Safety, Tolerability, and Immunogenicity of Gardasil Given Concomitantly With Menactra and Adacel
OBJECTIVES: Multinational phase III trials of a human papillomavirus vaccine, Gardasil, have shown the vaccine to be generally well-tolerated, efficacious, and immunogenic. We evaluated the immunogenicity and safety of Gardasil administered concomitantly with Menactra and Adacel.
METHODS: In this open-label study, boys (n = 394) and girls (n = 648) aged 10 to 17 were randomly assigned in a 1:1 ratio as follows: group A (concomitant administration) received a 0.5-mL dose of Gardasil at day 1, month 2, and month 6 and a 0.5-mL dose of Menactra and Adacel on day 1; group B (nonconcomitant administration) received Gardasil at day 1, month 2, and month 6 and Menactra and Adacel at month 1. Antibody levels for all vaccine components were measured. Systemic, injection-site, and serious adverse experiences (AEs) were monitored.
RESULTS: Immune responses after concomitant administration of the 3 vaccines were noninferior to nonconcomitant administration. Seroconversion for Gardasil was ≥99% in both groups A and B. For Menactra and Adacel, concomitant administration of the vaccines was demonstrated to be noninferior to nonconcomitant administration. Concomitant administration was generally well-tolerated. No participants withdrew because of an AE. One serious AE of transient muscular weakness of <24 hours' duration after the third Gardasil injection was reported in group B and was deemed possibly vaccine-related by the investigator.
CONCLUSIONS: Overall, concomitant administration was generally well-tolerated and did not interfere with the immune response to the respective vaccines. Concomitant administration should minimize the number of visits required to deliver each vaccine individually, leading to increased compliance and more effective disease prevention.
WHAT'S KNOWN ON THIS SUBJECT:
Previous studies have shown that co-administered Gardasil and Recombivax HB and co-administered Gardasil and Repevax were generally well tolerated and did not interfere with the immune responses to the respective vaccines.
WHAT THIS STUDY ADDS:
We have demonstrated that co-administration of Gardasil, Menactra, and Adacel, vaccines which are currently recommend by the ACIP for routine vaccination of adolescents, does not compromise the safety, tolerability, and immunogenicity of the individual vaccines.
Human papillomavirus (HPV) is one of the most prevalent sexually transmitted infections, with >50% of sexually active adults becoming infected during their lifetime.1 Genital HPV infection can result in several diseases in women, including cervical, vulvar, vaginal, and anal dysplasia, which may lead to cancer.2 In men and women, HPV infection also leads to benign genital warts (condyloma accuminata), anal dysplasia and cancer, and cancers of the head and neck.2 The association of anogenital cancers with HPV infection led to the development of a prophylactic, quadrivalent HPV-6/11/16/18 L1 virus-like particle vaccine (Gardasil [Silgard in the European Union] [Merck & Co, Inc, Whitehouse Station, NJ]). Gardasil is recommended by the Advisory Committee on Immunization Practice (ACIP)3 of the Centers for Disease Control and Prevention and was incorporated into the Vaccines for Children Program. In May 2009, Gardasil became the first cervical cancer vaccine to receive World Health Organization prequalification, which means that it is now eligible for procurement for use in national immunization programs. In October 2009, the Food and Drug Administration approved Gardasil for use in boys and men aged 9 to 26 for the prevention of genital warts caused by HPV types 6 and 11.
Because the incidence of HPV infection peaks soon after the onset of sexual activity,4 preadolescents and adolescents represent an appropriate target group to implement HPV vaccination programs. This age group is also at high risk for other infections that are preventable by currently available vaccines. The development of a combined immunization strategy may lead to better compliance for these vaccines, thereby contributing to the overall goal of protection against preventable diseases. Previous studies have shown that co-administered Gardasil and Recombivax HB (hepatitis B vaccine)5 and co-administered Gardasil and Repevax (diphtheria, tetanus, acellular pertussis, and poliomyelitis vaccine)6 were generally well-tolerated and did not interfere with the immune responses to the respective vaccines. To examine further the combined immunization strategies and to aid decisions by those who would be administering these vaccines together, we evaluated the immunogenicity and safety of Gardasil administered concomitantly with Menactra (meningococcal polysaccharide conjugate of serogroups A, C, Y, and W-135 [Sanofi Pasteur Inc, Lyon, France]) and Adacel (tetanus, diphtheria, and acellular pertussis [Sanofi Pasteur Inc]), two vaccines that are recommend by the ACIP for routine vaccination of adolescents.7,8
Between April 25, 2006, and September 19, 2006, 1058 healthy, sexually naive boys and girls aged 10 to 17 were enrolled across 21 sites in the United States. The study was 7 months in duration with a final follow-up date of April 9, 2007. Participants were to remain sexually naive throughout the study. Participants must not have been immunized within the previous 5 years against diphtheria, tetanus, and pertussis or have a history of known previous HPV or meningococcal vaccination. Participants were excluded if they were pregnant (as determined by a urine or serum pregnancy test sensitive to 25 IU of human chorionic gonadotropin), allergic to any vaccine component, had received any blood product or component in the previous 6 months, had any known immune or coagulation disorder, had received any inactivated vaccine product within 14 days before enrollment, or had received any live vaccine product within 21 days before enrollment.
An institutional review board for each clinical site approved the study protocol. Written consent was obtained from each participant and his or her legal guardian.
This was an open-label, randomized, multicenter, comparative study of healthy adolescents who were aged 10 to 17 years. Participants were randomly assigned by a computer-generated allocation schedule to either concomitant (group A) or nonconcomitant (group B) vaccination groups. Group A received a 0.5-mL dose of Gardasil at day 1, month 2, and month 6. Group A also received 0.5-mL doses of both Menactra and Adacel on day 1, administered in the opposite limb from Gardasil. Group B received Gardasil at day 1, month 2, and month 6 and Menactra and Adacel at month 1 (both to be administered in the opposite limb from the day 1 Gardasil vaccination).
Blood samples were drawn from participants in group A immediately before vaccination on day 1 and at months 1 and 7. Blood samples were drawn from participants in group B immediately before vaccination on day 1 and at months 1, 2, and 7. For each of the vaccines, sera were tested for relevant antibody levels as described previously.12,–,16
All participants were observed for a minimum of 30 minutes after each vaccination. By using a vaccine report card, participants were prompted to report temperatures and injection-site adverse experiences (AEs) for 5 days after each vaccination. Serious and systemic AEs were recorded on the vaccine report card for 14 days after each vaccination. Serious AEs that occurred after the 15-day reporting period were reported only when the serious AE was a death or was considered by the investigator to be vaccine- or study procedure–related.
Statistical Analysis and Primary Hypotheses
The primary hypotheses related to immunogenicity are shown in Table 1, along with the statistical criteria for success. Under the assumption that each end point to be tested is independent, the criterion for declaring study success had a corresponding type I error probability of α = .025. The estimated geometric mean titers (GMTs), fold difference, and associated 95% confidence intervals (CIs) were obtained by fitting an analysis of variance model on the natural logarithm of postvaccination titers with fixed effects for vaccination group, regions (Mid-Atlantic, Midwest, South, West), and region by vaccination group interaction. For seroconversion, point and interval estimates for the difference of proportions were obtained by using the methods developed by Miettinen and Nurminen.17
With 520 participants per group (1040 participants total), this study had an overall power of ∼90% for the primary hypotheses, accounting for the multiplicity adjustment made by using the step-up procedure. For the GMTs, power was computed on the basis of the distribution of the difference of means of natural logarithm (loge) titers in group A and group B, unadjusted for any baseline covariates. For seroconversion end points, power was computed on the basis of the distribution of the difference of proportions, under the null hypothesis of a nonzero difference, following the method of Farrington and Manning.18
The primary analysis of immunogenicity was based on the per-protocol populations for the individual vaccine components. This included all participants who did not have protocol violations that could affect immune responsiveness, who received all 3 Gardasil vaccinations and the single Menactra and Adacel vaccinations within acceptable day ranges, and who had a serology result within an acceptable day range. The per-protocol immunogenicity population for Gardasil was additionally restricted to those who were seronegative at day 1 to the respective HPV type(s). Because different numbers of participants were seropositive to the various HPV types at day 1 or had missing or invalid data for ≥1 of the 10 components in Menactra and Adacel, the numbers of participants who were evaluated for each component differ.
The secondary hypothesis related to safety stated that concomitant administration would be generally well-tolerated compared with nonconcomitant administration. AEs were summarized as frequencies and percentages according to study group and the type of AE reported. Risk differences, 95% CIs, and P values were computed across all sites combined and without adjustment for multiplicity. The method of Miettinen and Nurminen17 was used for all comparisons of vaccination groups. Risk differences were provided for any systemic AE that occurred in at least 1% of participants in either vaccination group.
A total of 1058 participants were assessed for eligibility (Fig 1), and 1042 were randomly assigned to either group A (n = 518) or group B (n = 524). The most common reason for discontinuation was withdrawal of consent by the participant or the parent (n = 26 [2.5%]), followed by loss to follow-up of the participant by the investigative site (n = 20 [1.9%]). Both vaccination groups were comparable with respect to baseline demographics (Table 2). The median age was 12.0 years in both groups.
Analysis Population for Immunogenicity
The most common reason for exclusion from the per-protocol analysis for Gardasil was missing month 7 serum samples or results (Table 3). Eleven (1.1%) participant were excluded from the per-protocol analysis for Gardasil because of positive testing for HPV-6 or -11 on day 1, and 3 (0.3%) were excluded because of positive testing for HPV-16 on day 1. No participant tested positive to HPV-18 on day 1.
The most common reason for exclusion from the per-protocol analysis for Menactra and Adacel was missing serum samples or results for ≥1 of the 10 Menactra and Adacel components (n = 132 and n = 105 for group A and group B, respectively). A participant was excluded from the immunogenicity population only for the missing component. Only 39 participants (22 from group A and 17 from group B) had missing data for all 10 Menactra and Adacel components.
Immune Response to HPV
The results of the analyses of noninferiority of anti-HPV responses are presented in Tables 4 and 5. Immune response after concomitant administration of the 3 vaccines was noninferior to nonconcomitant administration (P < .001). Seroconversion for each of the 4 HPV antigens was >99% in both concomitant and nonconcomitant vaccination groups. Only 2 participants in group A and 1 participant in group B did not seroconvert for HPV-6 and -18 by month 7.
Immune Response to Neisseria meningitidis Serogroups A, C, Y, and W-135
Table 6 presents the proportion of participants in the per-protocol population with a fourfold or greater rise in titers for Neisseria meningitidis serogroups A, C, Y, and W-135 at 1 month after vaccination with Menactra. At least 83% of participants achieved a fourfold or higher rise in titers to serogroup A in both the concomitant and nonconcomitant vaccination groups, and at least 93% achieved a fourfold or higher rise in titers for serogroups C, Y, and W-135 in both the concomitant and nonconcomitant vaccination groups. Immune response after concomitant administration of the 3 vaccines was noninferior to nonconcomitant administration (P < .001 with a lower limit of the 95% CI for percentage point difference greater than −10 for all components).
Immune Response to Diphtheria, Tetanus, and Pertussis Antigens
Table 7 presents the proportion of participants in the per-protocol population with diphtheria and tetanus titers ≥0.1 IU/mL at 4 weeks after vaccination. One hundred percent of participants in the nonconcomitant vaccination group and >99% of participants in the concomitant vaccination group achieved a diphtheria titer and tetanus titer ≥0.1 IU/mL. Noninferiority of diphtheria and tetanus titer responses in group A relative to group B was established (P < .001 with a lower limit of the 95% CI for percentage point difference greater than −10 for all components). Table 8 presents the results of the per-protocol analysis of noninferiority of anti-pertussis responses. The table shows that noninferiority of the anti-pertussis GMT responses in the concomitant vaccination group relative to the nonconcomitant vaccination group at 4 weeks after vaccination was established (P < .001 with a lower limit of the 95% CI for fold difference >0.67 for all components).
Table 9 displays the summary of clinical AEs reported on days 1 to 15 after vaccinations 1, 2, and 3. The AEs reported after vaccination 1 represent the combined AEs reported for any of the 3 vaccines. As expected, most (≥88%) participants, regardless of vaccination group, reported at least 1 clinical AE after vaccination 1. The proportion of participants who reported ≥ AE after vaccinations 2 and 3 was considerably lower than after vaccination 1, because these AEs were derived from a single Gardasil vaccination. For each vaccination, the rates of injection-site and systemic AEs were similar between the concomitant and nonconcomitant groups. There were no deaths and no discontinuations as a result of an AE. Syncope (after vaccination 1) deemed related to study vaccination occurred in 0.2% of participants in both vaccination groups.
There was one serious AE in group B that the study investigator believed was possibly vaccine-related. A 12-year-old boy was admitted to the emergency department for muscular weakness after the third dose of Gardasil (1 day after dose 3). The participant's neurologic examination was normal, and the participant recovered the same day. The investigator later confirmed that this was a 1-time event, with no recurrence of symptoms.
Table 10 provides a comparison of the number and percentage of participants with specific injection-site AEs and the associated degree of severity. The number of participants in group B was lower than the number in group A as a result of the incorrect administration of Menactra and Adacel in 2 different limbs in group B (n = 92). The proportion of participants who reported a severe injection-site AE was lower for Gardasil (0.5%–0.6%) compared with Menactra and Adacel (3.7%–4.1%), but no statistical difference was seen between the vaccination groups with respect to severity. For specific injection-site AEs after vaccination 1 for Gardasil, there were no statistical differences between group A and group B, with the exception of injection-site swelling, which was reported by a higher percentage of participants in group A as compared with group B (P = .037).
For injection-site AEs related to Menactra and Adacel, all of the 95% CI's included 0 except for bruising (risk difference: 3.6 [95% CI: 1.0–6.2]) and pain (risk difference: 6.3 [95% CI: 1.0–11.8]), both of which were reported by higher percentages of participants in group A compared with group B. The proportion of participants who reported ≥1 systemic AE was similar between groups A and B. The most common (>10%) systemic AE was headache. A significant difference in group A versus group B was noted for pain at the site of venipuncture (risk difference: 1.20 [95% CI: 0.4–2.5]).
There were no significant differences in rates of fever (maximum oral temperature ≥37.8°C [100°F]) between the concomitant and nonconcomitant vaccination groups (risk difference: 0.2 [95% CI: −2.7 to 3.1]. Most participants in each group (94.5%–94.7%) had a maximum oral temperature <37.8°C (<100°F).
The results of this study indicate that when Gardasil is administered concomitantly with Menactra and Adacel, the immune responses to all vaccine components are noninferior to the immune response achieved when the vaccines are administered nonconcomitantly. Concomitant administration of the first dose of Gardasil with Menactra and Adacel was generally well-tolerated. The proportions of participants who reported injection-site or systemic AEs were similar in both vaccination groups, as was the intensity of AEs. Overall, the co-administered vaccines had safety profiles similar to those of the individual vaccines10,11,19,20; however, some specific injection-site AEs were significantly higher in the concomitant vaccination group, such as injection-site swelling (Gardasil) and bruising and pain (Menactra and Adacel). In both vaccination groups, rates of syncope were low, although it should be noted that participants in all trials of Gardasil were observed for 30 minutes after vaccination and generally remained in a seated position during this time. Recognizing a heightened propensity for immediate postvaccination syncope among adolescents and young adults, the ACIP recommends a 15-minute postvaccination observation period for this age group, regardless of the type of vaccine being administered.21
Since 2005, 3 vaccines have been approved and recommended by the ACIP for administration to adolescents: (1) a single dose of meningococcal polysaccharide conjugate vaccine (2005) for prevention of meningococcal disease caused by serogroups A, C, Y, and W-135, types that account for the majority of disease in this age group8; (2) a single dose of an acellular pertussis vaccine (2006) to protect against diphtheria and tetanus and particularly pertussis, which has had a resurgence in recent years as a result of waning immunity in adolescents and young adults7; and (3) in females, a 3-dose series of Gardasil (2006)3 to protect against the most common HPV strains that cause both anogenital precancers/cancers and anogenital warts. Although this study was conducted only in the United States, given that vaccine efficacy and immunogenicity have been shown to be similar across geographic locations in young women, these trial findings may be generalized to other countries where these vaccines are recommended.22,23
Until recently, the United States had focused its vaccine strategies on protecting infants and young children. With the unprecedented number of new vaccination recommendations for adolescents that have been made by the ACIP in recent years, it has been recognized that vaccinating adolescents, who make significantly fewer visits to their doctor, has proved to be especially challenging.24 The concomitant administration of these vaccines should improve vaccine uptake and would ideally result in the same level of protection as when the vaccines are administered separately. We found no immune interference when Gardasil was administered at the same time as Menactra and Adacel, and the immune responses observed in this study were similar to those of the individual vaccines.10,11,19,20 In addition, ≥99% of the participants in both the concomitant and nonconcomitant vaccine groups seroconverted by month 7. Previous studies have shown that for all 4 vaccine HPV types, higher titers are observed in boys compared with girls, and adolescents mount higher responses than those of females aged 16 to 2619,20; however, the clinical significance of the magnitude of anti-HPV responses in not known because a seroprotective level and durability of protection against HPV after natural infection or vaccination has not been determined. Gardasil has been shown to elicit immune memory and to be highly effective for up to 5 years in the clinical trials.25,26 The HPV-16 component has demonstrated high efficacy for up to 9.5 years.27
This study is accompanied by some limitations. First, the study was unblinded. In addition, safety assessment could have been biased toward an overestimation of reporting of AEs in the concomitant vaccination group, because these participants were receiving 3 injections on the same day. In the analyses of specific injection-site AEs, the number of participants in the nonconcomitant group was lower than the number in the concomitant group, as a result of the incorrect administration of Menactra and Adacel in 2 different limbs in group B (n = 92). This error resulted in the removal of those participants from the comparative analyses, which should be considered when interpreting these results.
The inclusion of Gardasil in the adolescent vaccination schedule provides an opportunity for physicians to co-administer other recommended vaccines with the ultimate goal of increased compliance, enhanced implementation, and disease prevention. In summary, we have demonstrated that co-administration of Gardasil, Menactra, and Adacel does not compromise the safety, tolerability, and immunogenicity of the individual vaccines.
Merck Research Laboratories, a Division of Merck and Co, Inc, funded this study.
We thank all study participants and investigators.
- Accepted January 25, 2010.
- Address correspondence to Keith S. Reisinger, MD, MPH, 1580 McLaughlin Run Rd, Pittsburgh, PA 15241. E-mail:
The study was designed by the sponsor (Merck and Co, Inc). The sponsor collated the data, monitored the conduct of the study, performed the statistical analysis, and coordinated the writing of the manuscript with all authors. The authors were actively involved in the collection, analysis, or interpretation of the data; the revising of the manuscript for intellectual content; and approval of the final manuscript.
FINANCIAL DISCLOSURE: Drs Reisinger and Block have received research support from and are consultants for Merck and Co, Inc, and have received research grants from GlaxoSmithKline; in addition, Dr Reisinger has received research grants from Novartis, Sanofi-Pasteur MSD, and MedImmune; Drs Collins-Ogle and Marchant have received research support from Merck and Co, Inc. Dr Collins-Ogle has served as an advisor and has received research support from GlaxoSmithKline, Novartis, and Sanofi-Pasteur MSD; Ms Catlett, Mr Radley, and Drs Sings, Haupt, and Garner are employees of Merck and Co, Inc and hold stock/stock options.
- HPV =
- human papillomavirus •
- ACIP =
- Advisory Committee on Immunization Practice •
- AE =
- adverse experience •
- GMT =
- geometric mean titer •
- CI =
- confidence interval
- 1.↵Centers for Disease Control and Prevention (CDC). Human papillomavirus (HPV) infection. Available at: www.cdc.gov/hpv. Accessed March 18, 2010
- Kjaer SK,
- Chackerian B,
- van den Brule AJ,
- et al
- Vesikari T,
- Van Damme P,
- Lindblad N,
- et al
- Broder KR,
- Cortese MM,
- Iskander JK,
- et al
- 8.↵CDC. Factsheet: meningococcal diseases and meningococcal vaccines. Available at: www.cdc.gov/vaccines/vpd-vac/mening/vac-mening-fs.htm. Accessed March 18, 2010
- Villa LL,
- Costa RL,
- Petta CA,
- et al
- Sanofi Pasteur
- Sanofi Pasteur
- Reisinger KS,
- Block SL,
- Lazcano-Ponce E,
- et al
- Block SL,
- Nolan T,
- Sattler C,
- et al
- Giuliano A,
- Lazcano-Ponce E,
- Villa L,
- et al
- 23.↵The FUTURE II Study Group. Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3 and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet. 2007;369:1861–1868
- 24.↵Centers for Disease Control and Prevention. Adolescent immunization what is the public health issue?Available at: www.cdc.gov/NCIRD/progbriefs/downloads/adolescent.pdf. Accessed March 18, 2010
Milk and Nighttime Congestion: Why do some people believe that drinking milk leads to increased congestion, especially at night, and others do not? According to an article in The New York Times (O'Connor A, April 12, 2010), a recent study shows that not all milk is the same, and some types of milk from certain breeds of cow contain a protein called beta-CM-7. This protein apparently stimulates mucous glands in the digestive and respiratory tracts and can enhance mucus production in the setting of inflammatory conditions such as upper respiratory tract infections and asthma. This finding, according to the article, is further described in a recent article in Medical Hypotheses, a journal that focuses on publishing bold and radical theories. Will avoiding milk and other dairy products improve congestion associated with a cold? Thus far there is not a definitive answer, but further research on bovine beta CM-7 may move us in the right direction.
Noted by JFL, MD
- Copyright © 2010 by the American Academy of Pediatrics