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
Article Outline
Abstract
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 (≥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.
Keywords: Randomized controlled trial, Papillomavirus vaccines, Diphtheria-tetanus-acellular pertussis–inactivated poliovirus vaccine, Adolescent, Female, Immunology, Adverse effects
Cervical cancer is the second most common cancer affecting women [1], [2], and there is strong evidence that persistent infection with an oncogenic human papillomavirus (HPV) type is a necessary step in the pathogenesis of this disease [3], [4], [5]. The risk of HPV infection starts from the onset of sexual activity and continues throughout a woman's sexually active life; the acquisition of infection with oncogenic HPV types is highest in adolescent girls [6], [7]. Two prophylactic vaccines against oncogenic HPV infections have now been licensed [8], [9], [10], and immunization is generally recommended for girls in their early adolescence [11], [12].
In countries where an infrastructure for pediatric vaccination exists, it is likely that HPV vaccination will complement the current preadolescent or adolescent vaccination platform. Administration of the HPV vaccine with other routinely recommended vaccines would offer convenience for both the adolescent and the healthcare provider and would ensure optimal compliance. Therefore, it is pertinent to study the coadministration of HPV vaccines with other routinely used vaccines in this age group.
Our study was designed to evaluate coadministration of the HPV-16/18 AS04-adjuvanted vaccine [8] with a combined reduced-antigen content diphtheria-tetanus-acellular pertussis–inactivated poliovirus vaccine (dTpa-IPV) [13], [14]. The HPV-16/18 AS04-adjuvanted vaccine has been shown to be generally well-tolerated [15], immunogenic and efficacious against incident and persistent HPV-16/18 infections and associated cervical lesions for up to 6.4 years after vaccination [16], [17], [18], [19], [20].
Methods
Study participants and ethics
The study was carried out from February 2007 to March 2008 at 35 sites in France, Germany, and Spain. Healthy girls and young women aged 10–18 years were eligible if they were of non-childbearing potential or abstinent from sexual activity, or were using adequate contraceptive precautions, had a negative pregnancy test, and were not breastfeeding. Participants had to have completed routine childhood vaccinations against diphtheria, tetanus, pertussis, and poliomyelitis diseases, according to the recommended vaccination schedule in their country. Subjects were excluded if they had previously received HPV vaccine, 3-O-desacyl-4′-monophosphoryl lipid A or AS04; had received diphtheria, tetanus, pertussis vaccine, diphtheria-tetanus booster or dTpa vaccine, and/or oral or inactivated poliovirus vaccine within the previous 5 years; had known exposure to diphtheria or household exposure to pertussis, or diphtheria, tetanus, pertussis, or polio diagnosed within 30 days before vaccination.
Participants below the legal age of consent signed and dated a written informed assent and informed consent was obtained from their parents or legally acceptable representative(s) prior to the performance of any study specific procedures. Participants above the legal age of consent (≥18 years) provided written informed consent themselves. Each center's Ethical Review Committee approved the protocol and consent forms. This trial is registered with ClinicalTrials.gov (number NCT00426361).
Study design
This was an open study with 3 parallel groups. Participants were randomized (1:1:1) to receive HPV-16/18 AS04-adjuvanted vaccine alone at months 0, 1, and 6 (HPV group), HPV-16/18 AS04-adjuvanted vaccine coadministered with dTpa-IPV at month 0 and HPV-16/18 AS04-adjuvanted vaccine at months 1 and 6 (HPV+dTpa-IPV group), or dTpa-IPV alone at month 0 (dTpa-IPV group); in this dTpa-IPV group subjects were subsequently administered the HPV-16/18 AS04-adjuvanted vaccine at months 1, 2, and 7, so that all study participants were provided with the full benefit of HPV vaccination. A randomization list was generated at GlaxoSmithKline Biologicals (Rixensart, Belgium) using a standard program (SAS Institute, Cary, NC). Treatment allocation at the investigator site was performed using a central randomization system.
Study objectives
The primary objective was to demonstrate noninferiority of the dTpa-IPV immune response 1 month after the first vaccine dose when dTpa-IPV was coadministered with HPV-16/18 AS04-adjuvanted vaccine, compared to dTpa-IPV alone. The secondary objective was to demonstrate noninferiority of the HPV-16/18 immune response 1 month after the third HPV-16/18 AS04-adjuvanted vaccine dose when coadministered, compared to HPV-16/18 AS04-adjuvanted vaccine alone. Other objectives included evaluation of the booster response to dTpa-IPV 1 month after the first vaccine dose and vaccine safety.
Study vaccines
Each dose of HPV-16/18 AS04-adjuvanted vaccine (Cervarix, GlaxoSmithKline Biologicals) contained 20 μg each of HPV-16 and HPV-18 L1 protein, adjuvanted with AS04 (500 μg aluminum hydroxide and 50 μg 3-O-desacyl-4′-monophosphoryl lipid A), as described previously [16], [17], [18], [19]. Each dose of dTpa-IPV (Boostrix-IPV, GlaxoSmithKline Biologicals) contained ≥2 international units (IU) of diphtheria toxoid, ≥20 IU/mL tetanus toxoid, 8 μg pertussis toxoid, 8 μg filamentous hemagglutinin, 2.5 μg pertactin, and 40 D, 8 D, and 32 D of inactivated poliovirus types 1, 2, and 3, as described previously [14]. The HPV-16/18 AS04-adjuvanted vaccine was administered in three doses (.5 mL each dose) at months 0, 1, and 6 in the HPV and HPV+dTpa-IPV groups and at months 1, 2, and 7 in the dTpa-IPV group. The dTpa-IPV vaccine was administered as one dose (.5 mL) at month 0 in the HPV+dTpa-IPV and dTpa-IPV groups. When vaccines were administered alone they were given intramuscularly into the deltoid muscle of the nondominant arm. When vaccines were coadministered they were given in opposite arms (nondominant arm for dTpa-IPV and dominant arm for HPV-16/18 vaccine).
Serologic evaluation
Blood samples were collected from each participant before (month 0) and 1 month after the first vaccine dose (month 1), and 1 month after the third HPV-16/18 AS04-adjuvanted vaccine dose (month 7/8 depending on group), to evaluate immunogenicity. All serological assays were performed at a central laboratory, by personnel unaware of the study data.
The dTpa-IPV immune response was evaluated in terms of antibodies to diphtheria toxoid (anti-D), tetanus toxoid (anti-T), pertussis toxoid (anti-PT), pertactin (anti-PRN), filamentous hemagglutinin (anti-FHA), and poliomyelitis virus types 1, 2, and 3 (anti-polio types 1, 2, and 3) using standard techniques [21], [22]. Assay cut-offs were 0.1 IU/mL for anti-D and anti-T, 5 ELISA (enzyme-linked immunosorbent assay) units (EU)/mL for anti-PT, anti-FHA, and anti-PRN, and a neutralization titer of 1:8 for anti-polio types 1, 2, and 3. For anti-D, anti-T, and anti-polio types 1, 2, and 3, concentrations/titers greater than or equal to the assay threshold were considered to be indicative of seroprotection. As there is no established correlate of protection against pertussis, seropositivity was defined as a concentration greater than or equal to the assay threshold (≥5 EU/mL) for anti-PT, anti-FHA, and anti-PRN.
Anti-D and anti-T booster responses, for subjects with prevaccination concentrations <0.1 or ≥0.1 IU/mL, were defined as postvaccination concentrations ≥0.4 IU/mL or ≥4-fold increase, respectively. Anti-PT, anti-PRN, and anti-FHA booster responses, for subjects with prevaccination concentrations <5 EU/mL, ≥5 to <20 EU/mL, or ≥20 EU/mL, were defined as postvaccination concentrations ≥20 EU/mL, ≥4-fold increase, or ≥2-fold increase, respectively.
Anti-HPV-16 and HPV-18 antibodies were measured using a type-specific ELISA [16], [23]; seropositivity was defined as a titer greater than or equal to the assay threshold established at 8 ELISA Units/mL (EU/mL) for HPV-16 and 7 EU/mL for HPV-18. This ELISA was shown to have a high degree of sensitivity and correlation with a pseudovirion-based neutralization assay [23].
Vaccine safety
Solicited local symptoms at the injection site and general symptoms were recorded by the participant or her parent/legally acceptable representative for 7 days after each vaccine dose, using a diary card. In addition, urticaria or rash within 30 minutes of each vaccine dose was documented by the investigator.
Unsolicited signs and symptoms were reported within 30 days after each vaccine dose. Serious adverse events, new onset chronic diseases (e.g., autoimmune disorders, asthma, type I diabetes, allergies, etc.), other medically significant conditions (adverse events prompting a visit to the physician or emergency room, or serious adverse events, that were not related to common diseases), and pregnancies, were reported throughout the entire study period; pregnancies were followed up until delivery.
Statistical analysis
For anti-D and anti-T responses [24], non-inferiority was demonstrated if 1 month after the dTpa-IPV dose the upper limit of the 95% confidence interval (CI) for the difference in the percentage of subjects with antibody concentration ≥0.1 IU/mL (dTpa-IPV group minus HPV+dTpa-IPV group) was below the predefined clinical limit of 5%. For anti-PT, anti-FHA, and anti-PRN responses [25], noninferiority was demonstrated if the upper limit of the 95% CI for the geometric mean concentration (GMC) ratio (dTpa-IPV group divided by HPV+dTpa-IPV group) was below the predefined clinical limit of 2 (i.e., <2-fold difference in GMCs). For anti-polio type 1, 2, and 3 responses [24], non-inferiority was demonstrated if the upper limit of the 95% CI for the difference in the percentage of subjects with an antibody titer ≥8 (dTpa-IPV group minus HPV+dTpa-IPV group) was below the predefined clinical limit of 5%.
For anti-HPV-16 and anti-HPV-18 responses [26], [27], noninferiority was demonstrated if 1 month after the third dose of HPV-16/18 AS04-adjuvanted vaccine the upper limit of the 95% CI for the difference between the seroconversion rates (HPV group minus HPV+dTpa-IPV group) was less than the predefined clinical limit of 5%, and if the upper limit of the 95% CI for the geometric mean titer (GMT) ratio (HPV vaccine group divided by HPV+dTpa-IPV group) was less than the predefined clinical limit of 2 (i.e., <2-fold difference in GMTs). Tests were performed sequentially.
Statistical inferences were not made with regard to other secondary objectives, including dTpa booster responses and safety endpoints.
It was estimated that seroprotection rates for anti-D, anti-T, and anti-polio types 1, 2, and 3 would be 99% and standard deviations for GMC ratios for anti-FHA, anti-PRN, and anti-PT would be 0.4, 0.6, and 0.4, respectively. Based on these assumptions, enrollment of 750 subjects (to provide 235 evaluable subjects per group at month 1 assuming that up to 5% would be nonevaluable) would provide at least 98% power for evaluation of noninferiority for each of the individual components of the dTpa-IPV immune response (anti-D, anti-T, anti-FHA, anti-PRN, anti-PT, and anti-polio types 1, 2, and 3) and power for the evaluation of the primary objective globally of 91%. This sample size would also provide 210 evaluable subjects per group at month 7 (assuming that up to 15% would be nonevaluable) for evaluation of the secondary objective of noninferiority of the HPV-16/18 immune response with a global power of 92%. All sample size calculations were done with Pass 2000.
The two-sided confidence intervals for the ratio of GMCs/GMTs were computed using an analysis of covariance model on log10 transformed titers. The analysis of covariance model included the vaccine group as fixed effect and the prevaccination titer as regressor. Antibody concentrations below the assay cut-off were given an arbitrary value of half the cut-off for the purpose of GMC/GMT calculation.
Immunogenicity analyses were based on the according-to-protocol (ATP) cohort, which included all evaluable subjects (i.e., those meeting all eligibility criteria, complying with the procedures defined in the protocol, with no elimination criteria during the study) for whom assay results were available for antibodies against at least one vaccine antigen after vaccination. Analyses of anti-HPV-16 and anti-HPV-18 responses were stratified by initial serological status, with the analysis of subjects initially seronegative at baseline for the corresponding antigen being considered the primary analysis. Two ATP immunogenicity cohorts were defined: month 1 cohort for the primary immunogenicity objective and month 7 or 8 cohort for the secondary immunogenicity objective.
Safety analyses were based on the total vaccinated cohort for safety (all vaccinated subjects for whom data were available). Incidence rates of symptoms after each dose were tabulated with exact 95% CI for each group; missing or nonevaluable measurements were not replaced and included only subjects with documented safety data (i.e., symptom sheet completed) per dose.
Statistical analyses were performed with SAS version 9.1.3 (SAS Institute, Cary, NC) and ProcStatXact 7.0 (Cytel Inc, Cambridge, MA).
Results
A total of 751 girls and young women were enrolled and received at least one dose of vaccine (Figure 1). The majority received all scheduled doses of vaccine (at least 98% in all groups). In total, 739 subjects completed the study and 12 withdrew (none withdrew due to an adverse event); 702 and 655 subjects, respectively, were included in the month 1 and month 7/8 ATP immunogenicity cohorts. The mean age of subjects was approximately 14 years in each group and more than 94% of subjects in each group were Caucasian/European ethnic heritage (Table 1).
Figure 1
Flow of participants through study. The month 1 ATP cohort was used for analysis of the dTpa-IPV immune response 1 month after the first vaccine dose. The month 7 or 8 ATP cohort was used for analysis of the HPV-16/HPV-18 immune response 1 month after the third vaccine dose. ATP = according-to-protocol; HPV group = HPV-16/18 AS04-adjuvanted vaccine at months 0, 1, and 6; HPV+dTpa-IPV group = dTpa-IPV at month 0 and HPV-16/18 AS04-adjuvanted vaccine at Months 0, 1, and 6; dTpa-IPV group = dTpa-IPV at month 0 and HPV-16/18 AS04-adjuvanted vaccine at Months 1, 2, and 7.
Table 1. Summary of demographic characteristics
| HPV N = 248 | HPV+dTpa-IPV N = 255 | dTpa-IPV N = 248 | |
|---|---|---|---|
| Mean (SD) age (yr) | 13.9 (2.59) | 14.0 (2.43) | 13.9 (2.47) |
| Ethnic origin, n (%) | |||
 Caucasian/European Heritage | 233 (94.0) | 244 (95.7) | 236 (95.2) |
| Arabic/North African Heritage | 7 (2.8) | 8 (3.1) | 5 (2.0) |
| African Heritage/African American | 3 (1.2) | 0 (0.0) | 3 (1.2) |
| East Asian Heritage | 1 (.4) | 0 (0.0) | 1 (0.4) |
| South East Asian Heritage | 1 (.4) | 1 (0.4) | 0 (0.0) |
| Other | 3 (1.2) | 2 (0.8) | 3 (1.2) |
dTpa-IPV immunogenicity
Noninferiority of dTpa-IPV responses was demonstrated at month 1 when dTpa-IPV was coadministered with the HPV-16/18 AS04-adjuvanted vaccine, compared to dTpa-IPV administered alone, in terms of seroprotection rates for anti-D, anti-T, and anti-poliovirus types 1, 2, and 3, and group GMC ratios for anti-PT, anti-FHA, and anti-PRN (Table 2). For each antibody response the upper limit of the 95% CI for the difference in seroprotection rates or ratio of GMCs was below the predefined noninferiority criteria.
Table 2. Assessment of non-inferiority of dTpa-IPV immune response and HPV-16/18 immune response (ATP cohorts for immunogenicity)
| Antibody | dTpa-IPV Group | HPV+dTpa-IPV Group | Comparison | ||
|---|---|---|---|---|---|
| dTpa-IPV immune response 1 month after first vaccine dose | |||||
| Seroprotection rate (95% CI) | Difference (%) | LL | UL | ||
| Anti-D | n = 233 | n = 240 | 0.83 | −.80 | 2.99a |
| 100% (98.4, 100) | 99.2% (97.0, 99.9) | ||||
| Anti-T | n = 233 | n = 240 | 0.00 | −1.63 | 1.58a |
| 100% (98.4, 100) | 100% (98.5, 100) | ||||
| GMC (EU/mL) (95% CI) | GMC ratio | LL | UL | ||
| Anti-PT | n = 229 | n = 238 | 0.90 | 0.74 | 1.09a |
| 75.4 (65.6, 86.8) | 84.2 (73.6, 96.4) | ||||
| Anti-FHA | n = 233 | n = 240 | 1.01 | 0.87 | 1.16a |
| 615.2 (552.3, 685.2) | 611.7 (553.6, 675.9) | ||||
| Anti-PRN | n = 233 | n = 239 | 0.84 | 0.67 | 1.07a |
| 360.0 (299.3, 433.1) | 426.2 (368.1, 493.4) | ||||
| Seroprotection rate (95% CI) | Difference (%) | LL | UL | ||
| Anti-polio 1 | n = 231 | n = 240 | 0.42 | −1.23 | 2.33a |
| 100% (98.4, 100) | 99.6% (97.7, 100) | ||||
| Anti-polio 2 | n = 232 | n = 240 | .00 | −1.63 | 1.58a |
| 100% (98.4, 100) | 100% (98.5, 100) | ||||
| Anti-polio 3 | n = 232 | n = 239 | .00 | −1.63 | 1.59a |
| 100% (98.4, 100) | 100% (98.5, 100) | ||||
| HPV-16/HPV-18 immune response 1 month after third vaccine dose | |||||
| Seroconversion rate (95% CI) | Difference (%) | LL | UL | ||
| Anti-HPV-16 | n = 198 | n = 202 | .50 | −1.42 | 2.76a |
| 100% (98.2, 100) | 99.5% (97.3, 100) | ||||
| Anti-HPV-18 | n = 191 | n = 204 | .49 | −1.49 | 2.73a |
| 100% (98.1, 100) | 99.5% (97.3, 100) | ||||
| GMT (EU/mL) (95% CI) | GMT ratio | LL | UL | ||
| Anti-HPV-16 | n = 198 | n = 202 | 1.22 | 1.00 | 1.47a |
| 18965.1 (16849.0, 21346.8) | 15608.0 (13450.4, 18111.8) | ||||
| Anti-HPV-18 | n = 191 | n = 204 | 1.05 | 0.86 | 1.27a |
| 6902.4 (6060.6, 7861.1) | 6596.8 (5694.0, 7642.9) | ||||
aNoninferior. Anti-D and anti-T: upper limit of 95% confidence interval for difference in seroprotection rate (i.e., antibody concentration ≥.1 IU/mL) (dTpa-IPV group minus HPV+dTpa-IPV group) <5%. Anti-PT. Anti-FHA and anti-PRN: upper limit of 95% confidence interval for the GMC ratio (dTpa-IPV group divided by HPV+dTpa-IPV group) <2. Anti-polio types 1, 2, and 3: upper limit of 95% confidence interval for difference in seroprotection rate (antibody titer ≥8) (dTpa-IPV group minus HPV+dTpa-IPV group) <5%. Anti-HPV-16/HPV-18: upper limit of 95% confidence interval for difference in seroconversion rate (i.e., HPV-16 titer ≥8 EU/mL or HPV-18 titer ≥7 EU/mL) (HPV group minus HPV+dTpa-IPV group) <5% and upper limit of 95% confidence interval for the GMT ratio (HPV group divided by HPV+dTpa-IPV group) <2; seroconversion rates and GMT ratios were tested sequentially. |
Seroprotection rates for anti-D were 100% in the dTpa-IPV group and 99.2% in the HPV+dTpa-IPV group, and 100% for anti-T in both groups. Seroprotection rates for anti-polio type 1 were 100% in the dTpa-IPV group and 99.6% in the HPV+dTpa-IPV group, and 100% for anti-polio type 2 and anti-polio type 3 in both groups. With regard to the pertussis immune response, GMCs in the dTpa-IPV and HPV+dTpa-IPV groups were respectively 75.4 and 84.2 EU/mL for anti-PT antibodies, 615.2 and 611.7 EU/mL for anti-FHA antibodies, and 360.0 and 426.2 EU/mL for anti-PRN antibodies.
dTpa-IPV booster responses 1 month after vaccination appeared similar in HPV+dTpa-IPV and dTpa-IPV groups (66.7% and 68.5% for anti-D, 69.6% and 69.4% for anti-T, 84.3% and 79.8% for anti-PT, 89.4% and 90.7% for anti-FHA, and 93.3% and 90.0% for anti-PRN).
HPV-16/18 immunogenicity
Prior to vaccination, the percentage of girls and young women seropositive for HPV-16 or HPV-18 antibodies was comparable across all three groups: prevaccination in the HPV, HPV+dTpa-IPV, and dTpa-IPV groups, 7.0%, 9.0%, and 6.4% of subjects were seropositive for HPV-16 and 9.0%, 6.4%, and 6.0% of subjects were seropositive for HPV-18, respectively.
Noninferiority of the HPV-16/18 immune response 1 month after the third vaccine dose was demonstrated for both HPV-16 and HPV-18, in terms of seroconversion rates and group GMT ratios in initially seronegative subjects, when dTpa-IPV was coadministered with the HPV-16/18 AS04-adjuvanted vaccine, compared to HPV-16/18 AS04-adjuvanted vaccine administered alone (Table 2). For each antibody response the upper limit of the 95% CI for the difference in seroprotection rates or ratio of GMTs was well below the predefined noninferiority criteria.
Seroconversion rates in the HPV group and HPV+dTpa-IPV group were 100% and 99.5%, respectively, for both anti-HPV-16 and anti-HPV-18 antibodies; GMTs (95% CIs) at month 7 were 18965.1 EU/mL (16849.0, 21346.8) and 15608.0 EU/mL (13450.4, 18111.8) for anti-HPV-16 antibodies and 6902.4 EU/mL (6060.6, 7861.1) and 6596.8 EU/mL (5694.0, 7642.9) for anti-HPV-18 antibodies.
Administration of dTpa-IPV followed by administration of the HPV-16/18 AS04-adjuvanted vaccine at months 1, 2, and 7 tended to elicit lower anti-HPV-16 and anti-HPV-18 GMTs (Figure 2). GMTs (95% CIs) for initially seronegative subjects in this group at month 8 were 14214.1 EU/mL (12556.6, 16090.4) for anti-HPV-16 and 5147.4 EU/mL (4521.9, 5859.5) for anti-HPV-18.
Figure 2
Immune response to HPV-16/18 AS04-adjuvanted vaccine 1 month after the third vaccine dose in initially seronegative girls and young women (month 7/8 ATP cohort for immunogenicity). Bars show geometric mean titer (GMT) and associated 95% confidence interval. Seroconversion (%) shown within the bars. Blue solid lines represent GMTs for peak antibody levels 1 month after the third vaccine dose for HPV-16 (9341.5 EU/mL [95% CI: 8760.4, 9961.1]) and HPV-18 (4769.6 EU/mL [95% CI: 4491.2, 5065.3]) in a phase 3 efficacy study [19]. Red dashed lines represent GMTs for natural infection antibody levels in women who had cleared HPV-16 infection (29.8 [95% CI: 28.5, 31.0] EU/mL) or HPV-18 infection (22.6 [95% CI: 21.6, 23.6] EU/mL) in a phase 3 efficacy study [19]. HPV group = HPV-16/18 AS04-adjuvanted vaccine at months 0, 1, and 6; HPV+dTpa-IPV group = dTpa-IPV at month 0 and HPV-16/18 AS04-adjuvanted vaccine at months 0, 1, and 6; dTpa-IPV group = dTpa-IPV at month 0 and HPV-16/18 AS04-adjuvanted vaccine at months 1, 2, and 7.
In all three groups, GMTs for both HPV-16 and 18 antibodies were at least as high as peak levels observed 1 month after the third vaccine dose in a Phase 3 efficacy study conducted in girls and young women aged 15–25 years [19] (Figure 2). GMTs in the current study were also higher than GMTs observed previously in subjects who had cleared a natural infection [19] (Figure 2).
Safety
Compliance in returning symptom sheets was high (>99% for all groups). After the first dose, the frequency of solicited local symptoms at the injection site during the 7-day follow-up period appeared similar for the HPV-16/18 AS04-adjuvanted vaccine compared with dTpa-IPV, and did not appear to increase when the vaccines were coadministered (Table 3). Pain at the injection site was the most frequently solicited local symptom, with an incidence of 81%–85% for HPV-16/18 AS04-adjuvanted vaccine and for dTpa-IPV. The incidence of grade 3 pain at the injection site after the first dose was <6.5% for both vaccines. No urticaria or rash was reported within 30 minutes after vaccination dose in any group. There was no evidence that the incidence of solicited local symptoms increased with subsequent doses.
Table 3. Solicited local and general symptoms during the 7-day follow-up after the first vaccine dose (total vaccinated cohort)
| HPV | HPV+dTpa-IPV | dTpa-IPV | ||||||
|---|---|---|---|---|---|---|---|---|
| N = 253 for HPV Vaccine | ||||||||
| N = 246 for HPV Vaccine | N = 252 for dTpa-IPV | N = 247 for dTpa-IPV | ||||||
| Symptom | Injection site | Intensity | n | % (95% CI) | n | % (95% CI) | n | % (95% CI) |
| Local symptoms | ||||||||
| Pain | HPV vaccine | All | 209 | 85.0 (79.9, 89.2) | 214 | 84.6 (79.5, 88.8) | ||
| Grade 3a | 15 | 6.1 (3.5, 9.9) | 16 | 6.3 (3.7, 10.1) | ||||
| dTpa-IPV vaccine | All | 205 | 81.3 (76.0, 86.0) | 207 | 83.8 (78.6, 88.2) | |||
| Grade 3a | 16 | 6.3 (3.7, 10.1) | 11 | 4.5 (2.2, 7.8) | ||||
| Redness | HPV vaccine | All | 69 | 28.0 (22.5, 34.1) | 74 | 29.2 (23.7, 35.3) | ||
| >50 mm | 2 | 0.8 (0.1, 2.9) | 3 | 1.2 (0.2, 3.4) | ||||
| dTpa-IPV vaccine | All | 65 | 25.8 (20.5, 31.7) | 83 | 33.6 (27.7, 39.9) | |||
| >50 mm | 7 | 2.8 (1.1, 5.6) | 5 | 2.0 (0.7, 4.7) | ||||
| Swelling | HPV vaccine | All | 62 | 25.2 (19.9, 31.1) | 60 | 23.7 (18.6, 29.4) | ||
| >50 mm | 4 | 1.6 (0.4, 4.1) | 3 | 1.2 (0.2, 3.4) | ||||
| dTpa-IPV vaccine | All | 64 | 25.4 (20.1, 31.2) | 75 | 30.4 (24.7, 36.5) | |||
| >50 mm | 5 | 2.0 (0.6, 4.6) | 6 | 2.4 (0.9, 5.2) | ||||
| General symptoms | ||||||||
| Arthralgia | All | 32 | 13.0 (9.1, 17.9) | 44 | 17.4 (12.9, 22.6) | 33 | 13.4 (9.4, 18.2) | |
| Grade 3a | 0 | 0.0 (0.0, 1.5) | 3 | 1.2 (0.2, 3.4) | 2 | 0.8 (0.1, 2.9) | ||
| Fatigue | All | 73 | 29.7 (24.0, 35.8) | 104 | 41.1 (35.0, 47.4) | 88 | 35.6 (29.7, 41.9) | |
| Grade 3a | 3 | 1.2 (0.3, 3.5) | 9 | 3.6 (1.6, 6.6) | 2 | 0.8 (0.1, 2.9) | ||
| Fever | All | 14 | 5.7 (3.1, 9.4) | 24 | 9.5 (6.2, 13.8) | 18 | 7.3 (4.4, 11.3) | |
| Grade 3a | 1 | 0.4 (0.0, 2.2) | 1 | 0.4 (0.0, 2.2) | 2 | 0.8 (0.1, 2.9) | ||
| Gastrointestinal | All | 28 | 11.4 (7.7, 16.0) | 35 | 13.8 (9.8, 18.7) | 36 | 14.6 (10.4, 19.6) | |
| Grade 3a | 0 | 0.0 (0.0, 1.5) | 6 | 2.4 (0.9, 5.1) | 0 | 0.0 (0.0, 1.5) | ||
| Headache | All | 73 | 29.7 (24.0, 35.8) | 95 | 37.5 (31.6, 43.8) | 83 | 33.6 (27.7, 39.9) | |
| Grade 3a | 1 | 0.4 (0.0, 2.2) | 5 | 2.0 (0.6, 4.6) | 4 | 1.6 (0.4, 4.1) | ||
| Myalgia | All | 71 | 28.9 (23.3, 35.0) | 97 | 38.3 (32.3, 44.6) | 87 | 35.2 (29.3, 41.5) | |
| Grade 3a | 3 | 1.2 (0.3, 3.5) | 9 | 3.2 (1.4, 6.1) | 7 | 2.8 (1.1, 5.8) | ||
| Rash | All | 6 | 2.4 (0.9, 5.2) | 11 | 4.3 (2.2, 7.6) | 10 | 4.0 (2.0, 7.3) | |
| Grade 3a | 0 | 0.0 (0.0, 1.5) | 1 | 0.4 (0.0, 2.2) | 0 | 0.0 (0.0, 1.5) | ||
| Urticaria | All | 7 | 2.8 (1.2, 5.8) | 6 | 2.4 (0.9, 5.1) | 7 | 2.8 (1.1, 5.8) | |
| Grade 3b | 0 | 0.0 (0.0, 1.5) | 0 | 0.0 (0.0, 1.4) | 0 | 0.0 (0.0, 1.5) | ||
aSymptom that prevented normal activity. |
bUrticaria present over at least four body parts. |
The most frequently solicited general symptoms after the first dose in the HPV, HPV+dTpa-IPV, and dTpa-IPV groups, respectively, were fatigue (29.7%, 41.1%, and 35.6%), headache (29.7%, 37.5%, and 33.6%), and myalgia (28.9%, 38.3%, and 35.2%). The incidence of solicited grade 3 general symptoms after the first dose was low and appeared similar across groups (<4% for all groups and all general symptoms). There was no evidence that the incidence of solicited general symptoms increased with subsequent doses.
In general, the frequency of unsolicited symptoms reported during the 30-day postvaccination period after each dose was similar between groups. Upper respiratory infection, pharyngitis, dysmenorrhea, and headache were the most commonly reported unsolicited symptoms. There was no evidence that the incidence of unsolicited symptoms increased with subsequent doses.
No participant withdrew from the study due to an adverse event. Eight participants reported serious adverse events up to month 7 or 8: two in the HPV group (gastroenteritis and suicide attempt), four in the HPV+dTpa-IPV group (appendicitis, scoliosis, muscle rupture, and imminent abortion) and two in the dTpa-IPV group (streptococcal tonsillitis and ovarian cyst). None of the serious adverse events was fatal, none was considered by the investigator to be related to study vaccination, and all were reported to have resolved. Medically significant adverse events in the HPV, HPV+dTpa-IPV, and dTpa-IPV groups were reported by 14.1%, 10.6%, and 19.8% of participants up to month 7/8, respectively. New onset chronic diseases in the HPV, HPV+dTpa-IPV, and dTpa-IPV groups were reported by 2.0%, 3.5%, and 3.6% of participants up to month 7/8, respectively. Two pregnancies were reported up to month 7/8: one participant in the HPV+dTpa-IPV group experienced imminent abortion, which was reported as a serious adverse event; this event resolved and the participant gave birth to a healthy infant. For one participant in the dTpa-IPV group the pregnancy outcome was still unknown at the time of reporting.
Discussion
In this study we showed that coadministration of the HPV-16/18 AS04-adjuvanted vaccine with dTpa-IPV did not interfere with the immune response to either of the vaccines. The immune response to dTpa-IPV (in terms of seroprotection rates for anti-D, anti-T, and anti-poliovirus types, and GMCs for anti-PT, anti-FHA, and anti-PRN) was noninferior following coadministration with HPV-16/18 AS04-adjuvanted vaccine, compared with dTpa-IPV alone. Furthermore, the booster response rates to dTpa-IPV were similarly high in both groups. We also showed that the HPV immune response (in terms of seroconversion rates and GMTs for HPV-16 and HPV-18 antigens) was noninferior following coadministration, compared with HPV-16/18 AS04-adjuvanted vaccine alone.
The observation that administration of dTpa-IPV followed by administration of the HPV-16/18 AS04-adjuvanted vaccine tended to elicit lower anti-HPV-16 and anti-HPV-18 antibody titers is likely to be of little clinical significance. The levels of anti-HPV-16 and anti-HPV-18 antibodies observed in the three groups were comparable to peak antibody levels in girls and young women aged 15–25 years in a large phase 3 efficacy study [19], in which the HPV-16/18 AS04-adjuvanted vaccine has been shown to be efficacious against persistent infection and cervical intraepithelial neoplasia grade 2 or above associated with HPV-16 and/or HPV-18.
The safety and reactogenicity profiles of dTpa-IPV and HPV-16/18 AS04-adjuvanted vaccine in our study are generally comparable to those previously reported for each of the individual vaccines [14], [15], [24]. Reactogenicity of the first dose of the HPV-16/18 AS04-adjuvanted vaccine appeared similar to dTpa-IPV, which is licensed and used regularly in adolescents. The frequencies of injection site reactions, solicited general symptoms, unsolicited symptoms, serious adverse events, medically significant adverse events, and new onset chronic diseases appeared similar after coadministration, compared with administration of either of the vaccines alone.
A limitation of our study is that, due to operational and ethical considerations, the design was open (albeit randomized), rather than blinded. However, we do not consider that the open nature of the study introduced bias with respect to primary and secondary immunogenicity objectives, which were based on serological evaluation. It is recognized that safety outcomes might have been influenced by the open study design, although no statistical inferences are drawn with regard to such outcomes.
Although the majority of subjects enrolled in our study were of Caucasian/European heritage, no clinically relevant differences in HPV-16/18 immune responses have previously been observed among different ethnic subgroups in a large phase 3 efficacy study of the HPV-16/18 AS04-adjuvanted vaccine (ClinicalTrials.gov number NCT00122681; unpublished results). Furthermore, we are not aware of any clinically relevant differences in immune responses against diphtheria, tetanus, pertussis, or poliovirus on the basis of ethnicity after dTpa or IPV administration.
In summary, results from our study show that the coadministration of dTpa-IPV with HPV-16/18 AS04-adjuvanted cervical cancer vaccine to girls and young women does not affect the immune response to, or compromise the safety of, either vaccine. Results from our study support the coadministration of both vaccines as part of an adolescent vaccination program, allowing improved vaccination strategies.
Acknowledgments
This study was funded and coordinated by GlaxoSmithKline Biologicals, Rixensart, Belgium. We thank the participating subjects and their families and acknowledge and thank all clinical study site personnel who contributed to the conduct of this trial. Statistical analyses were performed by Toufik Zahaf, Gregory Catteau, and Bhavyashree Gunapalaiah at GlaxoSmithKline Biologicals, Rixensart, Belgium. Writing assistance was provided by Julie Taylor, Peak Biomedical Ltd, Macclesfield, Cheshire, UK, on behalf of GlaxoSmithKline Biologicals. Editorial assistance and manuscript coordination were provided by Monica Autiero, Veronique Delpire, and Denis Sohy at GlaxoSmithKline Biologicals, Rixensart, Belgium.
HPV Vaccine Adolescent Study Investigators Network: Drs J.P. Arsene, C. Baranes, P. Beignot-Devalmont, P. Boyer, Cabos, A. Campagne, S. Courtois, J. Debout, A. Duplan, Kassmann, D. Lejay, J-E Malkin, F. Spilthooren, F. Thollot, P. Tran, C. Albring, U. Behre, K.H. Belling, G. Boenig, J. Disselhoff, T. Grubert, P. Hillemanns, W.D. Höpker, Hörnlein, S. Jensen-El-Tobgui, K. Kirsten, U. Kohoutek, H.P. Loch, K. Peters, S. Schoenian, K. Schulze, T. Schwarz, C. Wackernagel, J. Garcia-Sicilia, A. Carmona, and E. Bernaola Iturbe.
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Conflict of interest: Gregory Catteau, Dominique Descamps, Kurt Dobbelaere, Gary Dubin, and Florence Thomas are employees of GlaxoSmithKline Biologicals; Jose Garcia-Sicilia has participated, as a principal investigator, in clinical trials on vaccines, funded by GlaxoSmithKline; Alfonso Carmona has participated, as an investigator, in several clinical trials funded by GlaxoSmithKline; Enrique Bernaola Iturbe is on the Speaker's Bureau for GlaxoSmithKline, Sanofi Pasteur, MSD and Wyeth and is also an advisory board member for AstraZeneca; Tino F. Schwarz, Klaus Peters, Jean-Elie Malkin, and Phu M. Tran have no conflict of interest with regard to this study.
PII: S1054-139X(09)00629-6
doi:10.1016/j.jadohealth.2009.11.205
© 2010 Published by Elsevier Inc.
