Journal of Travel Medicine, 2016, 1–6
doi: 10.1093/jtm/taw012
Original article
Original article
Comparative study of adverse events after yellow fever
vaccination between elderly and non-elderly travellers:
questionnaire survey in Japan over a 1-year period
Ryutaro Tanizaki, MD1†, Mugen Ujiie, MD1*†, Narumi Hori, MPH, Med1,
Shuzo Kanagawa, MD1, Satoshi Kutsuna, MD, PhD1, Nozomi Takeshita, MD, PhD1,
Kayoko Hayakawa, MD, PhD1, Yasuyuki Kato, MD, MPH1 and
Norio Ohmagari, MD, PhD1
1
Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan
*To whom correspondence should be addressed. Email: [email protected]
†
These authors contributed equally to this work.Accepted 22 February 2016
Abstract
Background: A live attenuated yellow fever (YF) vaccination is required of all travellers visiting countries where YF
virus is endemic. Although the risk of serious adverse events (AEs) after YF vaccination is known to be greater in elderly people than in younger people, information about other AEs among elderly travellers is lacking.
Methods: A prospective observational questionnaire study was conducted to investigate the occurrence of AEs after
YF vaccination in travellers who attended a designated YF vaccination centre in Tokyo, Japan, from 1 November
2011 to 31 October 2012. A questionnaire enquiring about any AEs experienced in the 2 weeks following YF vaccination was distributed to all vaccinees enrolled in this study, and responses were collected subsequently by mail or
phone. For child vaccinees, their parents were allowed to respond in their stead.
Results: Of the 1298 vaccinees who received the YF vaccine, 1044 (80.4%) were enrolled in the present study and 666
(63.8%) responded to the questionnaire. Of these 666 respondents, 370 (55.6%) reported AEs, of which 258 (38.7%)
were systemic and 230 (34.5%) were local. No severe AEs associated with YF vaccination were reported. Elderly vaccinees (aged 60 years) reported fewer total AEs than those aged <60 years (42.9% vs 60.3%; P < 0.001).
Conclusion: Our study showed that fewer general AEs after yellow vaccination reported among elderly vaccinees
than among non-elderly vaccinees. These results could provide supplementary information for judging the adaptation of vaccination in elderly travellers.
Key words: Yellow fever, vaccination, adverse event, traveller, elderly, questionnaire
Background
Yellow fever (YF), which is caused by a YF virus infection transmitted via mosquitoes of the Aedes, Haemagogus or Sabethes species, is an occasionally lethal viral haemorrhagic fever that is
endemic in 44 countries in Africa and South America.1,2 A traveller’s risk of acquiring YF depends on immunization status, location
of travel, season at destination, duration of exposure, occupational
and recreational activities while travelling and the local rate of
YF virus transmission during the travel period.3 A live attenuated
YF vaccine is the most effective tool in preventing YF infection,4
and International Health Regulation 2005 requires YF vaccination
for persons aged >9 months visiting countries where YF virus is
endemic.
YF vaccine appears to have high efficacy1 and to be safe for
use; adverse events (AEs) occur in 10–30% of patients receiving
YF vaccination and are generally mild and of short duration,1,2
although fatal AEs, such as YF vaccine-associated neurotropic
disease (YEL-AND) and YF vaccine-associated viscerotropic
disease (YEL-AVD), are known to occur. In particular, YFLAVD has been reported to be more frequent in elderly people
than in younger individuals,3–9 so health providers
may be hesitant to provide YF vaccinations to the elderly.
C International Society of Travel Medicine, 2016. All rights reserved. Published by Oxford University Press. For permissions, please e-mail: [email protected]
V
2
However, without YF vaccination, the risk of contracting YF is
increased10; therefore, in elderly travellers, careful consideration
of the risk and benefit of YF vaccination is necessary.
Recent years have seen a surge in the number of elderly people in Japan travelling abroad, and the number of travellers
requiring YF vaccination has risen as well. In our clinic, YF vaccination in elderly travellers is conducted based on an overall
risk assessment, considering intended destination, purpose of
travel, expected behaviour during travel and baseline health status or underlying diseases, with consideration of older age as a
risk factor for fatal AEs.
Given that relatively few prospective studies of AEs associated with YF vaccination have been performed in elderly travellers from non-YF-endemic areas, we conducted a questionnaire
survey to investigate the characteristics of AEs after YF vaccination in this population.
Methods
Study design and data collection
In collaboration with the Narita International Airport quarantine
office, we conducted a prospective observational study between 1
November 2011 and 31 October 2012, at the National Center
for Global Health and Medicine (NCGM) Travel Clinic in
Tokyo, Japan, which is 1 of 27 YF vaccination centres in Japan.
Eligible subjects were all patients receiving the YF vaccine during
the study period. The type of YF vaccine used in this study was
the 17D-204 strain vaccine (YF-VAX; Sanofi Pasteur,
Swiftwater, PA). The subcutaneous sites for YF vaccine administration were anterolateral thigh for infants <12 months of age
and upper outer triceps of arm for children >12 months and
adults.11 YF vaccination was avoided in those who had obvious
contraindications to YF vaccination,6 and whether to conduct YF
vaccination was decided by the clinician’s judgement based on a
risk assessment of each traveller’s health status and travel plan.6
A self-descriptive questionnaire sheet was distributed to all YF
vaccinees who agreed to enrol in this study, assessing the following: age, gender, presence of pre-existing YF immunization (YFI)
and simultaneous vaccination with any other vaccines. In addition, any abnormal symptoms occurring within 2 weeks after YF
vaccination were described on the sheet using a checklist completed by vaccinees. The timing of evaluation of AEs was just 14
days after YF vaccination. In the case that the vaccinees need to
set out on a travel within 14 days after vaccination, the timing of
the evaluation was changed on the day before departure. Missing
the appropriate timing of evaluation, the vaccinees were allowed
to evaluate and fill out the sheet when they could do, without limitation of a lag time. For child vaccinees who could not respond to
the correspondence required for this study by themselves, their
parents were allowed to complete the checklist in their stead.
Their reports were sent back to our clinic by mail, or answers
were collected via a telephone interview. Consent for this study
was obtained from all participants, and the study was approved
by the Human Research Ethics Committee of NCGM (approved
number: NCGM-G-001059-00).
Assessment of AEs
The participants were asked to report the following AEs in the 2
weeks following the injection: systemic AEs, such as malaise,
Journal of Travel Medicine, 2016, Vol. 23, No. 3
fever, headache, myalgia, arthralgia, abdominal discomfort, diarrhoea and nausea; and local AEs, such as redness, swelling,
pain, pruritus and induration at the injection site. If vaccinees
experienced these AEs, further information (timing, duration
and severity of events) were obtained.
Statistical analysis
Study participants were classified as either elderly (aged 60
years) or younger (aged <60 years) vaccinees. Baseline characteristics (age, gender, pre-existing YF vaccination and simultaneous vaccination with other vaccines) and details of AEs were
compared between the two groups using the Student’s t test or
Mann–Whitney U test for continuous variables and v2 test
(Fisher exact test when appropriate) for categorical variables.
To estimate risk factors for AEs, univariate and multivariate regression models were constructed. We used odds ratios (ORs)
with 95% confidence intervals (CIs) for logistic regression analyses. Age, female sex, pre-existing YFI and simultaneous vaccination were considered to be potential confounding factors for
AEs. Significant differences in rates of simultaneous vaccination
were noted between those aged <60 years and 60 years at
baseline; therefore, the results were assessed using multivariate
analysis, controlled for the influence of simultaneous vaccination, to evaluate the risk factors for AEs. In addition, the risk
factors for AEs among those aged 60 years were also evaluated. All statistical analyses were performed with Stata 11 (Stata
Corp, College Station, TX).
Results
Of the 1298 vaccinees who received YF vaccine during the study
period, 1044 (80.4%) consented to participate and were enrolled, and 666 (63.8%) responded to all questions in the questionnaire (Figure 1). Among 666 responses, 619 (92.9%) and
47 (7.1%) were collected through mail and phone, respectively.
The major reason for the lost in follow-up was lose contact with
not responding vaccinees. Although we tried to communicate on
the telephone to all study participants who had not sent back a
questionnaire sheet for >1 month from YF vaccination day,
most of them did not answer our phone for reasons such as during travel. The median lag time between injection and evaluation of AEs was 15 days (from minimum 1 day to maximum
384 days). The median age of those who completed the questionnaire, including 16 children (aged 0–5 years), was 42.0
[interquartile range (IQR), 31–61] years; 182 (27.3%) were
aged 60 years, with a median age of 65.0 (IQR, 63–67) years.
Elderly men comprised 26.2% of the total sample, whereas elderly women comprised 28.8% (P ¼ 0.483). Most vaccinees
were Japanese, but there were two foreign nationals (one
Chinese and one Brazilian). A past history of YFI was reported
in 69 subjects (10.4%), 23 of whom (33.3%) were aged 60
years.
Simultaneous vaccination with other vaccines was reported
by 226 subjects (33.9%); the rate of simultaneous vaccination
in those aged 60 years (22.0%) was significantly lower than in
those aged <60 years (38.4%) (P < 0.001) (Table 1). The types
of vaccines simultaneously administered with YF vaccine were
hepatitis A (n ¼ 181), tetanus (n ¼ 78), hepatitis B (n ¼ 74), rabies (n ¼ 60), diphtheria-pertussis-tetanus (n ¼ 4), Japanese
Journal of Travel Medicine, 2016, Vol. 23, No. 3
3
Table 2. Adverse events after YF vaccination
Total AEs
Total
Aged <60 years Aged 60 years P valuea
(n ¼ 666)
(n ¼ 484)
(n ¼ 182)
370 (55.6)
292 (60.3)
78 (42.9)
<0.001
Systemic AEs
258 (38.7)
203 (41.9)
55 (30.2)
0.006
Malaise
183 (27.5)
148 (30.6)
35 (19.2)
0.003
82 (12.3)
67 (13.8)
15 (8.2)
0.063
0.205
Fever
Mean
37.7 6 0.7
37.8 6 0.8
37.4 6 0.5
(37.0–38.6)
temperature, C
(37.0–40.5)
(37.0–40.5)
Headache
(Min–Max)
82 (12.3)
65 (13.4)
17 (9.3)
0.186
Myalgia
66 (9.9)
50 (10.3)
16 (8.8)
0.663
Arthralgia
51 (7.7)
43 (8.9)
8 (4.4)
0.071
Abdominal
36 (5.3)
28 (5.8)
7 (3.9)
0.436
Diarrhea
29 (4.4)
24 (5.0)
5 (2.8)
0.287
Nausea
23 (3.3)
15 (3.1)
7 (3.9)
0.630
Dizziness
2 (0.3)
2 (0.4)
Local AEs
230 (34.5)
189 (39.1)
41 (22.5)
< 0.001
Redness
135 (20.2)
107 (22.1)
27 (14.9)
0.040
Swelling
129 (19.2)
104 (21.5)
24 (13.2)
0.015
Pain
121 (18.0)
102 (21.1)
18 (9.9)
0.001
Pruritus
95 (14.3)
77 (15.9)
18 (9.9)
0.048
Induration
48 (7.1)
37 (7.6)
10 (5.5)
0.398
118 (17.7)
100 (20.7)
18 (9.9)
0.001
discomfort
Figure 1. Participant enrolment process
Table 1. Characteristics of participants
Total
(n ¼ 666)
Median age (IQR) 42.0 (31–61)
Female
285 (42.8)
Pre-existing YFI
69 (10.4)
Simultaneous
226 (33.9)
vaccination
a
Aged <60
years (n ¼ 484)
36 (28–45)
203 (41.9)
46 (9.5)
186 (38.4)
Aged
60 years
(n ¼ 182)
P value
a
65 (63–69) <0.001
82 (45.1)
0.483
23 (12.6)
0.253
40 (22.0)
<0.001
2
All values based on v test except median age (Mann–Whitney U test).
encephalitis (n ¼ 3), mumps (n ¼ 3), varicella (n ¼ 1), typhoid
(inactivated) (n ¼ 1), meningococcus (n ¼ 1), polio [inactivated]
(n ¼ 1) and seasonal influenza (inactivated) (n ¼ 1).
Of the 666 surveyed subjects, 370 (55.6%; 95% CI, 51.7–
59.3%) reported AEs, with systemic AEs in 258 (38.7%; 95%
CI, 35.0–42.6%) and local AEs in 230 (34.5%; 95% CI, 30.9–
38.3%). The predominant systemic AEs and local AEs were
malaise (27.5%; 95% CI, 24.1–31.0%) and redness (20.2%;
95% CI, 17.3–23.5%), respectively. The rates of systemic AEs
and local AEs were lower in elderly participants than in younger
participants (systemic AEs: 30.2% vs 41.9%; P ¼ 0.006 and local AEs: 22.5% vs 39.1%; P < 0.001), and the differences were
statistically significant for malaise (P ¼ 0.003) and redness
(P ¼ 0.040), swelling (P ¼ 0.015), pain (P ¼ 0.001) and pruritus
(P ¼ 0.048) at the injection site (Table 2). Among 16 children,
10 (62.5%; 95% CI, 35.4–84.8%) of them showed the AEs. No
serious AEs, such as hypersensitivity reaction, YFV-AVD, YFAND or death, were reported.
Most systemic AEs (73.8%; 95% CI, 69.9–77.4%) and local
AEs (82.3%; 95% CI, 78.8–85.5%) occurred within 5 days after YF vaccination, and most systemic AEs (86.5%; 95% CI,
83.6–89.1%) and local AEs (70.3%; 95% CI, 66.2–74.2%) subsided within 5 days after the onset of AEs (Figure 2). Most AEs
were not serious, and only two vaccinees (0.5%) visited the hospital. One patient complained of abdominal cramps, diarrhoea
and nausea 2–5 days after YF vaccination, and another complained of abdominal cramps 10–14 days after YF vaccination;
both recovered with symptomatic treatment only.
Both systemic and
0 (0)
1.000
local AEs
Min: minimum, Max: maximum.
a
All values based on v2 test except mean temperature (Student t test) and dizziness
(Fisher exact test).
Logistic regression analysis was performed to identify the
risk factors associated with systemic AEs among age 60 years,
gender, pre-existing YF vaccination and simultaneous vaccination. Multivariate analysis in all 666 subjects revealed that age
60 years was associated with decreased odds of both systemic
AEs (OR ¼ 0.6; 95% CI, 0.44–0.93; P ¼ 0.019) and local AEs
(OR ¼ 0.4; 95% CI, 0.29–0.66; P < 0.001), and pre-existing
YFI was associated with decreased odds of local AEs. In contrast, female sex was associated with increased odds of both systemic AEs (OR ¼ 1.4; 95% CI, 1.04–1.97; P ¼ 0.03) and local
AEs (OR ¼ 2.9; 95% CI, 2.06–4.06; P < 0.001). Simultaneous
vaccination was associated with systemic AEs (OR ¼ 1.6; 95%
CI, 1.13–2.21; P ¼ 0.008) but not with local AEs (Table 3).
In addition, we performed logistic regression analysis focusing on the 182 subjects who were aged 60 years. Multivariate
analysis demonstrated that female sex and simultaneous vaccination were associated with local AEs (female sex: OR ¼ 4.2;
95% CI, 1.85–9.40; P ¼ 0.001 and simultaneous vaccination:
OR ¼ 4.0; 95% CI, 1.64–9.58; P ¼ 0.002) (Table 4). In contrast,
age, female sex, pre-existing YFI and simultaneous vaccination
were not statistically significant risk factors for systemic AEs in
either univariate or multivariate analyses (Table 4).
Discussion
In our study, which was conducted in a non-endemic area, the
overall frequency of reported AEs (55.6%) was similar to the rates
reported in a study conducted among travellers in the US (65.3–
71.9%),1 but higher than rates reported from other studies in
Brazil (3.5–15.3%),12,13 where YF is endemic. A previous YFI
4
Journal of Travel Medicine, 2016, Vol. 23, No. 3
Figure 2. Proportion of timing, duration, and severity of AEs. Of all AEs, 73.8% of systemic AEs and 82.3% of local AEs occurred within 5 days after
vaccination, and 86.5% of systemic AEs and 70.3% of local AEs subsided within 5 days after vaccination. Regarding timing, the rates of systemic (local) AEs occurring on Day 1, Days 2–5, Days 6–9 and Days 10–14 after vaccination were 24.7% (27.5%), 49.1% (54.0%), 17.5% (15.0%) and 7.3% (1.5%),
respectively. Regarding duration, the rates of systemic (local) AEs lasting 1 day, 2–5 days, 6–9 days and 10–14 days were 40.3% (9.8%), 46.2% (60.5%),
7.9% (15.7%) and 1.7% (5.2%), respectively
Table 3. Risk factors of systemic and local adverse events on logistic regression analysis in all subjects (n ¼ 666)
Systemic AEs
Local AEs
Univariate
Age 60 years
Female
Pre-YFI
SV
Multivariate
Univariate
Multivariate
OR
95% CI
OR
95% CI
OR
95% CI
OR
95% CI
0.6
1.3
0.8
1.6
0.42–0.86
0.98–1.85
0.45–1.30
1.17–2.26
0.6
1.4
0.9
1.6
0.44–0.93
1.04–1.97
0.51–1.49
1.13–2.21
0.5
2.7
0.5
1.2
0.31–0.67
1.95–3.76
0.27–0.89
0.88–1.71
0.4
2.9
0.5
1.2
0.29–0.66
2.06–4.06
0.29–0.99
0.84–1.71
Pre-YFI: pre-existing yellow fever immunization, SV: simultaneous vaccination.
Table 4. Risk factors of systemic and local adverse events on logistic regression analysis in subjects aged 60 years (n ¼ 182).
Systemic AEs
Local AEs
Univariate
a
Age (years)
Female
Pre-YFI
SV
Multivariate
Univariate
Multivariate
OR
95% CI
OR
95% CI
OR
95% CI
OR
95% CI
1.1
1.6
0.8
1.5
0.99–1.13
0.82–2.94
0.29–2.11
0.73–3.20
1.1
1.5
0.9
1.8
0.99–1.14
0.76–2.84
0.32–2.38
0.82–3.81
1.1
4.0
0.3
2.7
0.99–1.15
1.89–8.53
0.65–1.30
1.24–5.77
1.1
4.2
0.4
4.0
0.99–1.17
1.85–9.40
0.08–1.80
1.64–9.58
Pre-YFI: preexisting yellow fever immunization, SV: simultaneous vaccination.
a
Per 1-year increase.
reduces the symptoms of AEs after subsequent YF vaccination,14
and in fact, one previous prospective observational study of patients aged 60 years, in which many vaccinees had received a
previous YF vaccination (41.7% of the vaccinees), showed that
84.7% of vaccinees did not experience any AEs following YF vaccination.12 In our study, the rate of AEs among 69 cases with preexisting YFI was 42.0%, which was significantly lower than
among 597 cases without pre-existing YFI (56.3%) (P ¼ 0.017).
Journal of Travel Medicine, 2016, Vol. 23, No. 3
Those who live in YF endemic countries would have frequent opportunities to acquire the immunity against YF virus through vaccination or natural infection and might also have more
opportunity to be exposed to other flaviviruses, which causes a serological response similar to that induced by prior YF vaccination.2,14,15 These findings suggest that the results of clinical
research conducted in countries where YF is endemic may tend to
result in lower frequency of AEs after YF vaccination than in nonendemic areas because repeated live-attenuated vaccination and
higher antibody titer against the virus contained in live attenuated
vaccines were usually associated with lower frequency of AEs after vaccination.1,16
Older age (generally 604,6 or 65 years3) is considered a risk
factor of serious AEs, such as YFV-AVD.3,7,8,17,18 Lawrence
et al.19 reported that rates of serious AEs, such as neurological
disorders leading to either or both hospitalization or death,
were significantly higher among elderly vaccinees. In contrast,
regarding general AEs, Monath et al.1 reported that older age
was associated with a reduced frequency of AEs. In their study,
non-serious general AEs occurred less frequently in those aged
60 years (47.4–54.1%) than in those aged <60 years (62.0–
69.7%). Similarly, our study results showed that the rate of AEs
in vaccinees aged 60 years (42.9%) was lower than in those
aged 60 years (60.3%) (P < 0.001). In general, the experience
of AEs leads to higher response rate, but despite the higher response rate of older people (85.4% in those aged 60 years vs
61.3% in those aged <60 years; P < 0.001), our study showed
that the rate of AEs in vaccinees aged 60 years was lower than
in those aged <60 years. This finding supports the fact that elderly people normally show lower frequency of AEs than nonelderly people. This reduced frequency of AEs in the elderly may
be due to the low reactogenicity of the immune system in older
people.20 Previous studies found that female sex was a risk factor for non-serious AEs after YF vaccination.8,12 Similarly, our
study showed that female sex was a risk factor for local AEs,
without response bias (the response rates of males and females
were 62.7% and 65.5%, respectively). Women are considered
to be more sensitive to skin pain than men,21 which may have
influenced the results in our study.
Several limitations to the present study warrant mention. First,
we only obtained response data from 666 (63.9%) of 1043 vaccinees who had agreed to participate in our study, so our results
may be influenced by non-response bias. The response rate in
young people is expected to be low in studies using self-administered questionnaires,22 and indeed, the response rate of those aged
60 years (85.4%) was higher than that of those aged <60 years
(58.3%) (P < 0.001) in our study. Thus, non-response bias should
be less in those aged 60 years, and the assessment of AEs should
be subsequently more reliable in this older age group. However,
the number of simultaneous vaccination is significantly higher in
the younger age group (Table 1), which could be possible reason
for the higher reporting of AEs. In addition, for child vaccinees,
their parents were allowed to complete checklist in their stead,
which could lead to false assessment as other vaccinees. Second,
recall bias should be considered because the AEs were evaluated
by the vaccinees and the timing between injection and evaluation
of AEs was seen in various intervals (from minimum 1 day to
maximum 384 days). Third, we collected reports on any abnormal symptoms that occurred 2 weeks after YF vaccination;
5
therefore, AEs not directly caused by YF vaccination might have
been reported as side effects. In addition, all symptoms that occurred in the 2 weeks after vaccination were mild; however, AEs,
including serious AEs (particularly YF-AND), could have developed beyond 14 days after YF vaccination6,23 and would not have
been detected in our study. Finally, the sample size of our study
was not sufficient to detect rare serious AEs. However, it was sufficiently large to detect most frequent and mild-to-moderate AEs.
In conclusion, AEs after YF vaccination were less frequent in
travellers aged 60 years compared with those aged <60 years,
and fatal AEs were not seen in any of the 666 travellers included
in our study. Most reported AEs were mild and subsided within
5 days, suggesting that YF vaccination is usually safe even for elderly travellers. Our data suggest that the use of YF vaccination
in elderly travellers should be evaluated based on a full individual risk assessment, not only based on their age.
Funding
This research is partly supported by funding from the Ministry of
Health, Labour and Welfare, Japan (H26-shinko-shitei-001).
Conflict of interest: None declared.
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