Clinical Context

Human papillomavirus (HPV) remains a major source of morbidity and mortality. An editorial by Perkins and colleagues, which accompanies the current study, puts the burden of HPV infection in context. The editorialists note that despite major gains over the course of decades in screening for cervical dysplasia, there was a 2.36% average annual increase in the prevalence of all HPV-related cancer types between 2001 and 2017. In fact, there are more cases of HPV-related oropharyngeal cancer than cervical cancer in the United States. The incidence rates of HPV-related cancers are 13.68 cases per 100,000 among women and 11 cases per 100,000 among men.

HPV vaccination rates trail those of other recommended adolescent vaccines. The authors of an accompanying editorial suggest the following interventions to increase rates of HPV vaccination: direct recommendation to apply the HPV vaccine on time, standing orders that allow staff to administer the HPV vaccine without physician interaction, and recall and reminder programs to remind patients of the need for the HPV vaccine.

What can healthcare professionals tell patients regarding the efficacy of HPV vaccines? The current study addresses this issue.

Study Synopsis and Perspective

Twelve years after the HPV vaccination program was introduced in the United States, the overall prevalence of cancer-causing HPV strains covered by the vaccine dropped by 85% among females (90% among vaccinated females and 74% among unvaccinated females), which is a strong sign of herd immunity, a new analysis of a nationally representative database shows.

The study was published online today in the Annals of Internal Medicine.^[1]

The authors used data from the National Health and Nutrition Examination Survey (NHANES) to examine the 4 HPV types in the quadrivalent vaccine before 2003 and 2006 (the prevaccine era) and then again between 2007 to 2010, 2011 to 2014, and 2015 to 2018 (the vaccine era). For females, the authors analyzed demographic and HPV prevalence data across each 4-year era.

"Analyses were limited to sexually experienced participants to ensure that all those included had an opportunity for HPV exposure and to participants aged 14 to 24 years with adequate self-collected cervicovaginal specimens," the authors explain.

This resulted in a sample size of 3197 females. Demographic and HPV prevalence data were also collected from males, but only during the 2013 to 2016 era, because those are the only years for which male HPV typing data are available in NHANES. Again, analyses were limited to sexually experienced males aged 14 to 24 years with adequate self-collected penile specimens, which resulted in a sample size of 661 males.

During the 12 years of follow-up for females, there was a steady increase in females reporting having received at least 1 dose of the HPV vaccine, increasing from slightly more than 25% during 2007 to 2010to 59% during 2015 to 2018. The percentage of males who reported having at least 1 HPV dose also increased.

During the earliest vaccine era (2007-2010), the prevalence of the 4 HPV strains covered by the vaccine was 7.3% among vaccinated females compared with 20.4% among unvaccinated females. By 2015 to 2018 the prevalence was 2.8% (prevalence ratio [PR], 0.15; 95% confidence interval [CI], 0.08-0.28). The prevalence of the 4 vaccine-covered types was only 1.9% in vaccinated females compared with 4.8% in unvaccinated females (PR, 0.40; 95% CI, 0.11-1.41).

In contrast, the prevalence of HPV types that were not covered by the vaccine showed little change, going from 51.1% in the prevaccine era to 47.6% during 2015 to 2018 (PR, 0.93; 95% CI, 0.80-1.08). The authors considered this a good sign because it indicates that vaccine-type HPV infections are not being replaced with other oncogenic HPV infections. Between 2013 and 2016, the difference in the prevalence of the 4 HPV vaccine types was smaller, at 1.8% among vaccinated males and 3.5% among unvaccinated males (PR, 0.49; 95% CI, 0.11-2.20).

Again, the prevalence of non-HPV vaccine types was not significantly different between vaccinated and unvaccinated males (30.7% vs 34.3%, respectively).

During the vaccine era, effectiveness for females ranged from 60% to 84%. For males, vaccine effectiveness could only be evaluated for the single 4-year period from 2013 to 2016, when it was estimated at 51%. Dr Rosenblum noted that vaccine efficacy estimates were lower on this national survey than the almost 100% efficacy rates observed in clinical trials in both males and females.

"This might be due in part to many participants receiving the vaccine at an older age than is recommended when they could have been infected [with HPV] at the time of vaccination," Dr Rosenblum said. She also noted that because males were incorporated into the HPV vaccination program years after females, they likely also experienced strong herd effects from the vaccine, making it challenging to estimate vaccine effectiveness.

Commenting on the findings, Rebecca Perkins, MD, from the Boston University School of Medicine, and colleagues point out that the COVID-19 pandemic has led to disruptions in HPV vaccination programs and has reversed much of the progress made in recent years. "During the pandemic, providers and health systems have deprioritized adolescent vaccination and particularly HPV vaccination, which in turn has led to more severe drops for HPV vaccination than for other adolescent vaccinations, and for adolescent vaccination compared with early childhood and adult vaccinations," Dr Perkins and colleagues write in an accompanying editorial.^[2]

Thus, the need to compensate for the cumulative deficit of missed vaccinations during the past 2 years has created a "serious and urgent threat" to cancer prevention efforts--"a shortfall from which it may take a decade to recover," the editorialists predict. To try and reverse this trend, several practices have been shown to improve HPV vaccination rates.

The first is a strong provider recommendation, such as, "Your child is due for an HPV vaccine today." The second is to give standing orders to allow nurses and medical assistants to administer vaccinations without requiring intervention by a physician. Last, programs to remind patients when vaccines are due; recalling them for appointments also works well.

"Using evidence-based methods and redoubling our efforts to prioritize HPV vaccination will be crucial to ensuring that we do not lose a generation to preventable HPV-associated cancer," write Dr Perkins and colleagues.

The study authors and editorialists have disclosed no relevant financial relationships.

Ann Intern Med. Published online May 16, 2022.

Clinical Implications

• Despite major gains over the course of decades in screening for cervical dysplasia, there was a 2.36% average annual increase in the prevalence of all HPV-related cancer types between 2001 and 2017. In fact, there are more cases of HPV-related oropharyngeal cancer than cervical cancer in the United States. The incidence rates of HPV-related cancers are 13.68 cases per 100,000 among women and 11 cases per 100,000 among men.
• The current study finds that the HPV vaccine was associated with lower prevalence of HPV infection among both sexually active females and males. Moreover, there was evidence of herd protection, as unvaccinated females also experienced a reduction in HPV infection that was less pronounced compared with that of vaccinated females.
• Implications for the healthcare team: The results of the current study should help guide members of the healthcare team when providing evidence-based education on HPV vaccination for adolescents.