Elsevier

The Lancet

Volume 398, Issue 10316, 4–10 December 2021, Pages 2084-2092
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(21)02178-4Get rights and content

Summary

Background

Human papillomavirus (HPV) immunisation with a bivalent vaccine (Cervarix) was introduced in England, UK, in Sept 1, 2008: routine vaccination was offered to girls aged 12–13 years with a catch-up programme for females aged 14–18 years in 2008–10. We quantified the early effect of this immunisation programme on cervical cancer and cervical carcinoma in situ, namely grade 3 cervical intraepithelial neoplasia (CIN3), registrations.

Methods

In this observational study, we used an extension of the age-period-cohort Poisson model to estimate the relative risk of cervical cancer in three vaccinated cohorts compared with earlier cohorts that were not eligible for HPV vaccination. Data from a population-based cancer registry were extracted on Jan 26, 2021, and were assessed for diagnoses of cervical cancer and CIN3 from Jan 1, 2006 to June 30, 2019 in women aged 20–64 years and who were a resident in England. We used three vaccinated cohorts to account for differences in the school year in which the vaccine was offered and its national coverage. Adjustment for confounding was made using information on changes in cervical screening policy and historical events that affected cervical cancer incidence. Results were compared across models with different adjustments for confounders.

Findings

We used data from a total of 13·7 million-years of follow-up of women aged 20 years to younger than 30 years. The estimated relative reduction in cervical cancer rates by age at vaccine offer were 34% (95% CI 25–41) for age 16–18 years (school year 12–13), 62% (52–71) for age 14–16 years (school year 10–11), and 87% (72–94) for age 12–13 years (school year 8), compared with the reference unvaccinated cohort. The corresponding risk reductions for CIN3 were 39% (95% CI 36–41) for those offered at age 16–18 years, 75% (72–77) for age 14–16 years, and 97% (96–98) for age 12–13 years. These results remained similar across models. We estimated that by June 30, 2019 there had been 448 (339–556) fewer than expected cervical cancers and 17 235 (15 919–18 552) fewer than expected cases of CIN3 in vaccinated cohorts in England.

Interpretation

We observed a substantial reduction in cervical cancer and incidence of CIN3 in young women after the introduction of the HPV immunisation programme in England, especially in individuals who were offered the vaccine at age 12–13 years. The HPV immunisation programme has successfully almost eliminated cervical cancer in women born since Sept 1, 1995.

Funding

Cancer Research UK.

Introduction

Human papillomavirus (HPV) vaccination has been introduced in over 100 countries and underlies the WHO's global strategy for the elimination of cervical cancer.1, 2 In 2019, the global market for vaccines against HPV infections reached approximately 41·4 million doses, with the bivalent one having an estimated market share, by volume, of around 23%.3 Vaccines have been shown in randomised controlled trials to prevent type-specific HPV infections and cervical intraepithelial neoplasia (CIN) in previously HPV uninfected cohorts, but there is an absence of high-quality empirical evidence regarding their effect on cervical cancer incidence.

HPV immunisation was introduced in England, UK, in Sept 1, 2008 using the bivalent HPV vaccine (Cervarix). The goal was to reduce cervical cancer incidence by preventing persistent infections from the two most common high-risk types of HPV (16 and 18), which are responsible for approximately 80% of all cervical cancers in the UK.4 Since the HPV vaccine is most effective when given before any exposure to HPV viruses (ie, before sexual activity starts) routine vaccination was offered to girls aged 12–13 years (school year 8). In England, students are 12 years of age at the start of year 8 (from Sept 1) and turn 13 years during the school year. A catch-up service was offered to girls aged 17–18 years (born Sept 1, 1990–Aug 31 1991) in the academic year 2008–09 and those aged 14–18 years (born Sept 1, 1991–Aug 31, 1995) in the academic year 2009–10. Annual three-dose HPV immunisation coverage between the academic years of 2008–09 and 2011–12 was very high for those in school year 8 (range 80·9–88·0%) but lower for the catch-up cohorts (70·8–75·7% for school years 10–11 and 38·9–48·1% for school years 12–13).5, 6, 7 The bivalent vaccine was replaced by the quadrivalent vaccine, Gardasil, in Sept 1, 2012 and is not evaluated in this paper.

Research in context

Evidence before this study

Randomised controlled trials and surveillance studies have shown the usefulness of Human Papilloma Virus (HPV) vaccination at preventing HPV infection and cervical intraepithelial neoplasia (CIN), but direct evidence of its effect on cervical cancer incidence is incomplete. Preliminary evidence that showed that vaccination protects against HPV-associated cancers was provided by a combined passive follow-up of women participating in two Finnish vaccination trials (one using the quadrivalent vaccine and the other the bivalent vaccine) compared with an unvaccinated cohort; however, the number of people with cancer was too small to estimate efficacy with precision. An analysis of cervical cancer rates in Sweden showed reduced risk of cervical cancer in individuals who received Gardasil (a quadrivalent HPV vaccine) but estimates of efficacy varied depending on the adjustments made.

Added value of this study

We observed a substantial reduction in cervical cancer and incidence of CIN3 in young women after the introduction of HPV immunisation in England, especially in individuals who were offered the vaccine at age 12–13 years. Our study provides the first direct evidence of the prevention of cervical cancer using Cervarix (a bivalent HPV vaccine). We defined our cohorts to account for the age at which women were offered HPV immunisation and the differences in national vaccination coverage. This definition allowed us to estimate the effect of the routine vaccination programme carried out in girls aged 12–13 years (school year 8) separately from the additional catch-up campaigns that targeted girls aged 14–16 years (school years 10–11) and 16–18 years (school years 12–13), who might have already been exposed to HPV before vaccination and among whom coverage was lower.

Implications of all the available evidence

Our findings add evidence to the very limited literature showing that national HPV immunisation programmes can lead to a substantial reduction in cervical cancer incidence, especially if vaccination coverage is high and women are offered the vaccine at a younger age. Although it is still too early to assess the full effect of the English HPV vaccination programme, our results contribute towards a better understanding and recognition of the benefits of HPV immunisation.

By 10 years after the introduction of the HPV vaccination in England, there had been substantial reductions in HPV 16/18 and HPV 31/33/45 infections among women aged 16–24 years undergoing chlamydia screening.8 In Scotland, a pronounced reduction in preinvasive cervical disease has been reported in women aged 20 years.9 Early modelling suggested that HPV vaccination would have no discernible effect on cervical cancer rates for at least 8 years after vaccination but that there would be substantial reduction in incidence in women aged 20–29 years in the UK by the end of 2019.10 In 2020, analysis of cervical cancer rates in Swedish women who did and did not receive the quadrivalent vaccine (Gardasil) showed reduced risk of cervical cancer but the magnitude of the effect was dependent on adjustments made for confounders.11

It has now been over 10 years since England introduced HPV immunisation. Although it is still premature to assess the full impact of the programme, we can now investigate its early effects on the incidence of cervical cancer. Others have shown the impact of HPV vaccination on HPV infection and CIN rates, 8, 12 but the only direct evidence of its effect on cervical cancer relates to the quadrivalent vaccine.11 We used population-based cancer registry data to estimate the early impact of the bivalent HPV immunisation programme (using Cervarix) on cervical cancer and, separately, cervical carcinoma in situ (CIN3) incidence in England.

Section snippets

Study design

We sought to estimate the effect of HPV vaccination on cervical cancer incidence from observed data. The individual-level relationship between being vaccinated and cervical cancer incidence is likely to be confounded by largely unmeasurable variables related to beliefs, behaviours, and lifestyle. By contrast, the relation between the offer of vaccination and cervical cancer diagnosis is confounded by recorded factors such as age, calendar time, and birth cohort (which determines whether or not

Results

During the study period there were 27 946 diagnoses of cervical cancer and 318 058 of CIN3 (table 1). The study included a total of 13·7 million-years of follow-up of women aged 20 years to younger than 30 years in the three vaccinated cohorts.

The crude incidence rates per 100 000 women-years (table 2) were particularly low for women offered the vaccine at age 12–13 years in cohort 7 (0·3 for cervical cancer and 2·0 for CIN3). We also noticed that crude incidence rates for both cervical cancer

Discussion

The introduction of national HPV immunisation programmes represents an important step forward in cervical cancer prevention. To the best of our knowledge, our study provides the first direct evidence of the effect of HPV vaccination using the bivalent Cervarix vaccine on cervical cancer incidence. We found a large reduction in cervical cancer rates in all three vaccinated cohorts and especially in those who were offered the vaccine in school year 8 (aged 12–13 years). The success of vaccination

Data sharing

The cancer registry data used in this paper are held by the National Cancer Registration and Analysis Service, PHE. Access to the data can be requested under PHE's data access arrangements through the Office for Data Release. Midyear population estimates are freely downloadable from the ONS website.

Declaration of interests

We declare no competing interests.

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