15. Safety: MMRV versus MMR/MMR+V ‐ febrile seizures.

Study ID and design	Population	Outcome definition	Exposure MMR/MMRV vaccine	Authors' conclusion	Crude data	Estimate (95% CI)
cb‐Jacobsen 2009 Retrospective cohort study	Index cohort (n = 31,298) all children ages 12 to 60 months vaccinated with MMRV at KPSC from February 2006 to June 2007. Children were excluded if they had a history of measles, mumps, rubella, or varicella disease or history of vaccination for any of these diseases. Comparison (matched) cohorts (1) children vaccinated with MMR+V concomitantly before the routine use of MMRV at KPSC (November 2003 to January 2006). Children were optimally matched without replacement to children vaccinated with MMRV, on the basis of age, sex, and vaccination calendar day and month, and had to fulfil the same enrolment criteria. (2) pre‐vaccination self‐comparison period defined by the period from 60 to 30 days prior to vaccination with MMRV. (3) postvaccination self‐comparison period defined by the period from 60 to 90 days following vaccination.	Febrile convulsion Potential convulsions were identified as occurring on any visit with a diagnosis coded as 779.0 (neonatal seizures), 333.2 (myoclonus), 345 (epilepsy), 780.39 (other convulsion), 780.3 (convulsion), 780.31 (simple febrile convulsion), 780.32 (complex febrile convulsion) regardless of setting (e.g. inpatient, outpatient, emergency department, or outside facility).	MMRV: ProQuad contains components of 2 Merck vaccines, MMR‐II (MMR) and VARIVAX (V), and was approved in the USA in September 2005. Before MMRV was available, MMR and V were usually given concomitantly as 2 separate injections. Risk interval (a) 0 to 4 days (b) 5 to 12 days (c) 13 to 30 days (d) 0 to 30 days	Conclusion: "These data suggest that the risk of febrile convulsion is increased in days 5–12 following vaccination with MMRV as compared to MMR+V given separately during the same visit, when post‐vaccination fever and rash are also increased in clinical trials. While there was no evidence of an increase in the overall month following vaccination, the elevated risk during this time period should be communicated and needs to be balanced with the potential benefit of a combined vaccine."	Cases versus cases MMRV versusMMR+V matched n = 31,298 (a) 9 versus 7 (b) 22 versus 10 (c ) 13 versus 23 (d) 44 versus 40 MMRV versusPre‐Vacc matched n = 31,298 (a) 9 versus 4 (b) 22 versus 3 (c ) 13 versus 9 (d) 44 versus 16 MMRV versusPost‐Vacc matched n = 31,298 (a) 9 versus 5 (b) 22 versus 5 (c ) 13 versus 13 (d) 44 versus 23	RR (95% CI) MMRV versusMMR+V (a) 1.28 (0.48 to 3.45) (b) 2.2 (1.04 to 4.65) (c ) 0.57 (0.29 to 1.12) (d) 1.1 (0.72 to 1.69) MMRV versusPre‐Vacc (a) 2.25 (0.69 to 7.31) (b) 7.33 (2.2 to 24.5) (c ) 1.44 (0.62 to 3.38) (d) 2.75 (1.55 to 4.87) MMRV versusPost‐Vacc (a) 1.8 (0.6 to 5.37) (b) 4.4 (1.67 to 11.62) (c ) 1 (0.46 to 2.16) (d) 1.91 (1.16 to 3.17)
cb‐Klein 2010 Retrospective cohort study	Index cohort Children aged 12 to 23 months who were members of the 7 participating versusD sites and had received their first dose of MMRV (n = 83,107) Comparison cohorts (1) children vaccinated with MMR+V between January 2000 and October 2008 (n = 376,354) (2) children vaccinated with MMR vaccine alone (n = 145,302) (2000 to 2008)	Seizureevent The first instance during the 42 days after MMRV vaccination with ICD‐9 codes 345* (epilepsy) or 780.3* (convulsion) in the emergency department or hospital. Postvaccination outpatient fever visits were examined by using ICD‐9 code 780.6 for fever or febrile illness at all 7 participating versusD sites from January 2000 through October 2008. Similar to seizure cases, fever visits were censored after the first occurrence within the 42 days.	MMRV (Merck & Co Inc, West Point, PA) Risk interval after vaccination (a) 7 to 10 days (b) 0 to 42 days (c) 0 to 30 days	Conclusion: Amongst 12‐ to 23‐month‐olds who had received their first dose of measles‐containing vaccine, fever and seizure were elevated 7 to 10 days after vaccination. Vaccination with MMRV results in 1 additional febrile seizure for every 2300 doses given instead of separate MMR varicella vaccines. Providers who recommend MMRV should communicate to parents that it increases the risk of fever and seizure over that already associated with measles‐containing vaccines.	Seizures cases from 2000 to 2008 MMRV n = 83,107 (a) 77 cases (b) 189 cases (c) not reported MMR+V n = 376,354 (a) 174 (b) 598 (c) not reported MMR n = 145,302 (a) 42 (b) 151 (c) not reported	rr (95% CI)(*) MMRV versusMMR+V (a) 1.98 (1.43 to 2.73) (b) 1.42 (1.11 to 1.81) (c) 1.40 (1.06 to 1.85) (*) Poisson regression due to rarity of the event rr (rate ratio) is very close to RR RR (95% CI) MMRV versusMMR (a) 3.21 (2.2 to 4.67) (b) 2.19 (1.77 to 2.71) (c) not reported
cb‐Klein 2012 Retrospective cohort study linked to cb‐Klein 2010	Children aged 48 to 83 months who were members of the 7 participating versusD sites between January 2000 and October 2008	Seizureevent Postvaccination seizure event as the first instance during the 42 days after a measles‐ or varicella‐containing vaccine of the ICD‐9 codes 345* (epilepsy) or 780.3* (convulsion) in the emergency department or hospital. The authors identified postvaccination medically attended outpatient fever events by using ICD‐9 code 780.6 (fever and other physiologic disturbances of temperature regulation).	1) MMRV (Merck & Co) 2) MMR (Merck & Co Inc, West Point, PA) + varicella (Merck & Co) separately administered on the same day 3) MMR Risk interval after vaccination (a) 7 to 10 days (b) 0 to 42 days	Conclusions: This study provides reassurance that MMRV and MMR+V were not associated with an increased risk of febrile seizures among 4‐ to 6‐year‐olds. The authors can rule out with 95% confidence a risk greater than 1 febrile seizure per 15,500 MMRV doses and 1 per 18,000 MMR+V doses.	Cases/PT MMRV n = 86,750 (a) 4/950.1 (b) 19/10,497.2 MMR+V n = 67,438 (a) 0/739 (b) 10/7874 MMR n = 479,311 (a) 9/5252.7 (b) 99/55,618	RR (95% CI) MMRV versusMMR+V (a) 7 (0.38 to 130.02) (b) 1.48 (0.69 to 3.18) MMRV versusMMR (a) 2.46 (0.76 to 7.99) (b) 1.06 (0.65 to 1.73)
cb‐Rowhani‐Rahbar 2013 Retrospective cohort study linked to cb‐Klein 2010	n = 840,348 children 12 to 23 months of age who had received a measles‐containing vaccine from 2001 through 2011	Fever events in the o utpatient setting was defined using ICD‐9 code 780.6*. Seizure events in the postimmunisation medically attended in the emergency department or hospital setting was defined using ICD‐9 code 780.3* (convulsion) or 345* (epilepsy). The authors do not distinguish between febrile and afebrile seizures.	1) MMRV (Merck & Co) 2) MMR (Merck & Co Inc, West Point, PA) + varicella (Merck & Co) separately administered on the same day 3) MMR Risk interval after vaccination (a) 7 to 10 days (b) 0 to 42 days	Conclusions: Measles‐containing vaccines are associated with a lower increased risk of seizures when administered at 12 to 15 months of age. Findings of this study that focused on safety outcomes highlight the importance of timely immunisation of children with the first dose of measles‐containing vaccines.	12 to 15 months Fever cases (0 to 42 days) (7 to 10 days) MMRV n = 105,578 (2191) (864) MMR+V n = 520,436 (11,300) (3553) MMR n = 102,537 (2558) (760) 16 to 23 months Fever cases (0 to 42 days) (7 to 10 days) MMRV n = 14,799 (300) (116) MMR+V n = 64,551 (1310) (399) MMR n = 32,447 (744) (227) 12 to 15 months Seizures cases (0 to 42 days) (7 to 10 days) MMRV n = 105,578 (255) (99) MMR+V n = 520,436 (997) (244) MMR n = 102,537 (172) (45) 16 to 23 months Fever cases (0 to 42 days) (7 to 10 days) MMRV n = 14,799 (68) (30) MMR+V n = 64,551 (231) (70) MMR n = 32,447 (87) (31)	MMRV versusMMR+V rr (95% CI)(*) Fever 12 to 15 months (a) 1.4 (1.3 to 1.5) 16 to 23 months (a) 1.4 (1.1 to 1.7) Seizures 12 to 15 months (a) 2.0 (1.4 to 2.8) 16 to 23 months (a) 2.1 (1.3 to 3.3) (*)Poisson regression MMRV versusMMR+V RR (95% CI) (a) 2 (1.63 to 2.45) (b) 1.28 (1.13 to 1.44) MMRV versusMMR RR (95% CI) (a) 1.9 (1.43 to 2.53) (b) 1.4 (1.19 to 1.65)
cb‐Gavrielov‐Yusim 2014 cb‐Gavrielov‐Yusim 2014 Retrospective cohort study	Index cohort All participants were aged 10 to 24 months. (intervention) n = 8344 MMRV immunised from 1 September 2008 to 31 December 2009 Comparison cohorts n = 90,294 MMR immunised from 1 January 2005 to 31 August 2008	Febrile convulsion Validation FC cases were retrieved using the following coded and free‐text diagnoses: “convulsions in newborn”, “convulsions”, “febrile convulsions”, “complex febrile convulsions”, “other convulsions”. Children diagnosed with FC differential diagnoses during the observational period, i.e. head trauma, epilepsy, or CNS infection, were excluded from the study. The exact coded and free‐text diagnoses used to depict coincidental differential conditions were “concussion”, “cerebral disease”, “acquired hydrocephalus”, “cerebral palsy”, “cerebral cyst”, “epilepsy”, “meningism”, types of “bacterial meningitis”, “encephalitis”, “meningococcal meningitis”, “aseptic viral meningitis”. Children were also excluded from the study if they had a history of mumps, measles, rubella, or varicella prior to vaccination.	MMRV Priorix‐Tetra MMR (Priorix) GSK Priorix‐Tetra combines the components of 2 of GSK's live attenuated vaccines: MMR (Priorix) and varicella vaccine (Varilrix). Risk intervals Postvaccination (a) 40 days (b) 5 to 12 days (c) 7 to 10 days	Conclusion: "The risk of FC is elevated in children immunized with GSK’s MMRV vaccine. This risk is transient and appears during the second week following immunization. The relative fraction of FC attributable to MMRV vaccine is very low in the target population, and is not detectable in extended follow‐up."	N cases MMRV/ N MMRV versus N cases MMR/ N MMR (a) 19/8344 versus 198/90,294 (b) 8/8344 versus 38/90,294 (c) 7/8344 versus 30/90,294	OR (95% CI) unadjusted estimates (a) 1.04 (0.65 to 1.66) (b) 2.28 (1.06 to 4.89) (c) 2.53 (1.11 to 5.76) adjusted estimate(**) (a) 1.00 (0.6 to 1.67) (b) 2.16 (1.01 to 4.64) (c) 2.36 (1.03 to 5.38) (**) 2 different types of multivariate models were used: (a) Cox regression HR (b) logistic‐regression OR (c) logistic‐regression OR Due to rarity of events, HR and OR are very close.
cb‐Schink 2014 Matched cohort study	All children born between 1 January 2004 and 31 December 2008 n = 226,267 received an immunisation with 1 of the index vaccines during the study period (2006 to 2008) Index cohort n = 82,656 MMRV Comparison cohorts n = 111,241 MMR n = 32,370 MMR+V	Febrile convulsions Diagnosis of FC, i.e. an ICD‐10‐GM code R56.0 in any of the hospital diagnoses. 2 outcome definitions, as follows. The primary outcome “FC narrow” was defined as hospitalisation where no alternative plausible cause of FC. This endpoint included: (i) all hospitalisation with FC as main discharge diagnosis; (ii) all hospitalisation with FC as main admission diagnosis and without a main discharge diagnosis of an infectious disease (except measles, mumps, rubella, or chickenpox) or a neurological condition; (iii) all hospitalisation with FC as secondary or ancillary diagnosis and a main discharge diagnosis coded as complication following immunisation (ICD‐10 code T88.0 infection following immunization or T88.1 other complications following immunization, not elsewhere classified). Due to exclusion of alternative causes of FC in this outcome definition, it was assumed that it would have higher specificity, but lower sensitivity. The secondary outcome “FC Jacobsen” was defined as follows: only hospitalisations for FC with a neurological condition coded as main discharge diagnosis were excluded (cb‐Jacobsen 2009). Consequently, “FC Jacobsen” included: (i) all hospitalisation with FC as main discharge diagnosis; (ii) all hospitalisation with FC as main admission diagnosis and without a main discharge diagnosis of a neurological condition; and (iii) all hospitalisation with FC as secondary or ancillary diagnosis and with a main discharge diagnosis coded as complication following immunisation. “FC narrow” cases are a subset of “FC Jacobsen” cases.	MMRV: Priorix‐Tetra (GSK) compared to MMR and V vaccines (MMR+V). Risk interval postvaccination (a) 0 to 4 days (b) 5 to 12 days (c) 13 to 30 days (d) 0 to 30 days .	Conclusion: This study suggests a similar risk of FC after a first dose of Priorix‐Tetra as has been observed for a first dose of ProQuad, pointing to a class effect of these quadrivalent vaccines. The elevated risk of FC observed for the quadrivalent vaccines has to be weighed against the advantage of only 1 injection for the child and the potential benefit of an increased varicella immunisation coverage.	FC narrow MMRV versusMMR matched n = 74,734 case versus cases (a) 4 versus 5 (b) 14 versus 3 (c) 4 versus 9 (d) 22 versus 17 FC narrow MMRV versusMMR+V matched n = 32,180 case versus cases (a) 2 versus 0 (b) 5 versus 1 (c) 4 versus 9 (d) 22 versus 17 FC narrow MMRV versusMMR/MMR+V matched n = 82,561 case versus cases (a) 4 versus 4 (b) 18 versus 4 (c) 4 versus 8 (d) 26 versus 16 FC Jacobsen MMRV versusMMR matched n = 74,734 case versus cases (a) 7 versus 13 (b) 45 versus 19 (c) 35 versus 31 (d) 87 versus 63 FC Jacobsen MMRV versusMMR+V matched n = 32,180 case versus cases (a) 5 versus 4 (b) 21 versus 14 (c) 18 versus 12 (d) 44 versus 30 FC Jacobsen MMRV versusMMR/MMR+V matched n = 82,561 case versus cases (a) 8 versus 15 (b) 51 versus 21 (c) 40 versus 31 (d) 99 versus 67	OR (95% CI) FC narrow MMRV versusMMR (a) 0.8 (0.3 to 2.5) (b) 4.1 (1.3 to 12.7) (c ) 0.5 (0.2 to 1.4) (d) 1.3 (0.7 to 2.4) FC narrow MMRV versusMMR+V (a) 5.3 (0.4 to 70) (b) 3.5 (0.76 to 19) (c ) 1.5 (0.3 to 8.7) (d) 3.9 (1 to 14.5) FC narrow MMRV versusMMR/MMR+V (a) 1 (0.3 to 3.3) (b) 4.1 (1.5 to 11.1) (c ) 0.5 (0.2 to 1.6) (d) 1.6 (0.9 to 3) FC Jacobsen MMRV versusMMR (a) 0.5 (0.2 to 1.3) (b) 2.3 (1.4 to 3.9) (c ) 1.1 (0.7 to 1.8) (d) 1.4 (1 to 1.9) FC Jacobsen MMRV versusMMR+V (a) 1.1 (0.3 to 3.5) (b) 1.5 (0.8 to 2.9) (c ) 1.6 (0.8 to 3.2) (d) 1.5 (1 to 2.4) FC Jacobsen MMRV versusMMR/MMR+V (a) 0.5 (0.2 to 1.2) (b) 2.4 (1.5 to 3.9) (c ) 1.3 (0.8 to 2) (d) 1.5 (1.1 to 2)
cb‐Klein 2017 Retrospective cohort study linked to cb‐Klein 2012; cb‐Klein 2010	n = 946,806 children < 36 months of age who had received a first dose of any measles‐containing vaccine from 2000 to 2012	Fever visit Fever visits using ICD‐9 code 780.6. Fever due to an MCV was defined as any clinic or emergency department visit with a fever code 7 to 10 days after a first dose of any MCV (henceforth known as ‘‘MCV‐associated fever”). This study analysed all fevers during postvaccination days 7 to 10 as if they were due to MCV.	1) MMRV (Merck & Co) 2) MMR (Merck & Co Inc, West Point, PA) + varicella (Merck & Co) separately administered on the same day 3) MMR Risk interval after vaccination (a) 7 to 10 days	Conclusion: This study identified risk factors associated with developing fever 7 to 10 days after a first dose of measles‐containing vaccines. The study confirmed previous findings that fever was more often associated with receipt of MMRV as compared with MMR vaccine and with older age at time of vaccination during the second year of life, and further found that prior fever and seizure events were associated with fever after measles vaccine and that being fever‐prone in general predicted fever after measles‐containing vaccine. Even after adjusting for general individual and familial susceptibility to fever, fever due to measles vaccine specifically clustered in families. This study suggests an important link between population health (surveillance of a large population for vaccine adverse events) and personalised medicine (possible genetic basis for susceptibility to fever after MCV). Future work is needed to further define this possible relationship of genetics and vaccine‐associated fever.	MMRV versus MMR (a) MCV‐associated fever (b) MCV‐associated fever (older sibling with MCV‐associated fever)	OR (95% CI)(*) (a) 1.3 (1.2 to 1.5) (b) 1.5 (1.2 to 1.8) (*)logistic regression

CI: confidence interval
CNS: central nervous system
FC: febrile convulsion
HR:hazards ratio
ICD: International Classification of Diseases
ICD‐10‐GM: International Classification of Diseases. Tenth Revision, German Modification
incidence: cases/PT
MCV: measles‐containing vaccine
MMR: measles, mumps, rubella vaccine
MMRV: measles, mumps, rubella, and varicella vaccine
MMR+V: measles, mumps, rubella, and varicella vaccine
OR: odds ratio
PT: person‐time
rr: rate ratio (relative incidence, incidence rate ratio)
RR: risk ratio (relative risk)