Drugs

, Volume 70, Issue 18, pp 2449–2474 | Cite as

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

A Review of its Use in the Prevention of Premalignant Genital Lesions, Genital Cancer and Genital Warts in Women
Adis Drug Evaluation

Abstract

Quadrivalent human papilloma virus (HPV) [types 6, 11, 16, 18] recombinant vaccine (Gardasil®; Silgard®) 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 15–45 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 35–40 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 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] High-risk HPV types are responsible for about 99–100% of cervical cancers, 40% of vulvar cancers, 70% of vaginal cancers, 85% of anal cancers and 20–26% of head and neck cancers.[6, 7, 8] Worldwide, it is predicted that >580 000 women will be newly diagnosed with cervical cancer in 2010 and that this would increase to >700 000 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 low-grade (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 90–100% 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 self-assembly 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 μg of each) [Cervarix®][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 μg, respectively) [Gardasil®; also marketed in certain countries as Silgard®].[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®). 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 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 V501-007,[15, 16, 17, 18, 19] V501-013 [FUTURE {Females United To Unilaterally Reduce Endo/ectocervical disease} I],[20,21] V501-015 [FUTURE II][21,22]), and the FUTURE I substudies (V501-011[23] and V501-012[24]), in girls and women aged 15–26 years, or 24–45 years (V501-019).[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 (V501-018)[26] or 10–15 years (V501-016);[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 15–26 Years

At month 7, 1 month after the third dose of vaccine, seroconversion rates were 99–100% for each vaccine HPV type in girls and women aged 15–26 years.[15,17,20, 21, 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]
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 16–23 years who were seronegative and negative for HPV DNA by polymerase chain reaction (PCR) assay at enrolment (n = 170–219 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 (V501-007).[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-of-principle study to be 100% effective at preventing persistent HPV 16 infection in young women (aged 16–23 years) over a median duration of 17.4 months after completing vaccination.[31]

A pooled analysis of immunogenicity data from five studies (V501-007, V501-016, V501-018, 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, 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 = 912–920 combined), while GMTs at month 7 were 808–959, 1187–1220, 4490–4697 and 916–1071 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 1.67–2.02 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 13–15 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 24–45 Years

The overall seroconversion rate 1 month after completing vaccination with quadrivalent HPV vaccine in women aged 24–45 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 24–34 years and those aged 35–45 years, and tended to be slightly lower in women aged 35–45 years when compared historically with those in women aged 16–23 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®) with quadrivalent HPV vaccine (Gardasil®) in girls and young women aged 16–23 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®) in male and female children aged 11–17 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®) and tetanus, diphtheria and acellular pertussis (Tdap) vaccine (Adacel®) in girls (n = 648) and boys (n = 394) aged 10–17 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 (Boostrix™) were coadministered with quadrivalent HPV vaccine in a study involving 1620 boys and girls aged 11–18 years, the immune responses to vaccine antigens were noninferior between concomitant versus sequential administration for quadrivalent 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 18–45 years in an observer-blinded 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 18–26 years, 5- and 9-fold higher in women aged 27–35 years, and 2- and 7-fold higher in those aged 36–45 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 = 0.0041), 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 15–26 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 (V501-007)[15] study in girls and young women aged 15–26 years and in three large, fully published, randomized, double-blind, placebo-controlled, multicentre, phase III trials; two in girls and young women aged 15–26 years (FUTURE I [n = 5455][20] and FUTURE II [n = 12 167][22]) and one in older women aged 24–45 years (V501-019 [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 V501-019,[25] which enrolled women aged 24–45 years. Subjects received three intramuscular injections of quadrivalent 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 (V501-007), 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 vaccine-type 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 (V501-019) 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, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45] have been performed on data pooled from between two and four randomized, double-blind, placebo-controlled trials involving girls and women aged 9–26 years and including Merck trial protocols V501-005 (phase IIa),[31] V501-007,[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 90–100% in the three trials in younger women[15,20,22] (compared with 97–100% efficacy against high-grade lesions [table I])[35] and 83–91% in the trial in older women (table II).[25]
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 15–26y in a pooled analysis[35] of three randomized, double-blind, placebo-controlled prophylactic efficacy trials (V501-007, FUTURE I and FUTURE II)

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 24–45y in a phase III, randomized, double-blind, placebo-controlled trial[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 (V501-007).[15] This compares with a vaccine efficacy of 91% observed for a very similar composite endpoint in older women aged 24–45 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 follow-up (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 = 10 565), the vaccine efficacy in preventing cervical lesions associated with HPV 16 and 18 was 98% (95% CI 86, 100).[22]

In study V501-019 in older women, most of the endpoints observed were persistent infection without identifiable disease.[25] The efficacy was 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 = 12 167) 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 = 15 729) [table I].

In the pooled ITT population (n = 17 683), 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 high-grade cervical lesions at the end-of-study timepoint (mean of 42 months) was 52% (table I).[35]

A pooled analysis of four clinical trials (V501-005, V501-007, FUTURE I and FUTURE II) involving 20 583 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 follow-up duration of 3.0 years after the first dose (compared with 99% 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 high-grade cervical lesions in the ITT populations appeared to increase over time.[35,44] For example, 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]
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 (V501-007,[15] FUTURE I[20] and FUTURE II[22]). Bars represent 95% confidence intervals. Adapted from Kjaer et al.[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 (V501-007), 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 V501-019 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]

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 high-grade 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 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 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 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 V501-019), 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 (V501-007).[15] The vaccine efficacy was sustained over the long term; the efficacy related to persistent infection after 5 years of follow-up 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 (V501-012) 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 98–100% 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 = 17 391), 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 100 000 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 V501-019, the efficacy of the vaccine in the subgroup of women aged 24–34 years was 24% (71 vaccine vs 94 placebo cases), while that in the subgroup of women aged 35–45 years was 41% (37 vaccine vs 60 placebo cases), suggesting a higher rate of prevalent HPV infection in the younger women.[25]

3.6 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 = 4370–4433), 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 = 2526–2569) in a pooled analysis of three trials (V501-007, 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 CIN1–3AIS 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, 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 CIN1–3AIS and 43% against CIN2–3/AIS. HPV 31 was the HPV type against which cross-protection was most frequently conferred. Overall, cross-protection 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 = 17 160), showed that, compared with placebo, the quadrivalent HPV vaccine reduced the incidences of CIN 1–3AIS and CIN 2–3/AIS related to the ten non-vaccine HPV types by 15% and 13%, respectively.[38] The incidence of CIN1–3AIS 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 V501-018)[13] or 9–23 years (V501-016 and V501-018).[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]
Table III

Treatment-related adverse events observed in clinical trials of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine. Pooled results from six clinical trials (five of which were placebo controlled) involving 8068 vaccine recipientsa and 5966 placebo recipients aged 9–45 years[13]

In a pooled analysis of five clinical studies (n = 21 464 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 = 10 224) of the pooled analysis, injection-site 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-to-moderate 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 quadrivalent HPV vaccine, according to a pooled analysis of three trials.[42] The incidence of adverse events following vaccination in women with serological evidence of prior exposure to vaccine HPV types was generally similar to that seen in women who were naive for the vaccine HPV types at enrolment.[42]

Among women aged 24–45 years (n = 3775), vaccine-related injection-site reactions occurred in 77% of women compared with 64% in the placebo group, while vaccine-related systemic adverse events occurred in 39% of vaccine recipients and 37% of placebo recipients.[25] Of the ten serious adverse events (three vaccine and seven placebo recipients), the three events occurring in vaccine recipients (rhinitis, vertigo and tension headache) were not considered to be related to vaccine administration. Overall, five vaccine and one placebo recipient discontinued treatment as a result of adverse events, none of which were serious events.[25]

In the direct comparison between quadrivalent HPV vaccine and bivalent HPV vaccine,[27] the respective incidences of solicited adverse events within 7 days of any vaccine dose were 85% and 95%, and the incidences of unsolicited adverse events within 30 days of any vaccine dose were 37% and 43%. With respect to the most common, solicited, individual adverse events, the incidences with the quadrivalent and bivalent HPV vaccines were 72% and 93% for injection-site pain, 26% and 44% for injection-site erythema, 22% and 37% for injection-site swelling, 42% and 48% for headache, 40% and 50% for fatigue, 27% and 33% for gastrointestinal symptoms, 20% and 28% for myalgia, 15% and 22% for arthralgia, 4% and 5% for urticaria, and 3% and 5% for rash.[27]

Quadrivalent HPV vaccine can safely be given concomitantly with other common vaccines. Concomitant administration with HBV vaccine was not associated with any serious adverse events and did not increase the incidence or severity of any adverse events over those seen with the vaccines given alone.[23] Similarly, there were no safety or tolerability issues associated with concomitant administration of quadrivalent HPV vaccine and DTP/P vaccine other than slight increases in the incidences of injection-site swelling (8.6% vs 4.8%) and headache (26.9% vs 19.4%).[32] Likewise, quadrivalent HPV vaccine was well tolerated when administered concomitantly with meningococcal conjugate vaccine,[34] or meningococcal conjugate vaccine and Tdap vaccine.[33] There were no clinically important differences in tolerability between concomitant and non-concomitant administration; no subjects discontinued for vaccine-related reasons and none had a serious vaccine-related adverse event. With respect to injection-site adverse events, quadrivalent HPV vaccine was associated with more swelling than the concomitant vaccines, while the concomitant vaccines were associated with more pain and bruising.[33]

Since the licensing of quadrivalent HPV vaccine in the US in June 2006 through to December 2008 there were 12 424 reports, including 46 932 adverse event codes, submitted to the Vaccine Adverse Event Reporting System (VAERS) following immunization with quadrivalent HPV vaccine.[49] Quadrivalent HPV vaccine was the sole vaccine identified in 9910 (80%) of these reports. During this period, the manufacturer reported that 23 051 336 doses of quadrivalent HPV vaccine had been distributed. The number of reports per 100 000 doses distributed was highest for syncope, injection-site reactions, dizziness, nausea and headache (figure 3). Syncope was not noted as a frequent adverse event in clinical trials, since subjects were observed for 30 minutes after vaccine administration and generally remained seated during this time.[48] Syncope occurred equally in vaccine and placebo recipients (0.1% vs 0.2%) in clinical trials.[48] Overall, there were 32 deaths and 740 nonfatal serious adverse events.[49]
Fig. 3

Postmarketing surveillance of quadrivalent human papilloma virus (HPV) [types 6, 11, 16, 18] recombinant vaccine. The most common adverse events related to immunization with quadrivalent HPV vaccine reported to the US Vaccine Adverse Event Reporting System between 1 June 2006 and 31 December 2008.[49]

Selected very rare but medically important events (e.g. autoimmune disorders, Guillain-Barré syndrome, anaphylaxis, transverse myelitis, pancreatitis and motor neuron disease) were examined in detail.[49] Of these, only venous thromboembolic events met the criteria (≥3 cases; proportional reporting rate ≥2; and chi-squared [χ2] ≥4) for a potential association between an adverse event and the vaccine, although 90% of those experiencing venous thromboembolism reported a known risk factor. Notably, death and Guillain-Barré syndrome (42 reports) did not meet these criteria.[49] Of the 12 confirmed cases of Guillain-Barré syndrome reported up to 1 June 2009, six subjects had concomitant vaccination with meningococcal conjugate vaccine and six received quadrivalent HPV vaccine alone.[48] However, the relationship was temporal only, with no evidence of a causal relationship. At present, there has been no demonstration of causality between the quadrivalent HPV vaccine and any serious adverse event reported to the VAERS.[50]

Following the introduction of a national school-based vaccination programme with quadrivalent HPV vaccine in Australia, all cases of suspected anaphylaxis in the state of New South Wales were reviewed in detail.[51] Of 11 suspected cases, eight met the Brighton case definition of anaphylaxis, seven of which derived from the school-based programme. Six cases occurred after one dose of the vaccine and two occurred after the second dose. Four of the subjects had a history of allergy or atopic disease. Of four subjects tested for allergy, all were negative to skin-prick testing with quadrivalent HPV vaccine. All 11 subjects recovered completely; rapidly after the administration of adrenaline in most subjects. Based on these data, the overall estimated rate of anaphylaxis following HPV vaccination in the school-based vaccination programme was very low (2.6 per 100 000 doses administered).[51]

In a follow-up assessment of 35 schoolgirls in Australia reporting suspected hypersensitivity reactions to immunization with quadrivalent HPV vaccine (over a duration in which >380 000 doses were administered in schools), 25 girls agreed to participate further.[52] Only 3 of the 25 schoolgirls were subsequently found to have probable hypersensitivity to the vaccine; most were skin prick test-negative and tolerated rechallenge with the vaccine.[52]

5. Pharmacoeconomic Considerations

The pharmacoeconomics of vaccination with quadrivalent HPV vaccine have been assessed in a number of fully published cost-utility analyses (table IV).[53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67]
Table IV

Cost effectiveness of mass vaccination of preadolescent girls with quadrivalent human papillomavirus (HPV) [types 6, 11, 16, 118] recombinant vaccine. Results of fully published cost-utility analyses comparing vaccination of all girls aged 11, 12 or 14 y in addition to the normal cervical screening programme with screening alone from the perspective of the healthcare provider[53, 54, 55, 56, 57, 58,60, 61, 62, 63, 64, 65,67,68] and/or a third-party payer[56,59,66] (direct costs only), and assuming a lifelong duration of vaccine effectiveness without the need for a booster. The cost effectiveness of additional catch-up campaigns for girls and women aged from 12 y up to 24 y were also evaluated

The cost-utility analyses were generally well conducted, in that relevant costs were included, sources of data were stated, clinical outcomes were relevant, appropriate discounting was applied and sensitivity analyses were conducted. However, as with all pharmacoeconomic analyses, there are study limitations. The analyses used a variety of models and different assumptions regarding such parameters as disease incidence, screening and treatment costs, utility values and outcomes, amongst others. The results may not be applicable to other geographical regions because of differences in healthcare systems, medical practice, unit costs and other factors. The selection of key studies and other data sources used to populate economic models, along with other factors, such as the study perspective and specific costs included, can have an important impact on results of these analyses.

Many analyses used static state-transition models of an age cohort,[53,55,56,58, 59, 60, 61,63,64] such as the Markov model, which did not consider the benefits of herd immunity, while the transmission dynamic[54,57,62,65, 66, 67, 68] and population[63] models considered the benefits afforded by herd immunity. The analyses assessed the cost effectiveness of adding vaccination with quadrivalent HPV vaccine to a particular country’s screening programme compared with screening alone from the perspective of the national healthcare provider[53, 54, 55, 56, 57, 58,60, 61, 62, 63, 64, 65,67,68] and/or a third-party payer,[59,63,66] and only considered direct costs. The base-case scenarios generally involved vaccinating all girls aged 11, 12 or 14 years (according to local recommendations) assuming a coverage of 70–90% of the target population (usually within 5 years), a protective efficacy of 85–100% against the vaccine HPV types and a lifelong duration of vaccine effectiveness. Only three of the analyses considered the benefits of preventing other neoplasias and cancers in addition to cervical disease and genital warts.[59,63,68] In addition to the base-case scenario, many analyses also included alternative scenarios involving temporary catch-up vaccination campaigns for older females over the first 1–5 years.[54,57,59,62,65, 66, 67, 68]

Despite differences between models and assumptions, as well as differences in screening programmes between countries, all cost-utility analyses found that vaccination of preadolescent, mostly 12-year-old, girls with quadrivalent HPV vaccine in the base-case scenario was cost effective compared with screening alone (table IV). The incremental cost-effectiveness ratios (ICERs) in all analyses were less than the commonly quoted willingness-to-pay thresholds of $US50 000,[59] 40 000 Canadian dollars,[61] £30 000, ;30 000–50 000,[53,56,58,60] 500 000 Norwegian kroner[67] or ≤3 times the per-capita gross domestic product[57,65] per quality-adjusted life-year (QALY) gained, below which interventions are considered to be cost effective. A high proportion of the costs avoided by vaccination, particularly in the early years, were the result of preventing genital warts caused by HPV 6 and 11.[54,61,65,67,68] ICERs were lower and/or QALYs were increased when the benefits of preventing vaccine-type HPV-related cancers other than cervical cancer were included.[59,63,68] ICERs were also generally lower in analyses using models that included the potential benefits of herd immunity.[54,57,62,63,65, 66, 67, 68]

The dynamic models also assessed the cost effectiveness of additional temporary catch-up campaigns to vaccinate girls and women aged from 12 years up to 26 years in various age steps.[54,57,59,62,65, 66, 67, 68] Most, but not all,[59] analyses found that temporary catch-up campaigns were cost effective for girls and women aged up to 18,[68] 24[54,57,62,65,67] or 26[66] years (table IV). Three analyses even found that vaccination plus catch-up was dominant (more effective and less costly) over vaccination of 12-year-olds alone for the 12–14[54,68] or 12–18[68] year age groups. Extending the age for catch-up programmes to 25 or 26 years in two analyses produced ICERs that were indicative of a low likelihood of the campaigns being cost effective.[59,68]

Sensitivity analyses generally indicated that the cost effectiveness of vaccination was most sensitive to the duration of vaccine protection, if protection was ≤20 years,[53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,65,67,68] and age at vaccination.[61] The base-case scenarios all assumed lifelong duration of protection from vaccination and ICERs increased substantially if the protection afforded by the vaccine was assumed to last only 10–20 years, although ICERs improved, generally remaining below cost-effectiveness thresholds,[53,55,56,60,61,66] if a booster dose (e.g. at 10 or 15 years) was assumed to provide lasting protection (20 years to lifelong). Varying the age of vaccination from 12 to 15 years had only minor effects on ICERs,[53,61] but ICERs were considerably higher for scenarios involving vaccination at 25 years of age.[61] Since the full benefits of vaccination are not apparent for many years, discount rates and time horizons used in the models also had major influences on cost effectiveness.[55,58,60,62, 63, 64, 65, 66,68] Varying the cost of vaccine was shown to have minor/moderate[53, 54, 55,58,62,63,65] and major[61,64,66, 67, 68] impacts on the ICER. Health utility values[54,62] and vaccine coverage rates[62,67] also had a major effect on ICERs in certain analyses.

6. Dosage and Administration

Quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine is approved in the EU for use from the age of 9 years for the prevention of premalignant genital lesions (cervical, vulvar and vaginal) and cervical cancer causally related to certain oncogenic HPV types, and for the prevention of external genital warts (condyloma acuminata) causally related to specific HPV types.[13] The indication is based on the demonstration of protective efficacy in females aged 16–45 years and on the demonstration of immunogenicity in 9- to 15-year-old girls and boys.[13] The decision to vaccinate an individual woman should consider a woman’s risk of previous HPV exposure and her potential benefit from vaccination.[13] The immunogenicity and safety of the quadrivalent HPV vaccine have been demonstrated in boys aged 9–15 years, but the protective efficacy in males has not been evaluated. Quadrivalent HPV vaccine has been shown to protect against diseases caused by HPV types 6, 11, 16 and 18, and to a limited extent against diseases caused by certain related HPV types (particularly HPV type 31).[13]

Quadrivalent HPV vaccine is approved in the US for use in girls and women aged 9–26 years for the prevention of precancerous genital lesions, genital cancer and genital warts caused by HPV types 6, 11, 16 and 18.[14] It is also approved for use in males aged 9–26 years for the prevention of genital warts caused by HPV types 6 and 11.[14]

The recommended dosage regimen is three separate 0.5 mL doses administered intramuscularly at 0, 2 and 6 months.[13,14] If an alternative vaccination schedule is necessary, the first and second doses should be administered ≥1 month apart, and the second and third doses should be administered ≥3 months apart, with all three doses administered within a 1-year period.[13] Routine cervical screening according to local recommendations should continue to be performed in vaccinated subjects.

Owing to insufficient information, vaccination with quadrivalent HPV vaccine should be avoided during pregnancy, although inadvertent administration to pregnant women during the clinical development programme did not have any adverse sequelae.[69,70] The quadrivalent vaccine may be administered to breast-feeding women.[13]

Quadrivalent HPV vaccine may be coadministered with hepatitis B recombinant vaccine, combined diphtheria/tetanus/pertussis/poliomyelitis vaccines and meningococcal polysaccharide conjugate vaccine (see section 2.4); for all combinations, the different vaccines do not significantly interfere with the immune response induced by the other vaccine.[13] Quadrivalent HPV vaccine is a prophylactic vaccine and is not useful in the treatment of current HPV infection or established HPV-associated disease.

Local prescribing information should be consulted for details regarding contraindications, warnings, precautions, indications and use in special populations.

7. Place of Quadrivalent HPV (Types 6, 11, 16, 18) Recombinant Vaccine in the Prevention ofPremalignant Genital Lesions, Genital Cancer and Genital Warts in Women

HPV represents one of the most clearly defined causality relationships between a virus and cancer, making cervical cancer and other HPV-related cancers potentially preventable diseases.

Prior to the introduction of prophylactic HPV vaccines, the control of cervical cancer has been dependent on routine cervical screening programmes using the Pap test for the early detection of high-grade precancerous neoplastic changes and subsequent treatment.[71]

Despite the effectiveness of these screening programmes, cervical cancer is still the third most common cancer in women worldwide, behind breast and colorectal cancer.[72] The WHO GLOBOCAN 2008 database estimates that there were 529 409 new cases of cancer of the cervix uteri worldwide in 2008 with 274 883 deaths in the same year.[72] Although the incidence of cervical cancer and the mortality rate are higher in developing countries than in many developed countries, estimates place the incidence of cervical cancer in the 27 EU nations at 31 419 new cases in 2008, with 13 568 deaths.[72] As mentioned, in the absence of intervention or a change in risk, the incidence of cervical cancer is predicted to keep increasing over time.[6,72] Therefore, cervical cancer remains a significant health issue requiring further intervention.

In pivotal clinical trials, the protective efficacy of quadrivalent HPV vaccine over a mean follow-up of 42 months ranged from 98% to 100% against vaccine HPV type-related high-grade cervical, vulvar and vaginal lesions in the PPS populations of girls and women aged 15–26 years who were seronegative and PCR negative for the vaccine HPV types at enrolment (section 3.1). The vaccine was not effective in women with existing infection by vaccine HPV types at day 1, as indicated by the lower vaccine efficacy observed in the ITT populations.

The full protective efficacy of quadrivalent HPV vaccine relies upon administration before extensive exposure to HPV, i.e. prior to sexual debut, which often occurs in the teenage period. The protective efficacy of the vaccine was not directly assessed in girls aged 9–15 years due to ethical issues and the long duration of follow-up required, but was inferred from bridging immunogenicity studies (section 2.2). It would be unethical to perform Pap smears in this age group solely for study purposes, while the level of HPV exposure post-vaccination and the development of precancerous lesions necessary to measure prophylactic efficacy would not be expected for many or most subjects in this group over a practical follow-up time period. Therefore, the efficacy demonstrated in older females is considered applicable for the younger age group, since antibody levels were 1.7- to 2.0-fold higher in the younger age group in immunogenicity studies.

Quadrivalent HPV vaccine also offers benefits for older women (section 2.3). Seroconversion rates in women aged 24–45 years were 97–99% for each of the vaccine HPV types. In prophylactic efficacy trials, approximately two-thirds of the enrolled women were naive to all four vaccine HPV types at enrolment and the protective efficacy of the quadrivalent HPV vaccine over 2.2 years was 91% in the PPS population for these women (section 3.1).

In the full study population of women aged 24–45 years regardless of baseline HPV status, the protective efficacy of the quadrivalent HPV vaccine at a mean follow-up of 2.2 years was substantially better in the older age stratum than the younger stratum (41% vs 24%), indicating a higher rate of active HPV infection in the younger group (section 3.5). Of those with previous HPV exposure, most were only seropositive for one of the four vaccine HPV types, meaning that they would gain full protection against the remaining three HPV types (section 3.1).

In women with known previous exposure to a vaccine HPV type, but no active infection (i.e. seropositive, but PCR negative), the quadrivalent vaccine was shown to protect against reinfection or reactivation of the HPV type to which they had previously been exposed, as well as protecting against the other vaccine HPV types (section 3.7). In contrast, natural infection that had been cleared was not fully protective. This is supported by immunogenicity studies which demonstrated that serum antibody levels were low in previously infected subjects who had eradicated HPV, but after vaccination, antibody titres were higher in these subjects than in those who were seronegative at baseline (section 2.1). Preliminary evidence suggests that quadrivalent HPV vaccine is of benefit in women who have undergone excisional therapy for CIN, VIN, VaIN or genital warts through the prevention of disease recurrence (section 3.7).

In addition to protecting against the four vaccine HPV types, quadrivalent HPV vaccine also provided cross-protection against persistent infection and lesions caused by non-vaccine high-risk HPV types including HPV 31, 33, 45, 52 and 58 that have 80% homology with HPV 16 and 18 (section 3.8). Protective efficacy against ten of the most common oncogenic HPV types varied considerably depending upon the nature of the subject population studied, but was often at a level that could be considered clinically relevant. However, cross-protection has only been shown against cervical lesions and would appear to provide only about 4% added benefit overall.

The duration of protection afforded by quadrivalent HPV vaccine is as yet uncertain. Although antibody levels wane after vaccination, they appear to plateau and remain stable for at least 5 years (section 2.1). It is noteworthy that the monovalent HPV 16 vaccine, which is the same as the HPV 16 VLP component used in the quadrivalent HPV vaccine, has demonstrated efficacy for up to 9.5 years (mean follow-up of 8.5 years) without any breakthrough disease.[73] Administration of a challenge dose of quadrivalent HPV vaccine 5 years after vaccination resulted in potent anamnestic immune responses to all four HPV types within 1 week, indicating that the vaccine induced a robust immune memory. As stated by the WHO, no correlation between seropositivity and clinical protection has been established for HPV vaccines.[74] In clinical trials, subjects who had become nominally seronegative 44 months after vaccination were still protected against vaccine HPV type-related disease (section 2.1). While evidence from modelling studies[75] and experience with other vaccines suggest that protection may be lifelong without the need for a future booster shot, this is still speculative and will be followed up over time.[76,77]

Since quadrivalent HPV vaccine is not a live or infectious vaccine, it can be coadministered at the same time as other common vaccines, such as HBV, DTP/P, Tdap and meningococcal conjugate vaccine (see section 2.4). Concomitant administration of quadrivalent HPV vaccine with these other vaccines was safe and well tolerated (section 4). Therefore, separate visits are not required for vaccination with quadrivalent HPV vaccine.

Pharmacoeconomic analyses consistently found routine vaccination of 11- to 14-year-old girls to be cost effective for the base-case scenarios which assumed lifelong duration of protection from a three-dose vaccination regimen (section 5). In many analyses, the addition of a booster at 10 years that provided lasting protection was still cost effective. Catch-up campaigns were also generally cost effective for girls up to about 18 years of age, while those including young women up to 26 years of age were less likely to be considered cost effective according to commonly cited willingness-to-pay thresholds.

Since HPV types 16 and 18 are also responsible for causing a high proportion of anal, mouth and oropharyngeal cancers,[6] the protective efficacy of quadrivalent HPV vaccine against these cancers needs to be fully assessed, since substantial efficacy in this regard would significantly enhance the cost effectiveness of HPV vaccination programmes.

Guidelines on HPV vaccination from WHO,[78] the European Centre for Disease Prevention and Control,[79] and the US Advisory Committee on Immunization Practices[80] all recommend that routine HPV vaccination of girls be included in national immunization programmes wherever it is considered relevant, practical and cost effective. They highlight that selection of the target population (usually girls aged between 9 and 13 years) needs to be based on vaccinating before the age of initiation of sexual activity and on the age-specific prevalence of HPV infections, both of which may vary between countries. The population should also be selected according to the ease of access over the 6-month duration of the vaccination regimen to gain the greatest possible coverage, such as through school-based programmes. School-based immunization is considered most likely to be the lowest-cost option and would simplify monitoring of vaccine uptake, but depends upon local issues, such as the availability of school-based health services, funding, administration and obtaining parent consent.[79] A catch-up programme to vaccinate older girls and women is usually recommended as a secondary objective, where practical and affordable. The US guidelines recommend catch-up vaccination of females aged 13–26 years, regardless of sexual experience.

Since both the quadrivalent and bivalent vaccines are highly effective and well tolerated, selection of the particular vaccine to use should be based on a number of considerations including the prevailing HPV problem (e.g. whether genital warts are a particular problem), vaccine safety and cost.[78] The bivalent and quadrivalent HPV vaccines should not be used interchangeably; the same vaccine should be used for all three doses. All guidelines emphasize that HPV vaccination is not a replacement for cervical screening, which should still occur later in life, and should not undermine screening programmes.[78, 79, 80]

Vaccination should be avoided during pregnancy.[12,13] However, during the clinical development programmes, thousands of subjects reported pregnancies during vaccination with each of the vaccines. Both vaccines appeared to have good safety profiles during pregnancy. There were no significant differences overall between those receiving vaccine and those receiving placebo with respect to types of anomalies or pregnancy outcomes for either vaccine. The quadrivalent HPV vaccine may be used during lactation, but information on the use of the bivalent vaccine during lactation is lacking.[78]

The effectiveness of HPV vaccination programmes depends upon high coverage rates, which in turn depend upon widespread acceptance of the value of HPV vaccination by health authorities, community leaders, physicians, target subjects and their parents or guardians. Barriers to acceptance include lack of knowledge regarding HPV and cancer, lack of perceived risk, fears that vaccination will promote sexual promiscuity, perceived high cost, fear of injections or vaccine adverse effects, and uncertainty about the duration of protection.[81, 82, 83, 84, 85] HPV vaccination coverage is highly variable by country in Europe.[86] Currently, only the UK and parts of Spain have implemented free-of-charge school-based programmes that are known to provide very high coverage rates. In Scotland, uptake rates in the first year of the HPV immunization programme (2008/2009) amongst girls in the second, fifth and sixth years of secondary school were 94.2%, 93.1% and 89.8% for the first, second and third doses, respectively.[87] In contrast, national vaccination coverage estimates for 2008 in the US indicate that 37% of 13- to 17-year-old females received one or more doses of quadrivalent HPV vaccine, but only half of these girls (18% of the total) received a full three-dose course.[88]

The effectiveness of quadrivalent HPV vaccine was highlighted in a recent analysis of surveillance data for 112 083 new patients attending any of eight sexual health service clinics from seven centres across Australia between January 2004 and December 2009.[89] A national vaccination programme with quadrivalent HPV vaccine free of charge began in schools in April 2007 (for girls aged ≥12 years) and in general practice in July 2007 (for females aged ≤26 years) until the end of 2009. A sampling of clinics in two centres during 2009 (n = 1203) indicated that 65.1% of females who were eligible for free vaccination had received quadrivalent or unknown HPV vaccine. After the vaccination programme began, the incidence of new diagnoses of genital warts declined by 59% (p < 0.0001) in young female Australian residents compared with before the vaccination programme. No such decline was noted in nonresident females, females who were older than 26 years in July 2007 or in men who have sex with men.[89] Herd immunity was clearly demonstrated, given that <5% of Australian men have received HPV vaccine. During the vaccine period, there was a 28% decline (p < 0.0001) in new diagnoses of genital warts in heterosexual men, which was statistically significant in men aged 12–26 years in July 2007 (39% decline; p < 0.0001), but not in men aged >26 years in July 2007 (13% decline).[89]

Quadrivalent HPV vaccine was safe and generally well tolerated, both in clinical trials and during postmarketing surveillance (section 4). Injection-site reactions and fever were the most common adverse events in clinical trials, while syncope was most common in postmarketing surveillance. Syncope, which occurred equally in vaccine and placebo recipients in clinical trials, can be managed by having subjects seated under observation for approximately 15 minutes after vaccination, as recommended in the prescribing information.[13] Severe injection-site reactions can be a barrier to subjects returning for the second and third injections in the vaccination regimen. Most injection-site adverse events with quadrivalent HPV vaccine were of mild or moderate intensity and were less frequent than with the bivalent HPV vaccine. It is important that all subjects return for at least the second, but also for the third injection, since protective efficacy has only been established for the three-dose schedule.

In conclusion, quadrivalent HPV (types 6, 11, 16, 18) recombinant vaccine administered as three doses over 6 months in placebo-controlled clinical trials provided high-level protection against infection or disease caused by the vaccine HPV types over 2–4 years of follow-up in females aged 15–45 years who were naive to the vaccine HPV types. A degree of cross-protection 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 females of all age ranges from 9 to 45 years who were naive to the vaccine HPV types. 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 (types 6, 11, 16, 18) recombinant 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.

Disclosure

The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Dr Joura has received advisory board fees from Merck, and lecture fees from Merck, sanofi pasteur MSD and GlaxoSmithKline. He has also received funding through his institution to conduct epidemiological HPV studies for GlaxoSmithKline and HPV vaccine studies for Merck.

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Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  1. 1.Adis, a Wolters Kluwer BusinessMairangi Bay, North Shore 0754, AucklandNew Zealand
  2. 2.Department of Obstetrics and Gynaecology, Division of Gynaecologic OncologyMedical University of ViennaViennaAustria

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