Human papilloma virus (HPV) prophylactic vaccination: Challenges for public health and implications for screening

Similar documents
SCCPS Scientific Committee Position Paper on HPV Vaccination

The promise of HPV vaccines for Cervical (and other genital cancer) prevention

Opinion: Cervical cancer a vaccine preventable disease

Luciano Mariani Istituto Nazionale Tumori Regina Elena, Roma

UICC HPV and CERVICAL CANCER CURRICULUM. UICC HPV and Cervical Cancer Curriculum Chapter 5. Application of HPV vaccines Prof. Suzanne Garland MD

Prevention strategies against the human papillomavirus: The effectiveness of vaccination

Cervical screening. Cytology-based screening programmes

Commonly asked questions on human papillomavirus vaccine

HPV vaccination: the promise & problems

HPV vaccination Where are we now? Where are we going? Margaret Stanley Department of Pathology Cambridge

Prophylactic HPV Vaccines. Margaret Stanley Department of Pathology Cambridge

A Short Review on Human Papillomavirus Vaccines

The HPV Vaccination Programme Early intervention in cancer prevention Northern Ireland

Strategies for HPV Vaccination in the Developing World

The devil is in the details

Largest efficacy trial of a cervical cancer vaccine showed Cervarix protects against the five most common cancercausing

HUMAN PAPILLOMAVIRUS VACCINES AND CERVICAL CANCER

The Korean Journal of Cytopathology 15 (1) : 17-27, 2004

HPV vaccine perspectives Dr. David Prado Cohrs

INTRODUCTION HUMAN PAPILLOMAVIRUS

How do we compare? IP724/BMTRY Introduction to Global and Public Health. Feb 21, 2012 Basic Science Rm Sharon Bond, PhD, CNM

Supplementary Appendix

Eradicating Mortality from Cervical Cancer

New paradigm for prevention of cervical cancer

An update on the Human Papillomavirus Vaccines. I have no financial conflicts of interest. Case 1. Objectives 10/26/2016

Pathology of the Cervix

The implications of HPV immunisation on cervical screening

OPPORTUNISTIC HPV VACCINATION: AN EXPANDED VISION

Chapter 13: Current findings from prophylactic HPV vaccine trials

Human papillomavirus and vaccination for cervical cancer

Goals. In the News. Primary HPV Screening 3/9/2015. Your PAP and HPV Update Primary HPV Testing- Screening Intervals- HPV Vaccine Updates-

HPV Vaccination: Myths and Misconceptions

HPV vaccines. Margaret Stanley Department of Pathology Cambridge

Northern Ireland cervical screening programme. Information for primary care and smear takers

In February 2007, the National Advisory Committee on

Who Should and Who Should Not Be Vaccinated Against Human Papillomavirus Infection?

Baseline HPV 2009: A route to evaluation of the HPV vaccination programme

VIRUS VACCINES & CANCER a story with two chapters

FREQUENCY AND RISK FACTORS OF CERVICAL Human papilloma virus INFECTION

Promoting Cervical Screening Information for Health Professionals. Cervical Cancer

Clinical overview of GSK s AS04 adjuvanted vaccine: data up to 6.4 years

Focus. A case. I have no conflicts of interest. HPV Vaccination: Science and Practice. Collaborative effort with Karen Smith-McCune, MD, PhD 2/19/2010

HPV AND CERVICAL CANCER

PRODUCT INFORMATION GARDASIL 9. [Human Papillomavirus 9-valent (Types 6, 11, 16, 18, 31, 33, 45, 52, 58) vaccine, Recombinant]

Cervical Cancer Screening. David Quinlan December 2013

Natural History of HPV Infections 15/06/2015. Squamous cell carcinoma Adenocarcinoma

What is the Safety and Efficacy of Vaccinating the Male Gender to Prevent HPV Related Neoplastic Disorders in Both the Male and Female Genders

The future of cervical cancer screening. Contents of this presentation. Prevention of cervical cancer. Prevention of cervical cancer HPV vaccines

Summary Dose Schedule 2. 9HPV vaccine 3. Primary HPV screening 4. Male vaccination 5. Update on Australia 6. Natural History 7.

The Future of Cervical Screening. Jenny Ross

HPV the silent killer, Prevention and diagnosis

The successful case of HPV prophylactic vaccines

Human Papillomavirus. Kathryn Thiessen, ARNP, ACRN The Kansas AIDS Education and Training Center The University of Kansas School of Medicine Wichita

2 HPV E1,E2,E4,E5,E6,E7 L1,L2 E6,E7 HPV HPV. Ciuffo Shope Jablonska HPV Zur Hausen HPV HPV16. HPV-genome.

SAGE evidence to recommendations framework i

[TRANSLATION] Ministry of Health. Higher Health Council Session XLVI Combined Sections II and III. Meeting of 11th January 2007

The impact of the HPV vaccine in Scotland.

De-Sexualizing the HPV Vaccine How to Counsel Your Families

Clinical Performance of Roche COBAS 4800 HPV Test

Silvia Franceschi Infections and Cancer Epidemiology Group International Agency for Research on Cancer Lyon, France

Cervical cancer is the second most common cancer affecting women worldwide. Cervical

Opinion 20 March 2013

Up date. sexually transmission HPV HPV HPV. high-risk HPV HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 66, 68 HPV

warts or papillomas in the upper respiratory tract, particularly the larynx, and that is associated with extensive morbidity (Table 1). RISK FACTORS G

Clinical Study Reducing the Health Burden of HPV Infection Through Vaccination

Questions and answers about HPV vaccination. Information for parents and caregivers

National Immunisation Conference 25th May 2018

O RIGINAL P APER. Extending Quadrivalent Human Papilloma Virus (HPV) Vaccination To Males What Is The Current Evidence?

Quick Reference: Immunization Communication Tool For Immunizers HPV 2010

HPV Vaccination. Dr. Vivien Tsu PATH. HPV Vaccination 1

Following microtrauma, HPV s bind to the basement membrane, infect basal cells, and replicate in suprabasal cells

Human Papillomaviruses and Cancer: Questions and Answers. Key Points. 1. What are human papillomaviruses, and how are they transmitted?

Update on Clinical Trials for Bivalent HPV Vaccine

Prophylactic human papillomavirus vaccines

Woo Dae Kang, Ho Sun Choi, Seok Mo Kim

Presexual adolescent girls and. Family Practice. Who should get. the HPV vaccine? For personal use only. Copyright Dowden Health Media

HPV-Negative Results in Women Developing Cervical Cancer: Implications for Cervical Screening Options

The new European (and Italian) guidelines for cervical screening will recommend PAP from 25 to 34 HPV (+ triage) from 35 to 64

HPV vaccine acceptance in male adolescents

The Global Burden of HPV Related Cancers and Their Prevention

Human Papillomavirus

RESEARCH. Economic evaluation of human papillomavirus vaccination in the United Kingdom

Focus. International #52. HPV infection in High-risk HPV and cervical cancer. HPV: Clinical aspects. Natural history of HPV infection

Innovations in Human Papillomavirus Vaccine

No HPV High Risk Screening with Genotyping. CPT Code: If Result is NOT DETECTED (x3) If Results is DETECTED (Genotype reported)

Lo screening come setting per la vaccinazione (nelle donne non vaccinate in età target e nelle donne trattate) Silvia Franceschi

Making Sense of Cervical Cancer Screening

HPV Vaccines: Background and Current Status

ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

Vaccination at school future challenges

Prophylactic HPV vaccines: Reducing the burden of HPV-related diseases

HPV - From Warts to Cancer

Human papilloma virus vaccination: practical guidelines

HPV/Cervical Cancer Resource Guide for patients and providers

HPV, Cancer Genes, and Raising Expectations

Cervical Cancer Screening - Improving PAP Rates. Objectives

NHSCSP proposals for cervical screening intervals. Comments and recommendations of Council of the British Society for Clinical Cytology

Human papilloma viruses and cancer in the post-vaccine era

National Surveillance System for Human Papillomavirus Infection and Related Disease in Scotland

Primary prevention of cervical cancer through HPV vaccination what is the future?

Transcription:

Vaccine 25 (2007) 3007 3013 Human papilloma virus (HPV) prophylactic vaccination: Challenges for public health and implications for screening M. Adams a,, B. Jasani b, A. Fiander b a Department of Oncology, Velindre Hospital, Cardiff CF14 2TL, Wales, UK b Wales College of Medicine, Cardiff University, Wales CF14 4XN, UK Available online 18 January 2007 Abstract Prophylactic vaccination against high risk human papilloma virus (HPV) 16 and 18 represents an exciting means of protection against HPV related malignancy. However, this strategy alone, even if there is a level of cross protection against other oncogenic viruses, cannot completely prevent cervical cancer. In some developed countries cervical screening programmes have reduced the incidence of invasive cervical cancer by up to 80% although this decline has now reached a plateau with current cancers occurring in patients who have failed to attend for screening or where the sensitivity of the tests have proved inadequate. Cervical screening is inevitably associated with significant anxiety for the many women who require investigation and treatment following abnormal cervical cytology. However, it is vitally important to stress the need for continued cervical screening to complement vaccination in order to optimise prevention in vaccinees and prevent cervical cancer in older women where the value of vaccination is currently unclear. It is likely that vaccination will ultimately change the natural history of HPV disease by reducing the influence of the highly oncogenic types HPV 16 and 18. In the long term this is likely to lead to an increase in recommended screening intervals. HPV vaccination may also reduce the positive predictive value of cervical cytology by reducing the number of truly positive abnormal smears. Careful consideration is required to ensure vaccination occurs at an age when the vaccine is most effective immunologically and when uptake is likely to be high. Antibody titres following vaccination in girls 12 16 years have been shown to be significantly higher than in older women, favouring vaccination in early adolescence prior contact with the virus. Highest prevalence rates for HPV infection are seen following the onset of sexual activity and therefore vaccination would need to be given prior to sexual debut. Since 20% of adolescents are sexually active at the age of 14 years, vaccination has been suggested at 10 12 years. However, parental concerns over the sexual implications of HPV vaccination may reduce uptake of vaccination thereby reducing the efficacy of an HPV vaccination programme. Concerns have already been raised over the acceptability of a vaccine preventing a sexually transmitted infection in young adolescents, particularly amongst parents or communities who consider their children to be at low risk of infection. This may be a particularly sensitive issue for ethnic minority groups. This paper considers the factors which will influence the efficacy of a public HPV vaccination programme and its impact on cervical screening. 2007 Elsevier Ltd. All rights reserved. Keywords: HPV vaccination; Implications; Public health 1. Introduction The recognition of the central role of high-risk high papilloma viruses in the aetiology of cervical cancer worldwide [1] has led to the development of prophylactic vaccination as a Corresponding author. Tel.: +44 29 20316944; fax: +44 29 20316901. E-mail addresses: malcolm.adams@velindre-tr.wales.nhs.uk (M. Adams), wptbj@cf.ac.uk (B. Jasani). new means of cervical cancer prevention. Two vaccines based on the LI capsid protein of human papilloma virus (HPV) 16 and 18 have demonstrated almost 100% efficiency in preventing persistent infection and related HPV pre-malignancy with these viruses in late stage trials [2,3]. The licensing of the first vaccine, Gardasil (Merck/Sanofi Pasteur MSD), by EMEA in 2006 and the imminent licensing of the second vaccine Cervarix (Glaxo Smith Kline, GSK) in 2007 offers the prospect of prophylactic vaccination programmes with 0264-410X/$ see front matter 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2007.01.016

3008 M. Adams et al. / Vaccine 25 (2007) 3007 3013 the ultimate potential of preventing approximately 70% of cervical cancer. In countries lacking a cervical screening programme a strategy of vaccination alone could have a major impact on the burden of HPV malignancy, providing funding for vaccine and the necessary infrastructure for vaccination was available. However, in a number of developed countries such as the UK, Canada and Scandinavia, the introduction in the 1980s of highly organised, systematic cervical screening programmes based on cervical cytology has led to a major reduction in mortality from cervical cancer. In the UK a comprehensive cervical screening programme based on cervical cytology is considered to have prevented an epidemic of cervical cancer and projected to have reduced mortality by up to 80% [4]. 2. Limitations of cervical screening Despite the major success of cervical screening programmes based on cervical cytology, important limitations have to be recognised. (a) Poor sensitivity of cervical cytology Whilst many cervical screening programmes claim sensitivity for cervical cytology of 60 70%, results may vary considerably. A metanalysis [5] suggested that in some countries the sensitivity of cervical cytology was as low as 51% for CIN1 although the average specificity was 98%. Limited sensitivity of cervical cytology may partly explain why 66% of women presenting with cervical cancer in 2003 had been screened [6]. The high false negative rate for a cervical smear has been the most important limitation of the test as false negative diagnoses may have major medical and medicolegal implications. It is the frequency of cervical cytology testing, i.e. three to five yearly, which ensures cervical screening programmes have achieved an acceptable level of sensitivity. (b) Anxiety and morbidity of screening investigations The investigation of abnormal cervical cytology inevitably causes significant morbidity and anxiety for large numbers of screened women, since up to 10% of all cervical smears will be found to be abnormal, albeit often with low-grade borderline atypia [7]. For a population of 20 million in England 2004/2005 almost 4 million smears were performed, resulting in 124,238 referrals for colposcopy following abnormal results [8]. Similarly, in Wales with a population of 1.5 million women, 200,000 smears were performed resulting in 22,000 colposcopy clinic visits in order to detect 3218 women with highgrade CIN and 41 cancers [9]. Women with low-grade abnormalities have been shown to experience similar anxiety to those with high-grade results and anxiety is greatest in young women who are likely to be highly concerned about future fertility [10]. (c) Poor uptake by some communities Even the most highly organised screening programmes may not reach 20 25% [8,9] of women, including women who may be particularly vulnerable to HPV associated malignancy from disadvantaged and ethnic minority communities. Women from ethnic minority communities may find it more difficult to access screening services particularly where there are language barriers. It has been demonstrated that the most important predictor of nonattendance is fear of the consequences of investigation. This may be a particular issue amongst less informed younger women [10]. (d) Falling screening coverage in the UK Recently, concern has been expressed about the fall of coverage for the screening programme in England from 77 to 71.6% amongst women age 25 29 [11]. The discomfort and embarrassment of the procedure and adverse experiences of other women may influence attendance. (e) Poor predictive value for adenocarcinoma Adenocarcinoma in situ (ACIS) is frequently missed by cervical cytology as a consequence of reduced accessibility to the cervical canal and the failure to recognise these lesions. In contrast to a declining incidence of squamous carcinoma the incidence of adenocarcinoma of the cervix has remained stable or has increased in some countries despite well organised screening programmes [12 14]. Prevention of HPV 16 and 18 infections by prophylactic vaccination in conjunction with cervical screening may be a means to further improve cervical cancer prevention. However, the size of the impact of this strategy on cervical cancer prevention and cervical screening is unclear at present. 3. Current commercial prophylactic HPV vaccines Both current commercially developed vaccines Gardasil (Sanofi Pasteur MSD/Merck) and Cervarix (GSK) consist of recombinant proteins of the LI capsid of HPV 16 and 18 viruses which self assemble to form virus like particles (VLPs), combined with an adjuvant. The key differences and characteristics of the vaccines are summarised in Table 1. Gardasil (Sanofi Pasteur MSD/Merck) is a quadrivalent vaccine, which contains the VLPs for 6 and 11 in addition to VLPs for 16 and 18 prepared with conventional alum adjuvant. HPV 6 and 11 are low risk human papilloma viruses responsible for 90% of genital warts and a proportion of low-grade cervical cytology abnormalities. Cervarix (GSK) is bivalent vaccine containing VLPs for 16 and 18 combined with a novel adjuvant AS04, containing 3D monophoryl lipid A (MPL). MPL acts as a toll-4 ligand and has been shown to enhance the titre of neutralising antibodies [16,17]. The combination of MPL and aluminium salts has been shown to induce enhanced humoral and cellular responses as compared with antigen alone or in combination with alum adjuvant [19]. This novel adjuvant has been

M. Adams et al. / Vaccine 25 (2007) 3007 3013 3009 Table 1 Comparison of commercial vaccines (randomised phase 2 studies) GSK Merck References Harper [3]; Harper et al. [15] Villa [2] HPV types 16/18 high risk 16/18 high risk; 6/11 genital wart types Expression system Baculovirus Yeast Vaccination schedule 0, 2, 6 months 0, 1, 6 months Antigen dose VLP 16,18 (20, 20 g) VLP 16, 18, 6, 11 (40, 20, 20, 40 g) Adjuvant ASO 4 [500 g Al(OH) 3 +50 g MPL] Alum 225 g [Al(PO 4 )] Trial size 560 vaccinees; 553 placebo 227 vaccinees; 275 placebo Trial countries United States of America, Canada, Brazil Age, trial subjects 15 25 years 16 23 years Duration of follow up Up to 54 months Up to 36 months Efficacy (% CI intervals) (a) HPV infection Incident infection 96.9 (81.3 99.9) Not available Persistent infection intention to treat 94% (63 99) 89% (73 96)[composite infection and lesion endpoint] (b) Cytological abnormalities 97% (84 100) Not published (c) HPV 16/18 pre-malignancy 100% (42 100) 100% (32 100) Serious adverse events reported Nil Nil Immune response (a) Seroconversion 100% 100% (b) Antibody titres 50 80 times natural infection 10 20 times natural infection shown to be safe and well tolerated when used to enhance immunogenicity of other vaccines [14]. To date clinical trial intention to treat analysis has suggested almost 100% efficacy against persistent HPV 16/18 infection in phase 2 studies in according to protocol analysis with the bivalent and similar results for overall analysis for the quadrivalent vaccine. All patients have sero-converted following vaccination in phase 2 studies. The titres of neutralising antibody observed were 10 80 times higher than observed in natural infection. However, the minimum serum antibody titre to protect from persistent HPV infection remains to be defined. Both vaccines appear safe and highly effective with almost 100% protection against persistent HPV infection 16/18 and related HPV pre-malignancy (see Table 1). A most recent interim analysis of the phase 3 quadrivalent vaccine has confirmed the efficacy for the prevention of CIN2/3 observed in the phase 2 trials [18,19]. Based on these results Gardasil has received approval of the European Agency for the Evaluation (EMEA) of medical products and the FDA in the United States of America. Both HPV 16/18 commercial vaccines would be expected to protect against approximately 70% of high risk HPV in most regions worldwide [21] and thus 70% of cervical cancer. However, HPV 16, 18 and 45 have been shown to be more prevalent in squamous cancer as compared with high-grade pre-malignancy. In contrast, some HPV types such as HPV 31, 33, 52 and 58 have been shown to be less prevalent in cervical cancer versus high-grade pre-malignancy [22]. Consequently, the cervical cancer protection offered by HPV 16/18 vaccination may be greater than initially anticipated. Whilst VLP vaccines would be expected to be type specific Harper et al. [15] have reported a degree of cross protection against cyto-histological outcomes beyond that anticipated from an HPV 16/18 vaccine. The vaccine provided 94% (95% CI 63.9 99.9) protection against HPV 45 and 54% (95% CI 11.5 77.7) protection against HPV 31. This may be the result of overlapping epitopes of HPV genotypes 16, 31, 18 and 45 which have similar sequencing [23]. Consequently, coverage of high-risk HPV types could rise from 70 to 75 80% by an HPV 16/18 vaccine. 4. Potential coverage HPV type coverage of current commercial vaccines In order to provide protection against greater than 90% of high HPV types responsible for cervical cancer a vaccine would have to contain LI VLPs for the eight most prevalent types of high risk human papilloma viruses [20]. The prevalence of these high risk HPV types is as follows: HPV 16 (53%), HPV 18 (17.2%), HPV 45 (6.7%), HPV 31 (2.9%), HPV 33 (2.6%), HPV 52 (2.3%), HPV 58 (2.2%), HPV 35 (1.4%) [17]. 5. Potential health gain for vaccination with current commercial vaccines Whilst promising phase 2/3 trials for HPV 16/18 vaccines have shown very high efficacy for vaccination it is difficult to predict the precise effect of vaccination on the incidence of pre-invasive and invasive cancer in the community, particularly when public vaccination is provided alongside a high quality cervical screening service. Nevertheless, mathematical models [24,25] support a high level of public health gain for the prevention of HPV malignancy in women for most

3010 M. Adams et al. / Vaccine 25 (2007) 3007 3013 Table 2 Lifetime impact of vaccination combine with cervical screening on outcomes for different scenario cohorts in the UK [25] Scenario Reduction in CIN2/3 (%) Reduction in cervical cancers (%) Reduction in cancer deaths (%) Age 10 years at vaccination with high coverage 70.2 76.0 76.1 Age 18 years at vaccination with low coverage 54.5 66.0 63.9 80% vaccine coverage 53.1 60.8 60.9 countries. The added value of male vaccination to attempt to improve herd immunity and further reduce female HPV malignancy is unknown. Mathematical modelling suggests there is little added advantage if HPV vaccination coverage in the females exceeds 70% [24]. In the UK Kohli et al. [25] have performed a cohort analysis to estimate the lifetime impact of an HPV 16/18 prophylactic vaccine on the burden of cervical disease in the UK according to different scenarios. They estimated that a 70% reduction of in the prevalence of high-grade cervical lesions and a 76% reduction in cervical cancer cases and deaths would be seen in the lifetime of a cohort of 12-yearold females if 100% coverage was achieved. If vaccination did not occur until 18 years the preventative effect of vaccination on the population would be diminished. In addition, there would be a proportionate fall off in population health gain for reduced vaccination coverage (see Table 2). The number of abnormal cytology results diagnostic tests, biopsies and colposcopies could fall by a half (see Table 3). Thus, HPV vaccination could lead to a substantial reduction in the morbidity and anxiety associated with cervical screening. 6. Factors which may influence vaccination health gain outcome It is likely that the following the key factors will exert a significant impact on the level of benefit in the population in terms of reduction of the burden of HPV malignancy and the morbidity of screening. (a) Age of vaccination There is no evidence to date that HPV LI VLPs have any therapeutic activity against persistent HPV infection. Consequently, for prophylactic vaccination to be most effective it should occur prior to sexual debut. The majority of girls will become infected with HPV, most commonly HPV 16 and 18, within 2 3 years of the onset Table 3 Lifetime impact of vaccination on outcomes for a cohort of 376,385 vaccinated (and unvaccinated) 12-year-old females in the UK [25] Scenario Abnormal cervical cytology Colposcopies Treated CIN lesions No vaccine 124,701 68,957 26,773 100% vaccination 59,411 31,160 10,876 coverage Reduction due to vaccine (%) 52.4 54.8 59.4 of sexual activity [26]. HPV 16 is particularly carcinogenic and the absolute risk of CIN approaches 40% 5 years after persistent infection [27], other HPV types being significantly less oncogenic [21]. HPV prevalence and incidence peak around 20 years and decline rapidly in women 30 years and older [26]. Persistent HPV infections occurring in the older teens or early twenties give rise to peak of CIN in the 25 30 year age group and cervical cancer at a later age [26]. The duration of induced HPV immunity needs therefore to be at least 10 years after adolescent vaccination to protect against persistent HPV infection in the late teens and twenties age group and the subsequent development of CIN2/3. Twelve-year-old girls have been shown to have a better serological response to the HPV vaccine as compared with older women which could theoretically lead to longer lasting immunity [28]. However, there is no definite evidence of this at present. The projected impact on life time risk of HPV malignancy of vaccinating a cohort of 12 year olds is likely to be greater than a cohort of women 18 years or more (see Table 2 above), largely because they have not been exposed to HPV infection. For women over the age of 25 years the level of benefit of HPV is unknown and awaits the results of ongoing trials. However, from available evidence to date one can project that for the small group of over 25s who have not been exposed to HPV there will be clear benefit. However, for women who have been exposed to infection and have detectable HPV DNA benefit is unlikely. The potential benefit of vaccinating women who have successfully eradicated infection with their natural immunity to prevent re-infection occurring in later life is unknown. If only cohorts of 12 year olds are vaccinated it will take at least 15 years before a major significant impact on the incidence of CIN2/3 and at least 30 years before an impact on cervical cancer incidence is observed. Therefore, a catch up vaccination programme may be appropriate for older adolescent girls and women. (b) Acceptability of vaccination Parental acceptance of adolescent HPV vaccination is unknown. Whilst there is a clear rationale for vaccination in adolescence, this may provoke concern in some parents that adolescent HPV vaccination will promote adolescent promiscuity or early sexual activity. This may be a consideration for parents in communities that consider their children to be at low risk of HPV infection, particularly in some religious and ethnic minority communities.

M. Adams et al. / Vaccine 25 (2007) 3007 3013 3011 To date information regarding acceptance is based on research questionnaires largely carried out in the United States of America indicating an acceptability level in most studies of 80% [28] or more. There is some evidence that educational intervention can improve the level of acceptability in undecided parents [29]. The only study performed in the UK in Manchester found that 81% of parents would probably or definitely would have their child vaccinated and 84% thought it would be important to vaccinate children before they were sexually active [30]. Parents worried about vaccine safety and with strong religious convictions were less likely to support adolescent vaccination [30]. The availability of a health care professional such as a school nurse to address parental and adolescent concerns over HPV vaccination may prove particularly important to alleviate the anxiety of undecided parents. Reduction of vaccination uptake to 80% or less as a result of limited acceptability of adolescent vaccination could reduce the lifetime impact of vaccination on CIN2/3 and cervical cancer incidence to 53.1 and 63.9%, respectively (see Table 2). (c) Duration of immunity Current evidence from clinical trials suggests that the immunity following vaccination exceeds 4 years and appears to be sustained [28]. At present there is no evidence of a falling immunity with time and whether vaccination boosting will be required is a key unknown. It is possible that re-infection will provide a means of naturally sustaining immunity in the absence of vaccine boosting. However, currently this is speculative and to what extent VLP vaccines, which are inherently highly immunogenic, together with the enhanced immunity of novel adjuvants will provide long HPV term immunity remains to be demonstrated. Continued monitoring of efficacy will be essential to determine the need or otherwise for booster doses. (d) Place and method of vaccine delivery One means of delivering the HPV vaccine would be by the school health service immunisation programme. School nurses in some parts of the UK are currently responsible for immunisation with dtap-ipv (diphtheria, tetanus, pertussis and inactivated polio) in adolescence with back up from primary care. Such programmes have traditionally achieved coverage of 80 90%. These nurses could also be a source of advice for both parents and adolescents on HPV vaccination as they usually have considerable experience in sex education and managing female adolescent issues which are relevant to HPV vaccination. A particular problem will be maximising compliance for three doses over a 6-month period. The immunisation programme will need to be timed to minimise disruption of school and pupil studies. Countries without school health services, such as France and Italy, have frequently been unable to introduce vaccination with high coverage [27]. A recent study [31] has assessed the feasibility of HBV vaccination in Greater Glasgow Scotland through a school health system. Vaccine uptake was 91.3, 89.3 and 80.2% for first and second and third doses, respectively, giving some optimism for the prospects of high compliance for three dose immunisation in the school environment. For older women the optimum service delivery for HPV vaccination is less clear and achieving high coverage in a catch up campaign maybe more difficult. The potential source of vaccination includes primary care family planning clinics, possibly obstetricians and gynaecologists and the private sector. (e) Effect on cervical screening Cervical cancer screening based on cytology has had a major impact on cervical cancer incidence and mortality. Screening will need to continue in the post vaccination era to ensure the continued surveillance of the large cohort of women who have been exposed to HPV infection prior to vaccination and to screen the 25 30% of HPV infections not prevented by the current HPV 16/18 vaccines. Whilst HPV vaccination in conjunction with cervical screening is projected to reduce abnormal cytology by 50 60% [25] paradoxically it may adversely affect the performance of screening as a result of: (i) Fall in screening population coverage: already the coverage of cervical screening is falling in some groups in younger women [11]. There is a danger that coverage could fall further if the public developed the misconception that HPV vaccination had removed the need for screening. Therefore any vaccination programme needs to be supported by public education to reinforce the continued role of screening for the foreseeable future. (ii) Reduced sensitivity and specificity of cervical cytology: reduction in the number of squamous abnormalities as a result of vaccination could lead to a fall in the negative predictive value of cytology as calculated in Table 4 below. In most developed countries the current prevalence of cytological abnormality is between 5 and 10%. Following vaccination a reduction of 50 60% in the prevalence of cytological abnormalities could ultimately lead to a fall in predictive value of between 10 and 20% when most of the population have been vaccinated. Reduction in prevalence of abnormal cytology could lead to fatigue and boredom within the cytology work force. There Table 4 The link between prevalence of cytological screening abnormalities and negative predictive value of cytology (after Franco et al. [32]) Cytological abnormality prevalence rate Negative predictive value of cervical cytology (%) 0.5 1 5 10 20 50 11.4 20.5 57.3 73.9 86.4 96.2

3012 M. Adams et al. / Vaccine 25 (2007) 3007 3013 may also be concern over missing abnormalities leading greater identification of inflammatory changes. Such loss of specificity for cervical cytology could lead to an increase in unnecessary screening investigations. Ultimately, HPV testing with its greater sensitivity but lower specificity could become the primary screening test, with HPV testing followed by cervical cytology in the presence of a positive HPV test. This would provide a population based means of monitoring the efficacy of HPV vaccination. The use of HPV/cytology triage would reduce the number of cervical smears overall but would artificially increase the prevalence and the predictive value of cytology. If only HPV positive individuals were subjected to cytology the prevalence of cytological abnormalities would artificially increase to up to 50% and the negative predictive value would rise (see Table 4). The use of HPV testing which could distinguish HPV genotype would be preferred for the future, which would enable changes in the natural history of HPV malignancy to be monitored. Reduction of prevalence of the highly malignant types, e.g. HPV 16 could lead to a predominance of less malignant HPV types leading to a more indolent natural history after many years which could lead ultimately to a prolonged screening interval. 7. Conclusions HPV vaccination in adolescence with continued cervical screening could ultimately lead to a 76% lifetime reduction in cervical cancer deaths after many years and a 50% reduction in cervical screening abnormalities if high coverage of vaccination was achieved. However, integrating HPV vaccination with screening is complex and it is difficult to anticipate the impact in the population from the phase 2/3 HPV trials. Therefore, large phase 4 population studies are needed to monitor the true efficacy of HPV vaccination. Cervical cytology screening programmes will in time require modification but could develop a new role in monitoring the long term efficacy of vaccination and the changes in the natural history of HPV malignancy, ultimately increasing the screening interval. References [1] Bosch FX, Lorincz A, Munoz N, Meijer CJM, Shah KV. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 2002;55:244 65. [2] Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Guilano AR, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16 and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase 11 efficacy trial. Lancet Oncol 2005;6(5):271 8. [3] Harper D, Franco E, Wheeler C, Ferris DG, Jenkins D, Schuind A, et al. Efficacy of a bivalent L1 virus-like particle in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet 2004;364:1757 65. [4] Peto J, Gilham C, Fletcher O, Mathews FE. The cervical cancer epidemic that screening prevented in the UK. Lancet 2004;364(9430): 249 56. [5] Nanda K, McCrory DC, Myers ER, Bastian LA, Hasselblad V, Hickey JD, et al. Accuracy of the Papanincolaou test in screening for and follow up of cervical cytologic abnormalities: a systematic review. Ann Int Med 2000;132:810 9. [6] Sasieni P, Adams J, Cuzick J. Benefit of cervical screening at different ages: evidence from UK audit of screening histories. Br J Cancer 2003;89:88 93. [7] Benard VB, Eheman CR, Lawson HW, Blackman DK, Anderson C, Helsel W, et al. Cervical screening in the National Breast and Cervical Cancer Early Detection Program 1995 201. Obstet Gynecol 2004;103:564 71. [8] Office of National Statistics Cervical Cancer Screening Programme. England 2004 2005. [9] Cervical Screening Wales Annual Report 2005. [10] Gray NM, Sharp L, Cotton SC, Mason LF, Little J, Walker LG, et al. Psychological effects of low grade abnormal cervical smear test result: anxiety and associated factors. Br J Cancer 2006;94:1253 63. [11] NHS Health & Social Care Information Centre. Community Health Services Statistics website: http://www.cnhs.uk/. [12] Krane JF, Ganter SR, Trask CE, Hogan CL, Lee KR. Papanicololaou smear sensitivity for the detection of adenocarcinoma of the cervix: a study of 49 cases. Cancer 2001;93:8 15. [13] Raab SS. Can glandular lesions be diagnosed in pap smear cytology? Diagn Cytopathol 2000;23:127 33. [14] Bulk S, Visser O, Roendaal L, Verheijen RH, Meijer CJ. Cervical cancer in the Netherlands 1989 1998: decrease of squamous carcinoma in older women, increase of adenocarcinoma in younger women. Int J Cancer 2005;1134:1005 9. [15] Harper DM, Franco EL, Wheeler CM, Mosicki AB, Romanowski B, Rotelli-Martins CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow up from a randomised control trial. Lancet 2006;367:1247. [16] Vogel FR. Improving vaccine performance with adjuvants. Clin Infect Dis 2000;30(Suppl. 3):469 75. [17] Stanberry LR, Spruance SL, Cunningham AL. Glycoprotein-dadjuvant vaccine to prevent genital herpes. N Engl J Med 2002;347: 1652 61. [18] Munoz N. Review of the initial phase 3 clinical data for the quadrivalent human papilloma virus vaccine. In: 6th international multidisciplinary congress of the European research organization on genital infection and neoplasia (EUROGIN). 2006. [19] Koutsky LA, Harper DM. Current findings from prophylactic HPV vaccine trials. Vaccine 2006;24S3:114 21. [20] Munoz N, Bosch FX, Castellsaque X, Diaz M, de Sanjose S, Hamouda D, et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 2004;111: 278 85. [21] Clifford GM, Gallus S, Herero R, Munoz N, Snijders PJ, Vacarella S, et al. Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis. Lancet 2005;366:991 8. [22] Clifford GM, Ran RK, Franceschi S, Smith JS, Gough G, Pimenta JM, et al. Human papilloma virus genotype distribution in low grade lesions: comparison by geographic region and with cervical cancer. Cancer Epidemiol Biomarkers Prev 2005;14:278 85. [23] Hagensee ME, Yaegashi N, Galloway DA. Self assembly of human papillomavirus type 1 capsids by expression of the LI protein alone or by coexpression of the LI and L2 capsid proteins. J Virol 1993;67:315 22. [24] Taira AV, Neukermans CP, Sanders GD. Evaluating human papilloma virus vaccination programs. Emerg Infect Dis 2004;10:1915 23. [25] Kohli M, Ferko N, Martin A, Franco EL, Jenkins D, Gallivan S, Sherlaw-Johnson C, Drummond M. Estimating the long term impact of a prophylactic human papilloma virus (HPV) 16/18 vaccine on the

M. Adams et al. / Vaccine 25 (2007) 3007 3013 3013 burden of cervical disease in the UK. In: 2006 poster P-200 23rd international papilloma conference and clinical workshop. 2006. [26] Moscicki AB, Schiffman M, Kjaer S, Villa LL. Updating natural history of HPV and anogenital cancer. Vaccine 2006;24S3:S3/42 51. [27] Wright TC, Van Damme P, Schmitt HJ, Meheus A. HPV vaccine introduction in industrialised countries. Vaccine 2006;24S3:S3/122 31. [28] Mao C, Koutsky LA, Ault KA, Wheeler CM, Brown DR, Wiley DJ, et al. Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomised controlled trial. Obstet Gynecol 2006;107:18 27. [29] Zimet GD, Liddon N, Rosenthal SL, Lazcano-Ponce E, Allen B. Psychosocial aspects of vaccine acceptability. Vaccine 2006;24S3:201 9. [30] Brabin L, Roberts SA, Farzaneh F, Kitchener HC. Future acceptance of adolescent human papillomavirus vaccination: a survey of parental attitudes. Vaccine 2006;24(16):3087 94. [31] Bramley JC, Wallace LA, Ahmed S, Duff R, Carman WF, Cameron SO, et al. Universal hepatitis B vaccination of UK adolescents a feasibility acceptability study. Commun Dis Public Health 2002;5(4):318 20. [32] Franco EL, Cuzick J, Hildesheim A, de Sanjosé S. Issues in planning cervical screening in the era of HPV vaccination. Vaccine 2006;24S3:S3/171 7.