Impact of the 13-Valent Pneumococcal Conjugate Vaccine on Invasive Pneumococcal Disease After Introduction Into Routine Pediatric Use.

BACKGROUND: In 2010, the 13-valent pneumococcal conjugate vaccine (PCV13) replaced 7-valent PCV (PCV7) for protection against invasive pneumococcal disease (IPD). This study used laboratory surveillance data to examine the effect of PCV13 on IPD before and after PCV13 introduction among children aged 6 weeks to <6 years and those aged ≥6 weeks. METHODS: Observational laboratory-based IPD surveillance data were compared for the periods May 2010-April 2018 and May 2008-April 2010 (the PCV7 period) using a database of Kaiser Permanente Northern California (KPNC) members with laboratory-confirmed IPD. RESULTS: Among children aged 6 weeks to 6 years, overall IPD incidence decreased from 11.57 per 100 000 during the PCV7 period to 4.09 per 100 000 after PCV13 introduction; PCV13-type IPD incidence decreased from 5.12 to 0.84 per 100 000. Non-PCV13-serotype IPD did not change significantly in this age group (PCV7 period, 1.71 per 100 000 and after PCV13, 2.52 per 100 000). Of cases occurring in this group, bacteremia was the most common clinical diagnosis. Across all ages, IPD decreased from 9.49 to 6.23 per 100 000 and PCV13-type IPD decreased from 4.67 to 1.89 per 100 000, changes being mostly due to decreases in serotypes 19A and 7F. IPD caused by non-PCV13 serotypes did not change (3.34 and 3.35 per 100 000). Overall, pneumococci isolated after PCV13 introduction had increased susceptibility to penicillin, cefotaxime, and ceftriaxone.This prospective, laboratory-based surveillance study in Kaiser Permanente Northern California members examined annual IPD incidence before and after PCV13 introduction. In children aged 6 weeks to <6 years, IPD caused by PCV13 serotypes decreased significantly (84%) during the surveillance period. CONCLUSIONS: IPD incidence decreased further in every age group after PCV13 introduction, suggesting both direct vaccination effects in the infant population and indirect effects in adults. CLINICAL TRIALS REGISTRATION: NCT01128439.

Incidence of Herpes Zoster Among Children: 2003-2014.

BACKGROUND AND OBJECTIVES: After the 1996 introduction of routine varicella vaccination in the United States, most studies evaluating pediatric herpes zoster (HZ) incidence reported lower incidence over time, with varying degrees of decline. Using the combined databases of 6 integrated health care organizations, we examined HZ incidence in children over a 12-year period in the varicella vaccine era. METHODS: This study included children aged 0 through 17 years from 2003 through 2014. Using electronic medical records, we identified HZ cases through International Classification of Diseases, Ninth Revision diagnosis code 053. We calculated HZ incidence rates per 100 000 person years of health plan membership for all children and among children who were vaccinated versus unvaccinated. We calculated rates for the 12-year period and examined temporal trends. Among children who were vaccinated, we compared HZ rates by month and year of age at vaccination. RESULTS: The study included 6 372 067 children with ≥1 month of health plan membership. For the 12-year period, the crude HZ incidence rate for all subjects was 74 per 100 000 person years, and the rate among children who were vaccinated was 38 per 100 000 person years, which was 78% lower than that among children who were unvaccinated (170 per 100 000 person years; P < .0001). Overall HZ incidence declined by 72% (P < .0001) from 2003 through 2014. Annual rates in children who were vaccinated were consistently lower than in children who were unvaccinated. CONCLUSIONS: With this population-based study, we confirm the decline in pediatric HZ incidence and the significantly lower incidence among children who are vaccinated, reinforcing the benefit of routine varicella vaccination to prevent pediatric HZ.

Long term risk of developing type 1 diabetes after HPV vaccination in males and females.

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.

Impact of an electronic medical record reminder on hepatitis B vaccine initiation and completion rates among insured adults with diabetes mellitus.

OBJECTIVE: The Advisory Committee on Immunization Practices recommends Hepatitis B (HepB) vaccine for previously unvaccinated adults <60 years with diabetes mellitus. This observational retrospective cohort study assessed the impact of implementing electronic provider reminders on HepB vaccine initiation and 3-dose series completion rates among insured adults with diabetes aged 19-59 years old. RESEARCH DESIGN AND METHODS: Difference-in-difference (DID) analyses compared changes in vaccine initiation and completion rates (ratio of the rate ratio [RRR] and 95% confidence interval [CI]) during 12 months pre- and post-implementation between intervention and control sites. We examined trends in vaccine initiation and completion rates by plotting monthly rates during the study period. We also calculated the overall HepB vaccine coverage rates with 95% CI among all adults with diabetes aged 19-59 years old at the start and end date of the study period. RESULTS: Baseline HepB vaccine initiation and completion rates were similar at both the intervention and control sites. Gender, age, and race/ethnicity distributions within both sites were similar during the 12 months pre- and post-implementation. DID analyses demonstrated statistically significant differences in the changes of the annual vaccine initiation rates (RRR: 70.7, 95% CI: 62.8-79.6) and the third dose completion rates (RRR = 18.7, 95% CI: 14.2-24.8) between the two sites. The coverage increased significantly at the intervention site while it remained low at the control site. CONCLUSIONS: Use of provider reminders is highly effective in increasing both HepB vaccine initiation and series completion rates among adults with diabetes.

Long-Term Effectiveness of the Live Zoster Vaccine in Preventing Shingles: A Cohort Study.

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.

Estimated rates of influenza-associated outpatient visits during 2001-2010 in 6 US integrated healthcare delivery organizations.

BACKGROUND: Population-based estimates of influenza-associated outpatient visits including both pandemic and interpandemic seasons are uncommon. Comparisons of such estimates with laboratory-confirmed rates of outpatient influenza are rare. OBJECTIVE: To estimate influenza-associated outpatient visits in 6 US integrated healthcare delivery organizations enrolling ~7.7 million persons. METHODS: Using negative binomial regression methods, we modeled rates of influenza-associated visits with ICD-9-CM-coded pneumonia or acute respiratory outpatient visits during 2001-10. These estimated counts were added to visits coded specifically for influenza to derive estimated rates. We compared these rates with those observed in 2 contemporaneous studies recording RT-PCR-confirmed influenza outpatient visits. RESULTS: Outpatient rates estimated with pneumonia visits were 39 (95% confidence interval [CI], 30-70) and 203 (95% CI, 180-240) per 10 000 person-years, respectively, for interpandemic and pandemic seasons. Corresponding rates estimated with respiratory visits were 185 (95% CI, 161-255) and 542 (95% CI, 441-823) per 10 000 person-years. During the pandemic, children aged 2-17 years had the largest increase in rates (when estimated with pneumonia visits, from 64 [95% CI, 50-121] to 381 [95% CI, 366-481]). Rates estimated with pneumonia visits were consistent with rates of RT-PCR-confirmed influenza visits during 4 of 5 seasons in 1 comparison study. In another, rates estimated with pneumonia visits during the pandemic for children and adults were consistent in timing, peak, and magnitude. CONCLUSIONS: Estimated rates of influenza-associated outpatient visits were higher in children than adults during pre-pandemic and pandemic seasons. Rates estimated with pneumonia visits plus influenza-coded visits were similar to rates from studies using RT-PCR-confirmed influenza.

Birth outcomes following immunization of pregnant women with pandemic H1N1 influenza vaccine 2009-2010.

BACKGROUND: Following the H1N1 influenza pandemic in 2009, pregnant women were recommended to receive both seasonal (TIV) and H1N1 influenza vaccines. This study presents incidence of adverse birth and pregnancy outcomes among a population of pregnant women immunized with TIV and H1N1 vaccines at Kaiser Permanente Northern California during 2009-2010. METHODS: We telephone surveyed pregnant Kaiser Permanente Northern California members to assess non-medically-attended reactions following H1N1, TIV or both vaccines during 2009-2010 (n=5365) in a separate study. Here we assessed preterm birth (<37weeks), very preterm birth (<32weeks), low birth weight (<2500 g, LBW), very low birth weight (<1500g), small for gestational age, spontaneous abortions, stillbirths and congenital anomalies among this cohort by comparing incidence and 95% confidence intervals between the following immunization groups: TIV only, H1N1 only, H1N1 prior to TIV immunization, TIV prior to H1N1 and both immunizations given at the same time. RESULTS: Results did not vary significantly between groups. Comparing H1N1 with TIV, incidence were similar for preterm births (6.37vs 6.28/100 births), very preterm births (5.30vs 8.29/1000 births), LBW (4.19vs 2.90/100 births), very LBW (4.54vs 5.52/1000 births), small for gestational age (9.99vs 9.24/1000 births), spontaneous abortion (7.10vs 6.83/1000 pregnancies), stillbirths (7.10vs 4.57/1000 pregnancies), and congenital anomalies (2.66vs 2.43/100 births). CONCLUSIONS: Although constrained by small sample size, complex vaccine groups, and differential vaccine availability during 2009-2010, this study found no difference in adverse birth outcomes between H1N1 vaccine and TIV.

Live Attenuated Influenza Vaccination Before 3 Years of Age and Subsequent Development of Asthma: A 14-year Follow-up Study.

BACKGROUND: Live-attenuated influenza vaccines (LAIVs) are not licensed in children younger than 2 years of age because of a wheezing safety signal that has not been fully elucidated. In 2000, the Kaiser Permanente Vaccine Study Center conducted a placebo-controlled randomized clinical trial (RCT) of LAIV in children. As many of these children were still enrolled in Kaiser Permanente in 2014, we could assess the possible long-term association between LAIV and subsequent asthma diagnosis. METHODS: We identified all children who were originally enrolled into the LAIV RCT at younger than 3 years of age. We followed up subjects until disenrollment from the health plan, a first diagnosis of asthma, or through the end of the study period in 2014. Asthma was defined by a first International Classification of Diseases, 9th revision, Clinical Modification code (493.*) assigned at an outpatient or emergency department encounter. We performed a survival analysis of time to first asthma diagnosis among children receiving LAIV or placebo with a Cox proportional hazards model. RESULTS: We identified 1151 children in the original RCT who were 12 through 35 months of age at the time of enrollment and who had received 2 doses of LAIV or placebo. A total of 767 (66.7%) RCT participants were still Kaiser Permanente Northern California members in 2014. There was no evidence of differential dropout by treatment group. The hazard ratio for new-onset asthma for LAIV recipients compared with placebo was 1.1 (95% confidence interval: 0.88-1.41; P = 0.38). CONCLUSIONS: We found no evidence of increased risk of subsequent asthma diagnosis among children younger than 3 years of age who received LAIV compared with placebo.

Waning protection following 5 doses of a 3-component diphtheria, tetanus, and acellular pertussis vaccine.

BACKGROUND: The effectiveness of diphtheria, tetanus, and acellular pertussis (DTaP) vaccines wanes substantially after the 5th dose given at ages 4-6years, but has not been described following 5 doses of the same type of DTaP vaccine. We investigated waning effectiveness against pertussis in California over nearly 10years, which included large pertussis outbreaks, following 5 doses of GSK DTaP vaccines (DTaP3). METHODS: We conducted a case-control study (NCT02447978) of children who received 5 doses of DTaP at Kaiser Permanente Northern California from 01/2006 through 03/2015. We compared time since the 5th dose in confirmed pertussis polymerase chain reaction (PCR)-positive cases with pertussis PCR-negative controls. We used logistic regression adjusted for calendar time, age, sex, race, and service area to estimate the effect of time since the 5th DTaP dose on the odds of pertussis. Our primary analysis evaluated waning after 5 doses of DTaP3. We also examined waning after 5 doses of any type of DTaP vaccines. RESULTS: Our primary analysis compared 340 pertussis cases diagnosed at ages 4-12years with 3841 controls. The any DTaP analysis compared 462 pertussis cases with 5649 controls. The majority of all DTaP doses in the study population were DTaP3 (86.8%). Children who were more remote from their 5th dose were less protected than were children whose 5th dose was more recent; the adjusted odds of pertussis increased by 1.27 per year (95% CI 1.10, 1.46) after 5 doses of DTaP3 and by 1.30 per year (95% CI 1.15, 1.46) after any 5 DTaP vaccines doses. CONCLUSIONS: Waning protection after DTaP3 was similar to that following 5 doses of any type of DTaP vaccines. This finding is not unexpected as most of the DTaP vaccines administered were DTaP3. Following 5 doses of DTaP3 vaccines, protection from pertussis waned 27% per year on average. NCT number: NCT02447978.

No association between influenza vaccination during pregnancy and adverse birth outcomes.

BACKGROUND: Pregnant women are recommended to receive inactivated influenza vaccination anytime during pregnancy. Studies have investigated the impact of influenza vaccination during pregnancy on birth outcomes and results on preterm birth have been inconsistent. METHODS: We conducted a retrospective cohort study among children born at a gestational age≥24weeks from January 1, 2010 to December 31, 2015 at Kaiser Permanente Northern California facilities (KPNC). We evaluated the association between maternal influenza vaccination during pregnancy and risk of preterm birth, small and large for gestational age, admission to the neonatal intensive care unit (NICU), respiratory distress syndrome, low birth weight, and low Apgar score. We ascertained the dates of maternal influenza vaccination, conception, and delivery, as well as birth outcomes from KPNC inpatient and outpatient databases. Conditional multivariate Cox regression and logistic regression analyses were used to determine the association between maternal vaccination during pregnancy and risk of each birth outcome. RESULTS: The study included 145,869 children. Maternal influenza vaccination during pregnancy was not associated with risk of small or large for gestational age births, preterm birth, need for mechanical ventilation at birth, respiratory distress syndrome, admission to the NICU, low birth weight, or low Apgar score. However, when we did not control for immortal time bias, the risk of preterm birth (odds ratio [OR]=0.69, 95% confidence interval [CI] 0.66-0.72) was lower among infants of vaccinated mothers. CONCLUSION: We found no association between maternal influenza vaccination during pregnancy and adverse birth outcomes. When investigating preterm birth outcome in association with vaccination during pregnancy, immortal time bias should be taken into account in the analysis.

Effectiveness of Vaccination During Pregnancy to Prevent Infant Pertussis.

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.

Live attenuated influenza vaccine use and safety in children and adults with asthma.

BACKGROUND: Live attenuated influenza vaccine (LAIV) might increase the risk of wheezing in persons with asthma or children younger than 5 years with a history of recurrent wheezing. OBJECTIVE: To describe the use and assess the safety of LAIV in persons with asthma in the Vaccine Safety Datalink population. METHODS: We identified persons with asthma using diagnosis codes and medication records in 7 health care organizations over 3 influenza seasons (2008-2009 through 2010-2011) and determined their influenza vaccination rates. Using the self-controlled risk interval method, we calculated the incidence rate ratio of medically attended respiratory events in the 14 days after LAIV compared with 29 to 42 days after vaccination in persons 2 through 49 years old. RESULTS: In our population of 6.3 million, asthma prevalence was 5.9%. Of persons with asthma, approximately 50% received any influenza vaccine but less than 1% received LAIV. The safety study included 12,354 LAIV doses (75% in children; 93% in those with intermittent or mild persistent asthma). The incidence rate ratio for inpatient and emergency department visits for lower respiratory events (including asthma exacerbation and wheezing) was 0.98 (95% confidence interval 0.63-1.51) and the incidence rate ratio for upper respiratory events was 0.94 (95% confidence interval 0.48-1.86). The risk of lower respiratory events was similar for intermittent and mild persistent asthma, across age groups, and for seasonal trivalent LAIV and 2009 H1N1 pandemic monovalent LAIV. CONCLUSION: LAIV use in asthma was mostly in persons with intermittent or mild persistent asthma. LAIV was not associated with an increased risk of medically attended respiratory adverse events.

Asthma exacerbations among asthmatic children receiving live attenuated versus inactivated influenza vaccines.

OBJECTIVE: To investigate whether there is a difference in the risk of asthma exacerbations between children with pre-existing asthma who receive live attenuated influenza vaccine (LAIV) compared with inactivated influenza vaccine (IIV). MATERIAL AND METHODS: We identified IIV and LAIV immunizations occurring between July 1, 2007 and March 31, 2014 among Kaiser Permanente Northern California members aged 2 to <18years with a history of asthma, and subsequent asthma exacerbations seen in the inpatient or Emergency Department (ED) setting. We calculated the ratio of the odds (OR) of an exacerbation being in the risk interval (1-14days) versus the comparison interval (29-42days) following immunization, separately for LAIV and IIV, and then examined whether the OR differed between children receiving LAIV and those receiving IIV ("difference-in-differences"). RESULTS: Among 387,633 immunizations, 85% were IIV and 15% were LAIV. Children getting LAIV vs. IIV were less likely to have "current or recent, persistent" asthma (25% vs. 47%), and more likely to have "remote history" of asthma (47% vs. 25%). Among IIV-vaccinated asthmatic children, the OR of an inpatient/ED asthma exacerbation was 0.97 (95% CI: 0.82-1.15). Among LAIV-vaccinated asthmatic children the OR was 0.38 (95% CI: 0.17-0.90). In the difference-in-differences analysis, the odds of asthma exacerbation following LAIV were less than IIV (Ratio of ORs: 0.40, CI: 0.17-0.95, p value: 0.04). CONCLUSION: Among children ≥2years old with asthma, we found no increased risk of asthma exacerbation following LAIV or IIV, and a decreased risk following LAIV compared to IIV.

Safety of quadrivalent live attenuated influenza vaccine in subjects aged 2-49years.

BACKGROUND: Quadrivalent live attenuated influenza vaccine (Q/LAIV) was licensed in 2012 and replaced trivalent live attenuated influenza vaccine in the United States during the 2013-2014 influenza season. This study assessed the safety of Q/LAIV in children and adults aged 2-49years. METHODS: This was a prospective observational cohort study using data collected from Kaiser Permanente Northern California. Post-vaccination events of interest were any hospitalization, hospitalization for lower respiratory tract infection, and the following medically attended events: hypersensitivity, seizures/convulsions, lower respiratory tract infection, wheezing, Guillain-Barré syndrome, Bell's palsy, encephalitis, neuritis, vasculitis, and narcolepsy/cataplexy. The rates of these events during the risk interval post-vaccination were compared with rates observed during reference periods later in the follow-up (within-cohort analysis) and with rates observed in frequency-matched unvaccinated controls and inactivated influenza vaccine (IIV) recipients. RESULTS: A total of 62,040 eligible Q/LAIV recipients were identified during the 2013-2014 influenza season. Within-cohort comparisons of all Q/LAIV recipients as well as comparisons between Q/LAIV recipients and unvaccinated controls or IIV recipients did not show any significantly higher risk of hospitalizations or medically attended events following administration of Q/LAIV. Additional analyses by setting (clinic visits, emergency department visits, and hospital admissions) and age group (2-4, 5-8, 9-17, and 18-49years) also did not reveal clinically consistent findings that suggested any increased risk after administration of Q/LAIV. CONCLUSION: In this large population study of individuals aged 2-49years, no safety signals associated with the administration of Q/LAIV were observed. A much larger study population would be needed to confidently reject any association between Q/LAIV and very rare events, specifically those with an incidence of <1 event/10,000 person-years. TRIAL REGISTRATION: ClinicalTrials.gov NCT01985997.

Risk factors and familial clustering for fever 7-10days after the first dose of measles vaccines.

BACKGROUND: 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. METHODS: Retrospective cohort study among children who were <36months 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 χ2 and multivariable logistic regression analyses. RESULTS: Among 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 had >3 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). DISCUSSION: 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.

Invasive Pneumococcal Disease Among HIV-Infected and HIV-Uninfected Adults in a Large Integrated Healthcare System.

It is unclear whether HIV-infected individuals remain at higher risk of invasive pneumococcal disease (IPD) compared with HIV-uninfected individuals. We conducted a cohort study of HIV-infected and demographically matched HIV-uninfected adults within Kaiser Permanente Northern California during the period 1996-2011. We used Poisson models to obtain rate ratios (RRs) for incident IPD associated with HIV infection and other risk factors. Among 13,079 HIV-infected and 137,643 HIV-uninfected adults, the IPD rate per 100,000 person-years was 160 (n = 109 events) for HIV-infected and 8 (n = 75 events) for HIV-uninfected subjects, with an adjusted RR of 13.0 [95% confidence interval (CI): 9.1-18.7]. For HIV-infected individuals, IPD incidence per 100,000 person-years decreased by 71% during study follow-up, from 305 in 1996-1999 to 88 in 2010-2011 (p < 0.001), with an adjusted RR of 6.6 (95% CI: 2.7-16.1) compared with HIV-uninfected subjects in 2010-2011. Risk factors for IPD among HIV-infected individuals included black compared with white race/ethnicity, smoking, cancer, and higher HIV RNA levels. The 23-valent pneumococcal polysaccharide vaccination was not associated with a reduced risk of IPD in HIV-infected or HIV-uninfected individuals. Among HIV-infected IPD cases, the most common serotype was 19A (33%), and 59% of serotypes were covered by the 13-valent pneumococcal conjugate vaccine (PCV13). Despite a dramatic decline in IPD incidence for HIV-infected adults since 1996, IPD rates were nearly sevenfold higher compared with HIV-uninfected adults in recent years, even after adjustment for risk factors. Timely antiretroviral therapy initiation, risk reduction strategies, and recent guidelines recommending PCV13 use may further reduce IPD incidence among HIV patients.

Kaiser Permanente Northern California pregnancy database: Description and proof of concept study.

BACKGROUND/OBJECTIVE: We describe the establishment of a dynamic database linking mothers to newborns with the goal of studying vaccine safety in both pregnant women and their children and provide results of a study utilizing this database as a proof of concept. METHODS: All Kaiser Permanente Northern California (KPNC) live births and their mothers were eligible for inclusion in the pregnancy database. We used the medical record number (MRN), a unique identifier, to retrieve information about events that occurred during the pregnancy and at delivery and linked this same MRN to newborns for post-partum follow up. We conducted a retrospective cohort study to evaluate the association between receipt of tetanus, diphtheria and acellular pertussis (Tdap) vaccine during pregnancy and fever 0-3days after the first dose of diphtheria tetanus and acellular pertussis (DTaP) vaccine in the infant. The study included infants who were born at ⩾37weeks gestation from January 1, 2009 - October 1, 2015 and who received their first DTaP vaccine between 6 and 10weeks of age. We utilized diagnostic codes from inpatient, emergency department, outpatient clinics, and telephone calls. We identified fever using ICD 9 code 780.6, recorded temperature ⩾101 degree Fahrenheit, or parental report. RESULTS: The database contained the starting and ending date of each pregnancy and basic demographic characteristics of mothers and infants. There were 859,699 women and 873,753 children in the database as of January 2016. The proof of concept study included 148,699 infants. In a multivariable logistic regression analysis, Tdap vaccination during pregnancy was not associated with infant fever 0-3daysafter first dose of DTaP (adjusted odds ratio=0.92, 95% CI 0.82-1.04). CONCLUSION: The KPNC pregnancy database can be used for studies investigating exposure during pregnancy and outcomes in mothers and/or infants, particularly monitoring vaccine safety and effectiveness.

Acute Demyelinating Events Following Vaccines: A Case-Centered Analysis.

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.

Post-licensure safety surveillance study of routine use of tetanus toxoid, reduced diphtheria toxoid and 5-component acellular pertussis vaccine.

An observational post-licensure (Phase IV) retrospective large-database safety study was conducted at Kaiser Permanente, a US integrated medical care organization, to assess the safety of Tetanus Toxoid, Reduced Diphtheria Toxoid and 5-Component Acellular Pertussis Vaccine (Tdap5) administered as part of routine healthcare among adolescents and adults. We evaluated incidence rates of various clinical events resulting in outpatient clinic, emergency department (ED), and hospital visits during various time intervals (windows) following Tdap5 vaccination using 2 pharmacoepidemiological methods (risk interval and historic cohort) and several screening thresholds. Plausible outcomes of interest with elevated incidence rate ratios (IRRs) were further evaluated by reviewing individual patient records to confirm the diagnosis, timing (temporal relationship), alternative etiology, and other health record details to discern possible relatedness of the health events to vaccination. Overall, 124,139 people received Tdap5 vaccine from September 2005 through mid-October 2006, and 203,154 in the comparison cohort received a tetanus and diphtheria toxoid adsorbed vaccine (and no live virus vaccine) during the year prior to initiation of this study. In the outpatient, ED and hospital databases, respectively, we identified 11/26, 179/700 and 187/700 unique health outcomes with IRRs significantly >1.0. Among the same unique health outcomes in the outpatient, ED, and hospital databases, 9, 146, and 385, respectively, had IRRs significantly <1.0. Further scrutiny of the outcomes with elevated IRRs did not reveal unexpected signals of adverse outcomes related to vaccination. In conclusion, Tdap5 vaccine was found to be safe among this large population of adolescents and adults.