine n=5824; control=5820). This study is registered with, number NCT00122681. Vaccine efficacy against CIN3+ associated with HPV-16/18 was 100% (95% CI 85·5-100) in the TVC-naive and 45·7% (22·9-62·2) in the TVC. Vaccine efficacy against all CIN3+ (irrespective of HPV type in the lesion and including lesions with no HPV DNA detected) was 93·2% (78·9-98·7) in the TVC-naive and 45·6% (28·8-58·7) in the TVC. In the TVC-naive, vaccine efficacy against all CIN3+ was higher than 90% in all age groups. In the TVC, vaccine efficacy against all CIN3+ and CIN3+ associated with HPV-16/18 was highest in the 15-17 year age group and progressively decreased in the 18-20 year and 21-25 year age groups. Vaccine efficacy against all AIS was 100% (31·0-100) and 76·9% (16·0-95·8) in the TVC-naive and TVC, respectively. Serious adverse events occurred in 835 (9·0%) and 829 (8·9%) women in the vaccine and control groups, respectively; only ten events (0·1%) and five events (0·1%), respectively, were considered to be related to vaccination. PATRICIA end-of-study results show excellent vaccine efficacy against CIN3+ and AIS irrespective of HPV DNA in the lesion. Population-based vaccination that incorporates the HPV-16/18 vaccine and high coverage of early adolescents might have the potential to substantially reduce the incidence of cervical cancer. GlaxoSmithKline Biologicals.
    The Lancet Oncology 11/2011; 13(1):89-99. · 25.12 Impact Factor
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    ABSTRACT: In the Phase III PATRICIA study (NCT00122681), the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix(®), GlaxoSmithKline Biologicals) was highly efficacious against HPV-16/18 infections and precancerous lesions in women HPV-16/18 deoxyribose nucleic acid (DNA) negative and seronegative at baseline. We present further data on vaccine efficacy (VE) against HPV-16/18 in the total vaccinated cohort including women who may have been exposed to HPV-16/18 infection before vaccination. In women with no evidence of current or previous HPV-16/18 infection (DNA negative and seronegative), VE was 90.3% (96.1% confidence interval: 87.3-92.6) against 6-month persistent infection (PI), 91.9% (84.6-96.2) against cervical intraepithelial neoplasia (CIN)1+ and 94.6% (86.3-98.4) against CIN2+ [97.7% (91.1-99.8) when using the HPV type assignment algorithm (TAA)]. In women HPV-16/18 DNA negative but with serological evidence of previous HPV-16/18 infection (seropositive), VE was 72.3% (53.0-84.5) against 6-month PI, 67.2% (10.9-89.9) against CIN1+, and 68.8% (-28.3-95.0) against CIN2+ [88.5% (10.8-99.8) when using TAA]. In women with no evidence of current HPV-16/18 infection (DNA negative), regardless of their baseline HPV-16/18 serological status, VE was 88.7% (85.7-91.1) against 6-month PI, 89.1% (81.6-94.0) against CIN1+ and 92.4% (84.0-97.0) against CIN2+ [97.0% (90.6-99.5) when using TAA]. In women who were DNA positive for one vaccine type, the vaccine was efficacious against the other vaccine type. The vaccine did not impact the outcome of HPV-16/18 infections present at the time of vaccination. Vaccination was generally well tolerated regardless of the woman's HPV-16/18 DNA or serological status at entry.
    International Journal of Cancer 08/2011; 131(1):106-16. · 6.20 Impact Factor
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    ABSTRACT: 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. 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. 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. 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.
    The Pediatric Infectious Disease Journal 08/2011; 30(12):e225-34. · 3.57 Impact Factor
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    ABSTRACT: To determine the prevalence of cervical human papillomavirus (HPV) infection and risk factors in young women from Brazil, Canada, and the USA. Cross-sectional study in 3204 healthy women, aged 15 to 25 years. Cervical samples were collected for cytology and for HPV DNA detection (SPF 10-LiPA 25 system). Serum samples were collected for the measurement of HPV-16 and HPV-18 antibodies by enzyme-linked immunosorbent assay. Risk factors were obtained through a questionnaire. Overall, 26.6% of women had DNA detected for at least 1 HPV type. The prevalence for oncogenic HPV types was 21.7% (25% in Brazil, 16.9% in Canada, and 19.1% in the USA). HPV-16 was the most prevalent oncogenic type (5.2%). The next most common oncogenic HPV types were 51 (3.3%), 52 (3.3%), 31 (2.9%), 66 (2.3%), and 39 (2.0%). Multiple oncogenic types were detected in one-third of the infections. The prevalence of HPV-16 and/or HPV-18 infections detected by DNA and/or enzyme-linked immunosorbent assay was 24.8%. The majority of women (85%) had a normal cervical cytology. Sexual behavior was the main determinant for HPV-16/18 infections and squamous intraepithelial lesions. The prevalence of HPV oncogenic infections was high and linked to sexual behavior. Strategies to reduce the burden of oncogenic HPV infection, such as prophylactic vaccination programs, are likely to impact the burden of disease due to cervical precancer and cancer.
    International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 03/2011; 30(2):173-84. · 2.07 Impact Factor
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    ABSTRACT: This pooled analysis of data from four Phase III clinical trials was undertaken to assess the correlation between levels of anti-human papillomavirus (HPV)-16/18 antibodies in serum and cervicovaginal secretions (CVS) in girls and women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine. Serum and CVS samples were collected from a subset of women aged 10-65 years (N=350) at pre-specified time-points from 7 to 36 months post-vaccination. Anti-HPV-16/18 antibody levels in serum and CVS were measured by enzyme-linked immunosorbent assay. Pearson correlation coefficients between serum and CVS antibody levels, standardized for total immunoglobulin G, were calculated at each time-point in women with detectable antibodies in both serum and CVS. All subjects had seroconverted at Month 7 and remained seropositive through Month 36 for both antigens. Geometric mean titers of anti-HPV-16/18 antibodies in serum were substantially higher at all time-points than those in a control group of women who had cleared a natural HPV infection in another trial. In women with detectable antibodies in both serum and CVS, good correlation was seen between HPV-16/18 antibody levels at all time-points (Pearson correlation coefficient: 0.84-0.92 for HPV-16 and 0.90-0.91 for HPV-18). The strong correlation between levels of HPV-16/18 antibodies in serum and CVS up to 36 months post-vaccination in girls and women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine supports transudation of serum antibodies as the mechanism by which antibodies are introduced into CVS. These CVS antibodies may play a role in the protective efficacy of this vaccine.
    Human vaccines 12/2010; 6(12):1054-61. · 3.14 Impact Factor

Publication Stats

5k Citations
507.17 Total Impact Points


  • 2013
    • Universitair Ziekenhuis Ghent
      • Centre for Vaccinology (CEVAC)
      Gent, VLG, Belgium
  • 2011–2013
    • Queen Mary, University of London
      • Centre for Cancer Prevention
      London, ENG, United Kingdom
    • Secretariat of Health, Sao Paulo
      San Paulo, São Paulo, Brazil
  • 2012
    • GlaxoSmithKline plc.
      Londinium, England, Belgium
  • 2009–2011
    • Albert Einstein College of Medicine
      • Department of Obstetrics & Gynecology & Women's Health
      New York City, NY, United States
    • University of Tampere
      • Department of Public Health
      Tampere, Western Finland, Finland
  • 2010
    • Hospital Universitario La Paz
      Madrid, Madrid, Spain
  • 2008–2010
    • Stiftung Juliusspital Würzburg
      Würzburg, Bavaria, Germany
  • 2007–2009
    • University of Helsinki
      • Department of Obstetrics and Gynaecology
      Helsinki, Province of Southern Finland, Finland
    • Odense University Hospital
      Odense, South Denmark, Denmark
  • 2006
    • Dartmouth College
      • Department of Obstetrics & Gynecology
      Hanover, NH, United States
  • 2005
    • University of Cincinnati
      Cincinnati, Ohio, United States
  • 2004
    • Geisel School of Medicine at Dartmouth
      • Department of Obstetrics and Gynecology
      Hanover, New Hampshire, United States
    • Saint Louis University
      • Department of Internal Medicine
      Saint Louis, MI, United States
  • 2002
    • University of Texas Medical Branch at Galveston
      Galveston, Texas, United States