Efficacy of Vaccination against HPV Infections to Prevent

Cervical Cancer in France: Present Assessment and

Pathways to Improve Vaccination Policies
Laureen Ribassin-Majed1*, Rachid Lounes1, Stephan Clemencon2
1 Laboratoire Mathematiques Appliquees a` Paris 5, Centre National de la Recherche Scientifique Unite Mixte de Recherche nu8145, Universite Paris Descartes, Sorbonne
Paris Cite, Paris, France, 2 Laboratoire Traitement et Communication de lInformation, Telecom ParisTech/Centre National de la Recherche Scientifique Unite Mixte de
Recherche nu5141, Paris, France

Abstract
Background: Seventy percent of sexually active individuals will be infected with Human Papillomavirus (HPV) during their
lifetime. These infections are incriminated for almost all cervical cancers. In France, 3,068 new cases of cervical cancer and
1,067 deaths from cervical cancer occurred in 2005. Two vaccines against HPV infections are currently available and
vaccination policies aim to decrease the incidence of HPV infections and of cervical cancers. In France, vaccine coverage has
been reported to be low.
Methods: We developed a dynamic model for the heterosexual transmission of Human Papillomavirus types 16 and 18,
which are covered by available vaccines. A deterministic model was used with stratification on gender, age and sexual
behavior. Immunity obtained from vaccination was taken into account. The model was calibrated using French data of
cervical cancer incidence.
Results: In view of current vaccine coverage and screening, we expected a 32% and 83% reduction in the incidence of
cervical cancers due to HPV 16/18, after 20 years and 50 years of vaccine introduction respectively. Vaccine coverage and
screening rates were assumed to be constant. However, increasing vaccine coverage in women or vaccinating girls before
14 showed a better impact on cervical cancer incidence. On the other hand, performing vaccination in men improves the
effect on cervical cancer incidence only moderately, compared to strategies in females only.
Conclusion: While current vaccination policies may significantly decrease cervical cancer incidence, other supplementary
strategies in females could be considered in order to improve vaccination efficacy.
Citation: Ribassin-Majed L, Lounes R, Clemencon S (2012) Efficacy of Vaccination against HPV Infections to Prevent Cervical Cancer in France: Present Assessment
and Pathways to Improve Vaccination Policies. PLoS ONE 7(3): e32251. doi:10.1371/journal.pone.0032251
Editor: Paulo Lee Ho, Instituto Butantan, Brazil
Received November 10, 2011; Accepted January 25, 2012; Published March 12, 2012
Copyright: 2012 Ribassin-Majed et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: These authors have no support or funding to report.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: laureen.majed@parisdescartes.fr

for about 3,000 new cases per year [6] while a thousand deaths are
due to these cancers annually. Moreover, cervical cancers occur
frequently in young women [7].
Vaccination against HPV infections represents an effective way
to decrease cervical cancer incidence, particularly among young
women. Two prophylactic vaccines against HPV infections are
available in France and have been found to be highly effective in
women who have never been infected with HPV [8].
The permanent Vaccines Advisory Committees (Comite
technique des vaccinations and Conseil superieur dhygie`ne
publique de France) recommend vaccinating 14 years old
females. Moreover, a catch-up program has been offered to
women aged from 15 to 23. Females eligible for the catch-up
program either not have been sexually active yet or may report a
first sexual relationship that occurred in the year prior to
vaccination (Haute Autorite de Sante, HAS). A recent paper has
estimated vaccine coverage in France to be low: about 30% of girls
aged 14 had been vaccinated with three doses in 2007 and 2008

Introduction
Human Papillomavirus infection (HPV) is the most frequent
sexually transmitted disease. At least 70 per cent of sexually active
men and women are infected with HPV during their life span [1].
Eighty per cent of HPV infections cases are cleared in a few
months by the immune system without treatment but in the
remaining 20%, infection becomes persistent. One hundred types
of HPV have been identified: low risk types, which are responsible
for benign anogenital lesions, and high risk types, which can lead
to precancerous and cancerous lesions in the cervix. HPV-16 is the
most common genotype in developed countries [2,3].
Epidemiological studies have established a causal relationship
between HPV infections and occurrence of cervical cancer [4].
These infections have also been incriminated in anogenital, head
and neck cancers, anogenital warts and recurrent respiratory
papillomatosis among women and men.
Invasive cervical cancer is the second most common cancer
among women worldwide [5]. In France, cervical cancer accounts
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Efficacy of Vaccination against HPV Infections

CIN2/3 were supposed to be infected with HPV 16/18 and

therefore could infect men.
Individuals exited the model by death (age and gender specific
using French data) or when they reached the age of 84. An
additional death rate for women with cervical cancer was
considered [6] (see Table S5).
The heterosexually mixing population was divided into 14 age
groups ([1419], [2024], [2529], [3034], [3539], [4044],
[4549], [5054], [5559], [6064], [6569], [7074], [7579],
[8084]) based on age groups of published data on cervical cancer
incidence in France [6]. We developed a demographic model
[20,25] which simulated the distribution of French population (see
Table S6, Figure S1 and Figure S2). Annual transition rates into
age groups were defined by the demographic model (see Appendix
S1).
Each age group was divided into 4 levels of sexual behavior.
The level of sexual activity was defined by the number of sexual
partners in last 12 months (0 sexual partners-including nonsexually-active individuals-, 1 partner, between 2 and 3 partners
and more than 4 partners in last year). Results from the French
survey on sexual behavior [26] were used to derive the distribution
between group of sexual behavior (see Table S1). Mixing between
sexual activity groups was quantified by the mixing matrix as
described by Garnett and Anderson [27]. The probability for
someone from group l defining sexual-behavior to form a
partnership with someone from group o is defined by:

[9]. Therefore, the potential impact of vaccination has to be

assessed considering observed vaccination coverage.
Since the recent introduction of vaccination policies in France, a
reduction of cervical cancers and pre-cancerous lesions has been
expected. As cervical cancers usually occur 15 years after HPV
infections, mathematical models are useful to assess an expected
reduction in cancer cases. In these models, vaccine coverage in
young women is taken into account.
Various dynamic models have been published to assess the
potential impact of HPV vaccination in several countries. Some of
them are cohort models [1018] and others are deterministic or
hybrid models [1923]. Deterministic models directly allow us to
estimate both the direct and indirect (herd immunity) benefits of
vaccination [24].
In this paper, we present a deterministic model for the
heterosexual transmission of HPV and its progression to cervical
lesions and cervical cancer. We estimated the potential impact of
vaccination on the reduction of cervical cancer incidence in
French women. We first studied the current vaccine coverage to
assess vaccine efficacy. Then, vaccine efficacy was assessed in
different settings: adding vaccine coverage in boys and young men,
achieving higher vaccine coverage in women and adding vaccine
coverage in females under 14.

Methods
Dynamic Model Structure
We used Scilab-5.1.1 software (http://www.scilab.org/fr) to
design a deterministic model for heterosexual transmission of HPV
types 16 and 18. We developed a system of 784 ordinary
differential equations (see Table S7). We set the population size in
the model to 100,000 individuals, equally divided into females and
males. The epidemiologic model simulated heterosexual transmission of HPV-16/18 infections in males and females and
progression to CIN1 (cervical intraepithelial neoplasia stage 1),
CIN2/3 (cervical intraepithelial neoplasia stage 2/3) and cervical
cancer for females (see flow diagram on Figure 1). Description of
variables and parameters can be found in Appendix S1 (Table S4).
Fourteen-year-old persons entered the model at a genderspecific and sexual activity-specific rate. Sexually active men and
women could be infected with HPV 16/18 if they had had sexual
intercourse with infected individuals. Women with CIN1 or

wlo ~e No Co z(1{e)dlo
4
P
Ns Cs
s~1

With No being the proportion of individuals in sexual-activity

group o, co representing the average number of annual partners in
group o, the parameter e described the degree of mixing between
sexual activity groups which may vary from fully assortative (e = 0,
when individuals have sexual partners in the same sexual activity
class) to fully random (e = 1). Mixing between sexual activity
groups was assumed to be preferentially assortative (e = 0.4).

Force of Infection
The force of infection by gender depends on: probabilities of
transmission by partnership (not per sex act) from an infected

Figure 1. Flow diagram in non-vaccinated population. For one age-group j (j = 114) and one group of sexual behavior l (l = 14): Black solid
arrows represent infection or progression of the disease; black dotted arrows represent clearance of infection or regression of the disease; gray
dotted arrows represent exit of the model (due to death or age .84); bold arrows represent specific mortality due to cervical cancer.
doi:10.1371/journal.pone.0032251.g001

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Efficacy of Vaccination against HPV Infections

individual to a susceptible (sf and sm); number of sex partner in

last 12 months (cl = 0, 1, 23, +4); proportion of infected
individuals in the pool of sexual partner according to their agegroup and level of sexual behavior. We developed a mixing matrix
rg,i,k appropriate for the sexually active population in France,
which gives the proportion of individuals of gender g, in age-group
i who have sexual partners in age-group k (see Table S2).

susceptible one) have been estimated to 0.25 (female) and 0.20

(male).
Among infected females, the rates of progression to various
stages of cervical disease (CIN1, CIN2/3 and cervical cancer) were
estimated for each age-group (Table S3). We compared the agespecific incidence of cervical cancer predicted by the model with
French published data [6,7]. Incidence rates of cervical cancer in
France are estimated using data from cancer registries (www.invs.
fr). Seventy percent of cervical cancers are due to HPV types 16/
18. Age-specific incidence rates of cervical cancer predicted by the
model were similar to the incidence rates of cervical cancers
attributed to HPV 16/18 in France within a precision of 10%.
Predicted HPV prevalence had a shape and a peak similar to that
reported in literature data [28,29,32]. Incidence rates of mortality
predicted by the model were also close to published rates [7,33].

Transmission model data

In a fitting procedure, we derived the probabilities of
transmission of HPV 16/18 (from an infected individual to a
susceptible) for both sexes and age-specific progression rates to
different stage of cervical disease (CIN1, CIN2/3 and cervical
cancer). A set of parameters which matched HPV 16/18
prevalence [28,29] and age-specific incidences of cervical cancer
[30] was selected. As HPV types 16 and 18 are responsible for
70% of all the causes of cervical cancer [31], we multiplied by 0.7
the published French incidence rate of cervical cancer to assess the
incidence rate of cervical cancer due to HPV types 16 and 18 (for
French women). Regression rates of cervix lesions were defined
using literature data [20].

Sensitivity analysis
Sensitivity analyses were conducted to assess the effect of
parameter variations on model results. The degree of sexual
mixing e, which can vary between 0 (fully assortative) and 1 (fully
random), was initially set to 0.4. We tested the effect of a value for
e closer to sexual mixing fully random (e = 0.8) on the endemic
prevalence of HPV infections in male and female. Although
vaccine efficacy was initially set to 90%, in sensitivity analyses, we
set vaccine efficacy to 60%. Thus, we studied the impact of
vaccination on HPV prevalence and cervical cancer incidence
using a low (60%) vaccine efficacy.

Vaccine characteristics
We divided the population into vaccinated and unvaccinated
categories. Individuals entered the model at 14 years old (being
vaccinated or not). Individuals in the youngest age groups ([1419]
and [2024]) could be vaccinated after entrance into the model in
accordance with the French vaccine program and then moved to
vaccinated categories. We considered several vaccination scenarios. Immunity from the vaccine was assumed to be sustained
lifelong and vaccine efficacy was assumed to be 90%. In the five
scenarios considered, vaccine coverage was assumed to be constant
in time. In the first scenario, coverage of vaccination (using 3 doses
of vaccines) was set to that observed in France in 2009 [9]: 30% of
women aged 1419 and 10% of women aged 2024 (Table 1). In
the second scenario, we added vaccination coverage in boys and
men with similar rates to the women in scenario 1. We thereafter
defined hypothetical high coverage in women only (80%) and both
genders in scenarios 3 and 4 respectively. Finally, in scenario 5,
young girls could be vaccinated before age of 14 with a highest
coverage than for girls aged 14 to 24 (50% versus 30%); in this
scenario, there was no vaccination in men.

Results
HPV infection prevalence
Tables 2 and 3 show predicted prevalence of HPV 16/18
infections in each considered scenario of vaccination coverage. All
vaccination strategies considered against HPV 16/18 led to a
sizeable decrease in prevalence in males and females 20 and 50
years after vaccination introduction (see Figure S4 and Figure S5).
There was a modest effect on the prevalence of HPV infections
when scenarios included vaccination coverage in men and women
compared to those considering vaccination coverage only in
females. For instance, in France, current vaccination coverage
among females lead to a 52% reduction of HPV infection
prevalence 20 years after the introduction of the vaccine, while
adding vaccination with a similar coverage in boys and young men
yielded a 59% reduction in HPV infection prevalence.
Improving vaccine coverage (scenario 3 and 4) decreased HPV
prevalence more importantly; in addition, the impact of the
vaccines was observed earlier in time.
Scenario 5, which considered an additional vaccination of girls
before 14, yielded a better impact on HPV prevalence among

Model validation
To validate the model, we considered the epidemiological data
before vaccination introduction and compared it with the steadystate estimates of the deterministic model for non-vaccinated
individuals (see Figure S3). Probabilities of transmission of HPV
16/18 (per partnership, from an infected individual to a
Table 1. Scenarios of vaccination considered in simulations.

Vaccine coverage

Scenario 1

Scenario 2

Scenario 3

Scenario 4

Women

Scenario 5
,14: 50%

[1419]

30%

30%

80%

80%

30%

[2024]

10%

10%

80%

80%

30%

[1419]

30%

80%

[2024]

10%

80%

Men

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Efficacy of Vaccination against HPV Infections

Table 2. Prevalence of HPV 16/18 for women in each scenario 10, 20 and 50 years after initiation of vaccination (t = 0).

Prevalence of HPV 16/18 for women

10 years

20 years

50 years

Without vaccination

20.2%

20.2%

20.2%

Scenario 1

14.4% (228.7%)

9.8% (251.7%)

2.6% (287.2%)

Scenario 2

13.7% (232.2%)

8.31% (258.9%)

0.85% (295.8%)

Scenario 3

11.0% (245.5%)

6.05% (270.0%)

0.6% (297.0%)

Scenario 4

10.1% (250%)

4.69% (276.8%)

0.09% (299.6%)

Scenario 5

12.2% (239.6%)

6.96% (265.6%)

0.9% (295.6%)

Vaccine coverage was supposed constant in each scenario. In parentheses, % of reduction in HPV prevalence compared to the case without vaccination.
doi:10.1371/journal.pone.0032251.t002

to HPV 16/18 may be expected 20 years after the introduction of

the vaccine (see Table 4 and Figure S6). A modest reduction may
be expected 10 years after vaccine introduction (27.3%) due to
the natural history of cervical cancer: indeed, cervical cancers can
occur several decades after HPV infections. Scenario 1 predicted
an 83% reduction of cervical cancer cases due to HPV 16/18 at 50
years after vaccine introduction, assuming constant vaccine
coverage and screening rates (Table 4).
Adding vaccination among males (scenario 2) to current
recommendations (considered in scenario 1) led to a similar
reduction in cervical cancer.
Considering a high coverage of vaccination (80% in scenario 3)
for women, a halving of numbers of new cervical cancers would be
expected 20 years after vaccine introduction. Adding vaccination
in men would not lead to a much better reduction in cervical
cancer cases (scenario 4).

females than scenario 2. This scenario considered vaccination with

a similar coverage in males and females aged 14 to 24.
The deterministic model that we developed takes into account
the reduction of male HPV 16/18 prevalence due to female
vaccination. Table 3 shows the expected reduction in male
prevalence for each scenario. The reduction of HPV prevalence in
men was similar to that in women in case of males and females
vaccination (in scenarios 2 and 4).
All in all, scenarios that considered vaccination only in females
had a lower impact on the reduction of HPV prevalence in males
compared to females.

Cervical cancer (Table 4)

Considering current vaccine coverage and screening in France
(scenario 1), a 32% reduction of incidence of cervical cancers due

Table 3. Prevalence of HPV 16/18 for men in each scenario 10, 20 and 50 years after initiation of vaccination (t = 0).

Prevalence of HPV 16/18 for men

10 years

20 years

50 years

Without vaccination

19.4%

19.4%

19.4%

Scenario 1

15.1% (222.2%)

10.9% (243.8%)

3.7% (280.9%)

Scenario 2

13.1% (232.5%)

7.8% (259.8%)

0.8% (295.9%)

Scenario 3

12.2% (237.1%)

7.3% (262.4%)

1.1% (294.3%)

Scenario 4

9.6% (250.5%)

4.3% (277.8%)

0.1% (299.5%)

Scenario 5

13.3% (231.4%)

8.2% (257.7%)

1.5% (292.3%)

Vaccine coverage was supposed constant in each scenario. In parentheses, % of reduction in HPV prevalence compared to the case without vaccination.
doi:10.1371/journal.pone.0032251.t003

Table 4. Incidence of cervical cancer due to HPV 16/18 in French women in each scenario 10, 20 and 50 years after initiation of
vaccination (t = 0).

Time after introduction of vaccine

10 years

20 years

50 years

100 years

Without vaccination

9.6

9.6

9.6

9.6

Scenario 1

8.9 (27.3%)

6.5 (232.3%)

1.6 (283%)

0.5 (294.8%)

Scenario 2

8.7 (29.4%)

6.0 (237.5%)

0.8 (291.7%)

0.02 (299.8%)

Scenario 3

8.1 (215.6%)

4.8 (250%)

0.5 (294.8%)

0.05 (299.5%)

Scenario 4

7.9 (217.7%)

4.2 (256.3%)

0.2 (297.9%)

,1025 (2100%)

Scenario 5

8.5 (211.5%)

5.3 (244.8%)

0.7 (292.7%)

0.07 (299.3%)

Vaccine coverage was supposed constant in each scenario. In parentheses, % of reduction in cervical cancer incidence compared to the case without vaccination.
doi:10.1371/journal.pone.0032251.t004

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Efficacy of Vaccination against HPV Infections

subpopulations of females due to vaccination coverage of other

individuals.
In the fitting procedure, probabilities of HPV 16/18 transmission for women and men were estimated to be of 0.25 and 0.20
respectively. The values that were yielded from our model are
close to published estimates from fitted deterministic models for
HPV [19,23]: in the susceptible-infected-susceptible (SIS) deterministic model developed by Taira et al [23], age-specific
probabilities ranged from 0.15 to 0.35.
Screening of precancerous lesions of the cervix and cervical
cancer using cervical smear tests is recommended in France.
Screening coverage has been estimated to be 58.7% in women of
25 to 65 years old in 2005; however, significant discrepancies were
observed between age-groups [34]. Screening was not directly
integrated in our model as we did not stratify on screening status.
Some authors distinguished between regularly screened women
and never-screened women [20]. Nonetheless, epidemiological
data regarding screening of cervical cancer and cervix precancerous lesions are limited in France. Therefore, our model was fitted
on incidence of cervical cancer in France and considered
regression of cervix precancerous lesions due to spontaneous
regression or treatment after screening. Screening represents a
complementary tool to prevent cervical cancers, especially in case
of precancerous lesions due to other high-risk HPV types than 16/
18 whereas current available vaccines protect against HPV16/18,
which are responsible for 70% of cervical cancers.
The study could not take into consideration future changes in
screening programs, using new screening policies or new screening
technologies on the market. In France, in 2010 Public Health
Agency (HAS) proposed to organize cervical cancer screening to
improve screening coverage. Moreover, use of new screening tools
may also modify current epidemiological data on HPV infections
and related cervical cancers. In the USA, the ACOG guidelines
(2009) and the American Cancer Society (2003) recommended
HPV-plus-pap testing in women aged 30 and older [35]. However,
in France, Public Health policies explicitly recommend the use of
HPV testing only in cases of abnormal cytology (www.has-sante.fr).
Efficacy of vaccination was assumed to last lifelong. Consequently, we did not include the need for vaccine booster shots in
our model. The protective effect of the vaccines is known to last at
least several years [36,37] and the need for boosters is currently
unknown.
The sophistication of deterministic models by adding strata
corresponding to uncertain data may lead to computational
difficulties and increase the uncertainty of outputs and parameters.
Thus, screening and use of booster shots were not included in our
model.
In sensitivity analyses that investigated the effect of an increase of
the sexual mixing parameter (e), we observed a decrease of HPV
16/18 prevalence after using a high value of e. This result is
consistent with that reported in Garnett and Anderson paper [27].
We observed that in the presence of frequent completely random
sexual mixing (when the value of e is far from the assortative sexual
mixing corresponding to e = 0), the infection is less likely to persist
endemically [27]. An explanatory mechanism regarding this finding
suggests that individuals in the higher sexually active group transmit
the infection to individuals in other sexual behavior groups which
are less sexually active and less likely to transmit infection.
This analysis shows that the value of e used in our base case
modeling is consistent with endemic prevalence of HPV infections.
Sexual mixing seems to be preferentially close to assortative case.
The modeling of sexual mixing that we developed in this paper
could be used in other models corresponding to the French sexual
behavior.

In scenario 5, females were vaccinated before 14 with a better

coverage than females over 14 (50% versus 30%). This scheme led
to better results than those from scenario 1 representing current
vaccination policy in France. A 45% reduction in cervical cancer
incidence could be expected 20 years after vaccine introduction in
scenario 5 while scenario 1 yielded a 32% reduction in cervical
cancer incidence.
Beyond discrepancies in terms of vaccination impact due to
vaccination policies, the scenarios we considered predicted a
significant reduction in cervical cancers and infections due to HPV
16/18. A disappearance of cervical cancer due to HPV 16/18
could be expected in a time horizon of 100 years (Table 4). The
impact of vaccination on the specific mortality due to cervical
cancer appears after decades (Table 5). A reduction by half of
annual deaths by cervical cancer could be expected 50 years after
the initiation of the vaccine.

Sensitivity analyses
In sensitivity analysis, we tested the impact of an increase of the
sexual mixing parameter that corresponded to an augmentation of
random mixing. A high value of the sexual mixing parameter
(e = 0.8) led to a 2% reduction of endemic prevalence of HPV
infections in males and females compared to the initial value of e
(0.4).
A lower efficacy of vaccine (60%) reduced the impact on HPV
prevalence and cervical cancer incidence. For instance, using
scenario 1, model predictions yielded 50 years after introduction of
vaccine a 25% higher HPV prevalence in females and a two-fold
increase of cervical cancer incidence compared to scenario 1 with
a 90% efficacy of vaccine.

Discussion
We developed a dynamical model for HPV transmission in a
heterosexual population to assess the impact of vaccination against
HPV infections on the incidence of cervical cancer in France. We
considered current vaccination policies and compared several
vaccination scenarios. We confirmed the effectiveness of vaccination against HPV to prevent infections and cervical cancers using
deterministic modeling [19,20,21,23]. However, the impact of
vaccination differed according to the various scenarios considered
in our paper. Vaccination coverage among young females under
14 and higher vaccination coverage in currently targeted females
(in France) improved the prevention of infections and cervical
cancers due to HPV 16/18 significantly.
The use of a deterministic model in our study allowed us to take
into account herd immunity, which corresponds to a decrease of
HPV 16/18 infections and cervical cancers in non-vaccinated
Table 5. Expected Diminution of number of deaths (per year)
due to cervical cancer after introduction of vaccine compared
to number of deaths without vaccine.

Time after introduction of vaccine

20 years 50 years 100 years

Scenario 1

25%

247%

288%

Scenario 2

26%

256%

297.5%

Scenario 3

28.84%

264%

297.2%

Scenario 4

210.58%

271%

299.4%

Scenario 5

27.16%

259%

296.17%

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Efficacy of Vaccination against HPV Infections

respiratory papillomatosis, cancers of the anus, penis, vagina,

vulva, and head and neck). Vaccination against HPV 16/18
infection is likely to reduce incidence of other cancers in the
anogenital area in males and female. Reduction of HPV-16/18
prevalence in men due to female vaccination could reduce the
incidence of some male cancers. These additional potential
benefits of HPV 16/18 vaccination have to be investigated by
developing specific dynamic models that consider the natural
history of the diseases.
Finally, some recent studies have shown the bivalent vaccines
protective effect against high-risk HPV types, which are not
targeted by it (HPV types 31 and 45) [48,49]. In this case, the
model may underestimate the benefit of vaccination on the
reduction of cervical cancer incidence as we did not take into
account cross-protection in our model.
In conclusion, we developed a deterministic model of HPV
heterosexual transmission and progression to cervical cancer to
assess the epidemiologic impact of HPV vaccination in France.
While current vaccination policies may decrease cervical cancer
incidence in France significantly, other complementary strategies
could be employed for females to improve vaccination efficacy.

Efficacy of both vaccines against HPV has been evaluated in

several randomized controlled trials [3638]. While vaccines are
highly effective in women who have never been infected with HPV
16/18, efficacy of vaccines could drop in women who have been
infected prior to vaccination. We considered in the base case
scenario a 90% efficacy of the vaccine against HPV 16/18
infection and 60% in sensitivity analysis. Sensitivity analysis
showed that if vaccine efficacy is poor, impact of vaccination on
the reduction of diseases linked to HPV 16/18 will be attenuated.
In previous papers assessing the impact of HPV vaccination,
assumed vaccine coverage had very high reaching values between 80% and 100%. Current vaccine coverage in France
has been estimated to be low, under 30%, and diminishing over
time [9]. Consequently, the impact of vaccination has to be
assessed using real life coverage data. In the first scenario, we
considered the female vaccine coverage (30%) that is currently
reached in France. In the other scenarios of female vaccination
(scenarios 3 and 5) we considered realistic alternatives. Finally, we
studied scenarios in which males were also vaccinated (scenario 2
and 4).
In the first scenario, we estimated the impact of vaccination on
HPV prevalence in male and female, on cervical cancer and on
specific mortality due to cervical cancer in the horizon of 10, 20,
50 and 100 years. We considered the vaccine coverage that was
observed in France at the beginning of the vaccination campaign
(in 2007 and 2008). This scenario predicts a decrease in cervical
cancer incidence due to HPV 16/18 by one third 20 years after
introduction of vaccine and a halving of deaths by cervical cancer.
In this scenario, we considered vaccine coverage to be constant in
time. However, female vaccine coverage in France is decreasing.
While 33.3% of girls aged 14 in 2007 were vaccinated with 3 doses
of the vaccine, only 23.7% and 5.4% of girls aged 14 were
vaccinated respectively in 2008 and 2009 [9]. Therefore, the
expected effect of the first scenario is probably over-estimated in
this paper.
In Scenario 3, we considered a high vaccine coverage for
women and young girls (80%), which yielded a better impact of
vaccination than scenario 1. In countries where school-based
vaccination programs have been implemented (The United
Kingdom and Australia), these vaccine coverage rates have been
reached [39,40]. It may be difficult to implement such a program
in France, as a previous school-based program of vaccination
against hepatitis B failed due to controversies [41].
In scenario 5, young girls could be vaccinated before 14. In
Europe, many countries recommend vaccination for females aged
12 [42]. Vaccination of young girls before 14 may improve vaccine
coverage and impact of vaccination in France. A better
compliance with complete vaccination (using 3 shots) is observed
in young females [9] who are little likely to be infected with HPV
prior to vaccination. However, the need of booster shots is still
unknown [36,37]. Nevertheless, if the long term efficacy of the
vaccine is to be confirmed, vaccination coverage among younger
girls will certainly improve the impact of vaccination. The French
committee of vaccination recommended the vaccine for girls aged
14 in 2006 [43]. We also investigated the possible vaccination of
boys and young men [4447]. In scenarios 2 and 4, we assessed
the impact of an additional male vaccination on the reduction of
HPV 16/18 prevalence (in males and females) and of cervical
cancer incidence in females. Performing vaccination in men
improves moderately the effect on HPV 16/18 prevalence and
cervical cancer incidence compared to vaccination strategies in
females only.
In this paper, we did not assess the impact of vaccination on
other cancers or diseases due to HPV 16/18 infections (Recurrent
PLoS ONE | www.plosone.org

Supporting Information
Appendix S1 Description of the mathematical model.

(DOC)
Figure S1 Distribution of women aged 14 to 84. Data
observed in France on 01/01/2006 in blue (www.insee.fr) versus
predicted by the demographic model in green.
(EPS)
Figure S2 Distribution of men aged 14 to 84. Data
observed in France on 01/01/2006 in blue (www.insee.fr) versus
predicted by the demographic model in green.
(EPS)
Figure S3 Number of new cases of cervical cancer due
to HPV 16/18 for 100,000 women per year. Published data
in blue [1], predicted by the model in green.
(EPS)
Figure S4 Female prevalence of HPV 16/18 infection
since introduction of vaccination (t = 0) in each scenario.
(TIF)
Figure S5 Male prevalence of HPV 16/18 infection since
introduction of vaccination (t = 0) in each scenario.
(TIF)
Figure S6 Evolution of cervical cancer incidence for
French women (number of new diagnosed cases annually per 100,000 women) after introduction of vaccination (t = 0).
(TIF)
Table S1 Initial distribution in the model in the 4
sexual-activity groups.
(DOC)
Table S2 Mixing matrix between age-group. Proportion

of individuals who have sexual contacts with partners in youngest

age-group (,), the same age-group ( = ) or older age group (.).
(DOC)
Table S3 Models parameters.

(DOC)
Table S4 Description of variables and parameters.

(DOC)
6

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Efficacy of Vaccination against HPV Infections

Table S5 French mortality rates.

Acknowledgments

(DOC)

The authors would like to thank the referees for their comments, Bilal
Majed for his invaluable help and Carole Birkan-Berz for her assistance in
the preparation of the manuscript in English.

Distribution of French population aged 14 to

84 (01/01/2006), source: National Institute of Statistics
(INSEE).
(DOC)
Table S6

Author Contributions

Table S7 Description of matrices used in implementa-

Conceived and designed the experiments: LM RL SC. Performed the

experiments: LM RL SC. Analyzed the data: LM RL SC. Contributed
reagents/materials/analysis tools: LM RL SC. Wrote the paper: LM RL.

tion.
(DOC)

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