Research

JAMA Pediatrics | Original Investigation

Evaluation of Combination Measles-Mumps-Rubella-Varicella

Vaccine Introduction in Australia
Kristine Macartney, MD; Heather F. Gidding, PhD; Lieu Trinh, PhD; Han Wang, MStats; Aditi Dey, PhD;
Brynley Hull, MPH; Karen Orr, RN; Jocelynne McRae, MPH; Peter Richmond, MBBS; Michael Gold, MB, CHB;
Nigel Crawford, PhD; Jennifer A. Kynaston, MBBS; Peter McIntyre, PhD; Nicholas Wood, PhD;
for the Paediatric Active Enhanced Disease Surveillance Network

Editorial page 944

IMPORTANCE Incorporating combination vaccines, such as the measles-mumps-rubella-
varicella (MMRV) vaccine, into immunization schedules should be evaluated from a
benefit-risk perspective. Use of MMRV vaccine poses challenges due to a recognized
increased risk of febrile seizures (FSs) when used as the first dose in the second year of life.
Conversely, completion by age 2 years of measles, mumps, rubella, and varicella
immunization may offer improved disease control.

OBJECTIVE To evaluate the effect on safety and coverage of earlier (age 18 months)
scheduling of MMRV vaccine as the second dose of measles-containing vaccine (MCV) in
Australia.

DESIGN, SETTING, AND PARTICIPANTS Prospective active sentinel safety surveillance

comparing the relative incidence (RI) of FSs in toddlers given MMRV and measles-mumps-
rubella (MMR) and a national cohort study of vaccine coverage rates and timeliness before
and after MMRV vaccine introduction were conducted. All Australian children aged 11 to
72 months were included in the coverage analysis, and 1471 Australian children aged 11 to
59 months were included in the FS analysis, with a focus on those aged 11 to 23 months.

MAIN OUTCOMES AND MEASURES MMRV vaccine safety, specifically, the RI of FSs after MMRV
vaccine at age 18 months, compared with risk following MMR vaccine and vaccine uptake for
2-dose MCV and single-dose varicella vaccine, focusing on timeliness.

RESULTS Of the 1471 children, the median age at first FS was 21 months (interquartile range
[IQR], 14-31 months). Three hundred ninety-one children were aged 11 to 23 months and had
at least 1 FS included in the analysis; of these, 207 (52.9%) were male. A total of 278 children
(71.1%) had received MMR followed by MMRV vaccine, 97 (24.8%) had received MMR vaccine
only, and 16 (4.1%) had received neither vaccine. There was no increased risk of FSs (RI, 1.08;
95% CI, 0.55-2.13) in the 5 to 12 days following MMRV vaccine given as the second MCV to
toddlers. Febrile seizures occurred after dose 1 of MMR vaccine at a known low increased risk
(RI, 2.71; 95% CI, 1.71- 4.29). Following program implementation, 2-dose MCV coverage at age
36 months exceeded that obtained at age 60 months in historical cohorts recommended to
receive MMR vaccine before school entry, and on-time vaccination increased by 13.5% (from
58.9% to 72.4%). Despite no change in the scheduled age of varicella vaccine, use of MMRV
vaccine was associated with a 4.0% increase in 1-dose varicella vaccine coverage.
Author Affiliations: Author
CONCLUSIONS AND RELEVANCE To our knowledge, this is the first study to provide evidence affiliations are listed at the end of this
article.
of the absence of an association between use of MMRV vaccine as the second dose of MCV
Group Information: Members of the
in toddlers and an increased risk of FSs. Incorporation of MMRV vaccine has facilitated
Paediatric Active Enhanced Disease
improvements in vaccine coverage that will potentially improve disease control. Surveillance Network are listed at the
end of this article.
Corresponding Author: Kristine
Macartney, MD, National Centre for
Immunisation Research and
Surveillance, The Children's Hospital
at Westmead, Locked Bag 4001,
Westmead, NSW 2145, Australia
JAMA Pediatr. 2017;171(10):992-998. doi:10.1001/jamapediatrics.2017.1965 (kristine.macartney@health.nsw
Published online August 14, 2017. .gov.au)

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 Evaluation of Measles-Mumps-Rubella-Varicella Vaccine in Australia
S
ome parents and health care workers are finding deci-
sion making regarding immunization increasingly com-
plex, presenting a barrier to timely vaccine uptake.1,2 A
commonly reported concern is the number of injections given
to children.1,2 Combination vaccines reduce the number of in-
jections needed and may improve vaccine acceptance, cover-
age, and, ultimately, disease control. However, various other
factors surrounding use of combination vaccines, including
cost-effectiveness, safety, availability, and country- or re-
gion- specific disease epidemiology, require consideration.3 In
the past decade, several countries have faced challenges in in-
corporating the combination measles-mumps-rubella-
varicella (MMRV) vaccine into their immunization sched-
ules. Although both available MMRV vaccines (Priorix-Tetra
[GlaxoSmithKline Biologicals SA] and ProQuad [Merck & Co
Inc]) offer the advantage of a single injection against 4 dis-
eases, prelicensure studies showed an increased risk of fever
in first-dose recipients aged 12 to 23 months compared with
children who received measles-mumps-rubella (MMR) and
varicella vaccines separately.4,5 This reaction was presumed
to be related to potentiation of the immune response to the
measles virus component. Postlicensure studies subse-
quently reported an approximately 2-fold increased risk of
febrile seizures (FSs) following MMRV compared with giving
separate MMR and varicella vaccines.6,7 This finding prompted
a withdrawal of a preferential recommendation for use of
MMRV as the first measles-containing vaccine (MCV) in the
United States and Germany.8,9
Before July 2013, MMRV vaccine was not used in Austra-
lia. Two doses of MMR vaccine were scheduled on the Na-
tional Immunisation Program (NIP) and spaced 3 years apart
at ages 12 months and 4 years, similar to the US and UK sched-
ules. However, data from the national Australian Childhood
Immunisation Register (ACIR) in 2012 showed that vaccine up-
take was suboptimal; approximately 92% of children had re-
ceived 2 MCVs by age 5 years,10 and modeling demonstrated
an increased risk of measles outbreaks associated with low
2-dose immunity in younger children. Disease outbreaks aris-
ing from measles importations11,12 demonstrated the need to
improve 2-dose coverage at all ages, but especially in the young.
A single dose of monovalent varicella vaccine had been sched-
uled under NIP at age 18 months since November 2005,13 but
coverage by age 2 years was only 86%, although it increased
to 92% by 5 years. Declines in varicella-related morbidity and
mortality had occurred,14-17 but modeling18 suggested that
improved 1-dose coverage was needed to decrease the risk of
shifting disease to older age groups where higher disease se-
verity occurs.
To address these challenges, the decision was made to in-
clude MMRV vaccine on the Australian NIP at age 18 months
as the second MCV dose from July 2013 onward, as reported
in Table 1. The risk-benefit assessment that underpinned this
change was based on 2 hypotheses: (1) higher and earlier popu-
lation-level vaccine coverage of 2 doses of MCV and 1 dose of
varicella vaccine would be achieved by bringing forward the
scheduled age for the second MCV dose to 18 months and re-
placing MMR with MMRV vaccine, and (2) when used as the
second instead of the first dose of MCV, MMRV vaccine would
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Original Investigation Research
Key Points
Question What is the effect of introduction of combination
measles-mumps-rubella-varicella vaccine at age 18 months as the
second dose of measles-containing vaccine on vaccine coverage
and risk of vaccine-associated febrile seizures in Australia?
Findings A national cohort study of vaccine coverage before and
after measles-mumps-rubella-varicella vaccine introduction
showed improvement in uptake and timeliness for all 4 vaccine
components. Despite the peak incidence of all-cause febrile
seizures occurring at age 18 months and a known increased risk
of febrile seizures following the first dose, in a self-controlled case
series analysis including 1471 children, use of measles-mumps-
rubella-varicella vaccine at 18 months was not associated with
an increased risk of febrile seizures.
Meaning Measles-mumps-rubella-varicella combination vaccine
was safely incorporated into the Australian National Immunisation
Program schedule and improved population-level protection
against these serious viral diseases.
not be associated with an increased risk of FSs, even though
it would be provided to children aged 18 months, when the in-
cidence of FSs peaks. The vaccine safety and evaluation plan
for MMRV vaccine introduction included active, prospective
sentinel FS surveillance using the Paediatric Active En-
hanced Disease Surveillance (PAEDS) network19,20 and analy-
sis of vaccine uptake using the ACIR. We aim to present the
findings of this evaluation, examining the effect of the pro-
gram change on (1) vaccine safety, specifically, the risk of
MCV-associated FS and (2) vaccine uptake and timeliness.
Methods
Febrile Seizure Risk Associated With Measles-
and Varicella-Containing Vaccine Exposure
Data Sources
Active, prospective sentinel FS surveillance was conducted
from May 1, 2013 (2 months before MMRV vaccine introduc-
tion), to June 30, 2014, by the PAEDS Network at 5 Australian
tertiary pediatric hospitals, as previously described.19,21 At each
site, emergency department and inpatient databases were
scanned daily by PAEDS surveillance nurses to ascertain pos-
sible FS presentations in all children younger than 5 years. Pe-
riodic review of all International Statistical Classification of
Diseases and Related Health Problems, Tenth Revision, Austra-
lian Modification–coded FS encounters (code R56.0) was also
conducted to capture additional cases. Clinical and demo-
graphic data were collected from the medical records and care-
giver interviews, and all FS diagnoses were confirmed. All chil-
dren had immunization records obtained from the ACIR, both
at FS presentation and at study end (to identify all vaccine
exposures).
Study Population and Exclusion Criteria
In Australia, the timing of vaccine administration is highly as-
sociated with NIP-recommended schedule points. There-
fore, our analysis cohort was restricted to children who were
(Reprinted) JAMA Pediatrics October 2017 Volume 171, Number 10 993
 Research Original Investigation
Table 1. Australian NIP Schedule Before and After Introduction of MMRV
From July 1, 2013
Age Before July 1, 2013 After July 1, 2013
12 mo MMR MMR
18 mo Monovalent varicellaa MMRVb
48 mo MMRb NA
Abbreviations: MMR, measles-mumps-rubella; MMRV, measles-mumps-rubella-
varicella; NA, not applicable; NIP, National Immunisation Program.
a
This vaccine was no longer routinely available under NIP after July 1, 2013.
b
To be eligible to receive the free MMRV vaccine from July 1, 2013, a child must
be aged 18 months, have received their 12-month MMR vaccine at least 4
weeks before presentation, and not have received their 18-month monovalent
varicella vaccination, as per the previous NIP schedule. The vaccine used
during the study was Priorix-Tetra.
aged 11 to 23 months. Analysis was further restricted to in-
clude only children who had (1) 1 dose of MMR vaccine fol-
lowed by 1 dose of MMRV vaccine at least 27 days later (con-
sistent with NIP recommendations), (2) 1 dose of MMR vaccine
(as some had not yet received MMRV vaccine), or (3) no MMR
or MMRV vaccine (unvaccinated children, who contribute to
the age-specific relative incidence [RI]).22 Children who re-
ceived MMRV vaccine as their first MCV were excluded be-
cause this schedule was not consistent with NIP recommen-
dations and occurred rarely.
Study Outcomes
The main study outcome was the RI of FS in the 5 to 12 days
after the first and second MCV doses compared with nonrisk
periods (baseline) within the same person. An additional risk
period of 13 to 30 days after each MCV was also included to
identify any longer-term risk.
Statistical Analysis
Relative incidences were calculated using the self-controlled
case series (SCCS) method of analysis.3,4 The SCCS method re-
quires FS cases only and compares the FS rate during biologi-
cally plausible, predetermined risk periods with nonrisk pe-
riods (baseline) within the same person using conditional
Poisson regression models; thus, all fixed confounders (eg, sex)
are automatically adjusted for.22 Because age is a strong pre-
dictor of FS and is time varying, all models were adjusted for
the effect of age (using 3 age groups in the base case: 11-14, 15-
18, and 19-23 months). We removed the −1- to −13-day period
before vaccination from the baseline time because it may be
associated with a lower FS risk (an FS occurrence may delay
receipt of scheduled vaccines).19,22
The primary analysis included children who had both first
and subsequent FS episodes (considered unique episodes), in
which the subsequent FS was separated by at least 7 days from
a previous episode.3,5 Two sensitivity analyses were con-
ducted: (1) adjustment for age using finer intervals (1-month age
groups) and (2) restriction of the analysis to first FS episodes.
Measles- and Varicella-Containing Vaccine Uptake
Data Sources
The ACIR is a nearly complete electronic population register.
It includes approximately 99% of all children registered with
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Evaluation of Measles-Mumps-Rubella-Varicella Vaccine in Australia
the national public health insurance scheme, Medicare, that
covers all citizens, permanent residents, and select visa hold-
ers. During the study period, the ACIR recorded receipt of all
vaccines provided up to age 7 years.23 Doses recorded on the
ACIR (renamed the Australian Immunisation Register [AIR]
from November 2016 and including all aged persons) are linked
to financial incentives for families and health care profession-
als, providing a basis for complete reporting.7,24
Study Population and Outcome
The study outcome was immunization coverage of consecu-
tive, 3-month national cohorts of children born between Janu-
ary 1, 2009, and December 31, 2012, who had reached the ages
of 24, 36, 48, and 72 months, respectively, for receipt of MMR,
varicella, and/or MMRV vaccine by December 2015 (Table 1).
Statistical Analysis
Coverage estimates for receipt of a second MCV dose and single
varicella vaccine dose, either on time (within 30 days of the
recommended age) or at scheduled assessments dates, were
compared between the pre-MMRV and post-MMRV periods.
Data were analyzed in SAS, version 9.3 (SAS Institute Inc); Stata,
version 12 (StataCorp); and Excel 2007 (Microsoft Corp).
Ethical Approval
Each PAEDS hospital obtained ethical approval to conduct
the FS safety study: Sydney Children’s Hospital Network
Human Research Ethics Committee; Princess Margaret Hos-
pital Human Research Ethics Committee; Women’s and
Children’s Hospital Network Human Research Ethics Com-
mittee; QLD Children’s Health Services (Royal Children’s
Hospital) Human Research Ethics Committee; and the Royal
Children’s Hospital Human Research Ethics Committee
(Melbourne). Specific ethics approval was not required for
vaccine coverage analysis, as we conducted our study using
deidentified ACIR data supplied by the Australian Govern-
ment Department of Human Services for the purposes of
program evaluation.
Results
Risk of FSs Following MMRV and MMR Vaccines
During the study analysis period, 1668 unique FS episodes were
identified in 1471 children younger than 5 years. Of these chil-
dren, 1335 (90.8%) had only 1 episode and 136 (9.2%) had 2 or
more episodes separated by at least 7 days. The median age at
the time of the first FS was 21 months (interquartile range [IQR],
14-31 months), similar to the median age at receipt of MMRV
vaccine of 18 months (IQR, 18-19 months) and the peak age at
FSs shown previously.19 After restriction to age 11 to 23 months
and the recommended vaccine sequence, there were 465 FS
episodes in 391 children. Ten children with 12 FSs (10 of 401
cases [2.4%]) were excluded because the recommended sched-
ule was not followed (only 4 had MMRV as dose 1, which was
an insufficient sample to analyze FS risk). Of the 391 children
included, 278 (71.1%) had received MMR followed by MMRV
vaccine, 97 (24.8%) had received MMR vaccine only, and
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 Evaluation of Measles-Mumps-Rubella-Varicella Vaccine in Australia Original Investigation Research

16 (4.1%) had received neither vaccine. Further data are pro-
vided in Table 2.
Table 3 provides the results of the primary and sensitiv-
ity self-controlled case series analyses. In the primary analy-
sis, which adjusted for age using 3 age groups, there was no
significantly increased risk of FSs within the 5- to 12-day risk
period following MMRV, the prevaccination period, or the 13-
to 30-day postvaccination period. The RI of FSs was raised in
the 5 to 12 days following MMR vaccine (MCV dose 1) (RI, 2.71;
95% CI, 1.71-4.29), and there was a significantly lower risk in
the 2 weeks before vaccination. The results of the sensitivity
analyses were similar to those of the primary analyses.

Table 2. Characteristics of Febrile Seizures in 391 Children Changes in Measles- and Varicella-Containing
Aged 11 to 23 Months in SCCS Analysis Vaccine Uptake
As reported in Table 4, within 2.5 years following MMRV intro-
Febrile Seizure
duction, 2-dose MCV coverage increased to 93.8% at age 36
Characteristic First Episode Unique Episodes
Febrile seizures, No. 391 465
months, which exceeded the most recent preprogram histori-
cal coverage level of 92% at age 60 months (1 year after the pre-
Male, No. (%) 207 (52.9) 249 (53.5)
vious age 48-month schedule point). Coverage with varicella-
No MCV, No. (%) 16 (4.1) 22 (4.7)
containing vaccine, consistently recommended at 18 months and
MMR during risk period,
No. (%)a assessed at age 24 months, increased by 4% after the change
Yes 23 (6.1) 24 (5.4) (Table 4). Overall, on-time immunization with the second MCV
No 352 (93.9) 419 (94.6) (defined as vaccine receipt within 30 days of the recom-
MMRV during risk period, mended age) improved by 13.5% (from 58.9% to 72.4%) (Figure).
No. (%)a,b During this time, there was virtually no change in the coverage
Yes 7 (2.5) 9 (2.7) of MMR dose 1 (recommended at age 12 months and measured
No 271 (97.5) 319 (97.3) at age 18 months), which increased by only 0.5% (Table 4).
Abbreviations: MCV, measles-containing vaccine; MMR, measles-mumps-
rubella; MMRV, measles-mumps-rubella-varicella; SCCS, self-controlled case
series.
a
Vaccinated between 5 and 12 days before febrile seizure; percentage denotes Discussion
total children receiving each vaccine.
b We present a comprehensive evaluation of the effect of 2
Includes only children who received a previous MMR vaccine.
simultaneous changes to the Australian NIP that are relevant

Table 3. FS Risk Following Dose 1 of MMR and a Subsequent Dose of MMRV in Young Children
RI RI RI
Method for −1 to −13 d 5 to 12 d 13 to 30 d
Analysis Age Control FS Episode Vaccine (95% CI) P Value (95% CI) P Value (95% CI) P Value
Primary 11-14, Uniquea MMR 0.41 (0.18-0.94) .04 2.71 (1.71-4.29) <.001 0.89 (0.54-1.48) .66
15-18,
and 19-23 mo Uniquea MMRV 1.26 (0.77-2.07) .36 1.08 (0.55-2.13) .82 1.08 (0.67-1.74) .74
a
Secondary 1-mo intervals Unique MMR 0.42 (0.18-0.97) .04 2.57 (1.56-4.23) <.001 0.83 (0.49-1.40) .48
Uniquea MMRV 1.25 (0.74-2.14) .40 1.17 (0.57-2.40) .67 1.10 (0.66-1.83) .72
Secondary 11-14, First MMR 0.37 (0.15-0.92) .03 2.85 (1.78-4.56) <.001 0.82 (0.47-1.43) .48
15-18,
and 19-23 mo First MMRV 1.37 (0.81-2.33) .24 1.06 (0.49-2.27) .89 1.21 (0.73-2.01) .73
a
Abbreviations: FS, febrile seizure; MMR, measles-mumps-rubella; MMRV, First FS episode or multiple FS episodes, with the episodes separated by at
measles-mumps-rubella-varicella; RI, relative incidence. least 7 days.

Table 4. One-Dose Varicella Vaccine and 2-Dose MCV Coverage Assessed at Ages Before and After MMRV Vaccine Introduction10

Vaccine Antigen and Age Assessed

Varicella MMR or MMRV
Timing 24 moa 36 moa 60 moa 12 mob 24 moc 36 moc 60 moc 72 moc
Before MMRV vaccine 85.9d 89.3e 91.2f 91.9 NA NA 92.0f 93.7g
introduction
After MMRV vaccine 89.9h 93.3h NC 92.4 89.8h 93.8h NC NC
introduction
Abbreviations: MCV, measles-containing vaccine; MMR, measles-mumps- vaccine after program change.
rubella; MMRV, measles-mumps-rubella-varicella; NA, not applicable; NC, not d
Cohort born January 1 to June 30, 2011.
calculated (due to cohort not yet reaching this age). e
Cohort born January 1 to June 30, 2010.
a
Only dose, provided as monovalent varicella vaccine before program change f
Cohort born January 1 to June 30, 2009.
and as MMRV vaccine after program change.
g
b Cohort born January 1 to June 30, 2008.
First dose provided as MMR vaccine at age 12 months throughout the study
h
period and assessed at age 18 months for all cohorts combined. Cohort born July 1 to December 3, 2012.
c
The second dose of MCV was MMR vaccine before program change and MMRV

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 Research Original Investigation
Figure. Proportion of Children With On-Time Vaccination for Dose 2
of Measles-Containing Vaccine Before and After Measles-Mumps-
Rubella-Varicella (MMRV) Vaccine Introduction
A MMR2 after MMRV B MMR2 before MMRV
100
90
80
Cumulative Vaccination, %
Cumulative Vaccination, %
70
On-time
60 vaccination
50
40
30
20
10
0 0
12 <12
18 <18
19 <19
20 <20
24 <24
<3
>3
to
to
to
to
to
Age at MMR2 Dose, mo
On-time vaccination was defined as vaccine receipt within 30 days of the
recommended age. MMR indicates measles-mumps-rubella; MMR2, dose 2 of
MMR-containing vaccine in cohort born between July 1 and December 31, 2012
(A) and cohort born between January 1 and June 30, 2009 (B).
to child immunization programs worldwide: introduction of
combination MMRV vaccine and bringing forward the sched-
uled age for provision of the second MCV. Our evaluation dem-
onstrates that MMRV vaccine introduction in Australia has been
associated with improved coverage and timeliness of protec-
tion against all 4 diseases, with on-time vaccination increas-
ing by 13.5%. This change has been done with no effect on the
overall safety profile of the program; use of MMRV vaccine as
dose 2 of MCV at the age of 18 months was not associated with
an increased risk of FSs.
Global efforts to control measles rely on achieving and
maintaining high 2-dose vaccine coverage (preferably >95%)
at a country and subnational (district) level.25 Australia was
1 of the first 4 countries in the World Health Organization West-
ern Pacific Region to reach measles elimination status, de-
clared in March 2014.12 However, before 2014 and despite an
overall reduction in the incidence of measles, notification rates
were highest in infants and children aged 1 to 4 years, out-
breaks often involved young children, and measles vaccine cov-
erage for 1 and 2 vaccine doses was suboptimal at 92%
nationally.11 This figure also masked small areas of lower cov-
erage and lack of timely uptake.26 Within 2.5 years of imple-
menting our compressed schedule at ages 12 and 18 months,
we have demonstrated that more children were fully pro-
tected against measles at an earlier age. In the United States,
which has recently experienced a resurgence of measles,25 MCV
dose 2 is recommended at ages 4 to 6 years, and uptake of dose
1 at age 12 months could be more timely. The 2014 US Na-
tional Immunization Survey estimated that 92% of children
aged 19 to 35 months had received 1 dose of MMR vaccine
(range, 84%-97%).27
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Evaluation of Measles-Mumps-Rubella-Varicella Vaccine in Australia
Each country needs to assess its own unique disease epi-
demiology, immunization program characteristics, and barri-
ers to vaccine uptake to determine the optimal timing of MCV
doses. However, for children in whom vaccination is delayed
whether due to missed opportunities, access issues, or vac-
100 cine hesitancy, earlier scheduled measles vaccination offers
90 more opportunities to provide catch-up vaccination, particu-
80
larly before school entry. One potential downside of earlier sec-
ond-dose vaccination is the potential for waning immunity.
70
Modeling the effect of this schedule change on population im-
60
munity to measles in Australia was sensitive to assumptions
On-time
50
vaccination regarding the extent of waning of vaccine-derived immunity.28
40 Waning immunity may also be an issue for the less-
30 efficacious mumps component of the vaccine; ongoing dis-
20 ease surveillance will be important to monitor for this poten-
10
tial outcome and, if needed, adjust policy recommendations
accordingly. However, several European countries, Canadian
provinces, and low- to middle-income countries under the
36 <36
42 <42
48 <48
49 <49
50 <50
0
<6
>6
Expanded Program on Immunization use a similarly com-
to
to
to
to
to
pressed MCV schedule.
Age at MMR2 Dose, mo
Australia has had a 1-dose varicella vaccination program
for children aged 18 months since late 2005.13,16 We show that
MMRV introduction has rapidly been associated with improve-
ments in the absolute level and timeliness of coverage against
varicella over that achieved with the single-antigen vaccine.
While our study design cannot confirm a direct cause-and-
effect relationship, reasons for this increase in coverage may
include (1) reduced prior attendance at the 18-month sched-
ule point due to parental (and clinician) perceptions of vari-
cella as a mild disease for which an appointment for the im-
munization was not considered sufficiently important (no other
vaccine was recommended at this schedule point between
2003 and 2016); (2) increased encouragement for children to
attend the 18-month immunization visit due to the inclusion
of other antigens, particularly measles, in the vaccine; and/or
(3) reduction of the overall number of scheduled injections,
which was appealing to caregivers and clinicians. Although a
routine 2-dose varicella immunization schedule, as adopted
in the United States in 2007, would offer improved protec-
tion against varicella, the addition of a second varicella dose
was previously rejected for NIP inclusion in Australia on the
basis of inadequate incremental cost-effectiveness.16
To our knowledge, this study is the first to demonstrate
that administration of MMRV vaccine as dose 2 of the MCV at
age 18 months is not associated with an increased risk of FSs
despite peak FS incidence at this age.29 A US assessment
showed no increased FS risk when MMRV dose 2 was given at
age 4 to 6 years30; however, overall FS incidence is much lower
in that age group. These results are also consistent with those
of the previous PAEDS study showing no increased risk of FSs
after monovalent varicella vaccine at age 18 months and con-
firming the well-described fold increase in FSs after MCV dose
1.19,29 Six postmarketing studies6,7,31-34 and a meta-analysis35
have consistently shown a 2-fold increase in FS risk in the risk
window of approximately 5 to 12 days after MMRV dose 1 in
toddlers compared with giving MMR or MMR and the vari-
cella vaccine separately. Although this finding equates to a rela-
tively low absolute excess of 4.3 FSs per 10 000 doses,7 even
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 Evaluation of Measles-Mumps-Rubella-Varicella Vaccine in Australia Original Investigation Research

a low risk has been viewed as concerning. In Australia, an un-
expected high rate of FSs occurred from 1 seasonal influenza
vaccine brand (Fluvax [Afluria in the United States]) in chil-
dren younger than 5 years in 2010. Although most FS cases re-
solved without sequelae, permanent neurologic damage oc-
curred in 2 children.36,37 In the United States, primary care
clinicians are reported as being unlikely to recommend
MMRV,38 and in Germany, there has been a decline in vari-
cella vaccination uptake.9
Limitations and Strengths
This study has a number of limitations and strengths. Al-
though we showed no statistically significant association be-
tween FSs and MMRV vaccine, the point estimate was above
1 and CIs were wide (RI, 1.08; 95% CI, 0.55-2.13), thereby not
excluding a very low level of risk. In addition, FS case capture
was taken from sentinel pediatric hospital surveillance and may
not be representative of all Australian children with FSs. How-
ever, each site also functions as a community-based hospital,
most children resided nearby and had simple FSs, and our
analysis was robust in demonstrating the known association
with MCV dose 1. Our ecologic cohort design to assess vac-
cine coverage changes is subject to unrecognized biases or con-
founding factors and does not prove that the schedule change
was the necessary or only causative factor in improving vac-
cine uptake. However, no other major programmatic or pro-
cedural changes occurred during the study period that would
otherwise have increased coverage, and, notably, MCV dose
1 uptake did not change substantially over time. In Australia,
all NIP vaccines are commonwealth government procured, and
our 8 state and territory health departments undertake over-
sight program delivery, resulting in more prescriptive use of
vaccine combinations and brands than in other countries where
vaccine choice is influenced by individual immunization cli-
nicians or insurers. Together with our comprehensive na-
tional vaccine register, this control enables accurate evalua-
tion of changes in coverage in response to new vaccine
introduction. Although our study primarily reports on 1 brand
of MMRV vaccine (Priorix-Tetra), based on first principles, we
believe that these results would likely be similar for the other
registered MMRV vaccine (ProQuad).
Conclusions
Data from this study help clinicians to better understand
the link between measles and varicella virus–containing live
vaccines and the risk of FSs—a common but serious early
childhood condition that occurs in response to fever from
any source. We present a comprehensive evaluation of the
incorporation of MMRV vaccine into the Australian NIP,
demonstrating an association with improved vaccine uptake
and timeliness while maintaining overall program safety.
Our findings should help to inform childhood immunization
policy decision making regarding use of these vaccines in
other countries.

ARTICLE INFORMATION
Accepted for Publication: May 10, 2017.
Published Online: August 14, 2017.
doi:10.1001/jamapediatrics.2017.1965
Author Affiliations: National Centre for
Immunisation Research and Surveillance, Sydney,
Australia (Macartney, Gidding, Wang, Dey, Hull, Orr,
McRae, McIntyre, Wood); School of Child and
Adolescent Health, University of Sydney, Sydney,
Australia (Macartney, Dey, McIntyre, Wood);
The Children’s Hospital at Westmead, Westmead,
Australia (Macartney, Orr, McRae, McIntyre, Wood);
School of Public Health and Community Medicine,
UNSW Medicine, The University of New South
Wales, Sydney, Australia (Gidding); Western Sydney
Local Health District, Sydney, Australia (Trinh);
School of Paediatrics and Child Health, University
of Western Australia, Perth, Australia (Richmond);
Wesfarmers Centre for Vaccines and Infectious
Diseases, Telethon Kids Institute, University of
Western Australia, Perth, Australia (Richmond);
Department of Paediatrics, University of Adelaide,
Adelaide, Australia (Gold); Women’s and Children’s
Hospital, Adelaide, Australia (Gold); Royal Children’s
Hospital, Melbourne, Australia (Crawford);
University of Melbourne, Melbourne, Australia
(Crawford); Lady Cilento Children’s Hospital,
Brisbane, Australia (Kynaston).
Author Contributions: Drs Macartney and Wood
had full access to all of the data in the study and
take responsibility for the integrity of the data and
the accuracy of the data analysis.
Study concept and design: Macartney, Gidding, Dey,
Richmond, Gold, Crawford, McIntyre, Wood.
Acquisition, analysis, or interpretation of data:
Macartney, Gidding, Trinh, Wang, Dey, Hull, Orr,
McRae, Richmond, Crawford, Kynaston, McIntyre.
Drafting of the manuscript: Macartney, Gidding,
Trinh, Dey, Richmond, Gold, McIntyre.
Critical revision of the manuscript for important
intellectual content: Macartney, Gidding, Wang, Dey,
Hull, Orr, McRae, Richmond, Crawford, Kynaston,
McIntyre, Wood.
Statistical analysis: Macartney, Gidding, Trinh,
Wang, Dey, Hull.
Obtained funding: Macartney, Wood.
Administrative, technical, or material support:
Macartney, Dey, Orr, McRae, Richmond.
Study supervision: Macartney, Gidding, Richmond,
Crawford.
Conflict of Interest Disclosures: None reported.
Funding/Support: Drs Gidding and Wood are
supported by Australian National Health and
Medical Research Council Career Development
Fellowships. Funding from the Australian
Government Department of Health and the NHMRC
Project Grant ID number 1049557 supported the
conduct of the study.
Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Group Information: Paediatric Active Enhanced
Disease Surveillance (PAEDS) Network members
include Kristine Macartney, MD, Karen Orr, RN,
Jocelynne McRae, MPH, Peter McIntyre, PhD,
Nicholas Wood, PhD, and Laura Rost, RN (National
Centre for Immunisation Research and
Surveillance); Peter Richmond, MBBS, and
Christopher Blyth, PhD (School of Paediatrics and
Child Health, University of Western Australia);
Michael Gold, MB, CHB (Department of Paediatrics,
University of Adelaide); Nigel Crawford, PhD (Royal
Children's Hospital); Jennifer A. Kynaston, MBBS,
Julia E. Clark, BM, BS, and Sonia Dougherty, RN
(Lady Cilento Children's Hospital); Robert Booy,
PhD, and Elizabeth Elliott, PhD (School of Child
and Adolescent Health, University of Sydney);
Jim Buttery, MD (School of Public Health and
Preventive Medicine, Monash University); Helen
Marshall, PhD (Robinson Research Institute,
The University of Adelaide); Thomas Snelling, PhD
(Wesfarmers Centre for Vaccines and Infectious
Diseases, Telethon Kids Institute, University of
Western Australia); Michael Nissen, PhD (previously
Royal Children's Hospital, Brisbane); Alissa McMinn,
RN, and Donna Lee, RN (Monash Children's
Hospital); Carolyn Finucane, RN, Christine Robins,
RN, Carol Orr, RN, and Jacki Connell, RN (Princess
Margaret Hospital); Christine Heath, RN, and Mary
Walker, RN (Women's and Children's Hospital);
Sharon Tan, RN, Helen Knight, RN, and Jennifer
Murphy, RN (The Children's Hospital at Westmead).
Additional Contributions: Alexandra Hendry, PhD,
of the National Centre for Immunisation Research
and Surveillance, assisted with manuscript
preparation. No compensation was received.
REFERENCES
1. Corben P, Leask J. To close the childhood
immunization gap, we need a richer understanding

jamapediatrics.com (Reprinted) JAMA Pediatrics October 2017 Volume 171, Number 10 997

© 2017 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 03/28/2019

 Research Original Investigation
of parents’ decision-making. Hum Vaccin Immunother.
2016;12(12):3168-3176.
2. Jarrett C, Wilson R, O’Leary M, Eckersberger E,
Larson HJ; SAGE Working Group on Vaccine
Hesitancy. Strategies for addressing vaccine
hesitancy—a systematic review. Vaccine. 2015;33
(34):4180-4190.
3. World Health Organization. Immunization,
vaccines, and biologicals: implementation research
in immunization. http://www.who.int/immunization
/research/implementation/en/. Accessed July 6,
2017.
4. Knuf M, Habermehl P, Zepp F, et al.
Immunogenicity and safety of two doses of
tetravalent measles-mumps-rubella-varicella
vaccine in healthy children. Pediatr Infect Dis J.
2006;25(1):12-18.
5. Shinefield H, Black S, Digilio L, et al. Evaluation
of a quadrivalent measles, mumps, rubella and
varicella vaccine in healthy children. Pediatr Infect
Dis J. 2005;24(8):665-669.
6. Jacobsen SJ, Ackerson BK, Sy LS, et al.
Observational safety study of febrile convulsion
following first dose MMRV vaccination in a
managed care setting. Vaccine. 2009;27(34):
4656-4661.
7. Klein NP, Fireman B, Yih WK, et al; Vaccine Safety
Datalink. Measles-mumps-rubella-varicella
combination vaccine and the risk of febrile seizures.
Pediatrics. 2010;126(1):e1-e8.
8. Marin M, Broder KR, Temte JL, Snider DE,
Seward JF; Centers for Disease Control and
Prevention (CDC). Use of combination measles,
mumps, rubella, and varicella vaccine:
recommendations of the Advisory Committee on
Immunization Practices (ACIP). MMWR Recomm Rep.
2010;59(RR-3):1-12.
9. Streng A, Liese JG. Decline of varicella
vaccination in German surveillance regions after
recommendation of separate first-dose vaccination
for varicella and measles-mumps-rubella. Vaccine.
2014;32(8):897-900.
10. Hull BP, Hendry AJ, Dey A, Beard FH,
Brotherton JM, McIntyre PB. Immunisation
coverage annual report, 2014. Commun Dis Intell
Q Rep. 2017;41(1):E68-E90.
11. Chiew M, Dey A, Martin N, Wang H, Davis S,
McIntyre PB. Australian vaccine preventable
disease epidemiological review series: measles
2000-2011. Commun Dis Intell Q Rep. 2015;39(1):
E1-E9.
12. Gidding HF, Martin NV, Stambos V, et al.
Verification of measles elimination in Australia:
application of World Health Organization regional
guidelines. J Epidemiol Glob Health. 2016;6(3):
197-209.
998 JAMA Pediatrics October 2017 Volume 171, Number 10 (Reprinted)
© 2017 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 03/28/2019
Evaluation of Measles-Mumps-Rubella-Varicella Vaccine in Australia
13. Macartney KK, Burgess MA. Varicella
vaccination in Australia and New Zealand. J Infect Dis.
2008;197(suppl 2):S191-S195.
14. Dey A, Knox S, Wang H, Beard FH, McIntyre PB.
Summary of national surveillance data on vaccine
preventable diseases in Australia, 2008-2011.
Commun Dis Intell Q Rep. 2016;40(suppl):S1-S70.
15. Kelly HA, Grant KA, Gidding H, Carville KS.
Decreased varicella and increased herpes zoster
incidence at a sentinel medical deputising service in
a setting of increasing varicella vaccine coverage in
Victoria, Australia, 1998 to 2012. Euro Surveill.
2014;19(41):pii: 20926.
16. Ward K, Dey A, Hull B, Quinn HE, Macartney K,
Menzies R. Evaluation of Australia’s varicella
vaccination program for children and adolescents.
Vaccine. 2013;31(10):1413-1419.
17. Heywood AE, Wang H, Macartney KK,
McIntyre P. Varicella and herpes zoster
hospitalizations before and after implementation
of one-dose varicella vaccination in Australia: an
ecological study. Bull World Health Organ. 2014;92
(8):593-604.
18. Gao Z, Wood JG, Gidding HF, et al. Control of
varicella in the post-vaccination era in Australia:
a model-based assessment of catch-up and infant
vaccination strategies for the future. Epidemiol Infect.
2015;143(7):1467-1476.
19. Macartney KK, Gidding HF, Trinh L, et al; PAEDS
(Paediatric Active Enhanced Disease Surveillance)
Network. Febrile seizures following measles and
varicella vaccines in young children in Australia.
Vaccine. 2015;33(11):1412-1417.
20. Zurynski Y, McIntyre P, Booy R, Elliott EJ, Group
PI; PAEDS Investigators Group. Paediatric Active
Enhanced Disease Surveillance: a new surveillance
system for Australia. J Paediatr Child Health. 2013;
49(7):588-594.
21. Zurynski YA, McRae JE, Quinn HE, Wood NJ,
Macartney KK. Paediatric Active Enhanced Disease
Surveillance inaugural annual report, 2014.
Commun Dis Intell Q Rep. 2016;40(3):E391-E400.
22. Whitaker HJ, Farrington CP, Spiessens B,
Musonda P. Tutorial in biostatistics: the
self-controlled case series method. Stat Med. 2006;
25(10):1768-1797.
23. Hull BP, McIntyre PB, Heath TC, Sayer GP.
Measuring immunisation coverage in Australia:
a review of the Australian Childhood Immunisation
Register. Aust Fam Physician. 1999;28(1):55-60.
24. Department of Human Services, Australian
Government. Australian Immunisation Register.
https://www.humanservices.gov.au/customer
/services/medicare/australian-immunisation
-register. Accessed July 7, 2017.
25. Bester JC. Measles and measles vaccination:
a review. JAMA Pediatr. 2016;170(12):1209-1215.
26. Hull BP, Dey A, Beard FH, Menzies RI,
Brotherton JM, McIntyre PB. Immunisation
coverage annual report, 2013. Commun Dis Intell
Q Rep. 2016;40(1):E146-E169.
27. Glasser JW, Feng Z, Omer SB, Smith PJ,
Rodewald LE. The effect of heterogeneity in uptake
of the measles, mumps, and rubella vaccine on the
potential for outbreaks of measles: a modelling
study. Lancet Infect Dis. 2016;16(5):599-605.
28. Wood JG, Gidding HF, Heywood A,
Macartney K, McIntyre PB, MacIntyre CR. Potential
impacts of schedule changes, waning immunity and
vaccine uptake on measles elimination in Australia.
Vaccine. 2009;27(2):313-318.
29. Principi N, Esposito S. Vaccines and febrile
seizures. Expert Rev Vaccines. 2013;12(8):885-892.
30. Klein NP, Lewis E, Baxter R, et al.
Measles-containing vaccines and febrile seizures in
children age 4 to 6 years. Pediatrics. 2012;129(5):
809-814.
31. Hambidge SJ, Newcomer SR, Narwaney KJ,
et al. Timely versus delayed early childhood
vaccination and seizures. Pediatrics. 2014;133(6):
e1492-e1499.
32. MacDonald SE, Dover DC, Simmonds KA,
Svenson LW. Risk of febrile seizures after first dose
of measles-mumps-rubella-varicella vaccine:
a population-based cohort study. CMAJ. 2014;186
(11):824-829.
33. Schink T, Holstiege J, Kowalzik F, Zepp F,
Garbe E. Risk of febrile convulsions after MMRV
vaccination in comparison to MMR or MMR+V
vaccination. Vaccine. 2014;32(6):645-650.
34. Rowhani-Rahbar A, Fireman B, Lewis E, et al.
Effect of age on the risk of fever and seizures
following immunization with measles-containing
vaccines in children. JAMA Pediatr. 2013;167(12):
1111-1117.
35. Ma SJ, Xiong YQ, Jiang LN, Chen Q. Risk of
febrile seizure after measles-mumps-rubella-
varicella vaccine: a systematic review and
meta-analysis. Vaccine. 2015;33(31):3636-3649.
36. Armstrong PK, Dowse GK, Effler PV, et al.
Epidemiological study of severe febrile reactions
in young children in Western Australia caused by a
2010 trivalent inactivated influenza vaccine. BMJ
Open. 2011;1(1):e000016.
37. Li-Kim-Moy J, Booy R. The manufacturing
process should remain the focus for severe febrile
reactions in children administered an Australian
inactivated influenza vaccine during 2010. Influenza
Other Respir Viruses. 2016;10(1):9-13.
38. O’Leary ST, Suh CA, Marin M; Vaccine Policy
Collaborative Initiative. Febrile seizures and
measles-mumps-rubella-varicella (MMRV) vaccine:
what do primary care physicians think? Vaccine.
2012;30(48):6731-6733.
jamapediatrics.com