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Background Hypotonic-hyporesponsive episode (HHE) after whole cell pertussis vaccination is a known adverse event. Less is known about the risk of HHE after administration of acellular pertussis vaccines. Methods Using parental interviews, this study actively surveyed for HHE among infants after doses 1 and 2 of acellular pertussis vaccine. Results We interviewed the parents of 52,531 infants. HHE was reported at a rate of 22.8 per 100,000 doses (95% CI: 11.8-39.9) of acellular pertussis vaccine, approximately 45 episodes per 100,000 children. Conclusions These rates are lower than HHE rates reported after whole cell pertussis vaccines and within the range of HHE rates reported in other studies of acellular pertussis vaccines.

We evaluated whether parental clinical conditions were associated with fever after a first dose of measles-containing vaccine (MCV) in the child in a cohort study including 244,125 children born in Kaiser Permanente Northern California between 2009 and 2016 who received MCV between ages 1 and 2 years. Each child was linked with his/her mother and father when possible. Parental clinical conditions present before and after their child’s birth were identified. We defined fever in the children as clinic and emergency department visits with a fever code 7–10 days after a first dose of MCV (“MCV-associated fever”). We evaluated parental clinical conditions associated with MCV-associated fever using multivariate logistic regression analyses. After adjusting for multiple factors, including healthcare utilization, maternal fever [odds ratio (OR) = 1.19, 95% confidence interval (CI) 1.06–1.32], fever after MCV (OR = 5.90, 95% CI 1.35–25.78), respiratory infections (OR = 1.20, 95% CI 1.10–1.31), migraine (OR = 1.14, 95% CI 1.05–1.24), syncope (OR 1.14, 95% CI 1.01–1.27), and essential thrombocythemia (OR = 1.93, 95% CI 1.15–3.25) were significantly associated with MCV-associated fever. Paternal respiratory infections (OR = 1.15, 95% CI 1.05–1.27), fever associated with respiratory infections (OR = 1.47, 95% CI 1.23–1.76), and vitiligo (OR = 1.63, 95% CI 1.06–2.53) were significantly associated with MCV-associated fever. Parental clinical conditions, specifically fever alone and fever associated with respiratory infection, are associated with fever in their child 7–10 days after MCV.

INTRODUCTION: Childhood immunization schedules often involve multiple vaccinations per visit. When increased risk of an adverse event is observed after simultaneous (same-day) vaccinations, it can be difficult to ascertain which triggered the adverse event. This methods paper discusses a systematic process to determine which of the simultaneously administered vaccine(s) are most likely to have caused an observed increase in risk of an adverse event. METHODS: We use an example from the literature where excess risk of seizure was observed one day after vaccination, but same-day vaccination patterns made it difficult to discern which vaccine(s) may trigger the adverse event. We illustrate the systematic identification process using a simulation that retained the observed pattern of simultaneous vaccination in an empirical cohort of vaccinated children. We simulated “true” effects for diphtheria-tetanus-acellular pertussis (DTaP) and pneumococcal conjugate (PCV) on risk of seizure the day after vaccination. We varied the independent and interactive effects of vaccines (on the multiplicative scale). After applying the process to simulated data, we evaluated risk of seizure one day after vaccination in the empirical cohort. RESULTS: In all simulations, we were able to determine which vaccines contributed to excess risk. In empirical data, we narrowed the association with seizure from all vaccines in the schedule to three likely candidates, DTaP, PCV, and/or Haemophilus influenzae type B (HiB) (p < 0.01, attributable risk when all 3 were administered together: 5 per 100,000). Disentangling their associations with seizure would require a larger sample or more variation in the combinations administered. When none of these three were administered, no excess risk was observed. CONCLUSION: The process outlined could provide valuable information on the magnitude of potential risk from individual and simultaneous vaccinations. Associations should be further investigated with independent data as well as biologically based, statistically independent hypotheses.

A live attenuated zoster vaccine was licensed in the United States in 2006 for prevention of shingles in persons aged 60 years or older; the indication was extended in 2011 to cover those aged 50–59 years. We assessed vaccine effectiveness (VE) against shingles for 8 years after immunization at Kaiser Permanente Northern California. VE was estimated by Cox regression with a calendar timeline that was stratified by birth year. We adjusted for demographics and time-varying covariates, including comorbidities and immune compromise. From 2007 to 2014, 1.4 million people entered the study when they became age eligible for vaccination; 392,677 (29%) received the zoster vaccine. During 5.8 million person-years of follow-up, 48,889 cases of shingles were observed, including 5,766 among vaccinees. VE was 49.1% (95% confidence interval (CI): 47.5, 50.6) across all follow-up. VE was 67.5% (95% CI: 65.4, 69.5) during the first year after vaccination, waned to 47.2% (95% CI: 44.1, 50.1) during the second year after vaccination, and then waned more gradually through year 8, when VE was 31.8% (95% CI: 15.1, 45.2). Unexpectedly, VE in persons vaccinated when they were aged 80 years or older was similar to VE in younger vaccinees, and VE in persons vaccinated when immune compromised was similar to VE in persons vaccinated when immune competent.

Seven to ten days after a first dose of a measles-containing vaccine (MCV; i.e., MMR or MMRV), children have elevated fever risk which can be associated with febrile seizures. This study investigated individual and familial factors associated with fever 7-10days after MCV.Retrospective cohort study among children who were36months of age at receipt of MCV in six sites of the Vaccine Safety Datalink from 1/1/2000 to 12/31/2012. We evaluated medically-attended clinic or emergency department visits with a code for fever 7-10days after any MCV ("MCV- associated"). We evaluated factors associated with MCV-associated fever using χAmong 946,806 children vaccinated with MCV, we identified 7480 (0.8%) MCV-associated fever visits. Compared with children without fever after MCV, children with MCV-associated fever were more likely to have received MMRV than MMR (OR 1.3 95% CI 1.2, 1.5), have had medically attended fever both following previous vaccines (OR 1.3 95% CI 1.1, 1.6) and at any other previous time (OR 1.7 95% CI 1.6, 1.8), have had at least 1 prior seizure (OR 2.2 95% CI 1.7, 2.7), and have had3 medical visits within the 6months before MCV (OR 1.7 95% CI 1.6, 1.8). In families with multiple MCV-immunized children, after adjusting for healthcare seeking behavior care for fever, those whose siblings had MCV-associated fever were more likely to also have MCV-associated fever (OR 3.5 95% CI 2.5, 4.8).Children who received MMRV vaccine or who had prior medically-attended fevers and seizures during the first year of life had increased risk of fever after a first dose of measles vaccine. After adjusting for familial propensity to seek care, MCV-associated fever still clustered within families, suggesting a possible genetic basis for susceptibility to developing fever due to measles vaccines.

BACKGROUND AND OBJECTIVES: Human papillomavirus is the most common sexually transmitted infection in the United States and causes certain anogenital and oropharyngeal cancers. The 9-valent human papillomavirus vaccine (9vHPV) provides protection against additional types not included in the quadrivalent vaccine. We conducted near real-time vaccine safety surveillance for 24 months after the vaccine became available in the Vaccine Safety Datalink. METHODS: Immunizations and adverse events were extracted weekly from October 2015 to October 2017 from standardized data files for persons 9 to 26 years old at 6 Vaccine Safety Datalink sites. Prespecified adverse events included anaphylaxis, allergic reaction, appendicitis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, injection site reaction, pancreatitis, seizure, stroke, syncope, and venous thromboembolism. The observed and expected numbers of events after 9vHPV were compared weekly by using sequential methods. Both historical and concurrent comparison groups were used to identify statistical signals for adverse events. Unexpected signals were investigated by medical record review and/or additional analyses. RESULTS: During 105 weeks of surveillance, 838 991 doses of 9vHPV were administered. We identified unexpected statistical signals for 4 adverse events: appendicitis among boys 9 to 17 years old after dose 3; pancreatitis among men 18 to 26 years old; and allergic reactions among girls 9 to 17 years old and women 18 to 26 years old after dose 2. On further evaluation, which included medical record review, temporal scan analysis, and additional epidemiological analyses, we did not confirm signals for any adverse events. CONCLUSIONS: After 2 years of near real-time surveillance of 9vHPV and several prespecified adverse events, no new safety concerns were identified.

[Figure: see text] OBJECTIVES: To determine pertussis risk by diphtheria-tetanus-acellular pertussis (DTaP) vaccination status and time since last DTaP dose. METHODS: Children born at Kaiser Permanente Northern California between 1999 and 2016 were followed from 3 months of age until they tested positive for pertussis; disenrolled from Kaiser Permanente Northern California; received the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis, adsorbed vaccine; turned 11 years of age, or the end of the study period. DTaP vaccination status was categorized on the basis of the number of doses received in relation to the number of doses expected according to the Advisory Committee on Immunization Practice–recommended ages. RESULTS: Among 469 982 children ages 3 months to 11 years, we identified 738 pertussis cases. A total of 99 cases were unvaccinated, 36 were undervaccinated, 515 were fully vaccinated, and 88 were fully vaccinated plus 1 dose. Pertussis risk was 13 times higher among unvaccinated (adjusted hazard ratio [aHR] = 13.53; 95% confidence interval [CI] 10.64–17.21) compared with fully vaccinated children and 1.9 times higher (aHR = 1.86; 95% CI 1.32–2.63) among undervaccinated children. Among vaccinated children ages 19 to

Background Postherpetic neuralgia (PHN) occurs in 5–30% of individuals with herpes zoster (HZ) and is characterized by long-lasting pain. Zoster vaccine live (ZVL) is licensed for people 50 years and older to prevent HZ and PHN. This study evaluated vaccine effectiveness (VE) of ZVL against PHN. Methods We conducted an open cohort study within Kaiser Permanente Northern California with continuous accrual of people as they became age-eligible for ZVL. We defined PHN using a PHN diagnosis between 90 and 365 days after an incident episode of HZ. We estimated VE against PHN using Cox regression with a calendar timeline stratified by year of birth and adjusted for sex, race, influenza vaccination, outpatient visit frequency, comorbidities, and immune compromise status. Results From 2007 to 2016, 1·5 million people entered the study population and 33% received ZVL. During 7·6 million person-years of follow-up, there were 62,205 HZ cases, 4150 (6·7%) of which went on to develop PHN. Overall VE for PHN was 64·8% (95% CI 61·3, 68). VE was 82·8% (95% CI 77·6, 86·7) during the first year after vaccination, 58·3% (95% CI 50.1, 65.2) during the third year, and then waned more gradually to 48·7% (95% CI 30·2, 62·3) during the eighth year. VE in persons vaccinated when aged 80 years or older was similar to VE in younger vaccinees. VE in persons vaccinated when immune compromised was similar to VE in immune competent. Conclusions Overall, ZVL was 65% effective against PHN. It was effective in all age groups and provided moderate protection through 8 years.

BACKGROUND: Case reports have suggested that vaccines may trigger transverse myelitis (TM) or acute disseminated encephalomyelitis (ADEM), but the evidence for a causal association is inconclusive. We analyzed the association of immunization and subsequent development of TM or ADEM. METHODS: We identified all cases of TM and ADEM in the Vaccine Safety Datalink population. Using a case-centered method, we compared vaccination of each case to vaccination of all matched persons in the study population, who received the same type of vaccine, with respect to whether or not their vaccination occurred during a predetermined exposure interval. We calculated a risk difference (excess risk) of TM and ADEM for each vaccine. RESULTS: Following nearly 64 million vaccine doses, only 7 cases of TM and 8 cases of ADEM were vaccinated during the primary exposure window 5–28 days prior to onset. For TM, there was no statistically significant increased risk of immunization. For ADEM, there was no statistically significant increased risk following any vaccine except for Tdap (adolescent and adult tetanus, reduced diphtheria, acellular pertussis) vaccine. Based on 2 exposed cases, the odds ratio for Tdap exposure 5–28 days prior to ADEM onset was 15.8 (95% confidence interval [CI], 1.2–471.6; P = .04), and the estimated excess risk was 0.385 (95% CI, −.04 to 1.16) cases per million doses. CONCLUSIONS: We found no association between TM and prior immunization. There was a possible association of ADEM with Tdap vaccine, but the excess risk is not likely to be more than 1.16 cases of ADEM per million vaccines administered.

Introduction Despite minimal evidence, public concerns that the human papillomavirus (HPV) vaccine can cause autoimmune diseases (AD) persist. We evaluated whether HPV vaccine is associated with a long-term increased risk of diabetes mellitus type 1 (DM1). Methods This was a retrospective cohort study in which we identified all potential DM1 cases from Kaiser Permanente Northern California (KPNC) members who were between 11 and 26 years old any time after June 2006 through December 2015. We chart reviewed a random sample of 100 DM1 cases to confirm diagnosis and to develop a computer algorithm that reliably determined symptom onset date. Our DM1 Analysis Population comprised all individuals who met membership criteria and who were age and sex eligible to have received HPV vaccine. We adjusted for age, sex, race, Medicaid, and years of prior KPNC membership by stratification using a Cox multiplicative hazards model with a calendar timeline. Results Our DM1 analysis included 911,648 individuals. Of 2613 DM1 cases identified, 338 remained in the analysis after applying our algorithm, HPV vaccine eligibility and membership criteria. Over the 10 years of the study period, comparing vaccinated with unvaccinated persons, we did not find an increased risk of DM1 associated with HPV vaccine receipt (hazard ratio 1.21, 95% Confidence Interval 0.94, 1.57). Conclusions We found no increased risk for development of DM1 following HPV vaccination. Our study provides reassurance that during the 10-year time period after HPV vaccine was introduced, there was no substantial increased risk for DM1 following HPV vaccination.

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

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.

BACKGROUND: Vaccination against pertussis during pregnancy is recommended to protect newborns, yet there is limited information about the effectiveness of maternal tetanus toxoid, reduced diphtheria toxoid, acellular pertussis (Tdap) vaccine before the first infant dose of diphtheria, tetanus and acellular pertussis (DTaP) vaccine and during the first year of life in infants who have received DTaP. METHODS: In a retrospective cohort study of infants born at Kaiser Permanente Northern California from 2010 to 2015, we estimated the effectiveness of maternal pertussis vaccination for protecting newborns against pertussis in the first 2 months of life and in the first year of life accounting for each infant DTaP dose. RESULTS: Among 148 981 newborns, the vaccine effectiveness of maternal Tdap was 91.4% (95% confidence interval [CI], 19.5 to 99.1) during the first 2 months of life and 69.0% (95% CI, 43.6 to 82.9) during the entire first year of life. The vaccine effectiveness was 87.9% (95% CI, 41.4 to 97.5) before infants had any DTaP vaccine doses, 81.4% (95% CI, 42.5 to 94.0) between doses 1 and 2, 6.4% (95% CI, −165.1 to 66.9) between doses 2 and 3, and 65.9% (95% CI, 4.5 to 87.8) after infants had 3 DTaP doses. CONCLUSIONS: Maternal Tdap vaccination was highly protective against infant pertussis, especially in the first 2 months of life. Even after infant DTaP dosing, there was evidence of additional protection from maternal Tdap vaccination for the first year of life. This study strongly supports the United States’ current recommendation to administer Tdap during each pregnancy.

Background. Guillain-Barre syndrome (GBS) is an acute polyradiculoneuropathy, thought to be an autoimmune process. Although cases of GBS have been reported following a wide range of vaccines, a clear association has only been established with the 1976 H1N1 inactivated influenza vaccine. Methods. We identified hospitalized GBS cases from Kaiser Permanente Northern California (KPNC) from 1995 through 2006. The medical record of each suspected case was neurologist-reviewed according to the Brighton Collaboration GBS case definition; only confirmed cases were included in the analyses, and cases of Miller Fisher syndrome were excluded. Using a case-centered design, we compared the odds of vaccination in the 6 and 10 weeks prior to onset of GBS to the odds of vaccination during the same time intervals in all vaccinated individuals in the entire KPNC population. Results. We confirmed 415 incident cases of GBS (including Brighton levels 1, 2, and 3) during the study period (>30 million person-years). Incidence peaked during the winter months. The odds ratio of influenza vaccination within a 6-week interval prior to GBS, compared with the prior 9 months, was 1.1 (95% confidence interval [CI], .4–3.1). The risk in the 6-week interval compared to the prior 12 months for tetanus diphtheria combination, 23-valent pneumococcal polysaccharide, and for all vaccines combined was 1.4 (95% CI, .3–4.5), 0.7 (95% CI, .1– 2.9), and 1.3 (95% CI, .8–2.3), respectively. Conclusions. In this large retrospective study, we did not find evidence of an increased risk of GBS following vaccinations of any kind, including influenza vaccination.

BACKGROUND: In the United States, children receive 2 doses of measles-mumps-rubella vaccine (MMR) and varicella vaccine (V), the first between ages 1 to 2 years and the second between ages 4 to 6 years. Among 1- to 2-year-olds, the risk of febrile seizures 7 to 10 days after MMRV is double that after separate MMR + V. Whether MMRV or MMR + V affects risk for febrile seizure risk among 4- to 6-year-olds has not been reported. METHODS: Among 4- to 6-year-old Vaccine Safety Datalink members, we identified seizures in the emergency department and hospital from 2000 to 2008 and outpatient visits for fever from 2006 to 2008 during days 7 to 10 and 0 to 42 after MMRV and MMR + V. Incorporating medical record reviews, we assessed seizure risk after MMRV and MMR + V. RESULTS: From 2006 through 2008, 86 750 children received MMRV; from 2000 through 2008, 67 438 received same-day MMR + V. Seizures were rare throughout days 0 to 42 without peaking during days 7 to 10. There was 1 febrile seizure 7 to 10 days after MMRV and 0 after MMR + V. Febrile seizure risk was 1 per 86 750 MMRV doses (95% confidence interval, 1 per 3 426 441, 1 per 15 570) and 0 per 67 438 MMR + V doses (1 per 18 282). CONCLUSIONS: This study provides reassurance that MMRV and MMR + V were not associated with increased risk of febrile seizures among 4- to 6-year-olds. We can rule out with 95% confidence a risk greater than 1 febrile seizure per 15 500 MMRV doses and 1 per 18 000 MMR + V doses.

Importance In recent years, rates of vaccination have been declining. Whether this phenomenon disproportionately affects children with autism spectrum disorder (ASD) or their younger siblings is unknown. Objectives To investigate if children after receiving an ASD diagnosis obtain their remaining scheduled vaccines according to the Advisory Committee on Immunization Practices (ACIP) recommendations and to compare the vaccination patterns of younger siblings of children with ASD with the vaccination patterns of younger siblings of children without ASD. Design, Setting, and Participants This investigation was a retrospective matched cohort study. The setting was 6 integrated health care delivery systems across the United States within the Vaccine Safety Datalink. Participants were children born between January 1, 1995, and September 30, 2010, and their younger siblings born between January 1, 1997, and September 30, 2014. The end of follow-up was September 30, 2015. Exposures Recommended childhood vaccines between ages 1 month and 12 years. Main Outcome and Measure The proportion of children who received all of their vaccine doses according to ACIP recommendations. Results The study included 3729 children with ASD (676 [18.1%] female), 592 907 children without ASD, and their respective younger siblings. Among children without ASD, 250 193 (42.2%) were female. For vaccines recommended between ages 4 and 6 years, children with ASD were significantly less likely to be fully vaccinated compared with children without ASD (adjusted rate ratio, 0.87; 95% CI, 0.85-0.88). Within each age category, vaccination rates were significantly lower among younger siblings of children with ASD compared with younger siblings of children without ASD. The adjusted rate ratios varied from 0.86 for siblings younger than 1 year to 0.96 for those 11 to 12 years old. Parents who had a child with ASD were more likely to refuse at least 1 recommended vaccine for that child’s younger sibling and to limit the number of vaccines administered during the younger sibling’s first year of life. Conclusions and Relevance Children with ASD and their younger siblings were undervaccinated compared with the general population. The results of this study suggest that children with ASD and their younger siblings are at increased risk of vaccine-preventable diseases.

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.

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.

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: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.

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 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.

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.

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.

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 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.

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

Objective. To assess the level of increased risk, if any, of hospitalizations for aseptic meningitis after Jeryl-Lynn mumps strain measles-mumps-rubella (MMR) vaccine in the Vaccine Safety Datalink population. Study design. A possible increased risk of aseptic meningitis 8 to 14 days after receipt of MMR was observed in a preliminary screening analysis of automated data from the Vaccine Safety Datalink (VSD) project Year 2 analysis. To further evaluate this association a retrospective 10-year matched case-control study was undertaken in the four health maintenance organizations (HMOs) in the VSD project. Cases ascertained from a broad scan of the automated data were validated against a standard case definition. Two controls matched on age, sex, HMO and HMO membership were assigned per case. Results. The VSD project involves the cooperative collection of automated vaccination and medical outcome data from four large HMOS that currently have 500 000 children younger than 7 years of age under surveillance. Review of automated screening results from the first 2 years of data revealed a possible increased risk of aseptic meningitis 0 to 14 days after MMR with a relative risk of 3.61 (95% confidence interval, 1.0 to 13.1) although the total number of cases was small. Although the automated data had suggested a possible association of aseptic meningitis with MMR containing the Jeryl-Lynn strain of mumps, review of validated hospitalized cases during the observation period did not reveal evidence of an increased risk of aseptic meningitis after MMR containing the Jeryl-Lynn strain of mumps (odds ratio

Efficacy of Heptavalent Conjugate Pneumococcal Vaccine (Wyeth Lederle) in 7,000 Infants and Children: Results of the Northern California Kaiser Permanente Efficacy Trial