In the United States, there were 12,831 new cases of cervical cancer and 4,207 women who died from the disease in 2017.¹ The majority of cervical cancers are caused by the human papillomavirus (HPV), with most being attributed to oncogenic HPV types 16 and 18.² Since 2006, HPV vaccination has been routinely recommended for US female teens aged 11–12 years.³ Although coverage was low at first introduction, HPV vaccination coverage has increased; coverage of ≥1 dose of HPV vaccine among female adolescents aged 13–17 years increased from 37% in 2008 to 73% in 2019.^4,5 The impact of HPV vaccine on cervical disease has been shown by decreasing incidence of cervical precancers and decreases in vaccine-type HPV prevalence in cervical precancer lesions in young women.^6–8 The HPV vaccine impact on invasive cervical cancer has not yet been fully shown because of the long duration for cancer development and a lower burden of invasive cervical cancer in younger women in whom HPV vaccination would have the most impact. However, recent studies have suggested that the HPV vaccine may be reducing the incidence of invasive cervical cancers.^9–11 In this study, we sought to examine the potential impact of HPV vaccine on HPV prevalence among cervical precancers and invasive cervical cancers using data collected from select US population-based cancer registries before and after the HPV vaccine introduction.

A total of 676 patients with CIN3+ (328 in the prevaccine study; 348 in the postvaccine study) and 1,140 patients with ICC (777 in the prevaccine study; 363 in the postvaccine study) were successfully genotyped and included in our analytic sample. Study characteristics of CIN3+ and ICC by study are reported in Table 1. Among women with CIN3+, the age distribution varied between the 2 studies, with an overall lower number of younger women in the second study. In both studies, the majority of the CIN3+ cases were non-Hispanic White (83.2% prevaccine, 79.0% postvaccine) and diagnosed with squamous cell histology (86.6% prevaccine, 95.1% postvaccine). Among women with ICC, most women were aged 50–94 years (44.4% prevaccine, 43.4% postvaccine) and non-Hispanic White (53.0% prevaccine, 70.9% postvaccine), and diagnosed with squamous cell carcinoma (73.4% prevaccine, 66.6% postvaccine).

HPV-type prevalence among women with CIN3+ by age group and study period are reported in Table 2. In the total sample, approximately two-thirds of cases were attributed to HPV 16, 18 both in the prevaccine and postvaccine study. When comparing HPV-type prevalence in the prevaccine to the postvaccine study, a statistically significant difference was found in the distribution among all age groups (P = .03). There was increased positive HPV 31, 33, 45, 52, 58 compared with both other oncogenic HPV (P = .029) and other HPV/HPV negative (P = .019) in the postvaccine study compared with the prevaccine study. However, no differences were observed between HPV-type prevalence by age. Notably, among women aged 15–24 years, the proportion attributed to HPV 31, 33, 45, 52, 58 was 14.2% in the prevaccine study versus 21.4% in the postvaccine study, but the difference was not statistically significant.

HPV-type prevalence among women with ICC by age group and study period are reported in Table 3. Among women aged 19–34 years, the proportion attributed to HPV 16, 18 was somewhat higher in the postvaccine period compared with the prevaccine period (84.4% vs 74.4%). However, no significant differences were observed in HPV-type prevalence between the prevaccine and postvaccine studies in any age strata. When we limited the analysis to the subset of cancer registries collecting data in both studies, similar results were observed but sample sizes within stratum of age and HPV type became very small for these comparisons (see supporting information).

In this population-based cancer registry study, we did not find a reduction in vaccine-type HPV prevalence among patients with CIN3+ or ICC from the prevaccine to the postvaccine study by age group. Although an overall significant difference was observed among all women with CIN3+, this difference appears to be driven by larger differences in the proportion attributed to HPV 31, 33, 45, 52, 58 compared with both other oncogenic HPV types and other HPV/HPV negative observed in the postvaccine study versus the prevaccine study. Vaccine impact would be expected to first be observed in the type distribution of CIN3+ detected in the age groups most likely to have been vaccinated. The lack of significant change in HPV 16, 18-type prevalence among patients with CIN3+ and ICC by age in this study could be explained by the low number of cases captured by the study (particularly in the youngest age groups), suboptimal HPV vaccination coverage in the postvaccine period of data collection, and that the time point of the postvaccine study collection may be too early in the natural history of ICC to observe this association fully.

Early evidence of population-level HPV vaccine impact on cervical cancer in the United States has been shown by the decreasing prevalence of vaccine-type HPV infections after vaccine introduction and the decreasing prevalence of cervical precancers. Analyses of large national data sets of cervicovaginal specimens have shown a 56% reduction in the prevalence of HPV types targeted by the 4-valent vaccine within 4 years of HPV vaccine introduction among women aged 14–19 years.¹³ Greater reductions in the prevalence of HPV types targeted by the 4-valent vaccine occurred 6 and 8 years after vaccine introduction as well as the observation of decreases in prevalence among women aged 20–24 years, which reflects increasing HPV vaccination coverage in these age groups over time.^14,15 Evidence of decreased vaccine-type HPV prevalence has also been observed in both vaccinated and unvaccinated women screened for cervical cancer in a large managed health care network 9 to 10 years after HPV vaccine introduction, which highlights the direct impact of HPV vaccine as well as herd protection.¹⁶ In the New Mexico HPV Pap Registry, which linked population-based cancer registry and screening data, significant declines from 2007–2014 among CIN grades 1–3 were observed among women aged 15–19 years and also among women with CIN2 aged 20–24 years.¹⁷ Findings from the CDC’s Human Papillomavirus Vaccine Impact Monitoring Project conducted in 5 US catchment areas showed significant declines in CIN2+ from 2008–2015 among screened women aged 18–24 years,⁷ and in adenocarcinoma in situ cases among women aged 21–24 years.⁶ In addition, this project found that the proportion of HPV 16, 18–positive CIN2+ cases declined from 2008–2014, with larger decreases among vaccinated women and younger age groups. However, these declines were limited to CIN2 and CIN 2/3 cases. With additional follow-up of these HPV-typing cohorts, it is reasonable to expect a reduction in CIN3+ to reflect increasing HPV-vaccination coverage.

The lack of reduction in vaccine-type HPV prevalence among patients with ICC in our study is not unexpected. First, there are a low number of cases in the United States, let alone among a subset of US cancer registries, and especially among younger age groups. Because of the long amount of time between HPV infection and development of ICC, more follow-up time is likely needed to observe vaccine effects on these more distal end points. Although some evidence suggests that HPV impact can be observed earlier in young women,¹⁸ vaccine coverage is likely quite low in the postvaccine study. Few studies have examined vaccine effectiveness on invasive cancers, but a recent Swedish study found a 63% reduction in ICC incidence among vaccinated women compared with unvaccinated women after HPV vaccine implementation (2006–2017), with an 88% greater reduction among women vaccinated before 17 years of age.⁹ In addition, studies in the United States using population-based cancer registry data suggest that incidence rates of ICCs have declined in the youngest age groups of women after the HPV vaccination program began.^11,19 Given these findings, we might expect to see an impact on the prevalence of HPV types targeted by HPV vaccines with additional years of follow-up.

There were several limitations to our study for consideration in the interpretation of these findings. First, almost all cancer registries discontinued the routine reporting of cervical cancer precursors in 1996 because of concerns about appropriate case definitions, changes in diagnostic terminology,²⁰ and increased diagnosis and treatment in outpatient settings. Since 2006, several additional cancer registries have collected cervical precancer incidence, but they did not contribute to the prevaccine period prevalence. Second, we were unable to collect postvaccine data from all 7 cancer registries that participated in the prevaccine study, resulting in the inclusion of different cancer registries when comparing HPV prevalence in patients with CIN3+ and ICC. Among ICC, we performed a sensitivity analysis including only the cancer registries that collected data during both periods and found similar results; however, sample sizes were limited for these comparisons. Third, the postvaccine study oversampled by age and racial/ethnic group, which required weighting the sample back to the total population. Differences in the racial/ethnic group distribution between the prevaccine and postvaccine study may have resulted from the oversampling strategy employed in the postvaccine study. In addition, the pre- and postvaccine samples were drawn from different states with different underlying distributions of race/ethnicity. To account for these sampling differences, statistical testing was based on regression models that adjusted for stratification factors. Finally, we were limited in the variables we could analyze to those collected routinely by the cancer registries; HPV vaccination status, cancer screening, and human immunodeficiency virus status are variables that are not collected. Some state health departments including Michigan and New Mexico have been working to link vaccination and screening information to cancer registry data, but the process is complex and takes collaboration with several stakeholders to build the infrastructure and capacity. Linking these data sources more routinely could help further determine the impact of HPV vaccine on HPV-associated cancers including cervical cancer.

The major strength of our study was the systematic, population-based framework for evaluating HPV-type prevalence using cancer registries. The framework that was developed for this study is novel, robust, and could be expanded for the purpose of monitoring the impact of HPV vaccination on cervical precancers and invasive cancers in younger US women. Although we were not able to detect differences in HPV-type prevalence between our studies, our sampling methodology was refined in the postvaccine study and could be used in future studies with a larger sampling frame. Nearly 15 years have passed since the HPV vaccine was introduced, and other US studies have noted declines in precancers.^6,7,17 A study of HPV-type prevalence using population-based cancer registries including larger geographical representation using the methodologies developed through these studies could help to further show HPV vaccine impact in precancers and early impact of HPV vaccine in invasive cancers among young women with generalizability to the US population.

In conclusion, in this study of high-grade cervical precancers and invasive cervical cancers, we did not find differences in HPV-type prevalence by age in prevaccine and postvaccine studies. These findings could be explained by the postvaccine study data being too early to observe cancer outcomes and the lagging coverage of HPV vaccine, particularly with regard to series completion. However, the methodologic framework developed by these studies could be used to develop a routine, population-based system for monitoring HPV-type prevalence using central cancer registry data with linkage to HPV vaccination data. Monitoring HPV-type prevalence of precancer and invasive cervical cancers will continue to be important in the coming years as HPV vaccine coverage improves, especially for the youngest age groups of women.