Vaccine 38 (2020) 1345–1351

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Vaccine
journal homepage: www.elsevier.com/locate/vaccine

The impact of HPV multi-cohort vaccination: Real-world evidence of

faster control of HPV-related morbidity
Madleen Orumaa a, Susanne K. Kjaer b, Christian Dehlendorff c, Christian Munk b, Anne Olaug Olsen d,
Bo T. Hansen a, Suzanne Campbell a, Mari Nygård a,⇑
a
HPV-related Epidemiological Research Unit, Department of Research, Cancer Registry of Norway, Oslo University Hospital, P.O. Box 5313 Majorstuen, N-0304 Oslo, Norway
b
Unit of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark
c
Unit of Statistics and Pharmacoepidemiology, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark
d
Department of Community Medicine and Global Health, Institute of Health and Society, University of Oslo, Forskningsveien 3A, 0373 Oslo, Norway

a r t i c l e i n f o a b s t r a c t

Article history: Background: In 2009, both Norway and Denmark initiated routine quadrivalent human papillomavirus
Received 16 July 2019 vaccination (qHPV) for 12-year-old girls; however, Denmark also introduced free-of-charge multi-
Received in revised form 8 December 2019 cohort vaccination for older age groups in 2008. We aim to describe trends in genital warts (GWs) inci-
Accepted 10 December 2019
dence rates (IRs) among men and women and qHPV vaccine coverage among women in Norway and
Available online 6 January 2020
Denmark in 2006–2015.
Methods: We linked multiple national health registries in Norway and Denmark via national personal
Keywords:
identifiers to access data on GWs incidence and qHPV vaccination among women and men aged
Real-world data
Immunization Program
12–35 years residing in Norway and Denmark in 2006–2015. We calculated age-specific and age-
Condylomata Acuminata standardized GWs IRs, GWs IR trends before (2006–2009) and after (2009–2015) the implementation
Human Papillomavirus Recombinant of qHPV vaccination, and qHPV vaccine coverage among women.
Vaccine Quadrivalent Results: In Norway and Denmark together, there were more than 200,000 cases of incident GWs and over
Papillomavirus Infections/prevention & 710,000 girls got at least one dose of qHPV vaccine during the study period. The total qHPV coverage in
control Norway and Denmark in 2015 was among women aged 12–35 years 24% and 70%, respectively. GWs IRs
Multi-cohort vaccination in Norway and Denmark decreased annually in 2009–2015 among women by 4.8% (95% confidence inter-
val: 4.3 to 5.3) and 18.0% (95%CI: 17.5 to 18.6), respectively, and among men 1.9% (95%CI: 1.4 to 2.4) and
10.7% (95%CI: 10.3 to 11.2), respectively. In Denmark, GWs IRs decreased rapidly among both sexes and
all age groups after qHPV vaccination, while Norway showed only a modest decrease.
Conclusion: Rapid decline in HPV-related morbidity is feasible with high coverage of multi-cohort vacci-
nation. However, the decision to vaccinate a single cohort of 12-years-old girls only will postpone HPV-
related disease control by at least a decade. Thus countries planning HPV vaccination programs should
also initiate multi-cohort vaccination for faster disease control.
Ó 2019 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).

1. Introduction incommodious disease, which is especially prevalent among people

High-risk human papillomavirus (HPV) causes HPV-related
anogenital cancers and certain types of head and neck cancers
[1,2]; whereas low-risk HPV types 6 and 11 causes most genital
warts (GWs) [3] and the majority of recurrent respiratory papillo-
matosis [4]. While the minimum average time from HPV infection
to cervical cancer is 10 years, GWs commonly manifest in
3–6 months [3,5]. Around 90% of all GWs are caused by HPV6/11
[3]. GWs are not life-threatening, but they represent an
⇑ Corresponding author.
E-mail address: mari.nygard@kreftregisteret.no (M. Nygård).
around 20 years of age [6]. The risk of GWs is associated with early
age at sexual debut, high number of sexual partners, and smoking
[6]. The main treatment for GWs includes a patient/specialist-
applied regimen of podophyllotoxin solution, imiquimod, or sinecat-
echins ointment [7,8]; cryotherapy; or laser treatment [7].
In 2006, the quadrivalent HPV (qHPV) vaccine, which targets
HPV6, 11, 16, and 18, was introduced. The qHPV vaccine has been
shown to be close to 100% effective against GWs [9] and against
persistent infection with HPV16 and 18 [10], which are responsible
for 70% of all cervical cancers [11]. However, it is not yet possible to
evaluate the effectiveness of the qHPV vaccine against cervical can-
cer because the progression to cancer often takes several decades

https://doi.org/10.1016/j.vaccine.2019.12.016
0264-410X/Ó 2019 The Authors. Published by Elsevier Ltd.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
1346 M. Orumaa et al. / Vaccine 38 (2020) 1345–1351
[12]. Therefore, GWs are often used to assess qHPV vaccine effec-
tiveness [13]. The World Health Organization currently recom-
mends routine HPV vaccination at age 9–13 years [14].
In 2009, Norway and Denmark included qHPV into the child-
hood vaccination program, targeting 12-year old girls. However,
already in the third quarter of 2008, Denmark started the first
free-of-charge multi-cohort qHPV vaccination program for girls
aged 15–17-years, which was extended to women aged up to
26 years in 2012. In contrast, Norway continued with single cohort
vaccination program until 2016. In both countries, the qHPV vac-
cine has been available for purchase since its introduction in
2006, but opportunistic vaccination rates have been low.
Although HPV transmission models show that multi-cohort
vaccination combined with a high vaccine coverage may accelerate
the reduction of HPV prevalence in the population [15], the effect
of multi-cohort vaccination has not yet been investigated in an
international comparison study. Comparable burdens of GWs have
been documented in Norway and Denmark [6], and the countries
share similar socioeconomic and sociodemographic characteristics,
offering a good opportunity to compare the effect of different HPV
vaccination strategies on HPV-related morbidity in these two
countries. The aim of the present study was to describe changes
in GWs incidence rates (IRs) and trends before (2006–2009) and
after (2009–2015) the implementation of qHPV vaccine in the
childhood vaccination programs, and qHPV coverage among
women in Norway and Denmark from 2006 to 2015.
2. Methods
2.1. Data sources and study cohort
In Norway and Denmark, each resident is assigned a unique
national identification number at birth or immigration. This num-
ber allows accurate data retrieval from national health and admin-
istrative registries for each individual. The study population was
identified from nation-wide population registries for Norwegian
and Danish residents in 2006–2015 and consisted of men and
women 12–35 years of age (details in the Supplementary Fig. 1).
Data on GWs incidence was obtained from national patient and
prescription registries, and data on qHPV vaccination status among
women was obtained from national vaccination and prescription
registries (Fig. 1, Supplement 1, Supplementary Fig. 1). The study
was approved by relevant authorities in each country (Ethical com-
mittee and/or Data Protection Agency).
2.2. Outcomes
Data on GWs diagnoses and prescriptions for GWs treatment
was combined to identify the date of GWs episodes. Only incident
GWs episodes [16–18] were included in the study. A GWs episode
was considered incident if preceeded by at least 12 months with-
out any registration of GWs diagnosis or treatment for GWs. One
person could contribute with several episodes during the study
period. Data on self-purchased qHPV vaccine and qHPV vaccines
provided in the childhood vaccination program was combined to
identify the date of the first dose of qHPV vaccine.
2.3. Statistical analysis
Age was categorized into seven groups: 12–15, 16–17, 18–19,
20–21, 22–25, 26–29, and 30–35 years [16]. GWs IRs were esti-
mated per 100,000 person-years, by age group, sex, country and
calendar year. Since qHPV vaccination was implemented in the
childhood vaccination program in 2009 in both countries, we also
assessed trends during 2006–2009 and 2009–2015 separately.
Annual age-standardized IRs were estimated by direct standardiza-
tion [19], using the combined population of Denmark and Norway
as standard. For each country, qHPV vaccine coverage was esti-
mated as percentages per calendar year, by dividing the number
of women who received at least one dose of qHPV by the total
number of women in each age group. To assess trends, we used
Poisson regression with the log of the population size as offset to
estimate annual percentage changes with corresponding 2-sided
95% confidence intervals (CI).
3. Results
We observed a total of 208,532 incident GWs episodes during
30,866,417 person-years among men and women aged 12–35 years
who were resident in Norway or Denmark during 2006–2015. Alto-
gether, 711,295 women received at least one dose of qHPV vaccine
during this period. In Norway, we observed 14,551,916 person-
years (7,111,395 woman-years and 7,440,521 man-years), 99,394
incident GWs episodes (51,205 women and 48,189 men), and
188,010 women with at least 1 dose of qHPV vaccine (Fig. 1). In
Denmark, we observed 16,314,501 person-years (8,035,575
woman-years and 8,278,926 man-years), 109,138 incident GWs
episodes (46,599 women and 62,539 men) and 523,285 women
with at least 1 dose of qHPV vaccine (Fig. 1). The overall coverage
of at least one dose of qHPV among women aged 12–35 years in
2015 was 24% in Norway and 70% in Denmark.
In 2009, when the childhood vaccination program was imple-
mented in both countries, the age-standardized GWs IRs for both
men and women were higher in Denmark compared to Norway
(Fig. 2, Table 1). GWs IRs for women were highest in age groups
18–19 and 20–21 years (Norway: 1513.0/105 and 1933.9/105,
respectively; Denmark: 1766.3/105 and 1818.1/105, respectively).
Among men in both countries, GWs IRs were highest in age groups
20–21 years and 22–25 years (Norway: 1142.6/105 and
1450.8/105, respectively; Denmark: 1898.9/105 and 1784.7/105,
respectively) (Table 1). In 2015, the age-standardized GWs IRs
were lower than in 2009 for both sexes and in both countries.
Moreover, for both sexes, GWs IRs was higher in Norway than in
Denmark (Fig. 2, Table 1).
GWs IRs among women were highest in age groups 20–21 and
22–25 years in Norway (1494.7/105 and 1090.1/105, respectively),
and in age groups 22–25 and 26–29 years in Denmark (411.1/105
and 375.6/105 person-years, respectively) (Table 1). GWs IRs for
men were highest in age group 22–25 years in Norway
(1200.8/105) and in age group 26–29 years in Denmark
(934.3.0/105) (Table 1).
Annual GWs IRs for both sexes (Panel A) and HPV vaccination
coverage in women (Panel B) by country and age groups for the
entire study period are provided in Fig. 3. Before the introduction
of qHPV into the childhood vaccination program, GWs IRs were
increasing in women and men in most age groups in both countries
(Fig. 3A, Table 2). Overall, GWs IRs among women decreased by
4.8% in Norway and 18.0% in Denmark each year after the introduc-
tion of qHPV into the childhood vaccination program. The corre-
sponding numbers for men were 1.9% and 10.7%. The strongest
decrease in GWs IRs after the introduction of qHPV vaccination
into the childhood vaccination program was among Danish women
(Fig. 3A, Table 2) with 51.4% and 39.8% per year in age groups
16–17 and 18–19 years, respectively. Among Norwegian women
the corresponding decreases were 24.5% and 9.1%. Among Danish
men, the decrease after the implementation of qHPV into child-
hood vaccination program was most profound in the age groups
18–19, and 16–17 years, with annual decreases of 33.6% and
32.7%, respectively. Among Norwegian men, the strongest annual
decrease in GWs IRs was 10.4% in the age group 16–17 years.
 M. Orumaa et al. / Vaccine 38 (2020) 1345–1351
Fig. 1. Data linkage between population-based registries. GWs: genital warts; qHPV: quadrivalent human papillomavirus vaccine
Fig. 2. Age-standardized genital warts (GWs) incidence rates (IRs) in Norway and
Denmark per 100,000 person-years.
Denmark started to vaccinate 15–17-year-old girls in 2008,
12-year-old girls in 2009, and girls up to 26 years of age in 2012,
therefore qHPV vaccine coverage reached over 50% in these age
groups the same year, or the year after qHPV vaccination imple-
mentation. Moreover, since 2013, qHPV coverage has been over
80% among girls aged 12–25 years (Fig. 3B). In Norway, qHPV vac-
cine total coverage increased slowly. By 2015, 37% of girls aged
18–19 years and 80% of girls aged 12–17 had received at least
one dose of qHPV (Fig. 3B).
4. Discussion
6 years after implementing a multi-cohort vaccination in Den-
mark, GWs burden was substantially lower in Denmark than in
Norway, where multi-cohort vaccination was absent. This demon-
strates the impact and importance of public health policy on
1347
disease control and highlight the impact of high vaccine coverage
in age groups that are outside of the vaccination schedule to
achieve a rapid reduction in disease burden. As the main aim of
HPV vaccination is to prevent HPV-related diseases including cer-
vical cancer, it is likely that the observed gap in GWs IRs in Norway
and Denmark will manifest in differences in cervical cancer inci-
dence in the near future.
The efficacy of the qHPV vaccine has been well documented in
randomized controlled trials (RCTs), which have convincingly
demonstrated the effect of HPV vaccination against HPV infection
[10], GWs [20], and cervical precancerous lesions [21]. RCTs alone,
however, could not address the strategical decision, crucial for
public health policy makers when they decide how to introduce
HPV vaccine in the population, i.e. whether to vaccinate single or
several birth cohorts. Indeed, only real-world data derived from
large population-based data registries can deliver this knowledge.
In this study, we compared two populations with documented
similarities regarding risk factors related to HPV infection [22]
and with comparable rates of HPV-related morbidity [23]. In Nor-
way, qHPV vaccination was limited to 12-year-old girls who are
unlikely to have been exposed to HPV, therefore, the implemented
program leveraged maximal cost-effectiveness on population level
[37]. In Denmark, qHPV vaccination was extended immediately to
a more heterogeneous population in terms of HPV exposure. Before
2009, the epidemiology of GWs among women in Norway and
Denmark was comparable, with an overall incidence of 805.4/105
in Norway and 855.2/105 in Denmark (Table 1). Similar difference
in GWs proportions was observed between the countries in a self-
administered questionnaire study performed in 2004–2005 [6].
As the questionnaire study included females only, the present
study is to our knowledge the first description of GWs IRs among
males in Norway. While in 2009 the overall GWs IR of 660.0/105
in Norwegian men was lower than that in Norwegian women
(805.4/105), the annual increase in age-specific GWs IRs in men
from 2006 to 2009 was more pronounced than in women, regard-
less of age. In 2009, GWs IRs peaked in both countries in women
20–21 years of age and in men 20–21 and 22–25 years of age. This
1348 M. Orumaa et al. / Vaccine 38 (2020) 1345–1351

Table 1
Number of cases, population, and genital warts (GWs) incidence rates (IRs) per 100,000 person-years by sex and age group in Norway and Denmark in 2009 and 2015.

Age 2009 2015

group
Norway Denmark Norway Denmark
No of GWs Population IR/105 No of GWs Population IR/105 No of GWs Population IR/105 No of GWs Population IR/
cases cases cases cases 105
Women
Total1 5617 693,534 805.4 6463 801,125 855.2 4633 789,550 577.2 2002 817,222 241.6
12–15 105 123,094 85.3 102 138,232 73.8 56 120,589 46.4 8 131,483 6.1
16–17 347 61,464 564.6 622 67,696 918.8 64 62,157 103.0 28 67,738 41.3
18–19 951 62,855 1513.0 1152 65,222 1766.3 448 64,143 698.4 77 70,701 108.9
20–21 1177 60,860 1933.9 1137 62,539 1818.1 962 64,362 1494.7 139 73,868 188.2
22–25 1434 113,770 1260.4 1604 122,059 1314.1 1479 135,680 1090.1 604 146,933 411.1
26–29 903 118,039 765.0 934 127,018 735.3 920 140,165 656.4 504 134,202 375.6
30–35 700 153,452 456.2 912 218,359 417.7 704 202,454 347.7 642 192,297 333.9
Men
Total1 5055 724,268 660.9 7814 824,729 944.7 5008 830,930 583.2 4015 848,038 471.9
12–15 50 130,337 38.4 61 145,525 41.9 49 125,770 39.0 14 137,458 10.2
16–17 90 65,104 138.2 257 71,340 360.2 50 65,716 76.1 34 71,390 47.6
18–19 310 66,347 467.2 862 68,586 1256.8 181 68,422 264.5 116 74,956 154.8
20–21 730 63,892 1142.6 1247 65,669 1898.9 518 68,612 755.0 230 77,225 297.8
22–25 1718 118,417 1450.8 2241 125,566 1784.7 1717 142,990 1200.8 1058 152,238 695.0
26–29 1204 121,717 989.2 1598 127,967 1248.8 1348 144,822 930.8 1298 138,932 934.3
30–35 953 158,454 601.4 1548 220,076 703.4 1145 214,598 533.6 1265 195,839 645.9
1
Total IR is age-standardized.

Fig. 3. Age-specific GWs IRs by sex and country (panel A) and qHPV initiation (%) among women by country (panel B). Danish and Norwegian estimates are shown in red and
blue, respectively. Women are represented by solid lines, men by dotted lines.

fit well with the known age patterns of sexual relationships
between men and women where men are usually older than their
partner [24]. The observed changes in GWs IRs in men and women
in Norway and Denmark before and after the implementation of
qHPV into childhood vaccination program illustrate the important
role of men in transmitting the sexually-transmitted HPV infection.
Consequently, the relevance of gender neutral vaccination must be
highlighted in order to control HPV-related diseases [25,26].
Other reasons for the observed strong decline in GWs IRs could
be be less exposure to HPV at the population level due to changes
in sexual behavior. However, other sexually-transmitted diseases
that are not vaccine-preventable, like chlamydia, show a constant,
increasing trend [27]. Secular trends in age at sexual debut and
number of sexual partners also go against this hypothesis
[28,29], leaving qHPV vaccination as the most plausible explana-
tion for the observed decreases in GWs IRs.
4.1. Comparison with other studies
Several countries have reported a rapid decline in GWs after
including the qHPV vaccine in their national vaccination programs
[16,18,30–32]. In Australia, large declines in GWs incidence were
observed among women who were likely to have received the vac-
cine before commencing sexual activity and among largely unvac-
cinated heterosexual men in the same age groups who presumably
benefitted from herd protection [33]. However, GWs incidence
among men who have sex with men and non-residents did not
change [34], suggesting that these groups did not experience herd
protection. In our study, both single and multiple cohort vaccina-
tion strategies resulted in an overall decline of GW incidence
among largely unvaccinated men. The overall decline in GW inci-
dence among men was, however, about five times greater in Den-
mark (10.7%) than in Norway (1.9%). Our results support the notion
that high uptake of HPV vaccine in multiple birth cohorts results in
substantial heard protection in men, while high uptake of HPV vac-
cine within a single cohort HPV vaccination strategy provide con-
siderably weaker herd protection. Nevertheless, the major drop
in GWs IRs is possible only with the qHPV or the nonavalent vac-
cine; countries that have implemented the bivalent HPV vaccine
are not experiencing a decrease in GWs incidence [35].
HPV vaccine effectiveness is highest when the vaccine is admin-
istrated before exposure to HPV, implying that vaccination should
 M. Orumaa et al. / Vaccine 38 (2020) 1345–1351 1349

Table 2
Incidence trend analysis of GWs IRs in Norway and Denmark by sex and age group before (2006–2009) and after (2009–2015) the implementation of school-based quadrivalent
human papillomavirus vaccination.

Sex Age group Subperiod Norway Denmark

APC (95% CI) APC (95% CI)
Women Total 2006–2009 0.8 ( 1.8 to 0.3) 6.4 (5.4 to 7.4)
2009–2015 4.8 ( 5.3 to 4.3) 18.0 ( 18.6 to 17.5)
12–15 2006–2009 12.9 (4.5 to 21.4) 8.9 ( 16.2 to 1.7)
2009–2015 8.8 ( 12.8 to 4.7) 39.6 ( 47.0 to –32.2)
16–17 2006–2009 11.1 (6.9 to 15.3) 1.0 ( 4.4 to 2.4)
2009–2015 24.5 ( 31.2 to 17.1) 51.4 ( 55.8 to 47.0)
18–19 2006–2009 4.0 (1.5 to 6.7) 11.5 (8.9 to 14.0)
2009–2015 9.1 ( 10.4 to 7.8) 39.8 ( 42.0 to 37.7)
20–21 2006–2009 2.9 (0.5 to 5.2) 8.5 (6.1 to 10.9)
2009–2015 4.3 ( 5.4 to 3.2) 27.7 ( 29.2 to 26.1)
22–25 2006–2009 3.0 ( 4.9 to 1.1) 8.5 (6.6 to 10.5)
2009–2015 2.3 ( 3.3 to 1.5) 16.6 ( 17.6 to 15.6)
26–29 2006–2009 0.5 ( 3.1 to 2.1) 5.2 (2.7 to 7.6)
2009–2015 2.1 ( 3.2 to 0.9) 9.1 ( 10.4 to 7.8)
30–35 2006–2009 0.1 ( 3.8 to 3.5) 7.7 (5.1 to 10.3)
2009–2015 3.7 ( 5.0 to 2.4) 3.5 ( 4.7 to 2.2)
Men Total 2006–2009 3.9 (2.7 to 5.0) 10.9 (9.9 to 11.8)
2009–2015 1.9 ( 2.4 to 1.4) 10.7 ( 11.2 to 10.3)
12–15 2006–2009 17.8 (6.1 to 29.6) 3.9 ( 7.1 to 14.9)
2009–2015 1.2 ( 6.0 to 3.7) –23.7 ( 31.0 to 16.5)
16–17 2006–2009 18.1 (8.5 to 27.9) 13.2 (7.5 to 18.8)
2009–2015 10.4 ( 14.9 to 5.8) –32.7 ( 36.8 to 28.6)
18–19 2006–2009 11.2 (6.6 to 15.8) 18.3 (15.1 to 21.5)
2009–2015 8.2 ( 10.4 to 6.1) –33.6 ( 35.8 to 31.4)
20–21 2006–2009 8.3 ( 5.2 to 11.3) 19.3 (16.8 to 21.7)
2009–2015 5.4 ( 6.8 to 4.1) 25.4 ( 26.7 to –23.9)
22–25 2006–2009 4.5 (2.6 to 6.4) 12.2 (10.5 to 13.9)
2009–2015 2.6 ( 3.5 to 1.8) 12.9 ( 13.8 to 12.1)
26–29 2006–2009 1.7 ( 0.6 to 3.9) 8.7 (6.8 to 10.6)
2009–2015 0.8 ( 1.8 to 0.2) 4.7 ( 5.6 to 3.8)
30–35 2006–2009 2.2 ( 5.3 to 0.9) 6.1 (4.2 to 8.1)
2009–2015 0.9 ( 2.1 to 0.1) 0.9 ( 1.8 to 0.0)

ideally take place before sexual debut. In Norway and Denmark, it
was decided to routinely provide vaccination for 12-years-old girls.
In 2015, the first vaccinated cohort (vaccinated in 2009) reached
17–18 years of age (born in 1997), and in both countries, we
observed the highest reduction in GWs IRs in these age groups. A
systematic review [36] found that multi-cohort vaccination has a
protective effect on high-grade cervical, vulvar, and vaginal
intraepithelial neoplasias and GWs among young women. Several
modelling studies have found an accelerated effect of multi-
cohort vaccination on the reduction of HPV prevalence [15,37].
Including boys into national, free-of-charge vaccination schemes
would protect against the loss of effectiveness that results from
temporary coverage reduction [15]. It is estimated that it would
take more than 2 decades to recover from a decline in vaccine cov-
erage among women [15]. By comparing a theoretical model with
routine-only vaccination to the observed GWs rates in the popula-
tion who received multi-cohort vaccination, a study from Australia
estimated that 5 years after of the initiation of the implementation
of qHPV into the childhood vaccination program, the multi-cohort
program was responsible for more than half of the reduction in
GWs incidence. Furthermore, they determined that this trend will
continue for decades and will affect future cervical cancer rates
[38].
During the last 2 decades, a continually increasing trend of cer-
vical precancerous lesions and other HPV-related cancers has been
documented [39–41]. While cervical cancer is the only HPV-related
disease that can be avoided by routine screening, the proportion of
people who would benefit from HPV vaccination is much larger.
Studies have shown that qHPV and bivalent HPV vaccines have
the potential to prevent 70% of cervical cancers and 80% of other
HPV-related cancers, and 9-valent HPV vaccine could prevent
90% of cervical cancers and 90% of other HPV-related cancers
[42]. In addition, it is estimated that if the qHPV and bivalent
HPV vaccines could prevent 42% of cervical intraepithelial neo-
plasia (CIN) grade 2 and 57% of CIN grade 3, then 9-valent HPV vac-
cines could increase this to 68% for CIN grade 2 and 85% for CIN
grade 3 [43].
We observed substantial decrease in GW incidence following
high uptake of HPV vaccine in 12–26 years old females, although
the decrease became gradually less pronounced with decreasing
age of vaccination. WHO issued in 2018 a call for action to reduce
the age-adjusted cervical cancer incidence rate below 4 per
100,000 women-years in the 21st century, with one of the goals
to fully vaccinate 90% of 15 year old girls by 2030 [44]. An increase
in global demands might result in vaccine supply shortage, forcing
countries to revisit the start and scope of HPV vaccination pro-
grams [45]. The urgent need to increase HPV vaccine supply needs
to be addressed globally either by increasing production of the
existing vaccines, or by supporting the development of new vacci-
nes [46–48].
4.2. Strengths and limitations of this study
Our study demonstrates the importance of the existence and
use of real-world data in health care. We used data from high-
quality national registries [49–53], and by using national identifi-
cation numbers, we ensured that the number of incident cases of
GWs concurred with the case definition and that the number of
women receiving qHPV vaccine was correct. We also provided
comparisons between two countries that are culturally similar
and have health care and health registration systems that are com-
parable. However, some limitations need to be considered. Firstly,
in Norway, 3 different drugs are reported to be used as patient-
applied regime, while in Denmark, information was collected for
1350 M. Orumaa et al. / Vaccine 38 (2020) 1345–1351
one drug only (Supplement 1), which may lead to underestimation
of Danish GWs IRs for the whole period. Secondly, Norwegian
Patient Registry was established in 2009, which may lead to an
underestimation of cases of GWs in Norway in the first years.
Thirdly, we use data from prescription registries, which is not a
direct diagnosis of GWs. However, it is a conventional method
how to estimate GWs IRs [16–18]. Lastly, while GWs IRs are widely
used proxies to estimate the future effect of HPV vaccines on HPV-
related cancers, it has been reported that GWs have a steeper
reduction than other HPV-related diseases [54].
5. Conclusions and policy implications
qHPV vaccination has a profound effect on diminishing the bur-
den of GWs. We observed a substantial decline in GWs IRs in a
wide range of age groups among women and men in Denmark,
with a multi-cohort women-only qHPV vaccination strategy. The
decline was probably caused by direct protection of vaccinated
individuals and herd protection of unvaccinated individuals. In
Norway, who employed a single-cohort woman-only qHPV vacci-
nation strategy, the GWs IRs also decreased, but in a narrower
range of younger age groups. Overall, the decline in GWs IRs was
far greater in Denmark than in Norway, both among women and
men. The difference demonstrates the effect and importance of
multi-cohort vaccination. To reduce the burden of HPV-related dis-
ease faster, countries that are planning HPV vaccination programs
should also initiate multi-cohort vaccination.
6. Contributions
MO and MN had full access to all of the data in the study and
take responsibility for the integrity of the data and the accuracy
of the data analysis. MO, SKK, CD, CM, AOO, BTH, SC, and MN were
responsible for the study concept and design. MO, SKK, CD, BTH, SC,
and MN were involved in the acquisition of data. All the authors
contributed to the analysis and interpretation of data and to the
critical revision of the manuscript for important intellectual con-
tent. MO drafted the manuscript. MN guarantees the integrity of
the work. The corresponding author attests that all listed authors
meet authorship criteria and that no others meeting the criteria
have been omitted.
7. Transparency declaration
The last author (MN) affirms that the manuscript is an honest,
accurate, and transparent account of the study being reported; that
no important aspects of the study have been omitted; and that any
discrepancies from the study as planned (and, if relevant, regis-
tered) have been explained.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
MO: Data curation, Formal analysis, Investigation, Methodology,
Project administration, Validation, Visualization, Writing - original
draft, Writing - review & editing. SKK: Investigation, Methodology,
Project administration, Validation, Writing - review & editing. CD:
Data curation, Investigation, Methodology, Validation, Writing -
review & editing. CM: Investigation, Methodology, Validation,
Writing - review & editing. AOO: Investigation, Methodology,
Validation, Writing - review & editing. BTH: Investigation,
Methodology, Project administration, Validation, Writing - review
& editing. SC: Data curation, Investigation, Methodology, Valida-
tion, Writing - review & editing. MN: Investigation, Methodology,
Project administration, Supervision, Validation, Writing - review
& editing.
Declaration of Competing Interest
The authors declare the following financial interests/personal
relationships which may be considered as potential competing
interests: SKK has received lectures fee from Sanofi Pasteur MSD
and Merck, scientific advisory board fee from Merck, and research
grant through her institution from Merck. CM received lecture fees
and travel grants from Sanofi Pasteur MSD. MN received research
grants from MSD Norway/Merck through the affiliating institute.
MO’s, BTH’s and SC’s affiliated institute has received research grants
from MSD Norway/Merck. CD and AOO report no conflicts of
interest.
Disclaimer/Acknowledgement
Data from the Norwegian Patient Registry, Norwegian Prescrip-
tion Database, and Norwegian Immunization Registry have been
used in this publication. The interpretation and reporting of these
data are the sole responsibility of the authors, and no endorsement
by the aforementioned registries is intended nor should be
inferred.
Appendix A. Supplementary material
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.vaccine.2019.12.016.
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