REVIEW 10.1111/j.1469-0691.2012.03946.

Prophylactic human papillomavirus vaccination and primary prevention

of cervical cancer: issues and challenges

M. Poljak
Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

Abstract

Two prophylactic human papillomavirus (HPV) vaccines have been recently approved: one quadrivalent and the other a bivalent vaccine.
When administered in a three-dose course to HPV-naive individuals, both vaccines exhibited excellent safety profiles and were highly
efficacious against targeted clinical endpoints in large-scale international phase III clinical trials. Where coverage has been high for the
appropriate target population, a reduction of HPV-related diseases with the shortest incubation periods has already been seen. By
March 2012, universal HPV vaccination had been introduced into national vaccination programmes in more than 40 countries, but only
in a few low-income and middle-income countries. With the growing market for HPV vaccines and competition between manufacturers,
negotiated prices are already beginning to decline although they still remain out of reach of many countries. The great majority of coun-
tries are struggling to reach a level of coverage that will have the most impact on cervical cancer rates. Increasing coverage and improv-
ing completion of the HPV vaccine schedule, particularly of sexually naive females, is now the most important public-health issue in HPV
vaccine efforts. A clear strategy for integrating primary (HPV vaccination) and secondary (screening) cervical cancer prevention must be
agreed as soon as possible. Several second-generation prophylactic vaccines are being developed with the aim of resolving some of the
limitations of the two current HPV prophylactic vaccines.

Keywords: Cervical cancer, human papillomaviruses, vaccination

Original Submission: 25 March 2012; Accepted: 9 May 2012
Editor: M. Paul
Clin Microbiol Infect 2012; 18 (Suppl. 5): 6469
Corresponding author: M. Poljak, Institute of Microbiology and
Immunology, Medical Faculty, Zaloska 4, 1105 Ljubljana, Slovenia
E-mail: mario.poljak@mf.uni-lj.si
Human papillomaviruses
Human papillomaviruses (HPV) are aetiologically linked to
various benign and malignant neoplastic lesions of mucosal
and skin epithelia. At present, 148 distinct HPV types are
officially recognized, ranging from HPV-1 to HPV-152 (HPV-
46, HPV-55, HPV-64 and HPV-79, which have not met the
criteria as unique HPVs, are now classified as subtypes) [1].
All known HPV types are classified on the basis of the simi-
larity of their genome into five genera (a, b, c, l, m) and 33
species. Approximately 40 HPV types from the a genus infect
the mucosal epithelium, with a subset of 12 types that are
associated with lesions that can progress to cancer [2].
These cancer-associated or high-risk HPVs are the aetiologi-
cal agents of virtually all cervical carcinomas and their
immediate precursorshigh-grade cervical intraepithelial
neoplasias. The two most important high-risk types are HPV-
16 and HPV-18, which are found in 70% of cases of cervical
cancer. In addition to cervical carcinoma, high-risk HPVs also
play the leading aetiological role in the development of anal
and vaginal cancers and a substantial proportion of penile,
vulvar and oropharyngeal (tonsillar) cancers. Low-risk HPV
genotypes (the most important are HPV-6 and HPV-11) are
causally involved in the development of virtually all genital
warts and laryngeal squamous cell papillomas of both
genders.
The burden of HPV-associated
vaccine-preventable tumours
Cervical cancer is the third most common cancer in women,
causing an estimated 530 232 cases and 275 008 deaths in
2008 [3]. Cytological screening has dramatically reduced the
burden of cervical cancer in countries that have implemented
wide-scale screening programmes. The major burden of cer-
vical cancer (over 85%) today therefore occurs in developing
countries with little or no access to screening programmes
[4]. Although other HPV-associated cancers are significantly
rarer than cervical cancer, a recent analysis of US cancer

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Clinical Microbiology and Infection 2012 European Society of Clinical Microbiology and Infectious Diseases
CMI Poljak HPV vaccination: issues and challenges 65

registry data estimated that the total HPV-related cancer
burden for non-cervical cancers in the USA is of the same
magnitude as their cervical cancer burden [5]. A recent study
showed a remarkable increase in the population-level inci-
dence of HPV-positive oropharyngeal cancers from 1988 to
2004 in the USA and predicted that by 2020, the annual
number of HPV-positive oropharyngeal cancers will surpass
that of cervical cancers [6]. Genital warts are common and
frequently self-limiting benign tumours but they pose a con-
siderable burden because of the embarrassment, shame, pain
and financial costs of treatment [4]. Laryngeal squamous cell
papillomas are a rare disease (incidence 14 per 100 000)
associated with high morbidity and with potentially devastat-
ing consequences for the patient.
Current HPV prophylactic vaccines
Two prophylactic HPV vaccines have so far been approved
by the European Medicines Agency and the US Food and
Drug Administration: a quadrivalent vaccine targeting HPV-6,
HPV-11, HPV-16 and HPV-18 (Gardasil or Silgard; Merck
and Co., Whitehouse Station, NJ, USA) and a bivalent vac-
cine targeting HPV-16 and HPV-18 (Cervarix; GlaxoSmithK-
line, London, UK). Current European Medicines Agency and
US Food and Drug Administration indications for both vac-
cines are presented in Table 1. Both vaccines contain L1
virus-like particles of the respective HPV types, which con-
tain no HPV DNA and are neither infectious nor oncogenic.
The quadrivalent vaccine uses an aluminium salts adjuvant
and the bivalent vaccine uses an AS04 adjuvant system.
When administered in a three-dose course to HPV-naive
individuals, both vaccines exhibited excellent safety profiles
and were highly efficacious against targeted clinical endpoints
in large-scale international phase III clinical trials [714]. In
addition, the first evidence of the impact of HPV vaccination
in the general population recently came from Australia, one
of the first countries to introduce free universal HPV vacci-
nation, with a three-dose coverage of 70% in women aged
1226 years [15]. Studies from Australian sexual health clin-
ics have shown a remarkable decline in the incidence of geni-
tal warts [16,17] and from the Victorian Cervical Cytology
Registry a modest but significant decline in histologically con-
firmed high-grade cervical lesions since the implementation
of HPV vaccination with the quadrivalent HPV vaccine in
2007 [18]. There was also a 39% decline in the incidence of
genital warts among heterosexual men of the same age (non-
vaccinated population), but not among older women or men
who have sex with men, which provides the first evidence of
a possible herd immunity effect of HPV vaccine [16].
Several in-depth reviews of the safety and efficacy of current
prophylactic HPV vaccines are available in the literature
[11,1923]. The purpose of this review is to provide a brief
summary of the most important current issues and challenges.
Current status of HPV vaccine
implementation
Since 2006, the quadrivalent and bivalent vaccines have each
been licensed in more than 110 countries. Over 120 million
doses of the vaccines have already been distributed. By
March 2012, universal HPV vaccination had been introduced
into national vaccination programmes in more than 40 coun-
tries across all continents. The USA, Australia and Canada
were among the first countries to introduce HPV vaccine
into their national immunization programmes, followed by sev-
eral European countries (currently 23 European countries).

TABLE 1. US Food and Drug Administration (FDA) and European Medicines Agency (EMA) indications for quadrivalent
vaccine (Gardasil) and a bivalent vaccine (Cervarix), as of March 2012

FDA EMA

Gardasil Gardasil is a vaccine indicated in girls and women 9 through 26 years of age for the prevention of the Gardasil is a vaccine for use from the age of 9 years
following diseases caused by human papillomavirus (HPV) types included in the vaccine: cervical, for the prevention of: premalignant genital lesions
vulvar, vaginal and anal cancer caused by HPV types 16 and 18 and genital warts (condyloma (cervical, vulvar and vaginal) and cervical cancer
acuminata) caused by HPV types 6 and 11 and the following precancerous or dysplastic lesions caused causally related to certain oncogenic human
by HPV types 6, 11, 16 and 18: cervical intraepithelial neoplasia (CIN) grade 2/3 and cervical papillomavirus (HPV) types and genital warts
adenocarcinoma in situ (AIS), cervical intraepithelial neoplasia (CIN) grade 1, vulvar intraepithelial (condyloma acuminata) causally related to specific
neoplasia (VIN) grade 2 and grade 3, vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3 and HPV types
anal intraepithelial neoplasia (AIN) grades 1, 2 and 3
Gardasil is indicated in boys and men 9 through 26 years of age for the prevention of the following
diseases caused by HPV types included in the vaccine: anal cancer caused by HPV types 16 and 18
and genital warts (condyloma acuminata) caused by HPV types 6 and 11 and the following
precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18: anal intraepithelial neoplasia
(AIN) grades 1, 2 and 3
Cervarix Cervarix is a vaccine indicated for the prevention of the following diseases caused by oncogenic human Cervarix is a vaccine for use from the age of 9 years
papillomavirus (HPV) types 16 and 18: cervical cancer, cervical intraepithelial neoplasia (CIN) grade 2 for the prevention of premalignant cervical lesions
or worse and adenocarcinoma in situ, and cervical intraepithelial neoplasia (CIN) grade 1. Cervarix is and cervical cancer causally related to certain
approved for use in females 9 through 25 years of age oncogenic human papillomavirus (HPV) types

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66 Clinical Microbiology and Infection, Volume 18 Supplement 5, October 2012
Unfortunately, only a few low-income and middle-income
countries had implemented vaccination in their national vacci-
nation programmes by March 2012, mainly because of the high
cost of vaccines. Panama and Mexico were among the first
middle-income countries to introduce the HPV vaccine;
Rwanda and Bhutan initiated national programmes only after
having received vaccine through donations. The majority of
countries implementing HPV vaccination have similar core vac-
cine recommendations, primarily targeting 914-year-old
females (several countries only a single age group) but they dif-
fer significantly in catch-up recommendations (from none to all
females of 1226 years of age). Public financing for HPV vacci-
nation applies several approaches, ranging from free of charge
availability to recommended populations (the majority of coun-
tries), free of charge availability to selected populations (e.g.
US Vaccines for Children Program) or availability against reim-
bursement, including patient co-payment (e.g. France) [24].
Unresolved fundamental issues
There are still several gaps in our understanding of the cur-
rent performance of HPV vaccines. The most important
unresolved fundamental issues are the duration of protection
and the question of whether booster vaccinations are neces-
sary and, if so, when. The duration of protection provided
by the current vaccines is unknown but is over 8.4 years for
the bivalent vaccine, over 5 years for the quadrivalent vac-
cine and over 9 years for the monovalent HPV-16 vaccinea
non-commercial precursor to the quadrivalent vaccine [4]. It
is also unclear whether a higher level of serum antibodies
correlates with longer disease protection, because the mini-
mum level of serum antibodies required to protect women
from genital infection (immune correlate of protection) has
not been established, and particularly because of the extre-
mely small number of breakthrough infections detected in
the clinical trials [25]. A recent finding that mice are pro-
tected from cervicovaginal challenge with HPV-16 pseudoviri-
ons, even if they have serum levels of antibodies that are
500-fold lower than the minimum that can be detected in an
in vitro neutralization assay [26], suggests the possibility that
detection of any vaccine-induced serum antibodies in women
using standard assays indicates a level that is well above the
minimum needed for protection [27].
Another important unresolved basic issue is the clinical
significance of cross-protection or the efficacy of HPV vac-
cines against HPV types not specifically targeted by inclusion
of the corresponding virus-like particles in the vaccine.
Cross-protection against non-vaccine types is an important
consideration, because non-vaccine HPV types are associated
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Clinical Microbiology and Infection 2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18 (Suppl. 5), 6469
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with c.30% of cervical cancers worldwide [27]. Although none
of the phase III trials was specifically designed to evaluate
cross-protection, both vaccines have been post hoc evaluated
for protection against infection and cervical disease associated
with HPV types phylogenetically related to HPV-16 and HPV-
18 [25]. Some cross-protection has been demonstrated for
both vaccines in these analyses [13,28], although with a lower
level of efficacy, with lower cross-neutralizing antibody titres
and an unknown duration of clinical efficacy [18]. Evidence
from a long-term follow up of a phase IIb trial of bivalent vac-
cine [29], suggests that the cross-protection recorded in the
clinical trials might preferentially wane over time.
Another question often raised is whether type replace-
menta viral population dynamics phenomenon defined as
the elimination of some types, causing an increase of others,
will be seen after the implementation of large-scale vaccina-
tion [30]. Type replacement occurs when partial competition
exists among different types during natural infection and the
vaccine does not provide cross-protection against competing
types [31]. In HPV, natural competition does not appear to
exist so type replacement is highly unlikely [30]. There is
also a potential theoretical risk that a vaccine will generate
new viral variants that are equally or even more oncogenic
but not recognized by vaccine-induced antibodies. However,
as HPV uses host cell DNA polymerases and has an extre-
mely slow mutation rate, this risk is also minimal [30].
Increasing coverage and improving
completion of the HPV vaccine schedule
The proof-of-principle phase of HPV vaccine development is
over [32]. Increasing coverage and improving completion of
the HPV vaccine schedule, particularly of sexually naive pre-
adolescent and adolescent females, is therefore now the
most important public-health issue in HPV vaccine efforts
[32,33]. At least 80% of sexually naive females need to be
vaccinated against HPV if a major reduction in cervical can-
cer rates in women aged 2029 years is to be achieved by
2025. Unfortunately, the great majority of countries are
struggling to achieve high coverage or to reach the level of
coverage that will have the maximum impact on cervical can-
cer rates [19,24,34]. Numerous factors have contributed to
the markedly different levels of coverage achieved to date,
including public financing for vaccines, organized outreach to
parents and girls, and acceptability, in addition to several
paramedical reasons. In general, countries with school-based
vaccination programmes have achieved higher coverage than
those with opportunistic, clinic-based or primary care based
programmes [35]. However, many countries lack any infra-
CMI
structure or experience in school-based vaccine delivery and
school attendance among girls is low in some developing
countries, so school-based vaccination is not necessarily the
best option for all countries [4]. Anti-immunization groups
spreading unfounded rumours and misinformation about
HPV vaccine safety and claims that the vaccine is licensed
and recommended only to increase corporate profits have
severely damaged HPV immunization efforts in many coun-
tries, including some European countries [24]. Most misinfor-
mation about HPV involves rumours that HPV vaccines have
caused deaths among vaccine recipients. Responsible investi-
gation of these incidents, however, has shown that no deaths
have ever been related to the vaccine [24,36]. In Romania, a
national school-based programme to vaccinate females aged
11 was launched but has already temporarily been suspended
twice (in 2008 and 2010/11) because of negative public reac-
tion, lack of proper communication and a resulting low cov-
erage of the target population, which did not reach 5%. In
contrast, the UK has achieved remarkably high coverage in
their targeted primary cohorts, through school-based deliv-
ery [24]. Whether this is a result of intensive follow up at
the local level, facilitated by the availability of identification of
individuals within each areas responsibility for vaccination,
effective social marketing or supportive community attitudes
following a highly publicized death of a young woman from
cervical cancer is unclear [4].
Monitoring long-term safety and vaccine
disease efficacy
Given the likely absence of further large phase III clinical tri-
als, it is extremely important that countries that have already
implemented national vaccination programmes comprehen-
sively evaluate long-term safety and any breakthrough infec-
tions of HPV vaccine types over the short and longer term
[37]. Additionally, there are various ongoing international
efforts to monitor the post-licensure impact of HPV vaccine
on a global scale. Both manufacturers have strict post-licen-
sure commitments to tightly monitor a proportion of
women who were enrolled in the phase III trials [35]. A sub-
stantial amount of post-licensure safety data have already
been accumulated and available data are reassuring [35,36].
Integration of primary and secondary
cervical cancer prevention
A clear strategy for integrating primary (HPV vaccination)
and secondary (screening) cervical cancer prevention must
Clinical Microbiology and Infection 2012 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18 (Suppl. 5), 6469
Poljak HPV vaccination: issues and challenges 67
be agreed as soon as possible [4,19,37]. An immediate neces-
sary step is the linkage of an individuals HPV vaccination and
cervical screening history. The implementation of HPV vacci-
nation in each country should therefore be accompanied by
the immediate establishment of a central (national/regional)
HPV vaccination register, which should be linked with the
cervical cancer screening register and central cancer register.
In addition, cervical screening guidelines must be reviewed in
the next 510 years. Because current HPV vaccines do not
cover all cancer-associated HPV types, vaccination cannot
yet replace screening. New cervical screening algorithms will
certainly incorporate an HPV DNA test as the initial screen-
ing test (at least for vaccinated cohorts), because it provides
superior and more durable negative predictive value against
high-grade cervical disease than cytology and allows safe pro-
longed screening rounds [4]. A primary HPV DNA test has
the advantage of immediately stratifying women into a cur-
rent risk group based on the presence of high-risk HPVs at
the time of screening, regardless of vaccination history
[4,38]. HPV DNA-positive women will need a further triage
using cytology, partial HPV typing or progression markers,
because >90% of these women will have transient HPV infec-
tion that will resolve spontaneously and not progress to can-
cer.
Gender-neutral HPV vaccination
HPV vaccination efforts have so far been primarily targeted
at females. However, after recent US Food and Drug Admin-
istration approval of a quadrivalent vaccine for males and the
recent recommendations of the Advisory Committee on
Immunization Practices of the US Centers for Disease Con-
trol and Prevention [39] and American Academy of Pediat-
rics [40] for the routine use of quadrivalent vaccine in boys
aged 11 or 12 years, HPV vaccination can no longer be
viewed as a female-only issue. Although the routine HPV vac-
cination of males is still controversial in many settings, par-
tially because of the conflicting results of cost-effectiveness
studies [41], ever more professionals are persuaded that
gender neutral HPV vaccination is the only way forward. A
universal HPV vaccination programme including males would
not only provide direct protection against HPV-related dis-
eases in males (genital warts, anal, penile and oropharyngeal
cancers, particularly among men who have sex with men)
but would also have significant indirect effects by providing
herd immunity benefits to their female partners [4]. Such
herd immunity benefits may be of utmost importance, and
be a fairly cost-effective option, especially in countries in
which female coverage cannot be feasibly increased [4,41].
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68 Clinical Microbiology and Infection, Volume 18 Supplement 5, October 2012
Achieving a more affordable price of HPV
vaccines
The arrival of HPV vaccines heralded a new era for cervical
cancer prevention but unless there are mechanisms to make
them affordable, their benefits will not be fully realized in
many settings. HPV vaccines are the most expensive vaccines
to have been developed [4]. Given the growing market for
HPV vaccines and competition between manufacturers, nego-
tiated prices are already beginning to decline, although they
still remain beyond the reach of many countries.
In 2009, the WHO issued important recommendations for
HPV vaccination and prequalified both HPV vaccines, so
allowing procurement by the United Nations Childrens Fund
(UNICEF) and other United Nations agencies. The GAVI Alli-
ance, which strongly supports widespread implementation of
vaccines in the developing world, recently added HPV vac-
cines to its list of vaccines subsidized in the poorest countries,
thanks in part to tiered pricing by the manufacturers, which
dramatically reduces the cost of each dose, even to as low as
US$5.00 per dose [27]. Other mechanisms include making
use of the collective purchase potential of countries in negoti-
ating prices together. The Pan American Health Organization
Revolving Fund is one such example, whereby countries pay
for vaccines obtained at very low prices and as negotiated by
the Pan American Health Organization; a price of US$14 per
dose has been recently achieved through this effort [34].
Another possibility of reducing the price of HPV vaccina-
tion is modification of the current three-dose vaccination
schedule. Recent studies of the efficacy of a two-dose sche-
dule versus the standard three-dose schedule have shown
that a two-dose schedule is immunogenic and generally well
tolerated, and may be sufficient for long-term efficacy
[42,43]; however, further data are required.
Second generation of HPV prophylactic
vaccines
Several second-generation prophylactic vaccines are being
developed, aimed at resolving some of the limitations of the
two current HPV prophylactic vaccines. A nonavalent vac-
cine, which, in addition to the four HPV types in the current
quadrivalent vaccine, contains L1 viral-like proteins of HPV-
31, HPV-33, HPV-45, HPV-52 and HPV-58, is in the advanced
stage of phase III efficacy trials. Other candidates for second-
generation vaccines that have shown promising results in
preclinical studies are vaccines based on L1-pentameric su-
bunits and vaccines based on the minor virion protein L2.
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For timely evaluation of the clinical efficacy of these poten-
tially broad-range vaccines targeting several HPV types, we
will need more frequent and shorter-term vaccine efficacy
endpoints, because clinical trials of second-generation vac-
cines against less-prevalent HPV types with cervical intraepi-
thelial grade 2+ as a primary outcome, will be prohibitively
expensive and will take many years to complete [37].
Conclusions
Two HPV vaccines have been proven to be safe and effective
and are licensed in more than 110 countries; they are
already implemented in national vaccination programmes in
over 40 countries across the globe. The primary focus must
now be on practical implementation issues and adaptations
to specific regional circumstances so as to maximize the
delivery of the vaccines to the individuals that are most likely
to benefit from them [32,37].
Transparency declaration
Dr Poljak has been an advisory board member for Glaxo-
SmithKline, has received speakers honoraria and travel
grants from GlaxoSmithKline and Merck and Co., and
research grants from Merck and Co.
Conflicts of interest
The author has no other conflicts of interest to declare
other then those listed in Transparency declaration.
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2012 The Author