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143（ 43 ）〈Original Article〉

Effectiveness of current and repeated vaccination
with quadrivalent influenza vaccine
during the 2017/18 season in Japan
Soichiro Ando
Ando Clinic(Received for publication March 26, 2019)

The effectiveness of repeated vaccination of the quadrivalent inﬂuenza vaccine iscurrently unknown. This study aims to estimate current and repeated vaccination
effectiveness (VE) of the quadrivalent inﬂuenza vaccine. A test-negative casecontrol study was performed during the 2017–2018 season. The participants wereJapanese children divided into four groups (6–11 months and ages 1–5, 6–12, and
13–15 years). Current VE: Overall, the adjusted VE was signiﬁcant for inﬂuenza B(36.4; 95% conﬁdence interval [CI]: 9.8–55.2); the adjusted VE was signiﬁcant for
any inﬂuenza (A＋B; 47.3%; 95% CI: 12.2–68.3) and inﬂuenza B (56.2%; 95% CI:
17.9–76.6) only in the 1–5 year age group. In other groups, VE was not observed.
Vaccine doses: Two vaccine doses signiﬁcantly decreased the incidence of any
inﬂuenza and inﬂuenza B compared to no vaccination or only one dose in only the
1–5 year old group. Repeated VE: The adjusted VE was signiﬁcant for any inﬂuenza(72.6%; 95% CI: 27.1–89.7) and inﬂuenza B (69.7%; 95% CI: 4.5–90.4) in only the
1–5-year age group without vaccination in the previous season. It was alsosigniﬁcant for inﬂuenza B (68.6%; 95% CI: 1.3–90.0) in the 6–12-year age groupwith two vaccination doses in the previous season. In other groups, repeated VE was
not observed for any inﬂuenza types. The reason for that repeated VE may dependon age, repeated vaccination with two doses may be valuable in the 6–12 year age
group, although current VE was not observed.

Corresponding author: Soichiro Ando, Ando Clinic, 4–6–7 Mimomi, Narashino City, Chiba 275–0002, Japan, Tel: ＋81–47–
476–1111, Fax: ＋81–47–476–1124, E-mail: ando.clinic@nifty.com

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Introduction
The effect of previous vaccination on current season inﬂuenza vaccine effectiveness (VE)
varies, and a conclusion has not yet been reached1,2). In response to the recommendation of theWorld Health Organization (WHO), quadrivalent inﬂuenza vaccines replaced trivalent vaccines
in the 2015–2016 season in Japan3). The test-negative case-control study has been validated byevaluating vaccine effectiveness (VE) against inﬂuenza4〜6). In Japan, several reports have described the efﬁcacy of quadrivalent inﬂuenza vaccines, using the test-negative case-control design7〜10). However, information on the effect of previous vaccinations on current season inﬂuenza VE of quadrivalent inﬂuenza vaccines has not yet been published.
This study aimed ① to estimate the effectiveness of quadrivalent inﬂuenza vaccines in children during the 2017–2018 season based on a test-negative case-control design and ② to conﬁrm
whether previous vaccinations affected the current seasonʼs inﬂuenza VE, particularly that of inﬂuenza B.

Patients and Methods
Patients
The examinees in this research were children who underwent the rapid inﬂuenza diagnostic
test (RIDT) in the Ando Clinic (Narashino City, Chiba, Japan) due to possible infections of inﬂuenza in the 2017–2018 season. Those patients ① were informed of the concept of this study, ②
fulﬁlled the criteria of inﬂuenza-like illness (ILI) and ③ divided into four age groups (6–11
months and 1–5, 6–12, and 13–15 years) in order to analyze age effects. In the course of thisstudy, following clinical information was collected: sex, age, vaccination status for quadrivalent
inﬂuenza vaccine (current and previous season), comorbidities, and month of inﬂuenza infection
onset. In this research comorbidities were deﬁned as: chronic pulmonary, cardiovascular (excluding hypertension), renal, liver, hematologic, and neurological disorders, diabetes mellitus, autoimmune disorders, and cancer.
Eligibility criteria
1) Patients who underwent RIDT due to an ILI, in the 2017–2018 season. ILI was deﬁned
based on the WHOʼs deﬁnition11) as follows:a) Patients with a fever (body temperature (BT) ≥38.0°C),b) Patients in whom inﬂuenza infection was suspected, evidenced by symptoms including acute onset, nasal discharge, sore throat, cough, arthralgia, and myalgia,
2) The interval from the time the quadrivalent inactivated inﬂuenza vaccination was administered was ≥14 days and ＜5 months12).

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145（ 45 ）3) If patients had multiple episodes:a) For patients with any inﬂuenza-negative episodes, the episode where the highest BT
was observed was employed,b) For patients with both inﬂuenza-positive and negative episodes, the positive episode
was employed,c) For patients with both inﬂuenza A and B-positive episodes, both episodes were employed.
Exclusion criteria
1) Already had an inﬂuenza infection during the 2017–2018 season.
2) Patients who had already been given the neuraminidase inhibitor due to negative resultsof RIDT.
3) The interval from the time of quadrivalent inactivated inﬂuenza vaccination was ＜14days or ≥5 months.
4) Patients ≥16 years of age.
Diagnosis of inﬂuenza
Nasopharyngeal swabs were obtained from all patients and tested using StatmarkTM FLU
stick-N® (Statmark®) (Nichirei Bioscience Co., Tokyo, Japan) and Alsonic® Flu (Alsonic®) (Alfresa Pharma Co., Osaka, Japan). These RIDT kits can detect and differentiate between inﬂuenzas
A and B, with high positive concordance (Statmark: Alsonic＝inﬂuenza A: 100%: 90.8%, inﬂuenza B: 93.3%: 88.8%) and negative concordance rates (Statmark: Alsonic＝inﬂuenza A: 99.1%:
98.1%, inﬂuenza B: 98.8%: 100%) with a viral isolation culture. Statmark® was used till January
27, 2018 covering the peak of the inﬂuenza epidemic. Alsonic® was used after January 27, 2018.
Vaccine
The quadrivalent inﬂuenza vaccine contained inﬂuenza A/Singapore/GP1908/2015 (IVR180) (H1N1) pdm09, A/Hong Kong/4801/2014 (X-263) (H3N2), B/Phuket/3073/2013 (Yamagata
lineage), and inﬂuenza B/Texas/2/2013 (Victoria lineage) viral strains.
At 2–4-week intervals, two 0.25 mL and 0.5 mL doses of vaccine were administered to children aged 6 months to 2 years and 3–12 years, respectively. A single 0.5 mL vaccine dose was
generally administered to children aged ≥13 years.
Test-negative case-control study
VE was estimated by a test-negative case-control design: patients who were ILI- and RIDTpositive for inﬂuenza infection were considered as cases, and patients who were ILI and RIDTnegative for inﬂuenza infection were considered as controls. VE was deﬁned as {1-odds ratio146（ 46 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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June 2019(OR)}×100 (%); OR was calculated as (number of inﬂuenza-positive among vaccinated patients
×inﬂuenza-negative among unvaccinated patients)/(number of inﬂuenza-negative among vaccinated patients×inﬂuenza-positive among unvaccinated patients)7〜10,13). OR was calculated using
the Wald test. First, the crude VE was calculated and adjusted for sex, month of onset of inﬂuenza
infection, comorbidity, and rapid-inﬂuenza diagnostic test to obtain the adjusted VE. Secondly, toensure statistical reliability, the VE was adjusted for sex, month of onset of inﬂuenza infection, andrapid-inﬂuenza diagnostic test for ages 13–15 years (only one patient had a comorbidity). Cases inwhich the statistical analyses results did not overlap among the month of onset of inﬂuenza infection, VE was adjusted for sex, comorbidity and rapid-inﬂuenza diagnostic test (sex and rapid-inﬂuenza diagnostic test in those aged 13–15 years) since RIDT (Statmark® was used by January
27, 2018 covering the peak of the inﬂuenza epidemic. Alsonic® was used after January 27, 2018)
could be substituted for month of onset of inﬂuenza infection to a certain degree.
Effect of previous vaccination on current season inﬂuenza VE
To estimate the effect of previous vaccinations on current season inﬂuenza VE, participants
were divided into subgroups (the number of previous vaccinations/none, once and twice).
Twenty-one patients ages 6–11 months were excluded. In each subgroup, VE was similarly estimated by a test-negative case-control design.
Statistical analysis
Studentʼs t-test was used to compare continuous variables (i.e., time from onset, age) between participants with and without inﬂuenza infection. χ2 tests were used to compare nominal
variables (i.e., sex, comorbidities, and month of onset). The VE was adjusted for sex, age group,
presence/absence of comorbidities, and month of onset of inﬂuenza infection6,8〜10,13). When considering the effect of age, the stratiﬁed analysis was performed. Treating both vaccine doses andage groups as continuous variables, the rates of incidence of inﬂuenza infection are shown bothusing the unit OR (i.e., the OR for an increase of 1; unit＝1 vaccine dose). The adjusted OR was
calculated, and the unit OR was adjusted for other continuous variables (age, body temperature,
time from onset, and vaccine doses). Two-sided P values ＜0.05 were considered signiﬁcant. Statistical analyses were performed using JMP® 13.2 (Statistical Analysis Software, SAS InstituteInc., Cary, NC, USA).
EthicsThis study was conducted according to the Declaration of Helsinki. Written informed consent was obtained from the patients, their parents, or both. Participants were recruited prospectively. The study design was approved by the Joint Institutional Review Board (approval number:
14000050.20171215-4550).

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147（ 47 ）Results
Enrollment
From December 20, 2017 to April 2018, 1,807 episodes were enrolled; 988 episodes were
those of patients aged 6 months to 15 years: 229 were excluded (819: patients ≥16 years old,
155: BT ＜38.0°C, 71: overlapped episodes, 1: uncertain vaccination, 1: the neuraminidase inhibitor had already been given before presentation, and 1: interval from the time of vaccination was≥5 months). In total, 752 patients and 759 episodes were analyzed (7 patients had episodes of inﬂuenza both A and B).
Patients characteristics
Patient characteristics are summarized in Table 1. In total, 402 episodes were RIDT-positive(case) and 357 were RIDT-negative (control). Comorbidities included bronchial asthma (n＝46),
febrile convulsions (undergoing treatment) (n＝3), epilepsy (n＝3), milk allergy (undergoingtreatment) (n＝2), and congenital anomalies such as Down syndrome (n＝2) (overlapping: yes).
Overall, Statmark® had more signiﬁcant positivity associated with RIDT than Alsonic® for bothinﬂuenzas. This may be because Statmark® was used till January 27, 2018 including the peak ofinﬂuenza epidemics. The distribution of inﬂuenza infection is shown in Figure 1. Both inﬂuenza
A and B epidemics peaked from January 2018 and both peaked out in February. The inﬂuenza B
epidemic also peaked in January 2018. Both inﬂuenza epidemics then sharply declined in March.
Vaccine effectivenessCurrent vaccine effectiveness (in the 2017–2018 season) is shown in Table 2. The adjusted
VE was only signiﬁcant against inﬂuenza B: 36.4% (95% CI: 9.8–55.2). When participants weredivided into three age groups (patients aged 6–11 months were excluded following analyses because of their small number), VE was only signiﬁcant in the group of those aged 1–5 years; it was
47.3% effective (95% CI: 12.2–68.3) against any inﬂuenza, 24.1% (95% CI: −52.9–62.4) against
inﬂuenza A, and 56.2% (95% CI: 17.9–76.6) against inﬂuenza B. The adjusted VE was not significant in the older age group (Table 2).
Vaccine doses
The relation between vaccine doses and the adjusted ORs of incidences of inﬂuenza isshown in Table 3. Vaccine doses also affected the incidence of inﬂuenza. Two doses signiﬁcantly
decreased the rates of RIDT-positive cases, compared to no vaccination or only one dose in theyounger age group (those 1–5 years old). Vaccination doses were correlated with decreasing therates of incidence of any inﬂuenza and inﬂuenza B in this age group. The adjusted VE was significant against any inﬂuenza: 0.68 (95% CI: 0.51–0.91) in cases with one dose, and 0.47 (95% CI:

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Table 1. Patient characteristics
Rapid inﬂuenza diagnostic test
Characteristics

Total

Test-positive (case)Test-negative (control)nType of inﬂuenza
Inﬂuenza A (%)
Inﬂuenza B (%)
Age (mean age)
Any inﬂuenza
Inﬂuenza A
Inﬂuenza B
Sex (Male : Female)
Any inﬂuenza
Inﬂuenza A
Inﬂuenza B
Comorbiditya (yes/no)
Any inﬂuenza
Inﬂuenza A
Inﬂuenza B
Vaccination (yes/no)
Any inﬂuenza
Inﬂuenza A
Inﬂuenza B
RIDTb (Statmark/Alsonic)
Any inﬂuenza
Inﬂuenza A
Inﬂuenza B
Body Temperaturec (°C)
Any inﬂuenza
Inﬂuenza A
Inﬂuenza B
Time from onsetd
Any inﬂuenza
Inﬂuenza A
Inﬂuenza B

759

402

357

6.7

389 : 370

53/706308/451

338 : 422

39.0±0.0

24.5±0.7130 (32.3)
272 (67.7)

P-value

Not available
Not available＜0.0001*

7.6
6.9
7.9

5.6

208 : 194
70 : 60
138 : 134

181 : 176

0.82730.60841.000030/372
11/11919/253

23/3340.66910.42710.8722

151/251
58/72
93/179157/200

0.07590.91810.0137*205/19790/40
115/157

127/230＜0.0001*39.0±0.039.2±0.1
38.9±0.0

38.9±0.0

24.7±1.0
22.0±1.726.1±1.2

24.3±1.0

0.0014*＜0.0001*＜0.0001*

0.09810.0148*＜0.0001*

0.792124.3±1.1

0.76900.23290.2783aComorbidities included chronic disease of the lung (bronchial asthma), neurological disease (such as epilepsy),and others such as (Down syndrome).
b
RIDT: Rapid-inﬂuenza diagnostic testc
Mean±standard errordHours±standard error

0.27–0.83) with two doses (trend P-value＝0.0090). The values were 0.57 (95% CI: 0.40–0.82)
in cases with one dose, and 0.33 (95% CI: 0.16–0.67) with two doses, against inﬂuenza B (trend
P-value＝0.0024). However, in those aged 6–12 and 13–15 years, the adjusted VE was not significant against any inﬂuenza, inﬂuenza A and inﬂuenza B (Table 3).
Repeated vaccine effectivenessCurrent vaccine effectiveness (in the 2017–2018 season) correlated to the status of vaccinations in the previous season (in the 2016–2017 season) shown in Table 4. The age group with

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Figure 1. Distribution of inﬂuenza infection in the 2017/18 season

Table 2. Vaccine effectiveness in children in the 2017–2018 seasonn
Total
Any inﬂuenza
Inﬂuenza A
Inﬂuenza B
Age groupa
1–5 years
Any inﬂuenza
Inﬂuenza A
Inﬂuenza B
6–12 years
Any inﬂuenza
Inﬂuenza A
Inﬂuenza B
13–15 years
Any inﬂuenza
Inﬂuenza A
Inﬂuenza B

Test-positive(vaccinated/
not vaccinated)

Test-negative(vaccinated/
not vaccinated)

Crude VE (95% CI)

Adjusted VEb (95% CI)(151/251)(58/72)(93/179)(157/200)(157/200)(157/200)

23.4% (−2.5 to 42.7)−2.6% (−53.7 to 31.5)
33.8% (8.3 to 52.2)*

23.2% (−4.4 to 43.5)−23.6% (−90.7 to 19.9)
36.4% (9.8 to 55.2)*(40/70)(20/25)(20/45)(97/91)(97/91)(97/91)

46.4% (13.2 to 66.9)*
24.9% (−44.3 to 61.0)
58.3% (24.1 to 77.1)*

47.3% (12.2 to 68.3)*
24.1% (−52.9 to 62.4)
56.2% (17.9 to 76.6)*(95/148)(33/37)(62/111)(52/77)(52/77)(52/77)

5.0% (−47.0 to 38.5)−32.1% (−137.4 to 26.5)
17.3% (−32.3 to 48.3)

1.6% (−53.9 to 37.1)c−81.4% (−252.1 to 6.5)
17.7% (−33.3 to 49.1)c(13/28)(4/7)(9/21)(7/20)(7/20)(7/20)−32.7% (−291.9 to 55.1)−63.3% (−631.7 to 63.6)−22.4% (−291.4 to 61.7)−66.1% (−452.6 to 50.0)−141.7% (−1228.5 to 56.0)c−32.5% (−365.0 to 62.3)c

759

298

372

68

VE: Vaccine effectiveness, CI: conﬁdence interval* Statistically signiﬁcantaTwenty-one patients in age with 6–11 months were excluded.
b
VE adjusted for sex, month of onset of inﬂuenza infection, comorbidity and rapid-inﬂuenza diagnostic test; VE
adjusted for sex, month of onset of inﬂuenza infection and rapid-inﬂuenza diagnostic test in age with 13–15 years.
c
VE adjusted for sex, comorbidity and rapid-inﬂuenza diagnostic test; VE adjusted for sex and rapid-inﬂuenza
diagnostic test in age with 13–15 years.

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Table 3. Vaccine effectiveness by vaccine doses
Vaccine doseTotal
Any inﬂuenza
Inﬂuenza A
Inﬂuenza B
Age groupb
1–5 years
Any inﬂuenza
Inﬂuenza A
Inﬂuenza B
6–12 years
Any inﬂuenza
Inﬂuenza A
Inﬂuenza B
13–15 years
Any inﬂuenza
Inﬂuenza A
Inﬂuenza B

Adjusted odds ratioa (95% CI)

Trend P-value

None

Once

Twice

1.0
1.0
1.0

0.91 (0.77–1.09)
1.11 (0.87–1.42)
0.83 (0.68–1.01)

0.83 (0.59–1.18)
1.24 (0.76–2.03)
0.69 (0.46–1.03)

0.30170.38350.0688

1.0
1.0
1.0

0.68 (0.51–0.91)
0.85 (0.57–1.25)
0.57 (0.40–0.82)

0.47 (0.27–0.83)
0.72 (0.33–1.56)
0.33 (0.16–0.67)

0.0090*0.39930.0024*

1.0
1.0
1.0

1.04 (0.80–1.34)
1.33 (0.92–1.90)
0.94 (0.71–1.24)

1.07 (0.64–1.80)
1.76 (0.86–3.63)
0.88 (0.50–1.54)

0.79430.12470.6565

1.0
1.0
1.0

1.07 (0.39–2.91)
1.39 (0.36–5.42)
1.02 (0.35–2.96)

1.15 (0.15–8.48)
1.93 (0.13–29.4)
1.04 (0.12–8.75)

0.89400.63750.9716

VE: Vaccine effectiveness, CI: conﬁdence interval* Statistically signiﬁcanta
VE adjusted for age, body temperature, time from onset and vaccine doses.
bTwenty-one patients in age with 6–11 months were excluded.

13–15 years was excluded because of their small numbers. In children aged 1–5 years, the current
adjusted VE was signiﬁcant: 72.6% (95% CI: 27.1–89.7) against any inﬂuenza and 69.7% (95%
CI: 4.5–90.4) against inﬂuenza B in only in the cohort without receiving vaccination in the previous season. Conversely, in children aged 6–12 years, the current adjusted VE was signiﬁcant:
68.6% (95% CI: 1.3–90.0) against inﬂuenza B in only those with two doses of vaccination in theprevious season. However, in other age groups, the current adjusted VE that correlated to the status of vaccination in the previous season was not signiﬁcant (Table 4).

Discussion
Here, the current signiﬁcant VE was observed against any inﬂuenza (47.3%: 95% CI:
12.2–68.3) and inﬂuenza B (56.2%: 95% CI: 17.9–76.6). The dose-dependent VE of the quadrivalent inﬂuenza vaccine was seen in children aged 1–5 years. This was similar to my previous
study which identiﬁed in the 2016–2017 season, signiﬁcant VE and dose-dependence of thequadrivalent inﬂuenza vaccine, but only for children aged 6 months to 4 years9). However, thisstudy failed to identify signiﬁcant VE against inﬂuenza A in both total patients or any speciﬁc age
group. The low VE in the season in which inﬂuenza A/H3N2 was dominant was possibly due tomutations in the egg-adapted A/H3N2 vaccine strain and mismatches due to the antigenic drift ofJune 2019

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151（ 51 ）Table 4. Vaccine effectiveness in the 2017–2018 season correlating to vaccination in the 2016–2017 season
Age groupa
1–5 yearsa) Any inﬂuenza
Vaccination in last season
None
Once
Twice
b) Inﬂuenza A
Vaccination in last season
None
Once
Twice
c) Inﬂuenza B
Vaccination in last season
None
Once
Twice
6–12 yearsa) Any inﬂuenza
Vaccination in last season
None
Once
Twice
b) Inﬂuenza A
Vaccination in last season
None
Once
Twice
c) Inﬂuenza B
Vaccination in last season
None
Once
Twice

Test-positive(vaccinated/
not vaccinated)

Test-negative(vaccinated/
not vaccinated)

Crude VE (95% CI)

Adjusted VEb (95% CI)(6/59)(7/6)(27/5)(29/80)(10/2)(57/9)

71.9% (28.1 to 89.1)*
76.7% (−51.3 to 96.4)
14.7% (−178.9 to 73.9)

72.6% (27.1 to 89.7)*
76.8% (−63.6 to 96.7)c
5.9% (−390.7 to 81.9)(2/20)(3/4)(15/1)(29/80)(10/2)(57/9)

72.4% (−25.4 to 93.9)
85.0% (−26.5 to 98.2)−136.8% (−1918.8 to 72.2)

77.1% (−12.4 to 95.3)c
88.9% (−48.8 to 99.2)c−147.4% (−2157.0 to 72.9)c(4/39)(4/2)(12/4)(29/80)(10/2)(57/9)

71.7% (13.9 to 90.7)*
60.0% (−290.0 to 95.9)
52.6% (−79.5 to 87.5)

69.7% (4.5 to 90.4)*
not available
56.3% (−80.7 to 89.5)c(8/110)(25/20)(62/18)(2/63)(11/8)(39/5)−129.1% (−1012.4 to 52.8)
9.1% (−168.8 to 69.3)
55.8% (−28.6 to 84.8)−407.8% (−3224.0 to 22.4)
not available
55.7% (−33.8 to 85.2)c(1/26)(6/7)(26/4)(2/63)(11/8)(39/5)

21.2% (−1294.9 to 89.5)
37.7% (−158.1 to 84.9)
16.7% (−239.7 to 79.6)−25.6% (−1455.6 to 89.9)c
6.0% (−355.1 to 80.6)c−56.6% (−720.6 to 70.1)(7/84)(19/13)(36/14)(2/63)(11/8)(39/5)−162.5% (−1206.8 to 47.3)−6.3% (−236.4 to 66.4)
67.0% (−0.7 to 89.2)−206.9% (−1476.4 to 40.2)c
not available
68.6% (1.3 to 90.0)*c

VE: Vaccine effectiveness, CI: conﬁdence interval* Statistically signiﬁcantaTwenty-one patients in age with 6–11 months were excluded.
b
VE adjusted for sex, month of onset of inﬂuenza infection, comorbidity and rapid-inﬂuenza diagnostic test.
c
VE adjusted for sex, comorbidity and rapid-inﬂuenza diagnostic test.
The age group with 13–15 years was excluded because of their small numbers.

the virus14). Recently, the discrepancy between the vaccine strain and epidemic strain of A/H3N2
has been extended but not for other inﬂuenza types15). The lack of effectiveness against inﬂuenza
A due to this discrepancy may become apparent in the 2017–2018 season.
VE and dose-dependent VE were not observed in children aged 6–12 years. This could be
due to extreme pandemics in elementary schools and the decline of VE associated with increasingage7). No VE or dose-dependent VE in those aged 13–15 years, and no VE in adults may be dueto the decline of VE with increasing age from a low rate of vaccinations7,9).
The effectiveness of a repeated vaccine is controversial and several hypotheses support152（ 52 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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this16〜19). Among them, the antigenic distance hypothesis (ADH) suggests that inﬂuenza VE isdetermined by the antigenic distances (AD) between prior (v1) and current (v2) seasonʼs vaccine,and between v1 and current epidemic inﬂuenza strain (e)16). The prior vaccination effects represent a balance between a preexisting v1-induced antibody potentially interfering with a v2 antigen
and v2 stimulation of rapid v1 memory responses potentially protective against e16). For example,
when previous and current seasonʼs vaccine is nearly equal (i.e., v1＝v2) and AD between v1 ande is small (i.e., v1＝e), a higher VE is possible16). One study showed the effectiveness of serial
vaccinations against inﬂuenza A/H3N2 based on this hypothesis20); however, in inﬂuenza A (A/H3N2), the AD becomes more variable by the antigenic drift and egg-adaptation7). Recent epidemic strains of A (H3N2) belong to the 3C.2a subclade. Although this subclade belongs to vaccine strain A/Hong Kong/4801/2014, within the 3C.2a subclade, there are several groups of subclades such as 3C.2a1, 3C.2a2, 3C.2a3, and 3C.2a4. Antigenic diversity has expanded, and adiscrepancy is developing between the vaccine and epidemic strains15). However, in inﬂuenza B,
the antigenic drift occurs more rarely. The prior and current seasonʼs vaccine was the same (B/Victoria: B/Texas/02/2013, B/Yamagata: B/Phuket/3073/2013) and additionally, the current epidemic inﬂuenza strain (B/Victoria: B/clade 1A, B/Yamagata: clade 3) was identical to the previous seasonʼs strain, which could be effective for the prior and current seasonʼs vaccine in the twolatest seasons17). Also, quadrivalent vaccines cover both lineages of inﬂuenza B. Therefore, the2017–2018 season showed the most effective with repeated vaccination against inﬂuenza B. This
study showed that in children aged 1–5 years, the current adjusted VE was signiﬁcant against any
inﬂuenza: 72.6% (95% CI: 27.1–89.7) and against inﬂuenza B in the cohort without vaccinationin the previous season 69.7% (95% CI: 4.5–90.4). The reason for this is uncertain. Among 152
patients who did not receive a vaccination in the previous season, 144 were not vaccinated in the
two years before the last season. Although the precise number is unknown, most patients in thisage group may be vaccine-naïve individuals. Since most hypotheses postulate that prior vaccination might interfere with current vaccinations, VE may be more clearly detected in vaccine-naïve
individuals.
In children aged 6–12 years, the current adjusted VE was signiﬁcant: 68.6% (95% CI: 1.3–90.0) effective against inﬂuenza B with only two doses of the vaccination administered during theprevious season. This age group may represent ADH in certain cases. Though current VE was notobserved in this age group, VE may be promising in patients who received two vaccine doses in
the previous season. In other age groups, the current adjusted VE correlating to the status of vaccination in the previous season was not signiﬁcant. This may be caused by the low rate of vaccination or the inﬂuence of more numerous prior vaccinations.
This study had several limitations. First, bias due to sample size may have affected the results, given the small size of this test-negative case-control study. Second, RIDT-negative cases
may have had inﬂuenza infections. If RIDT is performed at shorter intervals from the time ofJune 2019

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153（ 53 ）onset, it tends to provide negative results; such cases may be diagnosed as inﬂuenza infections
later. However, in this study, the time between RIDT and the time of onset was not signiﬁcantly
different between RIDT-positive and negative cases. This was likely due to a minimal number offalse-negative RIDT cases. Third, I did not perform the hemagglutination inhibition assay andcalculate precise ADs. Fourth, since this study was conducted in a single hospital, sampling bias
was unavoidable. Finally, RIDT is not 100% accurate. Precise identiﬁcation of the inﬂuenza virus
was not performed, such as by polymerase chain reaction (PCR); however, a previous study indicated no differences between the results estimated by RIDT and PCR data21).
In conclusion, this study is the ﬁrst to focus on the current and repeated VE and dose-dependent VE (in children) of the inactivated quadrivalent inﬂuenza vaccine through the 2016–2017 to
2017–2018 season in Japan. The quadrivalent inﬂuenza vaccine showed signiﬁcant VE and dosedependent VE against any inﬂuenza, as well as inﬂuenza B, in only children aged 1–5 years. As
for the effectiveness of repeated vaccination in children aged 1–5 years, the current adjusted VE
was signiﬁcant against inﬂuenza B only, without vaccination in the previous season. In children
aged 6–12 years, although the adjusted VE was not signiﬁcant against inﬂuenza B in this season,
the current adjusted VE was signiﬁcant against inﬂuenza B only, when two vaccine doses werereceived during the previous season. VE and current VE with or without prior vaccination were
not observed in other age groups. The effectiveness of repeated vaccine may vary with age.
Conﬂict of interest
The author has no potential conﬂict of interest to disclose.
FundingNone.
Acknowledgements
None.

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