**11. Future prospects and conclusions**

proficiency study on HPV 16 serology, where participating laboratories used the same

74 Human Papillomavirus and Related Diseases – From Bench to Bedside A Diagnostic and Preventive Perspective

Serologic assays for the evaluation of HPV vaccine responses are currently limited to an enzyme-linked immunosorbent assay (ELISA) [141], three multiplex assay systems [142-144], and a pseudovirus neutralization assay [145], and emerging data suggest that each system has some utility for characterizing HPV vaccine antibody specificity [136, 146]. Protection against vaccine types is thought to be mediated by neutralizing antibodies [147], and while the mechanism of vaccine-induced cross-protection is uncertain, the measurement of antibodies against nonvaccine types may be useful as a potential correlate or surrogate of cross-protection [148, 149]. Recently, Bissett *et al* [150] obtain a sera panel. These plasma pools could be useful as reference reagents. They are currently available as 250-µl aliquots of liquid plasma archived at −80°C and can be obtained from the National Institute for Biological Standards and Control.

Type-specificL1VLP-antibodies reachmaximumtitresatmonth7,i.e.1monthafteradministra‐ tionofthe thirddose.Titresdeclineuntilmonth24 andremainrather stable thereafter[151, 152]. At 3 years, antibody titres remain two- to 20-fold higher than in placebo controls [152]. Com‐ plete protection against HPV16 associated CIN lesions was observed over the whole followup duration of two Phase IIb trials: 6 years for the monovalent HPV16 vaccine, 5 5 years for the bivalent HPV16/18 vaccine [153, 154] and 4 years for the quadrivalent vaccine. Follow-up is continuing,andcontinuedprotectionagainstHPV16/18-associateddiseaseend-pointshasbeen

shown for the entire available observation time, even when specific antibody titres fall.

HPV infection is the most prevalent soon after sexual debut of a girl [155]. The current HPV vaccines, being prophylactic in nature, should be used before exposure of girls to HPV infection. National mass vaccination programs targeting adolescent girls between 12 and 17 years of age are available in most of the developed countries. The vaccine coverage varies greatly between countries, but school-based schemes have thus far demonstrated the highest coverage rate of 80% or higher [1, 156-158]. Australia is the first country to implement a schoolbased mass vaccination program with Gardasil in April 2007 and, within 3 years, has already witnessed a reduced incidence of high-grade abnormalities (HGAs) among women below 18

High coverage rates of adolescent vaccination with rubella and hepatitis B suggest that, with appropriate parental and public education, adequate HPV vaccine uptake rate of 50% or more is achievable. This coverage rate is critical for mass vaccination to attain cost-effectiveness as a public measure in controlling cervical cancer burden [159]. It will also remove the imbalance in accessing screening and effectively diminish the unequal distribution of cervical cancer burden among women in the metropolitan and rural areas, among women of different ethnic groups, and among women of various socio-economic status in developed countries. Adoles‐ cent HPV infection protects women from the first exposure to HPV infection at sexual debut and abolishes the opportunity for latent infection to occur with a resultant reduction of cervical cancer in old age. The current HPV vaccines induce very high levels of anti-HPV-16 and anti-HPV-18 antibody levels to sustain protection from infection by these aggressive oncogenic HPV subtypes for at least 20 years to cover the average age period of sexual debut [160].

standardized SOP and the same VLP reference reagent [140].

years of age [1].

HPV differs from most other vaccine-preventable diseases in that the major diseases to be prevented occur many decades after infection. Whereas clinical trials have documented prevention of infection and intermediate disease end-points (condylomas and precancers), surveillance following vaccine implementation will be required to document the expected gains in cancer prevention if there is appropriate population coverage. Surveillance will also provide data to indicate if type replacement or escape mutants occur. Other important tasks for the HPV surveillance include monitoring of the duration of protection, long-term safety and actual effects on health-care cost consumption. Monitoring the impact of vaccination on type-specific infection could be important as it is the earliest change that could be anticipated, and failure to detect protection from infection will indicate failure to impact cancer in the decades that follow and allow appropriate changes in strategy to be introduced. As countries differ in their health-care priorities and infrastructure as well as in their incidence and prevalence of various HPV infections, their HPV vaccination strategies are also likely to differ [168]. As has been mentioned, the waning in the levels of HPV antibodies post-vaccination appears to plateau after 5 years. It is not known whether waning of HPV antibody levels in the longer term will require a vaccine booster. In addition, antibody correlates of protection have not been defined because there have so far been almost no cases of vaccination failure. If a reliable immunological correlate of protection can be identified, this will help in assessing the requirement for booster vaccinations and greatly facilitate the evaluation of secondgeneration vaccines.

recently available HPV-16-specific and HPV-18-specific screening technology further enhan‐ ces the technical advances that makes the HPV DNA screening test even more attractive in the vaccination era than before. The high sensitivity of the HPV DNA test should allow the

HPV Diagnosis in Vaccination Era http://dx.doi.org/10.5772/55818 77

The reduction in background risk of cervical cancer by elimination of the most important HPV types will affect cost-effectiveness of screening programs and may, in the long term, allow increasing screening intervals. Co-ordinated quality assurance/monitoring of HPV vaccination and cervical screening is advisable for finding the most efficient strategies for cervical cancer control. Data on vaccination coverage will be essential for every country performing HPV vaccinations. HPV vaccination registries are preferable, but sales statistics and serosurveys

For rapid assessment of vaccine program efficacy, the continuous monitoring of which HPV types are spreading in the population will become necessary for early monitoring of 'type replacement' phenomena, inappropriate vaccination strategies or other reasons for vaccination failure. Surveys in sexually active teenagers and/or in younger participants of cervical

Department of Microbiology, School of Medicine and Clinical Microbiology Laboratory,

[1] Brotherton JM, Fridman M, May CL, Chappell G, Saville AM, Gertig DM. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia:

[2] Parkin DM, Bray F. Chapter 2: The burden of HPV-related cancers. Vaccine 2006;24

[3] Moscicki AB, Burt VG, Kanowitz S, Darragh T, Shiboski S. The significance of squa‐ mous metaplasia in the development of low grade squamous intraepithelial lesions

[4] Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer.

screening interval to be increased to a longer period [173].

screening programs should be contemplated.

Fátima Galán-Sánchez and Manuel Rodríguez-Iglesias

Puerta del Mar Univ. Hosp. University of Cádiz, Spain

an ecological study. Lancet 2011;377:2085-92.

in young women. Cancer 1999;85:1139-44.

Clin Sci (Lond) 2006;110:525-41.

may be alternatives.

**Author details**

**References**

Suppl 3:11-25.

As the type-specific prevalence of HPV infection is very high in young sexually active populations, the effect of a successful HPV vaccination programme should be detected quite rapidly by sentinel surveillance in these populations. The specific design of these sentinel studies will vary, but selecting clinics offering sexual counselling may be more efficient than school-based sampling. Reduction in the prevalence of types targeted by the vaccines as well as no increase in the prevalence of non-vaccine types are important end-points. Baseline data are needed to establish prevaccine prevalence as well as to determine the sample size required to observe impact beyond confidence intervals of sampling and testing errors. It is imperative that all HPV DNA prevalence surveys are performed using testing methodology that has been subjected to an international quality assurance, as comparability of data between countries or even before *versus* after will otherwise not be possible.

Screening remains an important strategy in cervical cancer control in the HPV vaccination era. Women who have received HPV vaccination should continue regular screening, as cases of HGAs and invasive cervical cancer among vaccinated women have been reported [169]. There is also a concern whether the protective effect of adolescent vaccination has an impact on the incidence of cervical cancer when the vaccinated cohort reaches older age. It is reassuring to see evidence that, in well informed communities, there appears to be no change in women's attitude toward continual screening [170]. Furthermore, screening remains the only effective method for cervical cancer prevention for women who opt out of vaccination. However, reduction in the incidence of HGAs in young women following adolescent mass HPV vaccination supports a strategy to delay screening to a later age than the current practice of starting screening once the girl becomes sexually active.

Evidence from meta-analysis has overwhelmingly demonstrated the superiority in sensitivity of HPV DNA test over cytology in cervical cancer screening. Indeed, retrospective analysis of invasive cervical cancer tissues in well screened populations showed that more than 80% of cases were related to HPV-16 or HPV-18 [171]. With elimination of HPV-16 and HPV-18 with mass vaccination, the remaining oncogenic subtypes of HPV, which have low neoplastic transformation rates, should significantly lower the incidence of HGAs. The sensitivity and positive predictive value of cytologic screening will be further compromised [172]. The recently available HPV-16-specific and HPV-18-specific screening technology further enhan‐ ces the technical advances that makes the HPV DNA screening test even more attractive in the vaccination era than before. The high sensitivity of the HPV DNA test should allow the screening interval to be increased to a longer period [173].

The reduction in background risk of cervical cancer by elimination of the most important HPV types will affect cost-effectiveness of screening programs and may, in the long term, allow increasing screening intervals. Co-ordinated quality assurance/monitoring of HPV vaccination and cervical screening is advisable for finding the most efficient strategies for cervical cancer control. Data on vaccination coverage will be essential for every country performing HPV vaccinations. HPV vaccination registries are preferable, but sales statistics and serosurveys may be alternatives.

For rapid assessment of vaccine program efficacy, the continuous monitoring of which HPV types are spreading in the population will become necessary for early monitoring of 'type replacement' phenomena, inappropriate vaccination strategies or other reasons for vaccination failure. Surveys in sexually active teenagers and/or in younger participants of cervical screening programs should be contemplated.
