Sharon K. Greene

Association between Guillain-Barré syndrome and influenza A (H1N1) 2009 monovalent inactivated vaccines in the USA: a meta-analysis

BACKGROUNDnThe influenza A (H1N1) 2009 monovalent vaccination programme was the largest mass vaccination initiative in recent US history. Commensurate with the size and scope of the vaccination programme, a project to monitor vaccine adverse events was undertaken, the most comprehensive safety surveillance agenda in the USA to date. The adverse event monitoring project identified an increased risk of Guillain-Barré syndrome after vaccination; however, some individual variability in results was noted. Guillain-Barré syndrome is a rare but serious health disorder in which a persons own immune system damages their nerve cells, causing muscle weakness, sometimes paralysis, and infrequently death. We did a meta-analysis of data from the adverse event monitoring project to ascertain whether influenza A (H1N1) 2009 monovalent inactivated vaccines used in the USA increased the risk of Guillain-Barré syndrome.nnnMETHODSnData were obtained from six adverse event monitoring systems. About 23 million vaccinated people were included in the analysis. The primary analysis entailed calculation of incidence rate ratios and attributable risks of excess cases of Guillain-Barré syndrome per million vaccinations. We used a self-controlled risk-interval design.nnnFINDINGSnInfluenza A (H1N1) 2009 monovalent inactivated vaccines were associated with a small increased risk of Guillain-Barré syndrome (incidence rate ratio 2·35, 95% CI 1·42-4·01, p=0·0003). This finding translated to about 1·6 excess cases of Guillain-Barré syndrome per million people vaccinated.nnnINTERPRETATIONnThe modest risk of Guillain-Barré syndrome attributed to vaccination is consistent with previous estimates of the disorder after seasonal influenza vaccination. A risk of this small magnitude would be difficult to capture during routine seasonal influenza vaccine programmes, which have extensive, but comparatively less, safety monitoring. In view of the morbidity and mortality caused by 2009 H1N1 influenza and the effectiveness of the vaccine, clinicians, policy makers, and those eligible for vaccination should be assured that the benefits of inactivated pandemic vaccines greatly outweigh the risks.nnnFUNDINGnUS Federal Government.

Signal identification and evaluation for risk of febrile seizures in children following trivalent inactivated influenza vaccine in the Vaccine Safety Datalink Project, 2010-2011.

In fall 2010 in the southern hemisphere, an increased risk of febrile seizures was noted in young children in Australia in the 24 h after receipt of trivalent inactivated influenza vaccine (TIV) manufactured by CSL Biotherapies. Although the CSL TIV vaccine was not recommended for use in young children in the US, during the 2010-2011 influenza season near real-time surveillance was conducted for febrile seizures in the 0-1 days following first dose TIV in a cohort of 206,174 vaccinated children ages 6 through 59 months in the Vaccine Safety Datalink Project. On a weekly basis, surveillance was conducted with the primary approach of a self-controlled risk interval design and the secondary approach of a current vs. historical vaccinee design. Sequential statistical methods were employed to account for repeated analyses of accumulating data. Signals for seizures based on computerized data were identified in mid November 2010 using a current vs. historical design and in late December 2010 using a self-controlled risk interval design. Further signal evaluation was conducted with chart-confirmed febrile seizure cases using only data from the primary approach (i.e. self-controlled risk interval design). The magnitude of the incidence rate ratio and risk difference comparing risk of seizures in the 0-1 days vs. 14-20 days following TIV differed by receipt of concomitant 13-valent pneumococcal conjugate vaccine (PCV13). Among children 6-59 months of age, the incidence rate ratio (IRR) for TIV adjusted for concomitant PCV13 was 2.4 (95% CI 1.2, 4.7) while the IRR for PCV13 adjusted for concomitant TIV was 2.5 (95% CI 1.3, 4.7). The IRR for concomitant TIV and PCV13 was 5.9 (95% CI 3.1, 11.3). Risk difference estimates varied by age due to the varying baseline risk for seizures in young children, with the highest estimates occurring at 16 months (12.5 per 100,000 doses for TIV without concomitant PCV13, 13.7 per 100,000 doses for PCV13 without concomitant TIV, and 44.9 per 100,000 doses for concomitant TIV and PCV13) and the lowest estimates occurring at 59 months (1.1 per 100,000 doses for TIV without concomitant PCV13, 1.2 per 100,000 doses for PCV13 without concomitant TIV, and 4.0 per 100,000 doses for concomitant TIV and PCV13). Incidence rate ratio and risk difference estimates were lower for children receiving TIV without concomitant PCV13 or PCV13 without concomitant TIV. Because of the importance of preventing influenza and pneumococcal infections and associated complications, our findings should be placed in a benefit-risk framework to ensure that population health benefits are maximized.

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

BACKGROUNDnThe 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.nnnPURPOSEnTo prospectively conduct safety monitoring of H1N1 and seasonal influenza vaccines during the 2009-2010 season.nnnMETHODSnThe 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.nnnRESULTSnAs 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).nnnCONCLUSIONSnNo 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.

Accuracy of Data on Influenza Vaccination Status at Four Vaccine Safety Datalink Sites

BACKGROUNDnStudies of influenza vaccination using electronic medical records rely on accurate classification of vaccination status. Vaccinations not entered into electronic records would be unavailable for study.nnnPURPOSEnThis study evaluated the sensitivity and negative predictive value (NPV) of electronic records for influenza vaccination and factors associated with failure to capture vaccinations.nnnMETHODSnIn four diverse medical care organizations in the Vaccine Safety Datalink, those aged 50-79 years with no influenza vaccination record during the 2007-2008 season were surveyed by telephone, and electronic records were analyzed in 2008. The sensitivity and NPV of electronic records were estimated, using survey responses as the gold standard. Logistic regression models determined associations between 1-NPV and demographic factors, risk of influenza complications, and healthcare utilization levels.nnnRESULTSnData were obtained for 933 survey participants and 1,085,916 medical care organization members. Sites varied significantly in the sensitivity (51%, 68%, 79%, 89%) and NPV (46%, 62%, 66%, 87%) of electronic records. In multivariate analysis, the rate of failure to capture vaccinations was significantly higher for those aged 65-79 years than for those aged 50-64 years at three sites. Of vaccinations not captured by electronic records, 58% were reportedly administered in nontraditional settings, usually workplaces; the rest were given within the sites.nnnCONCLUSIONSnInfluenza vaccination studies relying on electronic records may misclassify substantial proportions of vaccinated individuals as unvaccinated, producing biased estimates of vaccine effectiveness. Sites with limited sensitivity to capture vaccinations administered within their organization should seek possible remedies. More complete capture of vaccinations administered to older patients and in nontraditional settings would further reduce misclassification.

Challenges in the design and analysis of sequentially monitored postmarket safety surveillance evaluations using electronic observational health care data

Many challenges arise when conducting a sequentially monitored medical product safety surveillance evaluation using observational electronic data captured during routine care. We review existing sequential approaches for potential use in this setting, including a continuous sequential testing method that has been utilized within the Vaccine Safety Datalink (VSD) and group sequential methods, which are used widely in randomized clinical trials.

Near real-time vaccine safety surveillance with partially accrued data.

The Vaccine Safety Datalink (VSD) Project conducts near real‐time vaccine safety surveillance using sequential analytic methods. Timely surveillance is critical in identifying potential safety problems and preventing additional exposure before most vaccines are administered. For vaccines that are administered during a short period, such as influenza vaccines, timeliness can be improved by undertaking analyses while risk windows following vaccination are ongoing and by accommodating predictable and unpredictable data accrual delays. We describe practical solutions to these challenges, which were adopted by the VSD Project during pandemic and seasonal influenza vaccine safety surveillance in 2009/2010.

Adapting Group Sequential Methods to Observational Postlicensure Vaccine Safety Surveillance: Results of a Pentavalent Combination DTaP-IPV-Hib Vaccine Safety Study

To address gaps in traditional postlicensure vaccine safety surveillance and to promote rapid signal identification, new prospective monitoring systems using large health-care database cohorts have been developed. We newly adapted clinical trial group sequential methods to this observational setting in an original safety study of a combination diphtheria and tetanus toxoids and acellular pertussis adsorbed (DTaP), inactivated poliovirus (IPV), and Haemophilus influenzae type b (Hib) conjugate vaccine (DTaP-IPV-Hib) among children within the Vaccine Safety Datalink population. For each prespecified outcome, we conducted 11 sequential Poisson-based likelihood ratio tests during September 2008-January 2011 to compare DTaP-IPV-Hib vaccinees with historical recipients of other DTaP-containing vaccines. No increased risk was detected among 149,337 DTaP-IPV-Hib vaccinees versus historical comparators for any outcome, including medically attended fever, seizure, meningitis/encephalitis/myelitis, nonanaphylactic serious allergic reaction, anaphylaxis, Guillain-Barré syndrome, or invasive Hib disease. In end-of-study prespecified subgroup analyses, risk of medically attended fever was elevated among 1- to 2-year-olds who received DTaP-IPV-Hib vaccine versus historical comparators (relative risk = 1.83, 95% confidence interval: 1.34, 2.50) but not among infants under 1 year old (relative risk = 0.83, 95% confidence interval: 0.73, 0.94). Findings were similar in analyses with concurrent comparators who received other DTaP-containing vaccines during the study period. Although lack of a controlled experiment presents numerous challenges, implementation of group sequential monitoring methods in observational safety surveillance studies is promising and warrants further investigation.

Guillain-Barré Syndrome, Influenza Vaccination, and Antecedent Respiratory and Gastrointestinal Infections: A Case-Centered Analysis in the Vaccine Safety Datalink, 2009–2011

Background Guillain-Barré Syndrome (GBS) can be triggered by gastrointestinal or respiratory infections, including influenza. During the 2009 influenza A (H1N1) pandemic in the United States, monovalent inactivated influenza vaccine (MIV) availability coincided with high rates of wildtype influenza infections. Several prior studies suggested an elevated GBS risk following MIV, but adjustment for antecedent infection was limited. Methods We identified patients enrolled in health plans participating in the Vaccine Safety Datalink and diagnosed with GBS from July 2009 through June 2011. Medical records of GBS cases with 2009–10 MIV, 2010–11 trivalent inactivated influenza vaccine (TIV), and/or a medically-attended respiratory or gastrointestinal infection in the 1 through 141 days prior to GBS diagnosis were reviewed and classified according to Brighton Collaboration criteria for diagnostic certainty. Using a case-centered design, logistic regression models adjusted for patient-level time-varying sources of confounding, including seasonal vaccinations and infections in GBS cases and population-level controls. Results Eighteen confirmed GBS cases received vaccination in the 6 weeks preceding onset, among 1.27 million 2009–10 MIV recipients and 2.80 million 2010–11 TIV recipients. Forty-four confirmed GBS cases had infection in the 6 weeks preceding onset, among 3.77 million patients diagnosed with medically-attended infection. The observed-versus-expected odds that 2009–10 MIV/2010–11 TIV was received in the 6 weeks preceding GBS onset was odds ratiou200a=u200a1.54, 95% confidence interval (CI), 0.59–3.99; risk differenceu200a=u200a0.93 per million doses, 95% CI, −0.71–5.16. The association between GBS and medically-attended infection was: odds ratiou200a=u200a7.73, 95% CI, 3.60–16.61; risk differenceu200a=u200a11.62 per million infected patients, 95% CI, 4.49–26.94. These findings were consistent in sensitivity analyses using alternative infection definitions and risk intervals for prior vaccination shorter than 6 weeks. Conclusions After adjusting for antecedent infections, we found no evidence for an elevated GBS risk following 2009–10 MIV/2010–11 TIV influenza vaccines. However, the association between GBS and antecedent infection was strongly elevated.

Accuracy of influenza vaccination status in a computer-based immunization tracking system of a managed care organization.

Influenza vaccine safety and effectiveness studies conducted using electronic medical records rely on accurate assessment of influenza vaccination status. However, influenza immunization in non-traditional settings (e.g., the workplace) may not be captured in patient immunization tracking systems. We compared influenza vaccination status from electronic records with self-reported vaccination status for five hundred and two 50-79 years olds enrolled in a large managed care organization. Influenza vaccination status in the medical record had a high positive predictive value and specificity (both >99%). The negative predictive value was 80% and sensitivity was 78%. These data suggest that an electronic record of influenza vaccination reliably indicates immunization, while the absence of such a record is only moderately accurate, partly due to vaccines received in non-traditional settings.

Timely detection of localized excess influenza activity in Northern California across patient care, prescription, and laboratory data.

Timely detection of clusters of localized influenza activity in excess of background seasonal levels could improve situational awareness for public health officials and health systems. However, no single data type may capture influenza activity with optimal sensitivity, specificity, and timeliness, and it is unknown which data types could be most useful for surveillance. We compared the performance of 10 types of electronic clinical data for timely detection of influenza clusters throughout the 2007/08 influenza season in northern California. Kaiser Permanente Northern California generated zip code-specific daily episode counts for: influenza-like illness (ILI) diagnoses in ambulatory care (AC) and emergency departments (ED), both with and without regard to fever; hospital admissions and discharges for pneumonia and influenza; antiviral drugs dispensed (Rx); influenza laboratory tests ordered (Tests); and tests positive for influenza type A (FluA) and type B (FluB). Four credible events of localized excess illness were identified. Prospective surveillance was mimicked within each data stream using a space-time permutation scan statistic, analyzing only data available as of each day, to evaluate the ability and timeliness to detect the credible events. AC without fever and Tests signaled during all four events and, along with Rx, had the most timely signals. FluA had less timely signals. ED, hospitalizations, and FluB did not signal reliably. When fever was included in the ILI definition, signals were either delayed or missed. Although limited to one health plan, location, and year, these results can inform the choice of data streams for public health surveillance of influenza.