The human papillomavirus (HPV) vaccine demonstrated high efficacy in preventing HPV infection and disease in women aged 16 to 26 years, with the highest efficacy against HPV types 16 and 18 in women without prior HPV infection.1,2 In the United States, routine vaccination with the quadrivalent HPV vaccine (HPV types 6, 11, 16, 18) is recommended for girls 11 to 12 years of age, and catch-up vaccination is recommended for girls and women 13 through 26 years of age.3 Vaccine uptake and completion, however, has been low.4,5 In 2012, 54% of young girls initiated vaccination and 33% completed vaccination.6 The observed incomplete vaccination of low-income and minority women in the Unites States7 is particularly concerning because of the high rates of HPV infection and cervical cancer in these women.8,9 Additional surveillance of vaccine effectiveness of these women is needed.10–12
We conducted a cross-sectional study of HPV vaccination and (1) cervical cytology and (2) HPV infection among low-income, minority young women attending a large volume safety-net hospital clinic. We previously reported low vaccine uptake and completion in adolescents of this population.13
This study was conducted in an obstetrics and gynecology clinic of a safety-net hospital serving a low-income, minority population of inner-city Boston. Women 21 to 30 years of age who presented to the study clinic for a scheduled Papanicolaou (Pap) test from April 2011 to March 2012 were eligible for participation. Our selected age range for study participation was based on clinical care: (1) the HPV vaccine was implemented in 2007 for women 11 to 26 years of age, and thus, at the time of study enrollment, all participants had been eligible for vaccination in 2007 to 2011, and (2) because leftover clinical Pap test specimens were used in our study for HPV genotyping, we restricted the study to women 21 years or older who undergo routine Pap tests. All study participants signed an informed consent form in English or Spanish. Participants completed a short questionnaire on smoking status, HPV vaccination, age of first sexual intercourse, lifetime number of male sexual partners, and usual condom use with these male partners. Electronic medical records were used to supplement information on these variables and to obtain information on prior Pap test results. Participants received a US $5 pharmacy gift certificate as compensation for their time. This study was approved by the research review board of Boston University Medical Center.
Cytology specimens were collected per routine clinical practice by using the Thinprep system; cytopathology slides were prepared for Pap test staining. The remaining collections were resuspended in 2 mL of buffer and used for HPV genotyping with the technician blinded to the Pap test result. DNA extraction was performed using the QIAgen QIAamp DNA Kit. The sample was centrifuged to a pellet cellular material, and the pellet was digested overnight with ATL (tissue lysis buffer) and proteinase K. DNA quality was assayed by polymerase chain reaction (PCR) amplification of β-globin (500-base-pair product) concurrently to the HPV DNA PCR assay. HPV DNA PCR typing was performed using the PCR–restriction fragment length polymorphism assay; the method and primers are described by Ralston Howe et al.14 Briefly, a fragment of HPV DNA was amplified with a pair of consensus primers. Specimens with positive product were subject to 3 restriction enzymes (Pstl, Rsal, and Haelll) digestion. The digested PCR products were separated on polyacrylamide gels with a 600-base-pair DNA size standard. A digital image of the subsequent restriction fragment length polymorphism pattern was examined visually for HPV subtypes using the Access Genetics reference database.
Vaccine doses received before the study visit were classified into 2 ways in our statistical models: (1) any vaccination (at least 1 vaccine dose) versus unvaccinated and (2) 1 or 2 vaccine doses versus unvaccinated and complete vaccination versus unvaccinated. Differences in the characteristics of women by vaccination were assessed with the χ2 and Kruskal-Wallis tests. Abnormal cervical cytology result was classified as atypical cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL), or high-grade squamous intraepithelial lesions (HSIL). HPV genotypes were classified as (1) any HPV type, (2) HPV vaccine types (6, 11, 16, 18), and (3) high-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68). Prevalence ratios and 95% confidence intervals (CIs) between HPV vaccination and (1) abnormal cervical cytology result and (2) HPV genotype were estimated.15 Unadjusted prevalence ratios were first estimated and then were adjusted for potential confounding from participant age, race, smoking status, age at first sexual intercourse, lifetime number of male sexual partners, condom use, and history of an abnormal cervical cytology result. Minimal confounding was identified, and given the small sample size, models were adjusted for history of cervical abnormalities only. Statistical analyses were performed using SAS version 9.3 and Stata 11.0.
A total of 252 women agreed to participate in this study, 235 of whom were confirmed eligible and had a Pap test. These 235 women had a mean age of 26 years, almost 50% had five or more lifetime sexual partners, 50% of those with prior Pap test results had a history of an abnormal cervical cytology result, 18% had received 1 or 2 vaccine doses, and 23% had completed vaccination (Table 1). The mean age at the first vaccine dose was 22 years, and most women initiated vaccination after becoming sexually active. Women older than 25 years who were current or former smokers or had no prior Pap test in their medical records were less likely to be vaccinated.
Twenty-four (10%) of the 235 women had an abnormal Pap test result at the study visit including ASCUS (n = 10; 4%), LSIL (n = 12; 5%), and HSIL (n = 2; 1%); 1 woman had an unsatisfactory specimen for evaluation. Among women with an abnormal cervical cytology result, 14 had a prior Pap test at the study clinic, 8 of whom had an abnormal Pap result documented a mean of 10.1 months (range, 5.4–20.2 months) before the study visit. The adjusted prevalence ratio of abnormal cervical cytology (ASCUS, LSIL, or HSIL) was 65% lower (prevalence ratio, 0.35; 95% CI, 0.14–0.89; Table 2) in women who received any HPV vaccine doses before the study visit versus unvaccinated women. A greater reduction in abnormal cytology results was observed with complete vaccination.
Among 232 women with HPV genotyping results, 46 (20%; 95% CI, 15%–26%) had HPV infection detected, 9 of whom were infected with 2 HPV types. The HPV types detected are shown in Figure 1. The most prevalent HPV types were 16, 18, 45, 53, and 66. Human papillomavirus types could not be identified for 8 women with a single HPV type, and 1 of the 2 types could not be identified in 3 women with 2 HPV types. As expected, women with HPV infection were more likely to have ASCUS, LSIL, or HSIL than women without HPV infection (33% vs. 5%; data not shown). No associations between vaccination and HPV genotype were found, but there was limited power given our small sample size and number of HPV infections (Table 3).
Although the efficacy of complete HPV vaccination in HPV naïve populations is well documented, the efficacy of incomplete dosing and of vaccination after sexual debut remains unclear.16 In our study, less than half of women received at least 1 HPV vaccine dose, many of whom were incompletely vaccinated. Despite this low rate of vaccination and nearly all women being vaccinated after sexual debut, we found a lower prevalence of abnormal cytology results among vaccinated women. There also was a suggestion of greater protection in women who completed the vaccine, but results were limited by the small number of abnormal cytology results. Our findings are consistent with a recent study that observed decreases in high-grade cervical dysplasia among 21- to 24-year-old women in Connecticut despite low rates of complete vaccination.17 Continued surveillance of vaccination programs is necessary to monitor their success. Women younger than 30 years are the most relevant group for detecting an early impact of HPV vaccination on HPV prevalence.18
The overall prevalence of HPV infection in our study population was slightly lower than that of an American population of unvaccinated minority women whose age range extended beyond that of our population.18 The most prevalent HPV types in our population were 16, 18, 45, 53, and 66, and our prevalence of HPV-16 was lower than that in another study.18 A study of minority 13- to 26-year-olds documented a 15% increase in non-HPV vaccine types after vaccine implementation.19 Our study had too few HPV infections to statistically examine differences in nonvaccine types by vaccination. Furthermore, we were unable to examine associations between vaccination and HPV-16 and HPV-18.
Some limitations of our study are the cross-sectional design, which includes both incident and prevalent cervical dysplasia and HPV infection. We were, however, able to classify vaccination temporally with respect to the study visit and Pap test. Only 1 vaccinated woman with a prevalent cervical abnormality initiated vaccination after identification of cervical dysplasia, and results were unchanged when this woman was excluded from our analyses. Another limitation of our study is that HPV vaccination was implemented in 2007 at the study clinic, and therefore, very few women vaccinated before sexual debut were included in the study population. Finally, our HPV genotypes were based on Pap test specimens obtained for clinical care, and some genotypes could not be determined. We attribute this to infection with uncommon HPV types that were unavailable in the subtyping reference database.
Human papillomavirus vaccination rates remain low in the United States,6 with the lowest rates reported among 18- to 26-year-old women. Although data clearly indicate better immune responses and vaccine efficacy against both genital warts and cervical dysplasia when vaccination occurs before age 17 years,20 this cross-sectional study suggests that HPV vaccination may be effective in reducing abnormal Pap test results after sexual debut, as has been observed in other studies.17 Studies should continue to compare vaccine effectiveness before and after sexual debut and by vaccine doses received, and to explore the role of herd immunity.
1. Future II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med
2007; 356: 1915–1927.
2. Paavonen J, Jenkins D, Bosch F, et al.Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: An interim analysis of a phase III double-blind, randomised controlled trial. Lancet
2007; 369: 2161–2170.
3. Centers for Disease Control and Prevention. FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep
2010; 59: 626–629.
4. Laz TH, Rahman M, Berenson AB. An update on human papillomavirus vaccine uptake among 11–17 year old girls in the United States: National Health Interview Survey, 2010. Vaccine
2012; 30: 3534–3540.
5. Gefenaite G, Smit M, Nijman HW, et al.Comparatively low attendance during human papillomavirus catch-up vaccination among teenage girls in the Netherlands: Insights from a behavioral survey among parents. BMC Public Health
2012; 12: 498–506.
6. Centers for Disease Control and Prevention. National and state vaccination coverage among adolescents aged 13–17 years—United States, 2012. MMWR Morb Mortal Wkly Rep
2013; 62: 685–693.
7. Dorell CG, Yankey D, Santibanez TA, et al.Human papillomavirus vaccination series initiation and completion, 2008–2009. Pediatrics
2011; 128: 830–839.
8. Kahn JA, Lan D, Kahn RS. Sociodemographic factors associated with high-risk human papillomavirus infection. Obstet Gynecol
2007; 110: 87–95.
9. Watson M, Saraiya M, Benard V, et al.Burden of cervical cancer in the United States, 1998–2003. Cancer
2008; 113 (10 Suppl): 2855–2864.
10. Krogstad P, Cherry J. Quadrivalent human vaccine—A call to action and for additional research. Pediatr Res
2007; 62: 527.
11. Lynge E, Antilla A, Arbyn M, et al.What’s next? Perspectives and future needs of cervical screening in Europe in the era of molecular testing and vaccination. Eur J Cancer
2009; 45: 2714–2721.
12. Hariri S, Markowitz LE, Dunne EF, et al.Population impact of HPV vaccines: Summary of early evidence. J Adoles Health
2013; 53: 679–682.
13. Perkins RB, Brogly SB, Adams WG, et al.Correlates of human papillomavirus vaccination rates in low-income, minority adolescents: A multicenter study. J Womens Health (Larchmt)
2012; 21: 813–820.
14. Ralston Howe E, Li Z, McGlennen R, et al.Type-specific prevalence and persistence of human papillomavirus in women in the United States who are referred for typing as a component of cervical cancer screening. Am J Obstet Gynecol
2009; 200: e241–e247.
15. Spiegelman D, Hertzmark E. Easy SAS calculations for risk or prevalence ratios and differences. Am J Epidemiol
2005; 162: 199–200.
16. Szarewski A. HPV vaccination and cervical cancer. Curr Oncol Rep
2012; 14: 559–567.
17. Niccolai LM, Julian PJ, Meek JI, et al.Declining rates of high-grade cervical lesions in young women in Connecticut, 2008–2011. Cancer Epidemiol Biomarkers Prev
2013; 22: 1446–1450.
18. Wheeler CM, Hunt WC, Cuzick J, et al.A population-based study of human papillomavirus genotype prevalence in the United States: Baseline measures prior to mass human papillomavirus vaccination. Int J Cancer
2012; 132: 198–207.
19. Kahn JA, Brown DR, Ding L, et al.Vaccine-type human papillomavirus and evidence of herd protection after vaccine introduction. Pediatrics
2012; 130: e249–e256.
20. Markowitz LE, Hariri S, Lin C, et al.Reduction in human papillomavirus (HPV) prevalence among young women following HPV vaccine introduction in the United States, National Health and Nutrition Examination Surveys, 2003–2010. J Infect Dis
2013; 208: 385–393.