Document text
Febrile Seizures following Measles, Mumps, Rubella,
and Varicella (MMRV) vaccine
John Su
Acting Director
Immunization Safety Office
Centers for Disease Control and Prevention
September 18, 2025
September 2025: Request to CDC from ACIP Chair
Presentation on febrile seizures post administration of MMRV vs.
simultaneous administration of separate MMR and Varicella vaccines, by
two different age groups, 1 –2 and 4– 6-year -olds. Please use data both from
randomized trials and from the Vaccine Safety Datalink (VSD), presented
from the VSD project.
2
Timeline of recommendations for MMRV vaccine use in
the United States
3September 2005 :
MMRV vaccine licensed in
the U. S. in children 12
months –12 years of age
Use of MMRV vaccine
preferred over separate
administration of MMR and
varicella vaccinesFebruary 2008 :
Vaccine safety finding
from post -licensure
monitoring: increased risk
of febrile seizures after
first doseJune 2009
Updated
recommendations
ACIP issued interim recommendation: removed
preference for MMRV use vs. MMR and varicella
vaccines for both dose 1 and dose 2
Presentation of preliminary safety findings to ACIP
February 2008 to June 2009 that led to revised MMRV recommendations in June 2009
•Multiple presentations to ACIP from Vaccine Safety Datalink and Merck
•Evidence review and synthesis of data to ACIP: MMRV ACIP Working Group
assessed multiple sources of data
-Review of two post -licensure studies
•Merck -sponsored study
•Vaccine Safety Datalink study
-Review of literature and other data sources (e.g., parent/provider focus groups data)
-Consultation with experts
-MMRV Vaccine Safety Working Group (WG) discussions
-WG member surveys
•October 2008 and June 2009
Use of Combination Measles, Mumps, Rubella, and Varicella Vaccine 4
ACIP Updated Recommendations: June 2009
•For the first dose of measles, mumps, rubella, and
varicella vaccination at age 12 –47 months, either MMR
vaccine and varicella vaccine or MMRV vaccine may be used. Providers who are considering administering the MMRV vaccine should discuss the benefits and risks of
both vaccination options with the parents or caregivers.
-CDC implementation guidance: unless the parent or caregiver
expresses a preference for the MMRV vaccine, CDC recommends that MMR vaccine and varicella vaccine be
administered for the first dose in this age group.
•For the first dose at age ≥48 months and for the second
dose at any age (15 months –12 years), MMRV is
generally preferred over separate injections of MMR
vaccine and varicella vaccine
5
Marin, M, et al. Use of Combination Measles, Mumps, Rubella, and Varicella Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR May 7, 2010/59(RR03);1 -12
Background: MMRV vaccine
•Combination vaccine*
-Decreases the number of injections
-Increases vaccine compliance
-Increases vaccine coverage rates
•MMRV licensed for children 12 months through 12 years of age
-Routinely recommended ages:
•First dose: age 12 through 15 months
•Second dose: age 4 through 6 years
-In the United States, MMRV vaccine licensed is ProQuad (Merck & Co, Inc)
* https://www.cdc.gov/vaccines/hcp/imz -best -practices/timing -spacing -immunobiologics.html
6
Background: Febrile seizures
•By 5 years of age, 2 -4% of children have had ≥ 1 febrile seizure1
•Occurs primarily 6 months – 5 years of age, peak age is 14 -18 months
•Typically of short (<15 min) duration1,2; majority resolve without sequelae
•Observed during early childhood infections and diseases1, 2
-Middle ear infections, viral upper respiratory tract infections, roseola
-Can be associated with any condition that results in fever
•Observed following a fever associated with vaccination1,2
-DTaP , pneumococcal conjugate, MMR
•Family history of febrile seizures increases the risk of febrile seizures3
1 Marin, M, et al. Use of Combination Measles, Mumps, Rubella, and Varicella Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR May 7, 2010/59(RR03);1 -12
2https://www.cdc.gov/vaccine -safety/about/febrile -seizures.html
3 Sawires R, Buttery J, Fahey M. A Review of Febrile Seizures: Recent Advances in Understanding of Febrile Seizure Pathophysiology and Commonly Implicated Viral Triggers. Front Pediatr . 2022 Jan 13;9:801321. 7
Background: Pre -licensure MMRV studies
•MMRV prelicensure studies conducted among children aged 12 to 23 months
-Fever and measles- like rash were reported at significantly greater rate among children
receiving the first dose of MMRV vaccine than children receiving first doses of MMR
vaccine and varicella vaccine (at the same visit)
•Fever (reported as abnormal or elevated ≥102oF [≥39oC])
–21.5% of MMRV vaccine recipients compared with 14.9% of separate MMR vaccine and
varicella vaccine recipients (risk difference [RD]: 6.6%; 95% confidence interval [CI] = 4.6 -8.5)
•Measles -like rash:
–3.0% of MMRV vaccine recipients compared with 2.1% of separate MMR vaccine and
varicella vaccine recipients (RD: 1.0%; 95% CI = 0.1 -1.8)
•In light of these findings, CDC and Merck initiated separate post- licensure
studies to evaluate if an increased risk for febrile seizures might be associated
with the first dose of MMRV vaccine
8Marin, M, et al. Use of Combination Measles, Mumps, Rubella, and Varicella Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR May 7, 2010/59(RR03);1 -12
Merck ProQuad package insert, 2024
Febrile seizures following first dose of MMRV
9
Summary results from VSD and Merck -sponsored studies for chart
confirmed febrile seizures after first dose of MMRV vs. MMR and varicella (MMR+V) vaccines
*Klein NP, et al. Vaccine Safety Datalink. Measles -mumps- rubella -varicella combination vaccine and the risk of febrile seizures. Pediatrics. 2010 Jul;126(1):e1 -8
†Jacobsen SJ et al. Observational safety study of febrile convulsion following first dose MMRV vaccination in a managed care s etting. Vaccine. 2009 Jul 23;27(34):4656 -61.
§ Significant p <0.05
RR = relative risk; AR= attributable risk; CI: confidence interval10Post-
vaccination
IntervalVSD study*
All aged 12 -23 monthsMerck -sponsored study†
99% aged 12 -23 months
MMRV: N= 83,107
MMR+V: N= 376,354 MMRV: N=31,298
MMR+V: N=31,298
Weeks 1 -2 7–10 days
RR: 2.0 (95% CI: 1.4, 2.9)§
AR: 4.3 per 10,000
(95% CI: 2.6, 5.6)5–12 days
RR: 2.2 (95% CI: 1.0, 4.7)§
AR: 3.8 per 10,000 (95% CI: 0.3, 7.4)
Weeks 1 -4
0-30 days
RR: 1.4 (95% CI: 1.1, 2.0)§
AR: 4.7 per 10,000 (95% CI: 0.7, 7.6)0-30 days
RR: 1.1 (95% CI: 0.7, 1.7)
AR: 1.3 per 10,000
(95% CI: -4.5, 7.0)
Post -vaccination outpatient fever visits among 12 -23-
month -olds according to vaccine received by vaccine
type, VSD, 2000 –2008
11
Vaccine Days RR P-value
MMRV*
(N=83,107)7-10 6.1 0.001
MMR + V†
(N=376,354)7-10 4.4 0.001
MMR†
(N=145,302)7-10 4.3 0.001
Varicella†
(N=107,744)No temporal clustering of fever visits after varicella vaccination alone.Temporal Scan
* Vaccinated between January 2006 and October 2008; † Vaccinated between January 2000- October 2008
Klein NP, et al. Vaccine Safety Datalink. Measles -mumps -rubella -varicella combination vaccine and the risk of febrile seizures. Pediatrics. 2010 Jul;126(1):e1- 8
Post -vaccination febrile seizures among 12- 23-month -
olds by vaccine type, VSD, 2000 -2008
12
Temporal Scan
* Vaccinated between January 2006 and October 2008; † V accinated between January 2000 -October 2008
Klein NP, et al. Vaccine Safety Datalink. Measles -mumps- rubella -varicella combination vaccine and the risk of febrile seizures. Pediatrics. 2010 Jul;126(1):e1 -8Vaccine Days RR P-value
MMRV*
(N=83,107)8-10 7.6 0.001
MMR + V†
(N=376,354)7-10 4.0 0.001
MMR†
(N=145,302)7-11 3.7 0.001
V aricella†
(N=107,744)No seizure peak observable; no significant temp oral clustering
U.S. post -licensure experience: Febrile seizures after
MMR or varicella vaccination
•MMR vaccine: Study of ~137,000 children aged <7 years vaccinated with
MMR identified an increased risk for febrile seizures during 8 –14 days after
vaccination, compared with unvaccinated children1
-RR 2.83 (95% CI: 1.44, 5.55)
-~1 additional febrile seizure per 3,000 –4,000 children vaccinated
•Varicella vaccine: Study of ~35,000 children aged 12– 23 months vaccinated
with varicella vaccine identified no increased risk for febrile seizures during
0–30 days after vaccination, after controlling for co- administration of MMR
vaccine2
1. Barlow WE, Davis RL, et al. The risk of seizures after receipt of whole- cell pertussis or measles, mumps, and rubella vaccine. N Engl J Med. 2001 Aug 30;345(9):656 -61.
2. Black S; Shinefield H, et al. Postmarketing evaluation of the safety and effectiveness of varicella vaccine. The Pediatric Infectious Disease Journal 18(12):p 1041 -1046, D ecember
1999.
13
Risk of febrile seizure after MMRV vaccines:
A systematic review and meta -analysis
•Included some studies that had subjects as young as 9 months of age
•Clinical trial review and analysis (31 published or unpublished studies involving
about 40,000 subjects)
-No evidence of significant differences in incidence of febrile seizure or vaccine -related
febrile seizure between MMRV and MMR +/ - V after any doses, in the risk windows of 0 -28,
0-42, 0- 56, and 7- 10 days
-Receipt of concomitant MMRV and other pediatric vaccines was not a significant predictor
of febrile seizure
•Post -marketing review and analysis
-Included data from 8 post -marketing studies, involving more than 3,200,000 children*
-Approximately 2 -fold increase in risk of seizure or febrile seizure during 7 -10 days or 5- 12
days after MMRV in children aged 10-24 months
* One study included children ages 4 -6 years who received second dose MMRV: Study included both ProQuad (available in US) and Priorix -Tetra study (available internationally)
Ma SJ, Xiong YQ, Jiang LN, Chen Q. Risk of febrile seizure after measles -mumps -rubella -varicella vaccine: A systematic review an d meta -analysis. Vaccine . 2015;33(31):3636 -3649.
doi:10.1016/j.vaccine.2015.06.009 14
Cochrane review: MMRV vs MMR + V in children
•Febrile seizure review
-Risk of febrile seizures after MMRV vaccination compared to MMR+V vaccination
•Includes evidence from five cohort studies*
•Overall estimates:
–Within 42 days after vaccination: RR 1.31 (95% CI: 1.19 to 1.45)
–Within 7 to 10 days after vaccination: RR 1.98 (95% CI: 1.69 to 2.33)
-Risk of febrile seizure after MMRV studies (grouped by brand) compared to MMR+V
vaccination
•Priorix -Tetra study:
–Within 0 to 42 days after vaccination: RR 1.95 (95% CI: 0.85 to 4.48)
–Within 7 to 10 days after vaccination: RR 1.69 (95% CI: 0.93 to 3.07)
•ProQuad studiesᵻ:
–Within 0 to 42 days after vaccination: RR 1.30 (95% CI: 1.17 to 1.44)
–Within 7 to 10 days after vaccination: RR 2.01 (95% CI: 1.70 to 2.38)
* Four studies are dose 1; One study includes children ages 4 -6 years who received dose 2; ᵻ Includes one study of children ages 4 -6 years who received dose 2.
Di Pietrantonj C, Rivetti A, Marchione P, Debalini MG, Demicheli V. Vaccines for measles, mumps, rubella, and varicella in children. Cochrane Database Syst Rev . 2021;11(11):CD004407.
Published 2021 Nov 22. doi:10.1002/14651858.CD004407.pub5 15
Summary of evidence for febrile seizure risk after
first dose of MMRV vaccination
•Post -licensure studies assessed rates of febrile seizures in children aged 12 -
23 months who received dose 1 MMRV vaccine and compared these rates
with children who received separate dose 1 injections of MMR and varicella
vaccines at the same visit.
•The studies used different methods, populations of children, and different
formulations of MMRV.
•Despite these differences, studies show remarkable consistency in findings
16
Conclusion: Evidence for febrile seizure risk after first
dose MMRV vaccination
•During the 6 weeks after vaccination, an increased risk for febrile seizures
after dose 1 MMRV compared with dose 1 MMR+V is only present during
the 1 -2 weeks after vaccination
•The risk of febrile seizures occurring during other periods after
vaccination is similar between dose 1 MMRV and MMR+V
Klein NP, Fireman B, Yih WK, et al. Measles -mumps- rubella -varicella combination vaccine and the risk of febrile seizures. Pediat rics. 2010 Jul;126(1):e1 -8.
17
18Febrile Seizures following second dose of MMRV
Risk of febrile seizures and fever following second
dose of MMRV vaccine
•Risk for febrile seizures is lower among children aged 4 -6 years than
among children aged 12- 15 months
•Prelicensure trials:
-Lower fever rates in children aged 15 -31 months receiving dose 2 MMRV
compared with dose 1 MMRV (N=1035)1
-Similar fever rates in children aged 4 -6 years receiving dose 2 MMRV (N=397)
compared with dose 2 MMR + varicella vaccines (N=193)2
1 Merck ProQuad package insert, 2024
2 Reisinger KS, et al. Brown ML, Xu J, et al. A combination measles, mumps, rubella, and varicella vaccine (ProQuad ) given to 4 - to 6-year -old healthy children vaccinated previously with
MM- RII and Varivax . Pediatrics. 2006;117(2):265 -272.19
Merck -sponsored study findings of febrile seizures
following second dose of MMRV and MMR+V
•Among children aged 4- 6 years:
-No febrile seizures occurred during the 5- 12 days post -vaccination
•22,212 children receiving second dose MMRV vaccine
•24,778 children receiving second dose of MMR + V vaccine at same visit
Marin, M, et al. Use of Combination Measles, Mumps, Rubella, and Varicella Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR May 7, 2010/59(RR03);1 -1220
VSD findings for all seizures after second- dose of
measles -containing vaccine identified from electronic
medical records for children aged 4- 6 years
Klein NP, et al. Measles -containing vaccines and febrile seizures in children age 4 to 6 years. Pediatrics. 2012 May;129(5):809 -14.
21
-Very few seizures identified by ICD -9 codes in electronic data
VSD findings of chart -confirmed febrile seizures 7 to 10
days after second dose of measles -containing
vaccination for children aged 4–6 years, 2000 –2008
•Electronic medical record review of the 4 post- MMRV seizures:
-Febrile seizure: 1
-Afebrile seizures: 2
-Improbable seizure: 1
22
Klein NP, et al. Measles -containing vaccines and febrile seizures in children age 4 to 6 years. Pediatrics. 2012 May;129(5):809 -14.
Risk of febrile seizure after second dose of MMRV:
Systematic review and meta -analysis
•Pre-licensure studies:
•Po
•Post -licensure study:
-Only included one study of children 4-6 years; no evidence to suggest elevated risk of febrile seizure
23Ma SJ, et al. . Risk of febrile seizure after measles -mumps -rubella -varicella vaccine: A systematic review and meta -analysis. Vaccine . 2015;33(31):3636 -3649.
Conclusion: No evidence for febrile seizure risk after
dose 2 MMRV vaccination
•Among children aged 4- 6 years
-Data do not suggest that children who receive dose 2 MMRV have an increased
risk of febrile seizures after vaccination compared with those who receive dose 2
as MMR + varicella vaccination at the same visit
Marin, M, et al. Use of Combination Measles, Mumps, Rubella, and Varicella Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR May 7, 2010/59(RR03);1 -12
24
Conclusion
•There is a small increased risk for febrile seizures after first dose of MMR
and MMRV vaccines
•The risk is slightly higher with MMRV combination vaccine after the first
dose
-Studies have shown a small increased risk for febrile seizures during the 5 - 12
days after a child has received their first vaccination with MMR vaccine
-Studies have not shown an increased risk for febrile seizures after the varicella
vaccine
•There is no increased risk of febrile seizures after vaccination
with MMRV vaccine in children aged 4 through 6 years
25
Questions?
For more information, contact CDC
1-800- CDC- INFO (232 -4636)
TTY: 1 -888- 232- 6348 cdc.gov atsdr.cdc.gov
Follow us on X (Twitter) @CDCgov & @CDCEnvironment
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position
of the U. S. Centers for Disease Control and Prevention and the Agency for Toxic Substances and Disease Registry.
26