Between April 26, 2010 and June 16, 2011, 1054 sexually naïve, healthy boys and girls ages 11–15 years from 23 sites in Finland (n = 386), Germany (n = 196), Denmark (n = 165), Thailand (n = 140), Belgium (n = 119) and Austria (n = 48) participated in the study. Subjects were to be sexually naïve and not planning on becoming sexually active through the course of the study. Subjects were excluded if they had a known allergy to any vaccine component or had a history of severe allergic reaction. Subjects must also not have previously received a marketed HPV vaccine or had participated in any HPV vaccine clinical trial. The subject should not have had a history of a positive test for HPV. Subjects must not have been previously immunized against diphtheria, tetanus and pertussis in the last 5 years. Female subjects were excluded if they were pregnant (as determined by a serum pregnancy test or urine pregnancy test that is sensitive to 25 mIU/mL β-human chorionic gonadotropin). The study was conducted in conformity with applicable national or local requirements regarding ethical committee review, informed consent and the protection of the rights and welfare of human subjects participating in biomedical research. An external Data Monitoring Committee assessed safety findings throughout the study.
This was an open-label, randomized, multicenter, comparative study. Subjects were stratified by gender (1:1 ratio) and randomly assigned to 1 of 2 vaccination groups (concomitant group or nonconcomitant group) in a 1:1 ratio. At day 1, subjects in the concomitant group (referred to as group A) received the first dose of 9vHPV vaccine in the deltoid muscle of the nondominant arm and Tdap-IPV vaccine in the deltoid muscle of the opposite arm. Subjects in the nonconcomitant group (referred to as group B) received the first dose of the 9vHPV vaccine on day 1 and Tdap-IPV vaccine at month 1. Subjects in both vaccination groups received the second dose of the 9vHPV vaccine at month 2 and the third dose at month 6.
Blood samples were drawn from subjects in group A immediately before vaccination at day 1, as well as months 1 and 7. Blood samples were drawn from subjects in group B immediately before vaccination at day 1, as well as months 1, 2 and 7. Serum collected from all subjects at day 1 and month 7 underwent analysis of anti-HPV responses with a competitive luminex immunoassay, performed by PPD Vaccines and Biologics, Wayne, PA.33 Serum collected at day 1 and month 1 for group A and months 1 and 2 for group B underwent antibody testing for diphtheria, tetanus, pertussis and poliovirus types 1, 2 and 3. Diphtheria antibodies were measured by a diphtheria antitoxin cell culture assay performed by CSL Limited in Parkville, Victoria, Australia. Tetanus antibodies were measured by a tetanus antitoxin enzyme immunoassay performed by CSL Limited. Pertussis antibodies were measured by an anti-PT enzyme-linked immunosorbent assay (ELISA), anti-FHA ELISA, anti-PRN ELISA and anti-FIM ELISA performed by MEP Laboratory, Rochester, NY. Poliovirus antibodies were measured by a poliovirus antibody microneutralization assay performed by Focus Diagnostics, Inc., Cypress, CA. Laboratory personnel conducting the clinical assays were blinded to vaccination group.
All subjects received a vaccination report card (VRC), which was to be completed by the parent or guardian at the day 1 and month 1, 2, 6 and 7 visits. VRCs for all the subjects were to be completed after the month 1 visit to provide a common period of follow-up even though subjects in the group A were not vaccinated at month 1. On the VRC, the parent/guardian was asked to record the subject’s oral temperature in the evening of the day of each study vaccination and daily, at the same time each day for a total of 5 days. The parent/guardian was asked to record injection-site and systemic adverse experiences (AEs) on the VRC for a total of 15 days including the day of vaccination after each study vaccination. Serious AEs (SAEs) were collected for the whole duration of the study, regardless of causality, and were followed for outcome. For all injection-site AEs, except erythema and swelling, subjects were instructed by the VRC to estimate the severity of AEs as mild (awareness of symptom, but easily tolerated), moderate (discomfort enough to cause interference with usual activities) or severe (incapacitating with inability to work or do usual activity). For erythema and swelling, subjects were instructed by the VRC to measure an injection-site reaction at its greatest width (maximum size) from edge to edge in maximum units ranging from 0 to >7 inches (17.5 cm) on the VRC, rounding up to the next unit if in between 2 units [each unit on the VRC measured approximately 1 inch (2.5 cm)].
The primary and secondary endpoints for evaluating antibody responses to the 9vHPV vaccine were GMTs to HPV6/11/16/18/31/33/45/52/58 and the percentages of subjects who seroconverted for each HPV type by 4 weeks postdose 3. Anti-HPV cutoffs for determining serostatus were 30, 16, 20, 24, 10, 8, 8, 8 and 8 mMU/mL for HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58, respectively. The primary endpoints for evaluating antibody response to Tdap-IPV vaccine were the proportions of subjects who achieved acceptable levels of titers to diphtheria, tetanus and polio, and GMTs for pertussis (anti-PT, anti-FHA, anti-PRN and anti-FIM) 4 weeks postvaccination with Tdap-IPV vaccine. The targeted titer levels were ≥0.1 IU/mL for diphtheria and tetanus, and neutralizing antibodies at ≥1:8 dilution for all poliovirus types. As there are no unequivocal immunological correlates of protection against pertussis, there was no targeted titer level for the pertussis antigens.34
The primary immunogenicity analysis was done per protocol. Subjects in per-protocol analyses for the 9vHPV vaccine analyses had to receive all 3 doses of 9vHPV vaccine within acceptable day ranges and 1 dose of Tdap-IPV vaccine. In addition, the following additional criteria applied to per-protocol analysis for 9vHPV vaccine: (1) subjects had to have at least 1 postdose 3 serology result within acceptable day ranges; (2) to be included in the primary immunogenicity analysis for the HPV6 and HPV11 components, subjects had to be seronegative to both HPV6 and 11 at day 1; (3) to be included in the primary immunogenicity analysis for the other vaccine HPV types, subjects were required to be seronegative at day 1 only for the HPV type being analyzed and (4) to have no general protocol violations that were considered to impact the immune responses. The following criteria applied to per-protocol analysis for Tdap-IPV vaccine: (1) subjects needed to have received the Tdap-IPV vaccine within acceptable day ranges; (2) subjects had to have at least 1 serology result following administration of Tdap-IPV vaccine within acceptable day ranges and (3) subjects had to have no general protocol violations that were considered to impact the immune responses.
Noninferiority criteria for each immunogenicity hypothesis are shown in Table, Supplemental Digital Content 1, http://links.lww.com/INF/C95. Noninferiority of anti-HPV GMTs 4 weeks postdose 3 and pertussis GMTs 4 weeks postvaccination with Tdap-IPV vaccine was based on 1-sided tests of noninferiority (conducted at the 0.025 significance level) comparing GMTs between group A and group B for each component. An analysis of variance model (1 for each component) was used with a response of loge individual titers and fixed effects for vaccination group and gender. Noninferiority of anti-HPV seroconversion rates and of serologic responses to diphtheria, tetanus and polio was tested by 1-sided tests of noninferiority comparing proportions between group A and group B for each component. These tests were conducted based on methods developed by Miettinen and Nurminen.35 All tests were conducted at the 0.025 significance level. Success in this study was declared if the primary hypotheses of noninferiority were demonstrated for all components of both vaccines. With 520 subjects per group (1040 total), this study had an overall power >99% for the primary immunogenicity hypotheses (Tables 1 and 2).
All subjects who received at least 1 injection and had follow-up data were included in the primary analysis of safety. The number and percent of subjects reporting the following were compared between group A and group B: systemic AEs on days 1–15 following any vaccination; injection-site AEs on days 1–5 following any vaccination visit; maximum oral temperature ≥37.8°C (≥100.0°F) on days 1–5 following any vaccination; severe injection-site AEs on days 1–5 following any vaccination and the number of subjects reporting clinical SAEs from days 1 to 15 following any vaccination or vaccine-related clinical SAE at any time during the study. Risk differences, 95% confidence intervals (CIs) and P values were calculated for injection-site AEs and elevated temperatures day 1–5 for both vaccines.
A total of 1074 subjects residing in Europe and Southeast Asia were screened for inclusion in this study, and 1054 were randomized (526 to group A and 528 to group B) and 1053 received at least one vaccination (Fig., Supplemental Digital Content 2, http://links.lww.com/INF/C96). Of the 20 subjects who were screened and not randomized, 17 did not meet the exclusion/inclusion criteria, 2 withdrew from the study, and one was lost to follow-up. Among the 1054 randomized subjects, 16 (1.5%; 5 in group A and 11 in group B) discontinued during the study period, with none because of an AE.
Both vaccination groups were comparable with respect to baseline demographics (Table, Supplemental Digital Content 3, http://links.lww.com/INF/C97). The mean age of subjects in both groups was 12.4 years (median age, 12.0 years in both groups). Approximately 87% were from Europe and 13% from Asia-Pacific. The most common reason for exclusion from the per-protocol immunogenicity analysis for the 9vHPV vaccine was having a serum sample or result missing at month 7 (n = 20 and n = 34 for group A and group B, respectively; Table, Supplemental Digital Content 4, http://links.lww.com/INF/C98). The most common reason for exclusion from the per-protocol immunogenicity analysis for Tdap-IPV vaccine was having a serum sample or result missing at 4 weeks postinjection (n = 9 and n = 29 for group A and group B, respectively). The number of subjects excluded from the per-protocol immunogenicity analysis for 9vHPV vaccine because of testing positive for HPV on Day 1 ranged from 2.9% for HPV 6/11 to 0% for HPV52.
The results of the per-protocol analysis of noninferiority of anti-HPV responses in group A versus group B with respect to GMTs and seroconversion rates for each vaccine HPV type at 4 weeks postdose 3 (of the HPV vaccine) are presented in Tables 1 and 2. The anti-HPV GMTs against all HPV types observed at 4 weeks postdose 3 in group A were numerically lower than that in group B, with fold differences (ie, group A/group B) ranging from 0.89 for HPV58 to 0.97 for HPV11 and HPV45 (Table 1). The 95% CI for the GMT ratio (group A/group B) covered 1 for all HPV types except HPV58. The preestablished noninferiority criteria for the anti-HPV GMT responses in group A relative to group B were achieved. Seroconversion rates were ≥99.8% for all HPV types in both groups and were noninferior in group A compared with group B and the noninferiority criteria was met (Table 2).
The per-protocol immunogenicity analysis showed over 99.6% of subjects in both group A and group B achieved a diphtheria and tetanus titer ≥0.1 IU/mL at 4 weeks postvaccination with Tdap-IPV vaccine. There was a 0–0.2 percentage point difference (group A − group B) in the percentage of subjects who achieved titers ≥ 0.1 IU/mL, and the noninferiority criteria for both antigens were met (Table 3). Similarly, for all 3 poliovirus types, ≥99.6% of subjects had neutralizing antibodies at ≥1:8 dilution at 4 weeks after Tdap-IPV vaccination. The difference between the groups in percentage of subjects with neutralizing antibodies at ≥1:8 dilution was similarly low at 0% to −0.2%, and noninferiority criteria for poliovirus types were met (Table 4). For all 4 pertussis antigens tested (PT, FHA, PRN and FIM 2/3), the GMT ratios (group A/group B) ranged from 0.89 to 0.99, and the 95% CI for all GMT ratios covered 1. The per-protocol immunogenicity analysis also showed that anti-PT, anti-FHA, anti-PRN and anti-FIM 2/3 GMTs were noninferior in group A compared with group B (Table 5).
No subjects discontinued because of an AE, and no deaths were reported (Table 6). Throughout the entire study period, 9 subjects (1.7%) in group A and 7 subjects (1.3%) in group B reported nonfatal serious AEs; none were vaccine-related. Regarding injection-site AEs, a slightly higher proportion of subjects in group A reported erythema (8.2%) and swelling (13.0%) at the 9vHPV vaccination site compared with group B (5.7% and 8.2%; Table, Supplemental Digital Content 5, http://links.lww.com/INF/C99). The risk difference between the groups was statistically significant for injection-site AE of swelling (P = 0.011). Likewise, a slightly higher proportion of subjects in group A reported erythema (26.9%) and swelling (39.4%) at the Tdap-IPV vaccination site compared with group B (21.7% and 31.3%; Table, Supplemental Digital Content 5, http://links.lww.com/INF/C99). The risk difference between the groups was statistically significant for injection-site AE of swelling (P = 0.006). Most of the swelling was mild to moderate in intensity (ie, with a maximum size less than 5 cm) both at the 9vHPV vaccine injection site and the Tdap-IPV vaccine injection site (Table, Supplemental Digital Content 6, http://links.lww.com/INF/C100). Headache was the most common systemic AE and was reported slightly higher in the concomitant group (25.1%) versus the nonconcomitant group (21.4%; risk difference = 3.7%, 95% CI: −1.4%, 8.8%). Most subjects (98.5%) reported no fever or mild fever (<39.0°C) within 5 days of the first vaccination (Table 7). The proportions with elevated temperatures (≥37.8°C) within 5 days of the first vaccination were similar between group A and group B.
The results of this study demonstrated that when the first dose of 9vHPV vaccine is administered concomitantly with Tdap-IPV vaccine at a separate injection site, the immune response to all vaccine components is noninferior to the immune response achieved when the 2 vaccines are administered nonconcomitantly. Specifically, GMTs to all 9 vaccine HPV types at 4 weeks following the third dose of 9vHPV vaccine were noninferior in group A compared with group B, and nearly all subjects in both vaccination groups seroconverted after the third dose of 9vHPV vaccine. Also, antibody responses to diphtheria, tetanus, pertussis and poliovirus at 4 weeks following administration of Tdap-IPV vaccine were noninferior in group A compared with group B.
Concomitant administration of the first dose of 9vHPV vaccine with Tdap-IPV vaccine was generally well tolerated. The proportion of subjects reporting injection-site AEs postvaccination 1 was numerically higher in the concomitant vaccination group (93.9%) compared with the nonconcomitant vaccination group (90.1%), and significantly more subjects reported swelling at the 9vHPV vaccine injection site and at the Tdap-IPV vaccine injection site following the first vaccination. The intensity of injection-site AEs was mostly mild to moderate. Moreover, there were few discontinuations, and no discontinuation was because of an AE. Thus, the finding of increase rates of injection-site swelling is likely to be of minor clinical significance.
The observed nominal difference in HPV GMTs between concomitant and nonconcomitant groups was highest for HPV58 with a GMT ratio (group A/group B) of 0.89 and the 95% CI of GMT ratio (group A/group B) which did not cover 1. Nonetheless, noninferiority of anti-HPV responses in group A versus group B was demonstrated for all vaccine HPV types including HPV58. In other studies of the 9vHPV vaccine, (1) the efficacy of the 9vHPV vaccine was established in young women, 16–26 years of age28 and (2) the efficacy findings in young women were extended to adolescent girls and boys based on the demonstration of noninferior immunogenicity in an adult–adolescent immunobridging study.36 The immunogenicity results obtained in adolescent girls and boys in this study were numerically comparable with those obtained in adolescent girls and boys in the adult–adolescent immunobridging study. In the other study, the anti-HPV58 response was substantially higher in adolescents than in young women with an anti-HPV58 GMT ratio (boys or girls/women) greater than 2. Thus, the relatively modest numerical difference in anti-HPV58 GMT between group A and group B is unlikely to have a clinical significance.
Other studies have demonstrated that the 9vHPV vaccine was generally well tolerated in girls and boys 9–15 years of age and young women 16–26 years of age.28,36,37 In these studies, the safety and tolerability profile of the 9vHPV vaccine were similar to that of the qHPV vaccine, although injection-site AEs were more frequent with the 9vHPV vaccine than with the qHPV vaccine.37 This study extends these findings by showing that the 9vHPV vaccine is generally well tolerated in adolescent girls and boys when administered concomitantly or nonconcomitantly with a Tdap-IPV vaccine. Interestingly, in group B, the frequency of severe injection-site AEs was numerically lower at the 9vHPV vaccine injection site than at the Tdap-IPV vaccine injection site. This indicates that the tolerability profile of the 9vHPV vaccine with respect to injection-site AEs is consistent with that of the Tdap-IPV vaccine, further supporting previous findings that the 9vHPV vaccine is generally well tolerated.
The results of this study are similar to those of a previous study of concomitant administration of qHPV vaccine and Tdap-IPV vaccine, which showed that concomitant administration of qHPV vaccine and Tdap-IPV vaccine was generally well tolerated and did not interfere with the antibody response to any of the vaccine antigens.32 Similar to this study, in the qHPV vaccine study, anti-HPV GMT for each vaccine HPV type observed 4 weeks postdose 3 in the concomitant vaccination group was numerically lower than that in the nonconcomitant group [in the qHPV vaccine study, anti-HPV GMT ratios (concomitant group/nonconcomitant group) ranged from 0.84 to 0.92]. Other studies have indicated that the 9vHPV vaccine and qHPV vaccine exhibit similar immunogenicity profiles.28,36,37 The similarity of the immunogenicity findings between this study and the prior qHPV vaccine study further supports this conclusion. It should also be noted that the monoclonal antibodies utilized in the 9-valent competitive luminex immunoassay recognize unique epitopes, and each assay uses a different reverence sera; therefore, one cannot draw conclusions with regard to the relative immunogenicity of the 9 VLP components in the vaccine.33
As with the prior study with qHPV vaccine, the primary limitation of this study was its unblinded nature. As such, safety assessment could have been biased toward an overestimation of AEs being reported in the concomitant vaccination group, as subjects who are receiving 2 injections on the same day may more likely report injection-site or systemic AEs compared with subjects who receive only 1 injection. In this study, a slightly higher proportion of subjects in the both the concomitant and the nonconcomitant vaccination groups reported swelling at the 9vHPV vaccine injection site, compared with qHPV vaccine,32 and a lower proportion reported headache.
We conclude that concomitant administration of 9vHPV vaccine and Tdap-IPV vaccine was generally well tolerated, and the immune responses to components of either vaccine were noninferior compared with nonconcomitant administration. Concomitant administration would minimize the number of visits required to deliver each vaccine individually.
The authors thank Heather L. Sings, PhD and Ms. Karyn Davis (Merck) for assistance in the preparation of this manuscript.
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HPV vaccine; REPEVAX; GARDASIL; concomitant
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