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September 2008 marked the beginning of a nationwide immunisation programme designed to protect British women against the devastating impact of cervical cancer. Cervarix™, a GlaxoSmithKline vaccine (Brentford, London, UK), offers protection against human papillomavirus (HPV) types 16 and 18, which together are responsible for approximately 70% of cervical cancers. In future, girls aged 12–13 years will be immunised each year as part of the routine National Health Service immunisation programme. In addition, all girls aged 13–18 years are being offered the vaccine in a one-off ‘catch-up’ programme. This will ensure that by 2011 the 12–18-years cohort will all have been invited for free HPV vaccination.

Two prophylactic HPV vaccines, Cervarix™ and Gardasil® (Merck, Readington Township, NJ, USA), have been licensed for use in the UK. Both have been tested in large randomised placebo-controlled trials involving thousands of women from different countries across the world. Impressive protection against persistent vaccine-specific HPV infection has been demonstrated over short- to medium-term follow-up periods.1 Long-term follow-up data are still required to answer the question of longevity of immune protection and whether booster vaccination(s) will be necessary, and at what time interval. Because of ethical and consent issues, efficacy cannot be determined among pre-adolescent girls, but is assumed by extrapolating data from the young women involved in the original vaccination trials. ‘Bridging’ studies have also demonstrated 1.7- to 2.7-fold higher immune responses following vaccination among young adolescent girls (and boys) when compared with young adults,2 suggesting that vaccination at this younger age may result either in longer sustained immunity, improved long-term clinical efficacy, or both. Sanders and Taira3 estimated that 250 adolescent girls would need to be vaccinated to prevent one case of cervical cancer if the vaccine was protective over a lifetime. If vaccine efficacy waned after 10 years, 600 girls would need to be vaccinated to prevent one case of cervical cancer, and 1484 girls to prevent one cervical cancer death. Brisson et al.4 projected that the number needed to be vaccinated to prevent one case of cervical cancer was 324, based on the assumption that the vaccine procures lifelong protection; when the protection declined at a rate of 3% per year, the number needed to vaccinate was 9080. These studies illustrate the difficulty of assessing the impact of an immunisation strategy when so many factors are still unknown.

Many of the problems that were foreseen, in particular parental rejection of a vaccine against a sexually transmitted infection, have not occurred. This was indicated first in a pilot study,5 and subsequently in the provisional vaccine uptake figures published by the Department of Health. The national uptake figures for the first cohort of 12- to 13-year-old girls offered the vaccine in England will be published in September 2009. Provisional data indicate that 86% and 83% of eligible girls received the first and second doses of the vaccine, respectively.6 This high level of uptake largely results from the fact that the vaccine is delivered through schools in the majority of Primary Care Trusts (PCTs). The coverage for the third dose is critical as the vaccine is locally painful and girls may be reluctant to complete the course. The catch-up programme has largely been delivered through primary care, as many girls have left school. How the girls are contacted and subsequently reminded to attend for vaccination is determined by individual practices, and varies considerably across PCTs. GPs are reimbursed the cost of the vaccine and are generally paid per dose delivered, with other incentives (e.g. bonus payment for completion of the course) being offered by some PCTs. The coverage on the catch-up programme has been disappointing for the most part, with provisional data indicating that just 53% and 41% of 17- to 18-year-old girls received the first and second doses of the vaccine, respectively, although some PCTs have achieved satisfactory coverage.6

Provisional uptake figures for the first cohort of 12- to 13-year-old girls offered the vaccine in Scotland, Wales and Northern Ireland have shown coverage levels exceeding 80% for the first and second doses overall.7–9 Scotland have also reported high uptake figures for the catch-up programme delivered through school, but have not yet published figures for girls who have left school, as they are being targeted through community clinics and GP practices. Wales and Northern Ireland plan to introduce their catch-up programme in 2009–2010.

Comparing HPV immunisation programmes between countries is difficult because the delivery systems are often very different. Like the UK and Australia, Canada’s programme is school-based, but the various provinces target different cohorts of girls between the ages of 9 and 17. Coverage has varied from <60% in some provinces to more than 80% in others.10 The UK is the only European country that has a national school-based programme. School programmes generally achieve higher coverage than ‘on-demand’ systems, where the onus is on the parent to request the vaccine. A review of HPV vaccination policies and practices in 40 European countries revealed that only nine currently offer HPV vaccination free of charge to at least one age cohort of girls, whereas three provide it on a co-payment basis.11 It was noted that countries providing HPV vaccination have more efficient cervical screening programmes and lower cervical cancer rates than those yet to introduce it. Clearly HPV vaccination will be most beneficial in resource-poor countries lacking organised screening programmes, where cervical cancer remains a major cause of cancer-related death in women. In these settings, universal vaccination is unlikely while vaccines remain prohibitively expensive.

Although wide-scale immunisation could save hundreds of lives annually, some still question the rationale for HPV vaccination in countries like the UK that have well-run cervical screening programmes. There are still many unanswered questions about the long-term cost-effectiveness and safety of both of the current HPV vaccines. In the UK there has also been criticism of the choice of vaccine,12 and the decision to limit vaccination to adolescent girls.13,14 Issues such as these will continue to arise as more is known about the performance and costs of implementing routine vaccination. This article will examine some of these issues.

Choice of vaccine

  1. Top of page
  2. Choice of vaccine
  3. Girls only
  4. Challenges post-HPV vaccine introduction
  5. Disclosure of interest
  6. Contribution to authorship
  7. Details of ethics approval
  8. Funding
  9. Acknowledgements
  10. References

Merck was the first of two pharmaceutical companies to license its vaccine in October 2006, giving it a commercial head start. This quadrivalent vaccine confers immunity against the two oncogenic strains of HPV responsible for 70% of cervical cancers (HPV 16 and 18), as well as two strains that together cause 90% of genital warts (HPV 6 and 11). To many, a vaccine that protects against four strains has appeared to be inherently ‘better’ than one protecting against two strains.15 The bivalent vaccine Cervarix™ did not become available until almost a year later, in September 2007. Cervarix™ protects against HPV types 16 and 18, but does not prevent genital warts.

Gardasil® has been approved for vaccine programmes in the USA, Canada, Australia, New Zealand, Spain, France, Switzerland and Sweden. The UK Health Authority and, more recently, the Netherlands have chosen Cervarix™. Insofar as Cervarix™ does not prevent genital warts, some UK health professionals consider that its selection amounts to a ‘missed opportunity’, and some have accused the government of false economy.12 Genital warts are the most common sexually transmitted viral infection in the UK, responsible for unsightly lesions that are both difficult and costly to treat. The current cost of treating genital warts in England is estimated at more than £23m/year, and some claim that mathematical models have underestimated costs by as much as one-third to a half.16 Women with genital warts also risk spread of the infection to the respiratory tract of their newborn infant during childbirth. Recurrent respiratory papillomatosis is a rare, but chronic, debilitating disease characterised by hoarseness, stridor and respiratory distress in the newborn, and requires lifelong repeated surgical intervention and prolonged hospital stays, even causing death in a minority of cases.17 Nevertheless, a paper from the Health Protection Agency claimed that the cost analysis made before the government took its decision showed savings of up to £18.6 m a year if Cervarix™ was chosen.18 With this saving, the Department of Health was able to extend the catch-up programme to include girls of up to 18 years of age.

Published data do not distinguish either vaccine as superior in terms of clinical effectiveness or toxicity. However, recent data released by GlaxoSmithKline from their head-to-head comparison of the two vaccines reported that Cervarix™ induced significantly higher HPV 16 and 18 serum neutralising antibody titres, as well as higher levels of neutralising antibodies in cervicovaginal secretions and circulating HPV 16 and 18-specific memory B-cells.19 These results would suggest that a longer duration of protection against HPV infection may be conferred by Cervarix™. Declining antibody levels post-vaccination may not, however, indicate a loss of protection, as immunological memory may persist at low levels, and is difficult to measure. Natural viral challenge may be sufficient to ‘boost’ declining serological responses, although booster vaccination is superior.20

Girls only

  1. Top of page
  2. Choice of vaccine
  3. Girls only
  4. Challenges post-HPV vaccine introduction
  5. Disclosure of interest
  6. Contribution to authorship
  7. Details of ethics approval
  8. Funding
  9. Acknowledgements
  10. References

All national vaccine programmes have limited their target population to adolescent girls, a fact that continues to provoke debate. Vaccines to prevent infectious diseases usually protect not only the vaccinated individual but also the population as a whole, through the process of herd immunity. Gender-specific vaccination programmes may fail to create sufficiently high levels of herd immunity, as exemplified by the UK girls-only rubella immunisation programme of 1970. An initial decline in the incidence of rubella was quickly followed by a resurgence of the disease in young men and pregnant women. In 1995, the schedule was altered to include boys as well as girls, resulting in a decline in rubella infection rates to a level not previously seen in the UK.21,22 Although illustrating the concept of herd immunity, the adequacy or otherwise of gender-specific immunisation against rubella can not inform the HPV vaccination programme, because the two infections are transmitted differently. For rubella, despite the risk of disease being pregnancy-related, both genders have potentially infectious contacts within and between the genders. Thus, vaccinating girls alone achieves half the potential coverage achieved by vaccinating both genders. By comparison, the heterosexual spread of vaccine-related HPV infection can be interrupted by gender-specific vaccination, and vaccinating a certain number of one sex will always be more effective than vaccinating the same total number of either sex.23 As the purpose of HPV vaccination is the prevention of cervical disease, vaccinating girls alone is sufficient to achieve a linear reduction in prevalence amongst girls, and a non-linear reduction in prevalence amongst boys. It only becomes cost-effective to vaccinate boys if coverage levels fall below a threshold of 75%.24 Even at coverage levels below this threshold, vaccinating boys may still not be cost-effective. The point at which vaccination becomes cost-effective reflects the assumptions built into the economic models, and most have not taken into account the impact of vaccinating boys who subsequently exhibit very risky sexual behaviour. Parents apparently understand the economic rationale for vaccinating girls: the Manchester study reported that only half of parents offered vaccination indicated a wish to vaccinate boys.15

One of the problems of a sex-specific vaccine is that it may fail to educate males about their role in transmitting the virus.25 The risk of contracting HPV is linked to sexual behaviour, with early age at first coitus, as well as a greater number of lifetime sexual partners, being associated with higher infection rates. Men tend to be more promiscuous than women, with 35% of British men aged 16–44 years claiming more than ten lifetime sexual partners, compared with just 19% of women.26 Thus, British men are more likely to be exposed to genital HPV infection, and in turn pose a greater infection risk to others by transmitting vaccine-specific but also non-HPV 16 or 18 cancer-causing types. Without some understanding of HPV and cervical cancer, men might perceive themselves to be less at risk of contracting a sexually transmitted infection from women, and take fewer risk-reducing precautions. One recent study reported that informing men about the benefit of male HPV vaccination for reducing cervical cancer risk in their female partners did not increase men’s interest in receiving the vaccine, beyond informing them of the benefits for their own health.27

It is anticipated that HPV vaccination will reduce the incidence of other, less common malignancies linked to high-risk HPV infection, including vulval, vaginal, penile, anal and oropharyngeal cancers. Men who have sex with men are particularly at risk of anal and oropharyngeal cancers and, although uncommon in the UK, these malignancies are difficult to treat and are increasing in incidence. Protective efficacy has not yet been established in men, but early phase clinical trials have established vaccine immunogenicity with minimal toxicity levels.1 In an attempt to protect themselves and their partners from genital warts, anal, penile and oropharyngeal cancers, reports suggest that homosexual men are attending sexual health clinics to obtain Gardasil®‘off licence’.28 Although unlikely to do any harm, individuals who are already sexually active are unlikely to benefit from prophylactic vaccination, as they will almost certainly have been exposed to HPV already.

In developing countries there may be a better case for vaccinating young men, as in some settings increasing coverage of young women may not be possible beyond a certain threshold. In resource-poor countries some young women may never be reachable by the programme, either because of poor school attendance, early coitarche or lack of parental consent to vaccination. These women may also be less likely to have access to cervical screening, and represent the group of women at greatest risk of cervical cancer. Further mathematical models will be needed to decide whether to try and protect vulnerable women by vaccinating men.29

Challenges post-HPV vaccine introduction

  1. Top of page
  2. Choice of vaccine
  3. Girls only
  4. Challenges post-HPV vaccine introduction
  5. Disclosure of interest
  6. Contribution to authorship
  7. Details of ethics approval
  8. Funding
  9. Acknowledgements
  10. References

Future cervical screening

Cervical cancer develops after an infection period of a decade or more, and up to 30% of cervical cancers are caused by HPV types not included in either vaccine. Although some degree of cross-protection against similar high-risk HPV types has been presumed from trial data, vaccinated women are still clearly at risk of contracting other oncogenic HPV types that can cause cervical cancer, and cervical screening will still be necessary, even for vaccinated women.13,30 There is a danger that vaccinated women may feel protected against cervical cancer and be less likely to attend for cervical screening than unvaccinated women, who still consider themselves to be ‘at risk’. On the other hand, mothers of daughters offered HPV vaccination may, in future, have a better understanding of the purpose of cervical screening, and so be more motivated to attend. The main concern is that non-screened mothers and unvaccinated girls will cluster in the same socio-economic groups. In the Manchester pilot study, uptake rates were highest amongst girls from white, affluent backgrounds, who are at lowest risk of cervical cancer.5

Inevitably, the vaccine programme will have implications for the future structuring of the cervical screening programme. It may be that primary screening by HPV test will be used to triage women into those requiring regular assessment by cervical cytology, e.g. every 3 years for HPV-positive women, versus those who can be screened less frequently, e.g. 5-yearly if HPV negative. Emerging evidence from the USA suggests that the initiation of cervical screening may be safely delayed in vaccinated women, as non-vaccine-encoded HPV types typically cause cancer at a more advanced age than vaccine-encoded types.31 Furthermore, it is likely that the specificity of cervical cytology will be improved by cell cycle or other molecular markers able to identify precancerous changes with greater propensity for progression.32

Safety scares

In general, both Cervarix™ and Gardasil® appear to be safe and well tolerated. Injection site adverse events, including pain, swelling and redness, have been reported more frequently by women receiving the vaccine, compared with those receiving placebo in clinical trials. Cervarix™ is recognised to be a more painful inoculation than Gardasil®, but even so, most side effects disappear within the first day or two. Serious adverse events have been reported by similar proportions of Cervarix™, Gardasil® and placebo recipients across the studies. In New South Wales, Australia, following the introduction of Gardasil®, the anaphylaxis rate in the 2007 school-based programme was 2.6 per 100 000 doses (95% CI; 1.0–5.3 per 100 000 doses), which is higher than for other vaccines, although still rare.33 This might have been anticipated, because allergy-related conditions are common in young women. Since the introduction of the UK national vaccine programme, adverse publicity has surrounded the reporting on ‘Yellow Cards’ of over 1300 adverse reactions to the Medicines and Healthcare Products Regulatory Agency. One report concerned several cases of paralysis, convulsions and fits.34 The available evidence does not suggest that the vaccine was responsible for the adverse events, but scare stories have the potential to lead to public demand for vaccine withdrawal.

There have been no deaths attributable to either vaccine in any of the clinical trials to date. Pregnancy and congenital anomaly data have been reported for Gardasil®, but not for Cervarix™.35,36 Despite explicit instructions to avoid pregnancy, 2800 women became pregnant during the trial follow-up period (around 1400 in each group, vaccine and placebo). Sixty-six percent of the vaccine recipients and 63% of the placebo recipients who became pregnant had a live birth. One hundred and twelve women receiving Gardasil®, and 114 women receiving placebo, became pregnant within 30 days of injection. Twenty-three percent of women from each group had a miscarriage. Congenital anomalies were seen more frequently amongst vaccine recipients than placebo recipients (7.1% versus none), but the placebo group had an unusually low rate of congenital anomalies, as the background rate is around 2–4% in the USA. The abnormalities were not related in type. It was also observed that 12.9% of infants from the vaccinated group had other medical conditions, compared with 9.1% in the placebo group, although further details were not given.

Maintaining high vaccine coverage

Interim results for the uptake of the third dose in the national programme in England indicate an uptake of about 57% in the 12–13-years cohort, but data collection is not yet complete or comprehensive. In the Manchester study, coverage dropped by only 2% across the three doses,37 but in New South Wales, Australia, also a school-based programme, coverage dropped from 83% at the first dose to 74% for dose 3.33 Whether girls who receive only the first two doses of the vaccine will show sufficient immunity against HPV to prevent subsequent infection remains unclear. Furthermore, the effect of mis-timed doses is not fully understood. Data from hepatitis B vaccination studies suggest that longer intervals between second and third doses of the HPV vaccine may not be detrimental to the strength of the immunity generated,38 presumably as long as HPV exposure does not occur during the delay. In Quebec, girls participating in the immunisation programme were given the first two doses of the vaccine in grade 4, but the third dose will only be given in grade 9.10 There is no immunogenicity or efficacy data available to justify this approach at the present time.

Best practice for HPV vaccine implementation has still to be determined, and there is a certain level of inefficiency associated with over 150 PCTs devising their own implementation plans by trial and error.39 The National Institute for Clinical Excellence (NICE) has been conducting a review of best practice for delivering vaccines to children and adolescents, but the unpublished preliminary draft makes no recommendations for the HPV vaccination programme. The huge effort made to ensure that the HPV vaccine implementation succeeded this year must be sustained in the face of new challenges. The Department of Health has requested that PCTs accelerate their delivery of the catch-up programme, which will place more demands on vaccine teams and school nurses. Some PCTs have responded by offering vaccination to outstanding cohorts of girls, either through schools or primary care, although coverage details are not yet available. If there is a major swine flu outbreak in the autumn, this could have a detrimental impact on HPV vaccine delivery.

In conclusion, HPV vaccination is an unfolding story rather than a problem solved. The UK has performed exceptionally well in this first year of implementing the programme. The coming years are likely, nonetheless, to see new challenges and changes of policy in the light of new data from ongoing phase-IV trials and increasing experience in delivering the programme.

Disclosure of interest

  1. Top of page
  2. Choice of vaccine
  3. Girls only
  4. Challenges post-HPV vaccine introduction
  5. Disclosure of interest
  6. Contribution to authorship
  7. Details of ethics approval
  8. Funding
  9. Acknowledgements
  10. References

EJC reports no conflicts of interest. LB has received research funding and conference fees from GlaxoSmithKline, and travel and honoraria for presentation at meetings organised by both GlaxoSmithKline and SanofiPasteur.

Funding

  1. Top of page
  2. Choice of vaccine
  3. Girls only
  4. Challenges post-HPV vaccine introduction
  5. Disclosure of interest
  6. Contribution to authorship
  7. Details of ethics approval
  8. Funding
  9. Acknowledgements
  10. References

EJC and LB are full-time employees of the University of Manchester. No additional funding was required to complete this commentary.

Acknowledgements

  1. Top of page
  2. Choice of vaccine
  3. Girls only
  4. Challenges post-HPV vaccine introduction
  5. Disclosure of interest
  6. Contribution to authorship
  7. Details of ethics approval
  8. Funding
  9. Acknowledgements
  10. References

LB is supported by the Max Elstein Trust. We acknowledge support from the Manchester NIHR Biomedical Research Centre.

References

  1. Top of page
  2. Choice of vaccine
  3. Girls only
  4. Challenges post-HPV vaccine introduction
  5. Disclosure of interest
  6. Contribution to authorship
  7. Details of ethics approval
  8. Funding
  9. Acknowledgements
  10. References