Literature Review

“Human Papillomavirus (HPV) Vaccine Policy and Evidence-Based Medicine: Are They at Odds?”

Article· Literature Review (PDF Available)inAnnals of Medicine 45(2) · December 2011with 1,728 Reads
DOI: 10.3109/07853890.2011.645353 · Source: PubMed
Abstract
All drugs are associated with some risks of adverse reactions. Because vaccines represent a special category of drugs, generally given to healthy individuals, uncertain benefits mean that only a small level of risk for adverse reactions is acceptable. Furthermore, medical ethics demand that vaccination should be carried out with the participant's full and informed consent. This necessitates an objective disclosure of the known or foreseeable vaccination benefits and risks. The way in which HPV vaccines are often promoted to women indicates that such disclosure is not always given from the basis of the best available knowledge. For example, while the world's leading medical authorities state that HPV vaccines are an important cervical cancer prevention tool, clinical trials show no evidence that HPV vaccination can protect against cervical cancer. Similarly, contrary to claims that cervical cancer is the second most common cancer in women worldwide, existing data show that this only applies to developing countries. In the Western world cervical cancer is a rare disease with mortality rates that are several times lower than the rate of reported serious adverse reactions (including deaths) from HPV vaccination. Future vaccination policies should adhere more rigorously to evidence-based medicine and ethical guidelines for informed consent.
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REVIEW ARTICLE
Human papillomavirus (HPV) vaccine policy and evidence-based
medicine: Are they at odds?
Lucija Tomljenovic
1
& Christopher A. Shaw
1,2
1
Neural Dynamics Research Group, Department of Ophthalmology and Visual Sciences, University of British Columbia, 828 W. 10th Ave,
Vancouver, BC, V5Z 1L8, Canada and
2
Program in Experimental Medicine and the Graduate Program in Neuroscience, University of British
Columbia, Vancouver, BC, Canada
Introduction
In 2002 the US Food and Drug Administration (FDA) stated that
vaccines represent a special category of drugs aimed mostly at
healthy individuals and for prophylaxis against diseases to which
an individual may never be exposed (1).  is, according to the
FDA,places signi cant emphasis on vaccine safety (1). In other
words, contrary to conventional drug treatments aimed at man-
agement of existing, o entimes severe and/or advanced disease
conditions, in preventative vaccination a compromise in e cacy
for the bene t of safety should not be seen as an unreasonable
expectation. Furthermore, physicians are ethically obliged to
provide an accurate explanation of vaccine risks and bene ts to their
patients and, where applicable, a description of alternative courses
of treatment.  is in turn enables patients to make a fully informed
decision with regard to vaccination. For example, the Australian
guidelines for vaccination emphasize that for a consent to be
legally valid, the following element must be satis ed: ‘ it [consent]
can only be given a er the relevant vaccine (s) and their potential
risks and bene ts have been explained to the individual (empha-
sis added) (2). Likewise, the United Kingdom (UK) guidelines
pertaining to vaccination practices state that subjects must be given
Annals of Medicine, 2011; Early Online, 1–12
© 2011 Informa UK, Ltd.
ISSN 0785-3890 print/ISSN 1365-2060 online
DOI: 10.3109/07853890.2011.645353
Key messages
To date, the e cacy of HPV vaccines in preventing
cervical cancer has not been demonstrated, while
vaccine risks remain to be fully evaluated.
Current worldwide HPV immunization practices with
either of the two HPV vaccines appear to be neither
justi ed by long-term health bene ts nor economically
viable, nor is there any evidence that HPV vaccination
(even if proven e ective against cervical cancer) would
reduce the rate of cervical cancer beyond what Pap
screening has already achieved.
Cumulatively, the list of serious adverse reactions
related to HPV vaccination worldwide includes deaths,
convulsions, paraesthesia, paralysis, Guillain–Barré
syndrome (GBS), transverse myelitis, facial palsy,
chronic fatigue syndrome, anaphylaxis, autoimmune
disorders, deep vein thrombosis, pulmonary embolisms,
and cervical cancers.
Because the HPV vaccination programme has global
coverage, the long-term health of many women may be
at risk against still unknown vaccine bene ts.
Physicians should adopt a more rigorous evidence-based
medicine approach, in order to provide a balanced and
objective evaluation of vaccine risks and bene ts to their
patients.
All drugs are associated with some risks of adverse reactions. Be-
cause vaccines represent a special category of drugs, generally
given to healthy individuals, uncertain bene ts mean that only
a small level of risk for adverse reactions is acceptable. Further-
more, medical ethics demand that vaccination should be carried
out with the participant s full and informed consent. This neces-
sitates an objective disclosure of the known or foreseeable vac-
cination bene ts and risks. The way in which HPV vaccines are
often promoted to women indicates that such disclosure is not
always given from the basis of the best available knowledge. For
example, while the world s leading medical authorities state that
HPV vaccines are an important cervical cancer prevention tool,
clinical trials show no evidence that HPV vaccination can protect
against cervical cancer. Similarly, contrary to claims that cervical
cancer is the second most common cancer in women worldwide,
existing data show that this only applies to developing countries.
In the Western world cervical cancer is a rare disease with mor-
tality rates that are several times lower than the rate of reported
serious adverse reactions (including deaths) from HPV vaccina-
tion. Future vaccination policies should adhere more rigorously
to evidence-based medicine and ethical guidelines for informed
consent.
Key words: Cervarix , cervical cancer , Gardasil , HPV vaccines ,
informed consent , vaccine adverse reactions
Correspondence: Lucija Tomljenovic, Neural Dynamics Research Group, Department of Ophthalmology and Visual Sciences, University of British Columbia,
828 W. 10th Ave, Vancouver, BC, V5Z 1L8, Canada. E-mail: lucijat77@gmail.com
(Received 24 May 2011; accepted 31 October 2011)
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L. Tomljenovic & C. A. Shaw
adequate information on which to base their decision on whether
to accept or refuse a vaccine (3).  is includes having a clear
explanation on vaccine risks and side-e ects (3).
Surprisingly, in the United States (US), there are no governmen-
tal requirements for informed consent for vaccination (4). Such
an omission leaves the door open to a failure to obtain informed
consent. Nonetheless, there are regulatory agencies such as the
US FDA which are empowered to assure that only demonstrably
safe and e ective vaccines reach the market.In addition, health
authorities (i.e. US Centers for Disease Control and Prevention
(CDC)) are expected to provide expert advice concerning the
bene ts and risks related to particular drugs, including vaccines.
When these o cial bodies are not able to provide their normal
regulatory oversight and/or if  nancial interests take precedence
over public health, signi cant problems in true informed consent
guidelines can occur.
What is known about the currently licensed human papillo-
mavirus (HPV) vaccines? What are their bene ts, and what are
their risks? While medical authorities in a number of countries,
including the US, strongly advocate their use, some members of
the public have become increasingly sceptical for a variety of rea-
sons.  e key question posed by such sceptics is this: Is it possible
that HPV vaccines have been promoted to women based on inac-
curate information?  e present article examines the evidence in
order to answer this critical question.
Can the currently licensed HPV vaccines prevent
cervical cancer?
Gardasil s manufacturer, Merck, states on their website that
Gardasil does more than help prevent cervical cancer, it pro-
tects against other HPV diseases, too. Merck further claims
that Gardasil does not prevent all types of cervical cancer (5).
Similarly, the US CDC and the FDA claim that This [Garda-
sil] vaccine is an important cervical cancer prevention tool
that will potentially benefit the health of millions of women
(6) and Based on all of the information we have today, CDC
recommends HPV vaccination for the prevention of most
types of cervical cancer (7). All four of these statements are at
significant variance with the available evidence as they imply
that Gardasil can indeed protect against some types of cervical
cancer.
At present there are no signi cant data showing that either
Gardasil or Cervarix (GlaxoSmithKline) can prevent any type of
cervical cancer since the testing period employed was too short
to evaluate long-term bene ts of HPV vaccination.  e longest
follow-up data from phase II trials for Gardasil and Cervarix are
5 and 8.4 years, respectively (8 10), while invasive cervical cancer
takes up to 20 40 years to develop from the time of acquisition of
HPV infection (10 13). Both vaccines, however, are highly e ec-
tive in preventing HPV-16/18 persistent infections and the associ-
ated cervical intraepithelial neoplasia (CIN) 2/3 lesions in young
women who had no HPV infection at the time of  rst vaccination
(13 15). Nonetheless, although cervical cancer may be caused
by persistent exposure to 15 out of 100 extant HPVs through
sexual contact (11), even persistent HPV infections caused by
high-risk HPVs will usually not lead to immediate precursor le-
sions, let alone in the longer term to cervical cancer. e reason
for this is that as much as 90% HPV infections resolve spontane-
ously within 2 years and, of those that do not resolve, only a small
proportion may progress to cancer over the subsequent 20 40
years (10,11,16 18). Moreover, research data show that even
higher degrees of atypia (such as CIN 2/3) can either resolve
or stabilize over time (19).  us, in the absence of long-term
follow-up data, it is impossible to know whether HPV vaccines
can indeed prevent some cervical cancers or merely postpone
them. In addition, neither of the two vaccines is able to clear exist-
ing HPV-16/18 infections, nor can they prevent their progression
to CIN 2/3 lesions (20,21). According to the FDA, It is believed
that prevention of cervical precancerous lesions is highly likely
to result in the prevention of those cancers (emphasis added)
(22). It would thus appear that even the FDA acknowledges that
the long-term bene ts of HPV vaccination rest on assumptions
rather than solid research data.
Gardasil and Cervarix: do the benefi ts of vaccination
outweigh the risks?
Currently, governmental health agencies worldwide state that
HPV vaccines are safe and effective and that the benefits
of HPV vaccination outweigh the risks (6,23,24). Moreover,
the US CDC maintains that Gardasil is an important cervi-
cal cancer prevention tool and therefore recommends HPV
vaccination for the prevention of most types of cervical can-
cer (6,7). However, the rationale behind these statements is
unclear given that the primary claim that HPV vaccination
prevents cervical cancer remains unproven. Furthermore, in
the US, the current age-standardized death rate from cervi-
cal cancer according to World Health Organization (WHO)
data (1.7/100,000) (Table I), is 2.5 times lower than the rate
of serious adverse reactions (ADRs) from Gardasil reported
to the Vaccine Adverse Event Reporting System (VAERS)
(4.3/100,000 doses distributed) (Table II). In the Netherlands,
the reported rate of serious ADRs from Cervarix per 100,000
doses administered (5.7) (Table II) is nearly 4-fold higher
than the age-standardized death rate from cervical cancer
(1.5/100,000) (Table I).
Although it may not be entirely appropriate to compare
deaths alone from cervical cancer to serious ADRs from HPV
vaccines, it should be re-emphasized that (in accordance with
FDA guidelines) the margin of tolerance for serious ADRs for
a vaccine with uncertain bene ts needs to be very narrow, es-
pecially when such vaccine is administered to otherwise healthy
individuals (1).HPV vaccination, even if proven e ective as
claimed, is targeting 9 12 year old girls to prevent approximately
70% of cervical cancers, some of which may cause death at a rate
of 1.4 2.3/100,000 women in developed countries with e ective
Pap smear screening programmes (Table I). For a vaccine de-
signed to prevent a disease with such a low death rate, the risk
to those vaccinated should be minimal. Further, according to
some estimates, HPV vaccination would do little to decrease the
already low rate of cervical cancer in countries with regular Pap
screening (10).  us, any expected bene t from HPV vaccina-
tion will notably drop in the setting of routine Pap screening.
Accordingly, the risk-to-bene t balance associated with HPV
vaccination will then also become less favourable. On the other
hand, in developing countries where cervical cancer deaths are
much higher and Pap screening coverage low (Table I), the po-
tential bene ts of HPV vaccination are signi cantly hampered by
high vaccine costs (25).
It should be noted that for any vaccine the number of doses
that are eventually administered is lower than the number of
doses that are distributed.  us, calculations based on the latter
tend to under-estimate the rate of vaccine-associated ADRs (Fig-
ure 1). Supporting this interpretation, we show in Table II and
Figure 1 that for any of the two HPV vaccines, the reported rate of
ADRs per 100,000 doses administered is very similar across dif-
ferent countries and approximately seven times higher than that
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HPV vaccines and evidence-based medicine
calculated from the number of distributed doses.  e latter calcu-
lations also show a comparable range across several countries (Fig-
ure 1). Given that government-o cial vaccine surveillance pro-
grammes routinely rely on passive reporting (26), the rate of ADRs
from HPV and other vaccines may be further under-estimated.
According to some estimates, only 1–10% of the ADRs in the US
are reported to VAERS (27).
e lack of data on serious ADRs in countries where routine
HPV vaccination for young women is recommended and strongly
promoted (Table II) greatly hampers our understanding about the
Table I. Key data on cervical cancer, HPV-16/18 prevalence, and cervical cancer prevention strategies in 22 countries. Data sourced from the World Health
Organization (WHO)/Institut Catala d Oncologia (ICO) Information Centre on HPV and cervical cancer (105).
Country
Incidence per
100,000 women
(age-standardized)
Mortality per
100,000 women
(age-standardized)
Mortality ranking
among all cancers
(all ages) Pap screening coverage (%)
HPV-16/18
prevalence in
women with low-/
high-grade lesions/
cervical cancer (%)
HPV vaccine
introduced
Australia 4.9 1.4 17th 60.6 (All women aged 20 69 y
screened every 2 y)
3.8/44.6/76.2 Yes
Netherlands 5.4 1.5 16th
59.0 (All women aged 20 y
screened every 5 y)
1.5/61.6/87.9 Yes
US 5.7 1.7 15th
83.3 (All women aged 18 y
screened every 3 y)
7.7/55/76.6 Yes
France 7.1 1.8 15th 74.9 (All women aged 20 69 y
screened every 2 y
7.6/63.4/75.6 Yes
Canada 6.6 1.9 14th 72.8 (All women aged 18 69 y
screened every 3 y; Annual if at
high risk)
11.8/56.2/74.3 Yes
Spain 6.3 1.9 15th 75.6 (All women aged 18 65 y
screened every 3 y
2.3/46.9/55.9 Yes
UK and Ireland 7.2 2 16th 80 (All women aged 25 64 y
screened every 5 y)
2.4/61.9/79.1 Yes
Israel 5.6 2.1 14th 34.7 (All women aged 18 69 y
screened every 3 y)
2.2/44.8/68.5 Yes
Germany 6.9 2.3 13th 55.9 (Women aged 20 49 y
screened every 5 y)
1.4/54.1/76.8 Yes
China 9.6 4.2 7th 16.8 (All women aged 18 69 y
screened every 3 y)
2.3/45.7/71 No
Viet Nam 11.5 5.7 4th 4.9 (All women aged 18 69 y
screened every 3 y)
2.1/33.3/72.6 Yes
Russia 13.3 5.9 7th 70.4 (All women aged 18 69 y
screened every 3y)
9.3/56/74 Yes
Brazil 24.5 10.9 2nd 64.8 (All women aged 18 69 y
screened every 3 y)
4.3/54/70.7 Yes
ailand 24.5 12.8 2nd 37.7 (All women aged 15 44 y
ever screened
4.1/33.3/73.8 Yes
Pakistan 19.5 12.9 2nd 1.9 (All women aged 18 69 y
screened every 3 y)
6/59.3/96.7 Yes
South Africa 26.6 14.5 2nd 13.6 (All women aged 18 69 y
screened every 3 y
3.6/58.4/62.8 Yes
India 27 15.2 1st 2.6 (All women aged 18 69 y
screened every 3 y)
6/56/82.5 Yes
Cambodia 27.4 16.2 1st None 3.2/33.3/72.6 Yes
Nepal 32.4 17.6 1st 2.4 (All women aged 18 69y
screened every 3 y
6/59.3/82.3 No
Nigeria 33 22.9 2nd None 4.7/41.3/50 Yes
Ghana 39.5 27.6 1st 2.7 (All women aged 18 69 y
screened every 3 y)
4.6/41.3/50 Yes
Uganda 47.5 34.9 1st None 6.7/37.9/74.1 Yes
Table II. Summary of adverse reactions (ADRs) from HPV vaccines Gardasil and Cervarix. Note that the US FDA Code of Federal Regulation de nes a serious
adverse drug event as any adverse drug experience occurring at any dose that results in any of the following outcomes: death, a life-threatening adverse drug
experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or signi cant disability/incapacity, or a congenital anomaly/birth
defect ’ (106).
Vaccine Country Total n ADRs(ref.) Doses n (ref.)
Total n
ADRs/100,000
doses
Total n serious
ADRs(ref.)
Total n serious
ADRs/100,000 doses
Gardasil US 18,727 (7) 35,000,000
a
(7) 54 1,498 (7) 4.3
France 1,700 (34) 4,000,000
a
(34) 43 na
Australia 1,534 (39) 6,000,000
a
(39) 26 91
c
(26,28,29) 1.5
c
Ireland 314 (33) 90,000
b
(33) 349 na
Cervarix Netherlands 575 (32) 192,000
b
(32) 299 575 (32) 5.7
UK 8,798 (23) 3,500,000
b
(23) 251 na
na not available.
a
Doses distributed.
b
Doses administered.
c
Excluding 2010 data(unavailable at the time of writing of this report).
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L. Tomljenovic & C. A. Shaw
was still the number one vaccine on the list of AEFIs in Australia,
with 497 records (32% of all AEFIs), and accountable for nearly
30% of convulsions (13 out of 43) (28). During 2009, the Austra-
lian reported AEFI rate for adolescents decreased by almost 50%
(from 10.4 to 5.6/100,000) (29).  is decline in AEFI rates was
attributed to a reduction in the numbers of HPV vaccine-related
reports, following cessation of the catch-up component of the
HPV programme(29). Namely, the percentage of AEFIs related
to HPV vaccines was only 6.4 in 2009 (29) compared to 50 in
2007 (26). In spite of the overall signi cant decrease in AEFI rate,
the percentage of convulsions attributable to the HPV vaccine
remained comparable between 2007 and 2009 (51% (26) and 40%
(29), respectively).
Cumulatively, the list of serious ADRs related to HPV vaccina-
tion in the US, UK, Australia, Netherlands, France, and Ireland
includes deaths, convulsions, syncope, paraesthesia, paralysis,
Guillain Barr é syndrome (GBS), transverse myelitis, facial palsy,
chronic fatigue syndrome, anaphylaxis, autoimmune disorders,
deep vein thrombosis, pulmonary embolisms, and pancreatitis
(23,24,26,28 – 35).
It may be thus appropriate to ask whether it is worth risking
death or a disabling lifelong neurodegenerative condition such
as GBS at a preadolescent age for a vaccine that has only a theo-
retical potential to prevent cervical cancer, a disease that may de-
velop 20 40 years a er exposure to HPV, when, as Harper noted,
the same can be prevented with regular Pap screening (36)?
It is also of note that in the post-licensure period (2006 2011),
the US VAERS received 360 reports of abnormal Pap smears, 112
reports of cervical cancer dysplasia, and 11 reports of cervical
cancers related to HPV vaccines (35). In a report to the FDA (37),
Merck expressed two important concerns regarding administra-
tion of Gardasil to girls with pre-existing HPV-16/18 infection.
One was the potential of Gardasil to enhance cervical disease ,
and the other was the observations of CIN 2/3 or worse cases due
to HPV types not contained in the vaccine . According to Merck,
‘  ese cases of disease due to other HPV types have the poten-
tial to counter the e cacy results of Gardasil for the HPV types
contained in the vaccine. Table 17 in Merck s report to the FDA
shows that Gardasil had an observed e cacy rate of 44.6% in
subjects who were already exposed to relevant HPV types (37).
If, as implied by Merck s own submission, Gardasil may exacerbate
overall safety of the various HPV vaccination programmes. None-
theless, analysis of the UK Medicines and Healthcare products
Regulatory Agency (MHRA) vaccine safety data shows that there
may be valid reasons for concern. For example, the total num-
ber of ADRs reported for Cervarix appears to be 24 104 times
higher than that reported for any of the other vaccines in the
UK immunization schedule (Figure 2).
O cial reports on adverse events following immunization
(AEFI) in Australia also raise concerns (26). In 2008, Australia
reported an annual AEFI rate of 7.3/100,000, the highest since
2003, representing an 85% increase compared with AEFI rate
from 2006 (26).  is increase was almost entirely due to AEFIs
reported following the commencement of the national HPV vac-
cination programme for females aged 12 26 years in April 2007
(705 out of a total of 1538 AEFI records).  us, nearly 50% of
all AEFIs reported during 2007 were related to the HPV vaccine.
Moreover, HPV vaccine was the only suspected vaccine in 674
(96%) records, 203 (29%) had causality ratings of certain or
probable , and 43 (6%) were de ned as serious . e most severe
AEFIs reported following HPV vaccination were anaphylaxis and
convulsions. Notably, in 2007, 10 out of 13 reported anaphylaxis
(77%) and 18 out of 35 convulsions (51%) occurred in women
following HPV vaccination (26). During 2008, the HPV vaccine
Figure 1. e rate of adverse reactions (ADRs) from Gardasil and Cervarix
reported through various government-offi cial vaccine surveillance
programmes. For the data source, see Table II.
Figure 2. e rate of adverse reactions (ADRs) from Cervarix compared to that of other vaccines in the UK immunization schedule. Data sourced from the
report provided by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for the Joint Committee on Vaccination and Immunisation in
June 2010 (23).
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HPV vaccines and evidence-based medicine
the very disease it is supposed to prevent, why do the US FDA
and the CDC allow for preadolescent girls and young women
to be vaccinated with Gardasil without prescreening them for
HPV-16/18 infections?
Side-eff ects from HPV vaccines: are they a minor
concern?
According to governmental health agencies worldwide, including
the US CDC, Health Canada, the Australian  erapeutic Goods
Administration (TGA), the UK MHRA, and the Irish Medicines
Board (IMB), the vast majority of adverse reactions from either
Gardasil or Cervarix are non-serious (6,23,24,38,39).  ese sourc-
es further state that most participants report brief soreness at the
injection site, headache, nausea, fever, and fainting (6,23,24,38,39).
Moreover, the UK MHRA and the US FDA and the CDC main-
tain that fainting is common with vaccines (especially among
adolescents) and hence not a reason for concern (6,23). Speci -
cally, the UK MHRA states that Psychogenic events including
vasovagal syncope, faints and panic attacks can occur with any
injection procedure and that such events can be associated with
a wide range of temporary signs and symptoms including loss of
consciousness, vision disturbances, injury, limb jerking (o en
misinterpreted as a seizure/convulsion), limb numbness or tin-
gling, di culty in breathing, hyperventilation etc. (23).
e VAERS data show that since 2006 when it was  rst ap-
proved, Gardasil has been associated with 18,727 adverse reac-
tions in the US alone, 8% of which were serious (1498) including
68 deaths (Table II). A report to any passive vaccine surveillance
system does not by itself prove that the vaccine caused an ADR.
Systematic, prospective, controlled trials are needed to establish
or reject causal relationships with regard to drug-related adverse
reactions of any type. Nevertheless, the unusually high frequency
of reports of ADRs related to HPV vaccines (Figure 2), as well as
their consistent pattern (i.e. with only minor deviations, nervous
system-related disorders rank the highest in frequency across dif-
ferent countries, followed by general/administration site condi-
tions and gastrointestinal disorders) (Figure 3), indicates that the
risks of HPV vaccination may not have been fully evaluated in
clinical trials. Indeed, in their analysis of ADRs of potential auto-
immune aetiology in a large integrated safety database of ASO4
adjuvanted vaccines (a novel adjuvant system composed of 3-O-
desacyl-4-monophosphoryl lipid A and aluminum salts used in
Cervarix), Verstraeten et al. (40) acknowledge that It is important
to note that none of these studies were set up primarily to study
autoimmune disorders. If the purpose of the study was indeed to
assess ADRs of potential autoimmune aetiology , as the title itself
clearly states (40), then the study should have been designed to
detect them. All of the eight authors of the ASO4 safety study
are employees of GlaxoSmithKline (GSK), the manufacturer of
Cervarix (40).  ese authors noted that our search of the litera-
ture found no studies conducted by independent sources on this
subject and All studies included in this analysis were funded by
GSK Biologicals, as was the analysis itself. GSK Biologicals was
involved in the study design, data collection, interpretation and
analysis, preparation of the manuscript and decision to publish
(40).
Given that vaccines can trigger autoimmune disorders(41 44),
a more rigorous safety assessment than that provided by the
GSK-sponsored study would appear to have been warranted.
Figure 3. Percentages of reported ADRs associated with HPV vaccines for each system organ class. Data sourced from the Database of the Netherlands
Pharmacovigilance Centre Lareb (32), the UK Medicines and Healthcare products Regulatory Agency (MHRA) (62), and the Irish Medicines Board (IMB)
(24). e most commonly reported ADRs in the nervous system and psychiatric disorders class were headache, syncope, convulsions, dizziness, hypoaesthesia,
paraesthesia, lethargy, migraine, tremors, somnolence, loss of consciousness, dysarthria, epilepsy, sensory disturbances, facial palsy, grand mal convulsion,
dysstasia, dyskinesia, hallucination, and insomnia.
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Safety assessment of HPV vaccines in clinical trials:
was it adequate?
A double-blinded, placebo-controlled trial is considered the gold
standard for clinical trials as it is thought to prevent potential re-
searchers biases from distorting the conduct of a trial and/or the
interpretation of the results (63). Biases, however, may still occur
due to selective publication of  ndings from within such trials,
subject selection factors (inclusion/exclusion criteria), as well as
placebo choices. With regard to the latter, according to the FDA, a
placebo is an inactive pill, liquid, or powder that has no treatment
value (63). It is therefore surprising thus to note that no regulations
govern placebo composition, given that certain placebos can in u-
ence trial outcomes (64). Speci cally, placebo composition can, in
principle, be manipulated to produce results that are favourable to
the drug either in terms of safety or e cacy (64).
e clinical trials for Gardasil and Cervarix used an aluminum-
containing placebo (15,20,40,65 69). Both HPV vaccines, like
many other vaccines, are adjuvanted with aluminum in spite of
well documented evidence that aluminum can be highly neu-
rotoxic (70 72). Moreover, current research strongly implicates
aluminum adjuvants in various neurological and autoimmune
disorders in both humans and animals (41,73 80). It is thus be-
coming increasingly clear that the routine use of aluminum as a
placebo in vaccine trials is not appropriate (80,81).
Notably, safety data for Gardasil presented in Merck s pack-
age insert and the FDA product approval information (82) show
that compared to the saline placebo, those women receiving the
aluminum-containing placebo reported approximately 2 5 times
more injectionsite ADRs. On the other end, the proportion of
injection site ADRs reported in the Gardasil treatment group was
comparable to that of the aluminum control group (Table III).
us, Merck s own data seem to indicate that a large proportion
of ADRs from the HPV vaccine were due to the e ect of the alu-
minum adjuvant.
For the assessment of serious conditions, the manufacturer
pooled the results from the study participants who received the
saline placebo with those who received the aluminum-containing
placebo and presented them as one control group.  e outcome
of this procedure was that Gardasil and the aluminum control
group had exactly the same rate of serious conditions (2.3%)
(Table IV).
In a recent meta-analysis of safety and e cacy of HPV vaccines,
seven trials enrolling a total of 44,142 females were evaluated (83).
Two main populations of women were de ned in these trials: those
who received three doses of the HPV vaccine or the aluminum-
containing placebo within a year (denoted as the per-protocol popu-
lation (PPP)), and those who received at least one injection of the
vaccine or the placebo within the same period (intention-to-treat
population (ITT)). While HPV vaccine e cacy was evaluated in
both PPP and ITT cohorts, vaccine safety was primarily evaluated
in the ITT cohort (83). Although ITT analysis is conservative for
assessment of treatment bene ts (since dropouts may occur), it is
anti-conservative for assessment of ADRs, because ADRs will occur
Meanwhile, independent scienti c reports have linked
HPV vaccination with serious ADRs, including death (45,46),
amyotrophic lateral sclerosis (ALS) (45), acute disseminated
encephalomyelitis (ADEM) (47 49), multiple sclerosis (MS)
(50 52),opsoclonus-myoclonus syndrome (OMS) (which is char-
acterized by ocular ataxia and myoclonic jerks of the extremi-
ties)(53), orthostatic hypotension (54), brachial neuritis (55),
vision loss (56), pancreatitis (57), anaphylaxis (58), and postural
tachycardia syndrome (POTS)(59).
ADEM and MS are serious demyelinating diseases of the central
nervous system that typically follow a febrile infection or vaccina-
tion (49,50,60). Both disorders are also thought to be triggered by
an autoimmune mechanism (50). Clinical symptoms include rapid
onset encephalopathy, multifocal neurologic de cits, demyelinat-
ing lesions, optic neuritis, seizures, spinal conditions, and variable
alterations of consciousness or mental status (47,49,60). Regarding
POTS, the reported case had no other relevant factors or eventspre-
ceding the symptoms onset apart from Gardasil vaccination (59).
POTS is de ned as the development of orthostatic intolerance (61).
According to Blitshteyn, It is probable that some patients who
develop POTS a er immunization with Gardasil or other vaccines
are simply undiagnosed or misdiagnosed, which leads to under-
reporting and a paucity of data on the incidence of POTS a er
vaccination in literature (59). Patients with POTS typically present
with complaints of diminished concentration, tremulousness, diz-
ziness and recurrent fainting, exercise intolerance, fatigue, nausea
and loss of appetite (59,61). Such symptoms may be incorrectly la-
belled as panic disorders or chronic anxiety. Notably, symptoms of
POTS appear to be among the most frequent ADRs reported a er
vaccination with HPV vaccines (6,23,24,39). In spite of this, health
authorities worldwide do not regard these outcomes as causally re-
lated to the vaccine (6), but rather as psychogenic events (23,39).
In summary, it appears that many medical authorities may
have been too quick to dismiss a possible link between HPV
vaccines and serious ADRs by relying heavily on data provided
by the vaccine manufacturers rather than from independent
research.  e UK MHRA states that e vast majority of sus-
pected ADRs reported to MHRA in association with Cervarix
vaccine continue to be related to either the signs and symptoms
of recognized side e ects listed in the product information or
to the injection process and not the vaccine itself (i.e. psycho-
genic in nature such as faints) (23). It is interesting to note that
the entire group of system class disorders shown in Figure 3 is
regarded as unrelated to the HPV vaccine by the MHRA. Ac-
cording to the Agency, ese suspected ADRs are not currently
recognised as side e ects of Cervarix vaccine and the available
evidence does not suggest a causal link with the vaccine.  ese
are isolated medical events which may have been coincidental
with vaccination (23,62). However, the fact that a similar pattern
of system class ADRs to that in the UK has also been observed in
at least two other countries argues against the MHRA conclusion
and suggests the opposite, namely a causal relationship with the
HPV vaccine (Figure 3).
Table III. Injectionsite adverse reactions (ADRs) reported in Gardasil clinical trials among 8878 female participants aged 9–26 years, 1–5 days
post-vaccination(82).
ADR type Gardasil (n 5088)%
Aluminum (AAHS)
a
(n 3470)%
Saline placebo
(n 320)% Gardasil/saline Gardasil/AAHS AAHS/saline
Pain 83.9 75.4 48.6 1.7 1.1 1.6
Swelling 25.4 15.8 7.3 3.5 1.6 2.2
Erythema 24.7 18.4 12.1 2.0 1.3 1.5
Pruritus 3.2 2.8 0.6 3.5 1.1 4.7
Bruising 2.8 3.2 1.6 1.8 0.9 2.0
a
AAHS Control amorphous aluminum hydroxyphosphate sulfate.
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HPV vaccines and evidence-based medicine
e e cacy of regular Pap screening procedures in developed
countries is further emphasized by the fact that such programmes
helped to achieve a 70% reduction in the incidence of cervical
cancer over the last  ve decades (10,12,86,87). Conversely, in
Finland, when women stopped attending Pap screens, a 4-fold in-
crease in cervical cancer occurred within 5 years from screening
cessation (88,89).
It should be emphasized that HPV vaccination does not make
Pap screening obsolete, especially since the current HPV vaccines
guard only against 2 out of 15 oncogenic HPV strains. Harper not-
ed that if HPV-vaccinated women stopped going for Pap smears,
the incidence rate of cervical cancer would increase (36,86). A
similar concern was also raised by French and Canadian research-
ers who suggested the possibility that vaccinated women might be
less inclined to participate in screening programmes (87,90). Such
outcomes would in turn compromise timely specialist referral of
cases harbouring precancerous lesions, especially those related to
HPV genotypes other than 16/18 (90).
Are HPV vaccines cost-eff ective?
e currently licensed HPV vaccines are among the most expen-
sive vaccines on the market (i.e. Gardasil currently costs US $ 400
for the three required doses) (87), making it unlikely that those
countries with the heaviest burden of cervical cancer mortal-
ity (i.e. Uganda, Nigeria, and Ghana) would ever bene t from
them.  at is under the assumption that the long-term bene ts
from HPV vaccination (i.e. cancer prevention) were proven. For
example, preadolescent HPV vaccination in  ailand is cost-
e ective only when assuming lifelong e cacy and a cost of 10
international dollars (I $ , a currency that provides a means of
translating and comparing costs among countries) per vaccinated
girl (approximately I $ 2/dose) or less (91).  e cost-e ectiveness
analysis of HPV vaccination for Eastern Africa shows a similar
outcome (25). In countries where pricing is less of an issue, such
as the US, HPV vaccination is only cost-e ective based on the
assumption of complete and lifelong vaccine e cacy and 75%
coverage of the targeted preadolescent population (92,93). In the
Netherlands, HPV vaccination is not cost-e ective under similar
assumptions (e.g. that the HPV vaccine provides lifelong protec-
tion against 70% of all cervical cancers, has no side-e ects, and
is administered to all women regardless of their risk of cervical
cancer) (94). Note that the reason why high coverage is needed
for a vaccine to be cost-e ective in the developed countryset-
ting is the very low incidence of cervical cancer (due to e ec-
tiveness of Pap screening programmes). For example, to prevent
a single out of 5.7/100,000 cervical cancer cases (or one out of
1.7/100,000 cervical cancer deaths) in the US, nearly every girl
would need to be vaccinated for the HPV vaccine programme to
be cost-e ective.
e increased pressure to make the HPV vaccines manda-
tory for all preadolescent girls makes the cost of the HPV vac-
cination programme a signi cant issue. For example, according
to a 2006 report in e New York Times (95), to make Gardasil
mandatory would probably double the cost of the US vaccination
programme: North Carolina, for instance, spends $ 11 million
annually to provide every child with seven vaccines. Gardasil alone
would probably cost at least another $ 10 million. Under the as-
sumption that the HPV vaccine o ers full protection against HPV
infection for 5 years, an 11-year-old girl would need 13 booster
shots if she were to live to the age of 75. At a current cost of US
$ 120 per dose, the total cost for vaccinating one girl would thus
exceed US $ 1500. According to some estimates, to vaccinate every
11- and 12-year-old girl in the US would cost US $ 1.5 billion and to
less frequently if fewer doses of the vaccine are administered.  us,
such a selection procedure may explain why the meta-analysis found
the risk-to-bene t ratio to be in favour of the HPV vaccines (83).
e seven trials included in the meta-analysis were all sponsored
by the vaccine manufacturers (14,15,20,65 69). In a lengthy report
of potential con icts of interests of the FUTURE II trial study group
(15), the majority of authors declared receiving lecture fees from
Merck, Sano Pasteur, and Merck Sharp & Dohme . In addition, In-
diana University and Merck have a con dential agreement that pays
the university on the basis of certain landmarks regarding the HPV
vaccine. In the 2009 JAMA editorial (11), Haug noted that When
weighing evidence about risks and bene ts, it is also appropriate to
ask who takes the risk, and who gets the bene t. Patients and the
public logically expect that only medical and scienti c evidence is
put on the balance. If other matters weigh in, such as pro t for a
company or  nancial or professional gains for physicians or groups
of physicians, the balance is easily skewed.  e balance will also tilt
if the adverse events are not calculated correctly.
Are there safe and eff ective alternatives to HPV
vaccination?
Although approximately 275,000 women die annually from
cervical cancer worldwide, almost 88% of these deaths occur in
developing countries. Such disproportion of cancer deaths may
be surprising given that the prevalence of HPV-16/18 in women
with cervical cancer is equal in both developing and developed
countries (71.0% and 70.8%, respectively) (Table V). Furthermore,
HPV-16 and HPV-18 are the most oncogenic of all HPV subtypes
and increasingly dominant with increasing severity of cervical
cancer lesions (Table I) (84). Nonetheless, analysis of WHO data
in Figure 4 shows that HPV-16/18 prevalence in women with
high-grade lesions as well as cervical cancer is not a signi cant
promoter of high cervical cancer mortality in developing coun-
tries ( P 0.07 0.19), but rather it is the lack of or insu cient
Pap screening coverage ( P 0.0001). ese data do not dispute
that HPV-16/18 infection is a primary prerequisite for cervical
cancer. However, they do point to other co-factors as necessary
determinants of both disease progression and outcome (85).
Table IV. Number of girls and women aged 9–26 years who reported a
condition potentially indicative of a systemic autoimmune disorder a er
enrolment in Gardasil clinical trials (82).
Condition
Gardasil (n 10,706)
n (%)
Aluminum (AAHS)
a
(n 9412)
n (%)
Arthralgia/arthritis/arthropathy 120 (1.1) 98 (1.0)
Autoimmune thyroiditis 4 (0.0) 1 (0.0)
Coeliac disease 10 (0.1) 6 (0.1)
Insulin-dependent 2 (0.0) 4 (0.0)
Diabetes melitus insulin-dependent 2 (0.0) 2 (0.0)
Erythema nodosum 27 (0.3) 21 (0.2)
Hyperthyroidism 35 (0.3) 38 (0.4)
Hypothyroidism 7 (0.1) 10 (0.1)
In ammatory bowel disease 2 (0.0) 4 (0.0)
Multiple sclerosis 2 (0.0) 5 (0.1)
Nephritis 2 (0.0) 0 (0.0)
Optic neuritis 4 (0.0) 3 (0.0)
Pigmentation disorder 13 (0.1) 15 (0.2)
Psoriasis 3 (0.0) 4 (0.0)
Raynauds phenomenon 6 (0.1) 2 (0.0)
Rheumatoid arthritis 2 (0.0) 1 (0.0)
Scleroderma/morphea 1 (0.0) 0 (0.0)
Stevens–Johnson syndrome 1 (0.0) 3 (0.0)
Sytemic lupus erythematosus 3 (0.0) 1 (0.0)
Uveitis 3 (0.0) 1 (0.0)
Total 245 (2.3) 218 (2.3)
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L. Tomljenovic & C. A. Shaw
with a particular drug so that a patient is able to make an informed
decision regarding a treatment. If a physician fails to do so and/or
if  nancial interests take precedence over public health, breaches
of informed consent guidelines may occur. For instance, present-
ing information in a way which promotes fear of a disease while
undervaluing potential vaccine risks is likely to encourage patients
to give consent to the treatment, even when the latter has no proven
signi cant health bene t.
Both Gardasil and Cervarix were approved by the US FDA,
which in 2006 was found to be ...not positioned to meet current
or emerging regulatory responsibilities , because its scienti c base
has eroded and its scienti c organizational structure is weak (97).
According to the Science and Mission at Risk Report prepared by
the FDA Science Board in 2006 (97), the risks of an under-per-
forming FDA are far-reaching for two main reasons. First, e
FDA s inability to keep up with scienti c advances means that
American lives are at risk , and second, e world looks to the
FDA as a leader in medicine and science. Not only can the agency
not lead, it can t even keep up with the advances in science (97).
If the FDA s decisions to approve certain drugs could by its
own admission be unreliable, then the only other gate-keeper
for consumer safety is the expert advice provided by other health
protect only these girls for a lifetime would cost US $ 7.7 billion
(96). If we were to estimate just the cost of initial vaccination
excluding the booster shots for 11- and 12-year-old girls, in ten
years the US would spend at least 15 billion of limited health care
dollars on Gardasil alone (96). Who then reaps the bene t at no
risk from making the HPV vaccine mandatory?  e customer or
the manufacturer?
Altogether the above observations do not support the claim
made by the US CDC and the FDA, that is, is [Gardasil] vac-
cine is an important cervical cancer prevention tool that will
potentially bene t the health of millions of women (6) and, in-
stead, appear to suggest that current worldwide immunization
campaigns (Table I) with either of the two HPV vaccines are
neither justi ed by long-term health bene ts nor economically
viable.
How does HPV vaccine marketing and promotion
line up with international ethical guidelines for
informed consent?
e medical profession s ethical duty is to provide a full and
accurate explanation of the bene ts as well as the risks associated
Figure 4. Correlation between cervical cancer mortality rates and A: Pap test screening coverage; B:HPV-16/18 prevalence in women with high-grade lesions
(CIN 2/3, carcinoma in situ (CIS), and high-grade cervical squamous intraepithelial lesions (HSIL)); C: HPV-16/18 prevalence in women with cervical
cancer. Data were sourced for 22 countries from World Health Organization (WHO)/Institut Catala d’Oncologia (ICO) Information Centre on HPV and
cervical cancer (Table I). e correlation analysis was carried out using GraphPad Prism statistical so ware to derive Pearson correlation coeffi cients (r). e
level of signifi cance was determined using a two-tailed test. e correlation was considered statistically signifi cant at P 0.05.
Table V. Key cervical cancer statistics according to the 2010 World Health Organization (WHO)/Institut Catala d’Oncologia (ICO) report on HPV and related
cancers (107).
Wor ld
Developing countries
(% total)
Developed countries
(% total)
Women at risk for cervical cancer (aged 15 y)
2,336,986 1,811,867 (77.5) 525,120 (22.5)
Annual number of new cases of cervical cancer 529,828 453,321 (85.6) 76,507 (14.4)
Annual number of cervical cancer deaths 275,128 241,969 (87.9) 33,159 (12.1)
Prevalence (%) of HPV-16 and/or HPV-18 among women with cervical cancer 70.9 71.0 70.8
Ann Med Downloaded from informahealthcare.com by University of British Columbia on 12/22/11
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HPV vaccines and evidence-based medicine
disconcerting than the aggressive marketing strategies employed
by the vaccine manufacturers is the practice by which the medi-
cal profession has presented partial information to the public,
namely, in a way that generates fear, thus likely promoting vac-
cine uptake. For example, the US CDC and the FDA state that
Worldwide, cervical cancer is the second most common cancer
in women, causing an estimated 470,000 new cases and 233,000
deaths per year (6).  e Telethon Institute for Child Health
Research in Australia made a similar statement in 2006 while
recruiting volunteers for a HPV vaccine study. In the opening
paragraph the point was also made that cervical cancer was one
of the most common causes of cancer-related deaths in women
worldwide (103). A crucial fact was omitted in both instances
which is that while it is certainly true that approximately a quar-
ter of a million of women die of cervical cancer each year, 88%
of these deaths occur in the developing countries and certainly
not in the US nor Australia (Table V), where cervical cancer is
the 15th and 17th cause of cancer-related deaths, respectively,
and where mortality rates from this disease are the lowest on
the planet (1.4 1.7/100,000) (Table I). Finally, contrary to the
information provided by the CDC and the FDA, there is no evi-
dence that Gardasil is an important cervical cancer prevention
tool (6).
It thus appears that to this date, medical and regulatory entities
worldwide continue to provide inaccurate information regarding
cervical cancer risk and the usefulness of HPV vaccines, thereby
making informed consent regarding vaccination impossible to
achieve.
Concluding remarks
Regulatory authorities are responsible for ensuring that new
vaccines go through proper scienti c evaluation before they are
approved. An equal  duciary responsibility rests with the medi-
cal profession to only promote vaccinations with those vaccines
whose safety and e cacy have been thoroughly demonstrated.
e available evidence, however, indicates that health authorities
in various countries may have failed to provide an evidence-based
rationale for immunization with HPV vaccines and, in doing so,
may have breached international ethical guidelines for informed
consent. Contrary to the information from the US CDC, Health
Canada, Australian TGA, and the UK MHRA, the e cacy of
Gardasil and Cervarix in preventing cervical cancer has not been
demonstrated, and the long-term risks of the vaccines remain to
be fully evaluated.
Current worldwide HPV immunization practices with either
of the two HPV vaccines appear to be neither justi ed by long-
term health bene ts nor economically viable, nor is there any
evidence that HPV vaccination would reduce the rate of cervical
cancer beyond what Pap screening has already achieved. Further-
more, the frequency, the severity, as well as the consistency of
the patterns of ADRs reported to various governmental vaccine
surveillance programmes for both Gardasil and Cervarix (Figures
2 and 3) raise signi cant concerns about the overall safety of HPV
vaccination programmes. Because these programmes have global
coverage (Table I), the long-term health of many women may be
unnecessarily at risk against still unknown vaccine bene ts. Alto-
gether these observations suggest that a reduction in the burden
of cervical cancer globally might be best achieved by targeting
other risk factors for this disease (i.e. smoking, use of oral contra-
ceptives, chronic in ammation) (85) in conjunction with regular
Pap test screening.  e latter strategy has already been proven
successful in developed nations where the incidence of cervical
cancer is very low (Table I).
authorities.  e history of how HPV vaccines came to market,
however, indicates that such advice was not always given from
the basis of the best available evidence. A 2009 Special Commu-
nication from JAMA by Rothman and Rothman (98) provides
compelling evidence that Gardasil manufacturer Merck funded
educational programmes by professional medical associations
(PMAs) as a marketing strategy to promote the use of their vac-
cine.  e marketing campaign proceeded awlessly ’ , according to
Merck s chief executive o cer, and in 2006 Gardasil was named the
pharmaceutical brand of the year for building a market out of
thin air (98).  e reason why the marketing campaign for Gardasil
was so successful was that By making this vaccine s target disease
cervical cancer, the sexual transmission of HPV was minimized,
the threat of cervical cancer to all adolescents maximized, and
the subpopulations most at risk [women in developing countries]
practically ignored (98). at these arguments were delivered by
the PMAs is cause for concern, since PMAs are obligated to pro-
vide members with evidence-based data so that they in turn are
able to present relevant risks and bene ts to their patients (98).
India s medical authorities have also been publicly condemned
a er a civil society-led investigation revealed that trials for HPV
vaccines in the states of Andhra Pradesh and Gujarat violated
established national and international ethical guidelines on clini-
cal research as well as children s rights (99).  ese events appar-
ently occurred as a result of aggressive promotional practices of
the drug companies and their uncritical endorsement by India s
medical associations (99). Although proclaimed as a post-licen-
sure observational study of HPV vaccination against cervical
cancer, the project was in fact a clinical trial and, as such, should
have adhered to protocols mandated by the Drugs and Cosmetics
Act (DCA) and the Indian Council for Medical Research (ICMR)
(100). Instead, the trial was found in serious breach of both the
DCA s and the ICMR s guidelines for informed consent and was
terminated in April 2010, following six post-HPV vaccination
deaths (99).  e report in the 2011 issue of Lancet Infectious
Diseases further reveals that both ICMR and DCA subsequently
denied information on the study protocols as a trade secret
and commercial con dence of third party (100). According to
the authors, It remains unclear how information from a study
done in collaboration with government health organisations can
be regarded as a trade secret (100). It is worth emphasizing that
the termination of HPV vaccine trials in India occurred despite
an annual cervical cancer mortality rate of 15.2/100,000 women,
which is over 7 10 times greater than that in the developed world
(Table I). Such an outcome indicates that even situations of unmet
medical needs cannot be resolved at the expense of abandoning
ethical requirements for informed consent.
Questionable HPV vaccine marketing strategies were also seen
in France and were eventually stopped by the action of govern-
ment health authorities who found the sponsorship of several
Gardasil advertisements to be in direct violation of French public
health codes (101).  ese violations included, but were not lim-
ited to: 1) Claiming longer e cacy than was actually proven (8.5
versus 4.5 years) and 2) Making false claims (the ads in question
replaced the o cially approved use of Gardasil for the prevention
of low-grade lesions with statements indicating Gardasil should
be used for the prevention of pre-malignant genital lesions,
cancers of the cervix and external genital warts ).
In the US, Merck has been heavily criticized for the fact that
it spent vast sums in lobbying to make the vaccine mandatory
(12,98). According to an editorial from e American Journal
of Bioethics , even those who strongly favoured the vaccine were
stunned at the degree to which Merck has pushed its $ 400 vac-
cine as a mandatory measure (102). Nonetheless, what is more
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Reports to the Vaccine Adverse Events Reporting System (VAERS).
February 2009 [cited 2011 January 25]. Available from: http://www.
nvic.org/Downloads/NVICGardasilvsMenactraVAERSReportFeb-
2009u.aspx
According to the Helsinki Declaration and the International
Code of Medical Ethics (104), the well-being of the individual
must be a physician s top priority, taking precedence over all
other interests. Although the Declaration is addressed primarily
to physicians, the World Medical Association encourages other
participants in medical research involving human subjects to
adopt these same principles (104). Greater e orts should thus be
made to minimize the undue commercial in uences on academic
institutions and medical research, given that these may impede
unbiased scienti c inquiry into important questions about
vaccine science and policy.
e almost exclusive reliance on manufacturers sponsored stud-
ies, o en of questionable quality, as a base for vaccine policy-making
should be discontinued. So should be the dismissal of serious ADRs
as coincidental or psychogenic in spite of independent research
suggesting otherwise. It can hardly be disputed in view of all the
evidence (i.e. case reports and vaccineADR surveillance in various
countries) that HPV vaccines do trigger serious ADRs. What does
remain debatable, however, is the true frequency of these events
because all systems of monitoring for vaccineADRs currently in place
rely on passive reporting.Passive ADR surveillance should thus be
replaced by active surveillance to better our understanding of true
risks associated with particular vaccines (especially new vaccines).
e presentation of partial and non-factual information regarding
cervical cancer risks and the usefulness of HPV vaccines, as cited
above, is, in our view, neither scienti c nor ethical. None of these
practices serve public health interests, nor are they likely to reduce
the levels of cervical cancer. Independent evaluation of HPV vaccine
safety is urgently needed and should be a priority for government-
sponsored research programmes. Any future vaccination policies
should adhere more rigorously to evidence-based medicine as well
as strictly follow ethical guidelines for informed consent.
Declaration of interest: is work was supported by the Dwosk-
in, Lotus and Katlyn Fox Family Foundations. L.T. and C.A.S.
conducted a histological analysis of autopsy brain samples from
a Gardasil-suspected death case. C.A.S. is a founder and share-
holder of Neurodyn Corporation, Inc.  e company investigates
early-state neurological disease mechanisms and biomarkers.
is work and any views expressed within it are solely those of
the authors and not of any a liated bodies or organizations.
A portion of this information was presented at the Vaccine Safety
Conference, 3 8 January 2011 (www.vaccinesafetyconference.com).
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Supplementary resources

  • Article
    Full-text available
    p>Human papillomavirus (HPV) causes cervical cancer, which is the fourth most common cancer in women. Most of the cervical cancers are linked to genital infection with HPV and it is the most common viral infection of the reproductive tract. At present, there are three types of HPV vaccines available. Even though HPV vaccination is a primary prevention tool, that does not eliminate the need for routine cervical screening, since the vaccines do not protect against all high-risk HPV types. Ninety percent of HPV infections have no clinical consequences at all whether they are high-risk or low-risk subtypes of HPV. All three types of HPV vaccines have very high vaccine efficacy for prevention of HPV infection among females aged 14 to 26 years. Proper assessment of the safety of HPV vaccine is a problem even after proper systematic review since the most of the clinical trials on the safety of the vaccines were used Hepatitis A vaccine or high immunogenicity enhancing aluminium adjuvant as their placebo. HPV vaccination would be very cost effective for the countries when there is no cervical screening program or if the programme coverage is very poor. Bangladesh Journal of Medical Science Vol.17(3) 2018 p.329-336</p
  • Article
    Full-text available
    The issues of safety and efficacy of certain vaccines remains extremely contentious. The venues for this debate have included periodicals, documentary films, and an ever-increasing number of on-line sites. While debate in science is not only a common occurrence but a fundamental tenet of the scientific community, it only works when divergent opinions can be heard. When those who hold an opposing opinion are denigrated and/or marginalized by those holding the majority opinion such as in the issue of vaccination, where cultural authority for the issue is owned by the profession of medicine, both science and the public lose. What is often forgotten are the benefits derived from the questioning of drug safety that not only extends to the public but to physicians who rely on the truthfulness and accuracy of the information that is being supplied to them by manufactures and government agencies. While most physicians believe they are functioning in their patient’s best interest when making vaccine recommendations, these recommendations by in large have become a matter of rote and are made because most physicians have bought into the “vaccines are safe” mantra. What most physicians don’t realize is they have unknowingly been recruited by big pharma to assist in shutting down the vaccination debate. This suppression of vaccine opposition even among academics, is becoming more commonplace and will lead down a slippery slope that will silence opposition science, and the dangers that come with this. Those who question vaccine safety have been ostracized, misquoted and even made to appear mentally ill by those who hold the majority opinion on the issue. Physicians who question vaccine safety have had their licenses threatened or have been fired from positions. Tactics such as name calling and the use of terms such as pseudo-science, (even when the evidence being presented is from widely accepted peer-reviewed journals) or “conspiracy theorists” which has the effect of placing those holding the minority opinion in the category of such groups as 9/11 truthers, are not uncommon. Other methods of curtailing the presentation of opposing vaccine views have included pressuring venues not to allow anti-vaccination proponents to appear, or using the media to “expose” anti-vaccination groups as “crack-pots” while simultaneously presenting the majority opinion and the presenters as the sole arbiters on the issue. The more extreme elements of the pro-vaccine group will even make the statement that the issue is settled and there is no need for discussion. “Has there ever been a society which has died of dissent? Several have died of conformity in our lifetime.” Jacob Bronowski in Science and Human Values
  • Article
    The aim of this review is to promote the prevention of cervical cancer in Japan. Cervical cancer due to human papillomavirus (HPV) infection is a preventable cause of death, although HPV infection is very common and anyone who has had sexual intercourse can become infected. Cervical cancer is a serious disease that can significantly affect women’s lives; it can not only deprive women of their fertility but also lead to death if left untreated.
  • Preprint
    BACKGROUND Designing online informational materials regarding the human papilloma virus (HPV) vaccine has become a challenge for designers and decision-makers in the health authorities due to the scientific controversy in the literature regarding the vaccine's safety and effectiveness as well as the sexual and moral concerns related to the vaccine. OBJECTIVE To analyze how information on the HPV vaccine is presented on the online sites of the official health authorities in Israel with focus on cultural sensitivity measures and on means of communicating and framing information. METHODS The informational materials published on the websites of Israeli health authorities: The Ministry of Health and the health maintenance organizations were analyzed using two parallel methods: a) a cultural sensitivity index (constructed using two measures: deep and surface dimensions) coding the informational materials designated for the Arab minority population, constructed by the researchers based on a theoretical cultural sensitivity model; b) content analysis of all informational materials on the human papilloma virus vaccine aimed both at the Jewish population and the Arab minority population. RESULTS The research findings point to a paradox. On the one hand, cultural sensitivity emerged in that the sexual context of the vaccine was missing from appeals to the conservative Arab population. On the other hand, analysis of Resnicow's deep dimensions shows that neglecting the sexual context does not allow for reflective discussion regarding the barriers and concerns of the relevant target audience. In addition, the way the information was transmitted and framed emphasized the necessity of the vaccine and left no room for doubt or other alternatives, lacked transparency regarding the scientific controversy over the vaccine's effectiveness and safety, and used a fear appeal "drug narrative" in promoting the HPV vaccine. CONCLUSIONS Explanatory health informational materials in general and those geared towards the HPV vaccine must provide all relevant information from the literature in a detailed, culturally sensitive and evidence-based manner in order to enable individuals to make an independent and intelligent decision based on informed consent.
  • Article
    Birth rates in the United States have recently fallen. Birth rates per 1000 females aged 25–29 fell from 118 in 2007 to 105 in 2015. One factor may involve the vaccination against the human papillomavirus (HPV). Shortly after the vaccine was licensed, several reports of recipients experiencing primary ovarian failure emerged. This study analyzed information gathered in National Health and Nutrition Examination Survey, which represented 8 million 25-to-29-year-old women residing in the United States between 2007 and 2014. Approximately 60% of women who did not receive the HPV vaccine had been pregnant at least once, whereas only 35% of women who were exposed to the vaccine had conceived. For married women, 75% who did not receive the shot were found to conceive, while only 50% who received the vaccine had ever been pregnant. Using logistic regression to analyze the data, the probability of having been pregnant was estimated for females who received an HPV vaccine compared with females who did not receive the shot. Results suggest that females who received the HPV shot were less likely to have ever been pregnant than women in the same age group who did not receive the shot. If 100% of females in this study had received the HPV vaccine, data suggest the number of women having ever conceived would have fallen by 2 million. Further study into the influence of HPV vaccine on fertility is thus warranted.
  • Presentation
    Full-text available
    Private sector can do much to support the Sustainable Development Goals initiatives in low-middle income countries (LMICs) through investments in research and development for pharmaceuticals, medical devices, and other health interventions. This presents opportunities for cross-sector collaborations between researchers, policy-makers, academicians, and private sector industry. It also presents challenges in balancing the primacy research needs of implementing organizations with their moral, social, and political obligations. This conflict is often convoluted when planning for and conducting international clinical research. The researchers are currently conducting a scoping review to systematically identify and characterize the literature underpinning ethical research priorities of implementing clinical trials in low-middle income countries (LMICs). In acknowledgement of the potential impact of cultural complexity on collaboration and practicalities, the researchers propose to identify the stakeholders within each final selected article of the scoping review. Identification of all stakeholders would be accomplished by identifying the author's disciplinary bias; the stakeholders who are identified in the article; the stakeholder type of the journals’ reader populations; the geographic location of stakeholders; and the other disciplines that cite the articles. This knowledge will be value in exploring the anticipated conflicts between issues of ethics in initiating clinical research programs in LMIC, recognizing maximum benefits for research participants, and implementing solutions to address the challenges.
  • Article
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    Background and aims The role of the Papanicolou (Pap) smear in the early detection and prevention of cervical cancer is well established. However, many women fail to undertake the test because of embarrassment or other reasons. To address this problem, we evaluated the feasibility of implementing self‐sampling of cervical cytology as an alternative to clinician‐collected Pap smears and compared it with the gold standard of colposcopy in terms of specificity. Materials and methods A prospective preliminary study of 40 women recruited from the colposcopy clinic of a tertiary referral hospital was undertaken. Participants were instructed in the technique of self‐sampling and asked to collect their own Pap smears. Colposcopic examinations were performed and biopsies taken, if indicated. Clinician‐collected Pap smears were performed 4 weeks later. Pairwise agreement was calculated between the outcomes of self‐collected, colposcopic, and clinician‐collected samples using the weighted κ statistic. Results Self‐collected Pap smear had a high level of acceptability among the women, all of whom were able to collect adequate tissue. The agreement of self‐collected Pap smears with colposcopic assessment was no worse than that of clinician‐collected Pap smears (Cohen's κ statistic 0.54 [95% CI, 0.27‐0.82]; cf 0.49 [0.2‐0.78], respectively). The specificity of self‐collected Pap smears was almost identical to that of clinician‐collected samples (specificity: 86% vs 81%, respectively). Direct comparison between patient and clinician collected Pap smears showed fair agreement (κ statistic 0.38 [0.07‐0.68]). There were no adverse events in either group. Conclusions Self‐collection of Pap smears is an effective and acceptable alternative to clinician‐collected samples and may provide a strategy for improving compliance with cervical testing programs.
  • Chapter
    A large body of evidence supports the prevailing scientific opinion that human papillomavirus (HPV) vaccines are efficacious, safe, and cost-effective. Since first licensure in 2006, however, HPV vaccines have sparked unjustified controversy over their effectiveness, safety and risks, utility, and ethical implementation. We discuss various public criticisms relating to HPV vaccination and the weight of the evidence and counterarguments concerning each. These criticisms can be classified as follows: (1) effectiveness (lack of demonstrated efficacy against cervical cancer, lack of vaccine clinical trial data in targeted age groups, and limited HPV type protection of first-generation vaccines), (2) safety and risk (concerns regarding potential serious adverse health events linked with vaccination, effect of vaccines on prevalent infections, and potential sexual disinhibition caused by vaccination), (3) utility (disputing the added value of vaccination on the grounds of financial conflicts of interests, the low risk of cervical cancer consequent to screening, and the cost-effectiveness of vaccination), and (4) ethics (concerns regarding informed consent and self-determination in vaccination programs, the social justice of vaccine distribution, and gender equity). Most HPV vaccine controversies stem from misinformation and distrust of institutions. Public health institutions must deploy effective communication strategies to address ill-founded criticisms, enable informed consent, and foster public confidence in HPV vaccines.
Literature Review