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Using a new sequential analytic method, the safety of tetanus-diphtheria-acellular pertussis (Tdap) vaccine was monitored weekly among subjects aged 10-64 years during 2005-2008. Encephalopathy-encephalitis-meningitis, paralytic syndromes, seizures, cranial nerve disorders, and Guillain-Barré syndrome were selected as outcomes based on previous reports and biologic plausibility. The risk following Tdap was not significantly higher than the risk after Td. Statistical power was sufficient to detect a relative risk of 4-5 for Guillain-Barré syndrome and 1.5-2 for the other outcomes. This study provides reassurance that Tdap is similar in safety to Td regarding the outcomes studied and supports the viability of sequential analysis for post-licensure vaccine safety monitoring.

We evaluated the risk of optic neuritis (ON) after vaccines, using a case-centered analysis, comparing the time since vaccination for the patients with ON with that for all similar vaccinees in a large integrated health plan population. We did not detect any association between ON and receipt of any type of vaccine.

Objectives To assess the incidence of invasive pneumococcal disease (IPD) in all children younger than 5 years of age in the Northern California Kaiser Permanente (NCKP) health care system during a 5-year surveillance period (2000-2005) after the introduction in April 2000 of routine use of 7-valent pneumococcal conjugate vaccine (PCV7). Methods This was a laboratory-based surveillance study of all children younger than 5 years of age in the NCKP health care system from April 2000 to March 2005. The comparison group was all children younger than 5 years of age in the NCKP health care system from April 1996 to March 2000. Data obtained from clinical databases included microbiologic identification and susceptibility testing; serotyping of isolates; immunization records; and IPD diagnoses for inpatients and outpatients. IPD was defined as a positive culture of Streptococcus pneumoniae from a normally sterile body site. Results For all serotypes, the mean annual incidence of IPD during the postlicensure surveillance period was 15.3 cases/100,000 person-years (10(5) p-y) compared with 62.5 cases/10(5) p-y in the prelicensure years of 1996-2000. The average incidence of IPD caused by vaccine serotypes was reduced from 50.1 cases/10(5) p-y during the prelicensure years to 4.9 cases/10(5) p-y during the postlicensure period. The average incidences of IPD caused by cross-reactive and by nonvaccine serotypes were 5.8 and 5.3 cases/10(5) p-y, respectively, during the prelicensure years and 2.5 and 6.2 cases/10(5) p-y, respectively, during the postlicensure period. Of the 131 IPD cases observed during the postlicensure surveillance period, bacteremia (50.4%) and pneumonia (31.3%) were the most common diagnoses. During the 5-year postlicensure surveillance period, only 3 subjects who were identified to be fully vaccinated for age with PCV7 (3 doses by 7 months of age or 4 doses by 18 months of age) developed vaccine-serotype IPD. Conclusion The incidence of IPD has significantly decreased in a large population of children after the introduction of PCV7. Vaccine-type IPD was rare in patients who received full 4-dose immunization with PCV7. There is no clear evidence of a significant increase in nonvaccine-serotype IPD. Introduction of a 4-dose infant schedule of PCV7 into this population has resulted in a marked and sustained reduction of IPD in children.

Whole-cell pertussis (wP) and measles vaccines are effective in preventing disease but have also been suspected of increasing the risk of encephalopathy or encephalitis. Although many countries now use acellular pertussis vaccines, wP vaccine is still widely used in the developing world. It is therefore important to evaluate whether wP vaccine increases the risk of neurologic disorders.A retrospective case-control study was performed at 4 health maintenance organizations. Records from January 1, 1981, through December 31, 1995, were examined to identify children aged 0 to 6 years old hospitalized with encephalopathy or related conditions. The cause of the encephalopathy was categorized as known, unknown or suspected but unconfirmed. Up to 3 controls were matched to each case. Conditional logistic regression was used to analyze the relative risk of encephalopathy after vaccination with diphtheria-tetanus-pertussis (DTP) or measles-mumps-rubella (MMR) vaccines in the 90 days before disease onset as defined by chart review compared with an equivalent period among controls indexed by matching on case onset date.Four-hundred fifty-two cases were identified. Cases were no more likely than controls to have received either vaccine during the 90 days before disease onset. When encephalopathies of known etiology were excluded, the odds ratio for case children having received DTP within 7 days before onset of disease was 1.22 (95% confidence interval [CI] = 0.45-3.31, P = 0.693) compared with control children. For MMR in the 90 days before onset of encephalopathy, the odds ratio was 1.23 (95% confidence interval = 0.51-2.98, P = 0.647).In this study of more than 2 million children, DTP and MMR vaccines were not associated with an increased risk of encephalopathy after vaccination.

Background: Prevnar [heptavalent pneumococcal conjugate vaccine (PCV7)] is licensed in the United States for routine administration in infants and may be coadministered with other infant vaccines. Safety and immunogenicity data on the coadministration of the fourth dose of PCV7 with measles-mumps-rubella (MMR), varicella and Haemophilus influenzae type b (Hib) vaccines are limited. Methods: Children 12-15 months of age received either MMR with PCV7 (group 1) or MMR without PCV7 (group 2). All subjects received Hib and varicella vaccines. Group 2 received PCV7 6-9 weeks after MMR vaccination. Sera for analysis of all non-PCV7 antibodies were collected just before administration of MMR vaccine and 6 weeks later. Optimal antigen responses were assessed with the use of predetermined antibody titers. The primary end point was >90% response rate (all antigens). Noninferiority was defined as

Objective: To assess the direct and indirect effects of the introduction of routine use of pneumococcal conjugate vaccine in infants and toddlers at risk for invasive disease caused by vaccine serotypes and nonvaccine serotypes in vaccinated children and unvaccinated children of the same age. Secondary objectives included determination of the risk of pneumococcal infections in unvaccinated older children and adults in the same population and the impact of vaccine introduction on patterns of antimicrobial resistance. Methods: Northern California Kaiser Permanente provides integrated comprehensive care to 3.1 million people and has an annual birth cohort of 38,000 infants. Microbiology services use a regional laboratory. Automated laboratory results, immunization records as well as diagnoses for inpatient and outpatient utilization are available from clinical data bases. Beginning in April 2000, the heptavalent pneumococcal conjugate (PNCV7) vaccine was introduced into routine use in the Northern California Kaiser Permanente population. Cases of invasive pneumococcal disease were identified from the automated hospital diagnosis as well as laboratory databases for all individuals, vaccinees and nonvaccinees, inpatient and outpatient. For the purpose of these analyses, pneumococcal invasive disease was defined as a positive culture from a normally sterile site. Results: As of March 2003, 157,471 children had received 1 dose or more of PNCV7, but only 24% of those

Background: Hepatitis A is a major cause of epidemic hepatitis in the US. In pre-licensure trials, inactivated hepatitis A vaccine (HAV, VAQTA®, Merck) was shown to be generally well-tolerated and effective in inducing immunity to hepatitis A infection in adults and children over 2 years of age. Following the licensure of this vaccine, we began a Phase IV safety evaluation in adults and in children over 2 years of age. Methods: Safety was assessed by comparing the rates of diagnoses in clinic, emergency and hospital utilization. From April 1997 to December 1998, rates of diagnoses within 30 days for the clinic and emergency setting and 60 days for hospitalization were compared with unexposed follow-up time in the same individuals both before receipt of vaccine and after the 60 days interval post-vaccination. Results: There were a total of approximately 2000 comparisons between the risk and “before” or “after” period. Among them, 106 were found to have statistically significant differences in rates (30 elevated, 76 lowered). Among children/adolescents (2–17 year-old), in the hospitalization category, the only statistically significant elevated risk found was “elective procedures”, as compared with both “before” and “after” periods. In the outpatient visit category for children and adolescents, elevated risks were found for consultation/general medicine/exam when compared with both “before” and “after” periods, and ganglion and viral warts when compared with either “before” or “after” period. Among adults (≥18 year-old), in the outpatient visit category, a statistically significant elevated relative risk was seen for diarrhea/gastroenteritis for both “before” and “after” periods. There were additionally 17 diagnostic categories that showed a statistically significantly elevated relative risk compared with either “before” or “after” period. Except for diarrhea/gastroenteritis, the other eight events were elevated only in one comparison (either “before” or “after”). These eight elevated relative risks might be explained by chance resulting from multiple comparison or seasonal variations. There were no serious adverse events judged by the investigator to be associated with HAV. Conclusion: In this large Phase IV evaluation of the safety of HAV, the vaccine appeared to be generally well-tolerated. These data support the continued routine use of HAV for vaccination in children and adults.

Summary Objective: To assess the quality of automated diagnoses extracted from medical care databases by the Vaccine Safety Datalink (VSD) study. Methods: Two methods are used to assess quality of VSD diagnosis data. The first method compares common automated and abstracted diagnostic categories (“outcomes”) in 1-2% simple random samples of study populations. The second method estimates positive predictive values of automated diagnosis codes used to identify potential cases of rare conditions (e.g., acute ataxia) for inclusion in nested case-control medical record abstraction studies. Results: There was good agreement (64-68%) between automated and abstracted outcomes in the 1-2% simple random samples at 3 of the 4 VSD sites and poor agreement (44%) at 1 site. Overall at 3 sites, 56% of children with automated cerebella ataxia codes (ICD-9 = 334) and 22% with “lack of coordination” codes (ICD-9 = 781.3) met objective clinical criteria for acute ataxia. Conclusions: The misclassification error rates for automated screening outcomes substantially reduce the power of screening analyses and limit usefulness of screening analyses to moderate to strong vaccine-outcome associations. Medical record verification of outcomes is needed for definitive assessments.

Context. The heptavalent pneumococcal conjugate vaccine (PCV) is recommended for infants to protect against invasive disease, but its impact on otitis might also have public health importance. Objective. To examine the impact of PCV on the incidence of otitis media, frequent otitis media and tympanostomy tube procedures and to assess whether the effectiveness of the vaccine wanes after age 24 months and varies by race, sex or season. Design, setting and patients. From 1995 to 1998, 37 868 children at Kaiser Permanente in Northern California were randomized to receive PCV or a control vaccine in a double blind trial and were followed through April 1999. Interventions. Children received a primary series at 2, 4 and 6 months of age and a booster at 12 to 15 months. Main outcome measures. Visits for otitis, frequent visits for otitis and tympanostomy tube procedures. Otitis was ascertained from diagnosis checklists routinely marked by physicians. Results. Control children averaged 1.8 otitis visits per year. Children given PCV had fewer otitis visits than control children in every age group, sex, race and season examined. Intention-to-treat analysis permitted rejection of the null hypothesis that PCV is ineffective against otitis media (P < 0.0001). In children who completed the primary series per protocol, PCV reduced otitis visits by 7.8% [95% confidence interval (CI), 5.4 to 10.2%] and antibiotic prescriptions by 5.7% (CI 4.2 to 7.2%). Frequent otitis was reduced by amounts that increased with otitis frequency, from a 10% reduction in the risk of 3 visits to a 26% reduction in the risk of 10 visits within a 6-month period. Tube placements were reduced by 24% (CI 12 to 35%). Conclusion. In children followed up to 3.5 years, PCV provided a moderate amount of protection against ear infections while reducing frequent otitis media and tube procedures by greater amounts.

Objective. To determine the efficacy, immunogenicity and safety of the heptavalent CRM 197 pneumococcal conjugate vaccine (PCV) in low birth weight (LBW) and preterm (PT) infants against invasive pneumococcal disease caused by vaccine types. Methods. In a randomized double blind trial of 37 868 infants given either PCV or meningococcal type C conjugate vaccine (MCV), 1756 infants

Background Herpes zoster ophthalmicus (HZO), caused by reactivation of varicella-zoster virus in or around the eye, can be severe and often results in care-seeking that may be less discretionary than for uncomplicated herpes zoster (HZ). We compared the vaccine effectiveness (VE) of live zoster vaccine against HZO with the VE against HZ overall. Methods Kaiser Permanente Northern California (KPNC) members enter the ongoing cohort study when age-eligible for zoster vaccine starting in 2007. Incident HZ was defined as a new diagnosis of HZ with an antiviral prescription or a positive varicella viral test. Among those, an HZO case was defined as having an HZO diagnosis during an ophthalmology visit within 30 days of the initial HZ diagnosis. VE by age at vaccination and time since vaccination was estimated using Cox regression adjusted for age, race, sex and time-varying measures of healthcare use, comorbidities and immunocompromise status. Average VE over the first 5 years following vaccination was calculated as a weighted average of annual VE estimates. Results During 2007–2014, ~1.3 million individuals ≥50 years of age entered the study population and 29% were vaccinated. Among 48,889 incident HZ cases, 2,858 (6%) had HZO, 87% of whom were unvaccinated. For all ages combined, VE against HZO was 72% (95% CI, 64%-79%) in year 1, similar to 68% (95% CI, 65%-70%) against HZ. VE fell in years 2, 3, 4, and 5 to 47%, 45%, 42% and 27% for HZO and to 47%, 39%, 41% and 37% for HZ. For age groups 60 – 69 and 70 – 79, where we have the most data, initial VE and waning were similar for HZO and HZ. Numbers of HZO cases for 50–59 year olds were too small to evaluate at this time. Average VE against HZO over the first 5 years following vaccination was 52% (95% CI, 42%–60%) for ages 60–69, 51% (95% CI, 39%–61%) for ages 70-79, and 39% (95% CI, 14%-57%) for ages 80+; similarly, 5-year average VE against HZ was 49%, 46%, and 44% for these 3 age groups. Conclusion VE against HZO was similar to VE against HZ regardless of age at vaccination or time since vaccination. Effectiveness of live zoster vaccine in preventing HZO was highest in year one with subsequent waning. Disclosures E. Earley, Merck & Co.: Research Contractor, Salary; M. Marks, Merck and Co. Inc.: Employee, Restricted Stock and Salary; P. Saddier, Merck & Co., Inc.: Employee, Salary; N. P. Klein, GSK: Investigator, Grant recipient; sanofi pasteur: Investigator, Grant recipient; Merck & Co.: Investigator, Grant recipient; MedImmune: Investigator, Grant recipient; Protein Science: Investigator, Grant recipient Pfizer: Investigator, Grant recipient

Background Clostridium difficile is a major cause of severe diarrhea in the U.S. We described characteristics of Kaiser Permanente Northern California (KPNC) members with C. difficile infection (CDI), identified risk factors associated with CDI, and developed risk scores to predict who may develop CDI. Methods Retrospective cohort study with all KPNC members ≥18 years old from May 2011 to July 2014 comparing demographic and clinical characteristics for those with and without lab-confirmed incident CDI. We included CDI risk factors in logistic regression models to estimate the risk of developing future CDI after an Identification Recruitment Date (IRD), a time when an individual might be a good candidate for a C. difficile vaccine clinical trial. Two risk score models were created and cross validated (70% of the data used for development and 30% for testing). Results During the study period, there were 9,986 CDI cases and 2,230,354 members without CDI. CDI cases tended to be ≥65 years old (59% vs.. 21%), female (61% vs. 53%), and white race (70% vs. 53%), with more hospitalizations (42% vs. 3%), emergency room visits (51% vs. 14%), and skilled nursing facility stays (25% vs. 0.6%) in the year prior to CDI compared with members without CDI. At least 10 office visits within the prior year (53% vs. 16%), use of antibiotics in last 12 weeks (81% vs. 11%), proton pump inhibitors in the last year (36% vs. 7%), and multiple medical conditions within the prior year (e.g., chronic kidney disease, congestive heart failure, and pneumonia) were important risk factors for CDI. Using a hospital discharge event as the IRD, our risk score model yielded excellent performance in predicting the likelihood of developing CDI in the subsequent 31 – 365 days (C-statistic of 0.851). Using a random date as the IRD, our model also predicted CDI risk in the subsequent 1–30 days (C-statistic 0.658) and 31–365 days (C-statistic 0.722) reasonably well. Conclusion CDI can be predicted by increasing age, medications, comorbidities and healthcare exposure, particularly ≥10 office visits, hospitalizations, and skilled nursing stays in the prior year and recent antibiotics. Such risk factors can be used to identify high-risk populations for C. difficile vaccine clinical studies. Disclosures H. Yu, Pfizer, Inc.: Employee, Salary; B. Cai, Pfizer, Inc.: Employee, Salary; E. Gonzalez, Pfizer, Inc.: Employee, Salary; J. Lawrence, Pfizer, Inc.: Employee, Salary; N. P. Klein, GSK: Investigator, Grant recipient; sanofi pasteur: Investigator, Grant recipient; Merck & Co: Investigator, Grant recipient; MedImmune: Investigator, Grant recipient; Protein Sciences: Investigator, Grant recipient; Pfizer: Investigator, Grant recipient

BACKGROUND:When varicella vaccine was licensed in the United States in 1995, there were concerns that childhood vaccination might increase the number of adolescents susceptible to varicella and shift disease toward older age groups where it can be more severe.METHODS:We conducted a series of 5 cross-sectional studies in 1994 to 1995 (prevaccine), 2000, 2003, 2006, and 2009 in Kaiser Permanente of Northern California to assess changes in varicella epidemiology in children and adolescents, as well as changes in varicella hospitalization in people of all ages. For each study, information on varicella history and varicella occurrence during the past year was obtained by telephone survey from a sample of ∼8000 members 5 to 19 years old; varicella hospitalization rates were calculated for the entire membership.RESULTS:Between 1995 and 2009, the overall incidence of varicella in 5- to 19-year-olds decreased from 25.8 to 1.3 per 1000 person-years, a ∼90% to 95% decline in the various age categories (5–9, 10–14, and 15–19 years of age). The proportion of varicella-susceptible children and adolescents also decreased in all age groups, including in 15- to 19-year-olds (from 15.6% in 1995 to 7.6% in 2009). From 1994 to 2009, age-adjusted varicella hospitalization rates in the general member population decreased from 2.13 to 0.25 per 100 000, a ∼90% decline.CONCLUSIONS:In the 15 years after the introduction of varicella vaccine, a major reduction in varicella incidence and hospitalization was observed with no evidence of a shift in the burden of varicella to older age groups.

A 15-year postmarketing evaluation of the impact of varicella vaccine on the age distribution of varicella disease is being conducted at Kaiser Permanente Medical Care Program, Northern California (KPMCP). We report on a baseline assessment of the age-specific incidence and hospitalization rates of varicella and herpes zoster that was conducted before vaccine introduction.To assess the annual incidence of varicella, a telephone survey was conducted in a random sample of approximately 8,000 youths 5 to 19 years of age. The annual incidence of hospitalizations for varicella and herpes zoster in 1994 was assessed with the use of the computerized database at KPMCP.Varicella annual incidence was 10.3% in 5- to 9-year-olds, 1.9% in 10- to 14-year-olds and 1.2% in the 15- to 19-year age groups, respectively. Hospitalization rates among the entire KPMCP membership were 2.6 and 2.1 per 100,000 person years for varicella and zoster, respectively. Varicella incidence in the 15- to 19-year age group was higher among African-Americans than among Caucasians.Varicella rates were similar in the 5- to 9- and 10- to 14-year age groups to rates from other published studies conducted in 1972 to 1978, 1980 to 1988 and 1990 to 1992; however, the rate in 15- to 19-year-olds was 2 to 4 times higher than published rates in the same age category.

Objective.To determine the efficacy, safety and immunogenicity of the heptavalent CRM197 pneumococcal conjugate vaccine against invasive disease caused by vaccine serotypes and to determine the effectiveness of this vaccine against clinical episodes of otitis media.Methods.The Wyeth Lederle

Background A World Health Organization (WHO) working group in 2001 developed a method for standardizing interpretation of chest radiographs in children for epidemiologic purposes. We reevaluated radiographs from the Kaiser Permanente Pneumococcal Efficacy trial using this method. Methods Seven-valent pneumococcal conjugate vaccine was evaluated in a randomized, controlled study including 37,868 infants. Effectiveness against pneumonia was previously evaluated using the original treating radiologist reading. There were 2841 sets of radiographs from this trial and all available radiographs were scanned and read blindly by 2 WHO crosstrained readers (A and B); discordance between the 2 primary readers was resolved through a consensus reading by an adjudicating panel of 2 radiologists. Results Of the 2841 radiographs, 2446 were available for scanning and were reviewed using WHO-defined descriptive categories. Two hundred fifty of the 2446 radiographs were read as positive by both readers. An additional 129 were read as positive by reader A only and 142 by reader B only for a total of 521 radiographs that were read as positive by one or both of the reviewers. The concordance rate between the 2 reviewers was 250 of 521 (48%). Of the 271 discordant radiographs, 45 of 129 (34.9%) of reader A and 66 of 142 (46.5%) for reader B were finalized as positive by the adjudicating panel. Overall, 361 radiographs were finalized as positive (12.7%). With these 361 images as the standard, the sensitivity and specificity of reader A were 82% and 97%, respectively, and for reader B, 88% and 97%, respectively. Kappa between the 2 readers was 0.58. Of 25 control radiographs read as positive by both A and B, 80% were also read as positive by the panel and all 25 control negative radiographs were read as negative by the panel. Using original readings by point-of-care radiologists, efficacy against first episode of radiograph confirmed pneumonia was 17.7% (95% confidence interval [CI] = 4.8-28.9%) in intent-to-treat and 20.5% (95% CI = 4.4-34%) in per protocol. Using the WHO method, the efficacy against first episode of radiograph confirmed pneumonia adjusting for age, gender and year of vaccination of 25.5% (95% CI = 6.5-40.7%, P = 0.011) for intent-to-treat and 30.3% (95% CI = 10.7-45.7%, P = 0.0043) for per protocol. Conclusion Using WHO criteria for reading of radiographs increased point estimates of vaccine efficacy presumably as a result of improved specificity.

Objective. To evaluate the safety and immunogenicity of the recombinant acellular pertussis-diphtheria-tetanus (aPDT) vaccine (C-aPDT, Chiron/Biocine®). Study design. This is a randomized blinded trial evaluating the safety and immunogenicity of the recombinant aPDT vaccine (C-aPDT, Chiron/Biocine®) in 2000 infant recipients compared with 498 controls who received whole cell diphtheria-pertussis-tetanus (wDPT; Connaught) vaccine at 2, 4 and 6 months of age. In addition the safety and immunogenicity of the same C-aPDT vaccine were evaluated as a booster dose in a subset of the same population when given at 15 to 18 months of age and compared with licensed Lederle aPDT vaccine. Results. The C-aPDT vaccine was associated with very few local or systemic reactions when compared with wDPT. In toddlers the local and systemic side effects observed were similar after either acellular vaccine. When the immunogenicity of the C-aPDT vaccine was compared with the wDPT (Connaught) in infancy, the vaccines were equivalent for anti-diphtheria response, the wDPT developed higher anti-tetanus response and the C-aPDT vaccine was significantly more immunogenic for all other antigens tested. In toddlers the C-aPDT acellular vaccine exhibited equal or improved immunogenicity for antigens tested as compared with Lederle aPDT except for a higher anti-filamentous hemagglutinin response with the Lederle aPDT vaccine. Conclusion. The Chiron/Biocine® aPDT vaccine offers an improved safety profile as well as improved immunogenicity when compared with a licensed wDPT product.

Objective. To evaluate the effectiveness and cost effectiveness of computer-generated recall letters to parents of children overdue for immunizations. Methods. This randomized controlled trial included children of two facilities in a regional health maintenance organization. Parents of 20-month-olds who had not yet received a measlesmumps-rubella (MMR) immunization were identified via a computerized immunization tracking system. One half were mailed personalized letters that included the recommended immunization schedule and a request to call for an appointment; the other half served as a control group. Receipt of the MMR between 20 and 24 months of age was evaluated with the computerized tracking system. A telephone survey was conducted with parents whose children had not received the MMR by 24 months. Decision analysis was used to project the theoretical outcomes and costs of a recall letter policy for other populations. Results. Among 20-month-old children 10% had not received the MMR; 289 families were included in the analysis. Of families who were mailed letters, 54% (82 of 153) received the MMR by 24 months of age, compared with 35% (47 of 136) of those in the control group (P = 0.001). The telephone survey was completed with 110 parents of children who still did not appear on the health plan computer as having received the MMR by 24 months. Fifteen percent said the child had received an immunization at an outside provider, and of the rest 62% said they had not been aware that an immunization was due. In the cost effectiveness analysis it was projected that recall letters would increase the immunization rate for the regional population of approximately 30 000 children from 86% to 90% at a total cost of $5031 annually. The cost per additional child appropriately immunized was $4.04. In sensitivity analyses this cost effectiveness ratio varied depending on the baseline population coverage rate as well as the estimated effectiveness of recall letters. Conclusions. Computer-generated letters to recall children overdue for immunizations resulted in a higher proportion of children appropriately immunized in this setting. However, the strategy was not as cost-effective as intuition might suggest. Further studies in health maintenance organization (HMO) settings should compare the cost effectiveness of letters with other low cost strategies including automated telephone reminders.

Importance The first dose of live attenuated measles-containing vaccines is associated with an increased risk of febrile seizures 7 to 10 days following immunization among 12- to 23-month-old children. The combination measles, mumps, rubella, and varicella vaccine is associated with a 2-fold increased risk of febrile seizures 7 to 10 days following immunization compared with the separately administered measles, mumps, and rubella and varicella vaccines. It is unknown whether the magnitude of these increased risks depends on age at immunization. Objective To examine the potential modifying effect of age on the risk of fever and seizures following immunization with measles-containing vaccines. Design, Setting, and Participants Retrospective cohort study at 8 Vaccine Safety Datalink sites of a total of 840 348 children 12 to 23 months of age who had received a measles-containing vaccine from 2001 through 2011. Exposures Any measles-containing vaccines and measles-containing vaccines by type. Main Outcomes and Measures Fever and seizure events occurring during a 42-day postimmunization observation period. Results In the analysis of any measles-containing vaccines, the increased risk of seizures during the 7- to 10-day risk interval, using the remainder of the observation period as the control interval, was significantly greater among older children (relative risk, 6.5; 95% CI, 5.3-8.1; attributable risk, 9.5 excess cases per 10 000 doses; 95% CI, 7.6-11.5) than among younger children (relative risk, 3.4; 95% CI, 3.0-3.9; attributable risk = 4.0 excess cases per 10 000 doses; 95% CI, 3.4-4.6). The relative risk of postimmunization fever was significantly greater among older children than among younger children; however, its attributable risk was not. In the analysis of vaccine type, measles, mumps, rubella, and varicella vaccine was associated with a 1.4-fold increase in the risk of fever and 2-fold increase in the risk of seizures compared with measles, mumps, and rubella vaccine administered with or without varicella vaccine in both younger and older children. Conclusions and Relevance Measles-containing vaccines are associated with a lower increased risk of seizures when administered at 12 to 15 months of age. Findings of this study that focused on safety outcomes highlight the importance of timely immunization of children with the first dose of measles-containing vaccines.

BACKGROUND: Varicella vaccine was licensed in the United States in 1995 for individuals ≥12 months of age. A second dose was recommended in the United States in June 2006. Varicella incidence and vaccine effectiveness were assessed in a 14-year prospective study conducted at Kaiser Permanente Northern California. METHODS: A total of 7585 children vaccinated with varicella vaccine in their second year of life in 1995 were followed up prospectively for breakthrough varicella and herpes zoster (HZ) through 2009. A total of 2826 of these children received a second dose in 2006–2009. Incidences of varicella and HZ were estimated and compared with prevaccine era rates. RESULTS: In this cohort of vaccinated children, the average incidence of varicella was 15.9 per 1000 person-years, nine- to tenfold lower than in the prevaccine era. Vaccine effectiveness at the end of the study period was 90%, with no indication of waning over time. Most cases of varicella were mild and occurred early after vaccination. No child developed varicella after a second dose. HZ cases were mild, and rates were lower in the cohort of vaccinated children than in unvaccinated children during the prevaccine era (relative risk: 0.61 [95% confidence interval: 0.43–0.89]). CONCLUSIONS: This study confirmed that varicella vaccine is effective at preventing chicken pox, with no waning noted over a 14-year period. One dose provided excellent protection against moderate to severe disease, and most cases occurred shortly after the cohort was vaccinated. The study data also suggest that varicella vaccination may reduce the risks of HZ in vaccinated children.

Background Pregnant women are at greater risk of complications from influenza (flu) infection than the general population. Although vaccination is an effective method to prevent influenza, the vaccine is underutilized during pregnancy. A challenge to maternal flu vaccination is the paucity of data about the effectiveness of inactivated influenza vaccines (IIV) in preventing severe outcomes in pregnant women. To inform policy and address this knowledge gap, CDC developed a multi-country collaboration to investigate the preventive value of IIV during pregnancy during multiple flu seasons. We present the progress to date of this Network. Methods PREVENT was established in April 2016 to: i) estimate incidence of influenza and vaccination rates; ii) describe epidemiologic characteristics associated with illness; and iii) estimate IIV effectiveness in preventing hospitalizations during pregnancy associated with RT PCR -confirmed influenza. We selected sites that could identify the population of women known to be pregnant during flu seasons and integrate their hospitalization data, clinical laboratory testing, and vaccination records. We will assess VE using the case test-negative control design and use meta-analyses to pool VE estimates across sites and account for significant differences. Primary analyses will be completed by August 2017. Results Seven sites in Australia, Canada, Israel, and the US were selected; a protocol and data dictionary were finalized. We identified 1,024 pregnant women hospitalized with acute respiratory illness and RT-PCR tested, during six influenza seasons (2010–11 through 2015–16). Of the qualifying women, 550 (54%) tested positive for flu. Positivity varied by site (range 41% (US)–61.8% (Ontario, CAN)), and vaccination coverage varied across sites and seasons (range 7.3% (Ontario, CAN)–46% (US)). Analyses will examine flu season characteristics, vaccination patterns, and clinical and birth outcomes related to respiratory illness during pregnancy and flu incidence. Conclusion Laboratory-confirmed influenza hospitalization during pregnancy is a relatively low-frequency event. Pooling data across multiple sites offers a way to estimate VE against severe influenza outcomes in pregnant women that is informative to influenza vaccine policy. Disclosures A. Naleway, MedImmune: Investigator, Research grant; Pfizer: Investigator, Research grant; Merck: Investigator, Grant recipient; N. P. Klein, GSK: Investigator, Research grant; sanofi pasteur: Investigator, Grant recipient; Merck & Co: Investigator, Grant recipient; MedImmune: Investigator, Grant recipient; Protein Science: Investigator, Research grant; Pfizer: Investigator, Grant recipient; S. Irving, Medimmune/AstraZeneca: Investigator, Research support

We carried out an imaging survey for extrasolar planets around stars in the Pleiades (125 Myr, 135 pc) in the $H$ and $K_{S}$ bands using HiCIAO combined with the adaptive optics, AO188, on the Subaru telescope. We found 13 companion candidates fainter than 14.5 mag in the $H$ band around 9 stars. Five of these 13 were confirmed to be background stars by measurement of their proper motion. One was not found in the second epoch observation, and thus was not a background or companion object. One had multi-epoch image, but the precision of its proper motion was not sufficient to conclude whether it was background object. Four other candidates are waiting for second epoch observations to determine their proper motion. Finally, the remaining 2 were confirmed to be 60 $M_{J}$ brown dwarf companions orbiting around HD 23514 (G0) and HII 1348 (K5) respectively, as had been reported in previous studies. In our observations, the average detection limit for a point source was 20.3 mag in the $H$ band beyond 1''.5 from the central star. On the basis of this detection limit, we calculated the detection efficiency to be 90% for a planet with 6 to 12 Jovian masses and a semi-major axis of 50--1000 AU. For this we extrapolated the distribution of planet mass and semi-major axis derived from RV observations and adopted the planet evolution model of Baraffe et al. (2003). As there was no detection of a planet, we estimated the frequency of such planets to be less than 17.9% ($2\sigma$) around one star of the Pleiades cluster., Comment: 30 pages, 5 figures, accepted for publication in PASJ

The development of a varicella vaccine has raised questions about the cost effectiveness of vaccination, but little information on the costs of chickenpox exists. The purpose of this study was to evaluate medical costs and the value of work loss among families whose children had chickenpox. Interviews were conducted with 179 families who made advice nurse calls or urgent care clinic visits to three clinics in the Northern California Kaiser Permanente Medical Care Plan. Two-thirds of working mothers and one-third of working fathers missed work to care for children with chickenpox. The mean value of the work lost because of chickenpox was $293/family or $183/chickenpox case. The estimated costs of nonprescription medications were $20/family or $12.50/chickenpox case. Children were sick enough to need to stay home for only one-third as many days as chicken actually stayed home because of school exclusion policies. These empiric results differ from previous estimates of the medical and work loss costs of varicella and should be included in analyses of the cost effectiveness of proposed vaccination programs.

The Vaccine Safety Datalink (VSD) project is a collaborative project between the Centers for Disease Control and Prevention and 8 managed care organizations (MCOs) in the United States. Established in 1990 to conduct postmarketing evaluations of vaccine safety, the project has created an infrastructure that allows for high-quality research and surveillance. The 8 participating MCOs comprise a large population of 8.8 million members annually (3% of the US population), which enables researchers to conduct studies that assess adverse events after immunization. Each MCO prepares computerized data files by using a standardized data dictionary containing demographic and medical information on its members, such as age and gender, health plan enrollment, vaccinations, hospitalizations, outpatient clinic visits, emergency department visits, urgent care visits, and mortality data, as well as additional birth information (eg, birth weight) when available. Other information sources, such as medical chart review, member surveys, and pharmacy, laboratory, and radiology data, are often used in VSD studies to validate outcomes and vaccination data. Since 2000, the VSD has undergone significant changes including an increase in the number of participating MCOs and enrolled population, changes in data-collection procedures, the creation of near real-time data files, and the development of near real-time postmarketing surveillance for newly licensed vaccines or changes in vaccine recommendations. Recognized as an important resource in vaccine safety, the VSD is working toward increasing transparency through data-sharing and external input. With its recent enhancements, the VSD provides scientific expertise, continues to develop innovative approaches for vaccine-safety research, and may serve as a model for other patient safety collaborative research projects.

Background Associations between vaccinations, particularly hepatitis B, and onset of rheumatoid arthritis (RA) have been reported, but examined in few large-scale studies. Method Onset of RA cases and dates of vaccination against hepatitis B, tetanus, and influenza were identified in a retrospective chart review of approximately 1 million Kaiser Permanente Northern California members ages 15–59 years from 1997 through 1999. In a cohort analysis, rates of new-onset RA were compared between vaccinated and unvaccinated within 90, 180, and 365 days. In a case-control analysis, rates of vaccination during exposure intervals (90, 180, 365, and 730 days) were compared between cases and controls using conditional logistic regression. Results 378 RA cases were included in the cohort analysis; 37 additional cases were included in the case-control analysis. In the cohort analysis the relative risks of RA onset within 90, 180, or 365 days of hepatitis B vaccination were not significant (R.R. = 1.44, p = 0.53; R.R. = 1.67, p = 0.22; R.R. = 1.23, p = 0.59 respectively). We found a possible association between RA and influenza vaccine in the previous 180 and 365 days in the cohort analysis (R.R = 1.36, p = 0.03; R.R. = 1.34, p = 0.01 respectively), but in the case-control analysis, cases were no more likely than controls to have received any of the three vaccines. Conclusions In this large retrospective study we found no statistically significant association between exposure to hepatitis B vaccine and onset of RA. A possible association between RA and influenza vaccination in the cohort study was not borne out in the larger case-control analysis.

Influenza is a common and potentially serious infection in infants. Previous studies of influenza vaccine in this age group have reported widely varying estimates of vaccine effectiveness, and few have used laboratory confirmation of influenza diagnoses. We evaluated the effectiveness of 1 and 2 doses of the trivalent inactivated vaccine against laboratory-confirmed influenza in children aged 6 to 23 months within the Kaiser Permanente Northern California Medical Care Program for the 2003-2004, 2004-2005 and 2005-2006 influenza seasons. 1,648 children were included in the analyses, with an average of 4.5 controls matched to each of the 300 cases (213, 29 and 58 cases identified for each of the influenza seasons, respectively) based on birth month/year and zip code. Vaccination status was determined as of 14 days prior to the case patient's positive test result. Conditional logistic regression was used to calculate vaccine effectiveness for each season, adjusting for chronic medical conditions and other possible confounders. During the 2005-2006 influenza season, when predominant circulating virus strains and vaccine strains were well matched, vaccination was 76% [95% CI: 37-91%] effective against laboratory-confirmed infection. There was no statistically significant effect of vaccination, however, for the 2003-2004 or 2004-2005 seasons. Our results highlight the need for further study of influenza vaccine effectiveness in this age group.

OBJECTIVE: Exposure to thimerosal, a mercury-containing preservative that is used in vaccines and immunoglobulin preparations, has been hypothesized to be associated with increased risk of autism spectrum disorder (ASD). This study was designed to examine relationships between prenatal and infant ethylmercury exposure from thimerosal-containing vaccines and/or immunoglobulin preparations and ASD and 2 ASD subcategories: autistic disorder (AD) and ASD with regression. METHODS: A case-control study was conducted in 3 managed care organizations (MCOs) of 256 children with ASD and 752 controls matched by birth year, gender, and MCO. ASD diagnoses were validated through standardized in-person evaluations. Exposure to thimerosal in vaccines and immunoglobulin preparations was determined from electronic immunization registries, medical charts, and parent interviews. Information on potential confounding factors was obtained from the interviews and medical charts. We used conditional logistic regression to assess associations between ASD, AD, and ASD with regression and exposure to ethylmercury during prenatal, birth-to-1 month, birth-to-7-month, and birth-to-20-month periods. RESULTS: There were no findings of increased risk for any of the 3 ASD outcomes. The adjusted odds ratios (95% confidence intervals) for ASD associated with a 2-SD increase in ethylmercury exposure were 1.12 (0.83–1.51) for prenatal exposure, 0.88 (0.62–1.26) for exposure from birth to 1 month, 0.60 (0.36–0.99) for exposure from birth to 7 months, and 0.60 (0.32–0.97) for exposure from birth to 20 months. CONCLUSIONS: In our study of MCO members, prenatal and early-life exposure to ethylmercury from thimerosal-containing vaccines and immunoglobulin preparations was not related to increased risk of ASDs.

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.

Prelicensure clinical studies may not include sufficient numbers of subjects to assess the potential for rare postvaccination adverse events. The aim of this postlicensure study (NCT00297856) was to evaluate uncommon outcomes following vaccination with a tetanus, reduced-antigen-content diphtheria, and acellular pertussis vaccine (Tdap, Boostrix GlaxoSmithKline) in a large adolescent cohort.We monitored safety outcomes among 13,427 10 to 18-year-old adolescents enrolled in the Northern California Kaiser Permanente Health Care Plan who received Tdap vaccination as part of their normal health care. Subjects were evaluated using self-control analysis comparing days 0 to 29 to days 30 to 59 postvaccination for neurologic events, hematologic events and allergic reactions. We evaluated new onset chronic illnesses within 6 months of Tdap vaccination by comparing with historical Td controls matched for age at vaccination, season, sex, and geographic area. We also compared the incidence of events of interest between the Tdap and historical cohorts as exploratory analyses.No increased risk for medically attended neurologic (odds ratio [OR], 0.962; 95% confidence interval [CI], 0.533-1.733) or allergic reactions (OR, 1.091; 95% CI, 0.441-2.729) was observed following Tdap vaccination when comparing the first 30 postvaccination days to the second 30 postvaccination days. There was one hematologic event within 30 days of Tdap, compared with 0 events within days 30 to 59 (P = 1.0). When compared with matched historical Td recipients, no increase in new onset chronic illnesses (OR, 0.634; 95% CI, 0.475-0.840) was seen after Tdap. No deaths occurred in the Tdap cohort during the study.This study provides no evidence for an increased risk for neurologic, hematologic, allergic events, or new onset of chronic illnesses among adolescents vaccinated with Tdap.

A pentavalent, bovine-derived rotavirus vaccine (RotaTeq, Merck) was licensed in 2006 for use in infants. A previously licensed rotavirus vaccine was withdrawn due to elevated risk of intussusception. We prospectively evaluated the risk of intussusception and other pre-specified adverse events among RotaTeq recipients in the Vaccine Safety Datalink.The exposed population included children from age 4 to 48 weeks who received RotaTeq between May 2006 and May 2008. Adverse events over the subsequent 30 days were ascertained from inpatient, outpatient, and emergency department files; cases of intussusception were validated by medical record review. An adaptation of sequential probability ratio testing was employed to compare the cumulative number of observed and expected adverse events on a weekly basis, and a "signal" was generated if the log-likelihood ratio reached a predetermined threshold. This allowed near real-time monitoring to detect selected adverse events. The expected number of cases of intussusception was determined from historical rates in the VSD population.There were 207,621 doses of RotaTeq administered to the study population; 42% were first doses. Five children had computerized diagnosis codes for intussusception, and 6.75 cases were expected based on historical rates (relative risk = 0.74). No elevation in risk was identified for intussusception or any other adverse event. Two of five children with suspected intussusception based on diagnosis codes met the case criteria after medical record review.This study illustrates the feasibility of rapid vaccine safety assessment and provides additional evidence that RotaTeq is not associated with an increased risk of intussusception.

Safety monitoring following new vaccine introduction includes assessment of potential new onset autoimmune diseases (AID). As knowledge regarding AID background rates is limited, we evaluated the incidence of 11 AID in Northern California Kaiser Permanente. AID cases were identified using electronic records of members aged 10-62 years from 1998 to 2004, excluding those with AID diagnoses from 1996 to 1997. Using prespecified criteria, all identified cases of rare diseases were verified by medical record review, while a sample of cases was reviewed for common diseases; incidence rates were calculated based on the proportion of confirmed cases. Overall, the incidence of AID varied from 0.8/100,000 person-years (PY) for autoimmune hemolytic anemia (AIHA) to 54.1/100,000 PY for thyroiditis. Incidence rates in increasing order were AIHA, juvenile rheumatoid arthritis, Guillain-Barre Syndrome, idiopathic thromobocytopenia purpura, transverse myelitis, systemic lupus erythematosus, uveitis, multiple sclerosis, rheumatoid arthritis, Type 1 diabetes mellitus and thyroiditis; incidence rates also varied according to age and gender. These background incidence rates should prove useful for future observational vaccine safety studies and will help guide evaluation of potential vaccine AID events following introduction of new vaccines.

Acute flaccid paralysis is a standard outcome for detection of poliomyelitis globally and an ongoing potential vaccine-associated adverse event concern for polio, influenza, and meningococcal vaccines. No systematic population-based data on the epidemiologic and clinical features of this condition, or its potential association with immunization, have been reported from the United States. The present retrospective cohort study of acute flaccid paralysis in the Southern and Northern California Kaiser Permanente Health Care Plans was conducted using computerized diagnosis data and medical record review of potential cases among children aged 1 month to15 years and diagnosed from January 1, 1992 through December 31, 1998. In all, 3297 potential cases were identified; of these, 2682 cases (81%) did not meet the case definition, and of the remaining 615 cases, 245 (7% of the total) were included. The incidence of disease was 1.4 per 100,000 children/year (95% confidence interval = 1.2-1.6); predicting approximately 844 children/year in the United States. Disease incidence did not vary with season or sex, varied inversely with age, and declined 28% during the study period. No cases of vaccine-associated acute flaccid paralysis were identified. In nonendemic countries, ongoing acute flaccid paralysis surveillance is often conducted, because of the risk of poliovirus importation, but this practice may be difficult to justify, given low disease incidence and breadth of clinical presentation.

A large-scale, postmarketing observational database safety study was conducted following 7-valent pneumococcal conjugate vaccine (PCV7) licensure. A secondary outcome was the occurrence of predefined diagnoses among PCV7 vaccinees versus historic controls. Forty-two PCV7 recipients and 17 controls were hospitalized for Kawasaki disease (P = 0.012). After adjusting for potential confounding variables, this difference was not significant (P = 0.083). No association between Kawasaki disease and PCV7 was found.

The large-scale implementation of human papilloma virus (HPV) immunization will be followed by cases of autoimmune diseases occurring in temporal association with immunizations. To anticipate events that might be mistakenly assumed to be caused by immunization, their prevalence was monitored before vaccine introduction.Cohort study carried out within a database of female adolescents (n = 214,896) and young adults (n = 221,472) followed in the pre-HPV vaccine era (2005), computing rates of emergency consultations, hospitalizations and outpatient consultations, and estimation of risks of coincident associations.Immune-mediated conditions were a frequent cause (10.3%) of emergency room consultation by adolescent girls. Nonallergic immune-mediated conditions affected 86 per 100,000, diabetes ranking first. In 2005, 53 per 100,000 adolescents and 389 per 100,000 women were hospitalized for diseases of presumed autoimmune origin, thyroiditis being the most frequent diagnosis. If HPV immunization had been used with 80% coverage, 3 per 100,000 adolescents would have required emergency care for asthma/allergy within 24 hours and 2 per 100,000 for diabetes within 1 week of an injection. The risks of hospitalization in temporal association with immunization are 4 times higher for thyroiditis than for multiple sclerosis or Guillain-Barré's syndrome, and more than 20 times higher in young women than in adolescents.The distinction between HPV vaccine-caused adverse reactions and events only observed by chance in temporal association is difficult. The prior use of population-based data allows for identification of issues of potential concern, for monitoring the impact of large-scale interventions and for addressing rapidly vaccine-safety issues that may compromise vaccine programs.

Rare but serious adverse events associated with vaccines or drugs are often nearly impossible to detect in prelicensure studies and require monitoring after introduction of the agent in large populations. Sequential testing procedures are needed to detect vaccine or drug safety problems as soon as possible after introduction.To develop and evaluate a new real-time surveillance system that uses dynamic data files and sequential analysis for early detection of adverse events after the introduction of new vaccines.The Centers for Disease Control and Prevention (CDC)-sponsored Vaccine Safety Datalink Project developed a real-time surveillance system and initiated its use in an ongoing study of a new meningococcal vaccine for adolescents. Dynamic data files from 8 health plans were updated and aggregated for analysis every week. The analysis used maximized sequential probability ratio testing (maxSPRT), a new signal detection method that supports continuous or time-period analysis of data as they are collected.Using the new real-time surveillance system, ongoing analyses of meningococcal conjugate vaccine (MCV) safety are being conducted on a weekly basis. Two forms of maxSPRT were implemented: an analysis using concurrent matched controls, and an analysis based on expected counts of the outcomes of interest, which were estimated based on historical data. The analysis highlights both theoretical and operational issues, including how to (1) choose appropriate outcomes and stopping rules, (2) select control groups, and (3) accommodate variation in exposed:unexposed ratios between time periods and study sites.Real-time surveillance combining dynamic data files, aggregation of data, and sequential analysis methods offers a useful and highly adaptable approach to early detection of adverse events after the introduction of new vaccines.

BACKGROUND It has been hypothesized that early exposure to thimerosal, a mercury-containing preservative used in vaccines and immune globulin preparations, is associated with neuropsychological deficits in children. METHODS We enrolled 1047 children between the ages of 7 and 10 years and administered standardized tests assessing 42 neuropsychological outcomes. (We did not assess autism-spectrum disorders.) Exposure to mercury from thimerosal was determined from computerized immunization records, medical records, personal immunization records, and parent interviews. Information on potential confounding factors was obtained from the interviews and medical charts. We assessed the association between current neuropsychological performance and exposure to mercury during the prenatal period, the neonatal period (birth to 28 days), and the first 7 months of life. RESULTS Among the 42 neuropsychological outcomes, we detected only a few significant associations with exposure to mercury from thimerosal. The detected associations were small and almost equally divided between positive and negative effects. Higher prenatal mercury exposure was associated with better performance on one measure of language and poorer performance on one measure of attention and executive functioning. Increasing levels of mercury exposure from birth to 7 months were associated with better performance on one measure of fine motor coordination and on one measure of attention and executive functioning. Increasing mercury exposure from birth to 28 days was associated with poorer performance on one measure of speech articulation and better performance on one measure of fine motor coordination. CONCLUSIONS Our study does not support a causal association between early exposure to mercury from thimerosal-containing vaccines and immune globulins and deficits in neuropsychological functioning at the age of 7 to 10 years.

Pneumococcal conjugate vaccine was introduced for routine use in infants and toddlers in the United States in March 2000. We report on the impact of the introduction of this vaccine on disease epidemiology in young children as well as secondary effects due to herd immunity in unvaccinated children and adults. As of March 2003, 157,471 children had received one or more doses of PNCV7, but only 24% of those less than two years of age received all four doses as a result of shortages of vaccine. During the last year of observation, no cases of vaccine serotype disease were seen in children less than one year of age compared with an incidence ranging between 51.5 and 98.2 cases/100,000 person years (16-34 cases per year) in the years before vaccine introduction. Similar reductions were seen in children less than five years of age. There was no evidence of any concomittant increase in pneumococcal disease caused by non-vaccine serotypes. High-level resistance of pneumococci to penicillin fell from a peak of 15% in year 2000 to 5% in the first half of 2003.

There currently are no population-based systems in the United States to rapidly detect adverse events after newly introduced vaccines. To evaluate the feasibility of developing such systems, we used 5 years of data from 4 health maintenance organizations within the Centers for Disease Control and Prevention (CDC) Vaccine Safety Datalink.Within every year, each week's vaccinated children were followed for 4 weeks, and rates of adverse events were compared with rates among children of similar ages before the introduction of the new vaccine. We assessed risks for intussusception after rotavirus vaccination and risks for fever, seizures, and other neurologic adverse events after the change from whole cell diphtheria-tetanus-pertussis (DTPw) to acellular DTP vaccine (DTPa). We used sequential probability ratio testing, adjusted for age, sex, calendar time, season, and HMO, and with a stopping value based on the probability of an adverse event under the null hypothesis and under a preset alternative hypothesis.We detected an increase in intussusception after 2589 vaccine doses of rotavirus vaccine, about the same time initial reports of intussusception were made to the Vaccine Adverse Events Reporting System. Decreases in risk for fever, seizures, and other abnormal neurologic events became detectable within 12 weeks, 42 weeks, and 18 months, respectively, after the change from DTPw to DTPa.We conclude that it is feasible to develop systems for rapid and routine population-based assessments of new vaccine safety.

There have been no population-based studies of the potential association between neonatal death and newborn immunization with hepatitis B vaccine (HBV).As part of the Vaccine Safety Datalink Project, we defined a birth cohort at Southern and Northern California Kaiser Permanente Health Plans of more than 350,000 live births from 1993 to 1998 and ascertained all deaths occurring under 29 days of age. We compared the proportions of deaths among birth HBV-vaccinated and unvaccinated newborns and reviewed the causes and circumstances of their deaths. We performed detailed clinical reviews of all HBV-vaccinated neonates who died and a sample of unvaccinated neonates who died and who were matched to vaccinated deaths for days of life, sex, birth year and site of care. To avoid confounding, we categorized the causes of death as either "expected" or "unexpected" and performed a stratified analysis to compare mortality with immunization status.There were 1363 neonatal deaths during the study period. Whereas 67% of the entire birth cohort received HBV at birth, only 72 (5%) of the neonates who died were HBV-vaccinated at birth (P0.01). We found no significant difference in the proportion of HBV-vaccinated (31%) and unvaccinated (35%) neonates dying of unexpected causes (P = 0.6). Further we could not identify a plausible causal or temporal relationship between HBV administration and death for the 22 vaccinated neonates who died unexpectedly.A relationship between HBV and neonatal death was not identified.

To determine the safety of cold-adapted trivalent intranasal influenza virus vaccine (CAIV) in children and adolescents.A randomized, double blind, placebo-controlled safety trial in healthy children age 12 months to 17 years given CAIV (FluMist; MedImmune Vaccines, Inc.) or placebo (randomization, 2:1). Children9 years of age received a second dose of CAIV or placebo 28 to 42 days after the first dose. Enrolled children were then followed for 42 days after each vaccination for all medically attended events. Prespecified outcomes included 4 prespecified diagnostic groups and 170 observed individual diagnostic categories. The relative risk and the 2-sided 90% confidence interval were calculated for each diagnostic group and individual category by clinical setting, dose and age. More than 1500 relative risk analyses were performed.A total of 9689 evaluable children were enrolled in the study. Of the 4 prespecified diagnostic categories (acute respiratory tract events, systemic bacterial infection, acute gastrointestinal tract events and rare events potentially associated with wild-type influenza), none was associated with vaccine. Of the biologically plausible individual diagnostic categories, 3, acute gastrointestinal events, acute respiratory events and abdominal pain, had different analyses that demonstrated increased and decreased relative risks, making their association with the vaccine unlikely. For reactive airway disease a significant increased relative risk was observed in children 18 to 35 months of age with a relative risk of 4.06 (90% confidence interval, 1.29 to 17.86) in this age group. The individual diagnostic categories of upper respiratory infection, musculoskeletal pain, otitis media with effusion and adenitis/adenopathy had at least one analysis that achieved a significant increased risk ratio. All of these events were infrequent.CAIV was generally safe in children and adolescents. The observation of an increased risk of asthma/reactive airway disease in children36 months of age is of potential concern. Further studies are planned to evaluate the risk of asthma/reactive airway disease after vaccine.

We report an evaluation of the short-term safety of a pediatric bivalent combination vaccine containing RECOMBIVAXHB and Liquid PedvaxHIB, COMVAX. Safety was assessed through identification of medical utilization; potential adverse events were identified through computerized clinical databases for deaths, hospitalizations, emergency room visits, and outpatient clinic visits. We calculated relative risks whenever there was at least one diagnosis-specific event in the risk period following vaccination and compared the rates in specific time windows following vaccination with rates at 31-60 days following vaccination and also with rates in a historical cohort of children. A total of 27,802 doses of COMVAX were administered, with 127 separate adverse event codes with statistically significant elevated risks, and 66 codes with significantly decreased risks. Most potentially serious diagnoses appeared in four major categories: "Respiratory Events"; "Gastroenteritis"; "Adverse Effect of Medicinal and Biological Substance, NOS"; and "Fever". There was no consistent pattern to indicate increased risks for serious respiratory or gastrointestinal illness. For fever, most of the findings appeared to be explained by changes in data collection or by concomitant vaccination with M-M-R(-)II. There was an increased risk for fever hospitalizations following shot 1. The total number of children hospitalized with fever was seven out of 12,468 children; all recovered fully. In this study population of 27,802 vaccine recipients, COMVAX appeared to have a favorable safety profile.

We evaluated the effect of introduction of a combined hepatitis B-Haemophilus influenzae b vaccine on vaccine coverage rates in a large health maintenance organization and found a modest improvement in up-to-date immunization status.

To determine the effectiveness of the Wyeth heptavalent pneumococcal conjugate vaccine against clinical and radiograph-confirmed pneumonia in children.The heptavalent CRM(197) pneumococcal conjugate vaccine (PCV) was given to infants at 2, 4, 6 and 12 to 15 months of age in a randomized, double blind trial. Children were randomized to receive either the CRM(197) PCV (vaccine group) or the meningococcal type C CRM(197) conjugate vaccine (control group). The primary outcome of this trial was invasive pneumococcal disease. In addition children with the clinical diagnosis of pneumonia in the study population were identified through review of automated inpatient, emergency and outpatient databases. The subset of the cohort of these children who had chest radiographs obtained at the time of diagnosis was identified, and the original reading of their radiographs by the radiologist was obtained from automated databases. Rates of clinically diagnosed pneumonia, of pneumonia with a radiograph obtained regardless of result, of pneumonia with positive radiograph (consolidation, empyema or parenchymal infiltrate) and of pneumonia with only perihilar infiltrates were compared between vaccinated and nonvaccinated groups. In addition risk of disease pneumonia was evaluated by race and ethnicity.The incidence of a first pneumonia episode in the control group was 55.9 per 1000 person-years. A radiograph was obtained in 61% of episodes, a positive radiograph in 21% and perihilar findings in an additional 5%. In per protocol follow-up of children given PCV, first episodes of all clinically diagnosed pneumonia were reduced by 4.3% [95% confidence interval (CI), -3.5, 11.5%, = 0.27], episodes with a radiograph were reduced by 9.8% (CI 0.1, 18.5%,0.05) and episodes with a positive radiograph were reduced by 20.5% (CI 4.4, 34.0, = 0.02). In the intent to treat analysis including all episodes after randomization, episodes with a positive radiograph were reduced by 17.7%, =.01). The greatest impact was in the first year of life with a 32.2% reduction and a 23.4% reduction in the first 2 years, but only a 9.1% reduction in children2 years of age. Asians, blacks and Hispanics were at higher risk of pneumonia than were whites, but there was no evidence of ethnic variation in PCV effectiveness. Ten of the 11 cases of pneumococcal pneumonia with a positive blood culture were in the control group.The pneumococcal conjugate vaccine tested was effective in reducing the risk of pneumonia in young children.

We evaluated the effect of infant vaccination with HbOC Haemophilus influenzae type b (Hib) conjugate vaccine on the risk of onset of type 1 juvenile diabetes later in life by examining data from a large controlled prospective Phase III clinical efficacy trial conducted within Northern California Kaiser Permanente between 1988 and 1990. The overall study population included children who were offered the Hib conjugate vaccine (acceptors and refusers) as well as a cohort of children who were systemically excluded from the trial on the basis of their birth date. These children are now 10 to 12 years of age. We found no evidence that vaccination with Hib conjugate vaccine in infancy is associated with risk of diabetes later in life.

Objective. To determine whether hepatitis B vaccination of newborns increases the incidence of fever and/or suspected sepsis. Methods. A prospective clinical study was undertaken at the Kaiser Permanente San Francisco Medical Center involving normal full term newborns born between November 1, 1991, and April 30, 1994. During this time 3302 infants were vaccinated within 21 days of birth with hepatitis B vaccine, and 2353 were not. Clinical and demographic data were collected from Kaiser Permanente's existing clinical information systems, and laboratory data for blood and cerebrospinal fluid (CSF) cultures were obtained from the comprehensive automated regional laboratory reporting system. Results. There were no significant differences between vaccinated and unvaccinated newborns in the proportion of infants who received care for fever (0.8% vaccinated and 1.1% unvaccinated, P = 0.28), allergic reactions, seizures or other neurologic events in the first 21 days of life. Vaccinated newborns were significantly less likely to undergo microbiologic evaluation for possible sepsis. Among vaccinated newborns 4.0% had blood cultures and 1.6% had CSF cultures. Among infants who were not vaccinated 8.3% had blood cultures and 1.6% had CSF cultures (P

Accurate Automation Corporation has completed the conceptual design of a mortar launched air vehicle system to perform close range or over-the-horizon surveillance missions. Law enforcement and military units require an organic capability to obtain real time intelligence information of time critical targets. Our design will permit law enforcement to detect, classify, locate and track these time critical targets. The surveillance system is a simple, unmanned fixed-winged aircraft deployed via a conventional mortar tube. The aircraft's flight surfaces are deployed following mortar launch to permit maximum range and time over target. The aircraft and sensor system are field retrievable. The aircraft can be configured with an engine to permit extended time over target or range. The aircraft has an integrated surveillance sensor system; a programmable CMOS sensor array. The integrated RF transmitter is capable of down-linking real-time video over line-of-sight distances exceeding 10 kilometers. The major benefit of the modular design is the ability to provide surveillance or tracking quickly at a low cost. Vehicle operational radius and sensor field coverage as well as design trade results of vehicle range and endurance performance and payload capacity at operational range are presented for various mortar configurations.

Background and Aims: The worldwide introduction of influenza A (H1N1) vaccines in fall 2009 has raised widespread public questions about the safety of these new vaccines. The Vaccine Safety Datalink Project, a collaboration among CDC and eight health care systems in the HMORN, began accelerated monitoring of this vaccine’s safety in early fall 2009. Methods: The VSD Project conducts near real-time monitoring of potential adverse events following vaccination for all new vaccines. Each week, each site updates dynamic data files, and the coordinating center analyzes all data cumulatively. Repeated analysis of the same data requires adjustment for multiple testing. To address this issue, VSD uses sequential statistical methods. Evaluation of H1N1 vaccine safety poses special challenges, including confounding by indication, seasonality, and new priority groups including pregnant women. We are using several analytic methods, including: Self-controlled case-series, which compares exposed vs. unexposed time windows within the same individual; Poisson, which compares the outcomes during the current season with expected rates based on historical data for seasonal influenza vaccine; and Difference-in-difference, which compares the relative risk in exposed vs. unexposed time windows for H1N1 vaccine during the current season with the relative risk for seasonal influenza vaccine during cumulative prior seasons. Results: Pre-specified outcomes of interest include: Guillain-Barre syndrome, neuropathies, seizures, encephalitis, Bell’s palsy, ataxia, anaphylaxis, spontaneous abortion, pre-eclampsia, stroke, myocarditis and wheezing. Historical rates of these outcomes were calculated for time windows after seasonal influenza vaccination in prior seasons (2000/01–2008/09). The sequential analysis methods above will be used, and relative and absolute risks will be estimated for each outcome. For outcomes found associated with vaccination in preliminary analyses, additional evaluation will be conducted using temporal scan analyses, logistic regression, and when appropriate, medical record review.