There is now "compelling evidence" of the impact that human papilloma virus (HPV) vaccines have made on reducing the incidence of HPV infections, high-grade cervical lesions, and anogenital warts, according to a new meta-analysis.

"It is, however, too soon to see reductions in cervical cancers," said lead author Melanie Drolet, PhD, an epidemiologist and senior research associate at Laval University, Quebec, Canada. "But our results strongly suggest that cervical cancer will decrease since both the cause — HPV infections — and precancerous cervical lesions, are significantly declining."

The results were published online June 26, 2019, in The Lancet.

HPV vaccines have been marketed for more than 10 years. For example, Gardasil (Merck & Co) was first approved in the United States in 2016.

The new meta-analysis included data from 60 million individuals and up to 8 years of postvaccination follow-up.

It shows a significant reduction in HPV type 16 and 18 infections, as well as a significant reductions in diagnoses of anogenital warts in teenagers of both genders and young men and women.

In addition, there was a significant 51% reduction in cervical intraepithelial neoplasia grade 2+ (CIN2+) in girls aged 15-19 years and a 31% reduction in women aged 20-24 years.

These findings support the recently revised position of the World Health Organization (WHO), which now recommends that HPV vaccination be administered to multiple age cohorts of girls aged 9-14 years when the vaccine is introduced in a country, the authors say.

"Our results clearly show that programs that vaccinate multiple ages and achieve high vaccination coverage have faster and greater direct impacts and herd effects," Drolet told Medscape Medical News.

"However, for the years included in our study — up to 2015 — the great majority of countries were vaccinating girls only. Therefore, the results presented in our study are associated with girls-only vaccination."

Study coauthor Marc Brisson, PhD, also from Laval University, commented in a statement: "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."

/The WHO call for action to eliminate cervical cancer may be possible. —Dr Marc Brisson/

"Because of our findings, we believe the WHO call for action to eliminate cervical cancer may be possible in many countries if sufficient vaccination coverage can be achieved," Brisson commented.

Update of Previous Paper

The new meta-analysis is an update on a previous paper from the same group of authors (Lancet Infect Dis. 2015;15:565-580). That study showed substantial decreases in HPV 16 and HPV 18 infections and anogenital wart diagnoses among women in the targeted age groups. There was also evidence of herd effects among boys and older women, 4 years after the introduction of HPV vaccination.

The current paper is an update of this previous work, which also evaluates the population-level impact of girls-only HPV vaccination on CIN2+ occurrence among screened girls and women.

Reduced Infection in All Cohorts

The meta-analysis included 65 studies from 14 high-income countries: 23 for HPV infection, 29 for anogenital warts, and 13 for CIN2+.

It found that, at 5-8 years of vaccination, the prevalence of HPV 16 and 18 had significantly decreased by 83% (relative risk [RR], 0.17) among girls aged 13-19 years, and by 66% (RR, 0.34) in the older cohort, aged 20-24 years.

The prevalence of HPV 31, 33, and 45 also decreased significantly, by 54% (RR, 0.46) among girls aged 13-19 years, showing evidence of vaccine cross-protection.

Additionally, diagnoses of anogenital wart also decreased significantly in both females and males, demonstrating evidence of herd effects from girls-only vaccination programs. Among girls aged 15-19 years, it declined by 67% (RR, 0.33), by 54% (RR, 0.46) in women aged 20-24 years, and by 31% (RR, 0.69) among women aged 25-29 years.

Among boys aged 15-19 years, the prevalence of anogenital wart diagnoses decreased significantly, by 48% (RR, 0.52), and among men aged 20-24 years by 32% (RR, 0.68).

Data From High-Income Countries

A limitation of their paper, the authors note, is that all of the studies included in their review are from high­-income countries. The burden of HPV is much greater in low-­income and middle­-income countries, especially for cervical cancer, so it may be difficult to extrapolate these results to those settings.

However, data from low- and middle-income countries (LMIC) are hard to come by. As of October 2018, the date of their last literature search update, Drolet noted that there was no study from LMIC eligible for the meta-analysis.

"However, we have identified several studies from low/middle income countries presenting pre-vaccination data and we are looking forward for the post-vaccination results from these countries," she said.

Scaling Up Efforts

This lack of data from low-income and middle-income countries is also highlighted by the authors of an accompanying editorial, Silvia de Sanjose, PhD, from PATH, Seattle Washington, and Sinead Delany-Moretlwe MD, PhD, from Wits Reproductive Health and HIV Institute, University of Witwatersrand, Johannesburg, South Africa.

By the end of 2021, 39 LMICs and territories are projected to have HPV vaccination in their national schedules, the editorialists note. But gathering data on effectiveness in these regions may be problematic, because of "weak or inadequate surveillance systems that are unable to link vaccination process with population outcome data system."

They also predict that "implementation challenges, vaccine cost and competing budget priorities, and inadequate vaccine supply, together with lack of awareness of vaccine impact and vaccine hesitancy, are likely to slow the process of vaccine introduction."

Vaccine supplies are projected to be constrained and unable to accommodate demand during the next 5 years because of "fewer requirements to introduce HPV vaccines in countries supported by Gavi, the Vaccine Alliance, increased interest in multiple age-cohort vaccination, and introduction of a gender-neutral approach," they write. "The scale-up of HPV vaccine introduction in LMICs will be particularly affected by these constraints."

The data presented in this paper emphasized the importance of "redoubling our efforts to tackle the fiscal, supply, and programmatic barriers that currently limit HPV vaccine programs," the editorialists write.

"The robust estimates generated should prompt countries to re-evaluate their policies, especially given the global call to eliminate cervical cancer," they add.

This work was supported by WHO, a Fonds de recherche du Quebec – Sante research scholars award to MB, and a foundation scheme grant from the Canadian Institutes of Health Research. The study authors have disclosed no relevant financial relationships. De Sanjose was principal investigator in a research project with institutional support from Merck, and Delany-Moretlwe has disclosed no relevant financial relationships.

The Lancet. Published online June 26, 2019. Full text

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