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BACKGROUND: The risk of immune thrombocytopenic purpura (ITP) after childhood vaccines other than measles-mumps-rubella vaccine (MMR) is unknown. METHODS: Using data from 5 managed care organizations for 2000 to 2009, we identified a cohort of 1.8 million children ages 6 weeks to 17 years. Potential ITP cases were identified by using diagnostic codes and platelet counts. All cases were verified by chart review. Incidence rate ratios were calculated comparing the risk of ITP in risk (1 to 42 days after vaccination) and control periods. RESULTS: There were 197 chart-confirmed ITP cases out of 1.8 million children in the cohort. There was no elevated risk of ITP after any vaccine in early childhood other than MMR in the 12- to 19-month age group. There was a significantly elevated risk of ITP after hepatitis A vaccine at 7 to 17 years of age, and for varicella vaccine and tetanus-diphtheria-acellular pertussis vaccine at 11 to 17 years of age. For hepatitis A, varicella, and tetanus-diphtheria-acellular pertussis vaccines, elevated risks were based on one to two vaccine-exposed cases. Most cases were acute and mild with no long-term sequelae. CONCLUSIONS: ITP is unlikely after early childhood vaccines other than MMR. Because of the small number of exposed cases and potential confounding, the possible association of ITP with hepatitis A, varicella, and tetanus-diphtheria-acellular pertussis vaccines in older children requires further investigation.

The public health community faces increasing demands for improving vaccine safety while simultaneously increasing the number of vaccines available to prevent infectious diseases. The passage of the US Food and Drug Administration (FDA) Amendment Act of 2007 formalized the concept of life-cycle management of the risks and benefits of vaccines, from early clinical development through many years of use in large numbers of people. Harnessing scientific and technologic advances is necessary to improve vaccine-safety evaluation. The Office of Biostatistics and Epidemiology in the Center for Biologics Evaluation and Research is working to improve the FDA's ability to monitor vaccine safety by improving statistical, epidemiologic, and risk-assessment methods, gaining access to new sources of data, and exploring the use of genomics data. In this article we describe the current approaches, new resources, and future directions that the FDA is taking to improve the evaluation of vaccine safety.

BACKGROUND. In 1999, a previous rotavirus vaccine (RotaShield; Wyeth Laboratories, Marietta, PA) was withdrawn from the US market after postlicensure monitoring identified an association with intussusception. Although the new rotavirus vaccine (RotaTeq; Merck, West Point, PA) introduced in 2006 was not associated with intussusception in prelicensure trials, additional monitoring is important to ensure a complete safety profile. METHODS. We assessed intussusception reports after RotaTeq vaccination by using data from the Vaccine Adverse Event Reporting System and the Vaccine Safety Datalink, a cohort of children enrolled in managed care. Observed versus expected rate ratios were determined by using vaccine dose distribution data and Vaccine Safety Datalink background intussusception rates. RESULTS. Between February 1, 2006, and September 25, 2007, the Vaccine Adverse Event Reporting System received 160 intussusception reports after RotaTeq vaccination. With the assumptions that reporting completeness was 75% and that 75% of the distributed doses of RotaTeq were administered, the observed versus expected rate ratios were 0.53 and 0.91 for the 1–21 and 1–7 day interval after vaccination, respectively. In the Vaccine Safety Datalink, 3 intussusception cases occurred within 30 days after 111521 RotaTeq vaccinations, compared with 6 cases after 186722 non–RotaTeq vaccinations during the same period. If, like RotaShield, RotaTeq had a 37-fold increased risk of intussusception within 3 to 7 days after vaccination, then 8 intussusception cases would be expected within 3 to 7 days among the ∼84000 infants vaccinated with the first dose of RotaTeq in the Vaccine Safety Datalink (N = 49902) and the prelicensure trial (N = 34035) combined, whereas no cases have been observed. CONCLUSIONS. Available data do not indicate that RotaTeq is associated with intussusception. Although an intussusception risk similar in magnitude to that of RotaShield can be excluded, continued monitoring is necessary for complete assessment of the safety profile of RotaTeq.

The effort to vaccinate the US population against the 2009 H1N1 influenza virus hinged, in part, on public confidence in vaccine safety. Early in the vaccine program, >20% of parents reported that they would not vaccinate their children. Concerns about the safety of the vaccines were reported by many parents as a factor that contributed to their intention to forgo vaccination (see www.hsph.harvard.edu/news/press-releases/2009-releases/survey-40-adults-absolutely-certain-h1n1vaccine.html and www.med.umich.edu/mott/npch/reports/h1n1.htm). The safety profiles of 2009 H1N1 monovalent influenza vaccines were anticipated to be (and have been) similar to those of seasonal influenza vaccines, for which an excellent safety profile has been demonstrated. Here we describe steps taken by the US government to (1) assess the key federal systems in place before 2009 for monitoring the safety of vaccines and (2) integrate and upgrade those systems for optimal vaccine-safety monitoring during the 2009 H1N1 monovalent influenza vaccination program. These efforts improved monitoring of 2009 H1N1 vaccine safety, hold promise for enhancing future national monitoring of vaccine safety, and may ultimately help improve public confidence in vaccines. Pediatrics 2011;127:S78-S86

Objective. Varicella breakthrough, the occurrence of varicella disease >42 days after vaccina- tion, is indicative of vaccination failure. A sevenfold increased risk of breakthrough among vaccinated chil- dren with asthma was observed in a 1996 varicella out- break in a child care center. More recent outbreak inves- tigations have also identified age at vaccination as a potential risk factor for breakthrough. We assessed the association of varicella breakthrough with asthma, ste- roids, age at varicella vaccination, and timing of measles- mumps-rubella (MMR) vaccination. Methods. We performed a retrospective cohort study among children born after 1993 and followed up through 1999 at 2 health maintenance organizations ((HMOs) A and B) in the United States. Information was obtained from automated vaccination, clinic, hospital discharge, and pharmacy records. Results. We identified 268 and 97 breakthrough cases among 80 584 and 8181 children vaccinated against vari- cella at HMOs A and B, respectively. Varicella break- through was not associated with asthma, inhaled steroids prescribed at any time, and oral steroids prescribed be- fore vaccination. An increased risk of varicella break- through was found in the 3 months immediately after prescription for oral steroids at HMO A (adjusted rela- tive risk (aRR): 2.4; 95% confidence interval (CI): 1.3- 4.4) and HMO B (aRR: 2.8; 95% CI: 1.0 -7.8), when varicella vaccine was given before 15 months of age at HMO A (aRR: 1.4; 95% CI: 1.1-1.9), and when varicella vaccination followed MMR vaccine within 28 days at HMO A (aRR: 3.1; 95% CI: 1.5- 6.4). Conclusions. Varicella vaccine failure in children was not associated with asthma or the use of inhaled steroids, but with the use of oral steroids. Administration of vari- cella vaccine before the age of 15 months may be associ- ated with a slightly increased risk of breakthrough dis- ease. As currently recommended, varicella vaccination should not be administered for 28 days after MMR vaccination. Pediatrics 2003;112:e98 -e103. URL: http: //www.pediatrics.org/cgi/content/full/112/2/e98; varicella

Background. Previous studies of large-dose vitamin A supplementation on respiratory morbidity have produced conflicting results in a variety of populations. The influence of malnutrition has not been examined in the majority of these trials. We hypothesized that weekly low-dose vitamin A supplementation would prevent respiratory and diarrheal disease morbidity and that malnutrition might influence the efficacy of vitamin A supplementation. Methods. In a randomized, double-blind, placebo-controlled field trial of 400 children, 6 to 36 months of age in a high Andean urban slum, half of the children received 10 000 IU of vitamin A weekly and half received placebo for 40 weeks. Children were visited weekly at home by physicians and assessed for acute diarrheal disease and acute respiratory infections. Results. Acute diarrheal disease and acute respiratory infection did not differ globally or by severity between supplement-treated and placebo groups. However, the incidence of acute lower respiratory infection (ALRI) was significantly lower in underweight (weight-for-age z score [WAZ] −2 SD) supplement-treated children than in normal-weight children on placebo (9.8 vs 4.4 per 103 child-weeks; rate ratio: 2.21 [95% CI: 1.24–3.93]). By logistic regression analysis the risk of ALRI was lower in underweight supplement-treated children than in underweight children on placebo (point estimate 0.148 [95% CI: 0.034–0.634]). In contrast, risk of ALRI was higher in normal-weight supplement-treated children (WAZ >−1 SD to mean) than in normal-weight children on placebo in the same WAZ stratum (point estimate: 2.51 [95% CI: 1.24–5.05]). The risk of severe diarrhea was lower in supplement-treated children 18 to 23 months of age than in children on placebo in this age group (point estimate: 0.26 [95% CI: 0.06–1.00]). Conclusions. Weekly low-dose (10 000 IU) vitamin A supplementation in a region of subclinical deficiency protected underweight children from ALRI and paradoxically increased ALRI in normal children with body weight over −1 SD. Protection from severe diarrhea was consistent with previous trials. Additional research is warranted to delineate potential beneficial and detrimental interactions between nutritional status and vitamin A supplementation regarding ALRI.