Cervical cancer and prevention by vaccination: results from recent trials

educational session Cervical cancer Chair

John Green University of Liverpool, Department of Surgery and Oncology, Liverpool, United Kingdom Clatterbridge Centre for Oncology, Department of Medical Oncology, Wirral, United Kingdom

Peter Rose Cleveland Clinic Foundation, Case Western Reserve University, Division of Gynecologic Oncology, Cleveland, USA

Speakers

prevention by vaccination: results from recent trials Wiebren Tjalma University Hospital Antwerpen, Department of Gynecology and Gynecologic Oncology, Antwerp, Belgium

concomitant chemo-radiation Peter Rose Cleveland Clinic Foundation, Case Western Reserve University, Division of Gynecologic Oncology, Cleveland, USA

systemic treatment for recurrent and metastatic disease John Green University of Liverpool, Department of Surgery and Oncology, Liverpool, United Kingdom, Clatterbridge Centre for Oncology, Department of Medical Oncology, Wirral, United Kingdom

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Co-Chair

Annals of Oncology 17 (Supplement 10): x217–x223, 2006 doi:10.1093/annonc/mdl263

Cervical cancer and prevention by vaccination: results from recent trials W. A. A. Tjalma Department of Gynecology and Gynecologic Oncology, University Hospital Antwerpen, Edegem, Belgium

introduction

ª 2006 European Society for Medical Oncology

HPV

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Cervical cancer and breast cancer are the two most common cancers of women worldwide, with more than 510 000 and 100 0000 new patients per year, respectively. Cervical cancer will kill at least 288 000 women every year. This is about one woman every 2 min, making cervical cancer a bigger problem than AIDS. Cervical cancer can, unlike breast cancer, almost always be detected in a pre-cancerous phase if women are screened. This makes cervical cancer a preventable disease. The causal factor of cervical cancer is a genital infection with a human papillomavirus (HPV) [1]. Sexual contact is the main source of HPV infection. The lifetime risk of getting infected with HPV is 80%, making it the most prevalent sexually transmitted disease worldwide. It is estimated that for every three people who have sex with a HPV-positive person, two will develop an infection within the next few months [1, 2]. In the majority of patients (75%), the infection will be asymptomatic [1, 2]. An HPV infection is either transient or persistent. The majority of patients develop a transient infection, which leads to low-grade lesion and lasts only for 1 or 2 years. A persistent infection is the most important risk factor for developing cancer. The process from initial infection to pre-invasive and, ultimately, invasive disease lasts several years (Figure 1). HPV can be classified as a cutaneous or mucosal infection and in low-risk and high-risk types. There are more then 150 genotypes, of which 40 are anogenital types. Of the latter only 15 are considered as high risk or oncogenic. Table 1 shows the high-risk HPV types and their percentage in cervical cancer [3]. There are, however, regional variations. Invasive cervical cancer can be divided into squamous cell carcinoma (SCC) (80%–85%), adenocarcinoma (10%) and adenosquamous carcinoma (3%) and a miscellaneous group of rare tumors [1–5]. There are striking differences among these major cervical cancer types in incidence, HPV types and prevalence [1]. The incidence of SCC is declining (reduction 70%–75%), while the incidence of adenocarcinoma is increasing (almost doubling) [1, 2]. HPV-16 is seen more in SCC, while HPV18 is more frequent in adenocarcinoma. Furthermore, 95%–100% of all SCCs are HPV positive while only 80%–92% of the adenocarcinomas are HPV positive. The reasons are unclear and could be due to false-negative HPV detection, the difficulty in morphologically discriminating between adenocarcinoma of the cervix and endometrium (rarely HPV positive), or viral genome integration. The absence of an

episomal HPV genome in the majority of glandular tumors as opposed to squamous tumors may result in a significant underestimation of HPV prevalence in cervical adenocarcinoma. Within the adenocarcinoma, the HPV status seems to be related to age. Adenocarcinomas in women younger then 40 are HPV positive in more than 90% of patients, while in women older then 60 this is only 43%.

HPVs belong to the Papovaviridae family and are a heterogeneous group of double-stranded closed circular DNA viruses. The circular HPV genome can be divided into a long local control region (LCR), early proteins (E1–E8) and two late proteins (L1 and L2). The terms ‘early’ and ‘late’ are based on their functional action timing. In general the early proteins are involved in DNA replication, transcriptional regulation and cellular transformation and the late proteins form the capsomere and facilitate the entry of viral DNA into the cell [1, 2]. The HPV remains infectious in a moist environment for months due to the lack of an envelope and are relatively stable. The life cycle of HPV follows the differentiation stages of the epithelium and depends, therefore, on the differentiation stages of the keratinocytes. In an acute phase, the HPV infection (‘the cycle’) starts when the virus has access to the keratinocytes in the basal cells of the epithelial layer in the transformation zone. After binding to the keratinocytes they will infect them leaving a complete copy of the viral DNA as a circular episome within the cell nucleus [1]. The virus can now complete its life cycle and produce new infectious viral particles, using the host’s DNA and ribonucleic acid polymerase. This mechanism of viral reproduction is regulated by E6 and E7, tightly controlled by E2 and will not cause cancer [1]. The formation of infectious progeny viruses occurs on the surface of the epithelium, in cells that are shed. It is possible that new progeny could engage in multiple rounds of infection in the same host, as well as being transmitted to new hosts [2]. The following step is either a transient (majority) or persistent (minority) infection (Figure 1). A transient infection is synonymous for a low-grade lesion (Figure 1, step 2). The presence of complete viral particles within the cell (episomal HPV) causes a characteristic perinuclear clearing known as koilocytosis (hallmark of a low-grade squamous lesion). On cytology there are either no

Annals of Oncology

preventive strategies

Step 1: Infection with HPV

Screening can be divided into primary, secondary and tertiary screening. Tertiary screening is based on symptomatic patients with disease present. Secondary screening is based on asymptomatic patients with disease present. The Papanicolaou cytology (so called Pap test or smear) is used in secondary screening. The organized or opportunistic screening with a Pap test has led to a significant reduction in cervical cancer morbidity and mortality over the last 60 years in the industrialized world. Unfortunately there is no decline anymore, due to the coverage of only 50%–90%. Another problem is the lack of screening programs in the developing world. This explains why more then 80% of cervical cancer is in the developing world. If every woman would have a Pap test on a regular basis, one in 15 women would be confronted with a cervical lesion but cervical cancer would almost be eradicated. Primary prevention is based on asymptomatic patients with no disease. Primary prevention can be done by risk reduction and diet. But the cornerstone would undoubtedly be a vaccine against HPV infection.

Step 2: Transient infection = infection disappears within 2 years = low grade lesion Step 3: Persistent infection = infection remains present for more then 2 years Step 3a: progression to high grade lesion after 2 – 5 years Step 3b: progression to invasive cancer after 5 – 15 years Figure 1. Life cycle of Human Papilloma Virus (HPV) and possible stage of the cervical carcinogenesis

Table 1. High-risk HPV types, their distribution and their percentage in cervical cancer Type HPV HPV HPV HPV HPV HPV HPV HPV HPV HPV HPV HPV HPV HPV HPV HPV

16 18 45 31 33 52 58 35 59 56 51 39 68 73 82 other

Percentage

Total %

53.5 17.2 6.7 2.9 2.6 2.3 2.2 1.4 1.3 1.2 1.0 0.7 0.6 0.5 0.3 5.6

53.5 70.7 77.4 80.3 82.9 85.2 87.4 88.8 90.1 91.3 92.3 93.0 93.6 94.1 94.4 100

demonstrable changes or only minor changes associated with a productive viral infection [1]. Histologically, the lesions involve less then one-third of the epithelium. The overwhelming majority of these low-grade lesions regress spontaneously (60%–80%). In a small minority the circular viral genome will be integrated into host-cell DNA (genome) leading to the formation of a high-grade lesions (Figure 1, step 3a). Over time this high-grade lesion can progress to invasive carcinoma (Figure 1, step 3b). During the integration the viral genome is disrupted. If this interruption is in the E2 region, it will lead to the loss of the transcriptional control of E6 and E7. This causes the binding and inactivation by E6 and E7 of the two most important host-cell tumor suppressor genes, namely p53 and pRB, respectively, leading to the loss of cell-cycle control. This integration process forms the basis of cervical carcinogenesis. Due to the integration process the viral life cycle is not completed. Consequently no new virus particles are produced and high-grade dysplasia therefore does not show koilocytosis.

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vaccines A vaccine that would prevent a HPV infection is a prophylactic vaccine. This will induce the production of antibodies capable of neutralizing a viral antigen before it enters the host cell. Based on the life cycle of HPV, the antibodies (humoral response) should be directed against L1 and L2 proteins. To completely prevent sexual transmission of genital HPV infection, virusneutralizing antibodies must act at the mucosal surfaces, the natural site of infection [2]. Antibodies pass from plasma into the genital mucosal or are synthesized by local plasma cells [2]. A therapeutic vaccine is aimed at patients who are all ready infected with HPV. These vaccines should induce cellular components of the immune system to recognize and attack already infected cells. Based on the life cycle this means focusing on the overexpression of E6 and E7. This manuscript will only discuss the prophylactic vaccines.

prophylactic HPV vaccine trials The recognition that HPV is the causal factor of cervical cancer and the knowledge that L1 and L2 are the lead points are the basics for the development of a prophylactic vaccine. However there were several development problems. First, there was no effective culture system to grow an attenuated form. Secondly, the exposure of healthy subjects to an oncogenic virus encoded by HPV DNA is not acceptable. The observation that L1 has the intrinsic ability to self-assemble into a virus-like particle (a so called VLP) was a major breakthrough. A VLP mimics the natural structure of the virion, gives an immune response but does not have the viral genome and are therefore, at least theoretically, not harmful. Based on this experience several high-risk (HR) and low-risk (LR) HPV vaccines have been developed and used in trials. In this manuscript only the major and available phase 2 and 3 trials will be discussed. Table 2 gives a comparison and status of these trials. For each trial the end points or objectives will

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Step 0: Normal

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Table 2. Randomised controlled HPV vaccine trials HPV vaccine trials

Phase

Randomized

Age range

Status Published [6] 2002 Up-date published [7] 2006 Published [8] 2004 Up-date published [9] 2006 Published [10] 2005 Up-date presented [11] 2006 Oral presentation [12] 2005 Oral presentation [13] 2005

Monovalent

16

II

1533

16–23

Bivalent

16 and 18

II

1113

15–25

Quadrivalent

6, 11, 16, 18

II

552

16–23

Quadrivalent Quadrivalent

6, 11, 16, 18 6, 11, 16, 18

III III

5455 12167

16–23 16–26

be discussed together with the used vaccine, adjuvant, doses, posology, immunogenicity and vaccine efficacy.

monovalent HPV-16 VLP L1 trial [6, 7] The aim of this trial was to determine if a HPV-16 VLP L1 vaccine could prevent HPV-16 infection in women. The primary end point was persistent HPV-16 infection, defined as the detection of HPV-16 DNA in samples obtained at two or more visits. The primary analysis was limited to women who were treated according to protocol and who were negative for HPV-16 DNA and HPV-16 antibodies at enrolment and HPV-16 DNA at month 7. A second analysis of the primary end point was done on all women including those who had a protocol violation (intention-to-treat protocol). The study was divided in an initial phase for vaccination and follow-up that concluded at month 18 and in a blinded follow-up extension phase that concluded at month 27. The results were published after both phases were fulfilled. A final analysis by the same group within the same cohort of patients after 48 months of post-vaccination follow-up was published [7]. The goal of this publication was to give the estimates for the vaccine efficacy for the prevention of HPV16-related high-grade lesions (CIN 2–3). For the second publication there was the per-protocol analysis of efficacy, which included only participants who were treated according to the protocol. Women who violated the protocol in one way or another were analysed in two additional populations. This division was done in order to have more generalizable estimates of vaccine efficacy. The modified intention-to-treat population (MITT)-1 analysis included participants who received at least one vaccination, were HPV-16 seronegative and HPV-16 DNA-negative at day 1. The MITT-2 population included all MITT-1 subjects as well as subjects who tested positive for HPV-16 infection at enrolment. For both the per-protocol and MITT populations, vaccine efficacy was defined as the percentage reduction in risk of infection/disease in the vaccinated group relative to the risk of infection/disease in the placebo group. bivalent HPV-16 and 18 VLP L1 trial [8, 9] The primary objective of this trial was to assess vaccine efficacy in the prevention of infection with HPV-16, HPV-18, or both,

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aims of the trials

between months 6 and 18 in participants who were initially shown to be seronegative for HPV-16/18 by ELISA and negative for HPV-16/18 DNA by PCR. The secondary objective was the evaluation of vaccine efficacy in the prevention of persistent infection with HPV-16/18, and in the prevention of cytological and histological confirmed abnormality associated with HPV-16/18 infection between months 6 and 18, and months 6 and 27. The prevention of atypical squamous cells of undetermined significance (ASCUS) cytology associated with HPV-16/18 infection was added post hoc to the outcome analyses. Other objectives were the assessment of vaccine immunogenicity, safety and tolerability. An extended follow-up study was published after a mean follow-up of 48 months [9]. Only women who participated in the initial efficacy study and for whom treatment allocation remained double blinded were included in this analysis.

quadrivalent HPV (6, 11, 16, 18) L1 VLP trials [10–13] At the moment there is one published phase II trial and there are two oral presented phase III trials regarding a quadrivalent vaccine. The phase III studies are the FUTURE I and II trials (Females United To Universally Reduce Endo-ectocervical disease). The phase II study was done in two parts [10]. Part A was a sequential dose-escalation safety assessment and part B was a fully blinded dose-ranging assessment of immunogenicity and efficacy. The results presented here are from part B and were published after 36 months. An update of the study has been presented after 60 months [11]. The objective of this study was to assess the prevention (efficacy) of a persistent infection(s) associated with HPV-6, 11, 16 or 18, or cervical or external genital disease. Primary efficacy analyses were done in the HPV-6/11, 16 and 18 per-protocol efficacy cohorts, which consisted of women who were naive for the relevant HPV type at enrolment, remained free of infection with the same vaccine HPV type through completion of the vaccination regimen, had all three doses of vaccine or placebo, and did not violate the protocol. Secondary analyses were done for a modified intention-totreat population that included all participants who were naive (i.e. seronegative and PCR negative) to the relevant HPV type at enrolment and who had had at least one vaccination. Immunogenicity was measured in a per-protocol immunogenicity cohort, defined as members of the

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In the bivalent trial each dose of the bivalent HPV-16/18 virus-like particle vaccine contained 20 lg of HPV-16 L1 viruslike particle and 20 lg of HPV-18 L1 virus-like particle and the placebo contained 500 lg of aluminium hydroxide per dose, and was identical in appearance to the HPV-16/18 vaccine [8, 9]. The total carrier volume was 0
5 ml of vaccine or placebo. In the quadrivalent trial three preparations of a quadrivalent HPV types 6, 11, 16 and 18 L1 VLP were used [10]. The participants of part B were randomly assigned to quadrivalent HPV (20 lg type 6, 40 lg type 11, 40 lg type 16 and 20 lg type 18) L1 virus-like-particle (VLP) vaccine and to one of two placebo preparations (225 lg or 450 lg of amorphous aluminium hydroxyphosphate sulfate adjuvant)

vaccines used in the trials

posology In the monovalent and quadrivalent trials the participants received three intramuscular injections of either 0.5 ml vaccine or placebo at day 1, month 2 and month 6 [6, 7, 9]. In the bivalent trial every study participant received a 0
5 ml dose of vaccine or placebo at 0 months, 1 month and 6 months [8, 9].

When the papillomavirus major capsid protein L1 is overexpressed in mammalian, insect, yeast or bacterial cells it spontaneously assembles to form the VLPs. In the monovalent HPV-16 study the HPV-16 L1 virus-like particle vaccine (Merck Research Laboratories, West Point, PA) consisted of highly purified virus-like particles of the L1 capsid polypeptide of HPV-16 [6, 7]. The HPV-16 L1 polypeptide is expressed in a yeast host (Saccharomyces cerevisiae). Virus-like particles are isolated to achieve more than 97% purity and adsorbed onto an adjuvant. In the quadrivalent trials the active quadrivalent vaccine was a mixture of four recombinant HPV type-specific VLPs (Merck Research Laboratories, West Point, PA, USA) consisting of the L1 major capsid proteins of HPV 6, 11, 16 and 18 synthesized in Saccharomyces cerevisiae. The four VLP types were purified and adsorbed onto an adjuvant [10]. In the bivalent trial (16 and 18) (GlaxoSmithKline Biologicals, Rixensart, Belgium) each type of virus-like particle was produced by Spodoptera frugiperda Sf-9 and Trichoplusia ni Hi-5 cell substrate with an adjuvant [8, 9].

adjuvant In the trials in which VLP is expressed in a yeast host (Saccharomyces cerevisiae) an amorphous aluminium hydroxyphosphate sulfate without preservative is used as adjuvant [6, 7, 10–13]. In the bivalent trial in which the baculovirus was used, a substrate was formed with AS04 adjuvant containing 500 lg aluminium hydroxide and 50 lg 3-deacylated monophosphoryl lipid A (MPL, Corixa, Montana, USA) provided in a monodose vial [8]. The difference between the adjuvants is that combinations of the adjuvant MPL and aluminium salts induce an enhanced immune response at both the humoral and cellular level compared with antigen alone or with aluminum only [8, 9]. dose In the monovalent HPV-16 vaccine trial the contained 40 lg of HPV-16 L1 virus-like particle was formulated on 225 lg of aluminium adjuvant in a total carrier volume of 0.5 ml [6, 7]. The placebo contained 225 lg of aluminium adjuvant in a total carrier volume of 0.5 ml.

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side-effects In all trials no significant differences were seen between the placebo or vaccine arms. Both reported pain at the injection place and headache as a systemic event. Vaccines were generally well tolerated and appear to be safe. In the extended follow-up study it was noted that in the placebo group there were more adverse events than in the vaccine group [9]. One possible explanation for this finding is that the women who received the vaccine had fewer cytological abnormalities that required diagnostic follow-up. Controls, on the other hand, had probably more recalls with colposcopy and subsequently an increased opportunity to report adverse events [9]. immunogenicity The immunogenicity analyses are shown in Table 3. In all studies there was a decline in geometric mean titre values from peak responses 1 month after the third vaccine. The methods for assessment of immunogenicity in serum were different in the trials. For the monovalent HPV 16 trial a competitive radioimmunoassay developed by Merck Research Laboratories was used to quantitate serum titres of HPV-16 antibodies [6, 7]. Quantitation was by standard curve, corrected for dilution, and reported in arbitrary units (milli-Merck units or mMU/ml). For the bivalent trial, serological testing for antibodies to HPV-16 and HPV-18 virus-like particles was done by ELISA. Seropositivity was defined as a titre greater than or equal to the assay cut-off titre established at 8 ELISA units/ml for HPV-16 and 7 ELISA units/ml for HPV-18 [8, 9]. Typical natural titres were determined by use of blood samples obtained from women in the preceding epidemiology study who were found to be seropositive for HPV-16 or HPV-18 by ELISA. In the extended study at least a 133-fold difference in geometric mean titre values between the vaccine and placebo group for both HPV-16 and HPV-18 was seen after a mean follow-up of 48 months [9]. For the quadrivalent trial the serum concentrations of antibodies to HPV-6, 11, 16, and 18 were measured with

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per-protocol efficacy cohort who were vaccinated and who had serum samples obtained during the protocol-specified time frames, irrespective of HPV infection or disease status after month 7. The study presents the efficacy, immunogenicity and tolerability of this low-dose vaccine compared with the pooled placebo groups. This low-dose vaccine was chosen for phase III studies. The aim of FUTURE I is to assess the prevention of cervical dysplasia and external genital lesions by the vaccine [12]. The aim of FUTURE II is to assess the impact of the vaccine on the rates of cervical intraepithelial neoplasia 2/3 and cervical cancer [13].

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Table 3. Immunogenicity analysis Anti HPV 16 Seropositivity (%, 95%CI) Monovalent HPV 16 [6, 7] Vaccine Enrolment 0 (0.0–1.0) Month 7 100 (–) Months 48* – (–) Control group Enrolment 0 (–) Natural infection Enrolment – (–) Anti HPV 16 Seropositivity (%,95%CI)

Anti HPV 6 GMT (95%CI) Quadrivalent HPV 6, 11, 16, 18 [10] Vaccine Month 7 582 (527–643) Months 36 93 (81–108) Natural infection Months 7 55 (28–108) Months 36 68 (33–139)

– 1510 (1370–1660) 150–250* <6 25.7 (22.4–29.4) GMT (95%CI)

Anti HPV 18 Seropositivity (%,95%CI)

GMT (95%CI)

4.0 (4.0–4.0) 5335 (4797–5970) 801 (706–909) 617* (NA)

0 99.7 100 100

3.5 (3.5–3.5) 3365 (3015–3755) 481 (425–544) 371* (NA)

36.3 (33.8–38.9)

NA (NA)

(0.0–1.0) (98.4–100) (98.9–100) (NA)

26.5 (24.5–28.8)

4.0 (4.0–4.0) 4.2 (4.0–4.3) 4.2 (4.1–4.3)

0 (0.0–1.2) 1.3 (0.4–3.3) 0.3 (0.0–1.8)

3.5 (3.5–3.5) 3.6 (3.5–3.7) 3.5 (3.5–3.6)

Anti HPV 11 GMT (95%CI)

Anti HPV 16 GMT (95%CI)

Anti HPV 18 GMT (95%CI)

697 (618–785) 94 (81–110) 94 (5–1639) 96 (19–498)

3892 (3324–4558) 509 (436–593) 37 (17–85) 29 (12–69)

801 (694–925) 60 (49–74) 42 (23–75) 29 (15–59)

GMT geometric mean titres in mMu/ml (= milli-Merck Units or mMU per milli-liter); – = not mentioned in article. *High anti-HPV16 geometric mean titers waned over time, but at month 48 they seemed more or less stable no exact figures are given. GMT, geometric mean titre in ELISA units/mL; NA, Not Available; *an approximation, no precise figures were mentioned. GMT geometric mean titre in MU/L (95%CI).

a competitive immunoassay (Luminex Corporation, Austin, TX, USA) [10]. At present only vaccine induced type-specific titres after 36 months have been presented.

vaccine efficacy An overview of the vaccine efficacy for the different trials is given in Table 4. Additional data from the extended bivalent study 16/18 showed a substantial vaccine efficacy against incident infection with HPV-45 and HPV-31 of 94.2 (63.3 – 99.9) and 54.5 (11.5 – 77.7), respectively, after 48 months [9]. This cross-protection is not mentioned in any of the other trials. Cross-protection from L1 VLP vaccines was regarded as unlikely because there is very little similarity between the antigens (epitopes) of the different HPV types. The Papillomaviridae are a taxonomic family. The genital human papillomavirusses are higher-order phylogenetic assemblages of papillomavirus types and considered as the genus ‘Alpha-Papillomavirus’ [14]. In this

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Bivalent HPV 16 and 18 [8, 9] Vaccine Enrolment 0 (0.0–1.0) Month 7 100 (99.0–100) Month 18 100 (98.9–100) Months 51/53 100 (NA) Natural infection Months 51/53 NA (NA) Placebo Enrolment 0 (0.0–1.2) Month 7 3.2 (1.6–5.9) Month 18 3.2 (1.6–5.9)

GMT (95%CI)

phylogenetic tree the HPV types 18, 39, 45, 59, 68, 70, c85 form HPV species 7 and the HPV types 16, 31, 33, 35, 52, 58, 67 form HPV species 9 [13]. This phylogenetic relation is an explanation and suggests other possible cross-protections [14]. Natural HPV infection can give type-specific response with some serological cross-reactivity between phylogenetically related types [9].

discussion In the cervical carcinogenesis three steps can be identified (Figure 1). Based on the available randomized controlled trials and their follow-up time of several years it can be stated that a vaccine is highly effective against the prevention of an infection (Figure 1, steps 1 and 2). The recently published trials indicate that they are all very effective against persistent infections (step 3a). The high degree of protection after 4.5–5

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Table 4. Overview of the vaccine efficacy (Confidence Interval %) [6–13] Vaccine

Monovalent 16 6 17 91 (80–97) – 100 (90–100) 100 (90–100) – – 100 (24–100) – – – – –

16 7 40 – – 94 (88–98) – – – 100 (84–100) 83 (62–94) 100 (65–100) 78 (41–93) – –

16, 18 8 18/27* 92 (65–98) 83* (62–92) 100 (47–100) 95* (64–99) – – – – – – – –

Quadrivalent 16, 18 9 48 95 (84–99) 89 (77–95) 100 (52–100) 94 (61–100) – – – 100 (42–100) – NA – –

6, 11, 16, 18 10 36 – – 89 (70–97) 88 (72–96) 100 (16–100) 100 (56–100) NA 100 (32–100) – – NA NA

6, 11, 16, 18 11 60 – – 96 (83–100) 94 (83–98) 100 (12–100) 100 (55–100) NA 100 (31–100) – – NA NA

6, 11, 16, 18 12 7 – – – – – – 100 (87–100) 97 (87–100) – – 100 (88–100) 95 (84–99)

6, 11, 16, 18 13 17 – – – – – – – – 100 (76–100) 97 (83–100) – –

F-U (months), follow-up time in months; TI, transient infection; PI, persistent infection; DAL, disease associated lesion CXL + EGL; CX, cervical lesion defined as CIN 1 or more; CX+, cervix lesion defiend as more then CIN I; EGL, external genital lesion; NA, not applicable (number of events to small for meaningful efficacy analysis). The presentation by Mao et al. [7] is an update by Koutsky et al. [6]. In the study by Mao et al. [7] MITT 2 was taken as ITT; *only available for 27 months of follow-up; The presentation by Harper et al. [9] is an update of her previous publication [8]. The presentation by Villa [11] is an update of her previous publication [10].

years supports the hypothesis that a persistent infection is a valid virological end point in the clinical assessment of HPV vaccines [9]. The recently published trials also indicate a high effect against disease-associated lesions like cervical intraepithelial neoplasia (step 3a) and external genital warts. However, the follow-up time in respect of the reduction of high-grade lesions is still short. The follow-up time should be at least 5 years before we can make a true estimation on the impact of a vaccine against these high-grade lesions. At the moment there is no data regarding the effect of the vaccines on the incidence of cervical cancer. It will take decades before there will be an answer to this question. The US Food and Drug Administration Vaccines Advisory Committee recommended using a high grade lesion as a surrogate marker for cervical cancer in HPV vaccine trials because this lesion is the immediate precursor to cervical cancer [15]. Based on this assumption the vaccine has a very effective profile. However, it will take at least three to four decades before a reduction in cervical cancer death based on a vaccine program can be expected. Until these data are available, screening has to continue. At the moment there are no indications that the vaccine leads to selection and/or mutation of HPV types. Focusing on the two most frequent HPV types will cover 71% of cervical cancers. By the partial cross-protection against HPV-45 and 31 this could rise to 76%. More research is needed to explain and elucidate the mechanisms that are involved in the crossprotection. Future studies should examine the possibility of adding more HPV types to the vaccine in order to bypass regional differences. For instance a vaccine containing the eight most common HPV types would prevent 89% of all cervical cancers regardless of the regional variations. An open question is

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still whether the protection against HPV in women will be equal for men. There is no sufficient data currently available regarding the duration of vaccine-induced protection. Data is also lacking on the role of memory cells. Rough estimates suggest at least a 10-year protection. The immunogenicity analyses reveal a rapid decrease in antibodies over time. The question here is will they become stable or drop below the natural level. The latter could mean a loss of efficacy and the need of boosters. In this respects the age of vaccination and the initial height of the GMT after the vaccination seem important. Starting vaccination at a younger age (<15 years) will give higher titres then at older age. However, it can only be hypothesized that the height of the titre correlates with the length of protection. In this respect one should not forget the possible role of the ‘natural’ booster effect. After establishing the role of HPV as the causal factor for the development of cervical cancer, the scientific world has succeeded in the formation of a vaccine. It will, however, take decades before we known if the vaccine will fulfil its promising role. If the vaccine is protective we still have to face the final step: the acceptance of the vaccine by the general public and policy makers [16].

references 1. Tjalma WA, Van Waes TR, Van den Eeden LE, Bogers JJ. Role of human papillomavirus in the carcinogenesis of squamous cell carcinoma and adenocarcinoma of the cervix. Best Pract Res Clin Obstet Gynaecol 2005; 19: 469–483.

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HPV type(s) included References F-U (mnths) TI ATP ITT PI ATP ITT DAL ATP ITT CX ATP ITT CX+ ATP ITT EGL ATP ITT

Bivalent

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11.

12.

13.

14. 15.

16.

a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005; 6: 271–278. Villa LL, Costa RL, Petta CA et al. Efficacy of a prophylactic quadrivalent human papillomavirus (HPV) types 6, 11, 16, and 18 L1 virus-like particle (VLP) vaccine through up to 5 years follow-up. Presented at the European Research Organization on Genital Infection and Neoplasia, Paris, France, 26 April 2006. Sattler C for the FUTURE I investigators. Efficacy of a prophylactic quadrivalent human papillomavirus (HPV) (Types 6, 11, 16, 18) L1 virus-like particle (VLP) vaccine for prevention of cervical dysplasia and external genital lesions (EGL). Presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington DC, USA, 19 December 2005. Skjeldestad FE for the FUTURE II investigators. Prophylactic quadrivalent human papillomavirus (HPV) (types 6,11,16,18) L1 virus-like particle (VLP) vaccine (Gardasil
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