A meta-analysis including 60 million individuals in high-income countries finds significant decreases in HPV infections, anogenital wart diagnoses and precancerous cervical lesions (CIN2+) over 8-9 years after girls-only HPV vaccination.
The new study is the first to show pooled estimates of population-level impact of HPV vaccination on CIN2+ from several countries, the benefit of vaccinating more than one age group, along with substantial herd effects in countries achieving high vaccination coverage. Published in The Lancet, the results provide strong evidence of HPV vaccination working to prevent cervical cancer in real-world settings as both the cause (HPV infection) and precancerous cervical lesions are declining. These results have implications for policy makers around the world as it backs the recently revised WHO position on vaccinating multiple age groups rather than a single cohort when introducing the vaccine.
The HPV vaccination was first licensed in 2007 and since then it has been adopted into 99 countries* and territories. An earlier version of this meta-analysis with data for four years post-vaccination showed substantial decreases in two types of HPV - 16 and 18 - that cause the majority of cervical cancers and anogenital wart diagnoses among women who had received the vaccine along with herd effects among boys and older women. However, the past meta-analysis was unable to assess CIN2+ lesions, which is the most proximal outcome to cervical cancer, as it was too soon after vaccination to be able to estimate the impact.
In addition, since that publication many more countries have introduced vaccination programmes and in 2016 the WHO updated its advice to recommend HPV vaccination of multiple age cohorts of girls - from nine to fourteen.
To update their 2015 review which included 18 studies, the team added 47 new studies published between February 2014 and October 2018 that compared the frequency of one or more HPV endpoints (HPV infections, anogenital wart diagnoses, or histologically confirmed CIN2+) between pre and post-vaccination periods in the general population. In total, their analysis includes 65 articles in 14 high-income countries - including 23 for HPV infection, 29 for anogenital warts and 13 for CIN2+ lesions. It brings together data from over 60 million individuals over eight years.
They found that the two types of HPV that cause 70% of cervical cancers, HPV 16 and 18, were significantly reduced after vaccination. They report a decrease of 83% in girls aged 13-19 and of 66% in women aged 20-24 years after five to eight years of vaccination. An overall 54% reduction was seen in three other types of HPV, 31, 33 and 45 in girls aged 13-19 years.**
There were also significant reductions in anogenital wart diagnoses. After five to eight years of vaccination, they found decreases of 67% in girls aged 15-19, 54% in women aged 20-24 and 31% in women aged 25-29 as well as reductions of 48% in boys aged 15-19 and 32% in men aged 20-24 years.
Five to nine years after vaccination CIN2+ decreased significantly. The team reports a 51% reduction in screened girls aged 15-19 years and a 31% reduction in screened women aged 20-24 years.
The analysis shows the greater and faster impact and herd effects in countries with both multi-cohort vaccination and high vaccination coverage. In such countries after five to eight years of vaccination, anogenital wart diagnoses declined by 88% among girls and 86% in boys aged 15-19 years compared with 44% among girls and 1% among boys from countries with single-cohort or low routine vaccination coverage. In girls aged 15-19 years, CIN2+ decreased by 57% in countries with both multi-cohort vaccination and high vaccination coverage whereas there was no decrease in countries with single-cohort vaccination or low routine coverage.
Mélanie Drolet of the CHU de Quebec-Laval University Research Center says: "Our results provide strong evidence that HPV vaccination works to prevent cervical cancer in real-world settings as both HPV infections that cause most cervical cancers and precancerous cervical lesions are decreasing. We saw that programmes with multiple age cohorts of girls vaccinated and high vaccination coverage have greater direct impact and herd effects. This finding reinforces WHO's recently revised position on HPV vaccination to recommend HPV vaccination of multiple age cohorts of girls aged 9-14 years old when the vaccine is introduced in a country, rather than vaccination of a single cohort." 
Professor Marc Brisson of Laval University Canada says: "The landscape of HPV vaccination is rapidly changing, with several countries recently switching from three to two-dose schedules, gender-neutral vaccination, and a newer vaccine that targets more HPV types. It will be crucial to continue monitoring the population-level impact of HPV vaccination to examine the full effect of these changes in strategies and quantify the effect of vaccination in low-income and middle-income countries. Because of our finding, we believe the WHO call for action to eliminate cervical cancer may be possible in many countries if sufficient vaccination coverage can be achieved." 
The authors note some limitations, including that causality between HPV vaccination and observed changes in the three endpoints cannot be concluded definitively because the analysis is based on ecological studies. The authors believe the results strongly suggest that the decreases can be largely attributed to HPV vaccination because larger and faster decreases are observed among cohorts targeted for vaccination and in countries with high vaccination coverage, larger decreases are observed with longer follow-up since the introduction of vaccination, and results are consistent across countries and HPV endpoints. In addition, the authors were unable to tease out the specific impact of different programme characteristics (e.g. vaccine used, number of age cohorts vaccinated).
There is a lack of data from low and middle-income countries (LMICs), where the burden of disease is far greater than in high-income countries and results should be extrapolated to those countries with caution. At least 115 countries* and territories include HPV vaccine in their immunisation programmes and almost 40 LMICs are set to join by 2021.
In a linked Comment article, Professor Silvia de Sanjose of PATH, USA, notes that these results will aid the implementation of the vaccine globally during a time of challenges such as high vaccine cost and competing budget priorities, inadequate vaccine supply, and lack of awareness of vaccine impact and vaccine hesitancy - particularly in LMICs.
She says: "Drolet and colleagues can help implementers concentrate on priority targets. Specifically, items like gender-neutral vaccination, number of age cohorts to be included, expansion to adult populations, and number of doses can be modulated on the basis of impact and sustainability. The robust estimates generated should prompt countries to re-evaluate their policies, especially given the global call to eliminate cervical cancer. Finding the optimal number of age cohorts to be vaccinated could also have major budgetary and programmatic advantages, as multiple cohorts of younger individuals would need fewer vaccine doses. The authors emphasise the importance of redoubling our efforts to tackle the fiscal, supply, and programmatic barriers that currently limit HPV vaccine programmes; with these efforts, HPV vaccination could become a hallmark investment of cancer prevention in the 21st century."
Peer-reviewed / Meta-analysis / People
NOTES TO EDITORS
This study was funded by WHO, a Fonds de recherche du Québec - Santé research scholars award, and a foundation scheme grant from the Canadian Institutes of Health Research. It was conducted by researchers from the CHU de Québec Research Center, Laval University, Canada and 45 institutions across Europe, North America, and Australia.
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*The number of countries introducing HPV vaccination is rapidly increasing. Several countries also have pilot programs and/or are in the process of introducing HPV vaccination. The Lancet paper states 99 countries and territories and the Comment 115 countries and territories. The authors of the paper did not include pilot programmes or countries who are in the process of introducing vaccination programmes.
**Unfortunately it is not possible to provide absolute risks because the studies in the meta-analysis used relative risks and the meta-analysis was done using relative risks. Given that incidence of anogenital warts and CIN2+ vary by country and by age, it is not possible to estimate the pooled absolute risks without completely re-doing the meta-analysis. However, to obtain estimates of absolute reductions for a given country (by age groups), the authors suggest to apply the relative decreases estimated in our study to the pre-vaccination incidence/prevalence of the HPV endpoint(s) of the country.
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