Post-marketing active surveillance of Guillan Barré Syndrome following vaccination with anti-COVID-19 vaccines in persons aged ≥12 years in Italy: a multi-database self-controlled case series study

Background Case reports of Guillain Barrè syndrome (GBS) following the Coronavirus Disease 2019 (COVID-19) vaccines administration have been reported. This study investigated the risk of GBS after vaccination with anti-COVID-19 vaccines (BNT162b2/Tozinameran; mRNA-1273/Elasomeran, ChAdOx1-S and Ad26.COV2-S) in the population aged ≥12 years in Italy. Methods We conducted a self-controlled case series study (SCCS) using national data on COVID-19 vaccination linked to emergency care/hospital discharge databases. The outcome was the first diagnosis of GBS between 27 December 2020 and 30 September 2021. Exposure risk period were days 0 (vaccination day) through 42 days following each of the 2 vaccine doses. The remaining periods were considered as non at risk (baseline) period. The SCCS model, adapted to event-dependent exposures, was fitted using unbiased estimating equations to estimate relative incidences (RIs) and excess of cases (EC) per 100,000 vaccinated by dose and vaccine product. Calendar period was included as time-varying confounder in the model. Results The study included 15,986,009 persons who received at least one dose of Covid-19 vaccine. During the 42-day risk interval there were a total of 67 cases of GBS after the first dose and 41 cases after the second dose. In the 42-day risk interval, increased risks were observed after the administration of first dose (RI=6.83; 95% CI 2.14-21.85) and second dose (RI=7.41; 95% CI 2.35-23.38) for mRNA-1273 vaccine, corresponding to 0.4 and 0.3 EC per 100,000 vaccinated, respectively. Increased risk was also observed after the first dose of ChAdOx1-S vaccine (RI=6.52; 95% CI 2.88-14.77), corresponding to 1.0 EC per 100,000 vaccinated. There was no evidence of increased risk of GBS after vaccination with BNT162b2 and Ad26.COV2-S vaccines. In the subgroup analysis by sex an increased risk of GBS was observed among both males and females after mRNA-1273 vaccine. in males an increased risk was observed after the first dose, with a borderline significance (RI=5.26; 95% CI 0.94-29.42; p=0.06) and the second dose (RI=16.50; 95% CI 3.01-90.56) and in females after the first dose (RI=13.44; 95% CI 2.83-63.80). There was also evidence of an increased risk after a first dose of ChAdOx1-S in males (RI=4.94; 95% CI 1.84-13.28) and females (RI=7.14; 95% CI 1.94-26.19). In the subgroup analysis by age, there was evidence of an increased risk of GBS with mRNA-1273 vaccine among those aged ≥60 years after the first (RI=8.03; 95% CI 2.08-31.03) and second dose (RI=7.71; 95% CI 2.38-24.97). After a first dose of ChAdOx1-S there was evidence of an increased risk of GBS in those aged 40-59 (RI=4.50; 95% CI 1.37-14.79) and in those aged ≥60 years (RI=6.84; 95% CI 2.56-18.28). There was no evidence of increased risk of GBS after vaccination with BNT162b2 and Ad26.COV2-S vaccines in the subgroup analysis by age and sex. Study limitations include that the outcome was not validated through review of clinical records, the possibility of time-dependent residual confounding and the imprecision of the obtained estimates in the subgroup analysis due to the very low number of events. Conclusions It is important the continuous monitoring of the suspected adverse events of the COVID-19 vaccines as key component of any vaccination program. Results from this large SCCS study showed an increased risk of GBS after first and second dose of mRNA-1273 and first dose of ChAdOx1-S. However, these findings were compatible with a small number of EC. Our data are reassuring regarding BNT162b and Ad26.COV2-S vaccines with respect to GBS outcome. No increased risk of GBS was detected following each of BNT162b vaccine dose nor any increased risk after Ad26.COV2-S vaccine dose. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement The Istituto Superiore di Sanità received funding from AIFA (Italian Medicines Agency) [www.aifa.gov.it][1] for this study in the framework of the collaboration agreement Efficacia real world e sicurezza dei vaccini anti Covid-19: studio di coorte e Self-Controlled Case Series (Effectiveness and safety of COVID-19 vaccines: cohort and Self-Controlled Case Series studies). AIFA is the Italian national regulatory body for drugs and vaccines and a public organization. All authors are independent from the funder. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the National Unique Ethics Committee for the evaluation of clinical trials of medicines for human use and medical devices for patients with COVID 19 of the National Institute for Infectious Diseases Lazzaro Spallanzani in Rome (ordinance n. 335, 17/05/2021 and n. 399, 02/09/2021). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data cannot be shared publicly under article 9 of Regulation (EU) 2016/679. Data are available from the Data Protection Officer of Istituto Superiore di Sanità Dott. Carlo Villanacci, email: responsabile.protezionedati{at}iss.it, for researchers who meet the criteria for access to confidential data. [1]: http://www.aifa.gov.it