Incidence of Guillain-Barré Syndrome After COVID-19 Vaccination in the Vaccine Safety Datalink

IMPORTANCE Postauthorization monitoring of vaccines in a large population may detect rare adverse events not identified in clinical trials such as Guillain-Barré syndrome (GBS), which has a background rate of 1 to 2 per 100000 person-years. OBJECTIVE To describe cases and incidence of GBS following COVID-19 vaccination and assess the risk of GBS after vaccination for Ad.26.COV2.S (Janssen) and mRNA vaccines. DESIGN, SETTING, AND PARTICIPANTS This cohort study used surveillance data from the Vaccine Safety Datalink at 8 participating integrated health care systems in the United States. There were 10158003 participants aged at least 12 years. Data analysis was performed from November 2021 to February 2022.


Introduction
2][3] BNT162b2 and mRNA-1273 are both messenger RNA (mRNA) vaccines and administered as 2-dose primary series, whereas Ad.26.COV2.S is a replication-incompetent adenoviral vector vaccine and administered as a single dose primary series.mRNA vaccines were authorized for use in adults in December 2020, and use of BNT162b2 was expanded to adolescents in May 2021.Ad.26.COV2.S was authorized for use in adults on February 27, 2021; however, use of Ad.26.COV2.S was temporarily paused in mid-April 2021 due to concerns about a rare condition called thrombosis with thrombocytopenia syndrome (TTS) that was reported after Ad.26.COV2.S vaccination. 4In July 2021, data from the Vaccine Adverse Event Reporting System (VAERS) indicated that the reporting rate of Guillain-Barré syndrome (GBS), a rare neurological disorder, was higher after Ad.26.COV2.S than after mRNA vaccines. 5The Food and Drug Administration subsequently added a warning about GBS to the Ad.26.COV2.S vaccine fact sheet.
On December 16, 2021, the Advisory Committee on Immunization Practices made a preferential recommendation for use of mRNA vaccines over Ad.26.COV2.S as the benefit-risk balance was determined to be more favorable for mRNA vaccines than Ad.26.COV2.S, in part due to safety concerns regarding GBS and TTS after Ad.26.COV2.S. 6 Postauthorization monitoring of vaccines in a large population can detect rare adverse events not identified in clinical trials.GBS is being monitored in the Vaccine Safety Datalink as part of ongoing rapid and prospective COVID-19 vaccine safety surveillance efforts. 7Our objectives for this study were to (1) describe GBS cases and incidence following COVID-19 vaccinations from December 13, 2020, through November 13, 2021, and (2) assess the risk of GBS after vaccination for Ad.26.COV2.S and mRNA vaccines.

Setting and Population
Since December 2020, the Vaccine Safety Datalink has been conducting safety surveillance of COVID-19 vaccines, monitoring GBS and 22 other prespecified, serious outcomes after COVID-19 vaccines on a weekly basis.Methods are described in the study protocol and in a prior publication that includes interim results for mRNA vaccines. 7,11Weekly analyses compared outcome incidence observed during a risk interval after vaccination (eg, 1-21 days after Ad.26.COV2.S) with outcome incidence expected.Analyses were conducted separately by vaccine type.The expected was derived from 1 of 2 types of comparators: (1) similar vaccinated persons who were concurrently (on the same calendar day) in a postvaccination comparison interval following the same vaccine type (eg, 22-42 days after Ad.26.COV2.S) (vaccinated concurrent comparators), and (2) similar persons who were concurrently (on the same calendar day) unvaccinated (ie, had not received any doses of COVID-19 vaccine) (unvaccinated concurrent comparators), where similar means comparators were of the same age group, sex, race or ethnicity, and site as the vaccine recipient.Race and ethnicity data were captured in Vaccine Safety Datalink files in fixed categories based on self-reported data from the participating sites.Race and ethnicity data were used to adjust for confounding that may have arisen if the factor was associated with vaccination dates and outcome events.By protocol, vaccinated concurrent comparators were considered primary and unvaccinated concurrent comparators were considered supplemental owing to concerns about possible bias from unmeasured differences between vaccinated and unvaccinated individuals.This surveillance approach used 2 postvaccination risk intervals, 1 to 21 days and 1 to 42 days, with corresponding postvaccination comparison intervals for vaccinated concurrent comparator analyses, 22 to 42 days and 43 to 84 days, respectively.The 1 to 21-day risk interval allowed for timelier analyses and avoids bias introduced from the short interval between doses for mRNA vaccines.However, a 1 to 42-day risk interval was also used, because this interval is often used in vaccine safety studies of GBS and other outcomes. 12Individuals who received 2 doses of an mRNA vaccine contributed to analyses of mRNA vaccines when they were 1 to 21 (or 1 to 42) days after dose 1 and again when they were 1 to 21 (or 1 to 42) days after dose 2. However, receipt of dose 2 resulted in censoring of follow-up time after dose 1, therefore most comparison time in the vaccinated concurrent comparator analyses was after dose 2.
We reported on data through November 13, 2021, including descriptive characteristics of COVID-19 vaccine recipients and GBS cases, weekly analyses of GBS with vaccinated and unvaccinated concurrent comparators (previously described) for Ad.26.COV2.S and mRNA vaccines, and additional GBS analyses including comparisons of the incidence of GBS postvaccination by vaccine type to the incidence expected from prior studies, evaluation of the temporal clustering of GBS cases following Ad.26.COV2.S, and head-to-head comparisons of GBS incidence after Ad.26.COV2.S with GBS incidence after mRNA vaccination.
Potential cases of GBS were identified among Vaccine Safety Datalink members aged at least 12 years using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) code G61.0 in the emergency department or inpatient setting, specifically when G61.0 first appeared in an individual's record in the 1 to 84 days after dose 1 or dose 2 of an mRNA vaccine or after dose 1 of Ad.26.COV2.S.Because disease onset may begin before a diagnosis is recorded in the medical record, potential cases with the ICD-10 code in the 85 to 98 days postvaccination were also reviewed.After review, all cases underwent adjudication according to the Brighton Collaboration criteria. 13Briefly, GBS cases meeting Brighton level 1 had the highest level of diagnostic certainty, whereas level 4 included cases of suspected GBS (ie, insufficient information was available in the medical record to meet Brighton level 1-3).In this analysis, we considered Brighton level 1 to level 4 cases as confirmed and sensitivity analyses were conducted excluding level 4 cases.Cases of GBS among unvaccinated concurrent comparators were identified by applying the same algorithm to unvaccinated members of the Vaccine Safety Datalink population during the period of interest.Unvaccinated comparators did not undergo medical record review and adjudication.

JAMA Network Open | Infectious Diseases
Incidence of Guillain-Barré Syndrome After COVID-19 Vaccination in the Vaccine Safety Datalink

Statistical Analysis
As previously described, 7 primary weekly monitoring of GBS after each type of COVID-19 vaccine used conditional Poisson regression to compare individuals during a postvaccination risk interval with similar individuals who had been vaccinated earlier and were concurrently in a comparison interval.These analyses estimated rate ratios (ie, ratios of incidence rates in a risk interval divided by incidence rates in a comparison interval) that were adjusted for 5-year age group, sex, race and ethnicity, site, and calendar day by conditioning the Poisson regression on strata (risk sets) defined by these factors.Similarly, conditional Poisson regression was used in supplementary weekly analyses to compare individuals in a postvaccination risk interval with similar individuals who were concurrently unvaccinated.One-sided sequential testing was conducted weekly for vaccinated concurrent comparator analyses, with a signaling threshold of P < .0048(prespecified to keep the overall chance of making a type I error below .05during 2 years of weekly analyses).
Although our primary weekly analyses of GBS have not met the criterion for a safety signal, concerns about GBS after Ad.26.COV2.S arose from supplementary analyses with unvaccinated comparators and from reports to VAERS.To further investigate we conducted additional analyses.
We computed unadjusted incidence rates and 95% CIs of confirmed GBS in the 1 to 21 days and 1 to 42 days following COVID-19 vaccination per 100 000 person-years (PY) by vaccine type and used exact Poisson regression to compare observed incidence rates to the historical background rate of GBS (2 per 100 000 PY). 14,15 We also examined the temporal clustering of the GBS cases within 56 days of Ad.26.COV2.S by day of symptom onset, using a scan statistic. 16Lastly, we conducted headto-head comparisons of the 21-day and 42-day risk intervals after Ad.26.COV2.S vs the 21-day and 42-day risk intervals after mRNA vaccination, using conditional Poisson regression to estimate rate ratios (ie, the ratio of GBS incidence after Ad.26.COV2.S divided by GBS incidence after mRNA vaccination), adjusted for age group, sex, race and ethnicity, site, and calendar day as described above.All analyses of mRNA vaccines combined both products (BNT162b2 and mRNA-1273) and primary series doses (1 and 2) to increase statistical power.Analyses were 2-sided with a .05level of significance unless otherwise specified and were conducted using SAS version 9.4 (SAS Institute) from November 2021 to February 2022.

JAMA Network Open | Infectious Diseases
Incidence of Guillain-Barré Syndrome After COVID-19 Vaccination in the Vaccine Safety Datalink symptom onset in the 43 to 84 days postvaccination (Figure A).Scan statistics identified days 1 to 14 after vaccination as a statistically significant cluster (P = .003).Ten patients were hospitalized (91%) and all were treated with intravenous immune globulin.Patients with confirmed GBS after Ad.26.COV2.S had a mean (range) age of 50 (32-63) years, 9 (82%) were male, 10 (91%) were  A, Bars represent the number of confirmed cases of GBS after Ad.26.COV2.S vaccination (N = 11).The x-axis denotes the numbers of days between Ad.26.COV2.S vaccination and GBS symptom onset.The 84-day follow-up period has elapsed for all Ad.26.COV2.S vaccinations.A statistically significant cluster was identified from days 1 to 14 after Ad.26.COV2.S vaccination using scan statistics (P = .003). 16 Bars represent the number of confirmed cases of GBS after mRNA vaccination (N = 36).The x-axis denotes the numbers of days between most recent mRNA vaccination and GBS symptom onset.The 84-day follow-up period has elapsed for all mRNA vaccinations.
non-Hispanic White, and 10 (91%) had facial weakness or paralysis in addition to bilateral weakness or paralysis of the limbs (Table 2).
The unadjusted incidence rate of confirmed cases of GBS per 100 000 PY was 32.4 (95% CI,

GBS After mRNA Vaccines
During the 1 to 84 days after first and second doses of mRNA vaccines, 78 potential cases of GBS were identified: all were reviewed and adjudicated, and 36 (46%) were confirmed, including 23 after BNT162b2 and 13 after mRNA-1273.Patients with confirmed GBS after mRNA vaccines had a mean (range) age of 53 (14-92) years (Table 2) and symptom onset ranged from 0 to 84 days after vaccination (Figure B).Eleven cases (31%) had symptom onset in the 1 to 21 days postvaccination, 15 cases (42%) had symptom onset in the 22 to 42 days postvaccination, and 9 cases (25%) had symptom onset in the 43 to 84 days postvaccination.One case had symptom onset on the same day as mRNA vaccination (day 0) and was excluded from analyses.
The unadjusted incidence rate of confirmed cases of GBS per 100 000 PY in the 21 days after mRNA vaccines was 1.3 (95% CI, 0.7-2.4) and did not differ from the background rate of GBS (P = .20)(Table 3).Results were similar when excluding Brighton level 4 cases and when using a 42-day risk window, with incidence rates ranging from 1.1 to 2.0 cases of GBS per 100 000 PY.

Discussion
In this cohort study's interim analyses conducted in a large population-based surveillance system that included medical record review of all potential GBS cases after COVID-19 vaccination through November 13, 2021, findings were consistent with an increased risk of GBS after Ad.26.COV2.S.The incidence of GBS in the 21 days after Ad.26.COV2.S was 32.4 per 100 000 person-years, which was substantially greater than the expected background rate of 1 to 2 per 100 000 person-years. 14,15GBS incidence in the 21 days after mRNA vaccination was 1.3 per 100 000 person-years, similar to the overall expected background rate.In an adjusted head-to-head comparison, GBS incidence during the 21 days after Ad.26.COV2.S was 20.6 times higher than the GBS incidence during the 21 days after mRNA vaccination, amounting to 15.5 excess cases per million Ad.26.COV2.S vaccine recipients.The majority of cases of GBS after Ad.26.COV2.S occurred during the 1 to 21-day risk interval, with the period of most increased risk in the 1 to 14 days after Ad.26.COV2.S.
None of the primary analyses conducted in routine weekly safety surveillance of GBS after Ad.26.COV2.S met the criterion for a safety signal.However, these analyses had low power not only because the uptake of Ad.26.COV2.S was low, but also because Ad.26.COV2.S uptake was concentrated in a brief calendar period, meaning that relatively few vaccinated concurrent comparators were available while vaccine recipients were in their risk interval.The rate ratio estimate in the primary analyses of the 21-day risk interval after Ad.26.COV2.S had a very wide confidence interval extending from less than 1.0 to greater than 100; the CI was narrower for the corresponding Abbreviations: CSF, cerebrospinal fluid; EMG, electromyography; GBS, Guillain-Barré syndrome; ICU, intensive care unit; IVIG, intravenous immune globulin.
a Percentages may not add to 100% due to rounding.
b 53 cases were not confirmed after medical record review and adjudication, including 11 cases after Ad.26.COV2.S and 42 cases after mRNA vaccination.Reasons included history of GBS with no new or worsening symptoms (n = 19), GBS ruled out (n = 13), case did not meet Brighton criteria for GBS or Miller-Fisher syndrome (Brighton Level 5) (n = 12), no evidence that GBS was diagnosed on or around the automated diagnosis date in the medical record (n = 4), GBS symptom onset prior to COVID-19 vaccination (n = 3), history of chronic inflammatory demyelinating polyneuropathy (CIDP) with no new or worsening symptoms (n = 1), and indeterminate symptom onset (n = 1).
c Race and ethnicity categories were collapsed owing to the small number of cases observed.Other/unknown includes all persons with non-Hispanic ethnicity and from minoritized racial and ethnic groups, as well as those who identified as multiracial or had unknown race and ethnicity.
d Medical records were reviewed to determine if the patient received any non-COVID-19 vaccines in the 2 months prior to GBS diagnosis.
e Medical records were reviewed to determine if the patient had a gastrointestinal or respiratory illness (including COVID-19) in the 2 months prior to GBS symptom onset.Confirmatory laboratory testing was not required.
f Test not performed for all patients; number with test performed is shown in brackets and percentage in parenthesis is calculated out of those with test performed.
g Elevated protein defined as greater than laboratory reference, which is greater than 45 mg/dL at most laboratories.
h Elevated white blood cells defined as greater than or equal to 50 cells/μL.
i Hospital length of stay is not available for 1 case after Ad.26.COV2.S because they were treated in the emergency department and not admitted to the hospital.
j Outcome was assessed at the time of medical record review, which was typically around 30 days after their initial diagnosis.
k Both cases after mRNA vaccination that were noted as deceased at the time of medical record review were greater than 80 years of age and had multiple underlying health conditions.Cause of death was unknown for one individual, although they were noted to have been admitted to hospice care for bladder cancer.For the other individual cause of death was multiorgan failure with GBS listed as one of several contributory factors.
l Cases were adjudicated according to the Brighton Collaboration criteria. 13Briefly, levels 1 to 3 meet the Brighton case definition for GBS, with level 1 the highest level of diagnostic certainty, and level 4 are suspected cases (diagnosed as GBS but insufficient evidence to meet the Brighton case definition).Cases adjudicated as Brighton levels 1 to 4 were considered confirmed.
supplemental analyses, ranging from 5 to 20.Because our primary analyses for GBS after Ad.26.COV2.S were less powerful than our supplementary analyses (as evidenced by wider CIs), we gave more consideration to supplemental analyses, consistent with the study protocol.
Nevertheless, results of supplemental analyses should be interpreted with caution because of concerns about unmeasured differences between vaccinated and unvaccinated individuals, and because cases of GBS in unvaccinated comparators did not undergo medical record review and adjudication.
Our finding of an elevated risk of GBS after Ad.26.COV2.S was consistent with an observed-toexpected analysis in VAERS which found that the GBS reporting rate after Ad.26.COV2.S exceeded the background rate. 17Our analyses also included GBS cases confirmed by medical record review and adjudication, and thus provide validation of the preliminary VAERS findings based on presumptive GBS.
Interestingly, nearly all patients with GBS after Ad.26.COV2.S identified in this surveillance had facial weakness or paralysis, in addition to weakness and decreased reflexes in the limbs.Reports describing cases of GBS following Ad.26.COV2.S and ChAdOx1 (AstraZeneca) COVID-19 vaccine, another adenoviral vector vaccine used outside of the US, have also noted a preponderance of cases with unilateral or bilateral facial weakness or plegia, [18][19][20][21] with some suggesting that the presentation of GBS after COVID-19 adenoviral vector vaccine may be novel.However, a study in the United Kingdom did not find a significant difference in presence of unilateral or bilateral facial weakness between those with GBS onset in the 42 days after COVID-19 vaccination (majority first doses of ChAdOx1) and those with GBS onset more than 42 days after COVID-19 vaccination or those with GBS onset during the same period that were not vaccinated. 22More research is needed to determine if the presentation of GBS after adenoviral vector vaccine differs from GBS after other exposures such Abbreviations: BL, Brighton level; GBS, Guillain-Barré syndrome.
a Sensitivity analyses were conducted excluding Brighton level 4 cases (suspected cases).
b Follow-up time after dose 1 of either mRNA vaccine was censored after receipt of dose 2.
c The background rate of GBS is 1 to 2 per 100 000 person-years. 14,15Exact Poisson regression was used to compare the observed number of GBS cases with the expected number of cases, which was derived from a background rate of 2 per 100 000 person-years and the observed number of person-years.Abbreviations: GBS, Guillain-Barré syndrome; RR, rate ratio.
a Not all confirmed cases of GBS after mRNA vaccination are included in this analysis, such as cases that occurred prior to the authorization of Ad.26.COV2.S.
b Adjusted for 5-year age group, sex, race and ethnicity, site, and calendar day.
as Campylobacter jejuni, and to investigate the mechanism for how adenoviral vector vaccines may cause GBS.
In contrast to Ad.26.COV2.S, the unadjusted incidence rates of GBS in the 1 to 21 days and 1 to 42 days after mRNA vaccines were similar to the published background rate. 14,15In weekly analyses, the incidence of GBS following mRNA vaccination was also not significantly higher in the 1 to 21 days postvaccination compared with 22 to 42 days postvaccination, a finding consistent with similar results reported through June 22, 2021, from this same surveillance. 7These updated results provide further evidence that mRNA vaccines do not appear to be associated with GBS.

Limitations
This study had several limitations.First, as mentioned previously, substantially fewer doses of Ad.26.COV2.S were administered relative to mRNA vaccines, resulting in reduced statistical power and wide confidence intervals for some analyses.Second, in this observational study recipients of Ad.26.COV2.S may have differed from recipients of mRNA vaccines in unknown ways that affect GBS risk but were not adjusted for in analyses.Third, the incidence rate of confirmed GBS during the COVID-19 pandemic has not been established, and may differ from prepandemic background rates.
Fourth, we could not identify subgroups who may be at greatest risk for GBS after Ad.26.COV2.S given the small number of confirmed GBS cases identified in this surveillance.Fifth, this analysis only included GBS cases after primary COVID-19 vaccination and results may not be generalizable to additional or booster doses.

Conclusions
In this interim analysis of surveillance data of COVID-19 vaccines, findings were consistent with an elevated risk of GBS after primary Ad.26.COV2.S vaccination.No difference in GBS risk was found for mRNA vaccines.Surveillance is ongoing.

Table 1 .
COVID-19 Vaccine Doses According to Characteristics of the Vaccine Recipient a Percentages may not add to 100% due to rounding.bIncludes 8 806 595 doses of BNT162b2 and 5 830 425 doses of mRNA-1273.cEight combined race and ethnicity categories were created from available race and ethnicity information.Persons were classified as Hispanic or Latino if categorized as having Hispanic or Latino ethnicity, regardless of whether or not race was known.Persons with more than 1 non-Hispanic race or ethnicity and all other non-Hispanic races and ethnicities were classified as Multiple/Other.Persons were classified as having unknown race and ethnicity if both race and ethnicity were missing.

Table 3 .
Incidence Rate of Confirmed GBS in the 1 to 21 Days and 1 to 42 Days After COVID-19 Vaccination

Table 4 .
Head-to-Head Comparisons of Confirmed GBS Incidence After Ad.26.COV2.S vs mRNA Vaccination