T h e n e w e ng l a n d j o u r na l o f m e dic i n e

Original Article

HPV Vaccination and the Risk of Invasive
Cervical Cancer
Jiayao Lei, Ph.D., Alexander Ploner, Ph.D., K. Miriam Elfström, Ph.D.,
Jiangrong Wang, Ph.D., Adam Roth, M.D., Ph.D., Fang Fang, M.D., Ph.D.,
Karin Sundström, M.D., Ph.D., Joakim Dillner, M.D., Ph.D.,
and Pär Sparén, Ph.D.​​

A BS T R AC TBACKGROUND
From the Departments of Medical Epide­miology and Biostatistics (J.L., A.P., P.S.)
and Laboratory Medicine (K.M.E., J.W.,
K.S., J.D.) and the Institute of Environ­mental Medicine (F.F.), Karolinska In­
stitutet, the Regional Cancer Center
Stockholm Gotland (K.M.E.), and the
Karolinska University Laboratory, Karo­linska University Hospital (J.D.), Stock­holm, the Department of Communicable
Disease Control and Health Protection,
Public Health Agency of Sweden, Solna(A.R.), and the Department of Transla­
tional Medicine, Lund University, Lund
(A.R.) — all in Sweden. Address reprint
requests to Dr. Lei at Nobels väg 12A, 171
65 Solna, Sweden, or at ­jiayao​.­lei@​­ki​.­se.

The efficacy and effectiveness of the quadrivalent human papillomavirus (HPV)
vaccine in preventing high-grade cervical lesions have been shown. However, data
to inform the relationship between quadrivalent HPV vaccination and the subsequent risk of invasive cervical cancer are lacking.

N Engl J Med 2020;383:1340-8.
DOI: 10.1056/NEJMoa1917338

During the study period, we evaluated girls and women for cervical cancer until
their 31st birthday. Cervical cancer was diagnosed in 19 women who had received
the quadrivalent HPV vaccine and in 538 women who had not received the vaccine.
The cumulative incidence of cervical cancer was 47 cases per 100,000 persons
among women who had been vaccinated and 94 cases per 100,000 persons among
those who had not been vaccinated. After adjustment for age at follow-up, theincidence rate ratio for the comparison of the vaccinated population with the unvaccinated population was 0.51 (95% confidence interval [CI], 0.32 to 0.82). After
additional adjustment for other covariates, the incidence rate ratio was 0.37 (95%CI, 0.21 to 0.57). After adjustment for all covariates, the incidence rate ratio was
0.12 (95% CI, 0.00 to 0.34) among women who had been vaccinated before the ageof 17 years and 0.47 (95% CI, 0.27 to 0.75) among women who had been vaccinated at the age of 17 to 30 years.

Copyright © 2020 Massachusetts Medical Society.

METHODS

We used nationwide Swedish demographic and health registers to follow an open
population of 1,672,983 girls and women who were 10 to 30 years of age from2006 through 2017. We assessed the association between HPV vaccination and therisk of invasive cervical cancer, controlling for age at follow-up, calendar year,
county of residence, and parental characteristics, including education, householdincome, mother’s country of birth, and maternal disease history.
RESULTSCONCLUSIONS

Among Swedish girls and women 10 to 30 years old, quadrivalent HPV vaccination
was associated with a substantially reduced risk of invasive cervical cancer at the
population level. (Funded by the Swedish Foundation for Strategic Research andothers.)1340

n engl j med 383;14

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HPV Vaccination and the Risk of Cervical CancerT

he ultimate goal of human papillomavirus (HPV) vaccination is to prevent
invasive cervical cancer by preventing infection with major oncogenic types of HPV.1 Asof December 2019, a total of 124 countries andterritories had implemented national immunization programs for HPV vaccination.2 In Sweden,
HPV vaccination was approved in 2006, and thequadrivalent HPV vaccine, which covers HPV
types 6, 11, 16, and 18, has been used almost
exclusively.3
Previous studies of HPV vaccines, including
randomized trials that assessed efficacy4-6 or effectiveness,7-13 have shown that these vaccinesprotect against HPV infection, genital warts, andhigh-grade precancerous cervical lesions (i.e.,
cervical intraepithelial neoplasia of grade 2 orhigher [CIN2+] and grade 3 or higher [CIN3+]).
One study — which used pooled data from passive follow-up of two randomized, controlled
trials and from one community-randomized,
phase 4 trial — showed efficacy of HPV vaccination against HPV-related cancers, although thenumber of cancers was small (10 cases), and thecancer types were not limited to cervical cancers.14 Randomized, controlled trials cannot
readily evaluate vaccine effectiveness against invasive cervical cancer because of the long leadtime (the time from HPV infection to the clinicaldetection of cervical cancer) and the low risk ofcervical lesions after vaccination. We used nationwide registry data from Sweden to examine theassociation between HPV vaccination and therisk of invasive cervical cancer.

Me thods
Study Population

Beginning in May 2007, HPV vaccination was
subsidized for girls in Sweden who were 13 to
17 years of age. In 2012, Sweden introduced afree catch-up HPV vaccination program for girls
and women 13 to 18 years of age and a schoolbased HPV vaccination program for girls 10 to 12
years of age.3 Currently, women 23 to 64 years ofage are invited to participate in the populationbased, organized cervical cancer screening program, which issues invitations every 3 to 7 years
to women depending on their age.15
We used the Swedish Total Population Register to perform a registry-based cohort study fromn engl j med 383;14

2006 through 2017 that included an open population of girls and women 10 to 30 years of age
who were living in Sweden (Fig. 1).16 Information regarding the registries used in this study isprovided in the Supplementary Appendix, available with the full text of this article at NEJM.org.
Girls and women were followed starting either on their 10th birthday or on January 1, 2006,
whichever came later. Girls and women were
included if they had no previous HPV vaccination, had no previous invasive cervical cancer,
and had not immigrated to Sweden after January 1,
2006 (because the HPV vaccination status before
immigration would have been unknown). Alleligible girls and women were followed until
they received a diagnosis of invasive cervicalcancer, emigrated from Sweden, died, were lostfrom the registry, received bivalent HPV vaccination, or had their 31st birthday or until December 31, 2017, whichever came first. This study
was approved by the regional ethical review
board in Stockholm, which determined that informed consent from the persons included in the
study was not required.
Data Collection

The nationwide Swedish registers that we usedin this study were linked at the individual levelwith the use of the unique personal identity
number that is assigned to all Swedish residents,
which resulted in virtually complete coverage ofthe population.17 The Swedish Total Population
Register16 was used to identify the population atrisk and to retrieve information on immigration,
emigration, and death. Exposure to quadrivalent
HPV vaccination was determined with the use of
HPV vaccination records retrieved from the Swedish HPV Vaccination Register,18 the Prescribed
Drug Register,19 and the National Vaccination
Register20 (Fig. S2 in the Supplementary Appendix). A vaccination recorded in any of theseregistries was considered to be vaccine exposure.
The Swedish HPV Vaccination Register is a voluntary registry that has been in operation since2006 and has recorded all HPV vaccinations thatwere administered from 2006 through 2015.18
The Prescribed Drug Register19 has been in operation since 2005 and is a mandatory registryof dispensed pharmaceuticals; all quadrivalent
HPV vaccinations administered within a governmentally subsidized program from 2007 throughnejm.org

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T h e n e w e ng l a n d j o u r na l o f m e dic i n e

2,220,268 Swedish girls and women 10–30 yr
of age were included in the source population
between January 1, 2006, and December 31, 2017

538,824 Were excluded
439,699 Immigrated to Sweden afterJanuary 1, 2006
5,447 Died before January 1, 2006
89,960 Emigrated before January 1, 2006
3,638 Were lost from the registry before
January 1, 2006
80 Received diagnosis of invasive
cervical cancer before January 1, 2006

1,681,444 With no previous invasive cervicalcancer were living in Sweden on January 1, 2006

8461 Were excluded
561 Died before start of follow-up
7736 Emigrated before start of follow-up
72 Were lost from the registry before startof follow-up
1 Was vaccinated with bivalent vaccine
before start of follow-up
91 Were vaccinated with quadrivalent HPV
vaccine before 10 yr of age

1,672,983 With no previous HPV vaccination andno previous diagnosis of invasive cervical cancer
were included in the study population

527,871 Received at least one doseof quadrivalent HPV vaccine
during follow-up

1,145,112 Did not receive HPV vaccine
during follow-up

19 Received diagnosis of cervical cancer
during follow-up
308 Died
3,484 Emigrated
3 Were lost from the registry
5,738 Had 31st birthday
518,319 Were included in the study population
at the end of follow-up
on December 31, 2017

538 Received diagnosis of cervical cancer
during follow-up
2,348 Died
28,056 Emigrated
87 Were lost from the registry583,881 Had 31st birthday
1,855 Received bivalent HPV vaccine
528,347 Were included in the study population
at the end of follow-up
on December 31, 2017

Figure 1. Study Population.
HPV denotes human papillomavirus.

2012 were identified in this registry with theuse of Anatomical Therapeutic Chemical code
J07BM01. The National Vaccination Register20 isa mandatory registry of childhood vaccinations
that began in 2013 and has virtually complete
coverage for the school-based HPV vaccination
program. Administered doses of vaccine includ1342

n engl j med 383;14

ed in the Swedish HPV Vaccination Register forwhich consent was not obtained were recorded
without the personal identity number. Althoughmost vaccinations were also recorded in the Prescribed Drug Register, approximately 8% of administered quadrivalent HPV vaccine doses in
the Swedish HPV Vaccination Register could not

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HPV Vaccination and the Risk of Cervical Cancer

be confirmed in another database (Table S1).
The occurrence of invasive cervical cancer andthe date of diagnosis were identified in the
Swedish Cancer Register (a compulsory reporting registry founded in 1958 that covers the entire population)21 with the use of code C53 in theInternational Classification of Diseases, 10th Revision.
We identified the biologic and adoptive parents for each study participant through theMulti-Generation Register,22 which contains information on familial links for persons born in
Sweden from 1932 onward. We used the Longitudinal Integration Database for Health Insurance and Labor Market Studies,23 the Swedish
Cancer Register, and the Total Population Register to retrieve data regarding parental characteristics, including mother’s country of birth, highest parental education level, annual householdincome level, maternal history of CIN3+, andmaternal history of cancers other than cervicalcancer (a history of these cancers might affectboth vaccine uptake and the risk of cervical cancer). All covariates were measured as fixed values before the start of follow-up.
HPV Vaccination

Since 2006, the quadrivalent HPV vaccine has
been administered according to a three-dose vaccination schedule; from 2015 onward, a twodose schedule has been used for school-based
vaccination programs. We considered HPV vaccination as a time-varying exposure, and girls
and women were considered to have been vaccinated if they received at least one dose of quadrivalent HPV vaccine (Table S2). The index dateof vaccination was defined as the date the firstdose of vaccine was administered. Girls andwomen who were vaccinated during follow-up
were moved to the vaccinated population beginning on the index date of vaccination. If no vaccine was received during the study period, participants continued to contribute to person-timein the unvaccinated population (Fig. S3). Because
no HPV vaccination was available before 2006,
our design ensured that the comparison was
between persons who received the vaccine forthe first time and those who had never been vaccinated. The age at initiation of vaccination wasassessed with the use of two age cutoffs (vaccination before 17 years of age and vaccination
before 20 years of age) on the basis of previous
work that showed that initiation of vaccine at an engl j med 383;14

younger age was associated with greater effectiveness in preventing genital warts and highgrade precancerous cervical lesions.10-13
Sensitivity Analyses

We included an interaction term between thevariables of HPV vaccination and birth cohort totest whether the risk reduction with vaccination
varied among birth cohorts because of different
degrees of vaccination coverage. The purpose ofthis analysis was to examine whether herd effects (in addition to individual-level, vaccinationderived effects) might be present in our data.
Further, to exclude possible prevalent cervicalcancers at the date of HPV vaccination, we useda buffer period of 1 to 5 years at 1-year intervals
after the index date of HPV vaccination (Figs. S4and S5). Finally, we used multiple imputation toaddress the missing covariate data.
Statistical Analysis

We estimated the statistical power for the comparison of incidence rates among unvaccinatedand vaccinated girls and women before performing the analysis (Table S3). The median power
for this comparison in all assumed scenarios
was 0.94 (range, 0.43 to 1.00), which corresponds to an assumed vaccine coverage of 30%,
an assumed risk reduction of 70% in the vaccinated population, an incidence rate in the unvaccinated population of 4 per 100,000 person-years,
and no herd effect for 1 year of follow-up of 1.5
million persons, without censoring of data.
The cumulative incidence of cervical cancer
according to HPV vaccination status was plotted
according to age at follow-up. Incidence rates ofcervical cancer were estimated for girls andwomen until their 31st birthday. We used Poisson regression models to estimate incidence rate
ratios, comparing the incidence rate among vaccinated women with that among unvaccinatedwomen. We report 95% bootstrap confidence
intervals of the incidence rate ratios based on
bias-corrected percentiles from 2000 bootstrap
replications. We used age at follow-up as theunderlying timescale, controlling for age duringfollow-up (as a spline term with 3 degrees of
freedom), calendar year, county of residence,and parental characteristics. Missing values were
included as separate strata in the corresponding
covariate. Separate Poisson models were fitted toestimate the overall incidence rate ratio for quad-

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T h e n e w e ng l a n d j o u r na l o f m e dic i n eTable 1. Characteristics of the Study Population at Baseline.*
UnvaccinatedVaccinatedVaccinated before
Age 17 Yr

Vaccinated before
Age 20 Yr

1,145,112

527,871438,939498,524

1975–1979

258,244 (22.6)

190 (<0.1)

00

1980–1984

243,776 (21.3)

2,602 (0.5)

01985–1989

246,446 (21.5)

21,763 (4.1)

4 (<0.1)

Variable

Total population — no.
Birth cohort — no. (%)

04,604 (0.9)

1990–1994

174,458 (15.2)

117,758 (22.3)

61,683 (14.1)

108,409 (21.7)

1995–1999

100,162 (8.7)

129,796 (24.6)

121,585 (27.7)

129,749 (26.0)

2000–2007

122,026 (10.7)

255,762 (48.5)

255,667 (58.2)

255,762 (51.3)

Sweden882,560 (77.1)

448,652 (85.0)

373,292 (85.1)

424,223 (85.1)

Other country

195,601 (17.1)

77,810 (14.7)

64,673 (14.7)

73,094 (14.7)

Missing data‡

66,951 (5.8)

1,409 (0.3)

974 (0.2)

1,207 (0.2)

84,301 (7.4)

14,107 (2.7)

11,087 (2.5)

12,997 (2.6)

Mother’s country of birth — no. (%)†

Highest parental education level — no. (%)†§
Low
Middle528,999 (46.2)

206,050 (39.0)

169,608 (38.6)

195,522 (39.2)

High467,543 (40.8)

307,002 (58.2)

257,808 (58.8)

289,407 (58.1)

Missing data‡

64,269 (5.6)

712 (0.1)

436 (<0.1)

598 (0.1)

Highest annual household income level— no. (%)†¶
Low

204,079 (17.8)

69,323 (13.1)

57,651 (13.1)

65,871 (13.2)

Middle429,852 (37.5)

204,812 (38.8)

173,234 (39.5)

195,639 (39.2)

High446,765 (39.1)

253,337 (48.0)

207,812 (47.3)

236,718 (47.5)

Missing data‡

64,416 (5.6)

399 (0.1)

242 (0.1)

296 (0.1)

Yes

50,217 (4.4)

21,085 (4.0)

17,227 (3.9)

19,681 (3.9)

No

1,094,895 (95.6)

506,786 (96.0)

421,712 (96.1)

478,843 (96.1)

Maternal history of CIN3+ — no. (%)‖

Maternal history of noncervical cancer — no. (%)‖
Yes

47,293 (4.1)

13,570 (2.6)

10,730 (2.4)

12,404 (2.5)

No

1,097,819 (95.9)

514,301 (97.4)

428,209 (97.6)

486,120 (97.5)*	Percentages may not total 100 because of rounding.
†	When data were available for both biologic and adoptive parents, data from the adoptive parents were used.
‡	Missing data for mother’s country of birth, highest parental education level, and highest annual household income level were classified as aseparate stratum and were included in the regression model.
§	The highest parental education level was assessed in the year before the start of follow-up and was classified as “low” if the parent had 9 years
or less of primary education, “middle” if the parent had 2 to 3 years of secondary schooling (similar to senior high school), and “high” if theparent had postsecondary education and above (equivalent to university studies).
¶	The highest annual household income level was assessed in the year before the start of follow-up and was categorized as “low” if it was be­
low the 33rd percentile, “middle” if was from the 33rd to the 67th percentile, and “high” if it was above the 67th percentile, determined on
the basis of three levels of annual household income derived from data for all Swedish persons 35 to 65 years of age in the year that income
was assessed.
‖	Maternal history of CIN3+ (cervical intraepithelial neoplasia of grade 3 or worse) and noncervical cancer were considered to be a diagnosisof the disease at any time before the start of follow-up. When data were available for both a biologic and an adoptive mother, a maternal
diagnosis of CIN3+ or a diagnosis of noncervical cancer was recorded if both the biologic mother and the adoptive mother had the corre­
sponding disease.

1344

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HPV Vaccination and the Risk of Cervical Cancer

Table 2. HPV Vaccination and Invasive Cervical Cancer.
No. of Cases ofCervical Cancer

Crude Incidence Rateper 100,000 Person-Yr(95% CI)

Age-Adjusted Incidence
Rate Ratio(95% CI)

Adjusted Incidence
Rate Ratio(95% CI)*

Unvaccinated538

5.27 (4.84–5.73)

Reference

Reference

Vaccinated19

0.73 (0.47–1.14)

0.51 (0.32–0.82)

0.37 (0.21–0.57)

Vaccinated before age 17 yr

20.10 (0.02–0.39)

0.19 (0.05–0.75)

0.12 (0.00–0.34)

Vaccinated at age 17–30 yr

17

3.02 (1.88–4.86)

0.64 (0.39–1.04)

0.47 (0.27–0.75)

Vaccinated before age 20 yr

120.49 (0.28–5.73)

0.52 (0.29–0.94)

0.36 (0.18–0.61)

Vaccinated at age 20–30 yr

7

5.16 (2.46–10.83)

0.50 (0.24–1.06)

0.38 (0.12–0.72)

HPV Vaccination Status

Status according to age cutoffof 17 yr

Status according to age cutoffof 20 yr*	The adjusted incidence rate ratios were adjusted for age as a spline term with 3 degrees of freedom, county of residence, calendar year,
mother’s country of birth, highest parental education level, highest annual household income level, previous diagnosis in mother of CIN3+,
and previous diagnosis in mother of cancers other than cervical cancer. The 95% confidence intervals were bias-corrected percentile confi­
dence intervals that were estimated with the use of bootstrapping with a resampling frequency of 2000 times.

rivalent HPV vaccination as well as separate incidence rate ratios for age at initiation of vaccination. We used SAS software, version 9.4 (SASInstitute), for data management and power calculation and Stata software, version 15.0 (StataCorp), and R software, version 3.6.3 (R Foundation for Statistical Computing), for all otherstatistical analyses. All statistical tests were
two-sided. Additional details regarding statistical methods are provided in the Supplementary
Appendix.

R e sult s
Study Population

Our study population included 1,672,983 girls
and women 10 to 30 years of age, 527,871 ofwhom received at least one dose of HPV vaccine
during the study period (Table 1). Among all
vaccinated girls and women included in the
study population, 438,939 (83.2%) initiated vaccination before the age of 17 years. During thestudy period, cervical cancer was diagnosed in
19 women who had received the quadrivalent
HPV vaccine and in 538 women who had notreceived the vaccine (Table 2).
HPV Vaccination and Cervical Cancer

The cumulative incidence of cervical cancer increased rapidly at 23 years of age among bothn engl j med 383;14

vaccinated and unvaccinated women; this is theage when Swedish women are first invited toparticipate in the cervical cancer screening program. The cumulative incidence among unvaccinated women rose sharply to 94 cases per
100,000 persons by 30 years of age, whereas the
cumulative incidence among vaccinated women
was 47 cases per 100,000 persons by 30 years ofage. Among women who had initiated vaccination at the age of 17 to 30 years, the cumulative
incidence was 54 cases per 100,000 persons by
the age of 30 years. Among women who had
initiated vaccination before the age of 17 years,
the cumulative incidence was 4 cases per 100,000
persons by the age of 28 years (Fig. 2).
After adjustment for age at follow-up, the incidence rate ratio for the comparison of vaccinated women with unvaccinated women was
0.51 (95% confidence interval [CI], 0.32 to 0.82).
After additional adjustment for calendar year
and residential and parental characteristics, theincidence rate ratio was 0.37 (95% CI, 0.21 to0.57) (Table 2). With stratification according toage at initiation of vaccination, the fully adjusted
incidence rate ratios for cervical cancer among
women who had been vaccinated before the ageof 17 years and women who had been vaccinatedbetween the ages of 17 and 30 years were 0.12
(95% CI, 0.00 to 0.34) and 0.47 (95% CI, 0.27 to0.75), respectively. The fully adjusted incidence

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T h e n e w e ng l a n d j o u r na l o f m e dic i n e

HPV Vaccination Status

Cumulative Incidence of Cervical
Cancer per 100,000 Persons

100

UnvaccinatedVaccinated at 17–30 yr of age
Vaccinated <17 yr of age

75

50

25

0

18

20

22

24

26

28

30

Age at Follow-up (yr)Figure 2. Cumulative Incidence of Invasive Cervical Cancer According to HPV
Vaccination Status.
Age at follow­up is truncated in the graph because no cases of cervical can­cer were observed in girls younger than 18 years of age.

rate ratio was 0.36 (95% CI, 0.18 to 0.61) among
women who had been vaccinated before the ageof 20 years and 0.38 (95% CI, 0.12 to 0.72)
among women who had been vaccinated between the ages of 20 and 30 years.
Sensitivity Analysis

We did not find a significant difference in risk
reductions associated with HPV vaccination
among birth cohorts (Table S4). With the introduction of a buffer period, the risk of cervicalcancer among HPV-vaccinated women remained
consistently lower than that among unvaccinated women (Table S5). With the use of a 5-yearbuffer period, the risk reduction among HPVvaccinated women appeared more pronounced
than that among unvaccinated women: 8 casesof cervical cancer were diagnosed in vaccinatedwomen, and 549 cases were diagnosed in unvaccinated women. After multiple imputation, theestimated incidence rate ratios were almost identical to those in the main analysis (Table S6).

Discussion
In this population-based cohort study, we foundthat quadrivalent HPV vaccination was associated with a substantially lower risk of invasive
cervical cancer. When the analysis was stratified
according to age at vaccination, the reduction in1346

n engl j med 383;14

the incidence of invasive cervical cancer was
more pronounced among women who were vaccinated at a younger age.
Although the efficacy 4-6 and effectiveness7-13of the HPV vaccination against HPV infection,
genital warts, and high-grade cervical lesions(CIN2+ and CIN3+) have been established, ourresults extend this knowledge base by showingthat quadrivalent HPV vaccination is also associated with a substantially reduced risk of invasive
cervical cancer, which is the ultimate intent of
HPV vaccination programs. The greater risk reduction associated with younger age at initiationof vaccination is consistent with previous findings that showed a lower risk of genital warts
and high-grade cervical lesions with HPV vaccination.10-13 Our results also support the recommendation to administer quadrivalent HPV vaccine before exposure to HPV infection to achieve
the most substantial benefit, since vaccination
has no therapeutic effect against preexisting HPV
infection.24,25
Our findings are consistent with limited trial
data14 and with data from a previous ecologic
study.26 A study involving passive follow-up ofparticipants in HPV vaccine trials that used theFinnish Cancer Registry showed no HPV-related
cancers in vaccinated women, but there were 10
cases of HPV-related invasive carcinomas in unvaccinated women (including 8 cases of cervicalcancer), which corresponds to 100% (95% CI, 16 to100) vaccine efficacy.14 A study from the UnitedStates showed a significantly lower incidence of
cervical cancer among girls and women 15 to 34
years of age during the postvaccination period
than during the prevaccination period.26
We found that the risk of cervical cancer
among participants who had initiated vaccination before the age of 17 years was 88% lower
than among those who had never been vaccinated; the 95% confidence interval around therelative risk indicated that the plausible risk was
66 to 100% lower with vaccination. The overall
percentage of cases of cervical cancer caused by
HPV types 16 and 18 is approximately 70% globally,27 but the distribution of HPV types may bedifferent among younger women than amongolder women. We conducted an unpublished reanalysis of our previously published results inwhich we used HPV genotyping of 2850 cervicalcancer tumors; the analysis showed that 84.4%

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HPV Vaccination and the Risk of Cervical Cancerof invasive cervical cancers diagnosed in persons
30 years of age or younger were associated with
HPV types 16 or 18 (Table S7).28 It is also possible that the vaccine results in cross-protection
against other HPV types.29
Unvaccinated persons would indirectly benefit from HPV vaccination if vaccination coverageof girls and women in a population exceeds
50%.7 A herd effect of HPV vaccination against
genital warts has been observed previously in
the Swedish population.30 A vaccination coverageof at least 50% was recorded among womenborn in 1993 or later in our study, but our sensitivity analysis did not suggest herd effects withrespect to the risk of cervical cancer. This isunderstandable, since there is usually a span of
5 to 20 years between acquisition of persistent
HPV infection and development of cervical cancer,31 and we observed very few cases of invasive
cervical cancer among the relevant birth cohorts
during follow-up.
Our study has some limitations. A small proportion of vaccinated women were misclassified
as unvaccinated in the analysis. However, such
misclassification would be expected to produce
a bias toward the null. A potentially greater concern is the possibility that the relationship of
HPV vaccination and the risk of cervical cancer
is confounded by other factors — in particular,
HPV-vaccinated women could have been generally healthier than unvaccinated women (i.e.,
healthy volunteer bias). We adjusted for several
parental characteristics that might be associatedwith both vaccination uptake and underlying
risk of cervical cancer. However, confounding bylifestyle and health factors in the women (suchas smoking status, sexual activity, oral contraceptive use, and obesity) cannot be excluded;
these factors are known to be associated with arisk of cervical cancer,32-34 although their independent association with HPV vaccine uptake is
not conclusive.35,36 The adjustment for parental
education level and annual household income
level in our analysis may serve to some extent
References
1. Walboomers JM, Jacobs MV, ManosMM, et al. Human papillomavirus is anecessary cause of invasive cervical cancer worldwide. J Pathol 1999;​189:​12-9.
2. Global HPV vaccine introduction overview: projected and current national introductions, demonstration/pilot projects,

as proxies for lifestyle factors such as smoking
status.37 Whereas healthy volunteer bias would be
expected to be more prominent among women
who had paid for opportunistic vaccinations (apopulation that almost exclusively received vaccination after the age of 17 years), we foundgreater risk reductions among women who were
vaccinated before the age of 17 years. Moreover,the higher rate of screening for cervical cancer
among HPV-vaccinated women38,39 would be expected to increase the likelihood that asymptomatic cervical cancer would be detected onscreening, and this could potentially cause anunderestimation of the risk reduction. Because
the risk of CIN2+ among HPV-vaccinated womenis substantially lower than that among unvaccinated women, it is unlikely that differential rates
or types of treatment of premalignant cervicallesions between vaccinated and unvaccinatedwomen could account for the lower risk of invasive cervical cancer in the vaccinated population.6,11,12 Owing to the small number of cases ofcervical cancer observed among the vaccinatedwomen, we could not reliably estimate the association of vaccination with the risk of cervical cancer according to the number of doses ofvaccine.
In this large, nationwide study of girls andyoung women 10 to 30 years of age who had
been vaccinated through HPV vaccination programs, we found that HPV vaccination was associated with a substantially reduced risk ofinvasive cervical cancer.
This study was approved by the regional ethical review
board in Stockholm (Dnr. 02-556, 2011/921-32, 2012/216-32, and2014/246-32), which determined that written informed consent
was not required from the persons included in the study.
Supported by grants from the Swedish Foundation for Strategic Research (KF10-0046), the Swedish Cancer Society (CAN
2016/840), and the Swedish Research Council (2017-02346) andby the China Scholarship Council.
Disclosure forms provided by the authors are available withthe full text of this article at NEJM.org.
A data sharing statement provided by the authors is available
with the full text of this article at NEJM.org.
We thank Pouran Almstedt for data management and Arvid
Sjölander for discussions about the statistical analysis.

gender-neutral vaccination programs, andglobal HPV vaccine introduction maps
(2006–2022). 2019 (https://path​.­azureedge​.­net/​­media/​­documents/​­GlobalHPVVaccine
IntroOverview_Nov2019​.­pdf).
3. Wang J, Ploner A, Sparén P, et al. Modeof HPV vaccination delivery and equity inn engl j med 383;14

nejm.org

vaccine uptake: a nationwide cohort study.
Prev Med 2019;​120:​26-33.
4. Arbyn M, Xu L, Simoens C, MartinHirsch PP. Prophylactic vaccination against
human papillomaviruses to prevent cervical cancer and its precursors. Cochrane
Database Syst Rev 2018;​5:​CD009069.

October 1, 2020

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Downloaded from nejm.org by Chisato Kondo on October 3, 2020. For personal use only. No other uses without permission.
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HPV Vaccination and the Risk of Cervical Cancer

5. Paavonen J, Naud P, Salmerón J, et al.

Efficacy of human papillomavirus (HPV)16/18 AS04-adjuvanted vaccine against
cervical infection and precancer causedby oncogenic HPV types (PATRICIA): final analysis of a double-blind, random­
ised study in young women. Lancet 2009;​
374:​301-14.
6. The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions.
N Engl J Med 2007;​356:​1915-27.
7. Drolet M, Bénard É, Boily MC, et al.
Population-level impact and herd effects
following human papillomavirus vaccination programmes: a systematic review andmeta-analysis. Lancet Infect Dis 2015;​15:​565-80.
8. Drolet M, Bénard É, Pérez N, Brisson M.
Population-level impact and herd effects
following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis. Lancet 2019;​394:​497-509.
9. Garland SM, Kjaer SK, Muñoz N, et al.
Impact and effectiveness of the quadrivalent human papillomavirus vaccine: a systematic review of 10 years of real-world
experience. Clin Infect Dis 2016;​63:​51927.
10. Silverberg MJ, Leyden WA, Lam JO, etal. Effectiveness of catch-up human papillomavirus vaccination on incident cervical neoplasia in a US health-care setting:a population-based case-control study. Lancet Child Adolesc Health 2018;​2:​707-14.
11. Herweijer E, Sundström K, Ploner A,
Uhnoo I, Sparén P, Arnheim-Dahlström L.
Quadrivalent HPV vaccine effectivenessagainst high-grade cervical lesions by age
at vaccination: a population-based study.
Int J Cancer 2016;​138:​2867-74.
12. Herweijer E, Sundström K, Ploner A,
Uhnoo I, Sparén P, Arnheim-Dahlström
L. Erratum: quadrivalent HPV vaccine effectiveness against high-grade cervical lesions by age at vaccination: a populationbased study. Int J Cancer 2017;​141(1):​E1-E4.
13. Leval A, Herweijer E, Ploner A, et al.
Quadrivalent human papillomavirus vaccine effectiveness: a Swedish national cohort study. J Natl Cancer Inst 2013;​105:​469-74.
14. Luostarinen T, Apter D, Dillner J, et al.
Vaccination protects against invasive HPVassociated cancers. Int J Cancer 2018;​142:​
2186-7.
15. National Swedish guidelines for cervical cancer prevention, diagnosis, andtreatment. 2019. (In Swedish) (https://www​.­c ancercentrum​.­se/​­g lobalassets/​­vara​-­uppdrag/​­prevention​-­t idig​-­upptackt/​1348­g ynekologisk​-­cellprovskontroll/​­vardprogram/​­n ationellt​-­vardprogram​-­cervixcancerprevention​.­pdf ).
16. Ludvigsson JF, Almqvist C, Edstedt
Bonamy A-K, et al. Registers of the Swedish total population and their use in medical research. Eur J Epidemiol 2016;​31:​12536.
17. Ludvigsson JF, Otterblad-Olausson P,
Pettersson BU, Ekbom A. The Swedish
personal identity number: possibilities
and pitfalls in healthcare and medical research. Eur J Epidemiol 2009;​24:​659-67.
18. The Public Health Agency of Sweden.
Statistics for HPV vaccinations. 2019. (InSwedish) (https://www​.­folkhalsomyndigheten​.­se/​­folkhalsorapportering​-­statistik/​­statistikdatabaser​-­och​-­v isualisering/​­vaccinationsstatistik/​­statistik​-­for​-­hpv​-­vaccinationer/​­).
19. Wettermark B, Hammar N, Fored CM,
et al. The new Swedish Prescribed Drug
Register — opportunities for pharmacoepidemiological research and experiencefrom the first six months. Pharmacoepidemiol Drug Saf 2007;​16:​726-35.
20. The Public Health Agency of Sweden.
National Vaccination Register. 2019. (InSwedish) (https://www​.­folkhalsomyndigheten​.­se/​­smittskydd​-­beredskap/​­vaccinationer/​­vaccinationsregister/​­).
21. Barlow L, Westergren K, Holmberg L,
Talbäck M. The completeness of theSwedish Cancer Register: a sample survey
for year 1998. Acta Oncol 2009;​48:​27-33.
22. Ekbom A. The Swedish Multi-generation Register. Methods Mol Biol 2011;​675:​
215-20.
23. Statistics Sweden. Longitudinal integration database for health insurance andlabour market studies (LISA). 2017 (https://www​.­scb​.­se/​­lisa​-­en).
24. Hildesheim A, Herrero R, Wacholder S,
et al. Effect of human papillomavirus
16/18 L1 viruslike particle vaccine among
young women with preexisting infection:a randomized trial. JAMA 2007;​298:​74353.
25. Haupt RM, Wheeler CM, Brown DR,
et al. Impact of an HPV6/11/16/18 L1 viruslike particle vaccine on progression tocervical intraepithelial neoplasia in seropositive women with HPV16/18 infection.
Int J Cancer 2011;​129:​2632-42.
26. Guo F, Cofie LE, Berenson AB. Cervical cancer incidence in young U.S. females after human papillomavirus vaccine introduction. Am J Prev Med 2018;​55:​
197-204.
27. Crosbie EJ, Einstein MH, Franceschi S,
Kitchener HC. Human papillomavirus andcervical cancer. Lancet 2013;​382:​889-99.

n engl j med 383;14

nejm.org

28. Lei J, Ploner A, Lagheden C, et al.

High-risk human papillomavirus status
and prognosis in invasive cervical cancer:
a nationwide cohort study. PLoS Med
2018;​15(10):​e1002666.
29. Lehtinen M, Dillner J. Clinical trialsof human papillomavirus vaccines andbeyond. Nat Rev Clin Oncol 2013;​10:​400-10.
30. Herweijer E, Ploner A, Sparén P. Substantially reduced incidence of genital
warts in women and men six years after
HPV vaccine availability in Sweden. Vaccine 2018;​36:​1917-20.
31. Schiffman M, Castle PE, Jeronimo J,
Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet
2007;​370:​890-907.
32. Plummer M, Herrero R, Franceschi S,
et al. Smoking and cervical cancer: pooled
analysis of the IARC multi-centric case —control study. Cancer Causes Control
2003;​14:​805-14.
33. Poorolajal J, Jenabi E. The association
between BMI and cervical cancer risk:a meta-analysis. Eur J Cancer Prev 2016;​
25:​232-8.
34. Appleby P, Beral V, Berrington de
González A, et al. Cervical cancer andhormonal contraceptives: collaborative
reanalysis of individual data for 16,573
women with cervical cancer and 35,509
women without cervical cancer from 24
epidemiological studies. Lancet 2007;​370:​
1609-21.
35. Sundaram ME, Mason SM, Basta NE.
HPV vaccine uptake among overweight
and obese US adolescents: an analysis of
the National Health and Nutrition Examination Survey (NHANES) 2009-2014. Vaccine 2016;​34:​2501-6.
36. Canfell K, Egger S, Velentzis LS, et al.
Factors related to vaccine uptake by young
adult women in the catch-up phase of the
National HPV Vaccination Program inAustralia: results from an observational
study. Vaccine 2015;​33:​2387-94.
37. Cavelaars AE, Kunst AE, Geurts JJ,
et al. Educational differences in smoking:international comparison. BMJ 2000;​320:​1102-7.
38. Herweijer E, Feldman AL, Ploner A,
et al. The participation of HPV-vaccinatedwomen in a national cervical screening
program: population-based cohort study.
PLoS One 2015;​10(7):​e0134185.
39. Kreusch T, Wang J, Sparén P, Sundström K. Opportunistic HPV vaccination
at age 16-23 and cervical screening attendance in Sweden: a national registerbased cohort study. BMJ Open 2018;​8(10):​e024477.
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