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Gardasil 100% Effective in Preventing Anogenital Diseases
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Quadrivalent Vaccine against Human Papillomavirus to Prevent Anogenital Diseases
NEJM, May 10, 2007
Suzanne M. Garland, M.D., Mauricio Hernandez-Avila, M.D., Cosette M. Wheeler, Ph.D., Gonzalo Perez, M.D., Diane M. Harper, M.D., M.P.H., Sepp Leodolter, M.D., Grace W.K. Tang, M.D., Daron G. Ferris, M.D., Marc Steben, M.D., Janine Bryan, Ph.D., Frank J. Taddeo, Ph.D., Radha Railkar, Ph.D., Mark T. Esser, Ph.D., Heather L. Sings, Ph.D., Micki Nelson, B.S., John Boslego, M.D., Carlos Sattler, M.D., Eliav Barr, M.D., Laura A. Koutsky, Ph.D., for the Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I Investigators
"....The coprimary composite end points were the incidence of genital warts, vulvar or vaginal intraepithelial neoplasia, or cancer and the incidence of cervical intraepithelial neoplasia, adenocarcinoma in situ, or cancer associated with HPV type 6, 11, 16, or 18. .... Vaccine efficacy was 100% for each of the coprimary end points. These results of the FUTURE I study show that a prophylactic quadrivalent HPV vaccine is highly effective in preventing clinical disease, including anogenital warts and intraepithelial neoplasia of the cervix, vagina, and vulva, associated with HPV-6, HPV-11, HPV-16, and HPV-18. There were relatively few adverse events among the vaccine recipients.... Subjects in this ongoing trial were followed for an average of 3 years after administration of the first dose of vaccine or placebo...."
Anogenital infection with the human papillomavirus (HPV) can cause warts, intraepithelial neoplasia, and invasive cancers.1,2,3,4,5,6 The majority of HPV-associated diseases are caused by HPV types 6, 11, 16, and 18. HPV types 6 (HPV-6) and 11 (HPV-11) cause most anogenital warts, a portion of the cases of low-grade neoplasia,5,7,8,9,10 and recurrent respiratory papillomatosis, a rare but potentially life-threatening disease.11,12,13 HPV type 16 (HPV-16) is the most common cause of invasive cancers of the cervix and other anogenital cancers associated with HPV.4,6,14,15,16,17,18,19 HPV type 18 (HPV-18), the second most common cause of cervical cancer, is detected even more frequently in adenocarcinoma, the incidence of which is increasing.18,20,21 The precursor lesion of adenocarcinoma is difficult to detect on routine Papanicolaou testing or colposcopy.21,22 A phase 3 trial of the efficacy and safety of a quadrivalent HPV vaccine (targeting HPV-6, HPV-11, HPV-16, and HPV-18) was designed to include an intensive schedule of visits and aggressive regimens to identify cases of genital disease associated with HPV in the study population.
ABSTRACT
Background A phase 3 trial was conducted to evaluate the efficacy of a prophylactic quadrivalent vaccine in preventing anogenital diseases associated with human papillomavirus (HPV) types 6, 11, 16, and 18.
Methods In this randomized, placebo-controlled, double-blind trial involving 5455 women between the ages of 16 and 24 years, we assigned 2723 women to receive vaccine and 2732 to receive placebo at day 1, month 2, and month 6. The coprimary composite end points were the incidence of genital warts, vulvar or vaginal intraepithelial neoplasia, or cancer and the incidence of cervical intraepithelial neoplasia, adenocarcinoma in situ, or cancer associated with HPV type 6, 11, 16, or 18. Data for the primary analysis were collected for a per-protocol susceptible population of women who had no virologic evidence of HPV type 6, 11, 16, or 18 through 1 month after administration of the third dose.
Results The women were followed for an average of 3 years after administration of the first dose. In the per-protocol population, those followed for vulvar, vaginal, or perianal disease included 2261 women (83%) in the vaccine group and 2279 (83%) in the placebo group. Those followed for cervical disease included 2241 women (82%) in the vaccine group and 2258 (83%) in the placebo group. Vaccine efficacy was 100% for each of the coprimary end points. In an intention-to-treat analysis, including those with prevalent infection or disease caused by vaccine-type and non-vaccine-type HPV, vaccination reduced the rate of any vulvar or vaginal perianal lesions regardless of the causal HPV type by 34% (95% confidence interval [CI], 15 to 49), and the rate of cervical lesions regardless of the causal HPV type by 20% (95% CI, 8 to 31).
Conclusions The quadrivalent vaccine significantly reduced the incidence of HPV-associated anogenital diseases in young women.
Study Design
The Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I study is an ongoing, double-blind, placebo-controlled, randomized trial sponsored by Merck; the study was designed and managed and the results were analyzed by the sponsor in conjunction with external academic investigators and an external data and safety monitoring board. From January 2002 through March 2003, 6463 women underwent screening for eligibility; of these, we enrolled a total of 5455 (84%) subjects between the ages of 16 and 24 years at 62 study sites in 16 countries. The institutional review board at each site approved the protocol. Written informed consent was obtained from each subject. The study population was drawn primarily from communities near universities. Healthy women who were not pregnant and had no history of genital warts or abnormal results on cervical cytologic testing and had a lifetime number of no more than four sex partners were eligible. The women were required to use effective contraception during the vaccination period (day 1 through month 7) of the study.
The sponsor collated the data and monitored the conduct of the study. The cutoff date for this manuscript was June 15, 2006. The sponsor and the academic authors proposed the statistical analyses, which were performed by the sponsor. All authors had full access to these analyses and approved the final manuscript. The manuscript was drafted by employees of the sponsor in collaboration with academic authors. All authors vouch for the completeness and accuracy of the data presented.
Results
From January 2002 through March 2003, a total of 6463 women between the ages of 16 and 24 years were screened for eligibility at 62 study sites in the Asia-Pacific region, Europe, and North, Central, and South America. Of these women, 5455 met the inclusion criteria, and 2723 women were randomly assigned to receive quadrivalent vaccine and 2732 were assigned to receive placebo. Only a small percentage (8 of 5388 subjects [0.15%]) had serologic evidence or HPV DNA evidence of infection with all the HPV types covered by the quadrivalent vaccine (Table 1). The two study groups were well balanced with regard to baseline characteristics and were also similar in the numbers of subjects excluded from the populations analyzed. Subjects in whom vaccine-type HPV was detected at baseline were excluded from the analyses for prophylactic efficacy (Table 2).
Subjects in this ongoing trial were followed for an average of 3 years after administration of the first dose of vaccine or placebo. At least 83% of those who underwent randomization were included in one or more of the type-specific, per-protocol susceptible populations for external anogenital or vaginal lesions (2261 subjects in the vaccine group and 2279 in the placebo group). The HPV vaccine was 100% effective (95% CI, 94 to 100; 0 cases in the vaccine group vs. 60 cases in the placebo group) in preventing vaginal, vulvar, perineal, and perianal intraepithelial lesions or warts in association with vaccine-type HPV. In the type-specific, per-protocol susceptible populations, in the analysis for cervical end points, among 2241 subjects in the vaccine group and 2258 in the placebo group, the vaccine was 100% effective (95% CI, 94 to 100; 0 vs. 65 cases, respectively) in preventing cervical intraepithelial neoplasia of grades 1 to 3 or adenocarcinoma in situ in association with vaccine-type HPV (Table 3). The estimates of vaccine efficacy made on the basis of the diagnoses at the central laboratory were similar to the estimates made by the pathology panel (data not shown).
More than 95% of the subjects who underwent randomization were included in one or more of the type-specific, unrestricted susceptible populations. The vaccine efficacy was 95% when all grades of external anogenital or vaginal lesions were combined (4 cases in the vaccine group vs. 81 cases in the placebo group), 98% when all grades of cervical lesions were combined (2 vs. 89 cases, respectively), with an efficacy of 91% for high-grade vulvar or vaginal lesions (1 vs. 11 cases, respectively), and 100% for adenocarcinoma in situ (0 vs. 6 cases, respectively) (Table 3). Overall, more than 95% of the subjects received the complete regimen of three doses of vaccine or placebo.
Because the public health benefit of a safe and effective HPV vaccine will be measured by its effect in all vaccinated women, we estimated vaccine efficacy in an intention-to-treat population, regardless of the baseline HPV status of the subjects included in the analysis (Table 3). The analysis included women with prevalent infections with vaccine-type HPV or diseases associated with these HPV types. The efficacy against vaccine-type HPV was 73% (95% CI, 58 to 83) when all grades of external anogenital or vaginal lesions were combined (28 cases in the vaccine group vs. 102 cases in the placebo group) and 55% (95% CI, 40 to 66) when all grades of cervical lesions were combined (71 vs. 155 cases, respectively) (Table 3). In the intention-to-treat population, in the placebo group, the incidence of external anogenital or cervical disease associated with vaccine-type HPV continued to increase over time, whereas in the vaccine group the incidence began to plateau (Figure 2). There was no clear evidence that vaccination altered the course of disease or infection present before administration of the first dose (Table 2 in the Supplementary Appendix). No cancers associated with any vaccine-type HPV were identified.
A second intention-to-treat analysis in the population of all women who underwent randomization was performed to evaluate the effectiveness of the vaccine against all anogenital disease (i.e., caused by either a vaccine-type HPV or one not covered by the vaccine). For the primary composite disease end points, in the vaccine group there was a reduction of 34% (95% CI, 15 to 49; 104 cases in the vaccine group vs. 157 cases in the placebo group) in the incidence of external anogenital or vaginal lesions and a reduction of 20% (95% CI, 8 to 31; 344 vs. 421 cases, respectively) in cervical lesions, regardless of the causal HPV type (Table 3 and Figure 2).
For each HPV type covered by the quadrivalent vaccine, at least 99.5% of the subjects in the respective per-protocol immunogenicity cohort had seroconversion at 1 month after the third dose. (For details on the persistence of immune titers, see the Supplementary Appendix.) Five of six recipients of the quadrivalent vaccine in the unrestricted susceptible population who had a genital lesion associated with vaccine-type HPV had antibody titers for an anti-HPV response that were similar to the corresponding anti-HPV antibody response in the per-protocol immunogenicity population. The sixth subject had incorrectly received three doses of placebo.
Vaccine recipients (87%) were more likely than placebo recipients (77%) to have adverse events at the injection site, the most common of these being pain at the site (risk difference, 10 percentage points; 95% CI, 7.8 to 12.1). Erythema, pruritus, and swelling at the injection site were also more common among vaccine recipients than among placebo recipients (Table 4). With respect to systemic adverse events, a nominally higher proportion of vaccine recipients (13.3%), as compared with placebo recipients (10.3%), reported fever between 100F (37.8C) and 102F (38.9C) (risk difference, 3.0; 95% CI, 1.3 to 4.8) (Table 4). Similar proportions of vaccine and placebo recipients reported a serious adverse event. All systemic and serious adverse events, categorized according to organ system and treatment group, are shown in Tables 3 and 4 in the Supplementary Appendix.
Among the subjects who were seropositive for one or more of the four HPV types at day 1, the profile of adverse events was similar to that of the entire study cohort. For example, of 529 vaccine recipients, 452 (85%) reported one or more injection-site adverse events, as compared with 388 of 507 placebo recipients (77%), with injection-site pain reported as the most frequent adverse event in 84% of the vaccine recipients and 74% of the placebo recipients (risk difference, 10.1; 95% CI, 5.2 to 15.1) (Table 4). One subject in this subgroup had a serious vaccine-related adverse event (bronchospasm 1 day after receipt of the third dose). No multiplicity adjustments were made for these comparisons. For a summary of the pregnancy outcomes in the combined phase 3 quadrivalent vaccine studies, see the report by the FUTURE II study group (and Tables 2, 3, and 4 in that article's Supplementary Appendix).25
Discussion
These results of the FUTURE I study show that a prophylactic quadrivalent HPV vaccine is highly effective in preventing clinical disease, including anogenital warts and intraepithelial neoplasia of the cervix, vagina, and vulva, associated with HPV-6, HPV-11, HPV-16, and HPV-18. There appears to be no interference among the four HPV types covered by the vaccine, since 100% HPV-type-specific efficacy was observed in the per-protocol analysis. There were relatively few adverse events among the vaccine recipients.
Several steps were taken to ensure that this study would provide a high level of confidence in the safety and efficacy of the quadrivalent vaccine. A diverse population of young women participating in developed and developing countries were enrolled. Data on serious vaccine-related or procedure-related adverse events and pregnancy outcomes were collected for the entire follow-up period. Since HPV-associated vaginal and vulvar lesions may have an ambiguous clinical presentation, an intensive visit schedule with aggressive regimens for genital inspection, biopsy of suspect lesions and cytologic screening, and colposcopy with biopsy were used to ensure a high sensitivity for HPV-associated lesions. High diagnostic accuracy for end-point determinations was provided by a panel of expert pathologists who were unaware of the treatment assignments. Estimates of vaccine efficacy were high whether the diagnoses were made by the pathology panel or by the central laboratory, indicating robust efficacy measurements.
When we evaluated the quadrivalent vaccine's effectiveness against disease associated with the HPV types covered by the vaccine in the intention-to-treat population (as compared with the unrestricted susceptible population), all additional cases detected in the vaccine group occurred in subjects who were infected with vaccine-type HPV before vaccination. Among all randomized subjects with an end-point event within the first year of follow-up, both the vaccine group (57 [97%] cases of disease in 59 subjects) and the placebo group (59 [81%] cases of disease in 73 subjects) had evidence of infection or disease that was prevalent at enrollment. During the second year of follow-up, the incidence of disease associated with vaccine-type HPV in the placebo group continued to increase, whereas in the vaccine group the incidence appeared to reach a plateau, as cases of disease due to prevalent infection were no longer detected and vaccine appeared to reduce the incidence of new infections and associated disease.
A decrease (unadjusted for multiplicity) in overall rates of anogenital disease, regardless of causal HPV type, was also observed. The development of vulvar cancer, though rare, in one subject in the vaccine group highlights the importance of continued screening. Since vaccinated women remain at risk for cervical and genital disease resulting from infections with vaccine-type HPV that might be present at the time of vaccination and from newly acquired infections with HPV types that are not targeted by the quadrivalent HPV vaccine, such women should continue to undergo regular cervical screening for cancer and genital examination, as clinically indicated.
A limitation of our study is the lack of long-term follow-up. The duration of the efficacy of the quadrivalent HPV vaccine and whether boosters are needed are not known. Similarly, to date, no minimum protective anti-HPV antibody titers have been identified. A phase 2 trial of the quadrivalent vaccine showed that at 5 years the vaccine is highly efficacious against infection and disease associated with vaccine-type HPV and that vaccine-induced anti-HPV antibody levels are maintained at or above the levels observed in natural infection.28,29 At 5 years in this phase 2 study, an antigen challenge resulted in strong anamnestic responses, with sharp rises in antibody titer, indicating the presence of strong, long-lived immune memory.29 The FUTURE I study had limited power to definitively address individual components of the composite study end points; however, the consistency of the results for all components and the results of the FUTURE II study25 are encouraging.
As in other trials of prophylactic vaccines,30 our primary analysis focused on women who at baseline were not infected with vaccine-type HPV. Under conditions that may reflect deviations in vaccine dosing intervals, such as in the unrestricted susceptible population, the efficacy against these HPV types remained high - 95% for external anogenital or vaginal lesions and 98% for cervical lesions. These data also suggest that there is some flexibility in the timing of the vaccination regimen. Adolescent men and women mount higher antibody responses to the quadrivalent vaccine31 than do young adult women, but whether the quadrivalent HPV vaccine will prevent genital infection and lesions in men is unknown.
Our data demonstrate the efficacy of a prophylactic quadrivalent HPV vaccine against lesions caused by all the targeted types of HPV. There was also a reduction in the overall incidence of anogenital lesions in the vaccine group. Widespread vaccination of young women and adolescent girls should reduce the incidence of cervical and external anogenital disease associated with HPV-6, HPV-11, HPV-16, and HPV-18. Further research is needed to evaluate the effect of large-scale vaccination programs on the overall burden of HPV disease.
Supported by Merck Research Laboratories, a division of Merck, which funded the study in its entirety.
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