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9
Human Papillomavirus Vaccine
INTRODUCTION
Human papillomaviruses (HPVs) represent a family of more than
100 nonenveloped, double-stranded DNA viruses uniquely targeted to the
human epithelial cells (de Villiers et al., 2004; Schiller et al., 2008). HPVs
are numbered in order of discovery and can be classified into groups ac-
cording to the anatomic areas they infect (de Villiers et al., 2004; Schiller
et al., 2008). Common, plantar, and juvenile or flat warts are caused by
HPV1 and HPV2 (Bonnez and Reichman, 2010). These warts are common
among the general population and are most common in children (Bonnez
and Reichman, 2010). Genital warts and high-risk genital HPV infections,
caused by HPV6 and 11 and HPV16, 18, 33, and 65 respectively, occur in
an estimated 6.2 million people every year in persons aged 14 to 44 years,
74 percent among individuals between 15 and 24 years (Schiller et al.,
2008; Weinstock et al., 2004).
HPV is transmitted through direct contact with the lesions or warts
that develop as a result of HPV infection (Bonnez and Reichman, 2010).
Genital HPV infections may be spread by penetrative intercourse and non-
penetrative encounters such as oral-genital, manual-genital, and genital-
genital interaction (Marrazzo et al., 2000; Winer et al., 2003). According to
Schiller et al. (2008), up to 70 percent of sexually active young women will
be infected with at least one HPV within the first 5 years of initial sexual
encounter. The risk of infection increases with instances of sexual activity
and the number of lifetime sexual partners. Manhart et al. (2006) indicated
that among women 18 to 25, 14.3 percent with one lifetime sexual partner,
505
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506 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
22.3 percent with two lifetime sexual partners, and 31.5 percent with three
or more lifetime sexual partners experience at least one HPV infection.
HPV infection is often asymptomatic, but it may lead to the presence
of cervical lesions or warts in some individuals. HPV infection is considered
transient and usually lasts between 4 and 20 months in healthy individuals
(Trottier and Franco, 2006). High-risk types of HPV such as HPV16 and
HPV18 carrying the greatest risk of persistent infection constitute the most
important risk factor for cervical cell abnormalities and invasive cervical
cancer (Molano et al., 2003). Various approaches such as cryotherapy,
electrocautery, surgical excision, and topical therapies have been used to
treat HPV-associated lesions and warts (CDC, 2002).
Research and development of an HPV vaccine was spurred by evidence
that inactivated bovine papillomavirus (BPV) could immunize cattle against
BPV infection in the 1980s (Jarrett et al., 1990). However, owing to the
oncogenic nature of HPV, live attenuated or inactivated vaccines could not
be safely developed for humans (Schiller et al., 2008). In the 1990s, re-
searchers found that inoculation with virus-like particles (VLPs) developed
from the L1 protein of specific papillomaviruses (PVs) could protect against
PV infection, but the protection is not universal for all HPVs (Schiller and
Lowy, 1996).
Currently, two vaccines are licensed in the United States to prevent dis-
eases caused by HPV infection. The quadrivalent vaccine, Gardasil (Merck
& Co., Inc.) (HPV4), was licensed in 2006 by the Food and Drug Ad-
ministration (FDA) to protect girls and women age 9 through 26 against
angogenital warts and cancers (vulvar, vaginal, cervical, and anal) caused
by HPV6, 11, 16, and 18 (CDC, 2007). Each 0.5 mL dose contains 20 µg
each of HPV 6 and HPV 18 L1 protein and 40 µg each of HPV 11 and HPV
16 L1 protein (CDC, 2007). It also contains 225 µg of amorphous alumi-
num hydroxyphosphate sulfate (adjuvant), sodium chloride, L-histidine,
polysorbate 80, sodium borate, and water (CDC, 2007). In 2009, Gardasil
was also approved for use in males aged 9–26 years for the prevention
of anal cancer and genital warts; however, although it is licensed for use
in the same schedule and composition, as of May 2010, the Advisory
Committee on Immunization Practices did not recommend routine vac-
cination in this population (CDC, 2010b). The bivalent vaccine, Cervarix
(GlaxoSmithKline Biologicals) (HPV2), was also licensed in 2009 by the
FDA to protect girls and women age 10 through 25 against HPV 16 and
18 (CDC, 2010a). Each dose of Cervarix is 0.5 mL and contains 20 µg
each of HPV 16 and HPV 18 as well as 500 µg of aluminum hydroxide,
50 µg of 3-O-desacyl-4’monophosphoryl lipid A (adjuvant), sodium chlo-
ride, sodium dihydrogen phosphate dehydrate, and water (CDC, 2010a).
Both vaccines are recommended in a three-dose series of intramuscular
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507
HUMAN PAPILLOMAVIRUS VACCINE
inoculations with the second and third dose administered 2 and 6 months
after the first dose (CDC, 2010a). Both vaccines protect against 70 percent
of HPV16 and 18 associated cancers, with Gardasil providing additional
protection against 80 to 90 percent of genital wart–causing HPV infections
(Bonnez and Reichman, 2010; CDC, 2010a). In 2009, 44.3 percent of girls
in the United States aged 13 to 17 had received at least an initial dose of
either the HPV4 or HPV2 vaccine (CDC, 2010c).
ACUTE DISSEMINATED ENCEPHALOMYELITIS
Epidemiologic Evidence
No studies were identified in the literature for the committee to evalu-
ate the risk of acute disseminated encephalomyelitis (ADEM) after the
administration of HPV vaccine.
Weight of Epidemiologic Evidence
The epidemiologic evidence is insufficient or absent to assess an
association between HPV vaccine and ADEM.
Mechanistic Evidence
The committee identified four publications reporting ADEM after ad-
ministration of HPV vaccine. The publications did not provide evidence be-
yond temporality (Borja-Hart et al., 2009; Mendoza Plasencia et al., 2010;
Schaffer et al., 2008; Wildemann et al., 2009). In addition, Borja-Hart et al.
(2009) intimated that in some cases multiple vaccines were administered
concomitantly, making it difficult to determine which, if any, vaccine could
have been the precipitating event. The publications did not contribute to
the weight of mechanistic evidence.
Weight of Mechanistic Evidence
The symptoms described in the publications referenced above are con-
sistent with those leading to a diagnosis of ADEM. Autoantibodies, T cells,
and molecular mimicry may contribute to the symptoms of ADEM; how-
ever, the publications did not provide evidence linking these mechanisms
to HPV vaccine.
The committee assesses the mechanistic evidence regarding an as-
sociation between HPV vaccine and ADEM as lacking.
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508 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
Causality Conclusion
Conclusion 9.1: The evidence is inadequate to accept or reject a
causal relationship between HPV vaccine and ADEM.
TRANSVERSE MYELITIS
Epidemiologic Evidence
No studies were identified in the literature for the committee to evalu-
ate the risk of transverse myelitis after the administration of HPV vaccine.
Weight of Epidemiologic Evidence
The epidemiologic evidence is insufficient or absent to assess an
association between HPV vaccine and transverse myelitis.
Mechanistic Evidence
The committee identified two publications reporting the development
of transverse myelitis after administration of HPV vaccine. The publications
did not provide evidence beyond temporality (Borja-Hart et al., 2009; Slade
et al., 2009). In addition, Borja-Hart et al. (2009) intimated that in some
cases multiple vaccines were administered concomitantly, making it difficult
to determine which, if any, vaccine could have been the precipitating event.
The publications did not contribute to the weight of mechanistic evidence.
Weight of Mechanistic Evidence
The symptoms described in the publications referenced above are con-
sistent with those leading to a diagnosis of transverse myelitis. Autoanti-
bodies, T cells, and molecular mimicry may contribute to the symptoms
of transverse myelitis; however, the publications did not provide evidence
linking these mechanisms to HPV vaccine.
The committee assesses the mechanistic evidence regarding an as-
sociation between HPV vaccine and transverse myelitis as lacking.
Causality Conclusion
Conclusion 9.2: The evidence is inadequate to accept or reject a
causal relationship between HPV vaccine and transverse myelitis.
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HUMAN PAPILLOMAVIRUS VACCINE
NEUROMYELITIS OPTICA
Epidemiologic Evidence
No studies were identified in the literature for the committee to evalu-
ate the risk of neuromyelitis optica (NMO) after the administration of HPV
vaccine.
Weight of Epidemiologic Evidence
The epidemiologic evidence is insufficient or absent to assess an
association between HPV vaccine and NMO.
Mechanistic Evidence
The committee identified one publication reporting the development
of neuromyelitis optica after administration of HPV vaccine. Borja-Hart
et al. (2009) do not provide evidence beyond temporality. In addition, the
authors intimate that in some cases multiple vaccines were administered
concomitantly, making it difficult to determine which, if any, vaccine could
have been the precipitating event. The publication did not contribute to the
weight of mechanistic evidence.
Weight of Mechanistic Evidence
The symptoms described in the publication described above are con-
sistent with those leading to a diagnosis of NMO. Autoantibodies, T cells,
complement activation, and molecular mimicry may contribute to the
symptoms of NMO; however, the publication did not provide evidence
linking these mechanisms to HPV vaccine.
The committee assesses the mechanistic evidence regarding an as-
sociation between HPV vaccine and NMO as lacking.
Causality Conclusion
Conclusion 9.3: The evidence is inadequate to accept or reject a
causal relationship between HPV vaccine and NMO.
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510 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
MULTIPLE SCLEROSIS
Epidemiologic Evidence
No studies were identified in the literature for the committee to evaluate
the risk of multiple sclerosis (MS) after the administration of HPV vaccine.
Weight of Epidemiologic Evidence
The epidemiologic evidence is insufficient or absent to assess an
association between HPV vaccine and MS.
Mechanistic Evidence
The committee identified two publications reporting MS developing
after administration of HPV vaccine. One publication did not provide clini-
cal, diagnostic, or experimental evidence, including the time frame between
administration of HPV vaccine and development of symptoms (Verstraeten
et al., 2008). Sutton et al. (2009) did not provide evidence beyond tempo-
rality that for some cases was too short based on the possible mechanisms
involved. The publications did not contribute to the weight of mechanistic
evidence.
Weight of Mechanistic Evidence
The symptoms described in the publications referenced above are con-
sistent with those leading to a diagnosis of MS. Autoantibodies, T cells,
and molecular mimicry may contribute to the symptoms of MS; however,
the publications did not provide evidence linking these mechanisms to HPV
vaccine.
The committee assesses the mechanistic evidence regarding an as-
sociation between HPV vaccine and MS as lacking.
Causality Conclusion
Conclusion 9.4: The evidence is inadequate to accept or reject a
causal relationship between HPV vaccine and MS.
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HUMAN PAPILLOMAVIRUS VACCINE
GUILLAIN-BARRÉ SYNDROME
Epidemiologic Evidence
The committee reviewed three studies to evaluate the risk of Guillain-
Barré syndrome (GBS) after the administration of HPV vaccine. These three
studies (Borja-Hart et al., 2009; Slade et al., 2009; Souayah et al., 2010)
were not considered in the weight of epidemiologic evidence because they
provided data from passive surveillance systems and lacked unvaccinated
comparison populations.
Weight of Epidemiologic Evidence
The epidemiologic evidence is insufficient or absent to assess an
association between HPV vaccine and GBS.
Mechanistic Evidence
The committee identified three publications reporting GBS after ad-
ministration of HPV vaccine. One publication did not provide clinical,
diagnostic, or experimental evidence, including the time frame between
administration of HPV vaccine and development of symptoms (Verstraeten
et al., 2008). Two publications did not provide evidence beyond temporality
(Borja-Hart et al., 2009; Slade et al., 2009). In addition, two publications
reported the concomitant administration of vaccines, in some cases making
it difficult to determine which, if any, vaccine could have been the precipi-
tating event (Borja-Hart et al., 2009; Slade et al., 2009). The publications
did not contribute to the weight of mechanistic evidence.
Weight of Mechanistic Evidence
The symptoms described in the publications referenced above are con-
sistent with those leading to a diagnosis of GBS. Autoantibodies, comple-
ment activation, immune complexes, T cells, and molecular mimicry may
contribute to the symptoms of GBS; however, the publications did not
provide evidence linking these mechanisms to HPV vaccine.
The committee assesses the mechanistic evidence regarding an as-
sociation between HPV vaccine and GBS as lacking.
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512 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
Causality Conclusion
Conclusion 9.5: The evidence is inadequate to accept or reject a
causal relationship between HPV vaccine and GBS.
CHRONIC INFLAMMATORY DISSEMINATED POLYNEUROPATHY
Epidemiologic Evidence
No studies were identified in the literature for the committee to evalu-
ate the risk of chronic inflammatory disseminated polyneuropathy (CIDP)
after the administration of HPV vaccine.
Weight of Epidemiologic Evidence
The epidemiologic evidence is insufficient or absent to assess an
association between HPV vaccine and CIDP.
Mechanistic Evidence
The committee did not identify literature reporting clinical, diagnostic,
or experimental evidence of CIDP after administration of HPV vaccine.
Weight of Mechanistic Evidence
Autoantibodies, T cells, and molecular mimicry may contribute to the
symptoms of CIDP; however, the committee did not identify literature re-
porting evidence of these mechanisms after administration of HPV vaccine.
The committee assesses the mechanistic evidence regarding an as-
sociation between HPV vaccine and CIDP as lacking.
Causality Conclusion
Conclusion 9.6: The evidence is inadequate to accept or reject a
causal relationship between HPV vaccine and CIDP.
BRACHIAL NEURITIS
Epidemiologic Evidence
No studies were identified in the literature for the committee to evalu-
ate the risk of brachial neuritis after the administration of HPV vaccine.
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HUMAN PAPILLOMAVIRUS VACCINE
Weight of Epidemiologic Evidence
The epidemiologic evidence is insufficient or absent to assess an
association between HPV vaccine and brachial neuritis.
Mechanistic Evidence
The committee identified two publications reporting brachial neuritis
after administration of HPV vaccine. The publications did not provide
evidence beyond temporality, some too long (Gardasil—Brachial plexus
neuritis, 2009; Debeer et al., 2008). Long latencies between vaccine ad-
ministration and development of symptoms make it impossible to rule out
other possible causes. The publications did not contribute to the weight of
mechanistic evidence.
Weight of Mechanistic Evidence
The symptoms described in the publications referenced above are con-
sistent with those leading to a diagnosis of brachial neuritis. Autoantibod-
ies, T cells, and complement activation may contribute to the symptoms of
brachial neuritis; however, the publications did not provide evidence linking
these mechanisms to HPV vaccine.
The committee assesses the mechanistic evidence regarding an as-
sociation between HPV vaccine and brachial neuritis as lacking.
Causality Conclusion
Conclusion 9.7: The evidence is inadequate to accept or reject a
causal relationship between HPV vaccine and brachial neuritis.
AMYOTROPHIC LATERAL SCLEROSIS
Epidemiologic Evidence
No studies were identified in the literature for the committee to evalu-
ate the risk of amyotrophic lateral sclerosis (ALS) after the administration
of HPV vaccine.
Weight of Epidemiologic Evidence
The epidemiologic evidence is insufficient or absent to assess an
association between HPV vaccine and ALS.
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514 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
Mechanistic Evidence
The committee identified one publication and one abstract reporting
the development of ALS after administration of HPV vaccine. Slade et al.
(2009) did not provide clinical, diagnostic, or experimental evidence includ-
ing the time frame between administration of vaccine and development of
symptoms. This publication did not contribute to the weight of mechanistic
evidence.
Huang et al. (2009), in an abstract, described a 14-year-old girl present-
ing with a rapidly progressing motor neuron disease 2 months after admin-
istration of the third dose of the HPV vaccine Gardasil. Despite treatment
the patient’s weakness progressed leading to her death from respiratory
failure 23 months after vaccination. Laboratory examinations revealed in-
filtrates of macrophages and T lymphocytes in the grey and white matter of
the spinal cord and demyelination and loss of motor neurons. The patient
was diagnosed with a rapidly progressive form of juvenile ALS.
Further investigation revealed that the patient expressed a point muta-
tion in the fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene
leading to an amino acid substitution in a highly evolutionarily conserved
region of the protein (Huang et al., 2010). Immunohistochemistry staining
of motor neurons from the spinal cord revealed strongly FUS-positive ba-
sophilic inclusions in the patient. In contrast, patients with late-onset ALS
showed no FUS-positive inclusions in motor neurons from the spinal cord.
Similar basophilic inclusions were observed in the reticular formation in the
medulla oblongata, red nucleus, nucleus ambiguous, sensorimotor cortex,
and frontal cortex in the patient.
Based on the genetic analysis and neuropathology, the authors did not
attribute the rapidly progressive form of juvenile ALS in the patient to vac-
cination against HPV using the quadrivalent vaccine Gardasil.1
Weight of Mechanistic Evidence
The symptoms described in the publication referenced above are con-
sistent with those leading to a diagnosis of ALS. Autoantibodies, T cells,
and molecular mimicry may contribute to the symptoms of ALS; however,
the publications did not provide evidence linking these mechanisms to HPV
vaccine.
The committee assesses the mechanistic evidence regarding an as-
sociation between HPV vaccine and ALS as lacking.
1 C. Lomen-Hoerth, ALS Center, University of California San Francisco, personal commu-
nication, November 11, 2010.
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HUMAN PAPILLOMAVIRUS VACCINE
Causality Conclusion
Conclusion 9.8: The evidence is inadequate to accept or reject a
causal relationship between HPV vaccine and ALS.
ANAPHYLAXIS
Epidemiologic Evidence
The committee reviewed three studies to evaluate the risk of anaphylaxis
after the administration of HPV vaccine. These three studies (Brotherton
et al., 2008; Kang et al., 2008; Slade et al., 2009) were not considered in
the weight of epidemiologic evidence because they provided data from pas-
sive surveillance systems and lacked unvaccinated comparison populations.
Weight of Epidemiologic Evidence
The epidemiologic evidence is insufficient or absent to assess an
association between HPV vaccine and anaphylaxis.
Mechanistic Evidence
The committee identified three publications describing clinical, diagnos-
tic, or experimental evidence of anaphylaxis after administration of HPV
vaccine. Kang et al. (2008) identified individuals suspected of developing
a hypersensitivity reaction after administration of HPV vaccine; however,
hypersensitivity reactions were not observed upon the subsequent admin-
istration of additional doses of HPV vaccine. This publication did not
contribute to the weight of mechanistic evidence.
Described below are two publications reporting clinical, diagnostic,
or experimental evidence that contributed to the weight of mechanistic
evidence.
Brotherton et al. (2008) conducted telephone interviews with patients,
the patients’ guardians, and witnesses of adverse reactions to the HPV
vaccine Gardasil in Australian school children. The authors reported eight
cases of anaphylaxis in detail. Anaphylaxis developed in less than 5 minutes
in four cases, 5–10 minutes in three cases, and 10–15 minutes in one case.
Slade et al. (2009) analyzed reports on the HPV vaccine Gardasil
received by the Vaccine Adverse Event Reporting System (VAERS) from
June 2006 through December 2008. The authors identified 28 reports of
anaphylaxis, according to the Brighton case definition, after vaccination
with Gardasil.
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516 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
Weight of Mechanistic Evidence
The publications described above presented clinical evidence sufficient
for the committee to conclude the vaccine may be a contributing cause of
anaphylaxis after administration of HPV vaccine. The clinical descriptions
establish a strong temporal relationship between administration of the vac-
cine and the anaphylactic reaction.
The committee assesses the mechanistic evidence regarding an as-
sociation between HPV vaccine and anaphylaxis as intermediate
based on 36 cases presenting temporality and clinical symptoms
consistent with anaphylaxis.
Causality Conclusion
Conclusion 9.9: The committee concludes that the evidence fa-
vors acceptance of a causal relationship between HPV vaccine and
anaphylaxis.
TRANSIENT ARTHRALGIA
Epidemiologic Evidence
The committee reviewed one study to evaluate the risk of arthralgia
after the administration of HPV vaccine. This one controlled study (Bhatla
et al., 2010) contributed to the weight of epidemiologic evidence and is
described below.
Bhatla et al. (2010) conducted a double-blind, randomized controlled
trial in women (18 to 35 years of age) enrolled at four hospitals in India
from July 2006 through March 2007. The patients were randomized in 1:1
ratio to receive HPV vaccine or placebo, and were given three doses at 0, 1,
and 6 months. Diary cards were used to record any general symptoms that
occurred during the 0–6 days following each dose. A total of 354 women
were enrolled in the study and randomized to the vaccine group (176
women) or the placebo group (178 women). The safety analysis included
patients who received at least one vaccine (167 women) or one placebo (170
women) during the study period. The diary cards were completed by 97.5
percent of the vaccine group and 98.1 percent of the placebo group. The
incidence of arthralgia was similar among the two groups (approximately
10 percent of the women in both groups reported arthralgia); however, the
study size and short-term follow-up make it difficult to draw conclusions.
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HUMAN PAPILLOMAVIRUS VACCINE
Weight of Epidemiologic Evidence
The committee has limited confidence in the epidemiologic evi-
dence, based on one study that lacked validity and precision, to as-
sess an association between HPV vaccine and transient arthralgia.
Mechanistic Evidence
The committee identified two publications reporting arthralgia after
administration of HPV vaccine. The publications did not provide evidence
beyond temporality (Garcia-Sicilia et al., 2010; Rivera Medina et al., 2010).
In addition, Garcia-Sicilia et al. (2010) also reported the concomitant ad-
ministration of vaccines, making it difficult to determine which, if any, vac-
cine could have been the precipitating event. Neither publication reported
the persistence of symptoms after vaccination. The publications did not
contribute to the weight of mechanistic evidence.
Weight of Mechanistic Evidence
The symptoms described in the publications referenced above are con-
sistent with those leading to a diagnosis of transient arthralgia. Auto-
antibodies, T cells, complement activation, and immune complexes may
contribute to the symptoms of transient arthralgia; however, the publica-
tions did not provide evidence linking these mechanisms to HPV vaccine.
The committee assesses the mechanistic evidence regarding an as-
sociation between HPV vaccine and transient arthralgia as lacking.
Causality Conclusion
Conclusion 9.10: The evidence is inadequate to accept or reject a
causal relationship between HPV vaccine and transient arthralgia.
PANCREATITIS
Epidemiologic Evidence
The committee reviewed one study to evaluate the risk of pancreatitis
after the administration of HPV vaccine. This study (Slade et al., 2009) was
not considered in the weight of epidemiologic evidence because it provided
data from a passive surveillance system and lacked an unvaccinated com-
parison population.
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518 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
Weight of Epidemiologic Evidence
The epidemiologic evidence is insufficient or absent to assess an
association between HPV vaccine and pancreatitis.
Mechanistic Evidence
The committee identified two publications reporting pancreatitis after
administration of HPV vaccine. Das et al. (2008) did not provide evidence
beyond temporality. Slade et al. (2009) reported the development of pancre-
atitis in nine cases submitted to VAERS from June 2006 through December
2008. Two cases developed pancreatitis after the first dose and experienced
a recurrence of symptoms after the second and third doses. However, the
authors did not report the time frame between administration of the vaccine
and development of pancreatitis; long latencies make it impossible to rule
out other possible causes. In addition, all of the cases had preexisting risk
factors for pancreatitis. The publications did not contribute to the weight
of mechanistic evidence.
Weight of Mechanistic Evidence
The symptoms described in the publications referenced above are con-
sistent with those leading to a diagnosis of pancreatitis, but the only evi-
dence that could be attributable to the vaccine was recurrence of symptoms
upon vaccine rechallenge; however, when reported without indicating the
latency between vaccination and symptoms, these cases would not be con-
sidered cases of rechallenge. Antibodies and complement activation may
contribute to the symptoms of pancreatitis; however, the publications did
not provide evidence linking these mechanisms to HPV vaccine.
The committee assesses the mechanistic evidence regarding an as-
sociation between HPV vaccine and pancreatitis as lacking.
Causality Conclusion
Conclusion 9.11: The evidence is inadequate to accept or reject a
causal relationship between HPV vaccine and pancreatitis.
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HUMAN PAPILLOMAVIRUS VACCINE
THROMBOEMBOLIC EVENTS
Epidemiologic Evidence
The committee reviewed two studies to evaluate the risk of thrombo-
embolic events after the administration of HPV vaccine. These two studies
(Borja-Hart et al., 2009; Slade et al., 2009) were not considered in the
weight of epidemiologic evidence because they provided data from passive
surveillance systems and lacked unvaccinated comparison populations.
Weight of Epidemiologic Evidence
The epidemiologic evidence is insufficient or absent to assess an
association between HPV vaccine and thromboembolic events.
Mechanistic Evidence
The committee identified two publications reporting thromboembolic
events after administration of HPV vaccine. The publications did not pro-
vide evidence beyond temporality, some too short or too long based on
the possible mechanisms involved (Borja-Hart et al., 2009; Slade et al.,
2009). Long latencies between vaccine administration and development of
symptoms make it impossible to rule out other possible causes. In addition,
all of the cases reported in the publications had predisposing risk factors
for thromboembolic events including, but not limited to, pregnancy, the
use of oral contraceptives, inherited hypercoagulability syndromes, and an
aneurysm. The publications did not contribute to the weight of mechanistic
evidence.
Weight of Mechanistic Evidence
The symptoms described in the publications referenced above are con-
sistent with those leading to a diagnosis of thromboembolic events. Al-
terations in the coagulation cascade may contribute to the symptoms of
thromboembolic events; however, the publications did not provide evidence
linking this mechanism to HPV vaccine.
The committee assesses the mechanistic evidence regarding an as-
sociation between HPV vaccine and thromboembolic events as
lacking.
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520 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
Causality Conclusion
Conclusion 9.12: The evidence is inadequate to accept or reject
a causal relationship between HPV vaccine and thromboembolic
events.
HYPERCOAGULABLE STATES
Epidemiologic Evidence
No studies were identified in the literature for the committee to evaluate
the risk of hypercoagulable states after the administration of HPV vaccine.
Weight of Epidemiologic Evidence
The epidemiologic evidence is insufficient or absent to assess an
association between HPV vaccine and hypercoagulable states.
Mechanistic Evidence
The committee did not identify literature reporting clinical, diagnostic,
or experimental evidence of hypercoagulable states after administration of
HPV vaccine.
Weight of Mechanistic Evidence
Alterations in the coagulation cascade may contribute to the symptoms
of hypercoagulable states; however, the committee did not identify literature
reporting evidence of this mechanism after administration of HPV vaccine.
The committee assesses the mechanistic evidence regarding an
association between HPV vaccine and hypercoagulable states as
lacking.
Causality Conclusion
Conclusion 9.13: The evidence is inadequate to accept or reject
a causal relationship between HPV vaccine and hypercoagulable
states.
CONCLUDING SECTION
Table 9-1 provides a summary of the epidemiologic assessments, mech-
anistic assessments, and causality conclusions for HPV vaccine.
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TABLE 9-1 Summary of Epidemiologic Assessments, Mechanistic Assessments, and Causality Conclusions for HPV
Vaccine
Studies Contributing Cases Contributing
Epidemiologic to the Epidemiologic Mechanistic to the Mechanistic Causality
Vaccine Adverse Event Assessment Assessment Assessment Assessment Conclusion
HPV Acute Disseminated Encephalomyelitis Insufficient None Lacking None Inadequate
HPV Transverse Myelitis Insufficient None Lacking None Inadequate
HPV Neuromyelitis Optica Insufficient None Lacking None Inadequate
HPV Multiple Sclerosis Insufficient None Lacking None Inadequate
HPV Guillain-Barré Syndrome Insufficient None Lacking None Inadequate
HPV Chronic Inflammatory Disseminated Insufficient None Lacking None Inadequate
Polyneuropathy
HPV Brachial Neuritis Insufficient None Lacking None Inadequate
HPV Amyotrophic Lateral Sclerosis Insufficient None Lacking None Inadequate
HPV Anaphylaxis Insufficient None Intermediate 36 Favors Acceptance
HPV Transient Arthralgia Limited 1 Lacking None Inadequate
HPV Pancreatitis Insufficient None Lacking None Inadequate
HPV Thromboembolic Events Insufficient None Lacking None Inadequate
HPV Hypercoagulable States Insufficient None Lacking None Inadequate
521
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522 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
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