Nº 230
Impact of HPV vaccination on cervical cancer screening requirements
Quote this article as:
F Inturrisi & J Berkhof (May 2023). Impact of HPV vaccination on cervical cancer screening requirements. www.HPVWorld.com, 230
Women who received HPV vaccination as adolescents have recently reached or are now approaching cervical cancer screening age. Yet, most screening protocols have not changed and those for unvaccinated women are applied to vaccinated women as well. So far, Italy is the only country with screening recommendations specific for HPV-vaccinated women. The main change implemented in the Italian regions is to start screening of women who received two vaccine doses by age 15, directly at age 30 using primary HPV testing every 5 years, while unvaccinated, 25 to 29 year-old women continue being screened with Pap testing every 3 years.1
To support changes in the screening protocol for vaccinated cohorts, in particular about the screening interval, we do not only need data on the short-term risk (i.e., data on the first round of screening) of developing (pre-)cancer (cervical intraepithelial neoplasia grade 3 or higher: CIN3+), but we also need data on the long-term risk in order to assess the residual CIN3+ risk after the first screening round. Real-life data from the first round of screening of vaccinated women are becoming available in countries where HPV vaccination was first implemented. For example, recent landmark studies from Sweden and England showed a substantial reduction in cervical cancer.2 However, real-life data on the long-term risk of CIN3 and cancer will take decades to become available.
We utilized a data-driven approach to estimate CIN3+ risk directly from longitudinal data of a previously conducted population-based HPV screening study (POBASCAM) with two rounds of HPV genotype-level data and an interval of 5 years.3 For every age group, we estimated the risk of a new HPV infection and the risk of developing a genotype-specific CIN3+ lesion, thus obtaining the cumulative CIN3+ risk up to age 60 (i.e., screening lifetime risk). The calculation to estimate the screening lifetime risk of CIN3+ was done in absence of vaccination, then repeated assuming that the cohort was benefiting from genotype-specific protection against new infections induced by bivalent vaccination (with and without cross-protection) or nonavalent vaccination.
Our results clearly showed that HPV vaccination will lead to a strong decline in the screening lifetime risk of CIN3+ and that the residual CIN3+ risk among vaccinated women is very low. Figure 1 displays our estimated lifetime risk of CIN3+ of 4.1% amongst unvaccinated women, which decreased to 1.2% amongst women vaccinated with the bivalent vaccine (with cross-protection) and to 0.5% amongst women vaccinated with the nonavalent vaccine.3 Such low risks support less intensive screening among vaccinated cohorts through longer intervals between screens, in line with other work concluding that women vaccinated against HPV16/18/31/33/45/52/58 require two lifetime screens as compared to unvaccinated women needing seven lifetime screens.4
Our analysis focused on the direct benefit of HPV vaccination, meaning we present the lifetime risk of precancer in a cohort in which everyone is vaccinated. In real-life scenarios where not everyone is vaccinated, herd effects will build up and play a role in protecting unvaccinated women.5 Besides, we assumed that the vaccine reduces the risk of getting an HPV infection for all vaccinated participants by the same amount. This may lead to a slightly pessimistic estimate of the vaccine effect on CIN3+ detected after the first screening round for cross-protective genotypes.
Nevertheless, because of our large screening data combined with strong evidence on the long-term protection provided by the bivalent and nonavalent vaccine,6 we were able to produce solid estimates of the probability to develop a CIN3+ lesion, of the declined risk after the first screening round and of the residual cumulative risk over a lifetime, for different vaccination scenarios.
Analyses like ours are needed to reach consensus on the screening recommendations for vaccinated cohorts. In our study we answered the question “what would the lifetime risk of CIN3+ be in a vaccinated cohort if 5-yearly HPV-based screening is used starting at age 30?”. This question is very relevant because the 5-year interval and starting at age 30 are program features advised for HPV-vaccinated cohorts in several countries. A strong and unique point of our study is that a starting age of 30 and a 5-year screening interval were already used in the POBASCAM study 20 years ago. Thus, screening programs with these features already in place can expect, on the basis of our results, very low risks of precancer if women are vaccinated with the bivalent or nonavalent vaccine.
In countries with only a moderate vaccine uptake, in order to be able to tailor screening to vaccinated women based on long-term CIN3+ risk estimates, information on the vaccination status needs to be available. Therefore, it is recommended to have archives at the regional and national level that are reciprocally connected and to implement a link between screening registries and vaccination records (indicating the number of doses, vaccination date of each dose, and type of vaccine administered).
In conclusion, a considerable reduction in the lifetime risk of CIN3+ is to be expected among HPV-vaccinated women, supporting less intensive screening for vaccinated women and stressing on the need to link screening registries and vaccination records in order to fully integrate screening and vaccination programs.
DISCLOSURE
The Authors have no conflict of interest to disclose.
References
1. Giorgi Rossi P, Carozzi F, Federici A, et al. Cervical cancer screening in women vaccinated against human papillomavirus infection: recommendations from a consensus conference. Preventive Medicine 2017; 98:21-30. Available from: https://doi.org/10.1016/j.ypmed.2016.11.020
2. Falcaro M, Castañon A, Ndlela B, et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study. Lancet 2021; 398(10316):2084-2092. Available from: https://doi.org/10.1016/s0140-6736(21)02178-4
3. Inturrisi F, Lissenberg-Witte BI, Veldhuijzen NJ, et al. Estimating the direct effect of human papillomavirus vaccination on the lifetime risk of screen-detected cervical precancer. International Journal of Cancer 2021; 148(2):320-328. Available from: https://doi.org/10.1002/ijc.33207
4. Landy R, Windridge P, Gillman MS, Sasieni PD. What cervical screening is appropriate for women who have been vaccinated against high risk HPV? A simulation study. International Journal of Cancer 2018; 142(4):709-718. Available from: https://doi.org/10.1002/ijc.31094
5. Kavanagh K, Pollock KG, Cuschieri K, et al. Changes in the prevalence of human papillomavirus following a national bivalent human papillomavirus vaccination programme in Scotland: a 7-year cross-sectional study. Lancet Infectious Diseases 2017; 17(12):1293-1302. Available from: https://doi.org/10.1016/s1473-3099(17)30468-1
6. Hoes J, King AJ, Berkhof J, de Melker HE. High vaccine effectiveness persists for ten years after HPV16/18 vaccination among young Dutch women. Vaccine 2023;41(2):285-289. Available from: https://doi.org/10.1016/j.vaccine.2022.11.057
F Inturrisi & J Berkhof (May 2023). Impact of HPV vaccination on cervical cancer screening requirements. www.HPVWorld.com, 230
Women who received HPV vaccination as adolescents have recently reached or are now approaching cervical cancer screening age. Yet, most screening protocols have not changed and those for unvaccinated women are applied to vaccinated women as well. So far, Italy is the only country with screening recommendations specific for HPV-vaccinated women. The main change implemented in the Italian regions is to start screening of women who received two vaccine doses by age 15, directly at age 30 using primary HPV testing every 5 years, while unvaccinated, 25 to 29 year-old women continue being screened with Pap testing every 3 years.1
To support changes in the screening protocol for vaccinated cohorts, in particular about the screening interval, we do not only need data on the short-term risk (i.e., data on the first round of screening) of developing (pre-)cancer (cervical intraepithelial neoplasia grade 3 or higher: CIN3+), but we also need data on the long-term risk in order to assess the residual CIN3+ risk after the first screening round. Real-life data from the first round of screening of vaccinated women are becoming available in countries where HPV vaccination was first implemented. For example, recent landmark studies from Sweden and England showed a substantial reduction in cervical cancer.2 However, real-life data on the long-term risk of CIN3 and cancer will take decades to become available.
We utilized a data-driven approach to estimate CIN3+ risk directly from longitudinal data of a previously conducted population-based HPV screening study (POBASCAM) with two rounds of HPV genotype-level data and an interval of 5 years.3 For every age group, we estimated the risk of a new HPV infection and the risk of developing a genotype-specific CIN3+ lesion, thus obtaining the cumulative CIN3+ risk up to age 60 (i.e., screening lifetime risk). The calculation to estimate the screening lifetime risk of CIN3+ was done in absence of vaccination, then repeated assuming that the cohort was benefiting from genotype-specific protection against new infections induced by bivalent vaccination (with and without cross-protection) or nonavalent vaccination.
Our results clearly showed that HPV vaccination will lead to a strong decline in the screening lifetime risk of CIN3+ and that the residual CIN3+ risk among vaccinated women is very low. Figure 1 displays our estimated lifetime risk of CIN3+ of 4.1% amongst unvaccinated women, which decreased to 1.2% amongst women vaccinated with the bivalent vaccine (with cross-protection) and to 0.5% amongst women vaccinated with the nonavalent vaccine.3 Such low risks support less intensive screening among vaccinated cohorts through longer intervals between screens, in line with other work concluding that women vaccinated against HPV16/18/31/33/45/52/58 require two lifetime screens as compared to unvaccinated women needing seven lifetime screens.4
Our analysis focused on the direct benefit of HPV vaccination, meaning we present the lifetime risk of precancer in a cohort in which everyone is vaccinated. In real-life scenarios where not everyone is vaccinated, herd effects will build up and play a role in protecting unvaccinated women.5 Besides, we assumed that the vaccine reduces the risk of getting an HPV infection for all vaccinated participants by the same amount. This may lead to a slightly pessimistic estimate of the vaccine effect on CIN3+ detected after the first screening round for cross-protective genotypes.
Nevertheless, because of our large screening data combined with strong evidence on the long-term protection provided by the bivalent and nonavalent vaccine,6 we were able to produce solid estimates of the probability to develop a CIN3+ lesion, of the declined risk after the first screening round and of the residual cumulative risk over a lifetime, for different vaccination scenarios.
Analyses like ours are needed to reach consensus on the screening recommendations for vaccinated cohorts. In our study we answered the question “what would the lifetime risk of CIN3+ be in a vaccinated cohort if 5-yearly HPV-based screening is used starting at age 30?”. This question is very relevant because the 5-year interval and starting at age 30 are program features advised for HPV-vaccinated cohorts in several countries. A strong and unique point of our study is that a starting age of 30 and a 5-year screening interval were already used in the POBASCAM study 20 years ago. Thus, screening programs with these features already in place can expect, on the basis of our results, very low risks of precancer if women are vaccinated with the bivalent or nonavalent vaccine.
In countries with only a moderate vaccine uptake, in order to be able to tailor screening to vaccinated women based on long-term CIN3+ risk estimates, information on the vaccination status needs to be available. Therefore, it is recommended to have archives at the regional and national level that are reciprocally connected and to implement a link between screening registries and vaccination records (indicating the number of doses, vaccination date of each dose, and type of vaccine administered).
In conclusion, a considerable reduction in the lifetime risk of CIN3+ is to be expected among HPV-vaccinated women, supporting less intensive screening for vaccinated women and stressing on the need to link screening registries and vaccination records in order to fully integrate screening and vaccination programs.
DISCLOSURE
The Authors have no conflict of interest to disclose.
References
1. Giorgi Rossi P, Carozzi F, Federici A, et al. Cervical cancer screening in women vaccinated against human papillomavirus infection: recommendations from a consensus conference. Preventive Medicine 2017; 98:21-30. Available from: https://doi.org/10.1016/j.ypmed.2016.11.020
2. Falcaro M, Castañon A, Ndlela B, et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study. Lancet 2021; 398(10316):2084-2092. Available from: https://doi.org/10.1016/s0140-6736(21)02178-4
3. Inturrisi F, Lissenberg-Witte BI, Veldhuijzen NJ, et al. Estimating the direct effect of human papillomavirus vaccination on the lifetime risk of screen-detected cervical precancer. International Journal of Cancer 2021; 148(2):320-328. Available from: https://doi.org/10.1002/ijc.33207
4. Landy R, Windridge P, Gillman MS, Sasieni PD. What cervical screening is appropriate for women who have been vaccinated against high risk HPV? A simulation study. International Journal of Cancer 2018; 142(4):709-718. Available from: https://doi.org/10.1002/ijc.31094
5. Kavanagh K, Pollock KG, Cuschieri K, et al. Changes in the prevalence of human papillomavirus following a national bivalent human papillomavirus vaccination programme in Scotland: a 7-year cross-sectional study. Lancet Infectious Diseases 2017; 17(12):1293-1302. Available from: https://doi.org/10.1016/s1473-3099(17)30468-1
6. Hoes J, King AJ, Berkhof J, de Melker HE. High vaccine effectiveness persists for ten years after HPV16/18 vaccination among young Dutch women. Vaccine 2023;41(2):285-289. Available from: https://doi.org/10.1016/j.vaccine.2022.11.057