News Author: Laurie Barclay, MD
CME Author: Laurie Barclay, MD
March 18, 2008 — The Advisory Committee on Immunization Practices (ACIP) no longer prefers administering combination measles, mumps, rubella, and varicella vaccine (MMRV) vs separate injections of equivalent component vaccines, according to updated guidelines published in the March 14 issue of the Morbidity and Mortality Weekly Report.
“On February 27, 2008, new information was presented to the Advisory Committee on Immunization Practices (ACIP) regarding the risk for febrile seizures among children aged 12-23 months after administration of the combination measles, mumps, rubella, and varicella (MMRV) vaccine (ProQuad®, Merck & Co., Inc., Whitehouse Station, New Jersey),” write N.P. Klein, MD, PhD, from the Kaiser Permanente Vaccine Study Center in Oakland, California, and the Vaccine Safety Datalink (VSD) Rapid Cycle Analysis Team, and colleagues. “This report summarizes current knowledge regarding the risk for febrile seizures after MMRV vaccination and presents updated ACIP recommendations that were issued after presentation of the new information. These updated recommendations remove ACIP’s previous preference for administering combination MMRV vaccine over separate injections of equivalent component vaccines (i.e., measles, mumps, and rubella [MMR] vaccine and varicella vaccine).”
On September 6, 2005, the US Food and Drug Administration (FDA) licensed the combination tetravalent MMRV vaccine for use in children aged 12 months to 12 years. To prevent measles, mumps, rubella, and varicella, the MMRV vaccine can be used instead of the trivalent MMR and monovalent varicella vaccines. To fulfill the recommended 2-dose vaccine policies, the first dose is recommended at ages 12 to 15 months and the second at ages 4 to 6 years.
Compared with administration of MMR and varicella vaccines at the same visit, the MMRV vaccine was associated with a higher incidence of fever 5 to 12 days and 0 to 42 days after the first vaccine dose, based on prelicensure studies. Concern regarding the possible increased risk for febrile seizures potentially associated with MMRV vaccination led the Centers for Disease Control and Prevention (CDC) and Merck to conduct postlicensure studies.
According to data from the VSD, which routinely monitors vaccine safety with use of computerized patient data, there was an increased risk for seizures of any cause in children aged 12 to 23 months who received the MMRV vs the MMR vaccine (many children also received the varicella vaccine). When children given the MMRV vaccine were compared with those given the MMR and varicella vaccines at the same visit, both groups had statistically significant clustering of seizures 7 to 10 days after vaccination.
A subsequent VSD study compared the risk for febrile seizures 7 to 10 days after vaccination in 43,353 children aged 12 to 23 months who received the MMRV vaccine vs 314,599 children aged 12 to 23 months who received the MMR and varicella vaccines at the same visit. Preliminary findings show a rate of febrile seizures of 9 per 10,000 vaccinations among children who received the MMRV vaccine vs 4 per 10,000 vaccinations in those who received the MMR and varicella vaccines (adjusted odds ratio [OR], 2.3; 95% confidence interval [CI], 1.6 – 3.2; P < .0001).
Based on these findings, approximately 1 additional febrile seizure would occur in the 7- to 10-day postvaccination period among every 2000 children vaccinated with the MMRV vaccine vs children vaccinated with the MMR and varicella vaccines given at the same visit. Of 166 children who had febrile seizures after vaccination, 26 (16%) were hospitalized, and none died.
An interim analysis of an ongoing postlicensure study being conducted by Merck showed a 2.3-fold (95% CI, 0.6 – 9.0) higher relative risk (RR) for confirmed febrile seizures 5 to 12 days after MMRV vaccination vs a matched control group. Although the RR was not statistically significant, it was similar to the OR reported by the VSD study for the period 7 to 10 days after vaccination.
Neither the VSD nor the Merck study evaluated the risk for febrile seizures after the MMRV vaccine was given as a second dose at ages 4 to 6 years, but rates of febrile seizure are typically lower at ages 4 to 6 years vs 12 to 15 months, and previous studies have shown that the second dose of MMRV vaccine is less likely to cause fever than the first dose.
“Febrile seizures are not uncommon in young children and generally have an excellent prognosis, although they often are distressing to parents and other family members,” the authors of the guidelines write. “Febrile seizures can occur after certain vaccinations, although rarely. MMR vaccination has been associated previously with febrile seizures occurring 8-14 days later; approximately one additional febrile seizure occurs among every 3,000-4,000 children vaccinated with MMR vaccine, compared with children not vaccinated during the preceding 30 days.”
The 2007 ACIP recommendations for the prevention of varicella were consistent with the ACIP General Recommendations on Immunization in that they included a preference for use of a combination MMRV vaccine vs separate injections of equivalent component vaccines (MMR and varicella vaccines).
Based on the VSD and Merck studies that suggested an elevated risk for febrile seizures after the first dose of MMRV vaccine, the ACIP voted to change the preference language for the MMRV vaccine at its February 27, 2008, meeting. This change took into account the availability of alternative options for vaccination against measles, mumps, rubella, and varicella and the limited supply of MMRV vaccine because of manufacturing constraints unrelated to vaccine safety or efficacy.
The updated ACIP recommendation now reads as follows: “Combination MMRV vaccine is approved for use among healthy children aged 12 months-12 years. MMRV vaccine is indicated for simultaneous vaccination against measles, mumps, rubella, and varicella. ACIP does not express a preference for use of MMRV vaccine over separate injections of equivalent component vaccines (i.e., MMR vaccine and varicella vaccine).”
The ACIP also advocated that a work group be convened for in-depth analysis of data regarding the increased risk for febrile seizures after the first dose of MMRV vaccine. Based on these findings and other information that becomes available, the CDC, the FDA, and the ACIP will consider future policy options, communicate updates, and implement additional necessary actions.
The Vaccine Adverse Event Reporting System (VAERS) should be notified of clinically significant adverse events after vaccination (http://www.vaers.hhs.gov or 800-822-7967).
MMWR Morb Mortal Wkly Rep. 2008;57:258-260.