Sign Out
Pharmacology: Pharmacodynamics: Mechanism of Action: QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) contains L1 VLPs, which are proteins that resemble wild-type virions. Because the virus-like particles contain no viral DNA, they cannot infect cells or reproduce.
In preclinical studies, induction of anti-papillomavirus antibodies with L1 VLP vaccines resulted in protection against infection. Administration of serum from vaccinated to unvaccinated animals resulted in the transfer of protection against HPV to the unvaccinated animals. These data suggest that the efficacy of L1 VLP vaccines is mediated by the development of humoral immune responses.
Disease Burden: Disease Burden Worldwide, over 490,000 cases of cervical cancer are diagnosed annually. Cervical cancer prevention focuses on repeat screening [e.g., Papanicolaou's (Pap) testing and/or Human Papillomavirus (HPV) testing] and early intervention. This strategy has reduced cancer rates by approximately 75% in the developed world but has shifted the burden from managing cervical cancer to monitoring and treating a large number of premalignant lesions.
Cervical cancer is caused by Human Papillomavirus (HPV) infection. HPV infection is necessary for the development of squamous cell cervical cancer [and its precursor lesions Cervical Intraepithelial Neoplasia (CIN) 1 and CIN 2/3] and cervical adenocarcinoma [and its precursor lesion adenocarcinoma in situ (AIS)]. HPV also causes a subset of vulvar and vaginal cancers and their precursor lesions Vulvar Intraepithelial Neoplasia (VIN) and Vaginal Intraepithelial Neoplasia (VaIN).
HPV infection is very common. Most HPV infections clear without sequelae but some progress to cervical cancer and/or other HPV-related diseases. In the absence of vaccination, over 50% of sexually active individuals will become infected with HPV during their lifetime. Men play an important role in transmission of HPV to their sexual partners. Several prospective studies have shown a high level of HPV concordance between couples who recently became infected, indicating transmission of HPV between the couples (male to female, and female to male). These data consistently support the sexually transmitted nature of HPV and the role of men in infecting women, who subsequently can develop HPV-related anogenital cancers and warts. Based on these various lines of evidence it is expected that decreasing the risk of HPV infection in men through vaccination should decrease the risk of infection in their sexual partners, thereby providing additional public health benefit.
Infection with HPV types 6, 11, 16, and 18 can cause abnormal Pap test results and low-grade dysplastic lesions (CIN 1, VIN 1, and VaIN 1). HPV 6- and HPV 11-related lesions are unlikely to progress to cancer but are clinically indistinguishable from premalignant lesions caused by HPV 16 and HPV 18.
Infection with HPV 6 and HPV 11 also causes genital warts (condyloma acuminata) which are growths of the cervicovaginal, vulvar, perianal and intra-anal mucosa and the external genitalia that rarely progress to cancer. The lifetime risk for acquisition of genital warts has been estimated to exceed 10%. The incidence of this lesion is generally comparable between men and women.
Recurrent Respiratory Papillomatosis (RRP), a disease of infants and adults, is also caused by HPV 6 and HPV 11. RRP is characterized by repeated growth of warts in the respiratory tract. In the U.S., 5,900 cases are diagnosed annually. Therapy requires repeated surgery.
HPV infection is strongly associated with anal cancer. The great majority of anal cancers are squamous cell carcinoma (SCC). Anal canal SCC are HPV positive in 84% of cases in men and women. HPV 16 (73%) and HPV 18 (5%) are the most common associated types.
Approximately 560,000 new cases of head and neck squamous cell cancers (HNSCC) and 250,000 deaths due to HNSCC are reported annually worldwide. Overall, 2/3 of HNSCC cases occur in men. Oropharyngeal squamous cell carcinomas (OPSCC) are a type of HNSCC. OPSCCs that tend to occur in young, non-smoker/non-drinker men account for approximately 24-36% of OPSCCs worldwide. Oral HPV 16 infection has been associated with a significantly elevated risk for development of HNSCC. HPV 16 is detected in >90% of HPV-positive OPSCC cases.
QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) is a recombinant vaccine with L1 proteins resembling HPV types 6, 11, 16, and 18. HPV types 16 and 18 cause approximately: 70% of cervical cancer, AIS, and CIN 3 cases; 50% of CIN 2 cases; 70% of HPV-related vulvar and vaginal cancer, VIN 2/3, and VaIN 2/3 cases; 90% of HPV-related anal cancers and their precursor lesions; and 60% of HPV-related penile cancers.
HPV types 6, 11, 16, and 18 cause approximately: 35 to 50% of all CIN 1, VIN 1, and VaIN 1 cases.
HPV types 6 and 11 cause approximately: 90% of genital wart and RRP cases; and 9 to 12% of CIN 1 cases.
HPV type 16 causes approximately: 90% of Oropharyngeal squamous cell carcinomas.
The effects of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) have also been studied on HPV types 31, 33, 52, 56, 58 and 59. These types cause approximately: 11.6% of cervical cancer cases; 32.2% of CIN 1 cases; 39.3% of CIN 2 cases; and 24.3% of CIN 3 or AIS cases.
Clinical Studies: In female individuals, CIN 2/3 and AIS are the immediate precursors of invasive squamous cell carcinoma and invasive adenocarcinoma of the cervix, respectively. Their detection and removal has been shown to prevent invasive cancer (secondary prevention); thus, their primary prevention through vaccination will prevent invasive cancer.
Invasive cervical cancer cannot be used as an endpoint for efficacy studies of HPV vaccines because of the importance of employing secondary prevention measures. Therefore, the immediate precursors, CIN 2 (moderate-grade cervical dysplasia), CIN 3 (high-grade cervical dysplasia including carcinoma in situ), and AIS are the most appropriate endpoints for the demonstration of the prevention of cervical cancer by HPV vaccines.
CIN 3 and AIS are classified as Stage 0 cervical cancers according to FIGO (International Federation of Obstetrics and Gynaecology). VIN 2/3 and VaIN 2/3 are the immediate precursors to HPV-related vulvar and vaginal cancer, respectively.
In men, up to 84% of penile/perineal/perianal intraepithelial neoplasia (PIN) 1 (low grade) and over 90% of PIN 3 (high grade) has been associated with HPV. HPV 16 is the most common type detected. Erythoplasia of Queyrat (EQ), Bowen's disease (BD), and bowenoid papulosis (BP) are clinical presentations of high-grade PIN. As high as 33% of BD and EQ have been associated with invasive cancer. BP rarely progresses to malignancy.
The efficacy of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) was assessed in 6 placebo-controlled, double-blind, randomized Phase II and III clinical studies. The first Phase II study evaluated the HPV 16 component of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) (Protocol 005, N=2,391 girls and women) and the second evaluated all components of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) (Protocol 007, N=551 girls and women). Three Phase III studies, termed FUTURE (Females United To Unilaterally Reduce Endo/Ectocervical Disease), evaluated QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) in 5,442 (FUTURE I), 12,157 (FUTURE II), and 3,817 (FUTURE III) girls and women. A fourth Phase III study, Protocol 020, evaluated QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) in 4055 boys and men. Together, these studies evaluated 24,358 girls and women 16 through 45 years and 4055 boys and men 16 through 26 years of age at enrollment. The median duration of follow-up was 4.0, 3.0, 3.0, 3.0, 2.2, and 2.3years for Protocol 005, Protocol 007, FUTURE I, FUTURE II, FUTURE III, and Protocol 20, respectively. Individuals received vaccine or placebo on the day of enrollment and 2 and 6 months thereafter. Efficacy was analyzed for each study individually and for all studies conducted in girls and women combined.
The studies did not have a screening phase. Thus, individuals who had been exposed to a vaccine HPV type prior to enrollment were included in the studies. Overall, 73% of 16- through 26-year-old girls and women and 67% of 24- through 45-year-old women were naïve to all 4 vaccine HPV types at enrollment. Overall, 83% of 16- through 26-year-old boys and men were naïve to all 4 vaccine HPV types at enrollment. The naïve individuals continued to be at risk for infection and disease caused by all 4 vaccine HPV types. Among the 24- through 45-year-old women, only 0.4% had been exposed to all 4 vaccine HPV types. Among the 16- through 26-year-old boys and men, only 0.2% had been exposed to all 4 vaccine HPV types.
Prophylactic Efficacy-HPV Types 6, 11, 16, and 18 in 16- Through 26-Year-Old Girls and Women: QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) was highly efficacious in reducing the incidence of cervical, vulvar, and vaginal cancers; CIN (any grade); AIS; non-invasive cervical cancer (CIN 3 and AIS); and external genital lesions, including condyloma acuminata, VIN (any grade) and VaIN (any grade) caused by HPV types 6, 11, 16, and 18. Based on a pre-specified analysis of lesions evident beginning 30 days Postdose 1, there was evidence that the vaccine was already efficacious during the course of the 3-dose vaccination regimen.
The primary analyses of efficacy, with respect to HPV types 6, 11, 16, and 18, were conducted in the per-protocol efficacy (PPE) population, consisting of individuals who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naïve to the relevant HPV type(s) prior to dose one and through 1 month Postdose 3 (Month 7). Efficacy was measured starting after the Month 7 visit (Table 1).
Click on icon to see table/diagram/imageSupplemental Analysis of Efficacy for Cancer Endpoints in 16- Through 26-Year-Old Girls and Women: In a supplemental analysis, the efficacy of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) was evaluated against HPV 16/18-related FIGO Stage 0 cervical cancer (CIN 3 and AIS) and for the immediate precursors to vulvar and vaginal cancer (VIN 2/3 or VaIN 2/3) in the per-protocol efficacy (PPE) population and a modified intention to treat-2 (MITT-2) population. The MITT-2 population consisted of individuals who were naïve to the relevant HPV type(s) (types 6, 11, 16, and 18) prior to dose 1, received at least one dose of vaccine or placebo, and had at least one follow-up visit post-Day 30. The MITT-2 population differs from the PPE population in that it includes individuals with major protocol violations and who became infected with a vaccine HPV type during the vaccination period. Efficacy was measured starting 30 days Postdose 1 for the MITT-2 population.
QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) was equally efficacious against HPV 16/18-related CIN 3, AIS, VIN 2/3, and VaIN 2/3 in both the PPE and MITT-2 populations (Table 2).
Click on icon to see table/diagram/imageProphylactic efficacy against overall persistent infection or disease in an extension phase of Protocol 007, that included data through Month 60, was 95.8% (95% CI: 83.8%, 99.5%). In the group that received QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL), no cases due to waning immunity were observed.
QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) was equally efficacious against HPV disease caused by HPV types 6, 11, 16, and 18.
Efficacy in 16- Through 26-Year-Old Girls and Women with Current or Prior Infection with HPV Types 6, 11, 16, or 18: Individuals who were already infected with one or more vaccine-related HPV types prior to vaccination were protected from clinical disease caused by the remaining vaccine HPV types.
Individuals with evidence of a prior infection that had resolved by vaccination onset were protected from reacquisition or recurrence of infection leading to clinical disease.
Individuals who received QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL), but had ongoing HPV infection at the time of vaccination had a 21.6% (95% CI: <0.0%, 42.1%) lower incidence of CIN (CIN 1 or CIN 2/3) or AIS resulting from this infection as compared with placebo. Ongoing infection was defined as infection with a vaccine HPV type at enrollment, but no evidence of immune response to it.
Prophylactic Efficacy in a Generally HPV-naïve Population and the General Study Population - HPV Types 31, 33, 45, 52, 56, 58 and 59 in 16- Through 26-Year-Old Girls and Women: Women The cross-protective efficacy of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) was evaluated in the combined database of the FUTURE I and FUTURE II trials (N=17,599). The primary endpoint of this analysis was the combined incidence of HPV 31- and HPV 45-related CIN (grades 1, 2, 3) or AIS. The secondary endpoint of this analysis was the combined incidence of HPV 31-, 33-, 45-, 52-, and 58-related CIN (grades 1, 2, 3) or AIS. Analyses were also conducted to evaluate efficacy with respect to CIN (grades 1, 2, 3) or AIS caused by non-vaccine HPV types individually. In individuals who were naïve to the relevant vaccine HPV types at Day 1 (MITT-2 population, n=16,895 for the 31/45 composite endpoint and n=16,969 for the 31/33/45/52/58 composite endpoint), a trend towards a reduction in the incidence of HPV 31- and 45-related and HPV 31-, 33-, 45-, 52-, and 58-related CIN (grades 1, 2, 3) or AIS was observed. Administration of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) reduced the incidence of HPV 31- and HPV 45-related CIN (grades 1, 2, 3) by 37.3% (95% CI: 17.0%, 52.8%) compared with placebo. Administration of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) reduced the incidence of HPV 31-, 33-, 45-, 52-, and 58-related CIN (grades 1, 2, 3) or AIS by 26.4% (95% CI: 12.9%, 37.8%), compared with placebo. Efficacy was driven by reductions in HPV 31-, 33-, 52-, and 58-related endpoints. There was no clear evidence of efficacy for HPV 45. In a post-hoc analysis, prophylactic administration of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) also reduced the incidence of HPV 56-related and HPV 59-related CIN (grades 1, 2, 3) or AIS, compared with placebo in this population.
Further post-hoc analyses considered efficacy in 2 clinically relevant populations: (1) an HPV-naïve population (negative to 14 common HPV types and had a Pap test that was negative for SIL [Squamous Intraepithelial Lesion] at Day 1), approximating a population of sexually-naïve individuals plus individuals shortly after sexual debut; and (2) the general study population of individuals regardless of baseline HPV status, some of whom had HPV-related disease at vaccination onset. Administration of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) to HPV-naïve individuals reduced the incidences of HPV 31-, 33-, 52-, and 58-related CIN (grades 1, 2, 3) or AIS, HPV 56-related CIN (grades 1, 2, 3) or AIS, and HPV 59-related CIN (grades 1, 2, 3) or AIS. Reductions in the rates of these diseases were also observed in the general study population (which included HPV-naïve and HPV-infected individuals).
Cross-protection efficacy analyses demonstrate that prophylactic administration of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) to individuals reduces the risk of acquiring CIN 1, CIN 2/3, and AIS caused by HPV types 31, 33, 52, 56, 58, and 59 (Table 3).
Click on icon to see table/diagram/imageProtection Against the Overall Burden of Cervical, Vulvar, and Vaginal HPV Disease in 16- Through 26-Year-Old Girls and Women: The impact of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) against the overall risk for cervical, vulvar, and vaginal HPV disease (i.e., disease caused by any HPV type) was evaluated in a pre-specified analysis of 17,599 individuals enrolled in FUTURE I and FUTURE II. Among individuals who were naïve to at least one of 14 common HPV types and/or had a Pap test that was negative for SIL [Squamous Intraepithelial Lesion] at Day 1 (MITT-2 population), administration of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) reduced the incidence of CIN 2/3 or AIS caused by vaccine- or non-vaccine HPV types by 33.8% (95% CI: 20.7%, 44.8%).
Further efficacy analyses were conducted in 2 clinically relevant populations: (1) an HPV-naïve population (negative to 14 common HPV types and had a Pap test that was negative for SIL [Squamous Intraepithelial Lesion] at Day 1), approximating a population of sexually-naïve individuals plus individuals shortly after sexual debut; and (2) the general study population of individuals regardless of baseline HPV status, some of whom had HPV-related disease at vaccination onset.
Among HPV-naïve individuals and among the general study population (including individuals with HPV infection at vaccination onset), QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) reduced the overall incidence of CIN 2/3 or AIS; of VIN 2/3 or VaIN 2/3; of CIN (any grade) or AIS; and of Genital Warts (Table 4). These reductions were primarily due to reductions in lesions caused by HPV types 6, 11, 16, and 18. Among HPV-naïve individuals (Figure 1) and the general study population (Figure 2), the benefit of the vaccine with respect to the overall incidence of CIN 2/3 or AIS (caused by any HPV type) became more apparent over time. This is because QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) does not impact the course of infections that are present at vaccination onset. Such infected individuals may already have CIN 2/3 or AIS at vaccination onset and some will develop CIN 2/3 or AIS during follow-up. QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) reduces the incidence of CIN 2/3 or AIS caused by infections with HPV types 6, 11, 16, 18, 31, 33, 52, 56, 58 and 59 that occur after vaccination onset. (See Table 4, Figure 1 and Figure 2.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageQUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) has not been shown to protect against the diseases caused by every HPV type, and will not treat existing disease. The overall efficacy of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) will vary with the baseline prevalence of HPV infection and disease, the incidence of infections against which QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) has shown protection, and those infections against which QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) has not been shown to protect.
Impact on the Rates of Pap Test Abnormalities and Cervical, Vulvar, and Vaginal Procedures in 16- Through 26-Year-Old Girls and Women: The impact of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) on rates of abnormal Pap tests and cervical procedures (colposcopic biopsy, definitive therapy) regardless of causal HPV types was evaluated in 18,150 individuals enrolled in Protocol 007, FUTURE I and FUTURE II. The impact of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) on rates of genital excisional procedures to treat lesions caused by any HPV type was evaluated in 5,442 individuals enrolled in FUTURE I. Two populations were considered: (1) an HPV-naïve population (negative to 14 common HPV types and had a Pap test that was negative for SIL [Squamous Intraepithelial Lesion] at Day 1), approximating a population of sexually-naïve individuals plus individuals shortly after sexual debut; and (2) the general study population of individuals regardless of baseline HPV status, some of whom had HPV-related disease at vaccination onset.
In both populations, QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) reduced the proportions of individuals who experienced a Pap test abnormality suggestive of CIN, a colposcopic biopsy, a definitive cervical therapy procedure (Loop Electro-Excision Procedure or Cold-Knife Conization), a vulvar or vaginal biopsy, or a definitive excisional procedure of the vagina or vulva (Table 5).
Click on icon to see table/diagram/imageIn addition, administration of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) to a generally HPV naïve population of 16- through 26-year-old individuals reduced the incidence of HPV 16-related and HPV 18-related Pap abnormalities (ASC-US HR positive, LSIL, or worse) by 92.4% (95% CI: 83.7%, 97.0%) and 96.9% (95% CI: 81.6%, 99.9%) in the FUTURE I study.
Prophylactic Efficacy - HPV Types 6, 11, 16, and 18 in 24- Through 45-Year-Old Women: A minimum anti-HPV level that provides protection against HPV infection and disease has not been defined. Also, immune responses to vaccines are typically lower in older individuals compared to younger individuals. Therefore, to confirm the utility of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) to prevent cervical, vulvar, and vaginal cancers and related diseases caused by the types targeted by the vaccine in individuals up to and including age 45 years, an efficacy study (FUTURE III) was conducted.
QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) was highly efficacious in reducing the incidence of persistent infection; CIN (any grade); and external genital lesions (EGL) caused by HPV types 6, 11, 16, and 18. QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) was also highly efficacious in reducing the incidence of a HPV 16/18-related Pap Test diagnosis of ASC-US (Atypical Squamous Cells of Undetermined Significance) positive for high-risk HPV. The primary analyses of efficacy, with respect to HPV types 6, 11, 16, and 18, were conducted in the per-protocol efficacy (PPE) population. Efficacy was measured starting after the Month 7 visit (Table 6).
On the basis of these efficacy findings, the efficacy of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) with respect to prevention of cervical, vulvar, and vaginal cancers and related diseases in individuals up to and including age 45 years can be inferred. (See Table 6.)
Click on icon to see table/diagram/imageProphylactic Efficacy - HPV Types 6, 11, 16, and 18 in 16- Through 26-Year-Old Boys and Men: In clinical studies in boys and men, efficacy was evaluated using the following endpoints: external genital warts; penile/perineal/perianal intraepithelial neoplasia (PIN) grades 1/2/3 or penile/perineal/perianal cancer; and persistent infection. High grade PIN is associated with certain types of penile/perineal/perianal cancers. Persistent infection is a predictor of clinical disease.
The primary analyses of efficacy were conducted in the per-protocol efficacy (PPE) population. This population consisted of individuals who received all 3 vaccinations within 1 year of enrollment, did not have major deviations from the study protocol, and were naïve (PCR negative and seronegative) to the relevant HPV type(s) (Types 6, 11, 16, and 18) prior to dose 1 and through 1 month postdose 3 (month 7). Efficacy was measured starting after the Month 7 visit.
QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) was efficacious in reducing the incidence of external genital lesions (Condyloma and PIN grades 1/2/3) and persistent infection related to vaccine HPV types 6, 11, 16, or 18 in those who were PCR negative and seronegative at baseline (see Table 7).
Click on icon to see table/diagram/imageImmunogenicity: Assays to Measure Immune Response: Type-specific assays with type-specific standards were used to assess immunogenicity to each vaccine HPV type. These assays measured antibodies against neutralizing epitopes for each HPV type, rather than the total antibodies directed at the VLPs in the vaccine. The scales for these assays are unique to each HPV type; thus, comparisons across types and to other assays are not meaningful. The assays used to measure the immune responses to QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) were demonstrated to correlate with the capacity to neutralize live HPV virions.
Because of the very high efficacy of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) in clinical trials, it has not been possible to establish minimum anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 antibody levels that protect against clinical HPV disease.
The immunogenicity of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) was assessed in 23,951 9- through 45-year-old girls and women (QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) N=12,634; placebo N=11,317) and 5,417 9- through 26-year-old boys and men (QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) N=3,109; placebo N=2,308).
The primary immunogenicity analyses were conducted in a per-protocol immunogenicity (PPI) population. This population consisted of individuals who were seronegative and Polymerase Chain Reaction (PCR) negative to the relevant HPV type(s) at enrollment, remained HPV PCR negative to the relevant HPV type(s) through 1 month Postdose 3 (Month 7), received all 3 vaccinations, and did not deviate from the study protocol in ways that could interfere with the effects of the vaccine.
Immunogenicity was measured by (1) the percentage of individuals who were seropositive for antibodies against the relevant vaccine HPV type, and (2) the Geometric Mean Titer (GMT).
Immune Response to QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) at Month 7 in 9- Through 45-Year-Old Girls and Women (Time Point Approximating Peak Immunogenicity): In the per-protocol immunogenicity population of 9- through 45-year-olds, seropositivity at Month 7 ranged from 96.4% to 99.9% across all 4 vaccine types and across populations defined by age range. Anti-HPV GMTs for all types decreased with age (Table 8). This finding is expected, as the immune responses to vaccines generally decrease with age at vaccination. The efficacy of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) remained high despite the observed age-related decrease in anti-HPV GMTs. (See Table 8.)
Click on icon to see table/diagram/imageImmune Response to QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) at Month 7 in 9- Through 26-Year-Old Boys and Men (Time Point Approximating Peak Immunogenicity): In the per-protocol immunogenicity population of 9- through 26-year-olds, seropositivity at Month 7 ranged from 97.4% to 99.9% across all 4 vaccine types and across populations defined by age range. Anti-HPV GMTs for all types decreased with age (Table 9). This finding is expected, as the immune responses to vaccines generally decrease with age at vaccination. The efficacy of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) remained high despite the observed age-related decrease in anti-HPV GMTs. (See Table 9.)
Click on icon to see table/diagram/imageBridging the Efficacy of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) from Adults to Adolescents: A clinical study compared anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 responses in 10- through 15-year-old adolescent girls with responses in 16- through 23-year-old girls and women. Among the girls and women who received QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL), 99.1% to 100% became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive by 1 month Postdose 3. Anti-HPV responses in 10- through 15-year-old adolescent girls were significantly superior to those observed in 16- through 23-year-old girls and women.
Similar outcomes were observed in a comparison of the anti-HPV responses 1 month Postdose 3 among 9- through 15-year-old adolescent girls with anti-HPV responses in 16-through 26-year-old girls and women in the combined database of immunogenicity studies for QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL).
Anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 responses (GMTs) were compared between 9- through 15-year-old adolescent boys and 16- through 26-year-old boys and men. Among individuals who received QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL), 97.4% to 99.9% became anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositive by 1 month postdose 3. Anti-HPV responses in 9- through 15-year-old adolescent boys were significantly superior to those observed in 16- through 26-year-old boys and men.
On the basis of this immunogenicity bridging, the efficacy of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) in 9- through 15-year-old adolescent girls is comparable to the efficacy of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) observed in 16- through 26-year-old girls and women. Additionally, the efficacy of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) in 9- through 15-year-old adolescent boys is comparable to the efficacy of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) observed in studies in 16- through 26-year-old boys and men.
Persistence of The Immune Response to QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL): The duration of immunity following a complete schedule of immunization with QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) has not been established. After peaking at Month 7, anti-GMTs for all HPV types decreased through Month 24 and then stabilized at levels above baseline.
In Protocol 007, peak anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs were observed at Month 7. The GMTs decreased through Month 24 and then stabilized until at least Month 60 (see Figure 3).
Click on icon to see table/diagram/imageEvidence of Anamnestic (Immune Memory) Response: Evidence of an anamnestic response was seen in vaccinated individuals who were seropositive to relevant HPV type(s) prior to vaccination.
In a study to evaluate the capacity to induce immune memory, individuals who received a 3-dose primary series of vaccine were given a challenge dose of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) 5 years after the onset of vaccination. These individuals exhibited a rapid and strong anamnestic response that exceeded the anti-HPV GMTs observed 1 month Postdose 3 (Month 7). The GMTs 1 week post-challenge dose were 0.9-, 2.2-, 1.2-, and 1.4-fold higher than the Postdose 3 GMTs for types 6, 11, 16, and 18, respectively (Table 10). The GMTs 1 month post-challenge dose were 1.3-, 4.2-, 1.5-, and 1.7-fold higher than the Postdose 3 GMTs for types 6, 11, 16, and 18, respectively. At 1 week post-challenge dose, 87.2%, 94.9%, 86.4% and 95.2% of individuals had anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 GMTs higher than those detected at Month 60.
In addition, a subset of individuals that received a 3-dose primary series of vaccine became nominally anti-HPV 18 seronegative by Month 60. Although these individuals were nominally anti-HPV 18 seronegative, no cases of HPV 18-related disease were detected among these individuals. They also showed immune memory: When these individuals were given a challenge dose of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) (at Month 60), 93% and 97% became anti-HPV 18 seropositive by 1 week and 1 month post-challenge, respectively; 73% had anti-HPV 18 levels at 1 month post-challenge that were higher than their Month 7 (1 month Postdose 3) anti-HPV 18 level. (See Table 10.)
Click on icon to see table/diagram/imagePersistence of Immune Response in Phase III Studies of 9- Through 45-Year-Old Girls and Women for QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL): Anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 seropositivity was highest at Month 7, and then declined at persistence time points (Table 11). At Month 24, anti-HPV seropositivity was highest among 9- through 17-year-olds and lowest among 35- through 45-year-olds.
The decline in the percent seropositivity for anti-HPV 18 responses was greater than the decline in the percent seropositivity for anti-HPV 6, anti-HPV 11, and anti-HPV 16 responses. Despite this decline, the efficacy of the vaccine remained high, across all age groups. In the PPE population of the FUTURE I and FUTURE II studies, efficacy against HPV 18-related CIN 2/3 or AIS was 100.0% (95% CI: 86.6%, 100.0%) and efficacy against HPV 18-related CIN (any grade) or AIS was 98.4% (95% CI: 90.6%, 100.0%). In the PPE population of the FUTURE III study, efficacy against HPV 18-related persistent infection or cervical, vulvar, and vaginal disease was 100.0% (95% CI: <0.0%, 100.0%). (See Table 11.)
Click on icon to see table/diagram/imagePersistence of Immune Response in Phase III Studies of 9- Through 26-Year-Old Boys and Men for QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL): Anti-HPV 6, anti-HPV 11, and anti-HPV 18 seropositivity was highest at Month 7, and then declined at persistence time points. At Month 24, anti-HPV seropositivity was highest among 9- through 15-year-olds and lowest among 16- through 26-year-olds (Table 12). For anti-HPV 16, seropositivity declined from Month 7 to Month 24 in the 9- through 15-year-olds but did not decline in the 16- through 26-year-olds. Additionally, anti-HPV 16 seropositivity was comparable at Month 24 in the 16- through 26-year-olds as compared to the 9- through 15-year-olds.
The decline in the percent seropositivity for anti-HPV 18 responses was greater than the decline in the percent seropositivity for anti-HPV 6, anti-HPV 11, and anti-HPV 16 responses. Despite this decline, the efficacy of the vaccine remained high, across all age groups. (See Table 12.)
Click on icon to see table/diagram/imageSchedule Flexibility: All individuals evaluated in the PPE populations of the Phase II and III studies received the 3-dose regimen of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) within a 1-year period, regardless of the interval between doses. An analysis of immune response data suggests that flexibility of ±1 month for Dose 2 (i.e., Month 1 to Month 3 in the vaccination regimen) and flexibility of ±2 months for Dose 3 (i.e., Month 4 to Month 8 in the vaccination regimen) do not substantially impact the immune responses to QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) (see Dosage & Administration).
Studies with Other Vaccines: H-B-VAX II [hepatitis B vaccine (recombinant)]: The safety and immunogenicity of co-administration of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) with H-B-VAX II [hepatitis B vaccine (recombinant)] (same visit, injections at separate sites) were evaluated in a randomized study of 1,871 women aged 16 through 24 years at enrollment. Immune response and safety profile to both H-B-VAX II [hepatitis B vaccine (recombinant)] and QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) were similar whether they were administered at the same visit or at a different visit.
Repevax [Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine, (adsorbed, reduced antigen(s) content)]: The safety and immunogenicity of co-administration of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) with Repevax [Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine, (adsorbed, reduced antigen(s) content)] (same visit, injections at separate sites) were evaluated in a randomized study of 843 boys and girls 11 through 17 years of age at enrollment. Concomitant administration of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) with Repevax [Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine, (adsorbed, reduced antigen(s) content)] does not interfere with the antibody response to any of the components of either vaccine. In addition, the safety profile was generally similar (see Side Effects, Concomitant Administration with Other Vaccines).
Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)]: The safety and immunogenicity of co-administration of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) with Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)] (same visit, injections at separate sites) were evaluated in a randomized study of 1040 boys and girls 11 through 17 years of age at enrollment. Concomitant administration of QUADRIVALENT HUMAN PAPILLOMAVIRUS (TYPES 6, 11, 16, 18) RECOMBINANT VACCINE (GARDASIL) with Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine] and Adacel [Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap)] does not interfere with the antibody response to any of the components of any of the vaccines. In addition, the safety profile was generally similar (see Side Effects, Concomitant Administration with Other Vaccines).
Continue with Google