Stephanie A. Irving

Real-time surveillance to assess risk of intussusception and other adverse events after pentavalent, bovine-derived rotavirus vaccine.

Background: 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 A previously licensed rotavirus vaccine was withdrawn due to elevated risk of intussusception.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. Methods: 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. Results: 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. Conclusions: 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.

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.).

Evaluation of self-reported and registry-based influenza vaccination status in a Wisconsin cohort.

We evaluated influenza vaccination status as determined by self-report and a regional, real-time immunization registry during two influenza seasons when subjects were enrolled in a study to estimate vaccine effectiveness. We enrolled 2907 patients during the two consecutive seasons. The sensitivity and specificity of self-reported influenza vaccination when compared to immunization registry records were 95% and 90%, respectively. The positive predictive value of self-reported vaccination was 89% and negative predictive value was 96%. In our study population, self-reported influenza vaccine status was a sensitive and fairly specific indicator of actual vaccine status. Misclassification was more common among young children.

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.

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.

Influenza vaccine effectiveness in Wisconsin during the 2007–08 season: Comparison of interim and final results

BACKGROUND During the 2007-08 influenza season, we reported an interim vaccine effectiveness (VE) estimate of 44% for preventing medically attended influenza. In this analysis we report results for the entire season and compare them with the interim estimate. METHODS Patients with feverishness, chills, or cough <8 days duration were prospectively recruited over 10 weeks and tested for influenza by real-time reverse transcriptase PCR (rRT-PCR). Case-control analyses were performed using data from patients with rRT-PCR confirmed influenza (cases) and ill patients without influenza (test-negative controls). VE was estimated as 100×(1-adjusted odds ratio) in a logistic regression model adjusting for age, week, and high risk medical condition. A sample of influenza isolates was antigenically characterized. RESULTS Influenza was detected by rRT-PCR in 865 (44%) of 1972 patients; 73% were type A and 27% were type B. VE was 37% (95% CI, 22-49%) overall and 44% (95% CI, 27-58%) among participants tested 0-3 days after illness onset. VE was 39% (95% CI, 2-62%) in children 6-59 months old and 37% (95% CI, -2% to 61%) in adults ≥50 years old. VE was 41% (95% CI, 24-53%) for influenza A and 31% (95% CI, 3-51%) for influenza B. All 24 characterized influenza A viruses were antigenically matched to the H3N2 vaccine strain, although 14 viruses exhibited mild antigenic drift. There was a lineage mismatch with the vaccine strain for all 39 characterized influenza B viruses. CONCLUSIONS The 2007-08 influenza vaccine provided modest protection against medically attended influenza in this population. The interim estimate of VE after 17 days closely approximated the final season VE, supporting the potential use of interim VE estimates while influenza seasons are still in progress.

Comparison of clinical features and outcomes of medically attended influenza A and influenza B in a defined population over four seasons: 2004–2005 through 2007–2008

Please cite this paper as: Irving et al. (2012) Comparison of clinical features and outcomes of medically attended influenza A and influenza B in a defined population over four seasons: 2004–2005 through 2007–2008. Influenza and Other Respiratory Viruses 6(1), 37–43.

Risk of anaphylaxis after vaccination in children and adults

BACKGROUND Anaphylaxis is a potentially life-threatening allergic reaction. The risk of anaphylaxis after vaccination has not been well described in adults or with newer vaccines in children. OBJECTIVE We sought to estimate the incidence of anaphylaxis after vaccines and describe the demographic and clinical characteristics of confirmed cases of anaphylaxis. METHODS Using health care data from the Vaccine Safety Datalink, we determined rates of anaphylaxis after vaccination in children and adults. We first identified all patients with a vaccination record from January 2009 through December 2011 and used diagnostic and procedure codes to identify potential anaphylaxis cases. Medical records of potential cases were reviewed. Confirmed cases met the Brighton Collaboration definition for anaphylaxis and had to be determined to be vaccine triggered. We calculated the incidence of anaphylaxis after all vaccines combined and for selected individual vaccines. RESULTS We identified 33 confirmed vaccine-triggered anaphylaxis cases that occurred after 25,173,965 vaccine doses. The rate of anaphylaxis was 1.31 (95% CI, 0.90-1.84) per million vaccine doses. The incidence did not vary significantly by age, and there was a nonsignificant female predominance. Vaccine-specific rates included 1.35 (95% CI, 0.65-2.47) per million doses for inactivated trivalent influenza vaccine (10 cases, 7,434,628 doses given alone) and 1.83 (95% CI, 0.22-6.63) per million doses for inactivated monovalent influenza vaccine (2 cases, 1,090,279 doses given alone). The onset of symptoms among cases was within 30 minutes (8 cases), 30 to less than 120 minutes (8 cases), 2 to less than 4 hours (10 cases), 4 to 8 hours (2 cases), the next day (1 case), and not documented (4 cases). CONCLUSION Anaphylaxis after vaccination is rare in all age groups. Despite its rarity, anaphylaxis is a potentially life-threatening medical emergency that vaccine providers need to be prepared to treat.

Predictors of seasonal influenza vaccination during pregnancy.

OBJECTIVE: Although pregnant women are a high-priority group for influenza vaccination, vaccination rates in this population remain below recommended levels. This prospective cohort study followed a group of pregnant women during the 2010–2011 influenza season to determine possible predictors of vaccination. METHODS: Participants were 552 pregnant women who had not already received the influenza vaccine at the time of enrollment. Women completed a survey assessing knowledge, attitudes, and beliefs about vaccination (based on the Health Belief Model) by telephone and were then followed to determine vaccination status by the end of the 2010–2011 influenza season. RESULTS: Forty-six percent (n=252) of the women were vaccinated, and 54% (n=300) remained unvaccinated after enrollment in the study. Few baseline characteristics, with the exception of study site, month of enrollment, and maternal ethnicity, were predictive of vaccination status. Even after adjusting for significant baseline characteristics, we found that at least one item from each domain of the Health Beliefs Model was predictive of subsequent vaccination. Specifically, women who perceived they were susceptible to influenza, that they were at risk of getting seriously ill from influenza, that they would regret not getting vaccinated, and who trusted recommended guidelines about influenza vaccination during pregnancy were more likely to get vaccinated. Women who were concerned about vaccine side effects were less likely to get vaccinated. CONCLUSION: Trust in recommendations, perceived susceptibility to and seriousness of influenza, perceived regret about not getting vaccinated, and vaccine safety concerns predict vaccination in pregnant women. LEVEL OF EVIDENCE: II

Identifying pregnancy episodes, outcomes, and mother-infant pairs in the Vaccine Safety Datalink

BACKGROUND The need for research on the safety of vaccination during pregnancy is widely recognized. Large, population-based data systems like the Vaccine Safety Datalink (VSD) may be useful for this research, but identifying pregnancies using electronic medical record (EMR) and claims data can be challenging. METHODS We modified an existing data processing algorithm to identify pregnancies within seven of the ten VSD sites. We validated the algorithm by calculating the agreement in pregnancy outcome type, end date, and gestational age between the algorithm and manual medical record review. At each participating site, we randomly sampled 15 episodes within four outcome type strata (live births, spontaneous abortions, elective abortions, and other pregnancy outcomes) for a total of 60 episodes per site. We also developed and validated methods to link mothers to their infants in the electronic data. RESULTS We identified 595,929 pregnancy episodes ending in 2002 through 2006 among women 12 through 55 years of age. Of these pregnancies, 75% ended in live births, 12% in spontaneous abortions, and 9% in elective abortions. We were able to confirm a pregnancy within 28 days of the algorithm-estimated pregnancy start date for 99% of live births, 93% of spontaneous abortions, 92% of elective abortions, and 90% of other outcomes sampled. The agreement between the algorithm-identified and the abstractor-identified outcome date ranged from 70% (elective abortion) to 96% (live birth) depending on outcome type. When gestational age was available in the EMR, agreement ranged from 82% (other) to 98% (live birth) depending on outcome type. We confirmed 100% of the 350 sampled mother-infant linkages with manual medical record review. CONCLUSIONS The VSD algorithm accurately identifies pregnancy episodes and mother-infant pairs across participating sites. Additional manual record review may be needed to improve the precision of the pregnancy date estimates depending on specific study needs. These algorithms will allow us to conduct large, population-based studies of the safety of vaccination during pregnancy.