Guillain-Barré Syndrome After High-Dose Influenza Vaccine Administration in the United States, 2018-2019 Season.

BACKGROUND: The Vaccine Safety Datalink (VSD) identified a statistical signal for an increased risk of Guillain-Barré syndrome (GBS) in days 1-42 after 2018-2019 high-dose influenza vaccine (IIV3-HD) administration. We evaluated the signal using Medicare. METHODS: We conducted early- and end-of-season claims-based self-controlled risk interval analyses among Medicare beneficiaries ages ≥65 years, using days 8-21 and 1-42 postvaccination as risk windows and days 43-84 as control window. The VSD conducted chart-confirmed analyses. RESULTS: Among 7 453 690 IIV3-HD vaccinations, we did not detect a statistically significant increased GBS risk for either the 8- to 21-day (odds ratio [OR], 1.85; 95% confidence interval [CI], 0.99-3.44) or 1- to 42-day (OR, 1.31; 95% CI, 0.78-2.18) risk windows. The findings from the end-of-season analyses were fully consistent with the early-season analyses for both the 8- to 21-day (OR, 1.64; 95% CI, 0.92-2.91) and 1- to 42-day (OR, 1.12; 95% CI, 0.70-1.79) risk windows. The VSD's chart-confirmed analysis, involving 646 996 IIV3-HD vaccinations, with 1 case each in the risk and control windows, yielded a relative risk of 1.00 (95% CI, 0.06-15.99). CONCLUSIONS: The Medicare analyses did not exclude an association between IIV3-HD and GBS, but it determined that, if such a risk existed, it was similar in magnitude to prior seasons. Chart-confirmed VSD results did not confirm an increased risk of GBS.

A simulation study of the statistical power and signaling characteristics of an early season sequential test for influenza vaccine safety.

PURPOSE: The US Food and Drug Administration monitors the risk of Guillain-Barré syndrome (GBS) following influenza vaccination using several data sources including Medicare. In the 2017 to 2018 season, we transitioned our near real-time surveillance in Medicare to more effectively detect large GBS risk increases early in the season while avoiding false positives. METHODS: We conducted a simulation study examining the ability of the updating sequential probability ratio test (USPRT) to detect substantially elevated GBS risk in the 8- to 21-day postvaccination versus 5× to 30× the historical rate. We varied the first testing week (weeks 5-8) and the null rate (1×-3×) and evaluated power. We estimated signal probability and the risk ratio (RR) after signaling when high-risk seasons were rare. RESULTS: Applying fixed alternatives, we found >80% power to detect a risk 30× the historical rate in week 5 for the 1× null and in week 6 for the 1.5× to 3× nulls. Nearly all testing schedules had >80% power for a 5× risk by week 11. To test the robustness of USPRT, we further simulated seasons where 1% were true high-risk seasons. Using a 1× null led to 10% of seasons signaling by week 11 (median RR approximately 1.4), which decreased to approximately 1% with the ≥2.5× null (median RR approximately 16.0). CONCLUSIONS: On the basis of the results from this simulation and subsequent consultations with experts and stakeholders, we specified USPRT to test continuously from weeks 7 to 11 using the null hypothesis that the observed GBS rate was 2.5× the historical rate. This helped improve the ability of USPRT to provide early detection of GBS risk following influenza vaccination as part of a multilayered system of surveillance.