Allison L. Naleway

The Vaccine Safety Datalink: A Model for Monitoring Immunization Safety

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

Measles-Mumps-Rubella-Varicella Combination Vaccine and the Risk of Febrile Seizures

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.

Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink.

BACKGROUND In 7 large managed care organizations (MCOs), we performed a post-licensure safety assessment of quadrivalent human papillomavirus vaccine (HPV4) among 9-26 year-old female vaccine recipients between August 2006 and October 2009. METHODS Sequential analyses were conducted weekly to detect associations between HPV4 exposure and pre-specified outcomes. The pre-specified outcomes identified by ICD-9 codes using computerized data at the participating MCOs included: Guillan-Barré Syndrome (GBS), stroke, venous thromboembolism (VTE), appendicitis, seizures, syncope, allergic reactions, and anaphylaxis. For rare outcomes, historical background rates were used as the comparison group. For more common outcomes, a concurrent unexposed comparison group was utilized. A standardized review of medical records was conducted for all cases of GBS, VTE, and anaphylaxis. RESULTS A total of 600,558 HPV4 doses were administered during the study period. We found no statistically significant increased risk for the outcomes studied. However, a non-statistically significant relative risk (RR) for VTE ICD-9 codes following HPV4 vaccination of 1.98 was detected among females age 9-17 years. Medical record review of all 8 vaccinated potential VTE cases in this age group revealed that 5 met the standard case definition for VTE. All 5 confirmed cases had known risk factors for VTE (oral contraceptive use, coagulation disorders, smoking, obesity or prolonged hospitalization). CONCLUSIONS In a study of over 600,000 HPV4 vaccine doses administered, no statistically significant increased risk for any of the pre-specified adverse events after vaccination was detected. Further study of a possible association with VTE following HPV4 vaccination is warranted.

Risk of Intussusception after Monovalent Rotavirus Vaccination

BACKGROUND Although current rotavirus vaccines were not associated with an increased risk of intussusception in large trials before licensure, recent postlicensure data from international settings suggest the possibility of a small increase in risk of intussusception after monovalent rotavirus vaccination. We examined this risk in a population in the United States. METHODS Participants were infants between the ages of 4 and 34 weeks who were enrolled in six integrated health care organizations in the Vaccine Safety Datalink (VSD) project. We reviewed medical records and visits for intussusception within 7 days after monovalent rotavirus vaccination from April 2008 through March 2013. Using sequential analyses, we then compared the risk of intussusception among children receiving monovalent rotavirus vaccine with historical background rates. We further compared the risk after monovalent rotavirus vaccination with the risk in a concurrent cohort of infants who received the pentavalent rotavirus vaccine. RESULTS During the study period, 207,955 doses of monovalent rotavirus vaccine (including 115,908 first doses and 92,047 second doses) were administered in the VSD population. We identified 6 cases of intussusception within 7 days after the administration of either dose of vaccine. For the two doses combined, the expected number of intussusception cases was 0.72, resulting in a significant relative risk of 8.4. For the pentavalent rotavirus vaccine, 1,301,810 doses were administered during the study period, with 8 observed intussusception cases (7.11 expected), for a nonsignificant relative risk of 1.1. The relative risk of chart-confirmed intussusception within 7 days after monovalent rotavirus vaccination, as compared with the risk after pentavalent rotavirus vaccination, was 9.4 (95% confidence interval, 1.4 to 103.8). The attributable risk of intussusception after the administration of two doses of monovalent rotavirus vaccine was estimated to be 5.3 per 100,000 infants vaccinated. CONCLUSIONS In this prospective postlicensure study of more than 200,000 doses of monovalent rotavirus vaccine, we observed a significant increase in the rate of intussusception after vaccination, a risk that must be weighed against the benefits of preventing rotavirus-associated illness. (Funded by the Centers for Disease Control and Prevention.).

Effectiveness of Seasonal Trivalent Influenza Vaccine for Preventing Influenza Virus Illness Among Pregnant Women: A Population-Based Case-Control Study During the 2010–2011 and 2011–2012 Influenza Seasons

BACKGROUND Although vaccination with trivalent inactivated influenza vaccine (TIV) is recommended for all pregnant women, no vaccine effectiveness (VE) studies of TIV in pregnant women have assessed laboratory-confirmed influenza outcomes. METHODS We conducted a case-control study over 2 influenza seasons (2010-2011 and 2011-2012) among Kaiser Permanente health plan members in 2 metropolitan areas in California and Oregon. We compared the proportion vaccinated among 100 influenza cases (confirmed by reverse transcription polymerase chain reaction) with the proportions vaccinated among 192 controls with acute respiratory illness (ARI) who tested negative for influenza and 200 controls without ARI (matched by season, site, and trimester). RESULTS Among influenza cases, 42% were vaccinated during the study season compared to 58% and 63% vaccinated among influenza-negative controls and matched ARI-negative controls, respectively. The adjusted VE of the current season vaccine against influenza A and B was 44% (95% confidence interval [CI], 5%-67%) using the influenza-negative controls and 53% (95% CI, 24%-72%) using the ARI-negative controls. Receipt of the prior seasons vaccine, however, had an effect similar to receipt of the current seasons vaccine. As such, vaccination in either or both seasons had statistically similar adjusted VE using influenza-negative controls (VE point estimates range = 51%-76%) and ARI-negative controls (48%-76%). CONCLUSIONS Influenza vaccination reduced the risk of ARI associated with laboratory-confirmed influenza among pregnant women by about one-half, similar to VE observed among all adults during these seasons.

Active Surveillance for Adverse Events: The Experience of the Vaccine Safety Datalink Project

OBJECTIVE: To describe the Vaccine Safety Datalink (VSD) projects experience with population-based, active surveillance for vaccine safety and draw lessons that may be useful for similar efforts. PATIENTS AND METHODS: The VSD comprises a population of 9.2 million people annually in 8 geographically diverse US health care organizations. Data on vaccinations and diagnoses are updated and extracted weekly. The safety of 5 vaccines was monitored, each with 5 to 7 prespecified outcomes. With sequential analytic methods, the number of cases of each outcome was compared with the number of cases observed in a comparison group or the number expected on the basis of background rates. If the test statistic exceeded a threshold, it was a signal of a possible vaccine-safety problem. Signals were investigated by using temporal scan statistics and analyses such as logistic regression. RESULTS: Ten signals appeared over 3 years of surveillance: 1 signal was reported to external stakeholders and ultimately led to a change in national vaccination policy, and 9 signals were found to be spurious after rigorous internal investigation. Causes of spurious signals included imprecision in estimated background rates, changes in true incidence or coding over time, other confounding, inappropriate comparison groups, miscoding of outcomes in electronic medical records, and chance. In the absence of signals, estimates of adverse-event rates, relative risks, and attributable risks from up-to-date VSD data have provided rapid assessment of vaccine safety to policy-makers when concerns about a specific vaccine have arisen elsewhere. CONCLUSIONS: Care with data quality, outcome definitions, comparison groups, and length of surveillance are required to enable detection of true safety problems while minimizing false signals. Some causes of false signals in the VSD system were preventable and have been corrected, whereas others will be unavoidable in any active surveillance system. Temporal scan statistics, analyses to control for confounding, and chart review are indispensable tools in signal investigation. The VSDs experience may inform new systems for active safety surveillance.

H1N1 and Seasonal Influenza Vaccine Safety in the Vaccine Safety Datalink Project

BACKGROUND The emergence of pandemic H1N1 influenza virus in early 2009 prompted the rapid licensure and use of H1N1 monovalent inactivated (MIV) and live, attenuated (LAMV) vaccines separate from seasonal trivalent inactivated (TIV) and live, attenuated (LAIV) influenza vaccines. A robust influenza immunization program in the U.S. requires ongoing monitoring of potential adverse events associated with vaccination. PURPOSE To prospectively conduct safety monitoring of H1N1 and seasonal influenza vaccines during the 2009-2010 season. METHODS The Vaccine Safety Datalink (VSD) Project monitors ∼9.2 million members in eight U.S. medical care organizations. Electronic data on vaccines and pre-specified adverse events were updated and analyzed weekly for signal detection from November 2009 to April 2010 using either a self-controlled design or a current versus historical comparison. Statistical signals were further evaluated using alternative approaches to identify temporal clusters and to control for time-varying confounders. RESULTS As of May 1, 2010, a total of 1,345,663 MIV, 267,715 LAMV, 2,741,150 TIV, and 157,838 LAIV doses were administered in VSD. No significant associations were noted during sequential analyses for Guillain-Barré syndrome, most other neurologic outcomes, and allergic and cardiac events. For MIV, a statistical signal was observed for Bells palsy for adults aged ≥25 years on March 31, 2010, using the self-controlled approach. Subsequent analyses revealed no significant temporal cluster. Case-centered logistic regression adjusting for seasonality demonstrated an OR for Bells palsy of 1.26 (95% CI=0.97, 1.63). CONCLUSIONS No major safety problems following H1N1 or seasonal influenza vaccines were detected in the 2009-2010 season in weekly sequential analyses. Seasonality likely contributed to the Bells palsy signal following MIV. Prospective safety monitoring followed by rigorous signal refinement is critical to inform decision-making by regulatory and public health agencies.

The Vaccine Safety Datalink: successes and challenges monitoring vaccine safety

The Vaccine Safety Datalink (VSD) is a collaborative project between the Centers for Disease Control and Prevention (CDC) and 9 health care organizations. Established in 1990, VSD is a vital resource informing policy makers and the public about the safety of vaccines used in the United States. Large linked databases are used to identify and evaluate adverse events in over 9 million individuals annually. VSD generates rapid, important safety assessments for both routine vaccinations and emergency vaccination campaigns. VSD monitors safety of seasonal influenza vaccines in near-real time, and provided essential information on the safety of influenza A (H1N1) 2009 monovalent vaccine during the recent pandemic. VSD investigators have published important studies demonstrating that childhood vaccines are not associated with autism or other developmental disabilities. VSD prioritizes evaluation of new vaccines; searches for possible unusual health events after vaccination; monitors vaccine safety in pregnant women; and has pioneered development of biostatistical research methods.

Maternal safety of trivalent inactivated influenza vaccine in pregnant women

OBJECTIVE: To estimate the risks for medically attended events occurring within 42 days of receiving trivalent inactivated influenza vaccine and to evaluate specific risks of first-trimester vaccination. METHODS: This retrospective observational cohort study compared rates of medically attended adverse events in trivalent inactivated influenza-vaccinated and unvaccinated pregnant women in the Vaccine Safety Datalink. Using a Poisson distribution and log link, we calculated maternal adjusted incident rate ratios for composite safety outcomes for the full cohort and the subset vaccinated during the first trimester. RESULTS: The cohort included 75,906 vaccinated (28.4% in the first trimester) and 147,992 unvaccinated women matched by age, site, and pregnancy start date. In the first 3 days after vaccination, trivalent inactivated influenza vaccine was not associated with increased risk of specified medically attended events, including allergic reactions, cellulitis, and seizures (full cohort adjusted incident rate ratio 1.12, 95% confidence interval [CI] 0.81–1.55; P=.48; first-trimester adjusted incident rate ratio .97, 95% CI 0.53–1.78; P=.93). In the first 42 days, no incident cases of Guillain-Barré syndrome, optic neuritis, transverse myelitis, or Bells palsy were identified. Trivalent inactivated influenza vaccine was not associated with thrombocytopenia (full cohort adjusted incident rate ratio 0.90, 95% CI 0.68--1.19; P=.45; first-trimester adjusted incident rate ratio 0.56, 95% CI 0.22–1.39; P=.21) or an acute neurologic event (full cohort adjusted incident rate ratio 0.92, 95% CI 0.54–1.6; P=.75; first-trimester adjusted incident rate ratio 1.05, 95% CI 0.46–2.38; P=.91). CONCLUSIONS: Receipt of trivalent inactivated influenza vaccine during pregnancy was not associated with increased risk of adverse events in the 42 days after vaccination, supporting its safety for the mother. LEVEL OF EVIDENCE: II

Inactivated influenza vaccine during pregnancy and risks for adverse obstetric events.

OBJECTIVE: To compare risks for adverse obstetric events between females who did and did not receive trivalent inactivated influenza vaccine during pregnancy. METHOD: This retrospective, observational cohort study was conducted at seven Vaccine Safety Datalink sites. Pregnancies were identified from administrative and claims data using a validated algorithm. Females vaccinated while pregnant from 2002 to 2009 were matched one-to-two with replacement to unvaccinated pregnant females. Using a generalized estimating equation method with a Poisson distribution and log link, we evaluated the association of trivalent inactivated influenza vaccine with 13 outcomes. Given our large sample size and multiple comparisons (19 contrasts), a cutoff for significance of P<.005 was selected a priori. RESULTS: Our cohort included 74,292 vaccinated females matched on age, site, and pregnancy start date with 144,597 unvaccinated females. We did not observe increased risks within 42 days of vaccination for hyperemesis, chronic hypertension, gestational hypertension, gestational diabetes, proteinuria, or urinary tract infection. Using a risk window from vaccination through pregnancy end, we did not observe increased risks after vaccination for proteinuria, urinary tract infection, gestational hypertension, preeclampsia or eclampsia, chorioamnionitis, puerperal infection, venous complications, pulmonary embolism, or peripartum cardiomyopathy. A reduced risk for gestational diabetes after vaccination was detected (adjusted hazard rate ratio 0.88, 95% confidence interval 0.83–0.93), likely as a result of healthy vaccine bias or earlier detection among vaccinees. CONCLUSION: In this large cohort, influenza vaccination during pregnancy was not associated with increased risks for medically attended adverse obstetric events. LEVEL OF EVIDENCE: II