Quadrivalent HPV Vaccine Provides Poorer Protection in Women 18 and Older or With Abnormal Cytology

Key Points

  • Among subjects aged 15 to 17 years, vaccination was associated with risk reductions of 35% for high-grade squamous intraepithelial lesions, 21% for low-grade lesions, and −1% for atypical squamous cells of undetermined significance, with rates of 46%, 35%, and 23% among those who had at least one Pap smear after enrollment.
  • Effectiveness was lower in subjects aged ≥ 18 years, with vaccination being associated with a 23% reduction in high-grade squamous intraepithelial lesion risk among subjects without history of abnormal cytology, but no risk reduction in those with history of abnormal cytology.

In a study reported in the Journal of Clinical Oncology, Mahmud et al evaluated the effectiveness of the quadrivalent human papillomavirus (HPV) vaccine against cervical dysplasia using population-based individual level data routinely collected in Manitoba. They found that a high proportion of vaccinated women may not be protected against high-grade squamous intraepithelial lesions and lesser dysplasia, particularly those vaccinated at age ≥ 18 years and those with abnormal cytology before vaccination.

Study Details

In the study, 3,541 females aged ≥ 15 years who privately received the quadrivalent vaccine in Manitoba between September 2006 and April 2010 were matched for age with up to three unvaccinated females (n = 9,594). Cox regression models were used to estimate risk for atypical squamous cells of undetermined significance, low-grade squamous intraepithelial, and high-grade squamous intraepithelial lesions.

Most vaccinated subjects (61%) and unvaccinated subjects (64%) were aged 15 to 19 years. Vaccinated subjects were significantly more likely to reside in urban areas (73.5% vs 59%, P < .001) and affluent urban areas (60% vs 35.5%, P < .001), to have had Pap testing in the 3 years prior to the study (46% vs 41%, P < .001) and after enrollment (74% vs 60%, P < .001), and to have history of abnormal cytology prior to enrolment (12.5% vs 9.6%, P < .001).

The median length of follow-up after enrollment was 3.1 years. Overall, the 3-year cumulative rates of low-grade (3.3% vs 3.7%) and high-grade squamous intraepithelial lesions (2.3% vs 2.6%) were slightly lower in the vaccinated group, and the rates of atypical squamous cells of undetermined significance were identical (2.8%). No invasive cancers were observed, but 12 vaccinated subjects (0.3%) and 22 unvaccinated subjects (0.2%) had in situ cervical cancer during follow-up.

Risk Reductions in Younger Subjects

In a multivariate model adjusting for age, urban/rural residence, income quintile, history of Pap screening within 3 years prior to enrollment, and history of abnormal cytology, vaccine effectiveness estimates were 35% (95% confidence interval [CI] = −19% to 65%) against high-grade squamous intraepithelial lesions, 21% (95% CI −10% to 43%) against low-grade lesions, and −1% (95% CI = −44% to 29%) against atypical squamous cells of undetermined significance among 15- to 17-year-old subjects. The corresponding effectiveness rates were 46% (95% CI = 0% to 71%), 35% (95% CI = 10% to 54%), and 23% (95% CI = −8% to 45%) among those who had at least one Pap smear after enrollment.

Risk Reductions in Older Subjects

Effectiveness estimates were generally lower in subjects aged ≥ 18 years, particularly those with history of abnormal cytology. Vaccination was associated with an adjusted 23% (95% CI = −17% to 48%) reduction in high-grade squamous intraepithelial lesion risk among subjects without  history of abnormal cytology, but no risk reduction in those with history of abnormal cytology (−8%, 95% CI = −59% to 27%); corresponding estimates were 35% (95% CI = 2% to 57%) and −33% (95% CI = −96% to 10%) among those with at least one Pap test after enrollment.

Although other results were similar for low-grade squamous intraepithelial lesions and atypical squamous cells of undetermined significance, vaccination was associated with an adjusted 53% (95% CI = 8% to 76%) reduction in risk for atypical squamous cells in subjects with history of abnormal cytology. The investigators attributed this finding to the fact that subjects in this age group were more likely to present with high-grade squamous intraepithelial lesions rather than atypical squamous cells of undetermined significance.

The investigators concluded, “A significant percentage of vaccinated women may not be protected against [high-grade squamous intraepithelial lesions] and lesser dysplasia especially if they were vaccinated at older age (≥ 18) or had abnormal cytology before vaccination. These findings affirm the importance of vaccination before any significant exposure to HPV occurs and underscore the need for screening programs that cover all sexually active women, even if they were vaccinated.”

Salaheddin M. Mahmud, MD, PhD, of University of Manitoba, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported in part by Manitoba Health and the Manitoba Health Research Council. For full disclosures of the study authors, visit jco.ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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