Vaccine Reports
Influenza Vaccine Effectiveness in Preventing Influenza Illness
Among Children During School-based Outbreaks in the
20142015 Season in Beijing, China
Li Zhang, MD,* Peng Yang, MD,* Mark G. Thompson, PhD, Yang Pan, PhD,* Chunna Ma, MD,*
Shuangsheng Wu, MD,* Ying Sun, MD,* Man Zhang, MD,* Wei Duan, MD,*
and Quanyi Wang, MD, MPH*
Background: Little is known about vaccine effectiveness (VE) against non-
medically attended A(H3N2) influenza illness during 20142015 when the
vaccine component appeared to be a poor match with circulating strains.
Methods: Forty-three eligible school influenza outbreaks in Beijing, China,
from November 1, 2014, to December 31, 2014, were included in this study. The
VE of 20142015 trivalent inactivated influenza vaccine (IIV3) was assessed in
preventing laboratory-confirmed influenza among school-age children through
a case-control design, using asymptomatic controls. Influenza vaccination was
documented from a vaccination registry. VE was estimated adjusting for age
group, sex, rural versus urban area, body mass index, chronic conditions, onset
week and schools through a mixed effects logistic regression model.
Results: The average coverage rate of 20142015 IIV3 among students
across the 43 schools was 47.6%. The fully adjusted VE of 20142015 IIV3
against laboratory-confirmed influenza was 38% [95% confidence interval
(CI): 12%57%]. Receipt of previous seasons (20132014) IIV3 signifi-
cantly modified VE of the 20142015 IIV3; children who received both
20132014 and 20142015 vaccinations had VE of 29% (95% CI: 8%
to 53%), whereas VE for children who received 20142015 IIV3 only was
54% (95% CI: 8%77%).
Conclusions: VE for 20142015 IIV3 against A(H3N2) illness identified in
schools was modest. Children who did not receive the prior seasons vaccine
with a homologous A(H3N2) component may have enjoyed greater protec-
tion than repeated vaccinees.
Key Words: influenza; vaccine effectiveness; school; outbreak; China
(Pediatr Infect Dis J 2017;36:e69e75)
S chools provide opportunities for close contact between students
which aids the spread of influenza virus infections.1 School-
Accepted for publication August 03, 2016.
From the *Institute for Infectious Disease and Endemic Disease Control,
Beijing Center for Disease Prevention and Control, Beijing Research
Center for Preventive Medicine, and Capital Medical University, School
of Public Health, Beijing, China; and Influenza Division, Centers for
Disease Control and Prevention, Atlanta, Georgia.
The findings and conclusions in this report are those of the authors and do not
necessarily represent the views of the US Centers for Disease Control and
Prevention or the Beijing Center for Disease Prevention and Control.
L.Z. and P.Y. contributed equally to this article.
This study was supported by Beijing Health System High Level Health Tech-
nology Talent Cultivation Plan (2013-3-098), Beijing Municipal Science
and Technology Commission (D141100003114002), Beijing Talents Fund
(2014000021223ZK36) and The Capital Health Research and Development
of Special (2014-1-1011), expanding the use of seasonal influenza vaccines
in public health programs in China (1U51IP000819-01). The authors have no
conflicts of interest to disclose.
Address for correspondence: Quanyi Wang, MD, MPH, Institute for Infectious
Disease and Endemic Disease Control, Beijing Center for Disease Preven-
tion and Control, No.16 He Pingli Middle St, Dongcheng District, Beijing
100013, China. E-mail: bjcdcxm@126.com.
Copyright 2016 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0891-3668/17/3603-0e69
DOI: 10.1097/INF.0000000000001434
The Pediatric Infectious Disease Journal Volume 36, Number 3, March 2017 www.pidj.com|e69
Copyright 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
age children play a significant role in the transmission of influenza
within schools, families and communities.2,3 Influenza vaccina-
tion among school-age children has been recommended in many
countries as a way to reduce the incidence of influenza infections4,5;
indeed, some studies suggest that high vaccination coverage among
school-age children can reduce the transmission of influenza
among both vaccinated and unvaccinated school children through
herd immunity.6,7
Since 2007, a school-based vaccination campaign has been
administered in Beijing, providing seasonal trivalent influenza vac-
cines (IIV3) free-of-charge for elementary and high school students
before the wintertime influenza seasons. However, no evaluation of
vaccine effectiveness (VE) in preventing influenza illness in these
schools has been conducted to date.
IIV3 recommended by World Health Organization for the 2014
2015 influenza season in the Northern Hemisphere (NH) was used in
Beijing. This IIV3 contained hemagglutinin derived from an A/Califor-
nia/7/2009 (H1N1)-like virus, an A/Texas/50/2012 (H3N2)-like virus
and a B/Massachusetts/2/2012-like (Yamagata lineage) virus.8,9 The
virologic surveillance by Chinese National Influenza Center showed
that influenza A(H3N2) was the predominant circulating influenza
virus in the northern region of China during the 20142015 season,10
similar to most areas in the NH.11 Across the NH, circulating viruses
were noted to be antigenically drifted from the vaccine virus and anti-
genically similar to a new A/Switzerland/9715293/2013 (H3N2)-like
virus.12 Studies from the United States and other NH countries reported
relatively low VE against A(H3N2) influenza viruses, presumably
because of the poor match between the vaccine strain and circulating
strains during 20142015.1315
We report here on a case-control study to estimate the
effectiveness of influenza vaccine in preventing influenza ill-
ness among school-age children in Beijing, China, during the
20142015 influenza season.
METHODS
Study Design and Participants
This case-control study examines influenza outbreaks in
elementary, junior high and high schools reported to Beijing Cent-
ers for Disease Control and Prevention (CDC) between November
1, 2014, and December 31, 2014.
School outbreaks of influenza illness were found through
2 existing syndromic surveillance systems in Beijing that monitor
influenza-like illness (ILI) (measured or self-reported temperature
38C with either cough or sore throat) and febrile illnesses of any
etiology (measured or self-reported temperature 37.5C). We used
the existing outbreak definitions for each surveillance system:
1. ILI outbreak: Ten or more epidemiological-linked ILIs identi-
fied in a school within 1 week; local CDC staff used a broad
definition of potential links, including any opportunities for
Zhang et al The Pediatric Infectious Disease Journal Volume 36, Number 3, March 2017
face-to-face contact in a classroom or any school setting, though
(as noted below), most ILI outbreaks were identified within a
single classroom or within several adjacent classes.
2. Febrile outbreak: Ten or more febrile illnesses within a single
school classroom within 2 days.
The local CDC staff were notified of suspected outbreaks
fitting either criteria by school doctors; local CDC staff began
field epidemiological investigations within the same day (typically
within 2 hours). Epidemiological information for sick children
absent from school was collected through telephone interviews
with parents. We attempted to collect oral pharyngeal swabs that
were collected from up to 10 symptomatic cases from each school
where an ILI or febrile outbreak was reported. Priority was given to
students who were currently sick and attending school. If this num-
ber of cases was less than 10, CDC attempted to collect respiratory
specimens through home visits from sick children dismissed from
school within the 7 days before the outbreak because of illness.
During the 20142015 influenza season, the school vac-
cination campaign was conducted from 15 October, 2014, to 30
November, 2014. Because vaccinees are typically considered
immunized 14 days after vaccination,13 we examined school influ-
enza outbreaks that occurred at least 14 days after the start of each
schools vaccination campaign.
The time period of a school outbreak began with the earli-
est illness onset date (index case) among cases within an outbreak
and ended when no new cases with ILI or fever were found for 7
consecutive days (as determined by the investigating team based
on daily contact with school teachers and staffs).
Influenza Case
An influenza case was a student who had ILI or febrile ill-
ness connected with a reported school outbreak and was positive
for an influenza virus by real-time reverse-transcription polymerase
chain reaction (rRT-PCR) assay.
Asymptomatic Control
A control was a classmate of an influenza case who was fully
asymptomatic (ie, had no symptoms of fever, cough or sore throat)
during the period from the illness onset of the index case of the
outbreak to the end of the outbreak.
Data Collection
Information of enrolled schools and students was collected
using a standardized questionnaire. School information included the
type of school (elementary, junior and high schools), locale (urban or
rural areas), the total number of students and number of students who
received IIV3 vaccination. Individual-level information on participants
was provided by students and their parents, including age, sex, height,
weight, presence of chronic medical conditions, symptoms and ill-
ness onset date. Because most students were identified at the start of
their illness and no follow-up was conducted, we could not document
whether illnesses were medically attended. Documented influenza vac-
cination records for 20132014 and 20142015 IIVs were collected by
using Beijing Management System of Information on Immunization
Program. Staff administering vaccinations entered influenza vaccina-
tion records directly into the electronic registry during each schools
campaign. Local CDC staff then abstracted vaccination records of
cases and controls from the registry following each outbreak.
Laboratory Detection
Oral pharyngeal swabs were tested by rRT-PCR in the district
CDC collaborating laboratories managed by Beijing CDC using
PCR procedures recommended by the World Health Organization
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Collaborating Center for Reference and Research on Influenza at
the Chinese National Influenza Center.
Data Analysis
Questionnaire and laboratory data were entered in duplicate
using EpiData Software (EpiData Association, Odense. Denmark)
and analyzed using SAS 9.3 software (SAS Institute, Inc., Cary,
NC). Participant characteristics and vaccination status of cases and
asymptomatic controls were compared using 2 tests. We present
VE estimates in 4 steps. First, we present unadjusted VE (1 odds
ratios; the odds of IIV3 vaccination among cases divided by the
odds of IIV3 vaccination among controls) estimates using uncondi-
tional logistic regression models. Second, we present VE adjusted
for participant characteristics (age, sex, locale, body mass index
category and presence of 1 or more chronic conditions) and calen-
dar time (onset week of index case). Third, because schools differed
in vaccination coverage and may have also differed in factors asso-
ciated with influenza exposure (eg, classroom crowding, student
mixing and hand hygiene), we present VE adjusted for potential
confounding and clustering effects by school by using a mixed
effects logistic regression model.16,17 Fourth, we presented a fully
adjusted VE by using a mixed effects logistic regression model to
adjust the clustering effect of school, participant characteristics and
calendar time. To aid in interpretation, we also report VE stratified
by age group and by rural versus urban locale, given economic and
demographic differences between schools in these neighborhoods.
All statistical tests were 2-sided, and statistical significance was
defined as P value <0.05 or the lower bound of the 95% confidence
interval (CI) for VE >0.
Given recent observations from studies of children in the
United States18,19 and China20 that the VE of a current seasons IIV3
is influenced by vaccination history, we also tested for potential
effect modification by receipt of the prior seasons 20132014 IIV3.
Similar to previous studies,21 we did so by including main effects
for current and prior season vaccination status plus an interaction
term into each model; because standard errors in such models are
inflated,22 we used a P value of <0.2 for statistical significance.
Ethics Statement
This study was approved by the institutional review board
and human research ethics committee of Beijing CDC. Informed
consent was completed by parents by telephone before childrens
participation. A signed informed consent was required from their
parents or legal guardian for students <18 years of age.
RESULTS
Characteristics and Vaccination Status of
Participants
From November 1, 2014, to December 31 of 2014, a total of 70
influenza outbreaks in elementary and high schools were identified in
Beijing. According to the inclusion criteria, 43 school outbreaks were
eligible for this study (Fig.1); these outbreaks were reported from 38
schools in urban districts and 5 schools in rural districts, including
22 (51%) elementary schools, 15 (35%) junior high schools and 6
(14%) high schools. Most outbreaks affected a single school class-
room; 12 (28%) of 43 outbreaks affected more than 1 class. The num-
ber of cases per outbreak ranged from 10 to 76 (median: 16). The
average coverage rate of 20142015 IIV3 across students in the 43
schools was 48% (range across schools: 13%99%). The timing of
outbreak by school type is illustrated in Figure2.
In total, 3323 students 618 years old were recruited across the
43 outbreaks; 3101 (93%) of these students were included in the study,
excluding 222 with incomplete or missing 20142015 vaccination
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The Pediatric Infectious Disease Journal Volume 36, Number 3, March 2017 Influenza VE in 20142015 in Beijing Schools

FIGURE 1. The flow

chart of enrollment
of subjects in the
case-control study for
estimating influenza
vaccine effectiveness
in school-age
children in Beijing,
China, during
20142015 season.

FIGURE 2. The
time distribution of
the eligible school
influenza outbreaks
included in the case-
control study for
estimating influenza
vaccine effectiveness,
November 1, 2014,
to December 31,
2014.

records. Among the 3101 study sample, 313 students with ILI or
febrile illness for whom respiratory specimens were collected, 854
students with ILI or febrile illness but without respiratory specimens
collected, 236 students with at least 1 symptom (although not meeting
ILI or febrile illness case definitions) and finally 1698 with no illness
symptoms from the date of illness onset of the index case through the
end of the school outbreak (asymptomatic controls) (Fig.1).
Among the 313 students with ILI or febrile illness for
whom respiratory specimens were collected, we identified 210
rRT-PCRconfirmed influenza cases and 103 students who tested nega-
tive for influenza. Of the 210 confirmed cases, 195 had A(H3N2) influ-
enza viruses; the remaining 15 also tested positive for influenza A, and
although they were unsubtyped, are presumed to be A(H3N2) influenza
viruses. The average time from individual illness onset to specimen
collection was 2 days (standard deviation: 2 days) for the confirmed
influenza cases as well as for the influenza-negative illnesses.
Although the median age was 12 years old for both cases and
asymptomatic controls, there was a wider distribution of ages among

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Zhang et al The Pediatric Infectious Disease Journal Volume 36, Number 3, March 2017

TABLE 1. Participant Characteristics for Estimates of Influenza Vaccine Effectiveness for 20142015 Trivalent Influenza
Inactivated Vaccine During School Outbreaks of Influenza in Beijing, November 1, 2014, to December 31, 2014

Characteristics of Cases vs. Controls Vaccination Status Among Cases and Controls

Asymptomatic Confirmed Cases* Asymptomatic Controls

Confirmed Cases* Controls Vaccinated Vaccinated
Characteristics N (Col. %) N (Col. %) P N/Total (Row %) P N/Total (Row %) P

Overall 210 (100) 1698 (100) 91/210 (43.3) 692/1698 (40.8)

Age group, yr <0.001 <0.001 <0.001
610 73 (34.8) 677 (40.2) 22/73 (30.1) 297/677 (43.9)
1115 113 (53.8) 634 (37.6) 63/113 (55.8) 303/634 (47.8)
>15 24 (11.4) 374 (22.2) 6/24 (25.0) 88/374 (23.5)
Sex NS NS NS
Male 112 (53.3) 924 (54.4) 49/112 (43.8) 388/924 (42.0)
Female 98 (46.7) 774 (45.6) 42/98 (42.9) 304/774 (39.3)
Areas <0.001 <0.001 <0.001
Urban 172 (81.9) 1607 (94.6) 64/172 (37.2) 639/1607 (39.8)
Rural 38 (18.1) 91 (5.4) 27/38 (71.1) 53/91 (58.2)
BMI NS NS NS
Normal 136 (65.4) 1222 (73.4) 57/136 (41.9) 491/1222 (40.2)
Underweight 12 (5.8) 79 (4.7) 4/12 (33.3) 37/79 (46.8)
Overweight 34 (16.3) 193 (11.6) 16/34 (47.1) 80/193 (41.5)
Obesity 26 (12.5) 170 (10.2) 14/26 (53.8) 72/170 (42.4)
Chronic condi- 0.014 NS NS
tions
Yes 16 (7.7) 86 (5.1) 7/16 (43.8) 29/86 (33.7)
No 191 (92.3) 1586 (94.9) 82/191 (42.9) 644/1586 (40.6)
Because of small number with missing values, not all column categories sum to the total number of cases or controls.
*Confirmed cases: patients who tested positive for influenza virus in an influenza outbreak included in the study.
Asymptomatic controls: classmates of cases in an influenza outbreak included in the study who were asymptomatic (ie, without symptoms of fever, cough or sore throat) during
the period from the illness onset of the index case to the ending of the outbreak.
Pearson 2 test was used to assess differences between cases and controls in the distribution of participant characteristics.
Pearson 2 test was used to assess differences between participant characteristic groups (rows) in the percentage vaccinated.
BMI = weight (kg)/height (m)2; BMI of students were categorized into 4 levels (normal, underweight, overweight and obesity) according to the National Student Physical Health
Standard (2014).
Variables with data missing.
BMI indicates body mass index; NS, not statistically significant (P > 0.05).

TABLE 2. Percentage Vaccinated With 20142015 Trivalent Inactivated Influenza Vaccine by Cases and
Asymptomatic Controls, With Estimates of VE by Age Group and Area in School Outbreaks of Influenza in Beijing,
November 1, 2014, to December 31, 2014

Asymptomatic Adjusted for Participant Adjusted for School

Confirmed Cases* Controls Unadjusted Characteristics Only Cluster Only Fully Adjusted

Vaccinated Vaccinated
Characteristics N/Total (Row %) N/Total (Row %) VE% (95% CI) VE% (95% CI) VE% (95% CI) VE% (95% CI)

Overall 91/210 (43.3) 692/1698 (40.8) 11 (49 to 17) 18 (13 to 40) 36 (1055) 38 (1257)
Age group, yr
610 22/73 (30.1) 297/677 (43.9) 45 (767) 53 (1874) 73 (4786) NA
1115 63/113 (55.8) 303/634 (47.8) 38 (106 to 8) 11 (74 to 30) 2 (64 to 36) 3 (67 to 36)
>15 6/24 (25.0) 88/374 (23.5) 8 (181 to 58) 42 (67 to 80) 40 (67 to 79) NA
Area
Urban 64/172 (37.2) 639/1607 (39.8) 10 (24 to 35) 21 (12 to 44) 38 (1057) 38 (957)
Rural 27/38 (71.1) 53/91 (58.2) 76 (297 to 22) 26 (147 to 78) 40 (76 to 80) NA
VE was estimated by comparing the vaccination coverage in cases and controls and calculated as100 (1 odds ratio) using unconditional logistic regression and mixed effects
logistic regression model.
*Confirmed cases: patients who tested positive for influenza virus in an influenza outbreak included in the study.
Asymptomatic controls: classmates of cases in an influenza outbreak included in the study who were asymptomatic (ie, without symptoms of fever, cough or sore throat) during
the period from the illness onset of the index case to the end of the outbreak.
Adjusted for age group, sex, areas, BMI, chronic conditions and onset week by unconditional logistic regression.
Two hundred six confirmed cases and 1626 controls were included in adjusted models because 4 confirmed cases and 72 controls had missing data on variables.
Adjusted for the cluster effect (school in which influenza outbreak occurred) only by mixed effects logistic regression model.
Fully adjusted for the cluster effect (school in which influenza outbreak occurred) as well as age group, sex, areas, BMI, chronic conditions and onset week by mixed effects
logistic regression model.
BMI indicates body mass index; NA, not available because the models did not converge because of samples.

controls; 54% of cases were 1115 years old compared with 38% of Among both cases and asymptomatic controls, vaccination coverage
controls. Cases were also more likely to be from rural areas (18% vs. was highest among students 1115 years of age (cases: 56%, 63/113;
5%) and to have a chronic health condition (8% vs. 5%) (Table1). controls: 48%, 303/634) and among those in rural areas (cases: 71%,

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The Pediatric Infectious Disease Journal Volume 36, Number 3, March 2017 Influenza VE in 20142015 in Beijing Schools

27/38; controls: 58%, 53/91) (Table1). Vaccination coverage did not
differ by sex, body mass index category or chronic conditions.
VE of 20142015 IIV3
The unadjusted VE of 20142015 IIV3 against influenza ill-
ness was 11% (95% CI: 49% to 17%) for all children (Table2).
After adjusting for participant characteristics only, the VE point
estimate increased to 18%; after adjusting for school cluster only,
the VE point estimate increased to 36%. The VE fully adjusted
(using a mixed effects model) for participant characteristics, cal-
endar time and school/cluster was 38% (95% CI: 12%57%)
(Table2). This increase in VE after introducing adjustments was
reflected across age groups. However, we observed notably lower
VE point estimates among children of 1115 years of age (Table2).
VE for Combinations of 20132014
and 20142015 IIV3
After including the main effects for 20132014 IIV3 and
20142015 IIV3 in the fully adjusted model, a significant interac-
tion effect between these vaccine exposures was noted (P = 0.12),
suggesting effect modification by prior vaccination. Therefore,
we estimated VE for 3 IIV3 combinations with no IIV3 in either
year as the referent. In the fully adjusted model, the VE for receipt
of 20142015 vaccination only, 20132014 vaccination only and
vaccinations in both seasons was 54% (95% CI: 8%77%), 18%
(95% CI: 107% to 32%), and 29% (95% CI: 8% to 53%),
respectively (Table3).
DISCUSSION
As crowded places, schools provide an ideal environment
for spreading influenza, which is why the Beijing city government
began rolling out a school-located influenza vaccination program
starting in 2007. However, with the exception of a cohort study
of the effectiveness of the monovalent influenza A(H1N1)pdm09
vaccine among school-age children during the 2009 H1N1 pan-
demic,23 there have been no evaluations of influenza VE in Beijing
schools. Therefore, we took advantage of ongoing investigations
of ILI and febrile illness outbreaks in local schools to assess the
preventive benefit of IIV3. A strength of our study is its focus on
the preventive benefit of IIV3 against outbreaks of mild influenza
illness in schools, which is a key objective of school-located vacci-
nation programs and with few exceptions7,23 rarely evaluated for the
mild influenza illnesses. However, as our study design focused on
nonmedically attended influenza illness, it is unclear how our VE
estimates compare to those reported on medically attended cases.
We identified 43 school-based influenza outbreaks from
November 1, 2014, to December 31, 2014. The average vacci-
nation rate among investigated schools was 48%, which was
much higher than the IIV3 coverage of 9% observed among
ambulatory patients 317 years of age in Beijing 2 years earlier
(in 20122013).24 This is an encouraging finding and reinforces
the potential value of school-located influenza vaccination pro-
grams as a way to achieve high vaccination coverage in a rela-
tively short period of time.3
Our fully adjusted estimate of VE against influenza
A(H3N2) illness using asymptomatic controls, which took into
account variations in VE by age and other participant character-
istics, by calendar time and by any cluster effect associated with
schools, was 38%. The stepwise increase in VE we observed in
our adjusted models indicate that there were likely confounding
and substantial variations in VE by participant characteristics
and schools, and the school clustering had the largest and sta-
tistically significant effect. We could not disentangle these con-
founding and variations in our study given the limited number of
influenza cases and schools included. The null VE observed for
the strata of children 1115 years old, for example, was unex-
pected. Although others have also noted variations in VE when
smaller age strata are examined (including null VE among chil-
dren 1315 years old in Japan in 2013201425), examinations of
VE among older children are rare.
Our estimated VE of 38% against influenza predominated by
A(H3N2) influenza viruses among school children in 20142015
was higher than we expected given reports that the circulating
A(H3N2) influenza viruses in China10 (including unpublished sur-
veillance reports within Beijing) and other NH countries8,14 were
drifted from the vaccine strain and given the low or nonsignificant
VE estimates reported for 20142015 by Canada,15 the United King-
dom16 and the United States.13 However, direct comparison between
our findings and these studies is difficult because of differences in

TABLE 3. Percentage Vaccinated With 20142015 Influenza Vaccine and 20132014 Influenza Vaccine by Cases and
Healthy Controls, With Estimates of VE in School Outbreaks of Influenza in Beijing, November 1, 2014, to December
31, 2014

Confirmed Healthy Adjusted for Participant Adjusted for School

Cases* Controls Unadjusted Characteristics Only Cluster Only Fully Adjusted

Vaccinated Vaccinated
Vaccination Status N/Total (Col. %) N/Total (Col. %) VE% (95% CI) VE% (95% CI) VE% (95% CI) VE% (95% CI)

Overall 202 (100) 1624 (100)

Unvaccinated 91 (45.0) 818 (50.4)
20132014 vaccination only 23 (11.4) 148 (9.1) 40 (128 to 14) 11 (86 to 34) 25 (116 to 28) 18 (107 to 32)
20142015 vaccination only 13 (6.4) 203 (12.5) 42 (5 to 68) 53 (1275) 56 (1377) 54 (877)
Both 20142015 and 75 (37.1) 455 (28.0) 48 (105 to 7) 1 (44 to 29) 25 (13 to 50) 29 (8 to 53)
20132014 vaccinations
VE was estimated by comparing the vaccination coverage in cases and controls and calculated as 100 (1 odds ratio) using unconditional logistic regression and mixed effects
logistic regression model.
*Confirmed cases: patients who tested positive for influenza virus in an influenza outbreak included in the study.
Healthy controls: classmates of cases in an influenza outbreak included in the study who were asymptomatic (ie, without symptoms of fever, cough or sore throat) during the
period from the illness onset of the first case to the ending of the outbreak.
Adjusted for age group, sex, areas, BMI, chronic conditions and onset week by unconditional logistic regression.
Adjusted for the cluster effect (school in which influenza outbreak occurred) only by mixed effects logistic regression model.
Fully adjusted for the cluster effect (school in which influenza outbreak occurred) as well as age group, sex, areas, BMI, chronic conditions and onset week by mixed effects
logistic regression model.
BMI indicates body mass index.

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Zhang et al The Pediatric Infectious Disease Journal Volume 36, Number 3, March 2017
study design and population. These other studies applied the test-
negative design (with symptomatic influenza-negative controls vs.
our asymptomatic controls) and focused on patients in contrast to
our focus on illnesses identified in schools (of which many or most
were likely not medically attended). We also do not know the genetic
characterization of the A(H3N2) viruses infecting the students.
When a study of ambulatory patients in the US narrowed their focus
to 1 A(H3N2) genetic group (3C.3b), they observed a VE point esti-
mate of 35% among older children and adults, similar to our finding;
however, they noted null VE for another circulating group (3C.2a).26
Similar to recent studies, we found that current season VE was
not independent of prior season vaccination. Our study adds to the
small number of studies who have extended this finding to include
children,20,27 since most prior research excluded children. When we
examined VE for different combinations of current and prior vac-
cine exposure, we only observed significant VE for 20142015 IIV3
against influenza illness among children who were not vaccinated the
previous season. Similarly, Ohmit et al18 conducted assessments of
VE for ages 9 years old and older in the US for medically attended ill-
nesses in 20122013 and in households with children in 2010201119
and observed lower VE among those vaccinated in 2 consecutive sea-
sons, compared with those vaccinated in the current season only.
Most notably, Skowronski et al14 observed a similar pat-
tern of findings among patients 2 years old and older in Canada
for the same vaccine years as our study; specifically, VE against
influenza A(H3N2) among those who received the 20142015
influenza vaccine without prior vaccination in 20132014 season
(43%) was higher than that among participants vaccinated with
the same influenza A(H3N2) vaccine component in both 2013
2014 and 20142015 seasons (15%). The antigenic distance
hypothesis by Smith et al28 was presented as a possible expla-
nation since the 20132014 and 20142015 influenza A(H3N2)
vaccine components were homologous and may have interfered
with immunogenicity.
There are several study limitations. First, because of pos-
sible asymptomatic or atypical influenza virus infections,29 some
students who had been infected with influenza viruses might have
been misclassified as controls, which could result in underestima-
tion of VE. Second, our findings may not generalize beyond mild
influenza illness, since we collected respiratory specimens from
symptomatic children who were attending school or being cared for
at home and likely missed more severe manifestations of disease.
Third, although our study design was appropriate for given our
focus on nonmedically attended illness, it is unclear how our VE
estimates compare to those using the more commonly used test-
negative design in medical settings. Nonetheless, other studies of
children and adults that employed both healthy controls and influ-
enza-negative controls reported similar VE estimates using both
methods.30,31 Fourth, our evaluation focused on the initial month of
local influenza circulation; therefore, it is unclear whether similar
performance of IIV3 continued throughout the season. Fifth, we
lack data on the antibody or cell-mediated immune response of
children to IIV3; therefore, the mechanism of prior vaccination on
the study seasons VE is unclear. Sixth, certainly, unvaccinated and
vaccinated children may differ in multiple unmeasured ways (such
as hygiene habits, household income, type of dwelling, nutrition,
preventive care); so our results may be subject to residual and
unmeasured confounding.
In conclusion, this mid-season assessment of influenza VE
based on school influenza outbreaks indicated that the 20142015
IIV3 was modestly effective in protecting school-age children from
influenza A(H3N2) virus illness in Beijing. Further research is
needed to evaluate the protective benefit of annual school-located
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influenza vaccination campaigns to children and their families,
teachers and staff and the broader community.
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