Objective: In February 2008, we alerted the Advisory Committee on Immunization Practices to preliminary evidence of a twofold increased risk of febrile seizures after the combination measles-mumps-rubella-varicella (MMRV) vaccine when compared with separate measles-mumps-rubella (MMR) and varicella vaccines. Now with data on twice as many vaccine recipients, our goal was to reexamine seizure risk after MMRV vaccine.

Methods: Using 2000-2008 Vaccine Safety Datalink data, we assessed seizures and fever visits among children aged 12 to 23 months after MMRV and separate MMR + varicella vaccines. We compared seizure risk after MMRV vaccine to that after MMR + varicella vaccines by using Poisson regression as well as with supplementary regressions that incorporated chart-review results and self-controlled analyses.

Results: MMRV vaccine recipients (83,107) were compared with recipients of MMR + varicella vaccines (376,354). Seizure and fever significantly clustered 7 to 10 days after vaccination with all measles-containing vaccines but not after varicella vaccination alone. Seizure risk during days 7 to 10 was higher after MMRV than after MMR + varicella vaccination (relative risk: 1.98 [95% confidence interval: 1.43-2.73]). Supplementary analyses yielded similar results. The excess risk for febrile seizures 7 to 10 days after MMRV compared with separate MMR + varicella vaccination was 4.3 per 10,000 doses (95% confidence interval: 2.6-5.6).

Conclusions: Among 12- to 23-month-olds who 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.

Soreness at injection site: 1 child out of 4.


Fever: 1 child out of 7.


Rash: 1 child out of 25.





Because these studies showed an increased risk for fever after MMRV vaccination, compared with vaccination with MMR and varicella vaccines in separate shots at the same visit, there was concern about a potential increased risk for febrile seizures (seizures triggered by a rising or dropping fever) after MMRV vaccination. As part of routine monitoring of vaccine safety for all new vaccines, CDC conducted studies of the safety of MMRV vaccine. In these studies, CDC analyzed data reported to the VSD regarding MMRV vaccine given to children aged 12-23 months, the age when the first dose of MMRV or MMR and varicella vaccines is recommended. The study assessed the rate of several medical events after MMRV vaccination, including febrile seizures.
After MMRV vaccine was licensed

7-10 days after the first dose of vaccination, the rate of febrile seizures was about 2 times higher among children who received MMRV vaccine (8.5 per 10,000 children vaccinated) than among children who received measles, mumps, and rubella (MMR) and varicella vaccines separately at the same visit (4.2 per 10,000 children vaccinated), mainly before MMRV vaccine became available.


7-10 days after vaccination, about one additional febrile seizure would be expected to occur among every 2,300 children vaccinated with first-dose MMRV vaccine compared with children vaccinated with the first doses of MMR and varicella shots at the same visit.



Merck, the manufacturer of the MMRV vaccine, also sponsored an observational study (after MMRV vaccine was licensed) of febrile seizures after the first dose of MMRV vaccine was given to children aged 12-23 months. Here are some key findings from that study:

The rate of febrile seizures 5-12 days after first dose of vaccination was 7.0 per 10,000 children who received MMRV vaccine compared with a rate of 3.2 per 10,000 children who received measles, mumps, rubella (MMR) and varicella vaccines separately at the same visit (3.2 is the rate before MMRV vaccine became available).


5-12 days after vaccination, about one additional febrile seizure would be expected to occur among every 2,600 children vaccinated with the first dose of MMRV vaccine compared with children vaccinated with the first doses of MMR and varicella vaccines administered at the same visit.



These findings and other relevant data were presented to the Advisory Committee on Immunization Practices (ACIP) . In May 2010, CDC released new recommendations on the use of MMRV vaccine.
To help parents and healthcare providers better understand the ACIP recommendations, risks and benefits of MMRV vaccine, and febrile seizures, the following information is available:

For Parents and Caregivers: Fact Sheet on Measles, Mumps, Rubella, and Varicella


For Parents and Caregivers: Frequently Asked Questions on MMRV Vaccines


For Providers: Fact Sheet for Providers on MMR & Varicella Vaccines or MMRV Vaccine


For Providers: Frequently Asked Questions on MMRV Vaccines


Frequently Asked Questions about Febrile Seizures Following Childhood Vaccinations


Information on the VSD MMRV Vaccine Safety Study


Merck Package Insert for ProQuad (MMRV vaccine)



MMRV Vaccine and Febrile Seizures
Background
The study, "Measles-Mumps-Rubella-Varicella Combination Vaccine and the Risk of Febrile Seizures" uses computerized information from CDC's Vaccine Safety Datalink (VSD) Project . VSD consists of managed care organizations which gather vaccination and demographic information, as well as health outcomes of their patients (more than 9.2 million across the U.S.)
Researchers examined VSD data on more than 83,000 children who received their first dose of MMRV vaccine and over 376,000 children who received their first doses of MMR and varicella vaccines given at the same visit from the year 2000 to the year 2008.
Main findings 1

Main findings 1

For MMRV combination vaccine, there was 1 additional febrile seizure for every 2,300 doses given, compared to separate MMR plus varicella vaccines in the 7 to 10 days following vaccination.


Of the children identified as having seizures following the 7 to 10-day vaccination period, about 90% were found to be febrile seizures.


The rate of seizures in this timeframe was 85 per 1000 person-years in the MMRV vaccine group compared to 42 per 1000 in the MMR and varicella vaccine group. This risk was about 2 times higher in children who received the combination shot (MMRV) versus the single shots (MMR and varicella).



Conclusions
CDC recommends providers who choose to use the combination MMRV vaccine be aware of and clearly communicate to parents and caregivers the increased risk of fever and seizure within the 7 to 10 days following vaccination.
Parents should be educated on the risk of seizure following the combination MMRV vaccine and know their options. Most children recover quickly from febrile seizures and have no lasting effects.

Background: Considering the febrile seizure rate, there is no longer a clear preference for use of measles-mumps-rubella-varicella (MMRV) vaccine over separate measles-mumps-rubella (MMR) and varicella (V) vaccine. This work was undertaken to assess the risk of febrile seizure after MMRV vaccine in children.

Methods: We searched PubMed, Embase, BIOSIS Previews, Scopus, Web of Science, Cochrane Library and other databases through 12 December 2014. Meta-analysis was conducted using R version 3.1.2 and Stata version 12.0.

Results: A total of thirty-nine studies were included. Thirty-one published or unpublished clinical trials involving about 40,000 subjects did not show significant differences in incidence of febrile seizure or vaccine related febrile seizure between MMRV and MMR with or without varicella vaccine after any doses, in the risk windows of 0-28, 0-42 or 0-56 days and 7-10 days. In addition, these studies showed that the receipt of concomitant use of MMRV and other pediatric vaccines was not a significant predictor of febrile seizure. Eight post-marketing observations involving more than 3,200,000 subjects were included. No evidence suggested elevated risk of febrile seizure associated with MMRV vaccine among children aged 4-6 years old during 7-10 days or 0-42 days after vaccination. However, an approximately 2-fold increase in risk of seizure or febrile seizure during 7-10 days or 5-12 days after MMRV vaccination was found among children aged 10-24 months, although the highest incidence of seizure was still lower than 2.95‰.

Conclusions: First MMRV vaccine dose in children aged 10-24 months was associated with an elevated risk of seizure or febrile seizure. Further post-marketing restudies based on more rigorous study design are needed to confirm the findings.

Introduction: Studies have shown an increased risk of febrile convulsions (FC) after first immunization with the quadrivalent measles-mumps-rubella-varicella vaccine (MMRV) compared to a first dose of measles-mumps-rubella vaccine (MMR) only or in combination with separately administered varicella vaccine (MMR + V). Therefore, it is recommended to give MMR + V at first dose and MMRV or MMR + V at second dose. Little is known on the risk of FC after MMRV at second dose, especially whether the risk depends on age, sex, history of FC or type of first dose vaccine.

Methods: A retrospective cohort study using claims data from the German Pharmacoepidemiological Research database (GePaRD) was performed in children born between January 1st, 2004 and October 31st, 2015 who received two doses of MMRV, MMR + V or MMR. Cases were defined as hospitalization with a diagnosis of FC without neurological conditions coded as main discharge diagnosis. Unadjusted and adjusted odds ratios (OR) with 95% confidence intevals (CIs) were calculated to compare the risk of FC. Stratified analyses were performed to examine potential effect modification by age, sex, history of FC or type of first dose vaccine.

Results: In the first 30 days after second dose vaccination, 464 FCs were observed in a cohort of 528,639 children with a median age of 17 months. After adjustment for potential confounders, the adjusted OR for FC in the 30 days after vaccination was 1.25 (95% CI 0.67-2.30) for MMRV compared to MMR + V and 1.04 (0.82-1.32) for MMRV compared to MMR. History of FC was the most important risk factor with an OR of 36.26 (29.30-44.89). We found no effect modification by age, sex, history of FC, or type of first dose vaccine.

Conclusion: Use of MMRV at second dose is not associated with an increased risk of FC compared to MMR + V or MMR, irrespective of age, sex, history of FC, or type of first dose vaccine.

MMRV vaccine was licensed on the basis of non-inferior immunogenicity compared with administration of MMR and varicella at the same time, therefore the two vaccination options are considered to provide the same protection against the respective diseases. MMRV vaccine is associated with an increased risk for fever and febrile seizures among children aged 12-23 months of age during the 5-12 days after the first dose compared with the use of MMR vaccine and varicella vaccine at the same visit. However, among children who received the second dose of MMRV vaccine at age 4-6 years data do not suggest an increased risk for febrile seizures.

The relative risk of postimmunization fever was significantly greater among older children than among younger children; however, its attributable risk was not. In the analysis of vaccine type, measles, mumps, rubella, and varicella vaccine was associated with a 1.4-fold increase in the risk of fever and 2-fold increase in the risk of seizures compared with measles, mumps, and rubella vaccine administered with or without varicella vaccine in both younger and older children.

Conclusions and Relevance 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 immunization of children with the first dose of measles-containing vaccines.

Measles, mumps, and rubella (MMR) and measles, mumps, rubella, and varicella (MMRV) are the 2 live attenuated measles-containing vaccines currently licensed in the United States. These vaccines are effective, immunogenic, and generally well tolerated. Measles-containing vaccines are recommended as a 2-dose series in the United States, with the first dose administered at 12 to 15 months and the second dose at 4 to 6 years of age. Most children in the United States receive their first dose of a measles-containing vaccine between the ages of 12 and 23 months; approximately 85% of them receive this dose by 19 months of age.

Monitoring the safety of measles-containing vaccines remains an important public health issue. Previous studies have shown that these vaccines administered to children 12 to 23 months of age are associated with an increased risk of fever and febrile seizures 1 to 2 weeks following immunization; however, the exact nature of the relationship between fever and febrile seizures is not entirely understood. It is thought that, during this period, the vaccine virus replication is at its peak and can cause fever, which may in turn induce a seizure event by exceeding a certain threshold. Postlicensure studies have found that the safety profile of MMRV differs somewhat from that of the separately administered MMR and varicella (MMR+V) vaccines.

Introduction: Studies on quadrivalent measles, mumps, rubella, and varicella (MMRV) vaccines have indicated a twofold increased relative risk of febrile convulsion (FC) after the first dose compared to MMR and V administered at the same medical visit (MMR+V).

Areas Covered: This narrative review contextualizes FC occurrence after the first MMRV vaccine dose from a clinical perspective and outlines approaches to attenuate FC occurrence post-vaccination.

Expert Opinion: While the relative FC risk increases after the first dose of MMRV compared to MMR+V vaccine in measles-naïve infants, the attributable risk is low the overall FC risk in the pediatric population triggered by other causes, like natural exposure to pathogens or routine vaccination. No increased risk of FC has been reported after MMRV co-administration with other routine vaccines compared to MMRV alone. Based on our findings and considering the MMRV vaccination benefits (fewer injections, higher coverage, better vaccination compliance), the overall benefit-risk profile of MMRV vaccine is considered to remain positive. Potential occurrence of FC in predisposed children (e.g. with personal/family history of FC) may be attenuated if they receive MMR+V instead of MMRV as the first dose. It is also important to monitor vaccinees for fever during the first 2 weeks post-vaccination.