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Evaluation of Combination Measles-Mumps-Rubella-Varicella Vaccine Introduction in Australia
Evaluation of Combination Measles-Mumps-Rubella-Varicella Vaccine Introduction in Australia
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.
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)
S
ome parents and health care workers are finding deci-
sion making regarding immunization increasingly com- Key Points
plex, presenting a barrier to timely vaccine uptake.1,2 A
Question What is the effect of introduction of combination
commonly reported concern is the number of injections given measles-mumps-rubella-varicella vaccine at age 18 months as the
to children.1,2 Combination vaccines reduce the number of in- second dose of measles-containing vaccine on vaccine coverage
jections needed and may improve vaccine acceptance, cover- and risk of vaccine-associated febrile seizures in Australia?
age, and, ultimately, disease control. However, various other
Findings A national cohort study of vaccine coverage before and
factors surrounding use of combination vaccines, including after measles-mumps-rubella-varicella vaccine introduction
cost-effectiveness, safety, availability, and country- or re- showed improvement in uptake and timeliness for all 4 vaccine
gion- specific disease epidemiology, require consideration.3 In components. Despite the peak incidence of all-cause febrile
the past decade, several countries have faced challenges in in- seizures occurring at age 18 months and a known increased risk
corporating the combination measles-mumps-rubella- of febrile seizures following the first dose, in a self-controlled case
series analysis including 1471 children, use of measles-mumps-
varicella (MMRV) vaccine into their immunization sched-
rubella-varicella vaccine at 18 months was not associated with
ules. Although both available MMRV vaccines (Priorix-Tetra an increased risk of febrile seizures.
[GlaxoSmithKline Biologicals SA] and ProQuad [Merck & Co
Inc]) offer the advantage of a single injection against 4 dis- Meaning Measles-mumps-rubella-varicella combination vaccine
was safely incorporated into the Australian National Immunisation
eases, prelicensure studies showed an increased risk of fever
Program schedule and improved population-level protection
in first-dose recipients aged 12 to 23 months compared with against these serious viral diseases.
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 not be associated with an increased risk of FSs, even though
measles virus component. Postlicensure studies subse- it would be provided to children aged 18 months, when the in-
quently reported an approximately 2-fold increased risk of cidence of FSs peaks. The vaccine safety and evaluation plan
febrile seizures (FSs) following MMRV compared with giving for MMRV vaccine introduction included active, prospective
separate MMR and varicella vaccines.6,7 This finding prompted sentinel FS surveillance using the Paediatric Active En-
a withdrawal of a preferential recommendation for use of hanced Disease Surveillance (PAEDS) network19,20 and analy-
MMRV as the first measles-containing vaccine (MCV) in the sis of vaccine uptake using the ACIR. We aim to present the
United States and Germany.8,9 findings of this evaluation, examining the effect of the pro-
Before July 2013, MMRV vaccine was not used in Austra- gram change on (1) vaccine safety, specifically, the risk of
lia. Two doses of MMR vaccine were scheduled on the Na- MCV-associated FS and (2) vaccine uptake and timeliness.
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-
Methods
take was suboptimal; approximately 92% of children had re- Febrile Seizure Risk Associated With Measles-
ceived 2 MCVs by age 5 years,10 and modeling demonstrated and Varicella-Containing Vaccine Exposure
an increased risk of measles outbreaks associated with low Data Sources
2-dose immunity in younger children. Disease outbreaks aris- Active, prospective sentinel FS surveillance was conducted
ing from measles importations11,12 demonstrated the need to from May 1, 2013 (2 months before MMRV vaccine introduc-
improve 2-dose coverage at all ages, but especially in the young. tion), to June 30, 2014, by the PAEDS Network at 5 Australian
A single dose of monovalent varicella vaccine had been sched- tertiary pediatric hospitals, as previously described.19,21 At each
uled under NIP at age 18 months since November 2005,13 but site, emergency department and inpatient databases were
coverage by age 2 years was only 86%, although it increased scanned daily by PAEDS surveillance nurses to ascertain pos-
to 92% by 5 years. Declines in varicella-related morbidity and sible FS presentations in all children younger than 5 years. Pe-
mortality had occurred,14-17 but modeling18 suggested that riodic review of all International Statistical Classification of
improved 1-dose coverage was needed to decrease the risk of Diseases and Related Health Problems, Tenth Revision, Austra-
shifting disease to older age groups where higher disease se- lian Modification–coded FS encounters (code R56.0) was also
verity occurs. conducted to capture additional cases. Clinical and demo-
To address these challenges, the decision was made to in- graphic data were collected from the medical records and care-
clude MMRV vaccine on the Australian NIP at age 18 months giver interviews, and all FS diagnoses were confirmed. All chil-
as the second MCV dose from July 2013 onward, as reported dren had immunization records obtained from the ACIR, both
in Table 1. The risk-benefit assessment that underpinned this at FS presentation and at study end (to identify all vaccine
change was based on 2 hypotheses: (1) higher and earlier popu- exposures).
lation-level vaccine coverage of 2 doses of MCV and 1 dose of
varicella vaccine would be achieved by bringing forward the Study Population and Exclusion Criteria
scheduled age for the second MCV dose to 18 months and re- In Australia, the timing of vaccine administration is highly as-
placing MMR with MMRV vaccine, and (2) when used as the sociated with NIP-recommended schedule points. There-
second instead of the first dose of MCV, MMRV vaccine would fore, our analysis cohort was restricted to children who were
jamapediatrics.com (Reprinted) JAMA Pediatrics October 2017 Volume 171, Number 10 993
994 JAMA Pediatrics October 2017 Volume 171, Number 10 (Reprinted) jamapediatrics.com
16 (4.1%) had received neither vaccine. Further data are pro- period following MMRV, the prevaccination period, or the 13-
vided in Table 2. to 30-day postvaccination period. The RI of FSs was raised in
Table 3 provides the results of the primary and sensitiv- the 5 to 12 days following MMR vaccine (MCV dose 1) (RI, 2.71;
ity self-controlled case series analyses. In the primary analy- 95% CI, 1.71-4.29), and there was a significantly lower risk in
sis, which adjusted for age using 3 age groups, there was no the 2 weeks before vaccination. The results of the sensitivity
significantly increased risk of FSs within the 5- to 12-day risk 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
jamapediatrics.com (Reprinted) JAMA Pediatrics October 2017 Volume 171, Number 10 995
Cumulative Vaccination, %
70 70
On-time Modeling the effect of this schedule change on population im-
60 vaccination 60
munity to measles in Australia was sensitive to assumptions
On-time
50 50
vaccination regarding the extent of waning of vaccine-derived immunity.28
40 40 Waning immunity may also be an issue for the less-
30 30 efficacious mumps component of the vaccine; ongoing dis-
20 20 ease surveillance will be important to monitor for this poten-
10 10
tial outcome and, if needed, adjust policy recommendations
accordingly. However, several European countries, Canadian
0 0
provinces, and low- to middle-income countries under the
12 <12
18 <18
19 <19
20 <20
24 <24
36 <36
42 <42
48 <48
49 <49
50 <50
0
<3
>3
<6
>6
Expanded Program on Immunization use a similarly com-
to
to
to
to
to
to
to
to
to
to
996 JAMA Pediatrics October 2017 Volume 171, Number 10 (Reprinted) jamapediatrics.com
a low risk has been viewed as concerning. In Australia, an un- 1 uptake did not change substantially over time. In Australia,
expected high rate of FSs occurred from 1 seasonal influenza all NIP vaccines are commonwealth government procured, and
vaccine brand (Fluvax [Afluria in the United States]) in chil- our 8 state and territory health departments undertake over-
dren younger than 5 years in 2010. Although most FS cases re- sight program delivery, resulting in more prescriptive use of
solved without sequelae, permanent neurologic damage oc- vaccine combinations and brands than in other countries where
curred in 2 children.36,37 In the United States, primary care vaccine choice is influenced by individual immunization cli-
clinicians are reported as being unlikely to recommend nicians or insurers. Together with our comprehensive na-
MMRV,38 and in Germany, there has been a decline in vari- tional vaccine register, this control enables accurate evalua-
cella vaccination uptake.9 tion of changes in coverage in response to new vaccine
introduction. Although our study primarily reports on 1 brand
Limitations and Strengths of MMRV vaccine (Priorix-Tetra), based on first principles, we
This study has a number of limitations and strengths. Al- believe that these results would likely be similar for the other
though we showed no statistically significant association be- registered MMRV vaccine (ProQuad).
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
Conclusions
not be representative of all Australian children with FSs. How- Data from this study help clinicians to better understand
ever, each site also functions as a community-based hospital, the link between measles and varicella virus–containing live
most children resided nearby and had simple FSs, and our vaccines and the risk of FSs—a common but serious early
analysis was robust in demonstrating the known association childhood condition that occurs in response to fever from
with MCV dose 1. Our ecologic cohort design to assess vac- any source. We present a comprehensive evaluation of the
cine coverage changes is subject to unrecognized biases or con- incorporation of MMRV vaccine into the Australian NIP,
founding factors and does not prove that the schedule change demonstrating an association with improved vaccine uptake
was the necessary or only causative factor in improving vac- and timeliness while maintaining overall program safety.
cine uptake. However, no other major programmatic or pro- Our findings should help to inform childhood immunization
cedural changes occurred during the study period that would policy decision making regarding use of these vaccines in
otherwise have increased coverage, and, notably, MCV dose other countries.
ARTICLE INFORMATION Acquisition, analysis, or interpretation of data: Nicholas Wood, PhD, and Laura Rost, RN (National
Accepted for Publication: May 10, 2017. Macartney, Gidding, Trinh, Wang, Dey, Hull, Orr, Centre for Immunisation Research and
McRae, Richmond, Crawford, Kynaston, McIntyre. Surveillance); Peter Richmond, MBBS, and
Published Online: August 14, 2017. Drafting of the manuscript: Macartney, Gidding, Christopher Blyth, PhD (School of Paediatrics and
doi:10.1001/jamapediatrics.2017.1965 Trinh, Dey, Richmond, Gold, McIntyre. Child Health, University of Western Australia);
Author Affiliations: National Centre for Critical revision of the manuscript for important Michael Gold, MB, CHB (Department of Paediatrics,
Immunisation Research and Surveillance, Sydney, intellectual content: Macartney, Gidding, Wang, Dey, University of Adelaide); Nigel Crawford, PhD (Royal
Australia (Macartney, Gidding, Wang, Dey, Hull, Orr, Hull, Orr, McRae, Richmond, Crawford, Kynaston, Children's Hospital); Jennifer A. Kynaston, MBBS,
McRae, McIntyre, Wood); School of Child and McIntyre, Wood. Julia E. Clark, BM, BS, and Sonia Dougherty, RN
Adolescent Health, University of Sydney, Sydney, Statistical analysis: Macartney, Gidding, Trinh, (Lady Cilento Children's Hospital); Robert Booy,
Australia (Macartney, Dey, McIntyre, Wood); Wang, Dey, Hull. PhD, and Elizabeth Elliott, PhD (School of Child
The Children’s Hospital at Westmead, Westmead, Obtained funding: Macartney, Wood. and Adolescent Health, University of Sydney);
Australia (Macartney, Orr, McRae, McIntyre, Wood); Administrative, technical, or material support: Jim Buttery, MD (School of Public Health and
School of Public Health and Community Medicine, Macartney, Dey, Orr, McRae, Richmond. Preventive Medicine, Monash University); Helen
UNSW Medicine, The University of New South Study supervision: Macartney, Gidding, Richmond, Marshall, PhD (Robinson Research Institute,
Wales, Sydney, Australia (Gidding); Western Sydney Crawford. The University of Adelaide); Thomas Snelling, PhD
Local Health District, Sydney, Australia (Trinh); Conflict of Interest Disclosures: None reported. (Wesfarmers Centre for Vaccines and Infectious
School of Paediatrics and Child Health, University Diseases, Telethon Kids Institute, University of
of Western Australia, Perth, Australia (Richmond); Funding/Support: Drs Gidding and Wood are Western Australia); Michael Nissen, PhD (previously
Wesfarmers Centre for Vaccines and Infectious supported by Australian National Health and Royal Children's Hospital, Brisbane); Alissa McMinn,
Diseases, Telethon Kids Institute, University of Medical Research Council Career Development RN, and Donna Lee, RN (Monash Children's
Western Australia, Perth, Australia (Richmond); Fellowships. Funding from the Australian Hospital); Carolyn Finucane, RN, Christine Robins,
Department of Paediatrics, University of Adelaide, Government Department of Health and the NHMRC RN, Carol Orr, RN, and Jacki Connell, RN (Princess
Adelaide, Australia (Gold); Women’s and Children’s Project Grant ID number 1049557 supported the Margaret Hospital); Christine Heath, RN, and Mary
Hospital, Adelaide, Australia (Gold); Royal Children’s conduct of the study. Walker, RN (Women's and Children's Hospital);
Hospital, Melbourne, Australia (Crawford); Role of the Funder/Sponsor: The funders had no Sharon Tan, RN, Helen Knight, RN, and Jennifer
University of Melbourne, Melbourne, Australia role in the design and conduct of the study; Murphy, RN (The Children's Hospital at Westmead).
(Crawford); Lady Cilento Children’s Hospital, collection, management, analysis, and Additional Contributions: Alexandra Hendry, PhD,
Brisbane, Australia (Kynaston). interpretation of the data; preparation, review, or of the National Centre for Immunisation Research
Author Contributions: Drs Macartney and Wood approval of the manuscript; and decision to submit and Surveillance, assisted with manuscript
had full access to all of the data in the study and the manuscript for publication. preparation. No compensation was received.
take responsibility for the integrity of the data and Group Information: Paediatric Active Enhanced
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