Correspondence *Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, The Netherlands

Email cjlm.meijer@vumc.nl

Original article

Koutsky LA et al. (2007) Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 356: 1915–1927   PubMed

Synopsis

Background

Cervical cancer is the second most prevalent cancer among women. Papanicolaou screening has reduced cervical cancer mortality in the countries in which it has been introduced, but, because of the cost of providing screening, developing countries have generally not benefited from this advance. Virtually all cervical cancers are caused by human papillomaviruses (HPVs), and approximately 70% are associated with HPV types 16 and 18.

Objective

To demonstrate the efficacy of a quadrivalent vaccine against HPV types 6, 11, 16, and 18 (HPV-6/11/16/18) for preventing high-grade cervical lesions (classified as cervical intraepithelial neoplasia [CIN] grade 2 or 3), adenocarcinoma in situ, and cervical cancer.

Design and intervention

Between June 2002 and May 2003, this international phase III, double-blind, placebo-controlled, randomized trial—the Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) II trial—enrolled women (aged 15-26 years) at 90 centers in 13 countries. Eligibility criteria were a lack of abnormal results on Papanicolaou smear, a lifetime number of no more than four sexual partners, and a negative result on a pregnancy test of urine or blood. Women were requested to use effective contraception during the vaccination period (day 1 through month 7). Vaccination with the quadrivalent HPV-6/11/16/18 virus-like-particle vaccine or placebo was given in 3 doses, at day 1, during month 2 and during month 6.

Outcome measure

The primary composite end point was high-grade cervical lesions (classified as CIN grade 2 or 3), adenocarcinoma in situ or cervical cancer, with the detection of DNA from HPV-16, HPV-18 or both in at least one of three adjacent areas of the same lesion.

Results

After the first vaccination or administration of placebo, 12,167 women were followed for a mean period of 3 years; the study is still ongoing. Efficacy of the vaccine for prevention of the primary (composite) end point was 98% (95% CI 86-100%) for the per-protocol susceptible population and 44% (95% CI 26-58%) for the intention-to-treat population. This intention-to-treat population comprised all women who had undergone randomization, and included women infected with HPV-16 and HPV-18 as well as uninfected women. Vaccination did not seem to affect the course of infections or cervical lesions related to HPV-16 or HPV-18 that were already present at the time of randomization. The efficacy of vaccine against high-grade cervical lesions associated with any HPV type was estimated at 17% (95% CI 1-31%) in the intention-to-treat population. Relatively few side effects of vaccination were reported—the most common event was pain at the injection site. Similar proportions of women in the two arms of the study reported serious side effects.

Conclusion

The quadrivalent HPV-6/11/16/18 vaccine was effective in the prevention of high-grade cervical lesions caused by HPV-16 and HPV-18 in young women not already infected with HPV-16 or HPV-18.

Commentary

Prevention by nationwide cytological screening has proven effective in reducing the incidence of cervical cancer in areas of Canada, the Nordic countries and The Netherlands. On the basis of the insight that cervical cancer is caused by high-risk HPV types, two new directions have emerged for the prevention of cervical cancer: primary prevention by prophylactic vaccination against high-risk HPV-16 and HPV-18 (together responsible for approximately 70% of cervical cancers) and secondary prevention by cervical screening with HPV DNA testing.

Two commercial vaccines designed to prevent de novo HPV-16 and HPV-18 infection have been developed, one a bivalent L1 virus-like particle vaccine,¹ and one a quadrivalent vaccine against HPV-6/11/16/18, which was used in the FUTURE II trial. These vaccines induce high titers of neutralizing antibodies, preventing infection of cervical epithelial cells by vaccine HPV types. These vaccines have high efficacy against HPV-16/18-related high-grade CIN and adenocarcinoma in situ—the intermediate end points of cervical cancer, in women negative for HPV-16/18 DNA, as shown by Harper et al.¹ and Koutsky et al. The HPV-16/18 vaccines do not have a therapeutic effect on pre-existing HPV-16/18 infections nor pre-existing CIN lesions caused by these virus types. With regard to public health and in order to maximize the preventive effect of vaccination, women should be vaccinated before their sexarche, and coverage should be high (preferably >90%). This outcome can be achieved by incorporation of HPV vaccines into the national immunization programs offered to prepubertal women. Assuming a protective effect of at least 10–15 years, this initiative would have the highest impact on prevention of cervical cancers in younger women (<30 years of age), for whom cervical screening is less specific and less effective.

Given that a proportion of older, sexually active women are already infected with HPV-16 and/or HPV-18, the decision to vaccinate is likely to be one for each individual, and, therefore, outside of the public health domain. Screening at older age will still remain important to protect vaccinated women against cervical cancer caused by non-HPV-16/18 high-risk HPV types and to ensure protection of nonvaccinated women. In the near future, cervical screening with primary HPV testing is likely to replace cytological screening, since primary HPV testing has a substantially higher sensitivity for cervical cancer and high-grade precursor lesions than cytology.² The effect of implementing HPV testing is currently being investigated in several population-based screening trials, the results of which are expected in 2007–2009. In comparison with cytology, HPV testing detects 50% more high-grade lesions,³ and detects clinically relevant lesions at an earlier stage.⁴ The result is a markedly decreased risk of developing high-grade lesions in between screening sessions, permitting less frequent screening.³ These results are particularly important because HPV-16/18 vaccination will lower the probability of high-grade lesions after a positive screening result both for cytological and HPV testing, arguing for a prolonged screening interval. Notably, when high-grade cervical lesions become rare following widespread vaccination, cytology will be more prone to loss of accuracy because it is highly subjective. This is another reason for advocating primary HPV testing. It might be envisioned that in the future women could screen themselves by self collection of cervico-vaginal material for HPV testing. In short, we advocate a vaccine for prepubertal women and adapted cervical screening for older women (>30 years of age).

Acknowledgments

The synopsis was written by Petra Roberts, Associate Editor, Nature Clinical Practice.

References

1. Harper DM et al. (2006) 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 367: 1247–1255 | Article | PubMed | ISI | ChemPort |
2. Cuzick J et al. (2006) Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 119: 1095–1101 | Article | PubMed | ISI | ChemPort |
3. Ronco G et al. (2006) Human papillomavirus testing and liquid-based cytology: results at recruitment from the new technologies for cervical cancer randomized controlled trial. J Natl Cancer Inst 98: 765–774 | PubMed |
4. Bulkmans NW et al: High-risk human papillomavirus testing detects cervical intraepithelial neoplasia grade 3 and cancer earlier than cytology in cervical screening permitting extension of the screening interval: five-year follow-up results of the randomised controlled POBASCAM trial. Lancet, in press.

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Subject areas under which this article appears: Prevention