Timing Is Everything in First Dose of Measles-Containing Vaccines

Timing Is Everything in First Dose of Measles-Containing Vaccines CME/CE

News Author: Diedtra Henderson
CME Author: Charles P. Vega, MD, FAAFP

CME/CE Released: 10/30/2013; Valid for credit through 10/30/2014

Clinical Context

Failure to fully vaccinate children is a serious public health concern, and an editorial by Feemster and Offit, which accompanies the current study, examines the phenomenon of undervaccination. They cite a recent study that describes the prevalence of missing at least 1 vaccination by the second birthday at 48.7% among US children. There are many reasons for undervaccination, but approximately 12% of these cases were due to parental choice to delay vaccination or outright refusal of vaccination.

Many parents refuse vaccines because of safety concerns, although delayed vaccination places the child at increased risk for infectious disease. However, scarce data exist regarding how a delayed vaccine schedule affects vaccine safety. The current study by Rowhani-Rahbar and colleagues fills this gap by focusing specifically on vaccines against measles.

Study Synopsis and Perspective

Infants who received vaccines containing live, attenuated measles were less likely to have a seizure within 7 to 10 days if the vaccination was administered at the recommended time, between ages 12 and 15 months, compared with older infants whose first measles dose was delayed, according to a large retrospective cohort study.

Ali Rowhani-Rahbar, MD, MPH, PhD, from the Kaiser Permanente Vaccine Study Center, Oakland, California, and coauthors published their results online October 14 in JAMA Pediatrics.

Two US Food and Drug Administration–approved vaccines containing live, attenuated measles are administered to American children: the measles, mumps, and rubella vaccine (MMR) and the MMR and varicella vaccine. The first shot of the 2-dose series is recommended to be given to infants between ages 12 and 15 months. Approximately 85% of infants receive the vaccination by age 19 months.

To examine the effect of infant age on the risk for vaccine-related fever and seizures, the researchers tapped the Vaccine Safety Datalink, a collaborative effort between the Centers for Disease Control and Prevention (CDC) and 10 managed care organizations. The database pools information on more than 9 million members and is used to track vaccine safety in the United States. The authors focused on the records of children between 12 and 23 months old who had received measles-containing vaccine between January 2001 and December 2011, including 840,348 infants.

"We found that the magnitude of increased risk of seizures following immunization with measles-containing vaccines during the second year of life depends on age," Dr. Rowhani-Rahbar and colleagues write. "While measles-containing vaccines administered at 12 to 15 months of age are associated with an increased risk of seizures 7 to 10 days following immunization [relative risk, 3.4 (95% confidence interval [CI], 3.0 - 3.9); attributable risk, 4.0 excess cases per 10,000 doses (95% CI, 3.4 - 4.6)], their delayed administration at 16 to 23 months of age may result in an even greater increased risk of that adverse event following immunization [relative risk, 6.5 (95% CI, 5.3 - 8.1); attributable risk, 9.5 excess cases per 10,000 doses (95% CI, 7.6 - 11.5)]."

In an accompanying editorial, Kristen A. Feemster, MD, MPH, MSHPR, and Paul Offit, MD, both from the Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, and the Division of Infectious Diseases and the Vaccine Education Center, The Children's Hospital of Philadelphia, called the study "significant."

"First, it reinforces the well-established safety of the current recommended schedule, which is based on many years of prelicensure and postlicensure safety and effectiveness data, including concomitant use studies," Dr. Feemster and Dr. Offit write.

"Second, this study provides an example of the potential for current vaccine safety surveillance mechanisms to identify outcomes associated with alternate vaccine schedules."

Dr. Rowhani-Rahbar and colleagues note that a possible reason for the differing risk profiles is the ability of immune systems of 16- to 23-month-olds to mount a more rigorous response to the measles vaccine, compared with younger infants.

"Vaccines are typically recommended at an age that maximizes the likelihood of vaccine-induced protection and minimizes the risk of morbidity and mortality that would occur by delaying immunization. The safety profile of vaccines at different ages is another important consideration in immunization policy decision making," the authors conclude.

Support for this study was provided by the CDC. Nine of the 13 study authors have received institutional research support from the CDC, and 1 study author has disclosed being employed by the CDC. In addition, 1 coauthor has received institutional research support from GlaxoSmithKline; 1 coauthor, from MedImmune; 1 coauthor, from Merck & Co; 1 coauthor, from the National Institutes of Health, Novartis, Pfizer, and sanofi-pasteur; and 2 coauthors, from Merck & Co, Novartis, GlaxoSmithKline, Pfizer, and sanofi-pasteur. The remaining study authors and editorialists have disclosed no relevant financial relationships.

JAMA Pediatr. Published online October 14, 2013. Abstract

Study Highlights

• Researchers used data from the Vaccine Safety Datalink to determine the effect of age of administration of measles-containing vaccines on the rate of febrile seizures. This database includes information on more than 9 million members annually.
• Specifically, the study population included children between 12 and 23 months old who received vaccinations between 2001 and 2011.
• The main study outcomes were diagnosis codes for either fever or seizure in the 42 days after vaccination. The period from 7 to 10 days after vaccination was considered the major at-risk time for these outcomes. The remainder of the 42-day observation period served as a control.
• Researchers compared the rates of fever and seizures after vaccination among children ages 12 to 15 months vs ages 16 to 23 months. They also evaluated whether the addition of the varicella vaccine to the MMR vaccine as a combination vaccine affected the rate of febrile seizures.
• A total of 840,348 children provided data for study analysis. 51% of children were boys. The most commonly administered vaccine was MMR with varicella as a separate injection, and most vaccines were delivered at ages 12 to 13 months.
• There were 18,403 fever events after vaccination, 32.2% of which occurred 7 to 10 days after vaccination.
• There were 1810 seizure events after vaccination, 28.7% of which occurred 7 to 10 days after vaccination.
• The incidence rate ratios in comparing the at-risk time vs the control period for fever after vaccination were 4.4 and 5.9 among 12- to 15-month-old children and 16- to 23-month-old children, respectively. This difference was significant, but the attributable risk for excess fever associated with older age was not.
• Similarly, the relative risk for seizures was significantly higher among 16- to 23-month-old children (6.5; 95% CI, 5.3 - 8.1) compared with 12- to 15-month-old children (3.4; 95% CI, 3.0 - 3.9). Vaccination after age 15 months resulted in 9.5 excess cases of seizure compared with earlier vaccination (4.0 excess cases); this result was significant.
• The MMR vaccine, which included varicella as well in a single injection, was associated with a significant increase in the rates of fever (40%) and seizures (approximately 100%) compared with MMR with or without varicella as a separate injection.
• The higher rates of fever and seizures associated with the use of the combined MMR-varicella vaccine did not vary based on the child's age.

Clinical Implications

• The rate of undervaccination of children younger than 2 years is nearly 50% in the United States, and approximately 12% of cases of undervaccination are caused by parental choice against vaccines.
• The current study by Rowhani-Rahbar and colleagues demonstrates that the risk for seizures is higher when measles-containing vaccines are administered at ages 16 to 23 months vs ages 12 to 15 months. The rate of fever after vaccination was also higher among older children, and the use of the combined MMR-varicella vaccine was associated with higher risks for fever and seizures.