Papillomavirus Research 5 (2018) 96–103

Contents lists available at ScienceDirect

Papillomavirus Research
journal homepage: www.elsevier.com/locate/pvr

No association between HPV vaccine and reported post-vaccination
symptoms in Japanese young women: Results of the Nagoya study

T⁎

Sadao Suzuki , Akihiro Hosono
Department of Public Health, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 466–8601, JapanA R T I C LE I N FO

A B S T R A C T

Keywords:
Human papilloma virus vaccine
Post-vaccination symptom
Population based epidemiological study
Questionnaire

Nagoya City introduced free HPV vaccination in 2010 and in April 2013 the Ministry of Health, Labour andWelfare included the HPV vaccine in the National Immunization Program. However, in June 2013, the Ministrysuspended proactive recommendation of the vaccine after unconﬁrmed reports of adverse events. To investigate
any potential association between the vaccine and reported symptoms, Nagoya City conducted a questionnairebased survey.
Participants were 71,177 female residents of Nagoya City born between April 2, 1994 and April 1, 2001. The
anonymous postal questionnaire investigated the onset of 24 symptoms (primary outcome), associated hospital
visits, frequency, and inﬂuence on school attendance.
Totally, 29,846 residents responded. No signiﬁcant increase in occurrence of any of the 24 reported post-HPV
vaccination symptoms was found. The vaccine was associated with increased age-adjusted odds of hospital visits
for “abnormal amount of menstrual bleeding” (OR: 1.43, 95% CI: 1.13–1.82), “irregular menstruation” (OR:1.29, 95% CI: 1.12–1.49), “severe headaches” (OR: 1.19, 95% CI: 1.02–1.39), and chronic, persisting “abnormal
amount of menstrual bleeding” (OR 1.41, 95% CI: 1.11–1.79). No symptoms signiﬁcantly inﬂuenced school
attendance and no accumulation of symptoms was observed.
The results suggest no causal association between the HPV vaccines and reported symptoms.

1. Introduction
Cervical cancer is the fourth most common cancer among women
worldwide, with about 528,000 new cases and 266,000 deaths in 2012[1]. In Japan, mortality from cervical cancer is increasing in women of
reproductive age [2,3]. Furthermore, between 1994 and 2011, there
was a 4.4% annual percentage increase in incidence of cervical cancer
in women aged 15–39 years [4]. Most women who develop cervicalcancer are either under-screened or never-screened. The cervical cancer
screening rate in Europe and Northern America, is roughly 80%;
however, in Japan it was only 37.7% in 2011 [5].
The World Health Organization (WHO) recommends human papillomavirus (HPV) vaccination to prevent HPV infection and the development of cervical cancer and other HPV-related diseases [6]. The
bivalent HPV vaccine was licensed in Japan in October 2009. Soon after
this, Nagoya City, with a population of approximately 2,300,000 andlocated in the center of Japan, initiated a fully ﬁnanced HPV vaccination program to encourage vaccination of girls born between April 2,
1996 and April 1, 1998 and in the ﬁrst and second year of junior highschool. In April 2013, HPV was added to the list of recommended⁎

routine vaccinations in Japan. However, following unconﬁrmed reportsof unusual post-vaccination symptoms, the Japanese Ministry of Health,Labour and Welfare (MHLW) suspended its proactive recommendations
for the vaccine in June 2013 [7] and instructed local health authorities
to stop promoting the use of the vaccine until the suspected adverse
events had been investigated. This led to a rapid and dramatic decreasein vaccination coverage, even though the HPV vaccines were freely
available for the target age-group [8,9].
Epidemiological studies conducted globally since the launch of the
HPV vaccines have failed to ﬁnd any increased risk of developing
conditions claimed to be associated with the vaccine such as complex
regional pain syndrome (CRPS) [10,11], postural orthostatic tachycardia syndrome (POTS) [11], multiple sclerosis or other demyelinating
diseases [12], venous thromboembolism [13], or any other adverse
events following immunization [14]. A meta-analysis [15] and a recent
review [16] found that both the bi- and quadrivalent HPV vaccines
were safe. Descriptive studies such as case reports of CRPS, POTS [17]and a novel disease entity, HPV vaccination-associated neuro-immunopathetic syndrome (HANS) [18], have been published in Japan.
However, no analytical epidemiological studies investigating theCorresponding author.
E-mail address: ssuzuki@med.nagoya-cu.ac.jp (S. Suzuki).

https://doi.org/10.1016/j.pvr.2018.02.002
Received 4 October 2017; Received in revised form 29 January 2018; Accepted 22 February 2018
Available online 23 February 2018
2405-8521/ © 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).

Papillomavirus Research 5 (2018) 96–103

S. Suzuki, A. Hosono

feet. The month and year of symptom onset, hospital visits because of
symptoms, current frequency of the symptoms (i.e., always, sometimes,
rarely, or never), inﬂuence of symptoms on school attendance or employment, HPV vaccination history (the number of injections and theinjection schedule), type of HPV vaccine: the bivalent HPV vaccine(Cervarix, GlaxoSmithKline) or the quadrivalent HPV vaccine (Gardasil,
Merck & Co.), and reasons for not completing the full immunization
schedule, if applicable, were recorded. Items to be included in thequestionnaire items were selected after consultations with both thestudy investigators and the Aichi Branch of the All Japan Coordinating
Association of HPV Vaccine Suﬀerers. The original Japanese version of
the questionnaire [27] and an English language translation [28] areavailable online.

association between HPV vaccines and reported post-vaccination
symptoms, have been published.
In January 2014, following clinical evaluation of individual cases,
the MHLW concluded that the reported post-vaccination symptoms
were not causally associated with HPV vaccination but were psychosomatic responses [19]. Despite this statement, the MHLW insisted thatfurther studies were required before once again promoting the use of
HPV vaccines [20]. It has been argued that this decision was not basedon adequate scientiﬁc evidence because the Japanese vaccination
system suﬀers from a failure of governance [21]. The decision to suspend proactive recommendations for the HPV vaccines traveled globally through online networks and social media and was applauded byantivaccination groups but not by the global scientiﬁc community [22].
In August 2015, the Japan Society of Obstetrics and Gynecology demanded the resumption of proactive recommendations for HPV vaccination because it is recommended for the prevention of cervical cancer[23]. Others also argued that a fair and transparent policy, including
no-fault compensation, was required when implementing a new vaccination program, including the HPV vaccine, in Japan [24,25]. Furthermore, in December 2015, the WHO Global Advisory Committee on
Vaccine Safety (GACVS) noted in their Statement on the Safety of HPV
Vaccines that in Japan “young women are being left vulnerable to HPVrelated cancers that otherwise could be prevented. As GACVS has noted
previously, policy decisions based on weak evidence, leading to lack ofuse of safe and eﬀective vaccines, can result in real harm” [26]
In March 2014, Nagoya City council requested that the national
government investigate any possible causal association between HPV
vaccines and reported post-vaccination symptoms, and to recommend
treatments for such symptoms. In January 2015, the Aichi Branch of All
Japan Coordinating Association of HPV Vaccine Suﬀerers asked for andreceived approval from the Mayor of Nagoya City for an investigation
into reported symptoms after HPV vaccination. Consequently, Nagoya
City and the Nagoya City University agreed to conduct a large-scalequestionnaire-based study in April 2015 to investigate any association
between HPV vaccines and reported post-vaccination symptoms. The
results of this study are presented in this paper

2.1. Statistical analysis
Association of the HPV vaccination with one or more of the 24 reported symptoms was the primary outcome. This was evaluated in theentire study population. Other outcomes such as hospital visits for
symptoms, persistent and constant symptoms (answered “always” forcurrent frequency of the symptoms), inﬂuence on life activities, andoccurrence of multiple symptoms, were also investigated for any potential association with HPV vaccination. Logistic regression analysis
was used to calculate age-adjusted odds ratios (ORs) and 95% CIs. The
analysis was repeated for each vaccine individually (Cervarix or
Gardasil).
Subgroup analyses by age and year of ﬁrst injection (subgroup
analysis I), and after exclusion of subjects with early-onset symptoms(subgroup analysis II), were also conducted. In both subgroups, subjects
in each age category were selected by year of ﬁrst vaccine injection andgrouped to form 2-year age distribution as follows: ﬁrst and second
category in 2011; third category in 2010, fourth category in 2010 and2011, ﬁfth category in 2011 and 2012, sixth category in 2012 and2013, and seventh category in 2013, as shown in Fig. 1 (also numberedin bold in Table 1). The entire population of vaccinated and unvaccinated subjects, grouped as described above, comprised the “mainframe” of the study. For subgroup analysis I, ﬁve cohorts based on theyear of the ﬁrst injection were created. Each cohort included individuals born within two sequential years and comprising most vaccine recipients in the corresponding years. Girls of the same age who
had not been vaccinated were also included in each cohort as controls.
The structure of the cohorts is shown in Fig. 1. For example, cohort 3
consists of 1500 + 1300 vaccinated girls and 663 + 1260 unvaccinatedones (see Table 1). In the subgroup analysis I, two comparisons were
performed; in terms of age diﬀerence between cohort 1 and 3, (ﬁxedinjection year of 2010) and time trend among cohort 2, 3, 4, and 5(ﬁxed age in 11–14 years old).
Subgroup analysis II was also performed using data obtained fromthe main frame participants. Those with symptoms that had occurred
before the year of the ﬁrst HPV vaccination (i.e., not caused by thevaccine) were excluded (Fig. 2). The purpose of subgroup analysis II
was to allow for analyses after excluding “noise” attributable to the
grand analysis. This exclusion, performed regardless of vaccination
status, prevented biased results from consideration of symptoms invaccinated girls before they received the ﬁrst injection. The statisticalanalysis was performed using SAS version 9.4 (SAS Institute).

2. Methods
Participants eligible for the study were women born between April2, 1994 and April 1, 2001 (9–15 years old on April 1, 2010), who wereresidents of Nagoya City as of August 12, 2015. The survey tool was ananonymous postal questionnaire. The study protocol was reviewed andapproved by the Ethics Committee of the Nagoya City University,
Graduate School of Medical Sciences (approval number 1206).
The anonymous questionnaire was mailed to each eligible resident
in September 1, 2015; responses that were returned before November 2,2015 were evaluated. The responses included information on the birthdate of the person eligible for vaccination, which was stratiﬁed by year
to one of seven 1-year age groups (categories) beginning on April 2,1994 and ending on April 1, 1995 through 2001, and information on
the responder (the person eligible for vaccination, the person eligible
for vaccination with help from her parent or caregiver, or only theparent or caregiver). The onset of one or more of 24 symptoms between
the sixth year of elementary school and the time of the survey were theprimary outcomes. These included: irregular menstrual periods; abnormal amount of menstrual bleeding; pain in the joints or other partsof the body; severe headache; fatigue; poor endurance; diﬃculty concentrating; visual ﬁeld abnormalities; abnormal sensitivity to light;
sudden vision loss; dizziness; cold feet; diﬃculty falling asleep; abnormally long sleep duration; skin problems; hyperventilation; memory
decline;, loss of ability to perform simple calculations; loss of ability toremember fundamental Kanji [Chinese characters indispensable for life
in Japan]; involuntary uncontrollable body movements; loss of theability to walk normally; becoming dependent on a walking stick or
wheelchair; sudden loss of strength; and weakness in the hands and3. Results
A total of 71,177 questionnaires were sent, 217 were returned as notdeliverable, and 30,793 (43.4%) of the 70,960 distributed copies werereturned by the recipients. Of those, 947 were excluded because of
missing data on HPV vaccination status and/or age. The responses in
the remaining 29,846 questionnaires were included in the analysis.
Table 1 shows the birth-year distribution of participants, vaccination
status including year of dose one, and the overall number of doses
97Papillomavirus Research 5 (2018) 96–103

S. Suzuki, A. Hosono

Fig. 1. Subjects Included in the Five Main Frame Cohorts of the Subgroup Analyses. Cohorts 1 and 3 include girls who were vaccinated in 2011 plus their unvaccinated controls. Cohorts
2, 3, 4, and 5 include girls who were vaccinated at 11–14 years of age plus their unvaccined controls. Subjects belonging to any cohort were considered main frame subjects.

administered. Vaccination coverage in the ﬁrst to fourth category
was > 85%. It began to decline in the ﬁfth age category and dropped to
15% in the seventh category.
Table 2 shows the distribution of HPV vaccination status and occurrence of the 24 reported symptoms. The most common symptom wasmenstrual irregularity (26.3%) followed by cold feet (12.3%). Anothersix symptoms: severe headache, fatigue, poor endurance, dizziness,abnormally long duration of sleep, and skin problems were reportedby > 10% of participants. In contrast, four symptoms: unable to perform simple calculations; involuntary uncontrollable body movements;
loss of ability to walk in a normal way; and becoming dependent on awalking stick or wheelchair was reported by < 1.0% of participants.
In our analyses, we hypothesized age and the person responding to
the questionnaire (child versus parent) might be potential confounders.

Age, but not responder, confounded the association between HPV
vaccination and reported symptoms, therefore we decided all analyses
should be age-adjusted. Table 3 shows the age-adjusted ORs for the
association between HPV vaccination and occurrence of the 24 reported
symptoms (primary outcomes), hospital visits for the symptoms, andpersistent or continuing symptoms. None of the 24 reported symptoms
were signiﬁcantly associated with increased odds of occurring afteradministration of the HPV vaccine. Three symptoms had signiﬁcantly
increased odds of attending hospital: 1.43 (95% CI: 1.13–1.82) for“abnormal amount of menstrual bleeding”; 1.29 (95% CI: 1.12–1.49)
for “irregular menstruation”, and 1.19 (95% CI: 1.02–1.39) for “severe
headache”. Persistent occurrence of “abnormal amounts of menstrual
bleeding” was also statistically signiﬁcant, OR of 1.41 (95% CI:
1.11–1.79).

Table 1Birth date, age category, and vaccination status of the study participants.
Vaccine status

First injection (year)
2009
2010
2011
2012
2013
2014
2015
Year unknown
Number of
injections
1
2
3
Number unknown
Total vaccinatedTotal unvaccinatedVaccination
coverage
Total participants

Age category and birth dateTotal

1st category, April2, 1994-April 1,
1995

2nd category,
April 2, 1995-April
1, 1996

3rd category, April2, 1996-April 1,
1997

4th category, April2, 1997-April 1,
1998

5th category, April2, 1998-April 1,
1999

6th category, April2, 1999-April 1,
2000

7th category, April
2, 2000-April 1,
2001

98
265
2344
93
20
5
5
735

48
199
2629
180
29
4
1
659

80
2057
835
173
23
3
1
553

27
1239
1500
400
86
4
0
510

9
40
1300
1251
216
15
5
322

2
4
39
1354
495
24
10
195

0
1
5
40
507
29
7
73

264
3805
8652
3491
1376
84
29
3047

184
192
3014
175
3565
496
87.8%

133
207
3256
153
3749
428
89.8%

117
185
3280
143
3725
452
89.2%

106
207
3296
157
3766
663
85.0%

127
278
2650
103
3158
1260
71.5%

196
380
1476
71
2123
2038
51.0%

255
85
296
26
662
3761
15.0%

1118
1534
17,268828
20,748
9098
69.5%

4061

4177

4177

4429

4418

4161

4423

29,846

Participants shown in bold were selected for the main-frame sub-group analyses.

98Papillomavirus Research 5 (2018) 96–103

S. Suzuki, A. Hosono

Fig. 2. Subjects for subgroup analysis excluding symptoms that had occurred before the earliest target year of HPV vaccination.

0.70–0.84), and > 9 (or '10 or more'). symptoms (0.76, 95% CI:
0.63–0.93), decreased, indicating no associated with HPV vaccinationand multiple symptoms.
Because the bivalent vaccines was licensed two years before quadrivalent vaccine, 87.8% of recipients were vaccinated with the bivalentvaccine in 2010 and 2011 and 80.0% of recipients with the quadrivalent vaccine in 2012 and 2013. None of the ORs for association of

There was no statistically signiﬁcant association between any of the
24 reported symptoms and school performance, school activities otherthan studying, and job hunting and employment at 0.82 (95% CI:
0.74–0.91), 1.02 (95% CI: 0.89–1.15), and 0.71 (95% CI: 0.53–0.97),
respectively. The ORs for development of one or more symptoms (0.83,
95% CI: 0.78–0.88), and > 1 (0.81, 95% CI: 0.76–0.87), > 2 (0.80,
95% CI: 0.75–0.86), > 3 (0.79, 95% CI: 0.73–0.86), > 4, (0.77, 95% CI:
Table 2Distribution of vaccination status and occurrence of 24 symptoms.
Symptom

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24

Menstrual irregularity
Abnormal amounts of menstrual
bleeding
Pain in the joints or other parts ofthe body
Severe headache
Fatigue
Poor endurance
Diﬃculty concentrating
Abnormal ﬁeld of vision
Abnormal sensitivity to light
Sudden vision loss
Dizziness
Cold feetDiﬃculty falling asleep
Abnormally long duration of sleep
Skin problems
Hyperventilation
Memory decline
Loss of ability to perform simple
calculations
Loss of ability to remember
fundamental Kanji
Involuntary uncontrollable body
movements
Loss of ability to walk in a normal
way
Becoming dependent on a walking
stick or wheelchair
Sudden loss of strength
Weakness in the hands and feet

Vaccine (+)

Vaccine (−)

Total

Symptom (+)

Symptom (−)

Probability (％)

Symptom (+)

Symptom (−)

Probability (％)

Symptom
unknown

Probability (％)

5468
1625

15,13818,946

26.5%
7.9%

2310
561

6696
8434

25.6%
6.2%

234
280

26.3%
7.4%

1507

19,071

7.3%

720

8276

8.0%

272

7.5%

2150
2268
2261
1430
389
907
1381
2282
2508
1483
2454
2062
700
623
189

18,464
18,342
18,344
19,15920,193
19,696
19,21018,315
18,077
19,11818,11918,53819,91319,992
20,422

10.4%
11.0%
11.0%
6.9%
1.9%
4.4%
6.7%
11.1%
12.2%
7.2%
11.9%
10.0%
3.4%
3.0%
0.9%

925
1037
991
723
172
356
795
1089
1144
692
1058
1062
336
217
79

8097
7984
8028
8294
8845
8662
8221
7927
7873
8320
7955
7950
8694
8805
8940

10.3%
11.5%
11.0%
8.0%
1.9%
3.9%
8.8%
12.1%
12.7%
7.7%
11.7%
11.8%
3.7%
2.4%
0.9%

210
215
222
240
247
225
239
233
244
233
260
234
203
209
216

10.4%
11.2%
11.0%
7.3%
1.9%
4.3%
7.3%
11.4%
12.3%
7.3%
11.9%
10.5%
3.5%
2.8%
0.9%

416

20,196

2.0%

181

8846

2.0%

207

2.0%

201

20,413

1.0%

58

8964

0.6%

210

0.9%

72

20,534

0.3%

22

8990

0.2%

228

0.3%

31

20,577

0.2%

16

8994

0.2%

228

0.2%

283
354

20,311
20,189

1.4%
1.7%

100
124

8909
8862

1.1%
1.4%

243
317

1.3%
1.6%

99

Papillomavirus Research 5 (2018) 96–103

S. Suzuki, A. Hosono

Table 3Age-adjusted odds ratios of the association of vaccination and the occurrence of symptoms, hospital visits, and current symptoms.
Symptom

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24

Menstrual irregularity
Abnormal amounts of menstrual bleeding
Pain in the joints or other parts of the body
Severe headache
Fatigue
Poor endurance
Diﬃculty concentrating
Abnormal ﬁeld of vision
Abnormal sensitivity to light
Sudden vision loss
Dizziness
Cold feetDiﬃculty falling asleep
Abnormally long duration of sleep
Skin problems
Hyperventilation
Memory decline
Loss of ability to perform simple calculations
Loss of ability to remember fundamental Kanji
Involuntary uncontrollable body movements
Loss of ability to walk in a normal way
Becoming dependent on a walking stick or wheelchair
Sudden loss of strength
Weakness in the hands and feetOccurrence of the symptom (main outcome)

Hospital visits

Persistent and constant symptom

OR

95％ CIOR

95％ CIOR

95％ CI

0.92
1.10
0.87
0.95
0.81
0.88
0.84
0.82
0.98
0.78
0.84
0.79
.71
.91
0.78
0.77
1.00
0.70
0.73
1.20
0.94
0.55
1.05
1.19

(0.86–0.98)(0.98–1.23)(0.78–0.97)(0.87–1.05)(0.74–0.89)(0.81–0.97)(0.76–0.94)(0.67–1.01)(0.85–1.13)(0.70–0.87)(0.77–0.92)(0.73–0.87)(0.64–0.79)(0.83–0.99)(0.71–0.85)(0.66–0.90)(0.84–1.19)(0.52–0.94)(0.60–0.89)(0.87–1.66)(0.56–1.60)(0.28–1.09)(0.81–1.36)(0.94–1.50)

1.29
1.43
1.25
1.19
1.28
1.20
1.29
0.97
1.03
0.90
1.12
1.02
0.87
1.12
0.88
0.82
1.06
1.83
2.09
1.08
1.21
0.57
1.41
1.42

(1.12–1.49)(1.13–1.82)(1.00–1.56)(1.02–1.39)(1.00–1.64)(0.91–1.58)(0.89–1.88)(0.64–1.47)(0.73–1.44)(0.79–1.03)(0.92–1.37)(0.66–1.57)(0.65–1.19)(0.78–1.60)(0.79–0.99)(0.63–1.07)(0.55–2.06)(0.57–5.96)(0.66–6.63)(0.56–2.07)(0.61–2.39)(0.24–1.34)(0.73–2.73)(0.86–2.35)

1.10
1.41
0.71
1.08
0.83
0.97
0.96
0.80
0.98
1.03
0.96
0.91
0.75
1.12
0.87
0.31
0.74
0.35
0.44
0.81
0.42
0.36
0.59
1.02

(0.97–1.24)(1.11–1.79)(0.55–0.91)(0.81–1.43)(0.68–1.00)(0.81–1.15)(0.77–1.20)(0.45–1.44)(0.72–1.34)(0.83–1.29)(0.74–1.25)(0.79–1.05)(0.60–0.93)(0.95–1.33)(0.75–1.00)(0.10–0.91)(0.53–1.02)(0.21–0.58)(0.27–0.72)(0.32–2.07)(0.15–1.21)(0.11–1.25)(0.15–2.26)(0.37–2.79)

Signiﬁcant odds ratios are shown in bold.
Abbreviation: OR, odds ratio; CI, conﬁdence interval.

revealed increases in ORs in more recent years of vaccination. Althoughsigniﬁcant, high ORs were observed in cohorts 4 and 5, the involved
symptoms diﬀered in the two groups.
Table 6 shows the results of subgroup analysis II, wherein thesubjects with symptoms that occurred before the ﬁrst year of HPV
vaccination were excluded. “Weakness of the hands and feet” was the
only symptom with a signiﬁcantly higher OR (1.44, 95% CI: 1.09–1.82).
The ORs of the 24 reported symptoms that led to a hospital visit werehigher than those in the grand analysis shown in Table 3. Five of the 13
symptoms that led to a hospital visit had signiﬁcantly increased ORs
of > 2.0. The highest OR was 6.15 (95% CI: 1.03–23.78) for “inability
to remember fundamental Kanji”, followed by 4.59 (95% CI:
1.32–28.75) for “unable to do simple calculations”. There were only
two hospital visits among unvaccinated subjects for these two symptoms.

symptoms after vaccination with the bivalent vaccine were signiﬁcant,whereas the OR for experiencing “involuntary uncontrollable body
movements” was signiﬁcantly increased after vaccination with thequadrivalent vaccine (1.54, 95% CI: 1.04–2.29). However, the ORs for a
hospital visit (1.19, 95% CI: 0.50–2.84), and persistent and constant
symptom (0.52, 95% CI: 0.11–2.44), were not signiﬁcant. No othersymptoms were signiﬁcantly associated with the quadrivalent vaccine.
The analyses were repeatedly performed to evaluate main frame
data for each year of being administered the ﬁrst dose and in the unvaccinated controls. The 23,774 participants included 14,676 vaccinated and 9098 unvaccinated girls shown in bold numbers in Table 1,
and comprised 79.7% of the entire sample of 29,846 participants. We
obtained almost identical results (data not shown) with those of the
grand analysis shown in Table 3.
As shown in Table 4, the ﬁve cohorts diﬀered in age and year ofreceiving the ﬁrst dose of the HPV vaccine. Table 5 shows the ageadjusted ORs of the association between individual reported symptoms
and the year of ﬁrst vaccination. The ORs for occurrence of each of the
24 reported symptoms in cohorts 1 and 3 were all higher in cohort 3
participants compared to those in the older cohort 1 participants. No
signiﬁcant ORs were observed. Comparisons of cohorts 2, 3, 4, and 5

4. Discussion
To the best of our knowledge, this is the ﬁrst large-scale epidemiological study to investigate any association between HPV vaccinesand reported symptoms in Japanese young women by direct

Table 4Characteristics of the ﬁve age and immunization year cohorts for subgroup analysis.
Birth period

Cohort 1
April 2, 1994-April 1,
1996

Cohort 2
April 2, 1996-April 1,
1998

Cohort 3
April 2, 1997-April 1,
1999

Cohort 4
April 2, 1998-April 1,
2000

Cohort 5
April 2, 1999-April 1,
2001

Maximum diﬀerence of birth date within thecohortFirst injection (for vaccinated girls only)
Age at the year of ﬁrst injection
Number of vaccinated girls
Number of unvaccinated girls
Total number
Vaccination coverage (%)
Comparison of age at ﬁrst injection
Comparison of year of ﬁrst injection

2 years

2 years

2 years

2 years

2 years2011
14–17 years old
4973
0924
5897
84.3%
√

2010
11–14 years old
3296
1115
4411
74.7%

2011
11–14 years old
2800
1923
4723
59.3%
√
√

2012
11–14 years old
2605
3298
5903
44.1%

2013
11–14 years old
1002
5799
6801
14.7%

√

√

√

100

Papillomavirus Research 5 (2018) 96–103

S. Suzuki, A. Hosono

Table 5Age-adjusted odds ratio of association of individual symptoms and year of ﬁrst vaccination.
Symptom

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24

Menstrual irregularity
Abnormal amounts ofmenstrual bleeding
Pain in the joints or otherparts of the body
Severe headache
Fatigue
Poor endurance
Diﬃculty concentrating
Abnormal ﬁeld of vision
Abnormal sensitivity to light
Sudden vision loss
Dizziness
Cold feetDiﬃculty falling asleep
Abnormally long duration of
sleep
Skin problems
Hyperventilation
Memory decline
Loss of ability to perform
simple calculations
Loss of ability to remember
fundamental Kanji
Involuntary uncontrollable
body movement
Loss of ability to walk in anormal way
Becoming dependent on awalking stick or wheelchair
Sudden loss of strength
Weakness in the hands andfeet

Cohort 1 ﬁrst vaccination
2011

Cohort 2 ﬁrst vaccination
2010

Cohort 3 ﬁrst vaccination
2011

Cohort 4 ﬁrst vaccination
2012

Cohort 5 ﬁrst vaccination
2013

OR

95％ CIOR

95％ CIOR

95％ CIOR

95％ CIOR

95％ CI

0.74
0.90(0.64–0.86)(0.70–1.15)

1.01
1.30

(0.86–1.18)(0.99–1.71)

0.90
1.01

(0.79–1.03)(0.80–1.28)

0.95
1.03

(0.84–1.07)(0.83–1.27)

1.09
1.09

(0.93–1.27)(0.82–1.45)

0.56(0.45–0.70)

0.77(0.60–0.99)

0.80(0.63–1.00)

0.94(0.77–1.16)

1.00(0.77–1.30)

0.65
0.55
0.60
0.59
0.49
0.51
0.51
0.64
0.68
.43
.66

(0.53–0.80)(0.45–0.66)(0.49–0.73)(0.47–0.75)(0.33–0.73)(0.38–0.68)(0.40–0.65)(0.52–0.78)(0.56–0.82)(0.35–0.53)(0.55–0.80)

0.94
0.77
0.89
0.77
0.71
0.99
0.91
0.73
0.76
0.66
0.94

(0.76–1.17)(0.62–0.95)(0.71–1.10)(0.59–0.99)(0.44–1.13)(0.71–1.39)(0.70–1.19)(0.59–0.91)(0.62–0.92)(0.51–0.86)(0.76–1.16)

0.94
0.63
0.78
0.68
1.02
1.09
0.91
0.79
0.73
0.85
0.89

(0.78–1.14)(0.52–0.76)(0.64–0.94)(0.55–0.85)(0.66–1.58)(0.82–1.47)(0.72–1.14)(0.66–0.95)(0.61–0.87)(0.67–1.08)(0.74–1.08)

0.87
0.88
0.91
0.91
0.91
1.00
0.94
0.84
0.90
0.81
0.94

(0.73–1.04)(0.75–1.04)(0.77–1.08)(0.75–1.10)(0.58–1.42)(0.76–1.33)(0.78–1.14)(0.71–0.99)(0.76–1.05)(0.64–1.01)(0.80–1.11)

0.97
0.97
0.96
0.87
1.35
1.05
0.61
1.00
0.74
0.96
0.87

(0.77–1.23)(0.77–1.22)(0.76–1.21)(0.66–1.15)(0.83–2.22)(0.72–1.53)(0.46–0.81)(0.81–1.25)(0.58–0.94)(0.72–1.28)(0.70–1.10)

0.72
0.39
0.49
0.38

(0.59–0.89)(0.29–0.53)(0.36–0.68)(0.23–0.62)

0.68
0.93
0.78
0.46

(0.55–0.84)(0.66–1.31)(0.52–1.18)(0.24–0.87)

0.75
0.74
0.81
0.56

(0.62–0.91)(0.54–1.02)(0.57–1.15)(0.30–1.02)

0.86
0.77
1.19
1.16

(0.72–1.02)(0.57–1.02)(0.84–1.68)(0.58–2.31)

0.90
0.93
2.17
1.97

(0.72–1.13)(0.62–1.40)(1.43–3.30)(0.89–4.39)

0.32(0.23–0.46)

0.58(0.37–0.90)

0.69(0.43–1.09)

1.25(0.80–1.95)

1.61(0.99–2.62)

0.56(0.32–0.99)

1.78(0.79–4.05)

1.27(0.65–2.46)

1.64(0.87–3.10)

1.51(0.65–3.49)

0.49(0.19–1.26)

0.51(0.19–1.39)

2.80(0.61–13.01)

1.64(0.44–6.16)

2.00(0.54–7.48)

0.31(0.09–1.07)

0.56(0.14–2.21)

0.92(0.15–5.68)

0.61(0.11–3.35)

0.82(0.10–6.77)

0.69
0.82

(0.42–1.12)(0.49–1.35)

0.73
0.89

(0.40–1.30)(0.51–1.55)

1.48
1.48

(0.81–2.71)(0.92–2.37)

1.67
1.40

(1.03–2.73)(0.93–2.12)

1.13
1.13

(0.57–2.24)(0.63–2.02)

Signiﬁcant odds ratios are shown in bold.
Abbreviation: OR, odds ratio; CI, conﬁdence interval.
Table 6Age-adjusted odds ratios of association of vaccination with symptom, hospital visit, and current symptom after excluding subjects with early-onset symptoms.
Symptom

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24

Menstrual irregularity
Abnormal amounts of menstrual bleeding
Pain in the joints or other parts of the body
Severe headache
Fatigue
Poor endurance
Diﬃculty concentrating
Abnormal ﬁeld of vision
Abnormal sensitivity to light
Sudden vision loss
Dizziness
Cold feetDiﬃculty falling asleep
Abnormally long duration of sleep
Skin problems
Hyperventilation
Memory decline
Loss of ability to do simple calculations
Loss of ability to remember fundamental Kanji
Involuntary uncontrollable body movement
Loss of ability to walk in a normal way
Becoming dependent on a walking stick or wheelchair
Sudden loss of strength
Weakness in the hands and feetOccurrence of the symptom

Hospital visits

Persistent and constant symptom

OR

95％ CIOR

95％ CIOR

95％ CI

0.98
1.11
0.84
0.98
0.82
0.91
0.85
0.81
0.95
0.85
0.86
0.80
.68
.90
0.83
0.83
0.94
0.68
0.66
1.40
1.45
0.90
1.13
1.41

(0.91–1.06)(0.97–1.27)(0.74–0.95)(0.88–1.10)(0.74–0.91)(0.82–1.00)(0.75–0.96)(0.64–1.03)(0.81–1.13)(0.75–0.97)(0.78–0.96)(0.72–0.88)(0.60–0.76)(0.81–0.99)(0.75–0.92)(0.69–0.99)(0.77–1.14)(0.49–0.95)(0.53–0.82)(0.97–2.01)(0.75–2.82)(0.37–2.22)(0.85–1.50)(1.09–1.82)

1.34
1.54
1.44
1.41
1.60
1.64
1.71
1.25
1.19
1.07
1.33
1.34
1.09
1.30
1.01
1.06
1.69
4.95
6.15
1.99
2.65
1.02
2.61
2.00

(1.14–1.59)(1.15–2.06)(1.09–1.90)(1.16–1.72)(1.19–2.15)(1.17–2.29)(1.09–2.68)(0.77–2.02)(0.80–1.79)(0.90–1.27)(1.06–1.67)(0.78–2.29)(0.75–1.58)(0.85–1.99)(0.88–1.16)(0.76–1.47)(0.75–3.77)(1.03–23.78)(1.32–28.75)(0.89–4.47)(1.02–6.91)(0.30–3.52)(1.16–5.87)(1.11–3.61)

1.18
1.54
0.68
1.22
0.92
1.08
0.84
0.90
0.95
1.13
1.03
0.96
0.75
1.12
0.97
0.20
0.71
0.32
0.39
1.12
1.44
0.70
0.79
1.24

(1.01–1.39)(1.15–2.06)(0.49–0.94)(0.84–1.78)(0.73–1.15)(0.88–1.32)(0.64–1.09)(0.43–1.89)(0.65–1.38)(0.88–1.47)(0.76–1.41)(0.80–1.16)(0.58–0.98)(0.92–1.37)(0.81–1.15)(0.04–0.87)(0.49–1.01)(0.18–0.56)(0.22–0.67)(0.36–3.49)(0.23–8.99)(0.14–3.41)(0.17–3.63)(0.42–3.68)

Signiﬁcant odds ratios are shown in bold.
Abbreviation: OR, odds ratio; CI, conﬁdence interval.

101

Papillomavirus Research 5 (2018) 96–103

S. Suzuki, A. Hosono

questionnaire answers (reason C) became indistinguishable when therelationship of HPV vaccination and hospital visits was analyzed, resulting in a high OR regardless of a causal association. In addition, thehighest ORs of 6.15 and 4.95 were calculated on only two subjects
among the unvaccinated subjects, therefore they are not robust.
The most important study strength of this study was the inclusion ofboth recipients and non-recipients of HPV vaccine within the same
population. The comparison was performed internally and did not rely
on external data. Another study strength was very little missing data of
HPV vaccine status and occurrence of symptoms, which would havebeen frequent if the study had depended on data retrieved from medical
records only. Additionally, as we surveyed participant experiences ofvaccine injection and occurrence of symptoms over time, the data reﬂected incidence cases rather than prevalence cases, which allowed aclear description of causal inferences. Thus, we believe that the ﬁndingsof this study signiﬁcantly advance our understanding on the lack of
causal associations between HPV vaccines and post-vaccination symptoms. We also believe that the response rate of 43.4% is a strength of
this study, since it was set in an urban area. We believe it was due togreat eﬀorts by Nagoya City, which included sending reminder lettersto all of subjects, public broadcast via TV/subway news, and notiﬁcation by ﬂyers and posters, and so on. Finally, this survey allowed theparent or caregiver to respond and not just the child, which was aneﬀective strategy to obtain a higher response rate. If we did not allow
parents or caregivers to respond, the response rate might have been
23.0% (16,347/70,960) lower.
However, the ﬁrst major limitation of this study was also an imperfect response rate resulting in possible selection bias that may haveaﬀected the results [31]. The questionnaire was sent to all female residents of Nagoya City born in speciﬁc years, so the estimated association would be unbiased if the response rate was suﬃciently high.
However, restricting the evaluation only to responders with an insuﬃcient response rate would lead to selection bias of HPV vaccine andoccurrence of symptoms [32]. While we cannot assess the magnitude of
the bias theoretically, we have a base population and were could calculate the response rate, which provides stronger validation of the results than a smaller and/or unavailable response rate. Furthermore, theresults of the subgroup analysis without these answers from parents
only was quite close to the main analysis, i.e., no signiﬁcantly high OR(data not shown). The results might be robust if the response rate washigher.
A second limitation was that the study design did not solicit veryrare symptoms. Diﬀerent study designs (e.g., case-control or monitoring
system [33]) are necessary to investigate extremely rare or severe
symptoms, including serious adverse events [34]. Insofar as mild or
moderate symptoms may be extensions of corresponding severe symptoms, this study indirectly addressed that association. This study was
not able to detect the association of HPV vaccine with extremely severe
and rare events that do not have any relationship with the 24 reported
symptoms. However, as we wrote in the methods sections, symptoms tobe surveyed were chose in cooperation with the cooperation of the
Aichi Branch of the All Japan Coordinating Association of HPV Vaccine
Suﬀerers and reﬂect the symptoms they felt were associated with the
HPV vaccine.
The third limitation was the use of self-reported symptoms without
guidelines or diagnoses by a physician. Although we were unable totreat diseases based on a physician guidelines, the signiﬁcance of thisstudy derives from its design as an epidemiological study with internal
comparison of vaccinated and unvaccinated participants. Outcomes
were not diseases or syndromes but simple symptoms and their inﬂuence on daily life. Thus personal interpretation to questions is likely to
be rather homogeneous despite the fact that the validity of the symptoms using self-reporting is unknown in this population. If we requireda clinical diagnosis, there would have been more missing data, resulting
in less precise and even more biased results. We decided not to collectthe information on clinical diagnoses, since it was neither essential nor

comparison within the population.
None of the age-adjusted ORs of the primary study outcomes in themain analysis, namely the 24 symptoms that have been reported in the
media, by the victims’ supports group or proposed by some physicians
as being associated with HPV vaccination were signiﬁcant. The ORs of
three symptoms that led to a hospital visit were signiﬁcant. Of those,“abnormal amounts of menstrual bleeding” (OR = 1.43) was the only
one that persisted at the time of the study and had a signiﬁcantly highOR. No other symptoms that persisted at the time of the study had
signiﬁcantly higher ORs in the vaccinated group. Although the subgroup analyses revealed signiﬁcantly increased ORs for several symptoms, none remained consistently high in all three analyses. There wasalso no evidence of the occurrence of multiple concurrent symptoms asreported in the Japanese media after HPV vaccination or by a few
physicians. Signiﬁcant ﬁndings were also absent for each vaccine whenanalyzed separately, although signiﬁcantly higher ORs were occasionally observed in the secondary analyses. Additionally, the plannedalpha error of 5%, should be considered when interpreting these results.
Our ﬁndings support the reports of WHO and the Japanese Government
regarding the safety of these HPV vaccines.
The inﬂuence of age at vaccination is apparent from the diﬀerencein ORs between cohorts 1 and 3. However, the lower ORs seen in cohort
1 could be attributed to the higher vaccination coverage in that groupcausing the relatively poor health conditions of the unvaccinated girls(frailty selection bias) in cohort 1 [29,30]. However, the problem of thefrailty bias might be less serious in the relatively homogeneous school
population than in an aged population with various health conditions.
Furthermore, HPV vaccination is not contraindicated for the reported
post-vaccination symptoms. Therefore the presence of these symptoms
would not be a reason not to vaccinate against HPV. As for the yearly
trend in ORs, the number of symptoms with point estimates of ORs > 1
increased over time, i.e., 3, 7, 9, and 13 symptoms in cohorts 2, 3, 4,
and 5, respectively. These increases may have occurred within a short
4-year period because of the relatively poor health status of girls in theunvaccinated groups in the early study period when the vaccination
coverage was higher [30]. Other reasons include enhanced negative
psychological eﬀects in response to negative opinions about HPV vaccination and because memory of vaccine-associated symptoms faded astime passed. Marked changes in ORs over a short interval are unlikely
to have a biological cause and suggest the involvement of socio-psychological factors and/or changes in the characteristics of subjects withvaccination coverage.
Exclusion of subjects with symptoms that occurred before the ﬁrst
vaccination year did not alter the ORs for the primary outcome ofsymptom occurrence, but it did increase the ORs of symptoms that led
to a hospital visit compared with the grand (Table 3) and main frame
analyses (not shown). After exclusion, the ORs of 13 of 24 symptoms
that led to a hospital visit were signiﬁcantly increased. This could haveresulted from relatively more severe symptoms among HPV vaccine
recipients which needed a physician's diagnosis/treatment (reason A),
more frequent doctor visits by vaccine recipients because they were
anxious about causal relationship between HPV vaccine and symptoms(reason B), or a strong impression of HPV vaccination which had unconsciously moved the memory of the symptom onset to after thevaccination (reason C). The “loss of ability to remember fundamental
Kanji” and “loss of ability to perform simple calculations” high ORs(6.15 and 4.95, respectively), but exclusion of participants withsymptoms that occurred early in the study period, did not aﬀect theoccurrence or persistence of these symptoms. As shown in Table 6, theORs of symptoms that led to a hospital visit diﬀered signiﬁcantly fromthose of the other types of outcomes. This suggests that hospital visitswere not driven by the severity of symptoms but rather by changes in
the attitude toward seeking medical advice and/or an eﬀect of vaccination on the questionnaire responses. It is noteworthy that biologicalcausal association (reason A), inﬂuence of vaccination on hospital-visiting behavior (reason B), and inﬂuence of vaccination on the102

Papillomavirus Research 5 (2018) 96–103

S. Suzuki, A. Hosono

realistic for this type of study design.
The temporal relationship between vaccination and symptoms deserves mention as a potential limitation. We did not completely exclude
symptoms that occurred before vaccination because only vaccinatedparticipants had an immunization date and deleting those cases fromthe vaccinated groups would have violated the validity of comparison.
Instead, we devised two time frames for both vaccinated and unvaccinated girls (i.e., the grand analysis in Table 3 and the subgroup
analysis II in Table 6) and observed the changes in ORs. Symptoms prior
to vaccination may provide “noise”, but the validity of comparison
between vaccinated and unvaccinated was maintained. Every epidemiological study design has unique strengths and weaknesses. To moreclearly determine the association of vaccination and symptoms, manystudies of diverse design and objective are needed. Despite several
limitations, we believe that the results of the study are a signiﬁcant
addition to our knowledge on the safety of HPV vaccination in Japan.

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5. Conclusion
In this large-scale survey in Nagoya, Japan, we found that the HPV
vaccines were not signiﬁcantly associated with the occurrence of 24
reported symptoms, thus suggesting no causal association between thevaccines and reported symptoms or adverse events.
Acknowledgements
We thank Nagoya City for the planning and execution of the survey
as a part of policy of the city, especially, the Mayor of Nagoya City,
Takashi Kawamura, for his leadership in initiating the study. We also
thank the members of the Social Welfare Department, Health & Welfare
Bureau of Nagoya City Hall for the management of the study and Mr.
Tatsuya Isomura for his help in designing the questionnaire.
Conﬂicts of interest
None.
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