Answering human papillomavirus vaccine concerns; a matter of science and time
Infectious Agents and Cancer
Answering human papillomavirus vaccine concerns; a matter of science and time
David Hawkes 0
Candice E Lea 2
Matthew J Berryman 1
0 The Florey Institute of Neuroscience and Mental Health, The University of Melbourne , Victoria 3010 , Australia
1 SMART Infrastructure Facility, University of Wollongong , New South Wales 2522 , Australia
2 Research Centre for Injury Studies, Flinders University , Bedford Park, South Australia 5042 , Australia
Since the introduction of the HPV vaccine, questions have been asked about its efficacy in preventing cancer linked with HPV. Concerns about the HPV vaccine safety profile have also been raised. This paper highlights the rapidly growing body of evidence (including clinical trials and post-marketing surveillance) illustrating both the safety of the HPV vaccine, through a detailed investigation of reported adverse events, and its efficacy in reducing both HPV infections rates and the resulting drop in cervical lesions, which have been demonstrated to be good predictors of cervical cancer risk.
Human papillomavirus; HPV; Safety; Cervical cancer; Cancer prevention; Adverse events; Clinical trials
The first human papillomavirus (HPV) vaccine,
Gardasil, was registered in Australia in 2006 and was
followed in 2009 by Cervarix. However, since the
introduction of these HPV vaccines both their safety and
efficacy have been questioned . These include valid
questions such as whether these vaccines will reduce
vaccine-associated HPV infection rates, how long
vaccination will provide protection for and the role natural
exposure could play, and whether a compensatory
increase in non-vaccine HPV infection will be observed or
if the vaccine will provide some degree of
crossprotection. While there were some data available when
these vaccines were introduced it is not possible to
observe the effects of any medical intervention at a
population level before its introduction. According to the
manufacturers of Gardasil and Cervarix, over 120
million doses of these two HPV vaccines have been
distributed globally, with over 200 studies involving human
clinical trials and post-market surveillance undertaken
and published. This review will examine the questions
raised about the effectiveness and safety of the HPV
vaccine and how they have been, and are, being addressed
by the scientific/medical research community. It is
important to note that there are a number of concerns
about HPV vaccines, and indeed vaccination in general,
which are of a more social, economical or political
nature, such as whether people are given appropriate levels
of information prior to vaccination, and merit a more
in-depth discussion however they fall outside the scope
of this review.
Does vaccination against HPV prevent infection with
When examining any vaccine the primary question is:
does it reduce the impact of the targeted pathogen,
either through reducing infection itself or minimising the
clinical effects of infection? In the case of HPV vaccines;
Gardasil, a quadrivalent vaccine, targets HPV types 6,
11, 16, and 18 and Cervarix, a bivalent vaccine, targets
HPV types 16 and 18. Studies (described in Table 1)
have demonstrated that the HPV vaccine is able to
reduce the infection rate of vaccine-associated HPV types
(HPV 16/18) by over 90% [2,3] in HPV nave women
and this reduction is maintained for at least 5 years .
A rather elegant demonstration of how exposure to
HPV increases the efficacy of vaccination is described by
Herrero and colleagues  who looked at the rate of
protection against the vaccine associated HPV 16/18 at
different timepoints after vaccination. They showed that
at 22 months post HPV vaccination the vaccine was 71%
efficacious, by 34 months the efficacy is up to 92% and
beyond 46 months it is 100%, in the group of
participants who had all three doses of Cervarix and had a
Table 1 Characteristics of phase III efficacy studies in young women including end of study cohort numbers
Length of trials (years)
Hepatitis A Vaccine
Abbreviations: AIS Adenocarcinoma in situ, CIN cervical interepithelial neoplasia, VIN/VaIN Vulvar/vaginal intraepithelial neoplasia. FUTURE I/II study number of
subjects varies depending on endpoint or HPV type under analysis. Adapted from .
negative test for at least one of the vaccine types
(HPV16 or HPV18). Clinical trials often present data for
a number of subpopulations, but the most relevant for
HPV vaccination is the group that is HPV negative prior
to vaccination but may not get all three doses of the
vaccine. This group represents the most realistic model of
the population who receive the vaccine, pre-teen (so
unlikely to have been HPV exposed) but may not receive
all three doses over 6 months. This population has been
defined as either modified intention to treat- (MITT) or
total vaccine cohort- (TVC) nave . The other group
is the TVC [5,7] or intention to treat (ITT) [8,9] and
includes all participants in the trial irrespective of how
many doses they receive and over what time period,
whether they have had prior HPV exposure, and so on.
The major outcome that large scale clinical trials of
vaccines examined was the rate of pre-cancerous lesions,
such as cervical intraepithelial neoplasia (CIN, grades 1,
2, or 3 and above) or adenocarcinoma in situ (AIS)
associated with HPV (reviewed in ). Vaccination
demonstrated high efficacy against the HPV16/18 associated
CIN2 (approx. 99-100%), CIN3 (approx. 100%) and AIS
(approx. 100%) in MITT/TVC-nave subpopulations
(Table 2). Vaccination also provided high protection for
the TVC group, which includes individuals previously
exposed to HPV, against HPV16/18 type associated
CIN2 (>54.8%), CIN3 (>45.1%) and AIS (>60%) [7,8,10]
(Table 2). HPV vaccination is highly efficient at reducing
both HPV 16/18 and associated pre-cancerous lesions,
particularly when given to a HPV nave population such
as that targeted by mass vaccination programs.
Will HPV vaccination cause a compensatory rise in
non-vaccine HPV types?
There are more than 100 HPV types but only 15 have
been classed as being a high risk to progress from
infection to cancer (oncogenic); 16, 18, 31, 33, 35, 39, 45, 51,
52, 56, 58, 59, 68, 73, and 82 . Obviously HPV16/18
are targeted by vaccination but there have been
questions asked as to whether a decrease in HPV16/18 will
be counterbalanced by an increase in non-vaccine
oncogenic HPV types and even a possible overall increase in
Schiller and colleagues  reviewed the results of the
large scale clinical trials of both HPV vaccines (FUTURE
I/II , PATRICIA  and Costa Rica HPV Vaccine
Trial ). They examined the rates of 6 month
persistent infection of 12 non-vaccine HPV types and found
that both vaccines provided significant protection
against oncogenic HPV types similar to HPV16, (39, 45,
59, and 68). Both vaccines also provided significant
protection against HPV31; in addition Cervarix
significantly reduced rates of HPV33 and 52. While the
duration of vaccine coverage (95% protection) for
HPV16/18 has been demonstrated to remain for at least
5 years [4,14,15], long term trials for the duration of
cross-type protection are currently not available.
Table 2 HPV vaccine efficacy against genital disease in
FUTURE I/II (Gardasil) and PATRICIA (Cervarix) trials
% efficacy (95% CI)
Abbreviations: AIS Adenocarcinoma in situ, CIN cervical interepithelial
neoplasia, VIN/VaIN Vulvar/vaginal intraepithelial neoplasia, MITT modified
intention to treat, ITT Intention to treat, TVC Total vaccine cohort, CI
Confidence interval. Rate reduction is measured as per 100 women years.
Adapted from .
As outlined previously, one of the major outcomes
examined by clinical trials of these vaccines is the prevalence of
HPV positive AIS and CIN lesions. The PATRICIA study
 found Cervarix provided cross-protective efficacy
against four non-vaccine oncogenic HPV types (31, 33, 45,
and 55) measured by persistent infection and CIN2+ lesion
rates. When CIN2+ and CIN3+ lesion rates, associated with
the composite findings of 12 non-vaccine oncogenic HPV
types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) were
examined, the vaccinated group showed reduced incidence
in both HPV nave (56% [CIN2+] and 91% [CIN3+]) and
TVC (34% and 47%) groups compared with the
Other studies also provide evidence for vaccine
crossprotection against non-vaccine HPV types in a variety of
conditions, such as reduced HPV35  infection rates
in Finnish adolescents four years post-vaccination, and
the production of cross-reactive antibodies against
HPV31  in HIV positive children. Joura and
colleagues  examined data from the FUTURE I/II trial
and found women vaccinated with Gardasil after they
had undergone surgery for cervical disease or were
diagnosed with vulvar or vaginal disease (genital warts,
vulvar intraepithelial neoplasia, or vaginal intraepithelial
neoplasia), had lower rates of CIN (1+, 2+ or 3+),
genital warts, and vulvar (or vaginal) intraepithelial
neoplasia (1+ or 2+).
While both vaccines are very effective against HPV16/
18 and appear to provide cross-protection against some
non-vaccine oncogenic HPV types it is worth specifically
investigating whether vaccination is actually causing a
net reduction in HPV associated AIS and CIN lesions.
As Cervarix had better cross-protective properties it is
not surprising that the TVC displayed larger reductions
is all HPV associated markers; CIN2+ (33.1%), CIN3+
(45.6%) and AIS (76.9%) . However, Gardasil still
demonstrated reductions in CIN2 (19.3%), CIN3 (16.4%)
and AIS (62.5%) rates compared with the
nonvaccinated cohort [8,10]. It should also be noted that
when only HPV nave individuals were analysed, much
higher protection from CIN2+ (64.9), CIN3+ (93.2) and
AIS (100%) was observed . These data show that
vaccination is reducing the pathological signs of all HPV
type infections, particularly in HPV nave individuals.
Will vaccination against HPV prevent (cervical) cancer?
One of the most frequently raised concerns about HPV
vaccination is that one of the major outcomes of clinical
trials, cervical intraepithelial neoplasia (CIN) are not
good predictors for progression to cervical cancer, thus
making it impossible to say on that basis alone whether
HPV vaccines will reduce cervical cancer incidence. It is
worth taking a moment to investigate if firstly there is a
link between HPV and CIN in the first place. As
described above, clinical trials have demonstrated HPV
vaccination reduces CIN lesion incidence. This is not
surprising, as a systematic review and meta analysis of
over forty trials, and 22,000 women, found that,
although there was a lot of variation in methodology, a
persistent HPV infection was consistently and strongly
associated with CIN2/3 lesions . It has also recently
been shown that the average time from initial HPV
infection to the appearance of cervical lesions is 4350
months (~4 years) . The literature overwhelmingly
demonstrates that HPV is a, if not the, major cause of
cervical lesions such as CIN2 and CIN3. It was also
demonstrated as far back as 1976 that untreated CIN3
lesions result in cervical cancer 2839% of the time .
A review of over 40 years of published studies
determined that the likelihood of progression of CIN1 to
cancer was 1%, for CIN2 it was 5% and for CIN3 greater
than 12% .
A recent study demonstrated the importance of HPV
as a determinant of (pre)invasive cervical cancer when
they showed that 3.7% of the women, in a study of over
330,000 women, with normal cervical cytology (pap
smear) and positive HPV status experienced 34% of the
CIN3+, 29% of the cancers and 63% of the
adenocarcinomas . There is also other evidence in the literature
to support this finding, specifically that HPV vaccinated
individuals have lower rates of CIN2+ and CIN3+ [1,4]
and that HPV vaccine types significantly correlate with
progression from CIN2+ to CIN3+ .
In terms of a biological mechanism we know that
certain HPV types are strongly associated with different
chromosomal changes, in particular those associated
with sections of DNA containing tumor-suppressing
genes [25,26]. These changes are in turn strongly
associated with cervical cancer [25,27]. Although the
development of cancer is complex , the pathway variable
from person to person , and not every persistent
HPV infection progresses to cancer , a number of
papers have even examined the absolute risk of cervical
cancer from HPV infection [30,31]. Overall, HPV can be
associated with 99.7% of cervical cancers and can be
considered as a necessary cause of cervical cancer ,
even though not all HPV infections progress to CIN,
and then to cancer. It should be noted that while this
paper is primarily focussed on cervical cancer, HPV
infection is also associated with cancers of the penis (40%
HPV associated), vulvar/vaginal (40%), anal (90%),
mouth (3%) and oropharynx (12%) . In addition the
Gardasil vaccine targets two non-oncogenic types 6 and
11 which are a leading cause of genital warts. A recent
Australian study found a significant (P<0.001) decrease
in diagnosis of genital warts in women under 30 years of
age . This age group is the first to be vaccinated
against HPV and these decreases in genital warts were
not seen in older age groups.
Is HPV vaccination safe?
Since introduction, safety concerns have been raised
about reported serious adverse reactions to HPV
vaccination. A number of these concerns are about vaccine
ingredients in general but the safety of these ingredients
has been well established (reviewed in ). It is worth
noting that the Cervarix vaccine includes the Adjuvant
System 04 (AS04) which combines
3-0-desacyl4-monophosphoryl lipid A (MPL) and aluminium salt
to increase the immune response to vaccination.
Verstraeten and colleagues  reviewed the use of
AS04 in vaccines (68, 512 participants) to determine
whether its use could cause an increase in autoimmune
diseases. They determined that there was no increase
in relative risk (RR) of experiencing an autoimmune
event compared with a control group that containing
non-adjuvanted, or aluminium-/aluminium
hydroxideadjuvanted vaccines (RR 0.98, confidence intervals 0.8,
1.21). An examination of Gardasil safety studies 
revealed that the vaccine produced significantly higher
rates of injection site adverse events (82.9%) than the
aluminium containing placebo (77.4%) which in turn
produced significantly higher rates than the saline
placebo (49.5%). This is an expected outcome, as described
above aluminium containing adjuvants stimulate the
immune system. However when systemic adverse events
were examined there was no difference between vaccine
and placebo. The rest of the review will focus on the
safety profile of HPV vaccines as a whole, rather than
examining individual constituents.
Adverse events have been reported following HPV
vaccination (Table 3) but clinical trial data demonstrates
that there is no difference in the rate of serious adverse
events between the either HPV vaccine and controls (RR
1.00, 95% CI 0.91 1.09). A study examining the adverse
events reported following Gardasil vaccination found
that the overwhelming majority (>94%) of these
reactions are minor and are largely local injection site
reactions (for example redness, swelling, pain at injection
site) but do include other minor self limiting reactions
such as syncope (fainting episodes), headache and
nausea (reviewed in ). Similar data for Cervarix
vaccination does not appear to have been reported as yet.
Evidence from large scale clinical trials has been
utilised to assess whether serious adverse events are
more likely post HPV vaccination with a systematic
review and meta-analysis having been undertaken to
examine the combined results of 7 unique randomized
clinical trials (including the previously mentioned
FUTUREI/II and PATRICIA trials) of HPV vaccines
. These 7 trials included over 44,000 women.
When the authors examined whether vaccination was
associated with serious adverse events, they found
that the chance of having a serious adverse event
was identical whether the individual was vaccinated
or in the control group. Even when the trials were
Relative risk (95% CI)
Adapted from [6,38]. Original trial data from FUTURE I/II , Harper, Koutsky
, Munoz [3,40], Villa , and PATRICIA .
looked at individually there was still no difference in
adverse event incidence between the vaccinated and
Large scale clinical trials can provide information on
adverse events prior to mass vaccination but their
statistical power is limited by their participant numbers. The
clinical trials described above included over 44,000
women and as such may not be expected to reliably
detect rare (e.g. less than 1 in 100,000) adverse events.
Passive reporting systems such as the U.S. post-marketing
safety surveillance program database VAERS can provide
information that can help identify (rare) adverse events.
As VAERS is an open system where any member of the
general public can enter a vaccine reaction it is difficult
to directly analyze the publically available data to assess
causal relationship between notified events and vaccine
administration without further investigation. Gold and
colleagues  give an interesting example of the
peculiarities of passive reporting systems, focusing on the
Australian context. In 2009 the adverse event reporting
rate for Gardasil was 24 per 100,000 but the reporting
rate for exactly the same vaccine in the USA was 53.9
per 100,000. There are a number of possible causes for
these differences in adverse event rates such as uneven
denominators, ease of reporting, public knowledge of
the reporting system or even cultural/religious/political
reasons, and these variables provide yet another example
of the importance of follow-up investigations of adverse
A number of examinations of the VAERS data for
HPV vaccination have shown a low rate of adverse
reactions, and no link for any causal relationship between
HPV vaccination and reports [43,44]. There are a variety
of conditions that can occur in the absence of HPV or
other vaccinations, in young adolescent females, which
can be mistaken for HPV vaccination side-effects, and
therefore to draw conclusions from adverse event data
to HPV vaccination is to mistake (time) correlation for
causality . In 2009 Slade and colleagues 
investigated the 32 deaths attributed to Gardasil that had been
reported on VAERS. Of the 32 deaths there was not
enough information to identify or verify the death for 12
reports. The causes of the remaining 20 deaths were: 2
due to diabetic ketoacidosis, 3 due to pulmonary
embolism, 6 were cardiac-related (4 arrhythmias, 2
myocarditis), 2 were idiopathic seizure disorders, 4 were
unexplained, 1 was due to juvenile amyotrophic lateral
sclerosis, 1 case of Neisseria meningitidis serogroup B
caused meningoencephalitis and the final death was
related to prescription drug abuse. The authors concluded
that statistically (proportional reporting ratio of 1.2 for
8- to 29-year olds) these results were not significantly
(p=0.92) different from what you would expect from a
similar sized unvaccinated population.
A recent study by an Australian group 
systematically examined adverse events in the first years (2007
2009) of the HPV vaccination program during which
time over 5.8 million doses of Gardasil were distributed
nationally. They found 1394 suspected adverse events
were reported using a passive surveillance program. One
possible severe side effect of the HPV vaccine may be an
increased rate of anaphylaxis but as with much data
from passive reporting systems it is not definitive. New
South Wales reported a rate of 2.6 per 100,000 vaccines
compared with a rate of 0.5 per 100,000 in South
Australia and Victoria combined. Gold and colleagues
present a number of possible reasons for this including
the older age of recipients, different mechanisms of
surveillance and a number of other causes for this
discrepancy. Only 12 cases were reported during the timeframe
investigated so it is difficult to know whether this is a
vaccine induced event until more information becomes
It has also been suggested that HPV vaccination can
increase the probability of progression of established
persistent infection to CIN2+ or higher. This was based
on the report of a single small study , however
further analysis yielded evidence that the vaccinated cohort
had higher (pre-vaccination) risk factors than the
placebo group. The authors were concerned about the
effect of the biased risk factor profile and small numbers
on the data so further analysis was undertaken by
pooling data from three studies (including the risk factor
biased study). This larger data set showed no difference
in CIN2+ or higher presentation between the vaccinated
and placebo cohorts.
Other specific concerns about serious adverse events
following HPV vaccination such as the possibility of
increased autoimmune conditions in the vaccinated,
increased incidence of Guillain-Barr Syndrome (reviewed
in ) or increased severe adverse events caused by
interactions with other vaccines have so far been proven
The first HPV vaccine was introduced in 2006 and since
its introduction it has been a topic of controversy, with a
number of questions being asked about the vaccine; Did
it work? How long would the protection last? Would
there be an increase in HPV types not covered by the
vaccine? Did it actually prevent cancer? Was it safe?
In the seven years since the registration of the first
HPV vaccine these and many other questions have been
investigated by the scientific/medical research
community. This review describes a large number of studies that
have analysed the growing set of safety data, and have
demonstrated the safety of HPV vaccines and answered
the very specific concerns raised, particularly in regards
to nervous system reactions, interactions with other
vaccines, and HPV vaccine influencing the course of
existing lesions. In terms of virology the current
evidence shows that HPV vaccination is highly efficient at
preventing vaccine associated HPV types and that
protection is well over 90% if given to HPV nave
individuals [2-4]. Additionally it appears that HPV vaccination
may even also offer some cross-protection against the 13
non-vaccine oncogenic HPV types, including HPV31,
33, 35, 39, 45, 52, 59, and 68 [4,6,16]. The longevity of
the HPV vaccination has also been investigated and
there are currently studies that demonstrate
immunogenicity lasts at least 5 years for both Gardasil and
HPV vaccination has been introduced for less than 7
years and as such it is difficult to quantitate the effect it
will have on the incidence of cervical, vulvar/vaginal,
penile, anal and other cancers. There is very strong,
some say conclusive data, that HPV is the root cause of
over 99% of cervical cancers [22-24,27]. HPV vaccination
has been clearly demonstrated to reduce the incidence
of the pre-cancerous markers of cervical cancer, in trials
involving over 44,000 women , and the resulting
effects on cervical cancer incidence will become clearer
over time with the aid of post-marketing surveillance. A
recent meta-analysis of HPV testing has concluded that
HPV testing provides an advantage over equivocal
cytologic screening for CIN with the added benefit that
genotyping for HPV16 and HPV18 assists medical
professionals in better assessing HPV-associated risk .
Australia is uniquely positioned to be a world leader in
monitoring the efficacy and safety of HPV vaccines at a
population level due to its early adoption of Gardasil as
evidenced by the distribution of over 5.8 million doses
by 2009 .
The goal of this review was to investigate the
published scientific/medical literature to determine whether
the oft repeated queries about HPV vaccination safety
and efficacy have been examined. The rapidly growing
body of research, including immunology, virology, public
health, epidemiology and a number of other fields, can
allow the whole community including doctors, medical
researchers, parents and other interest groups to be
more confident that the benefits of HPV vaccination far
outweigh the risks and that mechanisms are in place to
continue monitoring possible adverse events into the
DH chose the topic and wrote and researched the initial version of the
review. CEL and MJB were involved in the literature research and
contributed to the writing and drafting of the manuscript. All authors have
read and approved the final manuscript.
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