Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine (Gardasil Ò )

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1 ADIS DRUG EVALUATION Drugs 2010; 70 (18): /10/ /$55.55/0 ª 2010 Adis Data Information BV. All rights reserved. Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine (Gardasil Ò ) A Review of its Use in the Prevention of Premalignant Genital Lesions, Genital Cancer and Genital Warts in Women Paul L. McCormack 1 and Elmar A. Joura 2 1 Adis, a Wolters Kluwer Business, Auckland, New Zealand 2 Department of Obstetrics and Gynaecology, Division of Gynaecologic Oncology, Medical University of Vienna, Vienna, Austria Various sections of the manuscript reviewed by: S.L. Block, Kentucky Pediatric Research, Bardstown, Kentucky, USA; S.-E. Olsson, Department of Obstetrics and Gynaecology, Karolinska Institute at Danderyd Hospital, Stockholm, Sweden; A. Rowhani-Rahbar, Department of Epidemiology, University of Washington, Seattle, Washington, USA. Data Selection Sources: Medical literature published in any language since 1980 on human papillomavirus vaccine recombinant quadrivalent, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug. Search strategy: MEDLINE, EMBASE and AdisBase search terms were quadrivalent human papillomavirus recombinant vaccine or human papillomavirus vaccine recombinant quadrivalent or quadrivalent human papillomavirus types 6, 11, 16, 18 recombinant or quadrivalent HPV recombinant vaccine. Searches were last updated 8 November Selection: Studies in children, adolescents and adult women who received quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine (Gardasil Ò ). Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant immunogenicity and pharmacoeconomic data are also included. Index terms: Quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine, Gardasil, immunogenicity, prophylactic efficacy, tolerability, pharmacoeconomics. Contents Abstract Introduction Immunogenicity In Girls/Women Aged Years In Girls Aged 9 15 Years In Women Aged Years In Children and Young Adults Receiving Other Vaccines Concomitantly Comparison with Bivalent Human Papillomavirus (HPV) Vaccine Effect of Adjuvant Prophylactic Efficacy

2 2450 McCormack & Joura 3.1 Primary Efficacy Analyses Cervical Dysplasia External Genital Lesions: Vulvar/Vaginal Dysplasia and Warts Persistent HPV Infection Population Effects Geographical Effects In Subjects with Prior HPV Infection Cross-Protection Safety and Tolerability Pharmacoeconomic Considerations Dosage and Administration Place of Quadrivalent HPV (Types 6, 11, 16, 18) Recombinant Vaccine in the Prevention of Premalignant Genital Lesions, Genital Cancer and Genital Warts in Women Abstract Quadrivalent human papilloma virus (HPV) [types 6, 11, 16, 18] recombinant vaccine (Gardasil Ò ; Silgard Ò ) is composed of virus-like particles (VLPs) formed by self-assembly of recombinant L1 capsid protein from each of HPV types 6, 11, 16 and 18. The VLPs are noninfectious, containing no DNA, and are highly immunogenic, inducing high levels of neutralizing antibodies against the particular HPV types when administered to animals or humans. Quadrivalent HPV vaccine is indicated for use from the age of 9 years for the prevention of premalignant genital lesions (cervical, vulvar and vaginal), cervical cancer and external genital warts (condyloma acuminata) causally related to certain oncogenic or specific HPV types. In placebo-controlled clinical trials, quadrivalent HPV vaccine administered as three doses over 6 months provided high-level protection against infection or disease caused by the vaccine HPV types over 2 4 years of follow-up in females aged years who were naive to the vaccine HPV types. A degree of crossprotection against certain other non-vaccine high-risk HPV types was also observed. The vaccine is not effective against current infection with a vaccine HPV type. Girls or women with current infection with one or more of the vaccine HPV types gained protection from infection or disease caused by the remaining vaccine HPV types and they were also protected against reinfection with the same HPV type after clearance of an infection caused by a vaccine HPV type. High seroconversion rates and high levels of anti-hpv antibodies were observed in all vaccinated individuals of all age ranges from 9 to 45 years. No correlation was found between antibody levels and protective efficacy of the vaccine. Rechallenge with quadrivalent HPV vaccine produced a potent anamnestic humoral immune response. The vaccine is generally well tolerated and is projected to be cost effective in most pharmacoeconomic models. Therefore, quadrivalent HPV vaccine offers an effective means, in combination with screening programmes, to substantially reduce the burden of HPV-related precancerous lesions and cancer, particularly cervical cancer, as well as anogenital warts. 1. Introduction Human papillomavirus (HPV) is a small, nonenveloped, double-stranded DNA virus of which there are at least 100 distinct types. HPV is a common sexually transmitted virus. Approximately HPV types are known to infect the epithelium of the skin or mucous membranes in the anogenital region [1] and about 46% of women will experience cervical HPV infection within 3 years of initiating sexual activity, with a median time of 3 months between first sexual intercourse and the

3 Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Vaccine: A Review 2451 first detection of HPV. [2] Amongst sexually active female university students, the 24-month cumulative incidence of HPV infection was 39%, regardless of pre-enrolment sexual activity history. [3] Of those with incident HPV infection, the 36-month cumulative incidence of squamous intraepithelial lesions was 47%. [4] Most anogenital HPV infections are cleared spontaneously, but if infection persists, all HPV types can cause intraepithelial dysplasia and produce squamous intraepithelial lesions, while a subgroup of 15 or more high-risk HPV types can cause cancer. [5] Highrisk HPV types are responsible for about % of cervical cancers, 40% of vulvar cancers, 70% of vaginal cancers, 85% of anal cancers and 20 26% of head and neck cancers. [6-8] Worldwide, it is predicted that > women will be newly diagnosed with cervical cancer in 2010 and that this would increase to > new cases per year by 2020 in the absence of intervention or a change in risk. [6] Therefore, genital HPV infection is considered a serious health issue worldwide. Persistent infection of the cervix with high-risk HPV types can result in the development of lowgrade (cervical intraepithelial neoplasia [CIN] grade 1) or high-grade precancerous lesions (CIN grades 2/3 and adenocarcinoma in situ [AIS]), which can progress to invasive cervical cancer. Similarly, persistent infection of the vulvar and vagina can lead to vulvar intraepithelial neoplasia (VIN) and vaginal intraepithelial neoplasia (VaIN), which can likewise progress to vulvar and vaginal cancers. Of cancers attributable to HPV, high-risk HPV types 16 and 18 are responsible for causing about 70% of cervical cancers, 80% of vulvar and vaginal cancers, 92% of anal cancers, 95% of mouth cancers and 89% of oropharyngeal cancers. [6] They are also responsible for about 25 35% of low-grade and 50 70% of high-grade cervical dysplastic lesions. [1] HPV 6 and 11 are low-risk HPV types that are usually not linked with cancer, but are responsible for causing % of all anogenital warts in women and men, although in 20 50% of cases the lesions are coinfected with high-risk HPV types. [9,10] They also cause recurrent respiratory papillomatosis. [9] The clear link between persistent HPV infection and anogenital cancers has led to the development of prophylactic HPV vaccines. These vaccines are composed of virus-like particles (VLPs), essentially empty capsids, formed by selfassembly of viral L1 protein (the major HPV capsid protein) produced by recombinant DNA technology. [11] The VLPs are geometrically almost identical to native HPV virions. They do not contain any DNA and are non-infectious. However, the VLPs are immunogenic, inducing high levels of neutralizing antibodies when administered to animals or humans. [11] Currently, there are two prophylactic HPV vaccines commercially available: a bivalent HPV vaccine containing VLPs of C-terminally truncated L1 protein from HPV types 16 and 18 (20 mg of each) [Cervarix Ò ] [12] and a quadrivalent HPV vaccine composed of VLPs of full-length L1 protein from HPV types 6, 11, 16 and 18 (20, 40, 40 and 20 mg, respectively) [Gardasil Ò ; also marketed in certain countries as Silgard Ò ]. [13,14] The bivalent HPV vaccine contains a proprietary adjuvant composed of monophosphoryl-lipid A absorbed to aluminium hydroxide, [12] while the quadrivalent HPV vaccine contains a proprietary adjuvant composed of amorphous aluminium hydroxyphosphate sulfate. [13,14] This article reviews the efficacy, safety, tolerability, cost effectiveness and immunogenicity of quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine (Gardasil Ò ). The review focuses primarily on use of the vaccine in females according to the approved indications in the EU, consisting of the prevention of premalignant genital lesions (cervical, vulvar and vaginal), cervical cancer and external genital warts that are causally related to HPV types 6, 11, 16 and 18. [13] Its use in the prevention of anal and possibly oropharyngeal cancer in both men and women, and warts in men is beyond the scope of this review. 2. Immunogenicity Although prophylactic efficacy is the most important measure of the effect of HPV vaccination, immunogenicity studies are important in terms of determining the immediate seroconversion after vaccination, for bridging the efficacy to other age groups where efficacy studies might not

4 2452 McCormack & Joura be appropriate and for evaluating the possibility of an anamnestic immune response. The immunogenicity of quadrivalent HPV vaccine has been assessed in several randomised, double-blind, placebo-controlled efficacy trials reviewed in section 3 (Merck trial protocols V , [15-19] V [FUTURE {Females United To Unilaterally Reduce Endo/ectocervical disease} I], [20,21] V [FUTURE II] [21,22] ), and the FUTURE I substudies (V [23] and V [24] ), in girls and women aged years, or years (V ). [25] In addition, bridging studies have assessed the immunogenicity, but not the prophylactic efficacy, of the quadrivalent vaccine in preadolescent/adolescent girls aged 9 15 (V ) [26] or years (V ); [1] the latter study also compared the immunogenicity in 10- to 15-year-old children with that in 16- to 23-year-old females. [1] The immunogenicity of quadrivalent HPV vaccine has been compared with that of bivalent HPV (types 16, 18) vaccine in a single-blind trial. [27] In all studies, the quadrivalent HPV vaccine was administered as three intramuscular injections at months 0, 2 and 6. The safety, tolerability and effectiveness of the adjuvant in the quadrivalent HPV vaccine has been well established globally in other vaccines; its specific effect on anti-hpv antibody responses has been assessed in rhesus macaques. [28] HPV type-specific serum antibodies were generally measured by competitive radioimmunoassay or competitive Luminex immunoassay (clia) [29] and the geometric mean titres (GMTs) expressed as milli-merck Units per millilitre (mmu/ml). [1,17,18,23,26,30] The clia measures antibodies to single neutralizing epitopes (not all epitopes and not necessarily the dominant epitope) specific to each vaccine HPV (6, 11, 16, 18) type in a single serum sample. [17] Seropositivity for antibodies to HPV 6, 11, 16 and 18 usually required clia GMTs at or above 20, 16, 20 and 24 mmu/ml, respectively; the lower limits of quantification were approximately 8, 8, 12 and 8 mmu/ml, respectively. [21,23,26] The physical presence of virus in samples was determined by the detection of HPV DNA using a polymerase chain reaction (PCR) assay. 2.1 In Girls/Women Aged Years At month 7, 1 month after the third dose of vaccine, seroconversion rates were % for each vaccine HPV type in girls and women aged years. [15,17,20-22] From month 7, anti-hpv antibody titres declined as expected, reaching a plateau by month 24 and remaining relatively stable at this level through to at least month 60. [18] Anti-HPV antibody responses to the vaccine were substantially greater than those seen following natural infection with HPV and were greater in subjects with previous HPV exposure (seropositive, but PCR negative) than in those naive to the virus (figure 1). [17] In a combined analysis of the FUTURE I and II trials, seroconversion rates remained at 90 99% for anti-hpv 6, 11 and 16 from 24 to 44 months after the start of vaccination. [21] There was no correlation found between anti-hpv antibody levels at month 7 and prophylactic efficacy of the vaccine. [21] For instance, 40% of vaccine recipients were anti-hpv 18 seronegative at the end-of-study assessment (»44 months) using the clia assay, yet efficacy against HPV 18-related disease remained at 98.4% (95% CI 90.5, 100.0), suggesting vaccine-induced protection through immune memory or by antibody titres below the limit of detection for the clia assay. [21] Administration of a challenge dose of quadrivalent vaccine performed at 60 months in a subgroup of women resulted in a potent anamnestic response, with antibody titres to HPV 6, 11, 16 and 18 reaching month 7 levels within 1 week of challenge and antibody titres after 1 month being greater than those seen at month 7 following initial vaccination. [18] In an immunobridging study, the quadrivalent HPV vaccine (n = 1047) was shown to be noninferior to monovalent HPV 16 vaccine (n = 181) at 4 weeks after the third dose with respect to GMTs of anti-hpv 16 antibody (2030 vs 1911 mmu/ml, respectively) and anti-hpv 16 seroconversion rates (99.8% vs 100.0%). [24] The monovalent HPV 16 vaccine was previously shown in a proof-ofprinciple study to be 100% effective at preventing persistent HPV 16 infection in young women (aged years) over a median duration of 17.4 months after completing vaccination. [31]

5 Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Vaccine: A Review 2453 GMT (mmu/ml) GMT (mmu/ml) a b qhpv vaccine seronegative qhpv vaccine seropositive Placebo seronegative Placebo seropositive HPV 6 HPV 11 HPV 16 HPV 18 HPV 6 HPV 11 HPV 16 HPV 18 Fig. 1. Immunogenicity of quadrivalent human papillomavirus (HPV) [types 6, 11, 16, 18] recombinant (qhpv) vaccine according to prior HPV exposure. Geometric mean titres (GMTs) of antibody against HPV 6, 11, 16 and 18 measured by competitive Luminex immunoassay at (a) month 7 and (b) month 36 among girls and women aged years who were seronegative and negative for HPV DNA by polymerase chain reaction (PCR) assay at enrolment (n = per group) versus those who were seropositive and PCR negative at enrolment (n = 4 17 per group) in a randomized, double-blind, placebo-controlled prophylactic efficacy trial of qhpv vaccine (V ). [17] A pooled analysis of immunogenicity data from five studies (V , V , V , and FUTURE I and II) assessed the effect of baseline characteristics on the immune response to quadrivalent HPV vaccine and found, as seen with other vaccines, that the anti-hpv response was inversely proportional to subject age at initiation of vaccination. [30] Vaccination with quadrivalent HPV vaccine induces antibodies capable of neutralizing HPV types other than those specific to the vaccine (see also section 3.8). [19] The L1 capsid protein of HPV 45 is 88% homologous to that of HPV 18 and serum from women taken 1 month after completing vaccination with quadrivalent HPV vaccine was able to bind epitopes on HPV 45 VLPs with 8.1-fold lower binding than that observed to HPV 18 VLPs in vitro. [19] IgG purified from the sera of six of ten vaccinated women was able to neutralize HPV 45 pseudovirions in vitro,

6 2454 McCormack & Joura although at concentrations at least one order of magnitude higher than that required to neutralize HPV 18 pseudovirions. [19] 2.2 In Girls Aged 9 15 Years Seroconversion rates at 1 month after the third dose of quadrivalent HPV vaccine in girls aged 9 15 years were 99.6% for all four vaccine HPV types in two bridging immunogenicity studies (n = combined), while GMTs at month 7 were , , and mmu/ml for antibodies against HPV 6, 11, 16 and 18, respectively. [1,26] The GMTs at month 7 in 10- to 15-year-old girls were higher than those in 16- to 23-year-old women (ratio of across HPV types), indicating noninferiority of preadolescents to women. [1] The GMTs 1 month after the second dose (month 3) in 10- to 15-year-old girls were 40 66% of the values seen 1 month after the third dose (month 7), and were numerically higher for each HPV type than those at month 7 in 16- to 23-year-old women. [1] Similarly, GMTs at 7 months in another study were 1.4- to 1.6-fold higher in girls and boys aged 9 12 years at first vaccination than in girls and boys aged years. [26] Subjects with a high body mass index (BMI) [ 28] had GMTs against HPV 16 and 18 that were 50% of those in subjects with a BMI <28. [26] The immune response to quadrivalent HPV vaccine persisted throughout the follow-up time, for at least 1 year, since seroconversion rates 12 months after completing vaccination were 97.9%, 99.2%, 99.8% and 91.5% for antibodies to HPV 6, 11, 16 and 18, respectively, in girls aged 9 15 years at first vaccination. [26] Anti-HPV antibody GMTs 1 year after completing vaccination were approximately 3.6- to 5.9-fold lower than at 1 month after completing vaccination in girls aged 9 15 years. [26] 2.3 In Women Aged Years The overall seroconversion rate 1 month after completing vaccination with quadrivalent HPV vaccine in women aged years was 98% and ranged from 97% to 99% for each of the four HPV types. [25] In general, seroconversion rates and GMTs were broadly similar between women aged years and those aged years, and tended to be slightly lower in women aged years when compared historically with those in women aged years, but the differences were small. [25] Women who were seropositive at baseline for a vaccine HPV type had higher GMTs against that HPV type at 2 years than subjects who were naive for that HPV type at enrolment. [25] 2.4 In Children and Young Adults Receiving Other Vaccines Concomitantly The coadministration of hepatitis B virus (HBV) recombinant vaccine (Recombivax HB Ò ) with quadrivalent HPV vaccine (Gardasil Ò )in girls and young women aged years (n = 1877) did not interfere with the immune response to HPV; coadministration was noninferior to quadrivalent HPV vaccine alone with respect to the GMTs of antibodies to each of the HPV types and for anti- HPV seroconversion rates. [23] The concomitant administration of quadrivalent HPV vaccine and combined diphtheria/tetanus/ pertussis/poliovirus (DTP/P) vaccine (Repevax Ò )in male and female children aged years (n = 843) did not significantly interfere with the immune response to either vaccine; noninferiority of concomitant versus nonconcomitant administration was demonstrated for each vaccine. [32] Likewise, when quadrivalent HPV vaccine was administered concomitantly with meningococcal polysaccharide conjugate (serotypes A, C, Y and W-135) vaccine (Menactra Ò ) and tetanus, diphtheria and acellular pertussis (Tdap) vaccine (Adacel Ò ) in girls (n = 648) and boys (n = 394) aged years, the immune responses to all vaccine components were noninferior to the immune responses observed when the vaccines were administered separately. [33] Similarly, when an investigational quadrivalent meningococcal conjugate vaccine (MenACWY- CRM) and a Tdap vaccine (BoostrixÔ) were coadministered with quadrivalent HPV vaccine in a study involving 1620 boys and girls aged years, the immune responses to vaccine antigens were noninferior between concomitant versus sequential administration for quadrivalent

7 Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Vaccine: A Review 2455 HPV vaccine and the meningococcal conjugate vaccine, and were robust, but slightly lower with concomitant administration for the Tdap vaccine (noninferiority was not demonstrated). [34] 2.5 Comparison with Bivalent Human Papillomavirus (HPV) Vaccine The immunogenicity of quadrivalent HPV (types 6, 11, 16, 18) vaccine has been compared with that of bivalent HPV (types 16, 18) vaccine in women (n = 1106) aged years in an observerblinded study performed in association with the manufacturer of the bivalent HPV vaccine. [27] Anti-HPV 16 and anti-hpv 18 GMTs measured using a pseudovirion-based neutralization assay (PBNA) at month 7 in the per-protocol population were approximately 4- and 7-fold higher, respectively, with bivalent HPV vaccine than with quadrivalent HPV vaccine in women aged years, 5- and 9-fold higher in women aged years, and 2- and 7-fold higher in those aged years. [27] At month 7, the rates of positivity for neutralizing antibody against HPV 16 and 18 in cervicovaginal secretions measured by PBNA were numerically higher in recipients of bivalent compared with quadrivalent HPV vaccine. [27] The proportions of women with a detectable memory B-cell response at 7 months, among those negative at baseline, were not significantly different between recipients of bivalent and quadrivalent HPV vaccine for HPV 16 (90% vs 94%), but were significantly higher in bivalent versus quadrivalent HPV vaccine recipients for HPV 18 (89% vs 66%; p= ), although the assay used potentially biased the results in favour of the bivalent HPV vaccine. [27] Clinical efficacy was not evaluated in this study. Currently, there is no known correlation between serum anti-hpv antibody titre and protective efficacy. [21,27] Antibody levels notwithstanding, published overall vaccine efficacy rates against high-grade cervical lesions (CIN 2/3 or AIS) associated with HPV 16 or 18 at 3 4 years in HPV-naive women (aged years) for bivalent HPV vaccine and quadrivalent HPV vaccine are 93% [12] and 98%, [13] respectively. 2.6 Effect of Adjuvant The quadrivalent HPV vaccine contains a proprietary adjuvant composed of amorphous aluminium hydroxyphosphate sulfate that has been widely used in other vaccines. [13,14] Studies in rhesus macaque monkeys demonstrated that anti- HPV 6, 11, 16 and 18 antibody GMTs at 1 month after completing vaccination (month 7) were approximately 42-, 37-, 13- and 27-fold higher, respectively, in animals receiving vaccine containing the aluminium adjuvant than in those receiving vaccine without the adjuvant. [28] At month 12, the respective GMTs for the adjuvant-containing vaccine were 4-, 5-, 6- and 27-fold higher than those for the vaccine without adjuvant. [28] The vaccine containing the aluminium adjuvant elicited a response consistent with a predominantly T helper type 2 response. The predominant IgG subtypes were IgG1 and IgG4, and levels of IgG2 were low. High levels of IgA were detected, theoretically consistent with good mucosal protection. [28] 3. Prophylactic Efficacy The prophylactic efficacy of quadrivalent HPV vaccine in the prevention of cervical, vaginal and vulvar dysplasia/cancer, and genital warts has been assessed in one small, fully published, randomized, double-blind, placebo-controlled, multicentre, phase IIb (V ) [15] study in girls and young women aged years and in three large, fully published, randomized, double-blind, placebo-controlled, multicentre, phase III trials; two in girls and young women aged years (FUTURE I [n = 5455] [20] and FUTURE II [n = ] [22] ) and one in older women aged years (V [n = 3819] [25] ). The studies enrolled healthy, nonpregnant women, with no history of genital warts or abnormal Papanicolaou (Pap) smears, irrespective of whether they had had previous HPV infection. In the studies restricted to girls and young women aged 26 years, [15,20,22] subjects had to have a lifetime history of four or fewer sex partners; no such restriction applied in study V , [25] which enrolled women aged years. Subjects received three intramuscular injections of quadrivalent

8 2456 McCormack & Joura HPV vaccine or placebo at day 1, month 2 and month 6. Gynaecological examination was performed and samples taken for Pap tests, and detection of HPV DNA (PCR assay) and anti-hpv serum antibodies at baseline on day 1 and at regular intervals thereafter (e.g. 3, 7, 12, 24, 36 and 48 months). Referral for colposcopy was algorithm-based and biopsies were HPV typed. Subjects were generally included in analyses even if cervical cytology was abnormal at day 1. In all four studies, primary prophylactic efficacy analyses (quadrivalent HPV vaccine compared with placebo) were performed on the per-protocol susceptible (PPS) population, defined as those who received all three doses (within 1 year [20,22,25] ), with no major protocol violations, and who were naive (seronegative and PCR negative) to the relevant vaccine HPV types at baseline and remained PCR negative 1 month after the third dose (month 7), with case counting beginning at month 7. [15,20,22,25] Supportive analyses were performed on the unrestricted susceptible population (URS), [15,20,22] defined as all randomized subjects who were naive to the relevant HPV types at baseline and received at least one dose of vaccine or placebo (also termed NRT [naive to the relevant type] [25] ) and, in three studies, the intent-to-treat (ITT) population, defined as all randomized subjects regardless of HPV status at baseline or protocol violations. [20,22,25] Case counting for these supportive analyses began at day 1. The primary efficacy endpoints differed between studies. In the phase II study (V ), the primary endpoint was a composite of persistent ( 4 months) infection associated with HPV 6, 11, 16 or 18, or HPV-associated cervical or external genital disease (cervical, vaginal or vulvar intraepithelial neoplasia or cancer, or genital warts). [15] The co-primary endpoints in FUTURE I [20] were the incidence of external genital disease (anogenital warts, VIN 1 3, VaIN 1 3, or vaginal or vulvar cancer related to vaccinetype HPV) and the incidence of cervical lesions (CIN 1 3, AIS or cervical cancer related to vaccine-type HPV), while that for FUTURE II [22] was limited to cervical disease (CIN 2 3, AIS or invasive carcinoma) related to HPV 16 or 18. The co-primary endpoints of the study in older women (V ) were the combined incidence of persistent infection ( 6 months), or cervical or external genital disease (cervical, vaginal or vulvar intraepithelial neoplasia or cancer; cervical AIS; or genital warts) due to HPV 6, 11, 16 or 18, or to HPV 16 or 18 alone. [25] A number of prespecified protective efficacy analyses [35-45] have been performed on data pooled from between two and four randomized, doubleblind, placebo-controlled trials involving girls and women aged 9 26 years and including Merck trial protocols V (phase IIa), [31] V , [15,16] FUTURE I [20] and FUTURE II. [22] 3.1 Primary Efficacy Analyses For the primary efficacy endpoints in the PPS populations after a mean follow-up duration of 2.2 [25] or 3 [15,20,22] years (primary analyses), the prophylactic efficacy of quadrivalent HPV vaccine ranged from % in the three trials in younger women [15,20,22] (compared with % efficacy against high-grade lesions [table I]) [35] and 83 91% in the trial in older women (table II). [25] The efficacy of the quadrivalent HPV vaccine was 90% (95% CI 71, 97) in preventing persistent infection or disease associated with all four vaccine HPV types 3 years after the first dose in the smaller (n = 468) phase II trial (V ). [15] This compares with a vaccine efficacy of 91% observed for a very similar composite endpoint in older women aged years (table II). [25] The vaccine efficacy in the phase II trial was 96% (95% CI 84, 100) after a total of 5 years of followup (241 subjects were enrolled in the 2-year extended follow-up). [16] The vaccine efficacy was 100% (95% CI 94, 100) in preventing cervical lesions (n = 4499), and 100% (95% CI 94, 100) in preventing external anogenital and vaginal lesions (n = 5455) associated with all four vaccine HPV types in the FUTURE I study. [20] In the FUTURE II trial (n = ), the vaccine efficacy in preventing cervical lesions associated with HPV 16 and 18 was 98% (95% CI 86, 100). [22] In study V in older women, most of the endpoints observed were persistent infection without identifiable disease. [25] The efficacy was

9 Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Vaccine: A Review 2457 Table I. Prophylactic efficacy of quadrivalent human papillomavirus (HPV) [types 6, 11, 16, 18] recombinant (qhpv) vaccine in women. Efficacy at the end-of-study timepoint (mean follow-up duration of 42 mo after dose 1) of a three-dose (0, 2 and 6 mo) regimen of qhpv vaccine in preventing high-grade cervical, vulvar and vaginal lesions associated with HPV 6, 11, 16 and 18 in women aged y in a pooled analysis [35] of three randomized, double-blind, placebo-controlled prophylactic efficacy trials (V , FUTURE I and FUTURE II) Analysis population Clinical endpoint qhpv vaccine Placebo Efficacy (%) n cases rate a n cases rate a [95% CI] PPS CIN 2 or worse [93.3, 99.8] CIN 3 or worse [88.7, 99.6] VIN 2/3, VaIN 2/3, or worse [82.6, 100.0] VIN 2/ [67.2, 100.0] VaIN 2/ [55.4, 100.0] ITT CIN 2 or worse [40.6, 60.6] CIN 3 or worse [32.0, 58.3] VIN 2/3, VaIN 2/3, or worse [56.4, 91.0] VIN 2/ [40.3, 89.4] VaIN 2/ [37.6, 98.4] a Rate per 100 person-years at risk. CIN = cervical intraepithelial neoplasia; ITT = intent-to-treat population (usually defined as women randomized, receiving at least one dose of vaccine or placebo, and with at least one follow-up visit; women were included despite infection or disease related to the relevant HPV types prior to vaccination, and despite protocol violations and abnormal cervical cytology at day 1); PPS = per-protocol susceptible population (usually defined as women naive [seronegative and polymerase chain reaction negative] for the relevant HPV types at enrolment and remaining free of infection through to 1 mo after dose three of the vaccination regimen, having received all 3 doses of the regimen within 1 y, and were without protocol violation); VaIN = vaginal intraepithelial neoplasia; VIN = vulvar intraepithelial neoplasia. lower in the ITT population that included women with vaccine-type HPV infection or disease at baseline (table II). Approximately two-thirds of the enrolled women were susceptible to all four vaccine HPV types at baseline, while most of those who were HPV positive were only positive for one of the vaccine HPV types. [25] In the FUTURE I trial, vaccine efficacy at 3 years in the ITT population, which included women irrespective of HPV infection or disease status at baseline, was 73% in preventing external anogenital or vaginal lesions associated with HPV 6, 11, 16 or 18, and 55% (n = 5455) in preventing cervical lesions associated with HPV 6, 11, 16 or 18. [20] The vaccine efficacy in the ITT population in FUTURE II was 44% (n = ) for the primary efficacy parameter of the prevention of cervical lesions associated with HPV 16 and 18. [22] 3.2 Cervical Dysplasia A pooled analysis [35] of all three trials [15,20,22] in younger women at the end-of-study timepoint (mean follow-up duration of 42 months after the first dose) indicated that the overall observed prophylactic efficacy of quadrivalent HPV vaccine was 98% in preventing high-grade cervical lesions (CIN 2 or worse) associated with HPV 6, 11, 16 and 18 in HPV-naive girls and young women (PPS population; n = ) [table I]. In the pooled ITT population (n = ), which included women who may have been infected with vaccine HPV types or had vaccine HPV type-related disease at enrolment or by month 7, the observed vaccine efficacy in preventing highgrade cervical lesions at the end-of-study timepoint (mean of 42 months) was 52% (table I). [35] A pooled analysis of four clinical trials (V , V , FUTURE I and FUTURE II) involving girls and women indicated that the vaccine efficacy in preventing HPV 16- or 18- related high-grade cervical lesions (CIN 2 or worse) was 44% in the ITT population after a mean followup duration of 3.0 years after the first dose (comparedwith99% in the PPS population). [44] Time-to-event curves over the duration of follow-up in both of these pooled analyses indicated that the vaccine efficacy against highgrade cervical lesions in the ITT populations appeared to increase over time. [35,44] For example,

10 2458 McCormack & Joura Table II. Prophylactic efficacy of quadrivalent human papillomavirus (HPV) [types 6, 11, 16, 18] recombinant (qhpv) vaccine in older women. Efficacy of a three-dose regimen (0, 2 and 6 mo) of qhpv vaccine in women aged y in a phase III, randomized, double-blind, placebocontrolled trial [25] Study (mean follow-up duration) Primary endpoints Analysis population the incidence rate of HPV 6-, 11-, 16- or 18- related CIN 2 or worse among vaccine and placebo recipients in the ITT population over a mean of 42 months of follow-up in the pooled analysis of three trials is shown in figure 2. [35] The efficacy of the quadrivalent HPV vaccine was 100% against cervical lesions (CIN 1 3) after 5 years of follow-up in the phase II study (V ), although the number of cases was small in both the PPS (3 placebo vs 0 vaccine) and URS (7 placebo vs 0 vaccine) populations. [16] All instances of cervical dysplasia in placebo recipients were apparent at the 3-year follow-up timepoint. [15] In FUTURE I and II, cervical lesions included in the endpoint were most commonly related to HPV 16 (55% in the placebo group in FUTURE I and 76% in FUTURE II). [20,22] In FUTURE I and FUTURE II, the vaccine efficacy in the URS populations against cervical lesions after 3 years of follow-up was 98% and 95%, respectively. [20,22] In study V in older women, the vaccine efficacy against CIN 2 3/AIS was not statistically significant compared with placebo in either the PPS (1 vaccine vs 4 placebo cases; 75% [95% CI -151, 100]) or ITT (19 vaccine vs 21 placebo cases; 10% [95% CI -76, 54]) populations. [46] qhpv vaccine Placebo Efficacy (%) [95% CI] n cases rate a n cases rate a V Infection, or cervical or external PPS b * [74, 98] (2.2 y) genital disease associated with NRT * [58, 85] HPV 6, 11, 16, 18 ITT * [11, 47] Infection, or cervical or external PPS b * [51, 96] genital disease associated with NRT * [48, 86] HPV 16, 18 ITT * [-3, 42] a Rate per 100 person-years at risk. b Co-primary efficacy analysis. ITT = intent-to-treat population (defined as women randomized, receiving 1 dose of vaccine or placebo, and with 1 follow-up visit; women were included despite infection or disease related to the relevant HPV types prior to vaccination, and despite protocol violations, with case counting starting at d 1); PCR = polymerase chain reaction; PPS = per-protocol susceptible population (defined as women naive [seronegative and PCR negative] for the relevant HPV types from d 1 until mo 7, having received all three doses of the regimen within 1 y, having 1 follow-up visit after mo 7, and were without protocol violation); NRT = naive to the relevant HPV type population (defined as women naive [seronegative and PCR negative] to the relevant HPV types at d 1 and having received 1 dose of vaccine or placebo, with cases counted from after d 1); * p vs placebo. 3.3 External Genital Lesions: Vulvar/Vaginal Dysplasia and Warts In the pooled analysis of the three trials in girls and young women, [35] quadrivalent HPV vaccine displayed 100% efficacy in protecting against highgrade vulvar and vaginal (VIN 2/3, VaIN 2/3, or worse) lesions associated with HPV 6, 11, 16 or 18 at the end-of-study timepoint (mean of 42 months follow-up) in the PPS population (table I). In the pooled ITT population, vaccine efficacy at the end-of-study timepoint against high-grade vulvar or vaginal lesions associated with HPV 6, 11, 16 or 18 was 79% (table I). [35] The efficacy against vaccine HPV type-related grade 2/3 vaginal lesions was 86%, while that against grade 2/3 vulvar lesions was 73%. As with high-grade cervical lesions, time-to-event analysis showed that vaccine efficacy against high-grade vulvar and vaginal lesions (VIN 2/3, VaIN 2/3 or worse associated with HPV 6, 11, 16 or 18) increased over time during follow-up in the ITT population (figure 2). [35] Vaccine efficacy in another pooled analysis of the same three trials at a mean follow-up duration of 3 years from the first dose was 100% for HPV 16- or 18-related VIN 2/3 or VaIN 2/3 in the

11 Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Vaccine: A Review 2459 PPS population and 71% in the ITT population. [45] Time-to-event analysis indicated that vaccine efficacy increased over time during follow-up for both HPV 16- or 18-related high-grade vulvar or Percentage with HPV 6/11/16/18-related VIN/VaIN 2/3 or worse Percentage with HPV 6/11/16/18-related CIN 2 or worse a vaginal lesions or any high-grade vulvar or vaginal lesion irrespective of causal HPV type. [45] Over 5 years of follow-up in the phase II study, there were no cases of external genital lesions in qhpv vaccine Placebo Time after first dose (mo) b Time after first dose (mo) qhpv vaccine Placebo Fig. 2. Time-to-event curves for the proportion of subjects experiencing (a) cervical intraepithelial neoplasia (CIN) grade 2 or worse associated with human papillomavirus (HPV) types 6, 11, 16 or 18, and (b) vulvar intraepithelial neoplasia (VIN) or vaginal intraepithelial neoplasia (VaIN) grades 2/3 or worse associated with HPV types 6, 11, 16 or 18 among recipients of quadrivalent HPV (qhpv) vaccine or placebo in the intent-to-treat population from a pooled analysis [35] of three randomized, double-blind, placebo-controlled, multicentre trials (V , [15] FUTURE I [20] and FUTURE II [22] ). Bars represent 95% confidence intervals. Adapted from Kjaer et al. [35]

12 2460 McCormack & Joura quadrivalent HPV vaccine recipients compared with three and four cases among placebo recipients in the PPS and URS groups, respectively, all of which were apparent at the 3-year assessment. [15,16] In both the PPS and URS populations, the incidence of external genital lesions among placebo recipients equated to a rate of 0.4 per 100 person-years at risk. [16] In FUTURE I, HPV 6 was responsible for 56 60% of all external anogenital and vaginal lesions across the populations in placebo recipients, while HPV 11 and HPV 16 were each responsible for 16 18% of these lesions in the placebo group. [20] In older women (study V ), vaccine efficacy against all CIN and external genital lesions was 82% (95% CI 47, 96) in patients naive to the relevant HPV type (NRT population) and 30% (95% CI -11, 56) in the ITT population. [25] The efficacy of the quadrivalent HPV vaccine against the secondary endpoint of persistent infection or disease related to HPV types 6 and 11 was 100% for the PPS population, 80% for the NRT population and 47% for the ITT population. [25] 3.4 Persistent HPV Infection The quadrivalent HPV vaccine demonstrated 89% efficacy (4 vaccine vs 35 placebo cases) in preventing persistent HPV (types 6, 11, 16, 18) infection (duration 4 months) over 3 years of follow-up in the PPS population and 88% efficacy (6 vaccine vs 47 placebo cases) in the URS population in the phase II trial (V ). [15] The vaccine efficacy was sustained over the long term; the efficacy related to persistent infection after 5 years of followup was 95.6% (2 vaccine vs 45 placebo cases) in the PPS population and 93.5% (4 vaccine vs 58 placebo cases) in the URS population. [16] Similarly, in a substudy (V ) of FUTURE I, the efficacy of the quadrivalent HPV vaccine against persistent infection, defined as an infection duration 6 months ( 1 month), was 98.7% for HPV 16 and 100.0% for HPV 18 during a mean of 3.6 years of follow-up. [13] Efficacy was 100% against each HPV type using a 12-month duration definition for persistent infection. [13] 3.5 Population Effects In a pooled analysis of the FUTURE I and II trials, the efficacy of the quadrivalent HPV vaccine was assessed over an average follow-up duration of 3.6 years in the subset of women who were seronegative for HPV 6, 11, 16 and 18, and PCR negative for the 14 most common oncogenic HPV types (HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59) at baseline (n = 9424), thereby approximating HPV-naive subjects (i.e. the primary target population of vaccination programmes). [43] The vaccine efficacy was % against various cervical lesions (CIN 1 3 or AIS) related to vaccine-type HPV and 95 96% against external genital lesions (VIN 1 3, VaIN 1 3 or warts) related to vaccine-type HPV. In the ITT population (n = ), including women previously exposed to HPV or with infection or abnormal cytology at day 1 or up to month 7, efficacy after 3.6 years was 45 69% against cervical lesions and 76 80% against external genital lesions related to vaccine-type HPV. [43] When analysed with respect to lesions related to any HPV type, rather than just to the four vaccine HPV types, the efficacy of the vaccine at 3.6 years in women negative for 14 HPV types at baseline was 43% for any CIN 2 or worse and 55 83% for any external genital lesion. [43] The respective efficacies in the ITT population at 3.6 years were 19% for any CIN 2 or worse and 30 62% for any external genital lesion. In the ITT population, vaccination prevented 1320 abnormal Pap tests and 990 procedures for external genital disease annually per women vaccinated. [43] The analysis indicated that vaccination would prevent a broadly similar number of Pap test abnormalities, diagnoses and procedures per year in the HPV-naive and ITT populations. [43] Within the ITT population in study V , the efficacy of the vaccine in the subgroup of women aged years was 24% (71 vaccine vs 94 placebo cases), while that in the subgroup of women aged years was 41% (37 vaccine vs 60 placebo cases), suggesting a higher rate of prevalent HPV infection in the younger women. [25]

13 Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Vaccine: A Review Geographical Effects Analyses pooling data from several trials of the quadrivalent HPV vaccine in girls and women aged 9 26 years have assessed the efficacy of the vaccine against lesions related to the vaccine HPV types in different geographical regions, namely Europe, [36] North America [39] and Latin America. [41] In European women (n = 9265), the efficacy in the PPS population was 100% against cervical lesions (CIN 2 or worse) and 99% against any external genital lesion. [36] The equivalent efficacy rates in Latin American women (n = 6004) were 95% against CIN 2 or worse and 100% against any external genital lesion. [41] In North American women (n = 5996), the efficacy rates of quadrivalent HPV vaccine in the URS and ITT populations, respectively, were 100% and 72% against CIN 1 or worse, and 95% and 58% against any external genital lesion. [39] 3.7 In Subjects with Prior HPV Infection In a pooled analysis of the FUTURE I and II trials, among women who were seropositive or PCR positive for one or more of the vaccine HPV types at enrolment (n = ), the efficacy of the quadrivalent HPV vaccine against lesions related to HPV vaccine types to which the women were naive at baseline was assessed and indicated that these women benefit from vaccination. [40] The vaccine was 100% effective against CIN 2 or worse and 94% effective against any external genital lesion. Most women in the analysis were positive for only one vaccine HPV type at enrolment; most commonly HPV 16 (11.3% seropositive) and least commonly HPV 11 (2.0% seropositive). The vaccine provided protection against lesions caused by the remaining HPV types. [40] The efficacy of the quadrivalent HPV vaccine was assessed against lesions related to vaccine HPV types (types 6, 11, 16 or 18) to which women were seropositive, but PCR negative (no active infection), at enrolment (n = ) in a pooled analysis of three trials (V , and FUTURE I and II). [42] The vaccine was 100% effective (0 vaccine vs 7 placebo cases) over 40 months of follow-up against CIN 1 or worse related to a vaccine HPV type with which they had previously been infected and also 100% effective (0 vaccine vs 8 placebo cases) against any external genital lesion. The seropositive placebo recipients had incidence rates of 0.2 per 100 person-years for both cervical and external genital lesions. [42] Thus, prior infection does not provide complete protection (as seen in the placebo group) from subsequent reinfection with the same HPV type or HPV reactivation, and these women also benefit from vaccination. [42] The vaccine is not effective in patients with current HPV infection (PCR positive at baseline) by vaccine HPV types or in patients with existing HPV-related lesions. [13] However, an analysis of subjects from the FUTURE I and II trials suggested that vaccination of women who have undergone cervical conization or excisional (definitive) therapy for external genital lesions would be of benefit in the prevention of recurring disease (published as an abstract). [47] In subjects undergoing definitive therapy (587 quadrivalent HPV vaccine recipients and 763 placebo recipients), the vaccine efficacy against any CIN 1 or worse post-therapy was 47% (95% CI 17, 66). [47] In the subset from FUTURE I who underwent definitive therapy (222 vaccine and 306 placebo recipients), the vaccine efficacy post-therapy was 44% (95% CI 14, 64) against any VIN 1 3, VaIN 1 3 or genital warts and 79% (95% CI 53, 92) against HPV 6-, 11-, 16- or 18-related VIN 1 3, VaIN 1 3 or genital warts. [47] The vaccine efficacy after definitive therapy was 74% (95% CI <0, 97) against CIN associated with vaccine-type HPV in subjects from FUTURE I. 3.8 Cross-Protection A pooled analysis of subjects from FUTURE I and II who were PCR negative for the 14 most common oncogenic HPV types on day 1 (n = 9296) demonstrated an efficacy for the quadrivalent HPV vaccine compared with placebo of 23% against CIN1 3/AIS and 33% against CIN 2 3/ AIS related to the ten non-vaccine HPV types. [37] The incidence of infection with HPV 31 or 45 was reduced by 40% and that for HPV types 31, 33,

14 2462 McCormack & Joura 45, 52 or 58 (HPV types 80% homologous with HPV 16 and 18 L1 protein) was reduced by 25%. The efficacy was 37% against HPV 31-/45-related CIN1 3/AIS and 43% against CIN2 3/AIS. HPV 31 was the HPV type against which cross-protection was most frequently conferred. Overall, crossprotection produced a 4.3% increment in preventative efficacy against cervical lesions. The observed cross-protection was not expected to be fully additive, since many women may have had multiple CIN related to different HPV types. [37] A similar pooled analysis of all evaluable subjects from FUTURE I and II, regardless of HPV status at baseline (n = ), showed that, compared with placebo, the quadrivalent HPV vaccine reduced the incidences of CIN 1 3/AIS and CIN 2 3/AIS related to the ten non-vaccine HPV types by 15% and 13%, respectively. [38] The incidence of CIN1 3/AIS related to HPV 31/45 was reduced by 22%, while that related to HPV 31/33/45/52/58 was reduced by 19%. [38] Vaccination reduced the incidence of persistent infection with HPV 31/45 and HPV 31/33/45/52/58 by 32% and 18%, respectively. Cross-protection was most frequent with HPV 31 for persistent infection ( 6 months) and with HPV 59 for CIN 1 or worse. [38] Although cross-protective efficacy was observed at up to 3.6 years, the duration of cross-protection is not known. [38] 4. Safety and Tolerability The safety and tolerability of quadrivalent HPV vaccine have been evaluated in a number of clinical trials, including efficacy and bridging immunogenicity studies discussed in sections 2 and 3. [1,15,20,22,25,26] In clinical trials evaluating the safety of quadrivalent HPV vaccine, subjects were monitored using vaccination report cards for 14 days after each injection of vaccine or placebo (aluminium adjuvant containing control or saline control). Pooled analyses have summarized the results from five [48] or six [13] clinical trials, with each pooled analysis including males, aged 9 15 years (protocol V ) [13] or 9 23 years (V and V ). [48] Additional tolerability data were also derived from post-licensure surveillance reporting. [48,49] Quadrivalent HPV vaccine was generally well tolerated in clinical trials. In a pooled analysis of six clinical trials, injection-site reactions were the most common adverse events observed in vaccine recipients (table III). [13] Pyrexia and pain in the extremity were the most common systemic adverse events. [13] In a pooled analysis of five clinical studies (n = females and males aged 9 26 years), only 42 subjects prematurely discontinued the study as a result of adverse events, of which 17 were considered treatment related (10 vaccine and 7 placebo). [48] Of the early discontinuations, 20 were due to serious adverse events (11 vaccine and 9 placebo), only 1 of which (hypersensitivity in a placebo recipient) was considered related to treatment. [48] There was no significant difference between vaccine and placebo recipients in the incidence of serious adverse events. [48] Among vaccine recipients, five subjects had serious systemic adverse events (vaginal haemorrhage, bronchospasm, gastroenteritis, ulcerative colitis and hypertension/ headache) that were deemed treatment-related and one subject had a serious injection-site adverse event (pain and joint movement impairment). Two placebo recipients had serious systemic adverse events (hypersensitivity and chills/fever/ headache). Overall, 18 deaths were observed during the clinical trials (11 vaccine and 7 placebo), although none were considered vaccine-related. [48] Among subjects in the detailed safety population (n = ) of the pooled analysis, injectionsite reactions (most commonly pain, swelling and erythema) were significantly (p < 0.05) more frequent in vaccine recipients (83%) than in recipients of aluminium-containing placebo (77%) or saline-containing placebo (49%). [48] Most injection-site adverse events (78%) were of mild-tomoderate severity; severe events were significantly more frequent in vaccine recipients compared with placebo recipients (4% vs 2%; p< 0.05). [48] Elevation of body temperature 37.8 C (100 F) was significantly more common in vaccine than placebo recipients (11% vs 10%; p < 0.05). A history of HPV infection did not appear to be associated with a higher frequency of adverse events in response to vaccination with quad-

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