Early Impact of Human Papillomavirus Vaccination on Cervical Neoplasia—Nationwide Follow-up of Young Danish Women
JNCI J Natl Cancer Inst (
e arly impact of Human Papillomavirus Vaccination on c ervical Neoplasia-Nationwide Follow-up of Young Danish Women
Christian Dehlendorff 0
Susanne K.Kjaer ) 0
0 Affiliations of authors: Virus , Lifestyle and Genes (BB-F, CM, SKK) and Statistics, Bioinformatics and Registry (CD) , Danish Cancer Society Research Center , Copenhagen , Denmark; Gynaecological Clinic, Juliane Marie Centre, Rigshospitalet, Copenhagen University Hospital , Copenhagen, Denmark (SKK)
Methods In clinical trials, vaccines against human papillomavirus (HPV) have been highly effective against HPV16- or HPV18-associated cervical lesions. The quadrivalent HPV vaccine was licensed in 2006 and subsequently implemented in the Danish vaccination program. The study aim was to use individual information on HPV vaccination status to assess subsequent risk of cervical lesions. Using a cohort study design, we identified all girls and women born in Denmark in the period from 1989 to 1999 and obtained information on individual HPV vaccination status in the period from 2006 to 2012 from nationwide registries. Incident cases of cervical lesions were identified by linkage to the nationwide Pathology Data Bank. We compared vaccinated and unvaccinated girls and women stratified by birth cohort in Cox proportional hazards models. Risk of atypia or worse (atypia+) and of cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) were statistically significantly reduced among vaccinated women in birth cohorts 1991 to 1994 (1991-1992atypia+: hazard ratio [HR]=0.46, two-sided 95% confidence interval [CI]=0.39 to 0.56; 1991-1992CIN2/3: HR=0.56, 95% CI=0.37 to 0.84; 1993-1994atypia+: HR=0.40, 95% CI=0.29 to 0.56; 1993-1994 CIN2/3: HR=0.27, 95% CI=0.10 to 0.67). The birth cohort 1989 to 1990 had a statistically significantly reduced risk of atypia+ (HR=0.75; 95% CI=0.65 to 0.86); the risk of CIN2/3 was also decreased but not statistically significant. No events occurred among girls in the birth cohort 1997 to 1999, whereas for the birth cohort 1995 to 1996 a hazard ratio could be calculated only for atypia+.
Six years after licensure of the quadrivalent HPV vaccine in Denmark, a reduced risk of cervical lesions is observed
at the population level.
Two vaccines are currently available against human papillomavirus
(HPV) (1,2), the main etiological factor for cervical cancer (3). The
bivalent vaccine contains viruslike particles of HPV types 16 and
18 (1), whereas the quadrivalent vaccine contains viruslike
particles of HPV types 6, 11, 16, and 18 (2). Both vaccines have been
shown to be highly effective against HPV16/18associated
cervical intraepithelial neoplasia grades 2 and 3 (CIN2/3) and
adenocarcinoma in situ, endpoints accepted in trials for vaccine efficacy
against cervical cancer (48). The quadrivalent HPV vaccine was
licensed in Denmark in 2006. Subsequently, the vaccine was
chosen by tender and included in the free-of-charge general childhood
vaccination program for girls aged 12 years on January 1, 2009
(birth cohort 19961997). A free-of-charge catch-up vaccination
program for girls aged 13 to 15-years was added in fall 2008 (birth
cohorts 19931995) (9). Older girls and women and boys and men
are not covered by the HPV vaccination program but can pay to
receive the vaccine.
HPV types are categorized into high risk and low risk based on
their biological properties and oncogenic potential (10). HPV16
and HPV18 are the most common high-risk types, accounting for
about 70% of all cervical cancer cases and about 50% of all CIN3
cases (10,11), whereas HPV6 and HPV11 are low-risk types
associated with nearly 90% of all genital warts cases (12). Thus, it is
estimated that HPV vaccination could prevent up to 70% of
cervical cancer cases (13,14). Because progression from infection with
a high-risk HPV to invasive cervical cancer can take decades (10),
it may be many years before the effect of HPV vaccination on the
incidence of cervical cancer can be assessed. Nevertheless, recent
ecological studies have shown a decrease in the incidence of
genital warts among young women since introduction of the vaccine
(1518). In another ecological study, Brotherton etal. (19) found a
statistically significant decrease in the incidence of high-grade
cervical lesions among girls aged less than 18years in Australia, which
began shortly after introduction of a nationally funded program for
vaccination with the quadrivalent vaccine. An important limitation
of these studies is that the data were not analyzed by individual
vaccination status. To our knowledge, data on individual
vaccination status was used in only four studies (2023) besides the studies
based on the vaccination trials. All showed a protective effect of
vaccination. However, so far no nationwide population-based study
has been published on the occurrence of cervical abnormalities in
vaccinated and nonvaccinated women based on information about
vaccination status on the individuallevel.
The aim of the study reported herein was to determine the
association between individual HPV vaccination status and subsequent
risk of cervical lesions in a nationwidestudy.
Cohort Data Collection
The study design is shown in Figure 1. In Denmark, all citizens
are assigned a unique personal identification number, which is used
throughout society, including in all health registries, and is
registered in the computerized Civil Registration System, which was
established in 1968 (24). From this system, we identified all women
born in the period from 1961 to 1999 and living in Denmark and
obtained information on their date of emigration, death, or
disappearance. To obtain information on HPV vaccination status, we
linked this cohort with the National Health Service Registry and
the Danish National Prescription Registry. The National Health
Service Registry holds data since 1990 on the activities of primary
health professionals and includes information about citizens,
providers, and health services (25). From this registry, we identified
girls who had received HPV vaccination within the general
childhood vaccination or catch-up program since it started in 2008 up
to July 1, 2011. Data on all girls and women who purchased an
HPV vaccine on prescription between October 1, 2006, and March
1, 2012 were obtained from the Danish National Prescription
Registry, which holds information on all prescription drugs sold in
Danish community pharmacies since 1994 (26) and information on
more than 90% of HPV vaccinations given outside the program.
Hence, we were able to identify almost all women in each birth
cohort who had been vaccinated and those who had not and the
date of vaccination for each vaccinated woman. We included only
birth cohorts with a vaccination coverage rate greater than 10%,
corresponding to birth cohorts 1989 to 1999. Because we examined
only the effect of the quadrivalent HPV vaccine used in the Danish
program, we excluded women who had received the bivalent
Cytology and Assessment of Outcomes
In Denmark, cervical cytology testing is recommended every third
year for women aged 23 to 49years and every fifth year for women
aged 50 to 64 years (9), but opportunistic screening is also
common. To identify cases of cervical lesions, the cohort was linked to
the nationwide Danish Pathology Data Bank, established in 1999,
which holds information on all cervical cytology (organized and
opportunistic) and all cervical biopsies and cones from all Danish
pathology departments (27). Abnormal cervical diagnoses are
usually reported as atypia, mild dysplasia, moderate dysplasia, severe
dysplasia, carcinoma in situ, or cancer. The Bethesda nomenclature
(28) is increasingly being used for cytological diagnoses, whereas
the CIN nomenclature is used for histological diagnoses, with
moderate dysplasia categorized as CIN2 and severe dysplasia and
carcinoma in situ as CIN3 (29).
We assessed three outcomes. The first, atypia or worse,
comprised cytological diagnoses of atypia or atypical squamous cells of
undetermined significance or worse. The second outcome, CIN2/3,
comprised histological diagnoses of CIN2, CIN3, carcinoma in
situ (CIS), and adenocarcinoma in situ (AIS). The third outcome,
CIN3, consisted of diagnoses of CIN3, CIS, and AIS. No
cervical cancers were detected during follow-up. To identify all cervical
lesions in the study period and before, we collected information on
all cervical examinations (cytology, biopsy, cone) undergone by the
women in our cohort registered in the Pathology Data Bank and
excluded women who had any cervical abnormalities before study
Collection of SocioeconomicData
Lastly, we investigated socioeconomic factors for vaccinees
and nonvaccinees. To obtain this information, our cohort was
linked with data from the population-based Statistics Denmark.
Socioeconomic position variables comprised mothers highest
attained education at the beginning of follow-up (basic school/
high school, vocational education, higher education, unknown) and
disposable income (categorized in tertiles).
Statistical Analysis A Cox proportional hazard regression model stratified by five birth cohorts (19891990, 19911992, 19931994, 19951996, and 1997 1999) was used to estimate hazard ratios (HRs) and corresponding
Figure1. Study design. HPV, human papillomavirus.
two-sided 95% confidence intervals (CIs) for the three outcomes
among vaccinees and nonvaccinees in each stratum. In model 1,
we included the entire cohort, on the assumption that women who
did not undergo cervical cytology during the follow-up period did
not have cervical lesions. In a more restricted model (model 2), we
included only women who had cervical cytology during
followup. Both models were fitted to the data with calendar time as the
underlying time scale. The assumption of proportional hazards was
checked by the scaled Schoenfeld residuals (ie, testing deviations
from zero slope with respect to time). Moreover, in a subset analysis,
we adjusted our risk estimates for socioeconomic position variables.
The follow-up period was from October 1, 2006, to March 1, 2012
in the Pathology Data Bank, the end date (ie, emigration or death)
in the Civil Registration System, the first abnormal examination or
the last normal examination (model 2 only), whichever occurred
first. A woman was considered as a nonvaccinee to 28 days after
the first HPV vaccination and subsequently as a vaccinee, the lag
time being included to allow the vaccine to take effect. We
nevertheless investigated the sensitivity of our results for this interval by
performing analyses with the lag time ranging from 7days after the
first vaccination until the second dose was usually given (60days).
P values of less than .05 were considered statistically significant,
and all statistical tests were two-sided. The statistical software
program R version 2.15.1 was used (30). The study was approved by
the Danish Data Protection Agency, and written informed consent
from individuals in the cohort was not required.
From the Civil Registration System, we identified 399 244 Danish
women in the birth cohorts 1989 to 1999. Characteristics of this
population are shown in Table1. Atotal of 247 313 (62%) women
were vaccinated during the period. The vaccination coverage was
high (>85%) in the youngest birth cohorts of 1993 to 1999, which
were included in the childhood and catch-up vaccination program,
and much lower in the birth cohorts not covered by the program
(19891990: 14%; 19911992: 27%). The total number of events
was 3629 for atypia or worse, 708 for CIN2/3, and 365 for CIN3.
The women constituting the study population contributed more
than 2 million person-years of follow-up in the analysis for each
outcome. Overall, the event rate for atypia or worse was 2.4 times
higher among unvaccinated women (0.22%) than among
vaccinated women (0.09%) and that for CIN2/3 and CIN3 were both
increased twice (nonvaccinees: 0.04%; vaccinees: 0.02%;
nonvaccinees: 0.02%; vaccinees: 0.01%, respectively). Screenings rates
for nonvaccinees and vaccinees were estimated separately using
the respective number of screenings records and person-years.
Subsequently we calculated screenings rate ratios (RRs) by
dividing the screenings rates of vaccinees by that of the nonvaccinees
and found that in all birth cohorts, vaccinees had higher screenings
rates than nonvaccinees (19891990: RR=1.55, 95% CI=1.48 to
1.63, P < .001; 19911992: RR=1.22, 95% CI=1.14 to 1.30, P <
.001; 19931994: RR=3.75, 95% CI=3.25 to 4.33, P < .001; 1995
1996: RR = 8.87, 95% CI = 5.19 to 15.13, P < .001; 19971999:
RR=17.03, 95% CI=1.99 to 143.76, P=.005).
Table2 shows the hazard ratios for cervical lesions among
vaccinated women compared with unvaccinated women in the birth
cohorts in the two models. There were too few events in birth cohort
1995 to 1996 to estimate hazard ratios for CIN2/3 or for CIN3,
and hazard ratios could not be calculated for any outcome for the
birth cohorts 1997 to 1999 because there were no events. In model
1 (Table2), the risk of atypia or worse was statistically significantly
lower among vaccinated women in the birth cohorts 1989 to 1994
(19891990: HR=0.75, 95% CI=0.65 to 0.86, P < .001; 19911992:
Atypia or worse
* Vaccination status attained at end of follow-up.
CIN2/3 = cervical intraepithelial neoplasia grade 2 or 3.
11 243 (14.3)
19 867 (26.7)
63 922 (88.1)
63 912 (89.8)
Screened population 7718 3412
Atypia or worse
HR (95% CI)
0.75 (0.65 to 0.86)
0.46 (0.39 to 0.56)
0.40 (0.29 to 0.56)
0.43 (0.16 to 1.12)
HR (95% CI)
HR (95% CI)
HR=0.46, 95% CI=0.39 to 0.56, P < .001; 19931994: HR=0.40,
95% CI=0.29 to 0.56, P < .001). The risk was also reduced for the
birth cohort 1995 to 1996, but the result was not statistically
significant. The risk for CIN2/3 was statistically significantly reduced
among vaccinees in the birth cohorts 1991 to 1994 (19911992:
HR=0.56, 95% CI=0.37 to 0.84, P=.005; 19931994: HR=0.27,
95% CI=0.10 to 0.67, P=.005). For birth cohort 1989 to 1990, we
found a reduced risk of 0.88, which was not statistically significant.
The results for CIN3 were similar to those for CIN2/3. However,
only the result for birth cohort 1993 to 1994 reached statistical
significance (HR=0.20, 95% CI=0.06 to 0.71, P=.01).
When we restricted the analysis to women who had cervical
cytology during follow-up, we still found statistically significantly
reduced risks for atypia or worse among all vaccinees, except for
those in the birth cohort 1995 to 1996, for whom the reduction
was not statistically significant (Table3). The risks for CIN2/3 and
for CIN3 were reduced for all birth cohorts 1989 to 1994, but only
the hazard ratio for the birth cohorts 1993 to 1994 reached
statistical significance (HRCIN2/3=0.33, 95% CI=0.13 to 0.83, P=.02;
HRCIN3=0.25, 95% CI=0.07 to 0.90, P=.03).
Mothers highest attained education and disposable income
are shown for vaccinees and nonvaccinees in Table 4. In all birth
cohorts, mothers of vaccinees had higher education and higher
disposable income compared with mothers of nonvaccinees, although
the difference was reduced in the youngest birth cohorts. However,
when we adjusted for the socioeconomic position variables, this did
not substantially alter the results (ie, the magnitude of the risk
estimates was virtually unchanged) (data not shown).
In the main analyses, we started the counting of outcomes among
vaccinated women 28days after the first dose. Because this is an
arbitrary cutpoint, we also estimated the hazard ratios using other
cutpoints (in the range 760days). The effect of vaccination was virtually
unchanged by time between first dose and time of counting cases of
cervical lesions when we started counting outcomes in vaccinated
women 7 to 60days after vaccination, and the results were similar in
the two models. Therefore, the risk of cervical lesions of vaccinated
girls was decreased in all birth cohorts (most reaching statistical
significance), regardless of the length of the interval (data not shown).
We found a protective effect of the quadrivalent HPV vaccine
against cervical precursor lesions among women in the Danish
birth cohorts 1989 to 1999. Among women who received at least
one dose of vaccine, the risk for atypia or worse was statistically
significantly reduced by up to 60%, and the risks for CIN2/3 and
CIN3 were statistically significantly reduced by up to 80%, when
compared with nonvaccinees. Thus, our results indicate that the
quadrivalent vaccine already offers good protection against cervical
precursor lesions in this population.
For all outcomes in both models, we found the greatest risk
reduction in the younger birth cohorts. These results are
comparable with those for cervical lesions in the quadrivalent HPV
vaccination clinical trials FUTURE Iand II (4,6,7,31). In those trials,
women were divided into three cohorts. The most restrictive was
an according to protocol population, which comprised of women
without HPV6/11/16/18 during the vaccination regimen, who
received all three doses of vaccine or placebo and did not violate the
protocol; the unrestricted susceptible population was comprised
of women with no cervical cytological abnormalities at baseline
and no HPV6/11/16/18 on day one; and the intention-to-treat
population was comprised of all women in the trials, including
those with prevalent HPV. Although we did not have information
on sexual debut or HPV status in our study, it is probable that the
youngest birth cohorts had limited exposure to HPV and were thus
comparable with the according to protocol or the unrestricted
susceptible population, whereas our older birth cohorts were
comparable with the intention-to-treat group. The clinical trials showed
a vaccine efficacy of 97% to 100% against all HPV16/18related
cervical lesions among women in the according to protocol and
unrestricted susceptible population groups (4,6,7,31), whereas the
efficacy against HPV16/18related CIN2 or worse was lower in the
intention-to-treat population (44%) (4,6). The results for vaccine
efficacy against all CIN2/3 and adenocarcinoma in situ, regardless
of causal HPV type, are comparable with our results, especially for
CIN2/3 and CIN3. The clinical trials showed a vaccine efficacy of
approximately 43% against CIN2 and CIN3 in the unrestricted
susceptible population, whereas the overall reduction in risk for
CIN2 or worse due to any HPV type was approximately 18% in the
intention-to-treat population (4,6). The lower efficacy of the
vaccine in the intention-to-treat population was attributed to the fact
that some women had prevalent HPV16/18 infection. In
comparison, we found a risk reduction against CIN2/3 of 73% and 44% for
birth cohorts 1993 to 1994 and 1991 to 1992, respectively, and 80%
and 36% against CIN3, whereas the risk reduction for birth cohort
1989 to 1990 was 12% against CIN2/3 and 22% against CIN3.
Atypia or worse
HR (95% CI)
0.75 (0.66 to 0.86)
0.64 (0.53 to 0.77)
0.47 (0.34 to 0.65)
0.63 (0.25 to 1.61)
HR (95% CI)
HR (95% CI)
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However, it should be noted that some of our estimates had quite
wide confidence intervals and not all reached statistical
significance. As in the trials, we believe that the smaller risk reduction
in our older birth cohorts was probably because of a higher
prevalence of HPV16/18 infection before vaccination.
The lower risk for cervical lesions among HPV-vaccinated
women in our study is almost certainly due to a reduced risk for
HPV16/18 lesions, although we had no information on the HPV
types responsible for the cervical lesions detected. Our results agree
with those of two other studies with individual data on vaccination
status (20,21). On the basis of preliminary data, Powell etal. (21)
reported that women with a diagnosis of CIN2 or worse who had
initiated HPV vaccination more than 2years before the abnormal
Pap test that triggered the diagnosis had a statistically significantly
lower risk for HPV16/18related CIN2 or worse. In a study with
a repeat cross-sectional design, Tabrizi etal. (20) found a
statistically significant decrease in the prevalence of HPV6/11/16/18 after
introduction of a national HPV vaccination program in Australia.
Although those authors investigated HPV prevalence and not
cervical neoplasia, their studies are comparable with ours because a
reduced prevalence of HPV16/18 is a good proxy for a reduced
risk for future cervical lesions (11). Both previous studies had some
limitations, however, such as use of preliminary data only, few
study subjects, and mainly self-reported information on
The results of our population-based study are also in agreement
with those of Rana etal. (32), who followed up 1749 Finnish
participants in the FUTURE II trial (874 vaccinated, 875
placebo-vaccinated) in the Finnish Cancer Registry and compared them with
an unvaccinated cohort of 15 719 women. They found no cases of
CIN3 or cervical cancer among the vaccinees, three cases of CIN3
among the placebo vaccinees (incidence rate=87.1 per 100 000),
and 59 cases of CIN3 and 3 cancer cases among the nonvaccinees
(incidence rate = 93.8 per 100 000). The authors concluded that
long-term surveillance by passive follow-up in a cancer registry is
feasible and will establish the efficacy of HPV vaccination against
cervical cancer within the next 5 to 10years. Our study supports
this conclusion because our results already show a reduced risk for
precursor lesions among vaccinees.
The main strength of our study is that it covers the entire female
Danish population in the birth cohorts 1989 to 1999, resulting in
reasonable statistical power. Another strength was our ability to
make precise linkages of our cohort with several unique
population-based registries. Thus, all cervical lesions were identified and
included, almost all vaccinees were identified, no women were lost
to follow-up, and we could exclude women who had cervical lesions
before HPV vaccination.
One limitation of our study is that we had no information on the
womens HPV status or sexual history at enrollment or on the HPV
types responsible for the cervical lesions. The aim of this study was
not, however, to investigate HPV16/18specific lesions in
HPVnaive women but rather to assess any reduction in disease burden
at general population level. Another weakness was the moderate
number of outcome cases and the small proportion of screened
women, with only 12 188 women examined among approximately
400 000 women in the investigated birth cohorts. Nevertheless, risk
estimates for the restricted model 2 confirmed the conclusion from
model 1 because the estimates were quite similar. The most
important limitation of our study is the possibility of self-selection bias
due to inclusion of women not covered by the vaccination program.
Socioeconomic position of the mothers could be a marker of this
self-selection bias because mothers of vaccinees, especially in the
older birth cohorts, generally had a higher socioeconomic position.
However, the adjustment for socioeconomic position virtually did
not change our results. Furthermore, because women in Denmark
are advised to undergo cervical cytology only from the age of 23,
only women in the birth cohort 1989 could have been examined
within the national screening program, but it is well known that
opportunistic screening is common in Denmark. Women may have
gynecological examinations and cytological tests before the age
of 23 (eg, because of an early sexual debut, having several sexual
partners, or having symptoms of cervical infections or neoplasia).
Therefore, the women who were screened may have differed from
those who were not screened by having another risk for cervical
neoplasia. Thus, it is possible that the effect of the quadrivalent
vaccine would be different in women with higher- or lower-risk
behavior. Lastly, a bias would have been introduced if the vaccinees
were screened less frequently than nonvaccinees; however, in all
birth cohorts, we found higher screening rates among vaccinees
compared with nonvaccinees. In conclusion, our results show that
vaccination with the quadrivalent HPV vaccine is already effective
in reducing the risk for cervical precursor lesions at population
level among young women in Denmark.
This work was supported by the Mermaid project (MERMAID 2).
The sponsor of the study had no role in the study design, data collection, data
analysis, data interpretation or writing the report. The corresponding author had
full access to all the data and had final responsibility for the decision to submit
S.K. Kjaer received scientific advisory board and speakers fees and research
grants through her institution from Sanofi Pasteur MSD and Merck and
scientific advisory board fee from Roche. C.Munk received travel and speakers
fees from Sanofi Pasteur MSD. The other authors report no potential conflict
of interest. We thank Thor Schtt Svane Nielsen for data management assistance and Kirsten Frederiksen for comments and advice on the statistical analysis.
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