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K. Soldan, L. Elliss-Brookes, P. Sasieni (February 2022). The impact of HPV vaccination program on CIN3 and cervical cancer incidence in England. www.HPVWorld.com, 189

A programme of human papillomavirus (HPV) vaccination was introduced in England in September 2008.¹ The programme initially used three doses of the bivalent vaccine (Cervarix) and comprised a “routine” offer to girls aged 12–13 years as well as a catch-up programme for females aged 17–18 years in 2008/09 and those aged 14-17 in 2009/10. Delivery largely in schools achieved a high uptake. We estimated the impact of this immunisation programme on cervical cancer and grade 3 cervical intraepithelial neoplasia (CIN3) up until June 2019.²

We analysed the rates of cervical cancer and (separately) CIN3 using data from the national population-based cancer registry for England covering diagnoses between January 2006 and June 2019 in women aged 20–64 years. Our focus was on the rate ratios comparing three birth cohorts offered HPV vaccination with the cohort that just missed the offer of HPV vaccination. We used a statistical model adjusted for the effects of other variables including age, calendar year, season, and changes in the age of first invitation to cervical screening and historical events that affected cervical cancer incidence.³ Since we did not include data on individual exposure to HPV vaccination, there was no need to adjust for factors that may confound the individual-level association between receiving the vaccine and cervical cancer risk.

Women who were eligible for HPV vaccination were split into three cohorts depending on the school-year in which the vaccine was offered. This was felt to be important both because the coverage of vaccination was very different in the routine programme and the catch-up campaigns and because the older the age at vaccination the greater the chance that the individual will have been infected with HPV prior to vaccination.

Our analysis included 13.7 million-years of follow-up of women aged 20 to 29 years (Table 1). There were 563 cancers and 17,279 diagnoses of CIN3 in the “reference” cohort that just missed-out on HPV vaccination (women born between May 1989 and August 1990) and 638 cancers and 18,662 cases of CIN3 in vaccine-eligible cohorts.



Amongst women who would not have been invited for cervical screening before age 24.5, the annual rates of cervical cancer per 100,000 women aged 20-24.5 were:

• 1.9 in the cohort not offered HPV vaccination,
• 1.0 in those offered vaccination aged 16-18,
• 0.7 in those offered vaccination aged 14-16, and
• 0.3 in those offered vaccination aged 12-13.

The estimated cumulative rates are illustrated in Figure 1.



The relative reduction in cervical cancer rates in the different birth compared with the reference unvaccinated cohort cohorts were:

• 34% (95% CI 25–41) for women born September 1990-August 1993, who would have been aged 16–18 years when vaccinated and among whom the 1-dose national coverage was 60.5% and the 3-dose coverage 44.8%;
  
• 62% (95% CI 52–71) for women born September 1993-August 1995, who would have been age 14–16 years at vaccination and who had 80.1% 1-dose coverage and 73.2% 3-dose coverage; and
• 87% (95% CI 72–94) for women born September 1995-June 1999, who would have been aged 12–13 years at vaccination and who had 88.7% 1-dose coverage and 84.9% 3-dose coverage.

The corresponding risk reductions for CIN3 in the three vaccine-eligible cohorts were 39% (95% CI 36–41), 75% (72–77), and 97% (96–98), respectively (Table 2).



These results were largely unaffected by different approaches to adjusting for confounding.²

The bivalent vaccine has been shown to have nearly 100% efficacy against persistent infection with HPV 16 and HPV 18 in women naïve to the virus at vaccination and very good cross-protection against closely related HPV types.⁴ Assuming these infections account for 80% of cervical cancers in women aged 20-29 years and that a single dose of the vaccine provides protection for at least 11 years, we might expect, based on 1-dose coverage (Table 1), 48%, 64%, and 71% efficacy in the three cohorts, respectively. The fact that the observed efficacy in those vaccinated aged 16-18 was slightly lower than expected may be due to pre-existing infections and possibly because more than one dose is needed in those aged over 15 years. The fact that the observed efficacy in the cohort offered vaccination aged 12-13 was higher than expected may indicate that even unvaccinated women have benefitted from herd-protection, and/or the vaccine prevented more than 80% of cervical cancers thanks to cross-protection against other HPV types.

These data show a substantial reduction in cervical cancer and CIN3 in young women after the introduction of an HPV immunisation programme. The effect was greatest in the cohorts offered the vaccine at age 12–13 years among whom the uptake was greatest. The HPV immunisation programme has successfully almost eliminated cervical cancer in England among women born since September 1995.


DISCLOSURE PS has received institutional grants from Cancer Research UK and the National Institute of Health Research, and provision of Gardasil 9 from MSD for the NOVEL trial on which the author is a coinvestigator. KS has received institutional grants from UK Health Security Agency (formerly Public Health England) and PHE has provided reports to GSK on a cost recovery basis. LEB has has received institutional grants from NHS digital (formerly Public Health England).


References

1. Public Health England (PHE). Human Papillomavirus (HPV) vaccine coverage in England, 2008/09 to 2013/14. A review of the full six years of the three-dose schedule. 2015. Available from: https://assets.publishing.service.gov.uk/government/uploads/system/uploads
/attachment_data/file/774074/HPV_Vaccine_Coverage_in_England_200809_to_201314.pdf (last accessed 15 Feb 2022)

2. Castanon A, Sasieni P. Is the recent increase in cervical cancer in women aged 20-24years in England a cause for concern? Prev Med 2018;107:21-8. Available from: https://pubmed.ncbi.nlm.nih.gov/29247658/

3. Falcaro M, Castañon A, Ndlela B, Checchi M, Soldan K, Lopez-Bernal J, Elliss-Brookes L, Sasieni P. 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://pubmed.ncbi.nlm.nih.gov/34741816/

4. GlaxoSmithKline Vaccine HPV-007 Study Group, Romanowski B, de Borba PC, Naud PS, Roteli-Martins CM, De Carvalho NS, Teixeira JC, Aoki F, Ramjattan B, Shier RM, Somani R, Barbier S, Blatter MM, Chambers C, Ferris D, Gall SA, Guerra FA, Harper DM, Hedrick JA, Henry DC, Korn AP, Kroll R, Moscicki AB, Rosenfeld WD, Sullivan BJ, Thoming CS, Tyring SK, Wheeler CM, Dubin G, Schuind A, Zahaf T, Greenacre M, Sgriobhadair A. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years. Lancet 2009;374(9706):1975-85. Available from: https://pubmed.ncbi.nlm.nih.gov/19962185/


OTHER ARTICLES INCLUDED IN HPW SPECIAL ISSUE ON HPV VACCINES:

Interview with Elmar Joura.

L Baandrup, P Valentiner-Branth, SK Kjaer. HPV Vaccination Crisis and Recovery: the Danish Case.

B Huber, RBS Roden, R Kirnbauer. L2-based Human Papillomavirus Vaccines: Current Status And Potential.

M Drolet, M Brisson. Population-level Impact and Herd Effects of HPV Vaccination Programs in High-Income Countries: Real-life Data.

SM Garland, GL Murray, DA Machalek. Prevention of HPV-Related Diseases Following 4-Valent Vaccination in Australia.

M Kane, M Stanley. Pre-school HPV Immunization?

PM Kotulka, A Luxembourg, A Shaw. Challenges in HPV Vaccine Development and Supply.

R Cameron, K Cuschieri, K Roy. Prevention of HPV Infection and Associated Disease Following Bivalent HPV Vaccination in Scotland.

L Xu, SM Garland, M Arbyn. Efficacy of HPV Vaccination To Prevent Vulvar and Vaginal Precancer.

QY Yan, MJ González-Méndez, YL Qiao. Current Status of HPV Vaccine in China.

J Lei, A Ploner, P Sparén. HPV Vaccination and the Risk of Invasive Cervical Cancer.