Safety of zoster vaccine in adults from a large managed-care cohort: a Vaccine Safety Datalink study.

OBJECTIVES: The aim of this study was to examine a large cohort of adults who received the zoster vaccine for evidence of an increased risk of prespecified adverse events requiring medical attention. DESIGN: Two self-comparison approaches, including a case-centred approach and a self-controlled case series (SCCS) analysis were used. SETTING: Eight managed-care organizations participating in the Vaccine Safety Datalink project in the United States. SUBJECTS: A total of 193 083 adults aged 50 and older receiving a zoster vaccine from 1 January 2007 to 31 December 2008 were included. MAIN OUTCOME MEASURES: Prespecified adverse events were identified by aggregated International Classification of Diseases, Ninth Revision (ICD-9) codes in automated health plan datasets. RESULTS: The risk of allergic reaction was significantly increased within 1-7 days of vaccination [relative risk = 2.13, 95% confidence interval (CI): 1.87-2.40 by case-centred method and relative rate = 2.32, 95% CI: 1.85-2.91 by SCCS]. No increased risk was found for the following adverse event groupings: cerebrovascular events; cardiovascular events; meningitis; encephalitis; and encephalopathy; and Ramsay-Hunt syndrome and Bell's palsy. CONCLUSIONS: The results of this study support the findings from the prelicensure clinical trials, providing reassurance that the zoster vaccine is generally safe and well-tolerated with a small increased risk of allergic reactions in 1-7 days after vaccination.

Risk of anaphylaxis after vaccination of children and adolescents.

OBJECTIVE: To quantify the risk of anaphylaxis after vaccination of children and adolescents. METHODS: The study population consisted of children and adolescents who were enrolled at 4 health maintenance organizations that participated in the Vaccine Safety Datalink Project. For the period 1991-1997, we identified potential cases by searching for occurrences of International Classification of Diseases, Ninth Revision (ICD-9) code 995.0 (anaphylactic shock), E948.0 through E948.9 (adverse reaction from bacterial vaccines), and E949.0 through E949.9 (adverse reaction from other vaccines and biological substances). At 1 study site, we also included a range of other allergy codes. We restricted to diagnoses on days 0 to 2 after vaccination (ICD-9 995.0) or day 0 (all other ICD-9 codes). We then reviewed the medical record to confirm the diagnosis. RESULTS: We identified 5 cases of potentially vaccine-associated anaphylaxis after administration of 7 644 049 vaccine doses, for a risk of 0.65 cases/million doses (95% confidence interval: 0.21-1.53). None of the episodes resulted in death. Vaccines that were administered before the anaphylactic episodes were generally given in combination and included measles-mumps-rubella, hepatitis B, diphtheria-tetanus, diphtheria-tetanus-pertussis, Haemophilus influenzae type b, and oral polio vaccine. One case of anaphylaxis followed measles-mumps-rubella vaccine alone. At the site at which we reviewed additional allergy codes, we identified 1 case after 653 990 vaccine doses, for a risk of 1.53 cases/million doses (95% confidence interval: 0.04-8.52). CONCLUSIONS: Patients and health care providers can be reassured that vaccine-associated anaphylaxis is a rare event. Nevertheless, providers should be prepared to provide immediate medical treatment should it occur.

Childhood vaccinations, vaccination timing, and risk of type 1 diabetes mellitus.

OBJECTIVES: To evaluate suggested associations between childhood vaccinations, particularly against hepatitis B and Haemophilus influenzae type b, and risk of developing type 1 diabetes; and to determine whether timing of vaccination influences risk. METHODS: We conducted a case-control study within 4 health maintenance organizations (HMOs) that participate in the Vaccine Safety Datalink project of the Centers for Disease Control and Prevention. Study eligibility was restricted to children who met the following criteria: 1) born during 1988 through 1997; 2) HMO member since birth; 3) continuously enrolled for first 6 months of life; and 4) at least 12 months of HMO membership before diabetes incidence date (or index date for controls) unless incidence date was before 12 months of age. All 4 HMOs maintain registries of their members who have diabetes, and we used the registries to identify potential cases of diabetes. We conducted chart reviews to verify that potential cases met the World Health Organization epidemiologic case definition for type 1 diabetes mellitus (ie, a physician's diagnosis of diabetes plus treatment with daily insulin injections). We defined the incidence date of diabetes as the first date that the child received a diagnosis of diabetes. We attempted to match 3 controls to each case. Controls had the same eligibility criteria as cases and were matched to individual cases on HMO, sex, date of birth (within 7 days), and length of health plan enrollment (up to the incidence or index date). The index date for controls was defined as the incidence date of the case to which the control was matched. Chart abstraction was performed by trained chart abstractors using standardized forms. In addition to complete vaccination histories, the chart abstraction forms for both cases and controls included information on sociodemographic characteristics, selected medical conditions, history of breastfeeding, and family medical history. We used conditional logistic regression to estimate the odds ratio (OR) of diabetes associated with vaccination, with vaccine exposure defined as before the diabetes incidence date (or index date for controls). RESULTS: Two hundred fifty-two confirmed cases of diabetes and 768 matched controls met the study eligibility criteria. The OR (95% confidence interval) for the association with type 1 diabetes was 0.28 (0.07-1.06) for whole cell pertussis vaccine (predominantly in combination as diphtheria, tetanus toxoids and pertussis vaccine), 1.36 (0.70-2.63) for measles-mumps-rubella, 1.14 (0.51-2.57) for Haemophilus influenzae type b, 0.81 (0.52-1.27) for hepatitis B vaccine, 1.16 (0.72-1.89) for varicella vaccine, and 0.92 (0.53-1.57) for acellular pertussis-containing vaccines. Compared with children who had not received hepatitis B vaccine, the OR of diabetes was 0.51 (0.23-1.15) for children vaccinated at birth and 0.86 (0.54-1.35) for those first vaccinated against hepatitis B at 2 months of age or later. Race and ethnicity and family history of diabetes were independently associated with risk of type 1 diabetes, but adjustment for these factors did not materially alter the ORs for any of the vaccines. CONCLUSIONS: In this large, population-based, case-control study, we did not find an increased risk of type 1 diabetes associated with any of the routinely recommended childhood vaccines. Our study adds to previous research by providing data on newer vaccines, including hepatitis B, acellular pertussis, and varicella vaccines. For the older vaccines, our results are generally in agreement with previous studies in not finding any increased risks. Ours is the first epidemiologic study to evaluate the possibility that timing of vaccination is related to risk of clinical diabetes in children. Our results on hepatitis B vaccine do not support the hypothesis; risk of type 1 diabetes was not different between infants vaccinated at birth and those who received their first vaccination later in life. The results of our study and the preponderance of epidemiologic evidence do not support an association between any of the recommended childhood vaccines and an increased risk of type 1 diabetes. Suggestions that diabetes risk in humans may be altered by changes in the timing of vaccinations also are unfounded.

Prospective, randomized, placebo-controlled evaluation of the safety and immunogenicity of three lots of intranasal trivalent influenza vaccine among young children.

BACKGROUND: Trivalent formulations of an experimental, cold-adapted, intranasal influenza (CAIV) vaccine have been shown to be safe, immunogenic and efficacious in young children. METHODS: We evaluated the safety and immunogenicity of three consistency lots of CAIV in children 12 to 36 months of age randomized to one of five groups: Groups 1, 2 and 3 received separate lots containing A/Shenzhen/227/95 (H1N1), A/Wuhan/359/95(H3N2) and B/Harbin/7/94-like viral strains. Group 4 received an earlier efficacy trial lot which included a different H1N1 strain (A/Texas/36/91-like); and Group 5 received placebo. We performed strain-specific serum hemagglutination inhibition antibody levels against type A (H3N2 or H1N1) or type B as appropriate. RESULTS: Overall 474 children received 2 doses, 2 months apart. Each lot was well-tolerated, and there were no significant group differences between consistency lots in the proportion of children with fever and local or systemic reactions after vaccination. The 3 consistency lots were not statistically different with regard to immunogenicity as measured by seroconversion or absolute geometric mean titer. Immune responses were more robust among initially seronegative children and for H3N2 and B strains than for H1N1 strains. After 2 doses of vaccine 97, 84 and 62% had hemagglutination inhibition titers > or = 1/32 against A/H3N2, B and H1N1 strains, respectively. For A/H3N2 only, immune responses after 1 dose of vaccine are similar to those seen after 2 doses. CONCLUSIONS: Each consistency lot of CAIV is as or more immunogenic than a lot used in a large efficacy trial.

Safety and immunogenicity of a pentavalent diphtheria, tetanus, pertussis, hepatitis B and polio combination vaccine in infants.

INTRODUCTION: The objectives of this study were to evaluate the safety and immunogenicity of a new combination vaccine (DTaP-HB-IPV) containing diphtheria, tetanus, acellular pertussis and hepatitis B (HB) and a new inactivated poliovirus vaccine (IPV) manufactured by GlaxoSmithKline (GSK). This vaccine was given in an all IPV or sequential IPV and oral polio vaccine (OPV) schedule. Another combination vaccine, DTaP-HB (GSK), was similarly evaluated given with OPV or IPV. METHODS: Four hundred infants were randomized into one of four study groups and immunized at 2, 4 and 6 months of age. Group A received three doses of DTaP-HB-IPV; Group B received DTaP-HB-IPV at 2 and 4 months and DTaP-HB with OPV (Orimune) at 6 months; Group C received three doses of DTaP-HB with licensed IPV (IPOL) administered separately; Group D received separate doses of OPV, DTaP (Infanrix; GSK) and HB (Engerix; GSK). All subjects received conjugate Haemophilus influenzae type b vaccine (Hib) (OmniHIB) at 2, 4 and 6 months of age given at a separate injection site. Subjects who returned at 12 to 18 months of age (229) received booster immunization with DTaP and Hib. Safety was evaluated after each vaccine dose. Blood was drawn before the first dose and one month after the third dose as well as before and after the booster dose. RESULTS: There were no vaccine-related serious adverse events in any group after any vaccine dose. Minor systemic and local adverse events were also not significantly different among the four groups after any dose. There were no differences in the immune response rates for Hib, HB, polio (types 1, 2 and 3), diphtheria, tetanus or pertussis antigens (pertussis toxin, filamentous hemagglutinin, pertactin) among groups, although there were some quantitative differences in specific antibody titers among groups. DTaP-HB-IPV and DTaP-HB combination vaccines had safety and immunogenicity equivalent to those of standard individually administered vaccines. The new IPV was not inferior to IPOL. CONCLUSION: Use of the pentavalent combination vaccine would greatly reduce the number of required injections during the first 2 years of life, thereby simplifying the immunization schedule, enhancing compliance and facilitating acceptance of additional injections engendered by introduction of newer vaccines.

The risk of seizures after receipt of whole-cell pertussis or measles, mumps, and rubella vaccine.

BACKGROUND: The administration of the diphtheria and tetanus toxoids and whole-cell pertussis (DTP) vaccine and measles, mumps, and rubella (MMR) vaccine has been associated with adverse neurologic events, including seizures. We studied the relation between these vaccinations and the risk of a first seizure, subsequent seizures, and neurodevelopmental disability in children. METHODS: This cohort study was conducted at four large health maintenance organizations and included reviews of the medical records of children with seizures. We calculated the relative risks of febrile and nonfebrile seizures among 679,942 children after 340,386 vaccinations with DTP vaccine, 137,457 vaccinations with MMR vaccine, or no recent vaccination. Children who had febrile seizures after vaccination were followed to identify the risk of subsequent seizures and other neurologic disabilities. RESULTS: Receipt of DTP vaccine was associated with an increased risk of febrile seizures only on the day of vaccination (adjusted relative risk, 5.70; 95 percent confidence interval, 1.98 to 16.42). Receipt of MMR vaccine was associated with an increased risk of febrile seizures 8 to 14 days after vaccination (relative risk, 2.83; 95 percent confidence interval, 1.44 to 5.55). Neither vaccination was associated with an increased risk of nonfebrile seizures. Analyses of automated data alone gave results similar to the analyses of the data from medical-record reviews. The number of febrile seizures attributable to the administration of DTP and MMR vaccines was estimated to be 6 to 9 and 25 to 34 per 100,000 children, respectively. As compared with other children with febrile seizures that were not associated with vaccination, the children who had febrile seizures after vaccination were not found to be at higher risk for subsequent seizures or neurodevelopmental disabilities. CONCLUSIONS: There are significantly elevated risks of febrile seizures on the day of receipt of DTP vaccine and 8 to 14 days after the receipt of MMR vaccine, but these risks do not appear to be associated with any long-term, adverse consequences.

Evidence assessment of management of acute otitis media: I. The role of antibiotics in treatment of uncomplicated acute otitis media.

CONTEXT: In 1995, >5 million episodes of acute otitis media (AOM) accounted for $3 billion in health care expenditures. OBJECTIVES: To synthesize the literature on the natural history of AOM, the effectiveness of antibiotic treatment in uncomplicated AOM, and the relative effectiveness of specific antibiotic regimens. DATA SOURCES: Seven electronic databases for articles published between 1966 and March 1999 and reference lists in proceedings, published articles, reports, and guidelines. STUDY SELECTION: Two physicians independently assessed each article. Studies addressing AOM in children 4 weeks to 18 years old were included; those addressing children with immunodeficiencies or craniofacial abnormalities were excluded. Randomized, controlled trials (RCTs) were used to assess antibiotic effectiveness, and RCTs and cohort studies were used to assess the natural history of AOM. Among the 3491 citations identified, 80 (2.3%) met our inclusion criteria. DATA EXTRACTION: Two physicians independently abstracted data and assessed the quality of studies using a validated scale for RCTs and 8 quality components for cohort studies. DATA SYNTHESIS: Random-effects estimates of pooled absolute rate differences of outcomes were derived, and heterogeneity of both the rates and rate differences was assessed. Children with AOM not treated with antibiotics experienced a 1- to 7-day clinical failure rate of 19% (95% confidence interval: 0.10-0.28) and few suppurative complications. When patients were treated with amoxicillin, the 2- to 7-day clinical failure rate was reduced to 7%, a 12% (95% confidence interval: 0.04-0.20) reduction. Adverse effects, primarily gastrointestinal, were more common among children on cefixime than among those on ampicillin or amoxicillin. They were also more common among children on amoxicillin-clavulanate than among those on azithromycin. CONCLUSIONS: The majority of uncomplicated cases of AOM resolve spontaneously without apparent suppurative complications. Ampicillin or amoxicillin confers a limited therapeutic benefit. There is no evidence to support any particular antibiotic regimens as more effective at relieving symptoms. Certain antibiotics are more likely than others to cause diarrhea and other adverse events.

Evidence assessment of management of acute otitis media: II. Research gaps and priorities for future research.

OBJECTIVES: To report research gaps and priorities of future research identified during an evidence assessment process on the management of acute otitis media (AOM). METHODS: A conceptual framework for management of AOM was developed to guide the evidence assessment. An 11-member technical expert panel guided the selection of key questions, prioritization of influencing factors, development of scope, definition of AOM, and search strategy through polling processes and conference calls. Quality of clinical trials was evaluated using established scales. Outcome measures were abstracted from each study. RESULTS: A total of 3461 titles and abstracts were screened, and 760 full-length articles were reviewed. Of the 760 articles, 80 studies addressed the key questions. In defining AOM, 42 (52.5%) of the 80 studies included the middle-ear effusion component, only 2 (2.5%) included the rapid onset component, and 26 (32.5%) included the signs/symptoms of inflammation component. None of the 80 studies used all 3 components. Of the 74 controlled trials, 39 (53%) were of acceptable quality (Jadad score of 3 or higher). The technical experts did not agree in the ranking of the importance of the 41 influencing factors (Kendall's coefficient of concordance was 0.0022). Another poll also indicated diverse opinions of the experts on the importance of 7 key questions derived from the conceptual framework (Kendall coefficient of concordance is 0.21). Furthermore, our review found that the type and definition of outcome measure varied. CONCLUSIONS: Despite the large body of literature on AOM, its quality is uneven and its findings are not generalizable. Future research should try to answer all key questions and investigate all risk factors in well-designed, scientific studies.

Cost-effectiveness analysis of an intranasal influenza vaccine for the prevention of influenza in healthy children.

OBJECTIVE: Intranasal influenza vaccine has proven clinical efficacy and may be better tolerated by young children and their families than an injectable vaccine. This study determined the potential cost-effectiveness (CE) of an intranasal influenza vaccine among healthy children. METHODS: We conducted a CE analysis of data collected between 1996 and 1998 during a prospective 2-year efficacy trial of intranasal influenza vaccine, supplemented with data from the literature. The CE analysis included both direct and indirect costs. We enrolled 1602 healthy children aged 15 to 71 months in year 1, 1358 of whom were enrolled in year 2. One or 2 doses of intranasal influenza vaccine or placebo were administered to measure the cost per febrile influenza-like illness (ILI) day avoided. RESULTS: During the 2-year study period, vaccinated children had an average of 1.2 fewer ILI fever days/child than unvaccinated children. In an individual-based vaccine delivery scenario with vaccine given twice in the first year and once each year thereafter at an assumed base case total cost of $20 for the vaccine and its administration (ie, per dose), CE was approximately $30/febrile ILI day avoided. CE ranged from $10 to $69/febrile ILI day avoided at $10 to $40/dose, respectively. In a group-based delivery scenario, vaccination was cost saving compared with placebo and remained so if vaccine cost was <$28 (the break-even price per dose). In the individual-based scenario, vaccination was cost saving if vaccine cost was <$5. In this scenario, nearly half of lost productivity in the vaccine group was attributable to vaccine visits, which overshadowed the relatively modest savings in ILI-associated costs averted. CONCLUSIONS: Routine use of intranasal influenza vaccine among healthy children may be cost-effective and may be maximized by using group-based vaccination approaches. cost-effectiveness, influenza, vaccine, children.

Measles-mumps-rubella and other measles-containing vaccines do not increase the risk for inflammatory bowel disease: a case-control study from the Vaccine Safety Datalink project.

CONTEXT: A link between measles virus-containing vaccines and inflammatory bowel disease (IBD) has been suggested by recent studies. OBJECTIVE: To address whether receipt or timing of measles-containing vaccine (MCV) increases risk for IBD. DESIGN: A case-control study. SETTING: Four large health maintenance organizations (HMOs) that are part of the Centers for Disease Control and Prevention's Vaccine Safety Datalink project. PATIENTS OR OTHER PARTICIPANTS: A total of 155 persons with codes from International Classification of Diseases, Ninth Revision specific for IBD, born between 1958 and 1989 and enrolled from birth to the onset of disease, were identified. Up to 5 controls were matched by sex, HMO, and birth year. INTERVENTION: None. MAIN OUTCOME MEASURES: Risk for IBD, Crohn's disease, and ulcerative colitis. RESULTS: Past vaccination was not associated with an increased risk for Crohn's disease (odds ratio [OR] for measles-mumps-rubella vaccine [MMR], 0.4; 95% confidence interval [CI], 0.08-2.0), ulcerative colitis (OR, 0.8; 95% CI, 0.18-3.56), or IBD (OR, 0.59; 95% CI, 0.21-1.68). Risk for IBD was not increased among children vaccinated who were younger than 12 months (OR for MMR, 0.61; 95% CI, 0.15-2.45) or aged 12 to 18 months (OR, 0.86; 95% CI, 0.28-2.59) relative to unvaccinated children. Children vaccinated with MMR who were older than 18 months were at significantly decreased risk for IBD (OR, 0.16; 95% CI, 0.04-0.68). Neither past vaccination nor age at vaccination with other MCV was associated with increased risk for Crohn's disease, ulcerative colitis, or IBD. Risk for Crohn's disease, ulcerative colitis, or IBD was not elevated in the time immediately following vaccination with either vaccine. CONCLUSIONS: Vaccination with MMR or other MCV, or the timing of vaccination early in life, did not increase the risk for IBD.

Does influenza vaccination prevent asthma exacerbations in children?

OBJECTIVE: Influenza can exacerbate asthma, particularly in children. The effectiveness of influenza vaccine in preventing influenza-related asthma exacerbations, however, is not known. We evaluated influenza vaccine effectiveness in protecting children against influenza-related asthma exacerbations. STUDY DESIGN: We conducted a population-based retrospective cohort study with medical and vaccination records in 4 large health maintenance organizations in the United States during the 1993-1994, 1994-1995, and 1995-1996 influenza seasons. We studied children with asthma who were 1 through 6 years of age and who were identified by search of computerized databases of medical encounters and pharmacy dispensings. Main outcome measures were exacerbations of asthma evaluated in the emergency department or hospital. RESULTS: Unadjusted rates of asthma exacerbations were higher after influenza vaccination than before vaccination. After adjustment was done for asthma severity by means of a self-control method, however, the incidence rate ratios of asthma exacerbations after vaccination were 0.78 (95% CI: 0.55 to 1.10), 0.59 (0.43 to 0.81), and 0.65 (0.52 to 0.80) compared with the period before vaccination during the 3 influenza seasons. CONCLUSIONS: After controlling for asthma severity, we found that influenza vaccination protects against acute asthma exacerbations in children.

The incidence of Kawasaki syndrome in West Coast health maintenance organizations.

BACKGROUND: Kawasaki syndrome (KS) causes an acute vasculitis of unknown etiology. It is a leading cause of acquired heart disease of children in Japan and the United States. METHODS: We examined the incidence of KS in a well-defined population group of children < or =6 years of age, using data collected through the Vaccine Safety Datalink (VSD) project. The VSD database contains information on >1 million children enrolled in four West Coast health maintenance organizations (HMOs). RESULTS: During 1993 through 1996 a total of 234 physician-diagnosed KS patients were reported in the 4 HMOs; 152 (65.0%) were boys and 195 (83.3%) were <5 years of age. The incidence of KS among children <5 years of age in the HMOs ranged from 9.0 to 19.1 per 100,000 person years. KS incidence was higher among boys in 3 of the sites. In the 2 sites with the highest number of KS patients, a seasonal occurrence of KS in winter and early spring was observed. Overall 226 (96.6%) of the KS patients were reported to have been hospitalized; hospitalization rates for children <5 years of age ranged from 9.0 to 16.8 per 100,000 person years. CONCLUSIONS: The incidence of KS in the HMOs was similar to that reported in other population-based studies in the United States and higher than estimates for Australia and several European countries.

The Vaccine Safety Datalink: immunization research in health maintenance organizations in the USA.

The Vaccine Safety Datalink is a collaborative project involving the National Immunization Program of the Centers for Disease Control and Prevention and several large health maintenance organizations in the USA. The project began in 1990 with the primary purpose of rigorously evaluating concerns about the safety of vaccines. Computerized data on vaccination, medical outcome (e.g. outpatient visits, emergency room visits, hospitalizations, and deaths) and covariates (e.g. birth certificates, census data) are prospectively collected and linked under joint protocol at multiple health maintenance organizations for analysis. Approximately 6 million persons (2% of the population of the USA) are now members of health maintenance organizations participating in the Vaccine Safety Datalink, which has proved to be a valuable resource providing important information on a number of vaccine safety issues. The databases and infrastructure created for the Vaccine Safety Datalink have also provided opportunities to address vaccination coverage, cost-effectiveness and other matters connected with immunization as well as matters outside this field.

Epidemiology of diarrheal disease among children enrolled in four West Coast health maintenance organizations. Vaccine Safety Datalink Team.

BACKGROUND: We used information from the Vaccine Safety Datalink (VSD) about approximately 1 million children enrolled in four health maintenance organizations to assess the morbidity from diarrhea and estimate the disease burden of rotavirus. METHODS: We examined trends of diarrhea-associated hospitalizations and emergency room (ER) visits among VSD children ages 1 month through 4 years during October, 1992, through September, 1994 (two rotavirus seasons) and estimated the morbidity from rotavirus on the basis of characteristic patterns of age and seasonality. RESULTS: Overall diarrhea was associated with 6.3% of hospitalizations and 4% of ER visits. During a child's first 5 years of life, we estimated that 1 in 57 was hospitalized and 1 in 21 required an ER visit because of diarrhea. Each year the number of diarrhea-associated hospitalizations and ER visits was greatest in winter among children ages 4 to 23 months and peaked in November in California and during February in Oregon and Washington. The winter seasonality of diarrhea-associated hospitalizations reflected the trends for diarrhea of presumed noninfectious and viral etiologies, which together accounted for most (92.9%) hospitalizations. CONCLUSIONS: Diarrhea is an important cause of morbidity among VSD children. The epidemiologic patterns of diarrhea-associated hospitalizations and ER visits resembled those reported previously for rotavirus diarrhea, suggesting that rotavirus may be a major contributor to the overall morbidity from diarrhea. Enhanced surveillance by screening for rotavirus in a sample of children with diarrhea will permit a more accurate assessment of the disease burden of this pathogen and the cost effectiveness of a rotavirus immunization program.