August 10, 2018
Girls and young women who initiate the human papillomavirus (HPV) vaccine series between ages 15 and 20 years and receive all three doses are adequately protected against cancers caused by HPV infection, new data suggest. Catch-up vaccination among those ages 21 to 26 does not provide the same benefit, however.
In the United States, immunization guidelines recommend a routine two-dose HPV vaccine schedule for adolescents who start the series before age 13 years and a three-dose "catch-up" schedule for those who start the series on or after they turn 13 through age 26 years. However, the population effectiveness of the catch-up protocol has not been studied extensively, Michael J. Silverberg, PhD, from the Division of Research at Kaiser Permanente in Oakland, California, and colleagues report in an article published online August 7 in The Lancet Child & Adolescent Health.
To determine whether age at first dose and the number of doses influence the effectiveness of the quadrivalent HPV vaccine in the catch-up population of girls and young women aged 13 to 26, the authors conducted a nested case-control study of women enrolled in a large integrated healthcare system in California.
The study population included 4357 women with cervical intraepithelial neoplasia (CIN) grade 2 or higher (CIN2+), including a subset of 1849 women with CIN grade 3 or higher (CIN3+), who were aged 26 years or younger when the quadrivalent HPV vaccine was introduced in 2006. Through use of 5:1 matching, 21,773 age-matched women without CIN2+ were randomly selected as a comparator group.
Compared with controls, women with CIN2+ or CIN3+ were more likely to be non-Hispanic white; had a higher mean number of outpatient visits per year; and were more likely to have a history of smoking, recent hormonal contraceptive use, and recent sexually transmitted infections, the authors report.
Of the 4357 CIN2+ cases, 20% had grade 2 lesions, 38% had grade 2/3, 40% had grade 3, 2% had adenocarcinoma in situ, and fewer than 1% had cancerous lesions.
CIN2+ Risk Drops With Earlier Age, Three Doses
After adjusting for demographic and health factors, the researchers found a decreased risk for CIN2+ among the groups compared with women with no prior HPV vaccination. Specifically, women who had received at least one HPV vaccine dose had an 18% lower risk for CIN2+ (relative risk [RR], 0.82; 95% confidence interval [CI], 0.73 - 0.93).
Women who received their first HPV vaccine dose at age 14 to 17 years had a 59% lower risk for CIN2+ (RR, 0.61; 95% CI, 0.46 - 0.81) and those who received their first dose at age 18 to 20 years had a 28% reduced risk (RR, 0.72; 95% CI, 0.58 - 0.90).
However, there was no risk reduction among those who received their first HPV vaccine dose at 21 years or older (RR, 0.94; 95% CI, 0.81 - 1.09).
Number of doses also appeared to be important. Women who received at least three HPV vaccine doses had a 24% reduction in risk (RR, 0.76; 95% CI, 0.64 - 0.89), but no significant benefit was seen among those who received one dose (RR, 0.84; 95% CI, 0.68 - 1.03) or two doses (RR, 0.98; 95% CI, 0.78 - 1.24).
When the investigators modeled both age and number of doses, significant protection was seen only among women who received at least three HPV vaccine doses starting at 14 to 17 years of age (RR, 0.52; 95% CI, 0.36 - 0.74) or 18 to 20 years (RR, 0.65; 95% CI, 0.49 - 0.88).
Women who received fewer than three vaccine doses were not significantly more protected against CIN2+, "although point estimates were protective for those aged 14–17 years and 18–20 years at time of first dose," the authors write. They note the test for interaction between age at first dose and number of doses in vaccinated women was not statistically significant, despite the apparent associations between age at first dose and receipt of at least three doses.
The results showed a similar pattern for vaccine protection against CIN3+, with both age at initial dose and number of doses being important in adjusted models.
Similarly, when the investigators considered both age at first dose and number of doses, the adjusted models showed protection against CIN3+ in women who had at least three HPV vaccine doses and received their first dose at age 14 to 17 years (RR, 0.27; 95% CI, 0.13 - 0.56) and in those with at least three HPV vaccine doses who received their first dose at age 18 to 20 years (RR, 0.59; 95% CI, 0.36 - 0.97). Women who received fewer than three doses were not significantly more protected within any age strata, although point estimates were protective for those age 14 to 17 years at time of first dose. As with the CIN2+ analysis, the test for interaction between age at first dose and number of doses in vaccinated women was not statistically significant in the CIN3+ model.
Stick With Catch-up Strategy, Experts Say
The authors note that the results support current vaccination guidelines that recommend the full three-dose series for girls and women who start the series after their 15th birthday, but they do not support catch-up vaccination of women age 21 to 26 years.
Because this latter consideration conflicts with recent calls to extend HPV vaccination to women of older ages, "our results should be confirmed in other settings, especially those that have adopted the nonvalent HPV vaccine," the authors stress.
However, the findings are not generalizable to the United States as a whole, write Sarah Dilley, MD, a fellow in the Department of Obstetrics and Gynecology at the University of Alabama at Birmingham, and Warner Huh, MD, professor and director of the Division of Gynecologic Oncology at the University of Alabama at Birmingham, in an accompanying editorial. They note that the study population is not representative of the most at-risk populations, "specifically women who are uninsured or underinsured with poor access to routine health care."
Further, they write, the study did not examine the effectiveness of the HPV vaccine on prevention of cervical cancer. "Only 23 women were diagnosed with cervical cancer in the study, and although only three (13%) of those women had received the HPV vaccine, the natural history of HPV infection and cervical cancer limits any researcher's ability to quantify the effect of the HPV vaccine on cervical cancer incidence."
The findings do point to the importance of increasing HPV vaccination rates in young adolescents given the increased protection conferred when it's given at younger ages, the editorialists emphasize. "The results of this study confirm existing research which showed that the HPV vaccine is most effective when given to females at younger ages, but no benefit was found in patients older than 21 years," they write. "Efforts towards increasing HPV vaccine uptake should be focused on younger adolescents — with a priority on vaccinating children aged 11–12 years — and providing catch-up dosing for older adolescents."
Despite evidence of the limited effectiveness seen in this study for the catch-up strategy among those who initiated the series at an older age, Dilley and Hug emphasize that catch-up dosing in young women should continue to be a priority in light of the comparatively low uptake of HPV vaccination in the United States. "Given that prospective efficacy studies have shown benefits for catch-up vaccination up to at least age 26 years, more data is needed before abandoning this practice."
The National Cancer Institute funded this study. The authors have disclosed no relevant financial relationships. The authors of the accompanying commentary report financial relationships with Merck, Antiva, and Pathovax.
Lancet Child Adolesc Health. Published online August 7, 2018. Abstract, Editorial