HPV Vaccination
Given the etiological role of human papillomavirus (HPV) in the pathogenesis of cervical neoplasia, vaccines to immunize individuals against HPV infection offer a primary prevention strategy for cervical cancer. A quadrivalent (HPV type 6 , type 11 , type 16 , and type 18 ) vaccine using a late protein L1 construct to induce antibody-mediated immunity was approved for use by the U.S. Food and Drug Administration in 2006; a bivalent (HPV-16, -18) vaccine was approved in 2009; and a vaccine targeting nine HPV types was approved in 2014. Vaccination during pregnancy has not been associated with adverse pregnancy outcomes.
Persistent infection with oncogenic types of HPV, such as HPV-16 and HPV-18, is associated with the development of cervical cancer. A vaccine to prevent HPV infection with oncogenic-type viruses has the potential to reduce the incidence of cervical cancer. A vaccine against HPV-16 using empty-viral capsids called virus-like particles (VLP) was developed and tested for efficacy in preventing persistent infection with HPV-16.
A multicenter, double-blind, placebo-controlled trial enrolled 2,391 women aged 16 to 23 years and randomly assigned them to receive either 40 µg of HPV-16 L1 VLP vaccine or placebo on day 1, at 2 months, and at 6 months. Papanicolaou (Pap) tests and genital samples for HPV-16 DNA were obtained on day 1, at 7 months, and every 6 months for 48 months. Colposcopy and cervical biopsies were obtained when clinically indicated at study exit. Serum HPV-16 antibody titers were obtained at study entry, at 7 months, and then every 6 months. A total of 1,505 women (755 receiving vaccine and 750 receiving placebo) completed all three vaccinations and had follow-up after month 7. After immunization, HPV titers peaked at month 7, declined through month 18, and then stabilized in months 30 through 48. There were no cases of cervical intraepithelial neoplasia (CIN) in the vaccine-treated women, but there were 12 cases in the placebo group (six CIN 2 and six CIN 3). HPV-16 infection that persisted for at least 4 months was seen in seven vaccine-treated women, compared with 111 placebo-treated women.
An international, double-blind, placebo-controlled trial of a bivalent HPV-16/HPV-18 VLP vaccine was performed in 1,113 women aged 15 to 25 years with normal cervical cytology who were seronegative for HPV-16, HPV-18, and 12 other oncogenic HPV types at enrollment. Women received either vaccine or placebo at 0, 1, and 6 months and were assessed by cervical cytology and self-obtained cervicovaginal samples for at least 18 months. A masked treatment-allocation follow-up study was performed for an additional 3 years, for a combined analysis of up to 6.4 years of follow-up. The 12-month persistent infection rate of HPV-16 or HPV-18 in an according-to-protocol cohort (i.e., women who received all three doses of vaccine or placebo on the correct schedule) was 0 of 401 women in the vaccine arm, compared with 20 of 372 women in the placebo arm, with a vaccine efficacy rate of 100% (95% confidence interval , 81.8%–100%). Diagnoses of CIN 2 or higher in a total vaccinated cohort (i.e., women who received at least one dose of vaccine or placebo) were 0 of 481 women in the vaccine arm compared with 9 of 470 women in the placebo arm, with a vaccine efficacy of 100% (95% CI, 51.3%–100%). Adverse events were similar in vaccinated and placebo-treated women. Neither analysis was intention-to-treat (ITT), making it difficult to know what the true vaccine efficacy for either virological or cytohistological end points would be in the routine clinical setting. Furthermore, cytohistological outcomes were reported only as composite end points (CIN 2+), making it impossible to distinguish the vaccine’s efficacy against invasive cervical cancer alone and potentially inflating the observed efficacy by including lesions with a relatively high probability (approximately 50% for CIN 2 ) of spontaneous regression. A register-based observational study in England reported the impact of a national bivalent vaccination program on cervical cancer and CIN 3. Routine vaccinations were offered to girls aged 12 to 13 years with a catch-up program for those aged 14 to 18 years. Data from 13.7 million years of follow-up in women aged 20 years to younger than 30 years showed a substantial reduction in cervical cancer and CIN 3 incidence after a national HPV program was introduced. This was especially true in individuals who were offered the vaccine between ages 12 and 13 years (see Table 1).
Table 1. Estimated Relative Reduction in Cervical Cancer or CIN 3 by Age When Vaccine Was Offered Compared With the Reference Unvaccinated Cohort
| Estimated Relative Reduction (95% CI) |
|---|
| Age Vaccine Was Offered | Cervical Cancer | CIN 3 |
|---|
| CI = confidence interval; CIN = cervical intraepithelial neoplasia. |
| 16–18 y | 34% (25–41) | 39% (36–41) |
| 14–16 y | 62% (52–71) | 75% (72–77) |
| 12–13 y | 87% (72–94) | 97% (96–78) |
A quadrivalent vaccine (HPV types-6, -11, -16, and -18) was evaluated in a multinational, double-blind, randomized controlled trial of 17,622 women aged 15 to 26 years (FUTURE I and II). Women received either the HPV vaccine or placebo at 0, 2, and 6 months; participants were assessed by clinical exam, Pap test, and HPV DNA testing for 4 or more years. Two analyses were reported. One group was considered to be HPV naive: negative to 14 HPV types. The second group was an ITT analysis, which approximates a sexually active population. The composite end point for cervical disease included the incidence of HPV-16/HPV-18–related, CIN 2, CIN 3, adenocarcinoma in situ, or invasive carcinoma. Outcomes were reported as follows:
Table 2. Vaccine Efficacy of the Quadrivalent HPV Vaccine
| Population | Point Estimate and 95% CI |
|---|
| CI = confidence interval; CIN = cervical intraepithelial neoplasia; HPV = human papillomavirus; ITT = intention-to-treat. |
| HPV-naive population for HPV-CIN 3 | 100% (90.5%–100%) for lesions associated with HPV-6, -11, -16, or -18 |
| ITT CIN 3 | 45.3% (29.8%–57.6%) for lesions associated with HPV-6, -11, -16, or -18 |
This study also demonstrated decreased rates of abnormal Pap tests and subsequent diagnostic procedures. No cases of invasive cervical cancer were identified during the trial.
A 9-valent HPV (9vHPV) vaccine was studied in another international randomized trial, which included 14,215 women. This new vaccine, 9vHPV, includes the four HPV types in the quadrivalent vaccine, qHPV (6, 11, 16, 18) and also 5 more oncogenic types (31, 33, 45, 52, 58). Sexually active women aged 16 to 26 years with fewer than five lifetime sexual partners received three intramuscular injections (day 1, month 2, and month 6) of either the qHPV vaccine or the 9vHPV vaccine. Women were evaluated every 6 months for up to 5 years. The rate of high-grade cervical, vulvar, or vaginal disease was the same in both groups (14.0 per 1,000 person-years) because of preexisting HPV infection, but the rate of disease related to HPV-31, -35, -45, -52, and -58 was lower in the 9vHPV vaccine group (0.1 vs. 1.6 per 1,000 person-years). Injection-site reactions were more common in the 9vHPV group. Although not addressed in this study, the benefit of HPV vaccination is optimal in younger females before the onset of sexual activity.
All forms of the HPV vaccine are currently recommended by the Centers for Disease Control and Prevention (CDC) in the United States as a two-dose schedule at least 6 months apart for adolescents younger than 15 years. The current CDC recommendation for older individuals is to receive the original three-dose series. Recently, given issues of cost and adherence, there has been published data investigating whether similar vaccine efficacy could be obtainable using a reduced-dose schedule. A post hoc combined analysis of two phase III randomized controlled trials of the bivalent HPV vaccine (the Costa Rica Vaccine Trial and the PApilloma TRIal against Cancer In young Adults Trial) found that among women who were not HPV positive at enrollment for the specific virus type being studied, vaccine efficacy against either one-time incident detection of HPV 16/18 or incident infection that persisted at least 6 months was not statistically significantly different for those who received all three, two, or only one of the scheduled HPV vaccine doses (resulting from nonadherence or other factors) for up to 4 years of follow-up. Vaccine efficacy rates for persistent HPV 16/18 infection ranged from 89.1% (95% CI, 86.8%–91.0%) for three doses, to 89.7% (95% CI, 73.3%–99.8%) for two doses, to 96.6% (95% CI, 81.7%–99.8%) for one dose. To date, there are no randomized controlled trials that directly assess this clinical question. A recent international study compared a two-dose schedule with a three-dose schedule in adolescents younger than 15 years who received the 9vHPV vaccine. The antibody response was noninferior in the two-dose schedule, leading to the current recommendation that two doses are sufficient for this age group. Long-term follow-up data from the Costa Rica Vaccine Trial suggested that all HPV-vaccinated women aged 18 to 25 years at the time of initial vaccination remained HPV-16/HPV-18 seropositive more than a decade after initial vaccination, regardless of the number of doses received. The antibody levels were lower in the women who received only one dose than in the women who received two or three doses of the bivalent vaccine, but the levels remained higher than estimated levels achieved via natural immunity. The long-term vaccine efficacy rates against prevalent HPV-16 or HPV-18 infection were 80.2% (95% CI, 70.7%–87.0%) among women who received three doses, 83.8% (95% CI, 19.5%–99.2%) among those who received two doses, and 82.1% (95% CI, 40.2%–97.0%) among those who received one dose. Additionally, there was prolonged efficacy against CIN 2 and CIN 3 after 7 to 11 years of follow-up. The women in this long-term follow-up study were not randomly assigned to one, two, or three doses, and the number of women who received only one dose is low. However, the promising findings of the long-term stability of HPV-antibody levels and vaccine efficacy in women who were older than the recommended age at the time of initial vaccination has influenced the design of a currently ongoing trial, which will answer the question of the efficacy of a single dose more definitively. The ESCUDDO study (NCT03180034) is a trial enrolling adolescent girls who will be randomly assigned to either one dose or two doses of the bivalent or nonavalent vaccines. A concurrent population survey of comparable, unvaccinated, age-matched females in the same region will be used for comparison. Results are anticipated in 2025.
On the basis of their mechanism of action, L1/2 HPV vaccines do not appear to impact preexisting infections. The FUTURE II trial demonstrated a markedly lower vaccine efficacy rate in the total randomized study population, which included individuals who were positive for HPV at baseline, compared with the per-protocol population (44% for lesions associated with HPV-16 or HPV-18, and 17% for lesions associated with any HPV type vs. 98%; see Table 2 above). Additionally, an intermediate analysis of a randomized controlled trial primarily evaluating the efficacy of the HPV-16/18 vaccine in preventing infection found no effect on viral clearance rates in women aged 18 to 25 years who were positive at the time of study enrollment.
The type-specific vaccines, if successful in preventing invasive cancer, will offer protection for only a subset of cases, the proportion of which will vary worldwide. Using data from a multicenter case-control study conducted in 25 countries, it was estimated that a vaccine containing the seven most common HPV types could prevent 87% of cervical cancers worldwide. A vaccine with the two most common strains, HPV-16 and HPV-18, would prevent 71% of cervical cancers worldwide.
There is growing evidence of population-level impacts and herd immunity with HPV vaccination. There are data that explore the impact of national HPV vaccination programs and report on vaccine effectiveness. These data come from studies conducted in different countries throughout the world including England, Denmark, Australia, Costa Rica, and the United States. In England, 15,459 residual genital specimens from women aged 16 to 24 years, collected for Chlamydia trachomatis screening between 2010 and 2016, were utilized for national HPV surveillance. In this study, vaccine effectiveness for HPV-16/HPV-18 was 82% (95% CI, 60.6%–91.8%) for women who were vaccinated before age 15 years. Within the younger age groups, the prevalence of HPV-16/HPV-18 significantly decreased within the postvaccination period between 2010 and 2011 to 2016 from 8.2% to 1.6% in 16 to 18 year olds and from 14.0% to 1.6% in 19 to 21 year olds (compared with 17.6% and 16.9% in the prevaccination era). Data from a Danish nationwide cohort study reported the dose-related effectiveness of the quadrivalent HPV vaccine. In this cohort of 590,083 women aged 17 to 25 years, 215,309 (36%) women were vaccinated at age 16 years or younger, and 40,742 (19%) women received less than three doses. Cervical cancer screening rates were similar in the vaccinated and unvaccinated cohorts. In the overall cohort, there were 5,561 cases of CIN 3+ during the follow-up period. Only 5% of cases were in vaccinated women. The incidence rate was 355 cases per 100,000 person-years in unvaccinated women compared with 41 cases per 100,000 person-years in vaccinated women. The incidence rate was independent of the number of vaccine doses administered (incidence rates 40, 41, 40 cases per 100,000 person-years for 1, 2 and 3 doses, respectively).
A study of cervical HPV DNA among 202 Australian women aged 18 to 24 years who were sampled between 2005 and 2007, before implementation of a national quadrivalent prophylactic HPV vaccine program, compared the results with a matched group of 1,058 women who were sampled in the postvaccination era (2010–2012). This study found an adjusted prevalence ratio (PR) among fully vaccinated women of 0.07 (95% CI, 0.04–0.14; P .0001) for vaccine-related HPV types and a smaller but statistically significant magnitude of protection of 0.65 (95% CI, 0.43–0.96; P .03) among unvaccinated women, suggesting herd immunity (protection of unvaccinated individuals). These data strengthen previous results that suggest herd immunity in this population, manifested as a reduction in genital warts among heterosexual men, a group that includes sexual partners of vaccinated women. Data also suggest cross protection against carcinogenic types that are not directly targeted by the quadrivalent vaccine but are included in the new nonvalent HPV vaccine. Pooled data from the Costa Rica Vaccine Trial and PATRICIA Study showed that the AS04-adjuvanted HPV-16/HPV-18 vaccine provides additional cross protection beyond established protected types (e.g., 34/35/39/40/42/43/44/51/52/53/54/56/58/59/66/68/73/70/74; efficacy 9/9%; 95% CI, 1.7%–1.4%). This may partially explain the high efficacy of the AS04-adjuvanted HPV-16/HPV-18 vaccine against CIN 3+ (87.8%; 95% CI, 71.1%–95.7%). A meta-analysis that included data from 14 high-income countries with cumulated data from more than 60 million individuals over 8 years reported an 83% decrease in prevalence of HPV-16 and HPV-18 (RR, 0.17; 95% CI, 0.11–0.25) among girls aged 13 to 19 years. There was also evidence of benefit to a more proximal cancer end point. After 5 to 9 years of HPV vaccination, decreased risk of CIN 2+ was also identified among screened girls aged 15 to 19 years (RR, 0.49; 95% CI, 0.42–0.58), and among women aged 20 to 24 years (RR, 0.69; 95% CI, 0.57–0.84) in comparison to an increase seen among screened and mostly unvaccinated women aged 25 to 29 years (RR, 1.19; 95% CI, 1.06–1.32) and aged 30 to 39 years (RR, 1.23; 95% CI, 1.13–1.34).
Data from the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2018 demonstrated an increasing impact of the HPV vaccination program and herd protection in the United States. Overall, the data demonstrated an increase in HPV vaccination coverage among sexually experienced females and males. Importantly, vaccination before age 15 years also increased from 2011 to 2014 and from 2015 to 2018 in both females (27.2%, 48.6%, respectively) and males (18.6%, 48.7%, respectively). From 2015 to 2018, the 4-valent HPV (4vHPV)-type prevalence among sexually experience females aged 14 to 24 years was 85% overall, 90% in vaccinated females, and 74% in unvaccinated females. Estimates of the vaccine's effectiveness and its impact among vaccinated females were similar from 2007 to 2010 (64% and 61%, respectively) and from 2011 to 2014 (84% and 89%, respectively). However, in 2015 to 2018, these statistics diverged (60% and 90%, respectively). This indicates that as herd protection increases and prevalence among unvaccinated individuals decreases, vaccine effectiveness can be difficult to estimate (1-prevalence ratio between vaccinated and unvaccinated individuals x 100). In 2013 to 2016, the prevalence of 4vHPV types was 1.8% in sexually experienced males who were vaccinated and 3.5% in sexually experienced males who were unvaccinated (PR, 0.49; 95% CI, 0.11–2.20), resulting in an estimated vaccine effectiveness of 51%. Significant declines were not observed in non–4vHPV-type prevalence for females or males. Although notable limitations of this survey study included self-report of HPV vaccine and dose, small sample sizes, and estimates of the impact and effectiveness based on history of at least one vaccine dose, this nationally representative data reflects an increasing impact of the U.S. vaccination program and herd protection.
Association of HPV vaccination with reduced incidence of invasive cervical cancer
In a nationwide population-based cohort study of the impact of the national vaccination program in Sweden using quadrivalent vaccine, more than 1.67 million women aged 10 to 30 years with no previous history of HPV vaccination were followed through the national registry using individual person linkage. The cumulative risk of cervical cancer by age 30 years was 47 cases per 100,000 in vaccinated women, compared with 94 cases per 100,000 in unvaccinated women (incidence rate ratio , 0.51; 95% CI, 0.32–0.82, adjusting only for age at follow-up). After adjusting for all collected potential confounding factors, the IRR for women vaccinated before age 17 years was 0.12 (95% CI, 0.00–0.34).
Use of Barrier Protection During Sexual Intercourse
Barrier methods of contraception are associated with a reduced incidence of squamous intraepithelial lesions (SIL) presumptively secondary to protection from sexually transmitted disease. The effectiveness of condom use for the prevention of HPV infections has been evaluated in a prospective study of women aged 18 to 22 years who were virgins. The number of vulvovaginal HPV infections was reduced with consistent condom use, and the HPV infection rate was 37.8 infections per 100 patient-years among women whose partners used condoms 100% of the time in the 8 months before testing, compared with 89.3 infections per 100 patient-years among women whose partners used condoms less than 5% of the time (P trend = .005). No cervical SIL were detected among women reporting 100% condom use by their partner.