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Background and Objectives: All measles-containing vaccines are associated with several types of adverse events, including seizure, fever, and immune thrombocytopenia purpura (ITP). Because the measles-mumps-rubella-varicella (MMRV) vaccine compared with the separate measles-mumps-rubella (MMR) and varicella (MMR + V) vaccine increases a toddler's risk for febrile seizures, we investigated whether MMRV is riskier than MMR + V and whether either vaccine elevates the risk for additional safety outcomes., Methods: Study children were aged 12 to 23 months in the Vaccine Safety Datalink from 2000 to 2012. Nine study outcomes were investigated: 7 main outcomes (anaphylaxis, ITP, ataxia, arthritis, meningitis/encephalitis, acute disseminated encephalomyelitis, and Kawasaki disease), seizure, and fever. Comparing MMRV with MMR + V, relative risk was estimated by using stratified exact binomial tests. Secondary analyses examined post-MMRV or MMR + V risk versus comparison intervals; risk and comparison intervals were then contrasted for MMRV versus MMR+V., Results: We evaluated 123,200 MMRV and 584,987 MMR + V doses. Comparing MMRV with MMR + V, risks for the 7 main outcomes were not significantly different. Several outcomes had few or zero postvaccination events. Comparing risk versus comparison intervals, ITP risk was higher after MMRV (odds ratio [OR]: 11.3 [95% confidence interval (CI): 1.9 to 68.2]) and MMR + V (OR: 10 [95% CI: 4.5 to 22.5]) and ataxia risk was lower after both vaccines (MMRV OR: 0.8 [95% CI: 0.5 to 1]; MMR + V OR: 0.8 [95% CI: 0.7 to 0.9]). Compared with MMR + V, MMRV increased risk of seizure and fever 7 to 10 days after vaccination., Conclusions: This study did not identify any new safety concerns comparing MMRV with MMR + V or after either the MMRV or the MMR + V vaccine. This study provides reassurance that these outcomes are unlikely after either vaccine., (Copyright © 2015 by the American Academy of Pediatrics.)

Background: Little is known regarding the timing of childhood vaccination and postvaccination seizures., Methods: In a cohort of 323 247 US children from the Vaccine Safety Datalink born from 2004 to 2008, we analyzed the association between the timing of childhood vaccination and the first occurrence of seizure with a self-controlled case series analysis of the first doses of individual vaccines received in the first 2 years of life., Results: In infants, there was no association between the timing of infant vaccination and postvaccination seizures. In the second year of life, the incident rate ratio (IRR) for seizures after receipt of the first measles-mumps-rubella vaccine (MMR) dose at 12 to 15 months was 2.65 (95% confidence interval [CI] 1.99-3.55); the IRR after an MMR dose at 16 to 23 months was 6.53 (95% CI 3.15-13.53). The IRR for seizures after receipt of the first measles-mumps-rubella-varicella vaccine (MMRV) dose at 12 to 15 months was 4.95 (95% CI 3.68-6.66); the IRR after an MMRV dose at 16 to 23 months was 9.80 (95% CI 4.35 -22.06)., Conclusions: There is no increased risk of postvaccination seizure in infants regardless of timing of vaccination. In year 2, delaying MMR vaccine past 15 months of age results in a higher risk of seizures. The strength of the association is doubled with MMRV vaccine. These findings suggest that on-time vaccination is as safe with regard to seizures as delayed vaccination in the first year of life, and that delayed vaccination in the second year of life is associated with more postvaccination seizures than on-time vaccination., (Copyright © 2014 by the American Academy of Pediatrics.)

Many reports associating uveitis after vaccination have been reported, including 2 cases after measles, mumps, and rubella (MMR) vaccine. We report the case of a 12-month-old girl who developed a unilateral anterior uveitis with rubeosis and cataract 3 months after an MMR vaccination at 9 months of age. Aqueous humor analysis showed the presence of more rubella-specific immunoglobulin G in the affected eye than in the unaffected one. This is the second report showing an association between MMR vaccine and anterior uveitis and the first supported by the presence of intraocular rubella antibodies.

Objectives: To investigate if changes in the national Swedish vaccination program coincided with changes in the celiac disease (CD) incidence rate in infants (ie, the Swedish CD Epidemic), and to assess the potential association between these vaccinations and CD risk., Methods: All studies were based on the National Swedish Childhood Celiac Disease Register. Using an ecological approach, we plotted changes over time in the national vaccination program in the graph displaying CD incidence rate. A population-based incident case-referent study of invited infants was performed. Exposure information was received through a questionnaire and child health clinic records. Vaccines explored were diphtheria/tetanus, pertussis (acellular), polio (inactivated), Haemophilus influenzae type b (conjugated), measles/mumps/rubella, and live attenuated bacillus Calmette-Guérin (BCG) in children with increased tuberculosis risk. Findings were subjected to a birth cohort analysis., Results: Introduction of pertussis vaccine coincided in time with decreasing CD incidence rates. In the infant case-referent study, however, neither vaccination against pertussis (odds ratio 0.91; 95% confidence interval 0.60-1.4), nor against Haemophilus influenzae type b or measles/mumps/rubella was associated with CD. Coverage for the diphtheria/tetanus and polio vaccines was 99%. BCG was associated with reduced risk for CD (adjusted odds ratio 0.54; 95% confidence interval 0.31-0.94). Discontinuation of general BCG vaccination did not affect the cumulative incidence of CD at age 15 years., Conclusions: Early vaccinations within the national Swedish program were not associated with CD risk, nor could changes in the program explain the Swedish epidemic. A protective effect by BCG was suggested, which could be subject to further studies.

Background: In the United States, children receive 2 doses of measles-mumps-rubella vaccine (MMR) and varicella vaccine (V), the first between ages 1 to 2 years and the second between ages 4 to 6 years. Among 1- to 2-year-olds, the risk of febrile seizures 7 to 10 days after MMRV is double that after separate MMR + V. Whether MMRV or MMR + V affects risk for febrile seizure risk among 4- to 6-year-olds has not been reported., Methods: Among 4- to 6-year-old Vaccine Safety Datalink members, we identified seizures in the emergency department and hospital from 2000 to 2008 and outpatient visits for fever from 2006 to 2008 during days 7 to 10 and 0 to 42 after MMRV and MMR + V. Incorporating medical record reviews, we assessed seizure risk after MMRV and MMR + V., Results: From 2006 through 2008, 86 750 children received MMRV; from 2000 through 2008, 67 438 received same-day MMR + V. Seizures were rare throughout days 0 to 42 without peaking during days 7 to 10. There was 1 febrile seizure 7 to 10 days after MMRV and 0 after MMR + V. Febrile seizure risk was 1 per 86 750 MMRV doses (95% confidence interval, 1 per 3 426 441, 1 per 15 570) and 0 per 67 438 MMR + V doses (1 per 18 282)., Conclusions: This study provides reassurance that MMRV and MMR + V were not associated with increased risk of febrile seizures among 4- to 6-year-olds. We 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.

Objective: We assessed the immunogenicity and safety of a combination measles, mump, rubella, and varicella vaccine (MMRV) (ProQuad [Merck & Co, Inc, West Point, PA]) administered to healthy children concomitantly with a pneumococcal 7-valent conjugate vaccine (PCV-7) (Prevnar [Pfizer, Philadelphia, PA])., Patients and Methods: Healthy 12- to 15-month-old children who lacked vaccination and clinical histories for measles, mumps, rubella, varicella, and zoster but had written documentation of receipt of a 3-dose primary series of PCV-7 were randomly assigned in a 2:1:1 ratio to receive either the MMRV and PCV-7 (group 1), PCV-7 followed 6 weeks later by MMRV (group 2), or MMRV followed 6 weeks later by PCV-7 (group 3). The primary safety analysis was 56 days (28 days after each visit). Immunogenicity was evaluated 6 weeks after each vaccination., Results: A total of 1027 children were enrolled (group 1: 510; group 2: 258; group 3: 259). For all 3 groups, the antibody response rate was ≥96.8% for measles, mumps, and rubella, ≥88.0% for varicella-zoster virus, and ≥98.3% for all of the 7 Streptococcus pneumoniae serotypes. The immune responses to all antigens present in MMRV and PCV-7 were similar whether administered concomitantly or sequentially. The incidence of local and systemic adverse experiences (AEs) was comparable between group 1 and groups 2 and 3 combined. No vaccine-related serious AEs were reported., Conclusions: Concomitant administration of the MMRV and PCV-7 is highly immunogenic and generally well tolerated. Similar immune responses between the groups support concomitant administration of the MMRV and PCV-7 to healthy children 12 to 15 months of age.

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.

Background: In industrialized countries vaccination coverage remains suboptimal, partly because of perception of an increased risk of asthma. Epidemiologic studies of the association between childhood vaccinations and asthma have provided conflicting results, possibly for methodologic reasons such as unreliable vaccination data, biased reporting, and reverse causation. A recent review stressed the need for additional, adequately controlled large-scale studies., Objective: Our goal was to determine if routine childhood vaccination against pertussis was associated with subsequent development of childhood wheezing disorders and asthma in a large population-based cohort study., Methods: In 6811 children from the general population born between 1993 and 1997 in Leicestershire, United Kingdom, respiratory symptom data from repeated questionnaire surveys up to 2003 were linked to independently collected vaccination data from the National Health Service database. We compared incident wheeze and asthma between children of different vaccination status (complete, partial, and no vaccination against pertussis) by computing hazard ratios. Analyses were based on 6048 children, 23 201 person-years of follow-up, and 2426 cases of new-onset wheeze., Results: There was no evidence for an increased risk of wheeze or asthma in children vaccinated against pertussis compared with nonvaccinated children. Adjusted hazard ratios comparing fully and partially vaccinated with nonvaccinated children were close to one for both incident wheeze and asthma., Conclusion: This study provides no evidence of an association between vaccination against pertussis in infancy and an increased risk of later wheeze or asthma and does not support claims that vaccination against pertussis might significantly increase the risk of childhood asthma.

Objective: The purpose of this work was to assess the association between media coverage of the MMR-autism controversy and MMR immunization in the United States., Methods: The public-use files of the National Immunization Survey were used to estimate annual MMR coverage from 1995 to 2004. The primary outcome was selective measles-mumps-rubella nonreceipt, that is, those children who received all childhood immunizations except MMR. Media coverage was measured by using LexisNexis, a comprehensive database of national and local news media. Factors associated with MMR nonreceipt were identified by using a logistic regression model., Results: Selective MMR nonreceipt, occurring in as few as 0.77% of children in the 1995 cohort, rose to 2.1% in the 2000 National Immunization Survey. Children included in the 2000 National Immunization Survey were born when the putative link between MMR and autism surfaced in the medical literature but before any significant media attention occurred. Selective nonreceipt was more prevalent in private practices and unrelated to family characteristics. MMR nonreceipt returned to baseline before sustained media coverage of the MMR-autism story began., Conclusions: There was a significant increase in selective MMR nonreceipt that was temporally associated with the publication of the original scientific literature, suggesting a link between MMR and autism, which preceded media coverage of the MMR-autism controversy. This finding suggests a limited influence of mainstream media on MMR immunization in the United States.

Objective: This study evaluated the safety, tolerability, and immunogenicity of live attenuated influenza vaccine administered concurrently with measles-mumps-rubella vaccine and varicella vaccine to healthy children 12 to 15 months of age., Methods: Children were assigned randomly to receive (1) measles-mumps-rubella vaccine, varicella vaccine, and intranasal placebo on day 0, followed by 1 dose of live attenuated influenza vaccine on days 42 and 72; (2) measles-mumps-rubella, varicella, and live attenuated influenza vaccines on day 0, followed by a second dose of live attenuated influenza vaccine on day 42 and intranasally administered placebo on day 72; or (3) 1 dose of live attenuated influenza vaccine on days 0 and 42, followed by measles-mumps-rubella and varicella vaccines on day 72. Serum samples were collected before vaccination on days 0, 42, and 72. Reactogenicity events and adverse events were collected through day 41 after concurrent vaccinations and through day 10 after administration of live attenuated influenza vaccine or placebo alone., Results: Among 1245 (99.5%) evaluable children, seroresponse rates and geometric mean titers for measles-mumps-rubella vaccine and varicella vaccine were similar with concurrent administration of live attenuated influenza vaccine or placebo (seroresponse rates of > or = 96% for measles-mumps-rubella vaccine and > or = 82% for varicella vaccine in both groups). Hemagglutinin-inhibiting antibody geometric mean titers and seroconversion rates to influenza strains in live attenuated influenza virus vaccine were similar after the vaccine was administered alone (seroconversion rates of 98%, 92%, and 44% for H3, B, and H1 strains, respectively) or with measles-mumps-rubella and varicella vaccines (seroconversion rates of 98%, 96%, and 43%). The incidences of reactogenicity events and adverse events were similar among treatment groups., Conclusions: Concurrent administration of live attenuated influenza vaccine with measles-mumps-rubella vaccine and varicella vaccine provided equivalent immunogenicity, compared with separate administration, and was well tolerated.

Background: The measles-mumps-rubella vaccine has been associated with immune thrombocytopenia purpura in 2 small studies., Methods: By using the Vaccine Safety Datalink, we identified measles-mumps-rubella-vaccinated children aged 1 to 18. A case of immune thrombocytopenia purpura was defined as a patient with a platelet count of < or = 50,000/microL with clinical bleeding and normal red and white blood cell indices. The immune thrombocytopenia purpura incidence rates during exposed (42 days after vaccination) and unexposed time periods were determined. A retrospective cohort of vaccinated children was used to determine incident rate ratios for children aged 1 to 18 years, 12 to 23 months, and 12 to 15 months., Results: A total of 1,036,689 children received 1,107,814 measles-mumps-rubella vaccinations; there were 259 confirmed patients with immune thrombocytopenia purpura. Because only 5 exposed cases occurred after age 2, analyses were limited to children aged 12 to 23 months. Exposed patients aged 12 to 23 months had lower median platelet counts than those who were unexposed and had similar median duration of illness (11 vs 10 days). The incident rate ratio was highest for children aged 12 to 15 months at 7.10. The incident rate ratio for boys aged 12 to 15 months was 14.59, and the incident rate ratio for girls in the same age group was 3.22. Seventy-six percent of immune thrombocytopenia purpura cases in children aged 12 to 23 months were attributable to measles-mumps-rubella vaccination. This vaccine causes 1 case of immune thrombocytopenia purpura per every 40,000 doses., Conclusion: Measles-mumps-rubella vaccine that is given in the second year of life is associated with an increased risk of immune thrombocytopenia purpura.

Objective: A refrigerator-stable formulation of ProQuad has been developed to expand the utility of ProQuad to areas in which maintenance of a frozen cold chain (-15 degrees C or colder) during storage and transport may not be feasible. The objective of this study was to demonstrate that the immunogenicity and safety profiles of a refrigerator-stable formulation of ProQuad are similar to the recently licensed frozen formulation., Methods: In this double-blind, randomized, multicenter study, healthy 12- to 23-month-old children with negative vaccination and clinical histories for measles, mumps, rubella, varicella, and zoster were vaccinated with either the refrigerator-stable formulation of ProQuad (N = 1006) or the frozen formulation of ProQuad (N = 513). Patients were followed for 42 days after vaccination for adverse experiences. Immunogenicity was evaluated 6 weeks after vaccination., Results: The refrigerator-stable formulation of ProQuad was generally well tolerated. The incidence of adverse experiences was similar between groups. No vaccine-related serious adverse experiences were reported. For both groups, the response rate was > or = 97.7% for measles, mumps, and rubella, and the percentage of patients with a varicella zoster virus antibody titer of > or = 5 U/mL glycoprotein antigen-based enzyme-linked immunosorbent assay after vaccination was > or = 88.8%. The geometric mean titers for all antigens were numerically slightly higher in patients who received the refrigerator-stable formulation., Conclusions: The refrigerator-stable formulation of ProQuad is generally well tolerated, highly immunogenic, and noninferior in terms of postvaccination antibody responses. This refrigerator-stable formulation may improve ease of vaccine administration, increase use of the vaccine throughout the world because of its improved storage conditions, and replace the frozen formulation of ProQuad or any dose of M-M-RII and Varivax in routine practice.

Objectives: Despite epidemiologic evidence to the contrary, claims of an association between measles-mumps-rubella vaccination and the development of autism have persisted. Such claims are based primarily on the identification of measles virus nucleic acids in tissues and body fluids by polymerase chain reaction. We sought to determine whether measles virus nucleic acids persist in children with autism spectrum disorder compared with control children., Patients and Methods: Peripheral blood mononuclear cells were isolated from 54 children with autism spectrum disorder and 34 developmentally normal children, and up to 4 real-time polymerase chain reaction assays and 2 nested polymerase chain reaction assays were performed. These assays targeted the nucleoprotein, fusion, and hemagglutinin genes of measles virus using previously published primer pairs with detection by SYBR green I. Our own real-time assay targeted the fusion gene using novel primers and an internal fluorescent probe. Positive reactions were evaluated rigorously, and amplicons were sequenced. Finally, anti-measles antibody titers were measured by enzyme immunoassay., Results: The real-time assays based on previously published primers gave rise to a large number of positive reactions in both autism spectrum disorder and control samples. Almost all of the positive reactions in these assays were eliminated by evaluation of melting curves and amplicon band size. The amplicons for the remaining positive reactions were cloned and sequenced. No sample from either autism spectrum disorder or control groups was found to contain nucleic acids from any measles virus gene. In the nested polymerase chain reaction and in-house assays, none of the samples yielded positive results. Furthermore, there was no difference in anti-measles antibody titers between the autism and control groups., Interpretation: There is no evidence of measles virus persistence in the peripheral blood mononuclear cells of children with autism spectrum disorder.

Background/objectives: In 1989, the American Academy of Pediatrics and the Advisory Committee on Immunization Practices recommended that school children receive 2 doses of measles-mumps-rubella vaccine. With measles and rubella eliminated from the United States, measles-mumps-rubella vaccine adverse events have come under scrutiny, but no study has compared the reactogenicity of the first (measles-mumps-rubella vaccine dose 1) and second (measles-mumps-rubella vaccine dose 2) doses at the most common ages of administration in the United States., Methods: From a health maintenance organization, 3 groups of children were recruited: (1) toddlers aged 12 to 24 months receiving measles-mumps-rubella vaccine dose 1; (2) kindergartners aged 4 to 6 years receiving measles-mumps-rubella vaccine dose 2; and (3) middle schoolers aged 10 to 12 years receiving measles-mumps-rubella vaccine dose 2. From 2 weeks before measles-mumps-rubella vaccine administration until 4 weeks afterward, families recorded in diaries the occurrence of potentially common symptoms. Postvaccination symptom rates were compared with the prevaccination baseline, with significance assessed by testing incidence rate ratios estimated by Poisson regression., Results: Of 2173 children enrolled, 373 (17%) were lost to attrition, producing a study population of 1800. Compared with the prevaccination baseline, rates of fever, diarrhea, and rash were significantly elevated postvaccination among 535 toddlers receiving measles-mumps-rubella vaccine dose 1. An estimated net 95 (18%) experienced measles-mumps-rubella vaccine-associated events (median onset 5-10 days postvaccination, duration 2-5 days), with high fever (temperature > or = 39.5 degrees C) occurring in 33 (6%). None required medical attention. For 633 kindergartners and 632 middle schoolers, symptom rates were not significantly elevated after measles-mumps-rubella vaccine dose 2 compared with baseline., Conclusions: Vaccination-associated adverse events occur in approximately 1 of every 6 toddlers receiving measles-mumps-rubella vaccine dose 1, with high fever occurring in 1 of 20. Adverse events are infrequent for measles-mumps-rubella vaccine dose 2 administered to school-aged children.

Background: In the United States, children receive primary doses of M-M-RII (Merck & Co, Inc, West Point, PA) and Varivax (Merck & Co, Inc) beginning at 12 months, often at the same health care visit. Currently a second dose of M-M-RII is given to 4- to 6-year-old children, to increase vaccination rates and to reduce the number of individuals without detectable antibodies. A second dose of a varicella-containing vaccine may result in similar benefits., Objectives: To demonstrate that ProQuad (measles, mumps, rubella, and varicella virus vaccine live; Merck & Co, Inc) may be given in place of a second dose of M-M-RII or second doses of M-M-RII and Varivax for 4- to 6-year-old children., Methods: Four- to 6-year-old children who had been immunized previously with M-M-RII and Varivax were assigned randomly to receive either ProQuad and placebo (N = 399), M-M-RII and placebo (N = 195), or M-M-RII and Varivax (N = 205) and were then monitored for safety and immunogenicity., Results: ProQuad was generally well tolerated. Similarity (noninferiority) was demonstrated in postvaccination antibody responses to measles, mumps, and rubella between recipients of ProQuad and all recipients of M-M-RII and in responses to varicella between recipients of ProQuad and recipients of Varivax. Postvaccination seropositivity rates for antibodies against all 4 viruses were nearly 100% in all 3 groups. Small fold increases were observed for measles, mumps, and rubella antibody titers. In contrast, substantial boosts in varicella antibody titers were observed among recipients of a second dose of varicella vaccine, administered as ProQuad or Varivax., Conclusions: ProQuad may be used in place of a second dose of M-M-RII or second doses of M-M-RII and Varivax for 4- to 6-year-old children.

Objectives: Ametop gel (4% amethocaine) is a relatively new topical anesthetic that produces anesthesia within 30 to 45 minutes and therefore may be appropriate for use in busy outpatient settings. The objective of this study was to assess the efficacy and safety of 4% amethocaine in reducing the pain of subcutaneous measles-mumps-rubella vaccination in 1-year-old infants., Methods: A double-blind, randomized, placebo-controlled trial was conducted in pediatric outpatient clinics., Results: A total of 120 infants participated in the study; 60 were followed up for assessment of antibody titers after 1 month. Either 1 g of amethocaine or placebo was applied for 30 minutes before vaccination. The Modified Behavioral Pain Scale was used to assess pain; the mean (standard deviation) pain scores for the amethocaine group (n = 61) was 1.5 (1.6) versus 2.3 (2.2) for the placebo group (n = 59). The rate of vaccination success (88% and 87%) was not different between treatment groups., Conclusions: 4% Amethocaine significantly reduces the pain of measles-mumps-rubella vaccination in infants when compared with placebo and does not seem to interfere with subsequent development of protective antibody levels. Because of its relatively short application time (30 minutes), 4% amethocaine may be suitable for busy clinics and emergency departments.

The annual number of reported measles cases in the United States has declined from between 3 million and 4 million in the prevaccine era to <100 cases in association with the highest recorded immunization rates in history. Because of continued importation of measles into the United States, young children who are not vaccinated appropriately may experience more than a 60-fold increase in risk of disease. Unsubstantiated claims suggesting an association between measles vaccine and neurologic disorders have led to reduced vaccine use and a resurgence of measles in countries where immunization rates have declined below the level needed to maintain herd immunity. To address the possibility of worldwide control of measles, efforts to ensure high immunization rates among people in both developed and developing countries must be sustained.

Objective: To compare ages at first measles-mumps-rubella (MMR) vaccination between children with autism and children who did not have autism in the total population and in selected subgroups, including children with regression in development., Methods: A case-control study was conducted in metropolitan Atlanta. Case children (N = 624) were identified from multiple sources and matched to control children (N = 1824) on age, gender, and school. Vaccination data were abstracted from immunization forms required for school entry. Records of children who were born in Georgia were linked to Georgia birth certificates for information on maternal and birth factors. Conditional logistic regression was used to estimate odds ratios (ORs)., Results: The overall distribution of ages at MMR vaccination among children with autism was similar to that of matched control children; most case (70.5%) and control children (67.5%) were vaccinated between 12 and 17 months of age. Similar proportions of case and control children had been vaccinated before 18 or before 24 months. No significant associations for either of these age cutoffs were found for specific case subgroups, including those with evidence of developmental regression. More case (93.4%) than control children (90.6%) were vaccinated before 36 months (OR: 1.49; 95% confidence interval: 1.04-2.14 in the total sample; OR: 1.23; 95% confidence interval: 0.64-2.36 in the birth certificate sample). This association was strongest in the 3- to 5-year age group., Conclusions: Similar proportions of case and control children were vaccinated by the recommended age or shortly after (ie, before 18 months) and before the age by which atypical development is usually recognized in children with autism (ie, 24 months). Vaccination before 36 months was more common among case children than control children, especially among children 3 to 5 years of age, likely reflecting immunization requirements for enrollment in early intervention programs.

Objective: Acellular pertussis vaccines were introduced with the promise of an improved safety profile compared with whole-cell vaccines. In 1997-1998, Canada adopted 1 combination acellular pertussis vaccine, having previously used 1 particular combination whole-cell pertussis vaccine. We hypothesized that the change would result in a decrease in hospitalization rates for seizures and reports of hypotonic-hyporesponsive episodes (HHEs) temporally related to pertussis vaccination., Methods: Active surveillance was performed between 1995 and 2001 by the Immunization Monitoring Program-Active monitors at 12 hospitals using standard case definitions. Seizures had to occur within 72 hours after immunization with a pertussis-containing vaccine or 5 to 30 days after immunization with measles-mumps-rubella vaccine. HHE episodes had to occur within 48 hours of receipt of a pertussis-containing vaccine. Poisson regression models were used to compare the average number of monthly admissions for seizures and HHEs before and after introduction of the acellular pertussis vaccine., Results: We found a 79% decrease in febrile seizures associated with receipt of pertussis vaccine but no significant decrease in febrile seizures temporally related to measles-mumps-rubella between 1995-1996 and 1998-2001. There was a 60% to 67% reduction in HHEs associated with pertussis-containing vaccines between the same time periods, depending on case definition., Conclusions: The risks of febrile seizures and HHEs after pertussis-containing vaccine declined significantly with the introduction of acellular pertussis vaccine in Canada. Active surveillance systems are important for detecting trends in uncommon adverse events after routine immunizations.

The package inserts of live viral vaccines include immunodeficiency as a contraindication. Nevertheless, patients with mild forms of immunodeficiency may benefit from vaccination. No published guidelines exist for the administration of these vaccines specifically to patients with chromosome 22q11.2 deletion syndrome. This syndrome is also sometimes called DiGeorge syndrome and is associated with thymic hypoplasia and diminished T-cell numbers and has a wide spectrum of phenotypic features that include cardiac anomalies, dysmorphic facial features, and hypocalcemia. Patients generally exhibit a mild to moderate decrement in T-cell numbers with preservation of T-cell function. The aims of this study were to investigate the incidence of side effects after live viral vaccine administration in a population with chromosome 22q11.2 deletion syndrome. The high frequency of this syndrome in the population (1:3000 children) mandates a greater understanding of the risks and benefits related to live viral vaccine administration. A retrospective analysis of vaccine adverse events was performed. The data acquisition form evaluated the frequency of live vaccine administration and the consequences of both vaccination and withholding the vaccine. Flow cytometric enumeration of T cells was performed as part of an immunologic evaluation. Thirty-two of 59 responders were vaccinated with the varicella vaccine. Only 9% of patients reported adverse events. However, 63% of unvaccinated children developed chickenpox. Comparison of patients who tolerated the vaccine with those who reported adverse events showed no statistically significant differences in current age (7 vs 5.7 years), age at vaccination (3 vs 2.5 years), or T-cell subset counts: CD3 (1951 vs 2083 cells/ microL), CD4 (1283 vs 1463 cells/ microL), and CD8 (530 vs 502 cells/ microL). Fifty-two of 59 responders were vaccinated with measles-mumps-rubella (MMR). Twelve (23%) of 52 reported mild side effects, including fever, rash, and constitutional symptoms. No severe adverse reactions were reported. No patient reported natural disease with measles, mumps, or rubella. There were no statistically significant differences between the T-cell counts in the vaccinated group reporting side effects versus the vaccinated group without side effects (mean CD3 counts: 1928 vs 1736 cells/ microL; CD4 counts: 1250 vs 1127 cells/ microL; and CD8 counts: 528 vs 483 cells/ microL). In our study, patients with chromosome 22q11.2 deletion syndrome had a similar incidence of adverse effects with varicella and MMR vaccines compared with that reported in the general population. All side effects were mild. However, in patients who did not receive the varicella vaccine, an overwhelming 63% contracted the disease. Patients who were not vaccinated against MMR did not develop natural disease. The data suggest that this is a cohort of patients with 22q11.2 deletion syndrome who have tolerated live viral vaccinations without evidence of significant side effects. A prospective study could address whether there are T-cell thresholds below which vaccination is unsafe; however, the information that we present suggests that vaccinating children with chromosome 22q11.2 deletion with live viral vaccines does not carry a significantly higher risk of adverse reactions compared with the general population, provided that they have no evidence of severe immunocompromise.

Objectives: To determine physician success at designing catch-up regimens for children delayed in immunizations and physician knowledge regarding contraindications to immunization., Methods: A self-administered survey was completed by pediatricians, general practitioners, and family practitioners in Cook County, Illinois. Surveys included 6 open-ended vignettes describing hypothetical children delayed in immunization for whom participants were asked to design catch-up regimens. Bivariate and multivariate logistic regression were used to determine predictors of correct response. The surveys also inquired about management of scenarios that might be perceived as contraindications to immunize with the Haemophilus influenzae type b or measles-mumps-rubella vaccines., Results: The mean score of correct responses was 1.83 of a possible 6.0. Almost one third of respondents answered all 6 vignettes incorrectly. The proportion of incorrect responses was high for all 6 vignettes (39%-86%), but higher for questions that addressed the immunization of children older than 12 months. Errors in vaccine administration were most commonly attributed to omitted vaccines, with varicella-zoster vaccine and pneumococcal conjugate vaccine omitted most frequently. Pediatricians were >4 times more likely to answer correctly than were family practitioners. Participants in the Vaccines for Children (VFC) program were more than twice as likely to answer correctly than were non-VFC providers. Knowledge of contraindications was inconsistent, particularly for measles-mumps-rubella vaccine., Conclusions: Childhood vaccine providers have substantial knowledge deficits of recommended immunization schedules and vaccine contraindications that may contribute to missed opportunities to immunize. Pediatricians and participants in the VFC program were more successful at designing catch-up regimens for children with immunization delay.

Objective: Anaphylaxis after immunization, although rare, is serious and potentially life-threatening. Understanding risk factors for this reaction is therefore important. Gelatin is added to many vaccines as a heat stabilizer. Japanese researchers have demonstrated a strong association between immediate hypersensitivity reactions to measles, mumps, rubella, varicella, and Japanese encephalitis immunizations and subsequent detection of anti-gelatin immunoglobulin E (IgE) antibodies. They suggested that previous receipt by these patients of diphtheria-tetanus-acellular pertussis vaccines with trace amounts of gelatin was responsible for the sensitization. We aimed to assess whether a similar association exists for vaccinees in the United States who reported anaphylaxis after receipt of measles-mumps-rubella (MMR) or measles vaccines and to review recent trends in reporting of hypersensitivity reactions., Methods: We conducted a retrospective case-control study. Cases of anaphylaxis that met a predefined case definition were identified from the US Vaccine Adverse Event Reporting System (VAERS). Mayo Clinic patients who received MMR vaccine uneventfully served as controls. The study subjects were interviewed to obtain the history of allergies. Sera from study subjects and their matched controls were tested for IgE antibodies to gelatin, whole egg, and vaccine viral antigens using solid-phase radioimmunoassay. Data from the Biologics Surveillance System on annual numbers of doses of MMR and varicella vaccines distributed in the United States were used to evaluate possible changes in reporting of selected allergic adverse events., Results: Fifty-seven study subjects were recruited into the study and interviewed. Of these, 22 provided serum samples for IgE testing. Twenty-seven subjects served as a comparison group and provided a sample for IgE testing; 21 of these completed an allergy history questionnaire. Self-reported history of food allergies was present more frequently in the interviewed study subjects than in the controls, whereas the proportions of people with other characteristics were similar in both groups. None of the interviewed people had a history of food allergy to gelatin. The level of anti-gelatin IgE antibodies was significantly higher among study subjects than among controls, whereas the levels of IgE antibodies against egg and all 3 viral antigens did not differ significantly. Of 22 study subjects, 6 (27%) tested positive for anti-gelatin IgE, whereas none of the 27 controls did. The rate of anaphylactic reactions reported to VAERS after measles virus-containing immunization in the United States between 1991 and 1997 is 1.8 per 1 million doses distributed. No substantial increase in the number of reported allergic events after frequently used gelatin containing MMR and varicella vaccines could be observed during the first 4 years (1997-2000) since the introduction of diphtheria-tetanus-acellular pertussis vaccines for use in infancy., Conclusion: Anaphylactic reactions to MMR in the United States are rare. The reporting rate has the same order of magnitude as estimates from other countries. Almost one fourth of patients with reported anaphylaxis after MMR seem to have hypersensitivity to gelatin in the vaccine. They may be at higher risk of developing anaphylaxis to subsequent doses of other gelatin-containing vaccines. These people should seek an allergy evaluation before such immunization.

Objective: The possibility of adverse neurologic events has fueled much concern about the safety of measles-mumps-rubella (MMR) vaccinations. The available evidence concerning several of the postulated complications is controversial. The aim of this study was to assess whether an association prevails between MMR vaccination and encephalitis, aseptic meningitis, and autism., Methods: A retrospective study based on linkage of individual MMR vaccination data with a hospital discharge register was conducted among 535 544 1- to 7-year-old children who were vaccinated between November 1982 and June 1986 in Finland. For encephalitis and aseptic meningitis, the numbers of events observed within a 3-month risk interval after vaccination were compared with the expected numbers estimated on the basis of occurrence of encephalitis and aseptic meningitis during the subsequent 3-month intervals. Changes in the overall number of hospitalizations for autism after vaccination throughout the study period were searched for. In addition, hospitalizations because of inflammatory bowel diseases were checked for the children with autism., Results: Of the 535 544 children who were vaccinated, 199 were hospitalized for encephalitis, 161 for aseptic meningitis, and 352 for autistic disorders. In 9 children with encephalitis and 10 with meningitis, the disease developed within 3 months of vaccination, revealing no increased occurrence within this designated risk period. We detected no clustering of hospitalizations for autism after vaccination. None of the autistic children made hospital visits for inflammatory bowel diseases., Conclusions: We did not identify any association between MMR vaccination and encephalitis, aseptic meningitis, or autism.

Objective: A link has been postulated between measles-mumps-rubella (MMR) vaccine and a form of autism that is a combination of developmental regression and gastrointestinal symptoms that occur shortly after immunization. This hypothesis has involved 3 separate claims: 1) that there is new phenotype of autism involving regression and gastrointestinal symptoms, 2) that this new variant is responsible for the alleged rise of autism rates, and 3) that this phenotype is associated with biological findings suggestive of the persistence of measles infection. We tested the first of these claims. If this new "autistic enterocolitis" syndrome had some validity, then 1 or several of the following 6 predictions should be supported by empirical data: 1) childhood disintegrative disorder has become more frequent, 2) the mean age of first parental concern for autistic children who are exposed to MMR is closer to the mean immunization age than in children who are not exposed to MMR, 3) regression in the development of children with autism has become more common in MMR-vaccinated children, 4) the age of onset for autistic children with regression clusters around the MMR immunization date and is different from that of autistic children without regression, 5) children with regressive autism have distinct symptom and severity profiles, and 6) regressive autism is associated with gastrointestinal symptoms and/or inflammatory bowel disorder., Methods: Three samples were used. Epidemiologic data on 96 children (95 immunized with MMR at a median age of 13.5 months) who were born between 1992 and 1995 and had a pervasive developmental disorder diagnosis as reported in a recent UK survey (post-MMR sample) were compared with data from 2 previous clinical samples (1 pre-MMR [n = 98] and 1 post-MMR [n = 68]) of autistic patients. All patients were assessed with the standardized Autism Diagnostic Interview (ADI), allowing rigorous comparison of age at first parental concerns and rates of regression across samples. Reliability was excellent on ADI scores, age of parental concern, and developmental regression. Furthermore, data on bowel symptoms and disorders were available in the epidemiologic survey from both pediatric and parental sources, and immunization dates were obtained from computerized records., Results: The prevalence of childhood disintegrative disorder was 0.6/10 000 (95% confidence interval: 0.02-3.6/10 000); this very low rate is consistent with previous estimates and is not suggestive of an increased frequency of this form of pervasive developmental disorder in samples of children who are immunized with MMR. There was no difference in the mean age at first parental concern between the 2 samples exposed to MMR (19.3 and 19.2 months) and the pre-MMR sample (19.5 months). Thus, MMR immunization was not associated with a shift toward an earlier age for first parental concerns. Similarly, the rate of developmental regression reported in the post-MMR sample (15.6%) was not different from that in the pre-MMR sample (18.4%); therefore, there was no suggestion that regression in the developmental course of autism had increased in frequency since MMR was introduced. In the epidemiologic sample, the subset of autistic children with regression had no other developmental or clinical characteristics, which would have argued for a specific, etiologically distinct phenotype. Parents of autistic children with developmental regression detected the first symptoms at a very similar age (19.8 months) to those of autistic children without regression (19.3 months). Moreover, the mean intervals from MMR immunization to parental recognition of autistic symptoms were comparable in autistic children with or without regression (248 vs 272 days; not significant). In the epidemiologic sample, gastrointestinal symptoms were reported in 18.8% of children. Constipation was the most common symptom (9.4%), and no inflammatory bowel disorder was reported. Furthermore, there was no association between developmental regression and gastrointestinal symptoms (odds ratio: 0.63; 95% confidence interval: 0.06-3.2; not significant), and only 2.1% of the sample experienced both problems, a rate that did not exceed chance expectations., Conclusions: No evidence was found to support a distinct syndrome of MMR-induced autism or of "autistic enterocolitis." These results add to the recent accumulation of large-scale epidemiologic studies that all failed to support an association between MMR and autism at population level. When combined, the current findings do not argue for changes in current immunization programs and recommendations.

Background: Parents and physicians are understandably concerned about the causes and treatment of autism, a devastating disease that affects the entire family. Although much has been learned about autism, there are many gaps in our knowledge about what causes the disorder and how it can be prevented. Autistic symptoms occur along a spectrum, often referred to as autistic spectrum disorder (ASD). Concern has been raised about a possible association between measles-mumps-rubella (MMR) vaccine and inflammatory bowel disease (IBD) and ASD, especially autism with regression. Also, increased requests for educational services related to ASD have raised concerns about possible increases in the incidence of ASD., Methods: On June 12-13, 2000, the American Academy of Pediatrics (AAP) convened a conference titled "New Challenges in Childhood Immunizations" in Oak Brook, Illinois. At this conference, parents, practitioners, and scientists presented information and research on MMR vaccine and ASD. Attendees included representatives from select AAP committees and sections as well as federal and other organizations that address related issues. The multidisciplinary panel of experts reviewed data on what is known about the pathogenesis, epidemiology, and genetics of ASD and the available data on hypothesized associations with IBD, measles, and MMR vaccine. Supplemental information was requested from authors who have proposed the hypotheses and other experts in relevant areas., Results: Autism is a complex disorder of uncertain and probably multiple etiologies. Genetic predisposition to ASD may involve as many as 10 genes. Many experts believe that the abnormal brain development in autism occurs before 30 weeks' gestation in most instances. In utero rubella is a known cause of autism. Animal model data support the biologic plausibility that exposure to yet unrecognized infectious or other environmental agents could cause ASD. Several factors may contribute to apparent increases in incidence of ASD in recent years. Most data indicate increased recognition and reporting as primary factors, but the epidemiologic data are insufficient to determine if there has been a true increase in the incidence of ASD. Increased reporting of ASD in recent years has occurred long after the introduction of MMR vaccine in the United States in 1971 and widespread use of this vaccine in the 1970s for routine immunization of children at 12 to 15 months of age. Appropriate detailed studies are needed to define the true incidence and prevalence of ASD. Epidemiologic studies in Europe indicate no association between MMR vaccine and ASD. Some children with ASD have gastrointestinal symptoms, but an increased rate of any specific gastrointestinal disorder in children with ASD has not been established. Studies to detect evidence of measles virus in intestinal tissue specimens from patients with IBD or autism with gastrointestinal symptoms have not used uniform techniques. Several laboratories have found no evidence of measles viruses in tissue specimens from patients with IBD, but 2 groups have found evidence of measles virus using different techniques. A group that found evidence of measles virus in affected tissue specimens from patients with IBD has also reported detecting portions of measles virus in peripheral blood lymphocytes and intestinal tissue specimens from patients with autism and gastrointestinal disorders. Finding a portion of a virus using molecular techniques does not constitute evidence for a causal relationship, because some viruses persist in unaffected hosts. Additional controlled studies in several laboratories are needed to determine if portions of measles virus persist in intestinal and other tissues of people with and without gastrointestinal disease and/or ASD., Conclusions: Although the possible association with MMR vaccine has received much public and political attention and there are many who have derived their own conclusions based on personal experiences, the available evidence does not support the hypothesis that MMR vaccine causes autism or associated disorders or IBD. Separate administration of measles, mumps, and rubella vaccines to children provides no benefit over administration of the combination MMR vaccine and would result in delayed or missed immunizations. Pediatricians need to work with families to ensure that children are protected early in the second year of life from these preventable diseases. Continued scientific efforts need to be directed to the identification of the causes of ASD.

Objective: Immunization of egg-allergic children against measles, mumps, and rubella (MMR) is often deferred or even denied, although the safety of this vaccination has been clearly shown. Moreover, the majority of severe allergic reactions have occurred in egg-tolerant vaccinees. Other allergenic vaccine components have been sought, and gelatin has been suggested as one cause of allergic adverse events. The aim of this study was to further characterize the actual allergenic vaccine components., Methods: Serum samples from 36 recipients of MMR vaccine with anaphylaxis, urticaria with or without angioedema, asthmatic symptoms, or Henoch-Schönlein purpura were analyzed by CAP System radioallergosorbent test (RAST) and immunospot methods to detect the allergenic vaccine component. To evaluate the correspondence between the findings in the CAP System RAST or the immunospot and clinical symptoms, histories of allergies and present hypersensitivity symptoms were assessed., Results: Of the 36 participants, 10 were demonstrated to be allergic to gelatin. Seven of them had persistent allergic symptoms, possibly attributable to foods containing gelatin or cross-reactive allergens. The results of the immunospot suggested concomitant allergy to gelatin and egg, chicken, and feathers, as well as cow's milk, or they reflected allergen cross-reactivity., Conclusions: Although severe allergic adverse events attributable to MMR vaccination are extremely rare, all serious allergic reactions should be further assessed to detect the likely causative vaccine component, including gelatin. The current recommendation for immunization of egg-allergic persons according to standard MMR vaccination schedules is reinforced. measles, mumps, and rubella vaccine, immunization, adverse effects, allergic reactions, gelatin allergy, CAP System, radioallergosorbent test, immunospot, immunoglobulin E.

Objective: Revaccination policies adopted in many countries to control measles have raised various safety issues including those concerning the second vaccine dose. We performed a prospective, double-blind, crossover trial among twins receiving a measles-mumps-rubella (MMR) vaccine., Study Design: The study comprised 1162 monozygous and heterozygous twins, each of whom randomly received placebo and then vaccine, or vice versa, 3 weeks apart, at 14 to 83 months of age. Most of the oldest children had previously been vaccinated against measles, and one half of the remainder of children had had the disease. Symptoms and signs were recorded daily on structured forms. Statistical methods included a complex analysis of the vaccine attributability of the symptoms and conditional logistic regression., Results: Vaccination-attributable events occurred in 6% overall. At 14 to 18 months of age, reactions developed between days 6 and 14, peaking at day 10. The clearest vaccine-attributable effect was fever exceeding 101.3 degrees F (38. 5 degrees C; odds ratio: 3.28; 95% confidence interval: 2.23-4.82; P <.001), but the same trend was found for rash, arthralgia, conjunctivitis, staying in bed, drowsiness, and irritability. At 6 years of age, systemic reactions occurred 5 to 15 times less frequently, only arthralgia being associated with vaccination. Zygocity, gender, history of allergy, or infections did not modify reactions. Instead, respiratory symptoms developed within days postinjection to a level of 15% to 20% without subsequent decline and with no difference between vaccinees and placebo recipients., Conclusion: Vaccination was avoided during infections, but many small children became mildly ill within a week or so with no relation to vaccination (the healthy vaccinee effect). MMR vaccine was virtually nonreactogenic when given at 6 years of age. vaccine, measles, mumps, rubella, reactogenicity, adverse events, zygocity, healthy vaccinee effect.