Vaccine 30S (2012) F139–F148
Contents lists available at SciVerse ScienceDirect
Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Review
Human Papillomavirus Vaccine Introduction – The First Five Years
Lauri E. Markowitz a,∗ , Vivien Tsu b , Shelley L. Deeks c , Heather Cubie d , Susan A. Wang e ,
Andrea S. Vicari f , Julia M.L. Brotherton g
a
Centers for Disease Control and Prevention, 1600 Clifton Rd, Atlanta, Georgia, 30333, US
PATH, P.O. Box 900922, Seattle, Washington, 98109, US
Public Health Ontario, 480 University Ave, Suite 300, Toronto, Ontario M5G1V2, Canada
d
National HPV Reference Laboratory, Royal Infirmary of Edinburgh, 51 Little France Cres, Edinburgh EH16 4SA, Scotland
e
Expanded Programme on Immunization, Department of Immunization, Vaccines and Biologicals, World Health Organization, Geneva, Switzerland
f
Comprehensive Family Immunization Project, Pan American Health Organization, Apartado 3745, San Jose, Costa Rica
g
Victorian Cytology Service Registries, PO Box 310, East Melbourne, Victoria 8002, Australia
b
c
a r t i c l e
i n f o
Article history:
Received 10 February 2012
Received in revised form 7 May 2012
Accepted 8 May 2012
Keywords:
HPV
vaccine introduction
vaccine acceptability
a b s t r a c t
The availability of prophylactic human papillomavirus (HPV) vaccines has provided powerful tools for primary prevention of cervical cancer and other HPV-associated diseases. Since 2006, the quadrivalent and
bivalent vaccines have each been licensed in over 100 countries. By the beginning of 2012, HPV vaccine
had been introduced into national immunization programs in at least 40 countries. Australia, the United
Kingdom, the United States, and Canada were among the first countries to introduce HPV vaccination. In
Europe, the number of countries having introduced vaccine increased from 3 in 2007 to 22 at the beginning of 2012. While all country programs target young adolescent girls, specific target age groups vary as
do catch-up recommendations. Different health care systems and infrastructure have resulted in varied
implementation strategies, with some countries delivering vaccine in schools and others through health
centers or primary care providers. Within the first 5 years after vaccines became available, few low- or
middle-income countries had introduced HPV vaccine. The main reason was budgetary constraints due
to the high vaccine cost. Bhutan and Rwanda implemented national immunization after receiving vaccine through donation programs in 2010 and 2011, respectively. The GAVI Alliance decision in 2011 to
support HPV vaccination should increase implementation in low-income countries. Evaluation of vaccination programs includes monitoring of coverage, safety, and impact. Vaccine safety monitoring is part of
routine activities in many countries. Safety evaluations are important and communication about vaccine
safety is critical, as events temporally associated with vaccination can be falsely attributed to vaccination.
Anti-vaccination efforts, in part related to concerns about safety, have been mounted in several countries.
In the 5 years since HPV vaccines were licensed, there have been successes as well as challenges with
vaccine introduction and implementation. Further progress is anticipated in the coming years, especially
in low- and middle-income countries where the need for vaccine is greatest.
This article forms part of a special supplement entitled “Comprehensive Control of HPV Infections and
Related Diseases” Vaccine Volume 30, Supplement 5, 2012.
Published by Elsevier Ltd.
1. Introduction
The availability of prophylactic human papillomavirus (HPV)
vaccines has provided powerful tools for primary prevention of cervical cancer and other HPV-associated diseases. The realization of
disease reduction from these vaccines requires a variety of steps
including policy, financing, communications, delivery through public health programs and acceptance by the public. Since 2006,
quadrivalent vaccine (Gardasil/Silgard® , Merck & Co., Whitehouse
∗ Corresponding author. Tel.: +1 404 639 8359; fax: +1 440 639 8610.
E-mail address: [email protected] (L.E. Markowitz).
0264-410X/$ – see front matter. Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.vaccine.2012.05.039
Station, NJ USA) and bivalent vaccine (Cervarix® , GlaxoSmithKline
Biologicals, Rixensart, Belgium) have each been licensed in over 100
countries worldwide. By the beginning of 2012, national vaccination programs had been introduced in at least 39 countries.
HPV vaccines could have their greatest impact in low- and
middle-income countries, where over 80% of new cervical cancers occur and where cervical cancer screening programs do not
exist or are limited [1]. However, within the first few years
after vaccines became available, few countries outside of North
America, Australia and Europe had implemented vaccination programs. The main reason was budgetary constraints; however, there
were other impediments to the introduction or realization of successful programs. This review summarizes the status of global
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L.E. Markowitz et al. / Vaccine 30S (2012) F139–F148
HPV vaccine introduction into national programs through the
beginning of 2012.
2. Vaccine introduction in high-income countries
The United States (US), Australia, Canada and the United Kingdom (UK) were among the first countries to introduce HPV vaccine
into their national immunization programs. In Europe, the number
of countries having introduced vaccine increased from 3 in 2007
to 22 at the beginning of 2012. While all country programs target
young adolescent girls, specific target age groups differ as do catchup vaccination recommendations (Table 1). Different health care
systems and infrastructure have resulted in varied implementation
strategies.
2.1. North America
In the US, quadrivalent vaccine was introduced in 2006 with
routine vaccination recommended for girls aged 11 or 12 years and
catch-up vaccination for females 13–26 years [2]. In 2009, bivalent
vaccine was licensed and either HPV vaccine was recommended
for routine and catch-up vaccination of females. Most HPV vaccine
administered has been quadrivalent vaccine. In the US, there is both
public and private financing for vaccines. The Vaccines for Children
Program (VFC) supplies private and public health care providers
with federally purchased vaccines for use among eligible children
ages 0–18 years. An estimated 32% of adolescents are eligible for
VFC [3]; most private insurance covers HPV vaccine for those in
the recommended target and catch-up groups. Most HPV vaccine is
delivered in traditional primary care settings. Coverage with at least
one dose of HPV vaccine among girls aged 13–17 years increased
from 25% in 2007 to 49% in 2010 [4]. In 2010, coverage with three
doses was 32%. There were wide variations by state, with vaccine
initiation ranging from 29–73%. HPV vaccine has raised philosophical, legal, policy and safety concerns in the US [5,6]. School entry
requirements or mandates have been effective in raising immunization coverage for other vaccines. However, proposals to use
state laws to mandate HPV vaccine soon after vaccine introduction
were controversial and enacted in only two jurisdictions.
In 2009, quadrivalent HPV vaccine was licensed for use in males;
the Advisory Committee on Immunization Practices (ACIP), which
makes recommendations for vaccine use in the US, provided guidance that the vaccine could be used in males, but did not include
vaccine for males in the routine adolescent vaccination schedule. In
2011, ACIP reconsidered HPV vaccine for males and recommended
routine vaccination at age 11 or 12 years and through age 21 years
for those not previously vaccinated [7].
National recommendations in Canada are that all provinces
and territories implement school-based vaccination for girls in
at least one grade (grade 4–8, ages approximately 9–13 years)
with optional catch-up vaccination [8]. Both bivalent and quadrivalent vaccines are available. All jurisdictions implemented publicly
funded school-based vaccination programs delivered by public
health between 2007 and 2009, in at least one of the recommended
grades [8–10]. Target age groups and dosing schedules vary, but
all provinces and territories offer quadrivalent HPV vaccine, free of
charge, to girls in at least one of grades 4–8. A time-limited catch-up
program was also offered in 10 of the 13 jurisdictions [10]. While
most jurisdictions used a 0, 2, 6 month dosing schedule, a modified schedule was introduced in Quebec. Two doses of vaccine are
given in grade 4 (aged 9 and 10 years) 6 months apart, with the third
dose 5 years later. British Columbia also began using this extended
dosing schedule for girls in grade 6 in 2010. Among jurisdictions
reporting, series coverage (three doses, or two doses in provinces
with the modified dosing schedule) ranged from 80–85% in the
eastern provinces to 51% in Ontario, after the first year of program
implementation; Ontario’s coverage increased to 58% in its second
year.
2.2. Australia
In Australia, a publicly funded program started in 2007 using
quadrivalent HPV vaccine. The vaccination program included
school-based vaccination of girls aged 12–13 years and a 2-year
catch-up program (2007–2009) for those 13–17 years, also delivered through schools. The government funded a 2-year catch-up
program for females not in school up to 26 years of age starting
in July 2007. Vaccine for this initiative was delivered by primary
care providers. The school-based vaccination program in Australia
achieved high coverage with over 70% of girls in the targeted age
groups having received three doses of vaccine [11]. Among women
in the catch-up age group of 18–26 years, 55% received at least one
dose and 32% three doses (as notified to the national register) [12].
True coverage was likely at least 5–10% higher, as notification to
the register in this age group is not compulsory.
2.3. Europe
At least 22 countries in Europe, including most countries in
Western Europe, had introduced HPV vaccine into their national
immunization programs by the beginning of 2012 [13–15]. Recommendations target adolescent girls and some provide for catch-up
to varying degrees for older age groups. Public funding of HPV vaccination varies [14]. The majority of countries are delivering vaccine
through health centers or primary care providers, while some vaccinate through school-based programs. Selected examples below
show the variation in vaccine implementation across Europe.
In the UK, bivalent HPV vaccine was introduced in a publicly
funded, school-based immunization program in September 2008
for girls aged 12–13 years. A catch-up program for females up to
the age of 18 years, both in- and out-of-school, was also offered
for 2 years in England, Wales and Northern Ireland and for 3
years in Scotland. In 2008/09, three-dose coverage for girls aged
12–13 years was 84% and 92% in England and Scotland, respectively. Uptake was largely maintained in 2009/10, at 74% and 90%,
respectively [16,17]. Starting in September 2012, the national HPV
immunization program will use quadrivalent vaccine across all four
countries of the UK.
In France, quadrivalent HPV vaccine has been available since
2007 and bivalent vaccine since 2008. Vaccination is recommended
for girls aged 14 years with catch-up for those 15–23 years (for
those who have not had sexual relations or are within one year of
onset of sexual activity) [18,19]. Vaccine is delivered through clinics and routine care providers. While there is public funding for
the program, 35% of the vaccine cost is not reimbursable by the
National Health Insurance. Coverage with at least one dose (based
on reimbursement data) in 14 year-old girls was 50%, 42% and 20%
in 2007, 2008, and 2009, respectively. Reasons for the low and
potentially decreasing coverage in France could include the partial price that is not reimbursable (ranging from 117 to 142 Euros)
[19], public or medical establishment concerns about vaccine safety
for an outcome that can be prevented by screening [20], concerns
about cost-effectiveness compared with increased screening coverage [19], or lack of active public health promotion.
Denmark introduced quadrivalent HPV vaccine in 2009, with a
target age of 12 years and a 2-year catch-up program for girls 13-15
years. Publically funded vaccine is delivered through general practitioners. HPV vaccine was given at the same time as the second dose
measles, mumps and rubella vaccine (MMR), an established part of
the immunization schedule in Denmark [21]. An invitation letter
was sent to all girls born in 1996 and their parents by mail, asking
L.E. Markowitz et al. / Vaccine 30S (2012) F139–F148
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Table 1
Countries that have included HPV vaccine in their national immunization programs, date, target age groups and coverage, 2006–2011a .
Region/Country
Europe
Austriad
Belgiume
Denmark
France
Germany
Greece
Greenland
Ireland
Italy
Latvia
Luxemburg
FYR Macedonia
Netherlands
Norway
Portugal
Romania
San Marino
Slovenia
Spain
Sweden
Switzerland
United Kingdom
Americas
Argentina
Canadaf
Mexicof
Panama
Peru
United Statesh
South East Asia
Bhutan
Eastern Mediterranean
Abu Dhabi, UAE
Western Pacific
Australia
Cook Islands
Fijii
Kiribati
Malaysia
FS Micronesiaj
Marshall Islandsj
New Zealand
Palauj
Singapore
Africa
Rwanda
Year introduced
Target age group or
grade for femalesb
2006
2007
2009
2007
2007
2008
2008
2010
2007–2008
2010
2008
2010
2010
2009
2009
2009
2009
2009
2008
2012
2008
2008
Females/males
12–18
12
14
12–17
12–15
12
12–13
11
12
12
12
12
11–12
13
9–12
NA
11–12
11–14
11–12
10–14
12–13
2011
2007–2009
2008
2008
2011
2006
11
Varies by province
9–12
10
10
11–12
2010
Catch-up age group
13–18
13–15
15–23
13–15
Varies by region [14]
13–18
13–26
13–16
17
13-18
through age 19
13–17
Delivery for primary
target group
Varies by region
PC/Health centers
PC/Health centers
PC/Health centers
PC/health centers
Mixed
PC/Health centers
PC/Health centers
Mixed
PC/Health centers
Schools
Mixed
Schools
PC/health centers
Mixed
Schools
Varies by region
Schools
Mixed
Schools
Estimated 3-dose
coveragec % (calendar year)
82% (2010) [91]
79%(2009) [15]
24% (2008) [13]
56% (2009) [13]
17% (2009) [13]
67% (2011) [92]
63% (2011) [15]
81% (2009) [13]
55% (2010) [92]
77% (2008) [23]
84-92% (2009) [16,17]
13–26
Mixed
Schools
Mixed
Mixed
Schools
PC/Health centers
12
13–18
Mixed
2008
15–17
18–26
Schools
59% (2011) [72]
2007
2011
2008
2011
2010
2009
2008
2008
2009
2010
12–13
9–13
NA
NA
PG 7 (age 13)
11-12
11-12
PG 8 (age 12)
11–12
9–26
13–26
Schools
71% (2009) [11]
13–18
Schools
PC/Health centers
PC/Health centers
Mixedk
PC/Health centers
PC/Health centers
2011
PG 6
In year 2 and 3, PG 6 and
SG 3 (9th school year)
Varies by province
13–18
Varies by province
67%g (2010) [35]
67% (2010) [35]
32% (2010) [4]
40% (2010) [93]
Schoolsl
PG: Primary school grade; SG: Secondary school grade; PC: Primary care providers; UAE: United Arab Emirates; FYR: Former Yugoslav Republic; NA: Not available; FS:
Federated States of Micronesia; Mixed: Schools, primary care and health centers.
a
Information in this table was obtained from published data, presentations or personal communications; completeness and quality of data may vary for the different
countries and data may not be complete.
b
Target age group in years. When a school grade is targeted, the age group desired for targeting is in ().
c
Data obtained from published data or data posted on official websites; data not available for all countries; different methods were used to evaluate vaccine coverage;
comparisons between countries not possible.
d
Vaccination recommended for males and females before sexual debut. No public funding of HPV vaccination.
e
Health care in Belgium is the responsibility of three different communities, Flemish, Germanophonic and French; Program and policies vary by community. Coverage
provided in table is for Flemish community.
f
Extended dosing schedule being used in Mexico, two provinces in Canada (Quebec and British Columbia): doses at 0, 6, and 60 months.
g
Two-dose coverage for the extended dosing schedule adopted in 2009, targeting girls aged 9–12 years for the first two doses.
h
In December 2011, quadrivalent HPV vaccine for males 11–12 years was included in the routine immunization schedule. Catch-up recommended through age 21 for
those not previously vaccinated.
i
Unsuccessful initial introduction; reintroduced in 2012.
j
Personal communication, M Larzelere, Project Officer, Immunization Services Division, CDC.
k
Mainly schools.
l
Out-of-school 12 year-old girls were also targeted.
them to contact their general practitioner for HPV vaccination. In
the first year of the program, three-dose coverage was estimated
to be 79% in the primary target age group and 81% in the catch-up
age group [15].
In several European countries, including Spain, Belgium, Italy
and Switzerland, strategies differ by region [22,23]. For example,
in Spain, vaccine was introduced into the national immunization
program in 2007 and regions decided on specific recommendations
and strategies. There is public financing of vaccine in all regions of
Spain. The target age group ranges from 11–14 years. Some regions
of Spain administer vaccine in schools (11) and others in health
centers (8) [23]. Type of vaccine used also varies, with 13 using
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quadrivalent and 6 using bivalent vaccine. A year after vaccine
introduction in Spain, coverage was 84% in regions implementing
vaccination in schools and 70% in those implementing in health
centers [23].
3. Vaccine introduction in low- and middle-income
countries
Introduction of vaccine in low- and middle-income countries
requires a variety of steps and cooperation between international
agencies and manufacturers (Kane M et al., Vaccine, this issue [24]).
These efforts started soon after vaccines were licensed; however,
few countries introduced vaccine into their national programs in
the first years after licensure, due to costs of HPV vaccines (initially
about US $120 per dose) and vaccine delivery, and competing public
health priorities.
3.1. Policy and financing
Recommendations from the World Health Organization (WHO)
and prequalification of vaccines are needed before procurement
by the United Nations Children’s Fund (UNICEF) and other United
Nations agencies for use in national immunization programs. In
2009, WHO issued recommendations [25] and both vaccines were
prequalified. The GAVI Alliance, which funds vaccines for children
in the world’s poorest countries, prioritized HPV vaccine in 2009
[26]; however, it did not commit resources until late 2011, when it
made a decision to make HPV vaccine available to eligible countries
if negotiations to secure a sustainable price from manufacturers
are successful [27,28]. One manufacturer offered HPV vaccine to
GAVI at US $5 per dose. The first GAVI country applications will be
considered in 2012 and introduction with GAVI funding should be
able to start in 2013.
Tiered pricing has resulted in vaccines becoming more affordable for middle-income countries. Also, in 2011, through the Pan
American Health Organization’s Revolving Fund, the price for HPV
vaccine was US $14 per dose [29]. Beyond vaccine financing, delivery of vaccine will be challenging, as many countries have limited
experience delivering vaccine to adolescents; national immunization programs have primarily focused on infant immunization.
3.2. Demonstration projects
To address questions about delivery of vaccine to adolescents
in low-resource countries, demonstration projects with systematic
evaluation were conducted in India, Peru, Uganda, and Vietnam
beginning in 2006. These projects found that high coverage could
be achieved using a variety of delivery strategies, including standalone, school-, and health center-based strategies, as well as those
coupling HPV vaccination with other health interventions [30,31]
(Table 2). All of these projects included carefully designed communication efforts. Immunization was carried out using existing
staff, although this occasionally created short-term disruptions of
other services [32]. In most cases, cold chain capacity was sufficient, as long as there were no pre-existing gaps in capacity. To
the extent that HPV immunization can be integrated with other
services (building on existing infrastructure and sharing costs like
transport and communication), as in Uganda’s integrated outreach
program (Child Days Plus) or India’s incorporation of HPV vaccine training into regular monthly meetings, it is more feasible and
affordable.
Other demonstration projects also have been conducted, including those through a manufacturer donation program that made HPV
vaccine available to special projects in low-income countries (most
conducted outside of the public sector) [33]. While the majority
were limited in scope, these projects allowed countries to gain
operational experience implementing HPV vaccination. Through
April 2012, over 980,000 doses of vaccine had been donated to 16
different countries through this program [34].
3.3. Latin America
Panama and Mexico were among the first middle-income
countries to introduce vaccine into national immunization programs. In Panama, bivalent HPV vaccine was added to the national
program in 2008 [35]. Vaccine has been delivered to 10 year-old
girls through adolescent health services in both clinics and schools.
In 2009, first and third dose coverage among 10 year-old girls was
89% and 46%, respectively. In 2010, third dose coverage increased
to 67%.
Mexico initiated a quadrivalent HPV vaccination program in
2008, limited to 125 municipalities (comprising about 5% of the
population) with the lowest human development index. HPV vaccine was delivered via mobile health clinics to girls aged 12–16
years. After the first year of the program, first and third dose coverage in the target age group were 98% and 81%, respectively. Mexico
expanded the program to include 182 municipalities in 2009. An
extended dosing schedule was adopted, targeting girls aged 9–12
years for the first two doses, delivered 6 months apart, followed by
the third dose 5 years later. Coverage for the first and second doses
using this schedule was reported to be 85% and 67%, respectively
Table 2
Demonstration projects and strategy refinements after evaluation of pilot programs in three low-resource countriesa .
Country
Pilot strategy (n = girls
eligible for vaccination)
Key evaluation findings
Strategy refinements
Peru
Schools (n = 8,092)
Easy to access girls in densely populated areas but very inefficient
for small schools in remote areas.
Uptake of first dose was slow and required additional reminders in
community.
Schools were a convenient location to find large number of girls,
but special outreach visits were costly to organize.
Program was more efficient but selection of girls by age resulted in
lower coverage, as age verification was difficult.
Parent meetings at schools facilitated information and education
activities.
Vaccination days scheduled outside normal school year
challenging.
Confirmed that health centers used for HPV vaccine could achieve
good coverage.
Combine HPV vaccine with routine EPI nurse visits
to remote areas.
Use school-based vaccination to reach the largest
percentage of eligible girls more easily.
Use schools as vaccination location but integrate
with another community health program.
Select girls by grade rather than age.
Health Centers (n = 8,060)
Uganda
Schools (n = 6,294)
Child Plus Days (n = 4,183)
Vietnam
Schools (n = 4,302)
Health Centers (n = 2,712)
Based on Tsu VD et al. [31].
EPI: Expanded Program on Immunization.
a
Demonstration projects conducted by PATH.
Set vaccination schedule during the school year if
school-based strategy used.
Consider health center-based approach for future
national scale up.
L.E. Markowitz et al. / Vaccine 30S (2012) F139–F148
[35]. Mexico expanded its HPV vaccination program nationwide,
targeting girls aged 9 years in 2012.
Peru, which conducted demonstration projects starting in 2007,
expanded to nationwide vaccination for girls aged 10–11 years
(primary grade 5) in 2011. Vaccination is mainly school-based.
Argentina also introduced vaccine in 2011. The national guidelines
recommend using school health programs for communications but
the delivery of vaccine is through routine health services. Other
Latin American countries planning national introduction of HPV
vaccine soon include Guyana and Suriname.
3.4. Asia and Africa
Malaysia introduced HPV vaccine in 2010, targeting girls aged
13 years. Vaccine is delivered through existing school clinics (grade
7—regardless of age) and to out-of-school girls aged 13 years.
Through donations from the manufacturer, two low-income
countries, Bhutan and Rwanda, initiated country-wide introduction of quadrivalent HPV vaccine in 2010 and 2011, respectively
[36]. The program in Bhutan is a 6-year joint effort by Merck,
the Australian Cervical Cancer Foundation and the government.
Girls 12–18 years were offered vaccination through school-based
vaccine delivery in the first year; in subsequent years, a single
cohort of 12-year-old girls will be offered vaccine at health centers in most regions. High three-dose coverage was achieved in
the first year. In Rwanda, a multi-year donation allowed quadrivalent HPV vaccination to be initiated in 2011. Vaccine was
targeted to girls in primary grade 6 in the first year of the program. Among girls attending school, high first dose coverage was
achieved (93%) [37]. In the second and third years of the program, girls in the third year of secondary school will be targeted
as well.
Both the small and large scale HPV vaccine donations have raised
some concerns about sustainability, coordination with ministries
of health, capacity for introduction and competing resources for
introduction of other new vaccines. Because of these concerns,
WHO and UNICEF published an updated joint statement on vaccine donations, outlining minimal requirements for these programs
[38].
4. Post-licensure evaluation: safety, impact and
acceptability
4.1. Safety
Post-licensure safety studies are important because, while large
phase III trials were conducted for both vaccines, rare adverse
events may not have been detected. Furthermore, monitoring and
communication about vaccine safety is critical, as events temporally associated with vaccination can be falsely attributed to
vaccination. Safety monitoring is part of routine activities postintroduction in many countries (Table 3) [39]. These passive
monitoring systems have limitations, including reporting of events
that may have occurred coincidentally following vaccination as
well as incomplete reporting. A formal evaluation of the passive
surveillance system in the US, the Vaccine Adverse Event Reporting System (VAERS), was conducted after over 23 million doses
of quadrivalent HPV vaccine were distributed (June 2006 through
December 2008) [40,41]. In Australia, a review of data after 6 million doses of quadrivalent vaccine were distributed did not reveal
unusual patterns of reports [42]. Similarly, in the UK, no pattern
of adverse events or reason for concern was found after 4.5 million doses of bivalent vaccine had been administered [43]. Many
other countries have safety monitoring systems as well. Registries
for women inadvertently vaccinated during pregnancy have been
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established or expanded, including those by both manufacturers;
data to date do not raise any concerns [44,45].
In the US, evaluation of specific events that might be associated
with vaccination is done through the Vaccine Safety Datalink (VSD),
a system which evaluates adverse events in those vaccinated compared to a control group [46]. Data were analyzed in VSD after more
than 600,000 doses of quadrivalent HPV vaccine had been administered to females and raised no concerns. Post-licensure studies by
the manufacturers comparing rates of adverse events in vaccinated
with unvaccinated groups are ongoing or have been completed [47].
WHO’s Global Advisory Committee on Vaccine Safety has
reviewed data on HPV vaccine three times, most recently after >60
million doses of the quadrivalent or bivalent HPV vaccine had been
distributed worldwide [48]. The Institute of Medicine also reviewed
data on quadrivalent HPV vaccine safety in 2011 [49]. All reviews
show that the accumulating evidence on the safety of HPV vaccines
is reassuring.
Specific events that have occurred temporally related to administration of HPV vaccine have impeded vaccine acceptance in
several countries, or resulted in disruption of immunization programs [50–52]. For example, two cases of status epilepticus
temporally related to receipt of quadrivalent vaccine resulted in
suspension of Spain’s vaccination program for over 2 months and
deaths temporally associated with vaccine receipt in Germany and
Austria caused concern across Europe [52]. When possible, determination of the cause of death can allay concerns that these are
vaccine-related [53]. Official national investigation and response to
these reports has been important for the vaccination programs [54].
4.2. Impact and effectiveness
A variety of efforts are ongoing to monitor impact of HPV
vaccine post-licensure. Because cancer endpoints take longer to
observe, efforts are ongoing to determine more proximal measures.
Both manufacturers have post-licensure commitments to monitor
duration of protection against precancerous lesions by following
women who had been enrolled in the phase III trials in the Nordic
countries where registries allow follow-up and determination of
cervical screening and biopsy results, as well as access to specimens [55,56]. For the quadrivalent HPV vaccine, women will be
followed for a total of 14 years (10 years after termination of the
phase III trial) in Denmark, Sweden, Norway and Iceland. The first
results from the quadrivalent HPV vaccine follow-up found no
cases of HPV-associated disease among vaccinees through 6 years
post-vaccination. For the bivalent vaccine, follow-up data will be
available from Finland in 2012.
Biologic outcomes ranging from HPV prevalence to cancer
are being monitored by public health efforts in some developed
countries [55,57–59]. Countries with cancer registries will be able
to monitor the incidence of cervical and other HPV-associated
cancers. Several more proximal outcomes are being monitored,
including HPV prevalence, genital warts and cervical precancerous
lesions. In Australia, where high coverage with the quadrivalent
vaccine was achieved soon after introduction, impact on genital
warts has been observed in the age group of women targeted for
vaccination, as well as in males [58]. The proportion of women
12–26 years of age diagnosed with genital warts decreased by
73% within 3 years of vaccine introduction [60]. There was also
a decrease observed for heterosexual men (25%), but none in men
who have sex with men. As men were not included in the vaccination program, this suggests impact from herd immunity. Decreases
in cervical precancerous lesions may also have been observed [59].
While monitoring vaccine impact is of interest for many
countries, it is difficult and can be expensive. WHO guidance states
that monitoring HPV-associated disease or infection is not a prerequisite to vaccination initiation [61].
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Table 3
Post-licensure HPV vaccine safety evaluations or reviews.
Organization
System or review
Country data reviewed
Description
Reference or website
Therapeutic Goods
Administration, Australia
Routine passive surveillance
Australia
http://www.tga.gov.au/safety/alerts-medicine-gardasil070624.htm
Public Health Agency of
Canada
Canadian Adverse Events
Following Immunization
Surveillance System (CAEFISS)
Canada
Public Health Agency of
Canada
Canadian Immunization
Program Active (IMPACT)
Canada
Ministry of Health,
Netherlands
Active follow-up study
Netherlands
Medicines and Healthcare
products Regulatory
Agency, UK
Centers for Disease Control
and Prevention, US
Yellow Card Scheme
United Kingdom
Vaccine Adverse Event
Reporting System (VAERS)
US
Centers for Disease Control
and Prevention, US
Vaccine Safety Datalink (VSD)
US
GlaxoSmithKline
Vaccine in Pregnancy Registry
US and European Union
Merck and Company, Inc.
Vaccine in Pregnancy Registry
US, France, Canada
Merck and Company, Inc.
Post marketing commitment
(to US FDA)
US
Global Advisory Committee
on Vaccine Safety, WHO
Institute of Medicine, US
Review
Worldwide
National passive reporting system that accepts reports
from the providers, public, and vaccine manufacturers
on adverse events associated with vaccines licensed in
Australia.
National passive reporting system that accepts reports
from the providers, public and vaccine manufacturers on
adverse events associated with vaccines licensed in the
Canada.
Hospital-based national active surveillance network;
reports the more serious hospitalized cases and selected
outpatient visits for adverse events and
vaccine-preventable diseases.
Investigation of adverse events within 7 days after
vaccination with the bivalent HPV vaccine. One week
after each of the three doses, the participants received by
e-mail a Web-based questionnaire focused on local
reactions and systemic events.
National passive reporting system that accepts reports
from the providers and the public on adverse events
associated with vaccines licensed in the UK.
National passive reporting system that accepts reports
from providers, the public and vaccine manufacturers on
adverse events associated with vaccines licensed in the
United States.
Large linked database that uses administrative data
sources from participating managed care organizations.
Rates of adverse events in people who have received a
particular vaccine are compared to rates among those
not vaccinated.
Registry of women who inadvertently receive vaccine in
pregnancy. Around the patient’s estimated date of
delivery, a short follow-up form is sent to the registering
healthcare provider to report on the pregnancy course
and outcome.
Registry of women who inadvertently receive vaccine in
pregnancy. Around the patient’s estimated date of
delivery, a short follow-up form is sent to the registering
healthcare provider to report on the pregnancy course
and outcome.
Retrospective cohort study with follow-up through
electronic medical records, supplemented with medical
record review conducted at two large managed care
organizations.
Review of existing or published data on vaccine safety.
Adverse Effects of Vaccines:
Evidence and Causality
Worldwide
http://www.cps.ca/English/surveillance/IMPACT/IMPACT.htm
Klooster TM et al. [94]
http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/
CON096806
Slade B et al. [40]
http://www.cdc.gov/vaccinesafety/vaccines/hpv/gardasil.html
Gee J et al. [46]
http://www.cdc.gov/vaccinesafety/Activities/vsd.html
http://pregnancyregistry.gsk.com/Cervarix.html
Dana A et al. [45]
http://www.merckpregnancyregistries.com/gardasil.html
Chao C et al. [47]
Velicer C. (presentation) [95]
http://www.who.int/vaccine safety/Jun 2009/en/
http://www.iom.edu/Reports/2011/Adverse-Effects-ofVaccines-Evidence-and-Causality.aspx
L.E. Markowitz et al. / Vaccine 30S (2012) F139–F148
FDA: Food and Drug Administration; WHO: World Health Organization.
Review of evidence to determine if adverse events
following vaccination are causally linked to a specific
vaccine.
http://www.phac-aspc.gc.ca/im/vs-sv/caefiss-eng.php
L.E. Markowitz et al. / Vaccine 30S (2012) F139–F148
4.3. Vaccine acceptability
Studies conducted post-licensure have determined predictors of
vaccination, reasons for non-vaccination and intent to receive vaccine among those unvaccinated. While vaccine acceptability has
generally been high, some studies in high-income countries have
found that a sizable minority of parents of unvaccinated daughters
reported that they did not intend to have their daughter vaccinated
in the near future. In British Columbia, even with public financing
for vaccine and school-based vaccination, 35% of parents decided
not to have their daughter vaccinated [62]. Reported major reasons
were concerns about vaccine safety (30%), wanting to wait until
their daughter is older (16%), and not having enough information
about the vaccine (13%). In the US, a national survey found that
33% of parents of unvaccinated girls did not intend to have their
daughter vaccinated in the next year. The most commonly reported
reasons included: lack of knowledge about the vaccine (19%), belief
that the vaccine is not needed (19%), belief that their daughter is
not sexually active (18%), lack of a provider recommendation (13%),
and concerns about vaccine safety (7%) [63]. Smaller, qualitative
studies also found that the recommended age for receipt of vaccine
in early adolescence is a concern [64–66]. Consistent with studies of other vaccines, a strong provider recommendation has been
found to be important for vaccine initiation [63,67–69]. With regard
to concerns that vaccination might promote early sexual debut or
risky behavior, studies have not identified this as a major reason for
vaccine refusal [68]; however, concern about adverse behavioral
consequences has been identified in some studies and has been
associated with lower vaccine acceptance [65,70].
Concerns raised about vaccine safety and information spread by
some anti-vaccination groups have impacted acceptability in some
countries. Intention to vaccinate in Greece was found to decrease
significantly between 2006 and 2010 [71]. Reasons for refusal
changed during this time period, with safety concerns becoming the
most common reason for rejecting vaccination in 2010. Safety concerns have resulted in decreased vaccine uptake in other countries
as well (Jumaan A et al., Vaccine, this issue [72]).
In the four countries where PATH demonstration projects were
conducted, vaccine acceptance was high [30]. Factors inhibiting
vaccine acceptance varied by country but included fears about possible fertility effects and general concerns because the vaccine was
new. While completion of the three-dose series was above 95%
in all but one setting, the main reasons for non-completion were
logistical, such as missing school the day vaccines were given.
5. HPV vaccine debate and anti-immunization efforts
HPV vaccine introduction has generated considerable debate
in many countries [15,73]. Issues include concerns about cost and
affordability, benefits of vaccination, which of the two vaccines to
introduce, extent of catch-up vaccination, and the role of manufacturers and special interest groups in promotion. In Germany,
publication of a ‘Manifest’ in 2008 that criticized the recommendation for HPV vaccination and implementation in the national
vaccination schedule, led to widespread public debate. Written by a
group of 13 prominent public health professionals and physicians,
this document stated that the effectiveness of vaccination had not
been sufficiently studied and the efficacy for prevention of precancer and cancer had not been adequately communicated [74].
This publication and the ensuing debate likely resulted in decreased
vaccine promotion by the medical community and increased skepticism by the public. Similar debate occurred in some Nordic
countries [15]. Concerns have also been expressed by religious
communities in several countries. A public letter released from
the Catholic Bishops of Ontario stating concern about vaccine
F145
introduction without further study of the program effects might
have contributed to low uptake in some provinces [75].
Manufacturer efforts to promote HPV vaccination requirements
for school attendance soon after vaccine introduction in the US
resulted in widespread debate [76]. The backlash against these
requirements included many groups, including not only those
opposed to vaccination but also those opposed to government
interference with parental autonomy and those concerned that HPV
vaccine would promote risky sexual behavior [6]. While the manufacturer abandoned these lobbying efforts, consequences of these
efforts were still evident in 2011 [77].
Several countries have active anti-vaccine movements, which
have capitalized on the HPV vaccine debate. Some anti-vaccination
groups are well established and organized to oppose HPV vaccine
soon after introduction [78,79]. Many of these groups focus on
concerns about safety and use reports of adverse events temporally related to vaccination to promote opposition to vaccination
programs; groups in the US regularly post anti-vaccine messages
to their website or issue press releases [80,81]. An article which
misused post-licensure safety data was published in a medical journal in 2011 [82]. While these groups are mainly in high-income
countries, access to the internet has facilitated spread of antivaccination information around the globe.
6. New policy issues
6.1. HPV vaccine for males
While both vaccines are licensed for use in females, the quadrivalent HPV vaccine is also licensed in some countries for use in
males; data from clinical trials show high efficacy for prevention
of genital warts and anal precancerous lesions in males [83]. Several countries have or are considering recommendations for male
vaccination. In late 2011, quadrivalent HPV vaccine for males was
included in the routine adolescent vaccination schedule in the US
[7]. Considerations for this decision included the low vaccine coverage among females, burden of HPV-associated disease in females
and males in the US, cost-effectiveness, and issues of equity. With
high coverage in females, the risk of infection in males would
decline due to herd immunity and cost-effectiveness of vaccinating males would decrease. In Australia and Canada, where high
coverage has been achieved in females, quadrivalent vaccine was
recommended for males 9 through 26 years of age in late 2011
and early 2012, respectively [84,85], but vaccine for males had not
been implemented in publicly-funded programs in those countries
as of May, 2012. Countries have made, and will need to continue
to make decisions based on the epidemiology of HPV-associated
disease, cost-effectiveness, and affordability. For most low- and
middle-income countries, the burden of cervical cancer far exceeds
the burden of HPV-associated cancers in males.
6.2. Alternative dosing schedules
Because of the challenges and cost of delivering three doses
of HPV vaccine to adolescents, there has been interest in twodose schedules or schedules with alternative intervals between
doses. High efficacy for prevention of infection with fewer than
three doses was found in a subgroup analysis of a randomized controlled trial of bivalent vaccine [86]. While data are
limited and further studies to address this are ongoing, a modified three-dose schedule was adopted by two provinces in
Canada and in Mexico. This schedule provides two doses of
quadrivalent HPV vaccine in early adolescence with the third
dose to be administered 5 years later. Ongoing studies will
determine if the third dose is needed [87]. In early 2012,
Switzerland changed to a two-dose schedule for females younger
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L.E. Markowitz et al. / Vaccine 30S (2012) F139–F148
than 15 years [88]. A variety of studies of two-dose schedules
are ongoing or planned. Immunogenicity studies of alternative
three-dose schedules suggest that longer intervals between vaccine
doses do not have a negative impact on antibody titers [89,90].
7. Conclusions
Since HPV vaccines first became available in 2006, an increasing number of countries have introduced these vaccines into their
national programs. While high-income countries were the first to
introduce vaccine, more middle-income countries have introduced
vaccine in the past 2 years. HPV vaccines are still too expensive for widespread use in low–income countries and the only
low-income countries that have introduced vaccine have done so
through donation programs. The availability of subsidized HPV
vaccine through the GAVI Alliance will increase feasibility of introduction by low-income countries, but challenges will remain to
support infrastructure, a sustainable vaccine delivery platform and
co-payments for the vaccine. In middle-income countries, affordability remains an obstacle to timely HPV vaccine introduction.
In general, countries with school-based delivery and publicly
financed vaccine have achieved higher coverage than those with
opportunistic, clinic-based or primary care-based programs. However, school-based programs are not without challenges and may be
more costly. Furthermore, in low-income countries there are concerns about reaching out-of-school children. Nevertheless, there
are some clear advantages of school-based delivery for this hard to
reach age group. Factors other than delivery can contribute to levels
of coverage achieved, including public financing, public health promotion of vaccine and good communication strategies, organized
outreach to parents, and medical profession and public acceptance
[21]. The causes of low coverage achieved in some countries are
likely multifactorial.
Substantial post-licensure safety data have been accumulated
and data available to date are reassuring. Nevertheless, concerns
about safety arise and communication messages are needed to
explain events that occur in temporal association with vaccination.
Safety concerns are not the only factors limiting acceptability of
HPV vaccine in some countries. Perceived lack of need, or misunderstanding about the optimal time for vaccination—before onset of
sexual activity—are among the various factors contributing to low
uptake.
In the 5 years since HPV vaccines were first introduced, there
have been successes as well as challenges with vaccine implementation. Further progress is anticipated in the coming years,
especially in low- and middle-income countries where the need for
vaccine is greatest. Policies and programs need to be reviewed and
re-evaluated as new research findings and data from monitoring
systems become available.
Acknowledgements
We thank Nina Buttman for providing some information
regarding HPV vaccine in Germany and Hélène Sancho-Garnier for
providing some information regarding HPV vaccine in France.
Disclosed potential conflicts of interest
JB is an investigator on an Australian Research Council Linkage
Grant, for which CSL Biotherapies is a partner organization and was
a chief investigator (2005–2008) on a study of HPV prevalence in
Australian women, which was funded by a grant from the Cooperative Research Centre for Aboriginal Health, as well as education
grants from GlaxoSmithKline and CSL Limited.
HC has been on Expert Advisory Boards for SPMSD and GlaxoSmithKline and currently holds a GlaxoSmithKline educational
grant.
Other authors have disclosed no potential conflicts of interest.
Disclaimers
a The findings and conclusions in this report are those of the
author and do not necessarily represent the official position of the
Centers for Disease Control and Prevention.
e The author is a staff member of the World Health Organization.
The author alone is responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy
or views of the World Health Organization.
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