Clinical effectiveness of HPV vaccine by age at vaccination: a matched case-control study

Abstract

Background: Important questions remain about the extent to which human papillomavirus (HPV) vaccines are realizing their full potential in real-world settings. This study aimed to assess how age at the time of vaccination influences its effectiveness against HPV-attributable high-grade cervical lesions (HGCL).

Methods: In this matched case-control study conducted in New Haven County, Connecticut, cases were vaccine-eligible women diagnosed with HGCL associated with HPV 16 or 18 from 1/1/2010 to 12/31/2019. Controls were women with normal Pap smear results, matched to cases by age, medical practice, and date of Pap test. Participants were interviewed and records were reviewed to ascertain vaccination history and possible confounders including sexual behaviors. Vaccine effectiveness (VE) by age at the time of vaccination was assessed using matched odds ratios (OR) and 95% confidence intervals (CI) derived from multivariable conditional logistic regression models. VE was calculated as (1 - OR) × 100%.

Findings: A total of 524 women (132 cases and 392 controls) were included. The adjusted VE of >1 dose of HPV vaccine was 54% (95% CI: 8-77%, p = 0·03). When the first dose was given at ≤18 years of age VE was 75% (95% CI: 13-93%, p = 0·03), and when vaccinated >18 years VE was 43% (95% CI: -22 to 74%, p = 0·15).

Interpretation: These data demonstrate that the full benefit of HPV vaccines may not be realized when administered at older ages. Continued and strengthened efforts should be made to ensure that recommendations for HPV vaccination of younger adolescents are followed.

Funding: National Institutes of Health, American Cancer Society, Robert E. Leet and Clara Guthrie Patterson Trust, and Centers for Disease Control and Prevention.

Keywords: Case-control study; HPV vaccination; High-grade cervical lesions; Vaccine effectiveness.

Fig. 1

Estimated effectiveness of HPV vaccine by age at the time of immunization. Shown is the overall adjusted and unadjusted HPV vaccine effectiveness (VE) against high-grade cervical lesions that are attributable to HPV types 16 or 18. Adjusted models control for insurance, age of first intercourse, number of sex partners, smoking history, self-reported race/ethnicity, and history of other sexually transmitted infections. Bars indicate 95% confidence intervals. The reference category was unvaccinated at least 2 years before focal time.

Fig. 2

Exposure definition, outcome definition, and other sensitivity analyses. Shown is the overall HPV vaccine effectiveness (VE) against high-grade cervical lesions that are attributable to HPV types 16 or 18 and sensitivity analyses exploring possible heterogeneity in overall VE based on different exposure and outcome definitions. Bars indicate 95% confidence intervals. The reference category was unvaccinated at least 2 years before focal time. hr-HPV type = high-risk HPV type, which includes HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68. Δ VE is the difference between primary VE results and sensitivity analysis. ∗Excluding 42 cases and 16 controls who had 1 or more missing or unavailable vaccine records.

Fig. 3

Modeling distribution of vaccine effectiveness by age of immunization, N = 8192 models. aOR = adjusted odds ratio; VE = vaccine effectiveness; SE = standard error; Significance rate = the percentage of models that report a statistically significant VE. ∗BMA = Bayesian model averaging. Only includes models that had a Posterior Model Probability ≥0·01. Relative Frequency refers to the proportion of models that support a specific VE estimate within the ensemble of models considered.