A randomised controlled trial

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Influenza vaccine efficacy in young children attending childcare:
A randomised controlled trial
Jean P Li-Kim-Moy,1,2 Jiehui K Yin,1,2 Leon Heron,1,2 Julie Leask,3 Stephen B Lambert,4,5 Michael Nissen,5,6,7
Theo Sloots4,5 and Robert Booy1,2,8,9
1National Centre for Immunisation Research and Surveillance and 8Department of Microbiology and Infectious Diseases, The Children’s Hospital at
Westmead, and 2Sydney Medical School3School of Public Health and 9Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of
Sydney, Sydney, New South Wales, 4UQ Child Health Research Centre and 7Department of Health, The University of Queensland5Queensland Paediatric
Infectious Diseases Laboratory, Queensland Children’s Medical Research Institute, Children’s Health Queensland and 6Lady Cilento Children’s Hospital,
Brisbane, Queensland, Australia
Aim: Influenza causes a substantial burden in young children. Vaccine efficacy (VE) data are limited in this age group. We examined trivalent influenza vaccine (TIV) efficacy and safety in young children attending childcare.
Methods: A double-blind, randomised controlled trial in children aged 6 to <48 months was conducted with recruitment from Sydney childcare
centres in 2011. Children were randomised to receive two doses of TIV or control hepatitis A vaccine. Efficacy was evaluated against polymerase
chain reaction-confirmed influenza using parent-collected nose/throat swabs during influenza-like-illness. Safety outcomes were assessed during
6 months of follow-up.
Results: Fifty-seven children were allocated to influenza vaccine and 67 to control; all completed the study. The influenza attack rate was 1.8 vs
13.4% in the TIV and control groups, respectively; VE 87% (95%CI: 0–98%). For children aged 24 to <48 months, 0 vs 8 (18.6%) influenza infections
occurred in the TIV and control groups respectively, giving a VE of 100% (16–100%). Efficacy was not shown in children 6 to <24 months, probably
due to insufficient power. Injection site and systemic adverse events were mostly mild to moderate with no significant differences, apart from
more mild diarrhoea following dose 2 in TIV recipients (11.8 vs 0%).
Conclusions: Influenza vaccine appeared efficacious in the subgroup of children aged 24 to <48 months, although caution is required due to
the small number of participants. There were no serious adverse events and most parents would vaccinate again. Influenza vaccination in a childcare setting could be valuable and a larger confirmatory study would be helpful.
Key words: childcare; children; influenza; randomised controlled trial; vaccination.
What is already known on this topic
1 Influenza vaccination causes a large burden of disease in young
children, who have the highest rates of hospital admission compared to any other age group.
2 Influenza in preschool-aged children can have under-recognised
economic and social costs for parent carers.
3 Influenza vaccination is the most effective way at preventing
infection, but efficacy data in young children are scarce.
What this paper adds
1 Influenza vaccination showed good efficacy in this small randomised controlled trial of influenza vaccination in childcareattending young children within the subgroup aged 24 to
<48 months.
2 Parental acceptance was good and adverse events reported
were mostly mild and similar in frequency to the control group
(hepatitis A vaccine).
Correspondence: Dr Jean P Li-Kim-Moy, National Centre for Immunisation Research and Surveillance (NCIRS), The Children’s Hospital at Westmead, Locked Bag 4001, Sydney, NSW 2145, Australia. Fax: +61 29845
1418; email: jean.likimmoy@health.nsw.gov.au
Conflicts of interest: JKY received an educational grant from Sanofi Pasteur for influenza economic research in 2012. RB and LH have received
financial support from Baxter, CSL, Sanofi, GSK, Merck, Novartis, Roche,
Romark, and Wyeth/Pfizer to do research and present at scientific meetings. Any funding received is directed to research accounts at The
Children’s Hospital at Westmead and is not personally accepted by RB or
LH. SBL reports not having shares, paid employment, or consultancies
with any influenza vaccine manufacturer; he has been an investigator on
vaccine and epidemiological studies sponsored by bioCSL, Merck, GSK,
Novartis, and Sanofi; his institute has received honoraria from Merck for
talks he has given on rotavirus epidemiology and vaccines, and he has
received sponsorship from Merck for conference attendance. The other
authors declare that they have no conflict of interest.
Accepted for publication 19 June 2016.
Journal of Paediatrics and Child Health 53 (2017) 47–54
© 2016 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)
Influenza causes a substantial disease burden, especially in high-risk
populations such as young children.1,2 Globally attempts to reduce
this burden are being made through the introduction of national
universal paediatric vaccination programmes against influenza. The
United States and United Kingdom (UK) now have universal
recommendations for influenza vaccination in all children aged
from 6 months (United States) or 2 years (United Kingdom).3,4 The
WHO Strategic Advisory Group of Experts on Immunisation recommended, in a 2012 position paper, that children aged 6–59 months
be considered as a group for incorporation into seasonal vaccination
programmes in all countries.5 In Australia, recommendations for
routine trivalent influenza vaccine (TIV) administration for all children are in place in one state (Western Australian children aged
6–59 months), with only a targeted programme for high-risk children throughout the rest of the country.6,7
The body of evidence supporting the use of TIV in healthy children aged below 24 months is weaker than that in older children.
A 2012 Cochrane systematic review found insufficient evidence
to support TIV use in healthy children below 2 years of age.8
Research supporting TIV use has previously relied on immunogenicity data or efficacy/effectiveness studies with various methods
of case identification (clinical diagnosis, serology, antigen testing,
or viral culture). 9–15 More accurate estimates of vaccine efficacy
(VE)/effectiveness may now be possible with improved testing for
influenza through reverse-transcription polymerase chain reaction (RT-PCR).
In order to provide a better level of evidence for influenza VE
in childcare-attending Australian children, a pilot randomised
controlled trial (RCT) was conducted in 2007.16 Subsequently the
Paediatric Influenza Vaccine Outcome Trial (PIVOT) for 2010 was
funded by the Australian Research Council. Because the 2009
pandemic led to a one-off year when influenza vaccination was
recommended for all persons aged 6 months or above in 2010, a
RCT was not possible and a prospective cohort study design17
was used in 2010 and included collection and analysis of data on
the economic and social impacts of influenza-like illness (ILI) in
the included families.18–21 The current study, a double-blind RCT,
was conducted during the 2011 southern hemisphere influenza
season. It used hepatitis A vaccine (HAV) as the control and RTPCR to identify influenza cases. This paper reports the efficacy of
inactivated influenza vaccine against PCR-confirmed influenza
infection as well as the adverse event profile in children aged 6 to
<48 months attending childcare.
Study design
The study was registered with the Australian New Zealand Clinical Trials Registry (ANZCTR, ACTRN12610000319077), and
approved by the Human Research Ethics Committee at The Children’s Hospital at Westmead. Informed consent for participation
in the study was obtained, at the time of enrolment, from children’s parents or legal guardians.
Our primary analysis was of efficacy and safety of TIV in all
participants. A secondary analysis involved assessing efficacy
within two age groups, 6 to <24 months, and 24 to <48 months.
The study recruited children from 56 childcare centres in Sydney,
Australia starting from January 2011. Siblings of childcareattending children, who were within the appropriate age range,
were also eligible to take part in the study and were allocated to
the same vaccine. Participants were enrolled and had the first
vaccination from 9 March to 22 July 2011.
Inclusion criteria were children aged 6 to <48 months at the
time of first dose of vaccine. Exclusion criteria included:
1 Clinically significant chronic illness or immunosuppression
2 A history of allergy to egg, or any of the vaccine component
3 A history of Guillain-Barré Syndrome
4 Children who had previously received a previous priming
course of seasonal TIV (two doses in a single year), TIV in the
current season, or HAV.
5 Any child for whom influenza vaccination was specifically
recommended, or for whom it was contraindicated as listed in
the Australian Immunisation Handbook 9th Edition.22 Further
details of exclusion criteria are available in Appendix S1, Supporting Information.
We calculated a necessary sample size of 380 in each study
group to achieve a power of 80% to detect levels of VE as low as
55%, with a two-sided significance of 0.05 and assuming an
influenza attack rate of 9% in control and 4% in vaccinated
Study vaccines
Participants were randomly assigned (1:1 ratio according to a
table of random numbers generated by Microsoft Excel 2010) to
receive either two doses of unadjuvanted influenza vaccine
(VAXIGRIP® or VAXIGRIP® Junior, Sanofi Pasteur) or HAV
(VAQTA® Paediatric, Merck), 4 weeks apart (28–33 days). Children aged 6 to <36 months received 0.25 mL of VAXIGRIP® Junior per dose, and those aged 36 to <48 months, received 0.5 mL
of VAXIGRIP® per dose. The influenza vaccine contained the
recommended strains for the 2011 Southern Hemisphere TIV
(A/California/7/2009 (H1N1)-like virus, A/Perth/16/2009
(H3N2)-like virus, B/Brisbane/60/2008-like virus).
All subjects, parents and study staff were blind to vaccine allocation apart from two unblinded vaccinators who assigned vaccine to participants and conducted vaccinations. These
vaccinators were not involved with subject enrolment or assessment of outcomes. After study completion and unblinding of participants, recipients of HAV were offered a further dose of
vaccine to complete a three-dose immunisation schedule for this
vaccine, with the final dose given ≥6 months after dose 1.
Data collection
PIVOT 2011 collected information on clinical outcomes after vaccination as well as economic and psychosocial impacts after ILI in
both study arms, similar to methodology for PIVOT 2010.18–21
This paper reports the clinical outcomes, safety, and analysis of VE.
Vaccine safety assessment
Parents recorded in diary cards both solicited injection site (redness, swelling, bruising, pain) and systemic adverse events (fever
measured by axillary temperature, irritability, drowsiness, loss of
appetite, vomiting, diarrhoea) on days 0–6 after each vaccination.
48 Journal of Paediatrics and Child Health 53 (2017) 47–54
© 2016 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)
Influenza vaccine efficacy in young children attending childcare JP Li-Kim-Moy et al.
Unsolicited adverse events and serious adverse events (SAEs)
were reported for 28 days and 6 months, respectively, after each
vaccine dose. A severity grading (Appendix S1, Supporting Information) was applied to each adverse event. For our analysis, we
tabulated fever rates ≥38.0C as per Brighton Collaboration
ILI case reporting and laboratory methods
From 1 May to 15 November 2011, during which influenza activity
was detected in the local laboratory, families received a reminder
to contact the study team whenever their enrolled children developed an ILI (defined as: axillary temperature ≥37.8C or feverishness according to the carer’s judgement plus at least one of the
following respiratory symptoms: cough, rhinorrhoea, or sore
throat). With each separate ILI during the follow-up period, parents/guardians notified study staff and were directed how to collect
nose and throat swabs from their enrolled children using virus
transport swabs (Copan Italia S. p. A, Brescia, Italy). Parents mailed
the swabs to the Queensland Paediatric Infectious Diseases Laboratory, where the swabs were immediately stored at -80C until
tested. Qualitative real-time PCR was performed for Influenza A
and B and other 13 respiratory viruses.24,25 This method is well
established and short delays between swab collection and processing in the laboratory do not impact on the likelihood of identifying
any/total respiratory virus(es) from nasal swabs.26
Future influenza vaccination intentions
After the completion of the 6-month follow-up period and prior
to unblinding, parents were contacted by telephone and were
asked whether they would vaccinate their child again in the
future. Responses were classified into yes, no, or unsure. Parents
were informed of their group allocation and results of any ILI
investigations at that time.
Statistical analyses and VE
Differences between study and control vaccine recipients were
assessed using independent sample t-tests for continuous variables and Fisher’s exact test for categorical variables. Two-tailed
P values were calculated and a value 0.05 or lesser was considered significant. For VE calculations, influenza relative risk
(RR) with 95% confidence intervals (CIs) were determined using
STATA® 12 software. VE and CIs against PCR-confirmed influenza were calculated using the formula VE = (1 – RR) × 100%,
both at an individual and household level. We performed an
intention-to-treat analysis using every child vaccinated.
Fewer children than planned were enrolled to the study as a
result of recruitment difficulties, including parental concern
regarding influenza vaccine safety, and difficulties for some parents to attend study visits on work days. Exclusions included
seven children who had already received HAV, eight children
who had previously received TIV, five children with egg allergy,
and two children with definitive indications for TIV (Fig. 1). Subsequently, 124 children were enrolled (including 17 sibling pairs),
of which 115 children attended 50 separate childcare centres
(1–13 enrolled children per centre), with 9 children being siblings
who did not attend childcare. Overall 57 children (including 6 sibling pairs) were assigned to TIV and 67 (11 sibling pairs) to HAV;
age and gender were similar between groups (Table 1). All
enrolled children received two allocated vaccine doses and completed study follow-up. Approximately 70% of participants were
enrolled before the onset of influenza season. The second vaccine
dose was delayed in 23 children, 8 TIV and 15 HAV recipients
(median 41 days after dose 1, interquartile range 35–47) due to
illness or difficulties attending the clinic.
There were 56 children who experienced a total of 75 ILI
events. On 71 occasions, swabs were collected and mailed to the
testing laboratory; 37% of specimens were received between
0 and 3 days after collection, a further 51% were received
between 4 and 7 days after collection (cumulative 88%), with
the remaining 12% received 8 and 13 days after collection. There
were 11 distinct episodes of PCR-confirmed influenza (seven episodes A/H1N1, two each of A/H3N2 and influenza B) which
occurred in 10 children. Nine children with confirmed influenza
had received HAV and one had received TIV (Table 1). One child
in the HAV group had two separate influenza infections (A/H1N1
then influenza B two months later). Four children (no sibling
pairs), all in the HAV group, experienced influenza infection
between the first and second vaccinations. VE for protection
against PCR-confirmed influenza infection in all ages was 87%
(95% CI: 0–98%). Analysing by households led to slightly wider
CIs but the point estimate for VE was the same.
Within children aged 24 to <48 months, there were no influenza cases detected in TIV vaccinees, but 8 of the 43 HAV recipients (18.6%) reported at least one PCR-confirmed influenza
infection (Table 1). VE of TIV in this age group was 100% (95%
CI: 16–100%). In children aged 6 to <24 months, only two had
influenza; one in the control group, and one in the TIV group.
The RR was 0.89; VE, 11% (95%CI: -1245 to 94%). The one TIV
recipient who developed influenza (A/H3N2) was 20 months of
age at enrolment and received two doses of TIV. ILI was reported
19 days after the second dose of TIV and the subject was swabbed
the following day.
The influenza-infected participants attended seven different
childcare centres. Two centres had more than one influenza
infection; the first had two cases among four enrolled children
and a second had three cases (including one sibling pair) among
seven enrolled children.
From the 71 swabs collected during ILI episodes, 44 children
had viruses other than influenza detected by RT-PCR (18 TIV
recipients and 26 in the control group). A further five children
had swabs collected which tested negative. TIV showed no evidence of efficacy against parent-reported ILI or laboratory confirmed non-influenza infection (Table 1).
Influenza vaccination was generally well tolerated. Irritability
(33.3–46.4% of influenza vaccine recipients, dependent on dose
number) and loss of appetite (26.8–29.4%) were the commonest
systemic adverse events (Table 2). Rates of fever 38C or above
during day 0–6 post vaccination were 3.6% after the first dose
and 8.0% after the second dose. Pain (25.0–30.0%) and redness
(24.0–26.8%) were the most commonly reported injection site
reactions (Table 3). The majority of systemic and injection site
reactions were of mild or moderate severity. After dose 2, more
Journal of Paediatrics and Child Health 53 (2017) 47–54
© 2016 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)
JP Li-Kim-Moy et al. Influenza vaccine efficacy in young children attending childcare
diarrhoea occurred among TIV recipients (11.8% – including one
sibling pair) than among HAV recipients (0%, P = 0.01). No
other significant differences in patterns of adverse events were
noted between the TIV and HAV groups and no SAEs were
After 6 months of follow-up, 119 of 124 participants’ parents
were able to be contacted. Parents were surveyed prior to learning
their child’s allocation. While blinded to their allocated group, 56%
of parents of children who received influenza vaccine (n = 57)
stated that they would vaccinate their child against influenza in
future years (Table 4), and only 5% stated that they would not,
while 39% were unsure. There were no significant differences in
the pattern of responses between the TIV and HAV groups.
This study adds important evidence to the literature and suggests,
within the limitations of its small size, a high-point estimate of
Table 1 Demographics of study subjects, study group allocation overall and by household. Influenza PCR Results and calculated vaccine efficacy with
95% confidence intervals
Influenza vaccine
Hepatitis A vaccine
Vaccine efficacy (95%
confidence interval) P-value
Number of subjects Overall 57 67 — 0.42†
Households 51 56 — 0.70†
<24 months 27 24 — 0.21
≥24 months 30 43 — 0.21
Mean age in years (SD‡) 2.24 (0.97) 2.33 (1.02) — 0.63
Male 57.9% (33/57) 64.2% (43/67) — 0.58
Number of influenza-positive cases Overall 1.8% (1/57) 13.4% (9/67) 87% (0 to 98%) 0.02
Households 2.0% (1/51) 14.3% (8/56) 86% (-6 to 98%) 0.02
<24 months 3.7% (1§/27) 4.2% (1¶/24) 11% (-1245 to 94%) 1.00
≥24 months 0 (0/30) 18.6% (8††/43) 100% (16 to 100%) 0.02
Parent-reported influenza-like illness Overall 38.6% 22/57 50.7% 34/67 24 (-14 to 49%) 0.21
Laboratory confirmed virus other than
influenza A or B
Overall 31.6% 18/57 38.8% 26/67 19 (-32 to 50%) 0.45
†Binomial test. ‡Standard deviation. §Influenza A/H3N2. ¶Influenza A/H1N1. ††One child had influenza A/H1N1 followed by influenza B, one had Influenza A/H3N2 only, one had influenza B, and the other five had Influenza A/H1N1.
Recruitment from 56 childcare
Assessed for eligibility (n=146)
ed (n=124)
Excluded (n=22)
Not meeting inclusion criteria (n= 20)
Pre-existing indications for TIV (n=2)
Analysed (n=57)
Lost to follow-up (n=0)
Discontinued intervention (n=0)
Allocated to influenza vaccine (n=57, 51
Received allocated intervention (n=57)
Did not receive allocated intervention (n=0)
Lost to follow-up (n=0)
Discontinued intervention (n=0)
Allocated to hepatitis A vaccine
(n=67, 56 families)
Received allocated intervention (n=67)
Did not receive allocated intervention (n=0)
Analysed (n=67)
Fig. 1 CONSORT flow diagram.
50 Journal of Paediatrics and Child Health 53 (2017) 47–54
© 2016 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)
Influenza vaccine efficacy in young children attending childcare JP Li-Kim-Moy et al.
VE (albeit with a wide CI) for TIV preventing PCR-confirmed
influenza in childcare-attending children aged 24 to <48 months.
Of interest, there was a non-significant trend towards protection
after one dose of TIV with zero vs four infections, in TIV and
control groups, respectively, between first and second
doses (P = 0.12).
Our study had difficulty demonstrating efficacy in the youngest
children aged 6 to <24 months due to insufficient power. Given
Table 2 Solicited systemic adverse events during 7-day post vaccination period
Trivalent influenza vaccine (%) (n = 57) Hepatitis A vaccine (%) (n = 67) P-value
Fever ≥38C Dose 1 3.6 (2/55) 11.9 (8/67) 0.11
Dose 2 8.0 (4/50) 5.3 (3/57) 0.70
≥38.0–38.4C Dose 1 1.8 (1/55) 4.5 (3/67)
Dose 2 4.0 (2/50) 1.8 (1/57)
≥38.5–38.9C Dose 1 0 (0/55) 3.0 (2/67)
Dose 2 2.0 (1/50) 0 (0/57)
≥39.0-39.4C Dose 1 0 (0/55) 1.5 (1/67)
Dose 2 2.0 (1/50) 1.8 (1/57)
≥39.5C Dose 1 1.8 (1/55) 3.0 (2/67)
Dose 2 0 (0/50) 1.8 (1/57)
Irritability Any Dose 1 46.4 (26/56) 38.8 (26/67) 0.46
Dose 2 33.3 (17/51) 37.5 (21/56) 0.69
Grade 1 Dose 1 30.4 (17/56) 22.4 (15/67)
Dose 2 19.6 (10/51) 25.0 (14/56)
Grade 2 Dose 1 8.9 (5/56) 11.9 (8/67)
Dose 2 11.8 (6/51) 10.7 (6/56)
Grade 3 Dose 1 7.1 (4/56) 4.5 (3/67)
Dose 2 2.0 (1/51) 1.8 (1/56)
Drowsiness Any Dose 1 19.6 (11/56) 23.9 (16/67) 0.66
Dose 2 17.6 (9/51) 17.9 (10/56) 1.0
Grade 1 Dose 1 14.3 (8/56) 16.4 (11/67)
Dose 2 17.6 (9/51) 16.1 (9/56)
Grade 2 Dose 1 3.6 (2/56) 6.0 (4/67)
Dose 2 0 (0/51) 1.8 (1/56)
Grade 3 Dose 1 1.8 (1/56) 1.5 (1/67)
Dose 2 0 (0/51) 0 (0/56)
Loss of appetite Any Dose 1 26.8 (15/56) 29.9 (20/67) 0.84
Dose 2 29.4 (15/51) 14.3 (8/56) 0.06
Grade 1 Dose 1 19.6 (11/56) 22.4 (15/67)
Dose 2 19.6 (10/51) 12.5 (7/56)
Grade 2 Dose 1 7.1 (4/56) 6.0 (4/67)
Dose 2 7.8 (4/51) 1.8 (1/56)
Grade 3 Dose 1 0 (0/56) 1.5 (1/67)
Dose 2 2.0 (1/51) 0 (0/56)
Vomiting Any Dose 1 10.7 (6/56) 16.4 (11/67) 0.44
Dose 2 3.9 (2/51) 1.8 (1/56) 0.60
Grade 1 Dose 1 7.1 (4/56) 10.4 (7/67)
Dose 2 3.9 (2/51) 1.8 (1/56)
Grade 2 Dose 1 1.8 (1/56) 4.5 (3/67)
Dose 2 0 (0/51) 0 (0/56)
Grade 3 Dose 1 1.8 (1/56) 1.5 (1/67)
Dose 2 0 (0/51) 0 (0/56)
Diarrhoea Any Dose 1 19.6 (11/56) 10.4 (7/67) 0.20
Dose 2 11.8 (6/51) 0 (0/56) 0.01
Grade 1 Dose 1 12.5 (7/56) 7.5 (5/67)
Dose 2 9.8 (5/51) 0 (0/56)
Grade 2 Dose 1 5.4 (3/56) 3.0 (2/67)
Dose 2 2.0 (1/51) 0 (0/56)
Grade 3 Dose 1 1.8 (1/56) 0 (0/67)
Dose 2 0 (0/51) 0 (0/56)
Based on returned diary cards with valid responses. P-values calculated using Fisher’s exact test. Bold values indicate statistically significant differences
between groups.
Journal of Paediatrics and Child Health 53 (2017) 47–54
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JP Li-Kim-Moy et al. Influenza vaccine efficacy in young children attending childcare
that a 2012 Cochrane review27 on influenza vaccine use in
healthy children reported TIV/LAIV to be efficacious in children
aged 2 years or above, but found a lack of studies in the below
2 years age group to conclude that TIV was better than placebo,
it is hoped that our data will at least contribute to future metaanalyses to clarify uncertainty about VE particularly in this young
age group.
There has been growing use of the test-negative case–control
design (TND) as a method of calculating vaccine effectiveness in
prospective observational studies. A recent Western Australian
study using TND showed influenza vaccine effectiveness of
64.7% (95% CI: 33.7–81.2%) against RT-PCR confirmed influenza in children aged 6–59 months.28 The point estimate of effectiveness for the subgroup of children aged 6–23 months was also
significant at 85.8% (95% CI: 37.9–96.7%).
Results from numerous other observational studies using
laboratory-confirmed influenza appear to confirm the direct benefit of vaccinating children aged 2 years or above.29–32 However
Table 3 Solicited injection site adverse events during 7-day post vaccination period
Trivalent influenza vaccine (%) (n = 57) Hepatitis A vaccine (%) (n = 67) P-value
Redness Any Dose 1 26.8 (15/56) 38.8 (26/67) 0.18
Dose 2 24.0 (12/50) 24.6 (14/57) 1.0
<10 mm Dose 1 19.6 (11/56) 35.8 (24/67)
Dose 2 24.0 (12/50) 24.6 (14/57)
10–30 mm Dose 1 1.8 (1/56) 3.0 (2/67)
Dose 2 6.0 (3/50) 0 (0/57)
>30 mm Dose 1 0 (0/56) 0 (0/67)
Dose 2 0 (0/50) 0 (0/57)
Swelling Any Dose 1 7.1 (4/56) 17.9 (12/67) 0.11
Dose 2 16.0 (8/50) 7.0 (4/57) 0.22
<10 mm Dose 1 7.1 (3/56) 13.4 (9/67)
Dose 2 20. (10/50) 5.3 (3/57)
10 to 30 mm Dose 1 1.8 (1/56) 4.5 (3/67)
Dose 2 2.0 (1/50) 1.8 (1/57)
>30 mm Dose 1 0 (0/56) 0 (0/67)
Dose 2 2.0 (1/50) 0 (0/57)
Bruise Any Dose 1 12.5 (7/56) 17.9 (12/67) 0.46
Dose 2 6.0 (3/50) 8.8 (5/57) 0.72
<10 mm Dose 1 10.7 (6/56) 13.4 (9/67)
Dose 2 6.0 (3/50) 8.8 (5/57)
10–30 mm Dose 1 1.8 (1/56) 4.5 (3/67)
Dose 2 0 (0/50) 0 (0/57)
>30 mm Dose 1 0 (0/56) 0 (0/67)
Dose 2 0 (0/50) 0 (0/57)
Pain Any Dose 1 25.0 (14/56) 29.9 (20/67) 0.69
Dose 2 30.0 (15/50) 24.6 (14/57) 0.66
Grade 1 Dose 1 17.9 (10/56) 25.4 (17/67)
Dose 2 16.0 (8/50) 24.6 (14/57)
Grade 2 Dose 1 5.4 (3/56) 4.5 (3/67)
Dose 2 12.0 (6/50) 0 (0/57)
Grade 3 Dose 1 1.8 (1/56) 1.5 (1/67)
Dose 2 2.0 (1/50) 0 (0/57)
Based on returned diary cards with valid responses. P-values calculated using Fisher’s exact test.
Table 4 Survey results of parents’ future intentions, at study completion and prior to unblinding, regarding future vaccination
Intention to vaccinate again in the future Influenza vaccine group Hepatitis A vaccine group P-value
Yes % (n) 56.1 (32) 66.1 (41) 0.35
No % (n) 5.3 (3) 11.3 (7) 0.32
Unsure % (n) 38.6 (22) 22.6 (14) 0.07
Total % (n) 100 (57) 100 (62)
P-values calculated using Fisher’s exact test.
52 Journal of Paediatrics and Child Health 53 (2017) 47–54
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Influenza vaccine efficacy in young children attending childcare JP Li-Kim-Moy et al.
for those aged below 2 years, there have been conflicting results
with some studies showing evidence of effectiveness29,31 while
others were unable to demonstrate a protective effect.32
We found TIV to be well tolerated by young children with
adverse events experienced being predominantly mild or moderate in severity. Rates of fever after TIV were consistent with
recent observational studies and systematic reviews of fever after
inactivated influenza vaccination.33–35 No febrile seizures or SAEs
were reported. Importantly, prior to unblinding, parents of study
participants found vaccination to be acceptable with more than
half of the TIV group stating that they would vaccinate their children in future years and only 5% saying they would not; the
caveat being that parents of study recruits had a possible bias
towards acceptance of vaccination. For influenza vaccination to
be accepted by parents of preschool-aged children, perceptions
that influenza vaccines are safe, well tolerated and effective are
important considerations.36,37
It is clear from the previous studies that influenza contributes
to a significant burden of disease in young children in the childcare setting. An Australian study showed that a case of community managed influenza infection in preschool-aged children had
a mean cost of $904 (2003 AUD)38, and caused an average of
one medically attended visit per illness.39 In addition, the 2010
PIVOT cohort study found that an average of 13 hours of work
were lost by carers of sick preschool-aged children per ILI18 and
that ILI in children resulted in a significant negative impact on
the quality of life in parents due to disruptions of normal life routine, social isolation and stress coping with the sick child.20,21
Costs were similar regardless of whether infections were due to
influenza or other respiratory viruses.18 In light of these factors
and the suggestion of valuable point estimate of VE in children
24 to <48 months of age, the medical and socioeconomic benefits
of vaccinating preschool children against influenza warrant further investigation.
Limitations of this study relate primarily to its lack of power.
While TIV appeared efficacious in children aged 24 to
<48 months, our point estimates had wide CIs. The study did not
have sufficient power to assess the benefit of vaccinating the
youngest children in our study, aged 6 to <24 months, who are
at higher risk of hospitalisation than older children.1 The inclusion of siblings in the same study group may have affected
VE. Multiple TIV-vaccinated children in a household could further decrease the likelihood of influenza infection and increase
the calculated VE point estimate. The finding of an unchanged
VE when analysing by household, however, makes this effect less
likely in our study population. While parents were instructed to
notify the clinical team and collect a swab with any ILI, there
may have been other episodes which were not notified, and
which could have had an effect on overall VE estimates.
The overlap of recruitment with the onset of the influenza season and the delay giving some second vaccine doses may have
meant that a few children had influenza exposure prior to enrolment or development of immunity. The effect of this on the estimate of efficacy was likely to be minor as both groups were
equally affected and, in addition, no TIV recipients developed
influenza between doses 1 and 2. Delay in vaccination is likely to
be an issue in any population-based delivery of a funded childhood influenza immunisation programme delivered just prior to
influenza season.
In summary, within the limitations of a small RCT, we were
able show efficacy of inactivated influenza VE in children aged
24 to <48 months but not in children aged 6 to <24 months.
While cautious interpretation due to limited power is required,
our data can add to other studies used in meta-analyses to better
understand the issue of efficacy of influenza vaccination in young
children. It is clear that young children suffer a high burden of
influenza with high rates of hospitalisation, in addition to poorly
recognised social and economic costs. Our results, if confirmed in
larger studies or meta-analysis, would support influenza vaccination of preschool-aged children as an effective intervention to
address this burden, with reasonably good parental acceptance.
This and future studies of VE/effectiveness in young children will
inform policy making and provide evidence for decisions around
universal paediatric influenza vaccination in Australia.
This study is funded by the Australian Research Council (Linkage
Project Scheme LP0884126 with the Kindergarten Union Children’s Services as partner); Sanofi Pasteur provided the influenza
vaccines and additional funding but had no role in data analysis
or preparation of the manuscript. The authors thank the participants and their parents, Australian Research Council, Sanofi Pasteur, KU Children’s Services (Sydney), Catherine King, and other
persons who assisted in undertaking this study.
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Supporting information
Additional supporting information may be found in the online
version of this article at the publisher’s web-site:
Appendix S1. Exclusion criteria.
54 Journal of Paediatrics and Child Health 53 (2017) 47–54
© 2016 Paediatrics and Child Health Division (The Royal Australasian College of Physicians)
Influenza vaccine efficacy in young children attending childcare JP Li-Kim-Moy et al.

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