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 (preprint)

Background Case reports of Guillain Barre 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.

Post-marketing active surveillance of myocarditis and pericarditis following vaccination with COVID-19 mRNA vaccines in persons aged 12-39 years in Italy: a multi-database, self-controlled case series study (preprint)

Objectives To investigate the association between SARS-CoV-2 mRNA vaccines, BNT162b2 and mRNA-1273, and myocarditis/pericarditis. Design Self-Controlled Case Series study (SCCS) using national data on COVID-19 vaccination and emergency care/hospital admissions. Setting Italian Regions (Lombardia, Friuli Venezia Giulia, Veneto, Lazio). Participants 2,861,809 individuals, aged 12-39 years, vaccinated with the first doses of mRNA vaccines (2,405,759 BNT162b2 and 456,050 mRNA-1273) between 27 December 2020 and 30 September 2021. Main outcome measures First diagnosis of myocarditis/pericarditis within the study period. The incidence of events in the exposure risk periods (0-21 days from the vaccination day, subdivided in three equal intervals) for first and second dose was compared with baseline period. The SCCS model was fitted using conditional Poisson regression to estimate Relative Incidences (RI) and Excess of Cases (EC) per 100,000 vaccinated by dose, age, gender and brand. Results During the study period, 441 participants aged 12-39 years developed myocarditis/pericarditis (346 BNT162b2 and 95 mRNA-1273). During the 21-day risk interval there were 114 cases of myocarditis/pericarditis (74 BNT162b2 and 40 mRNA-1273) corresponding to a RI of 1.27 (0.87-1.85) and 2.16 (1.50-3.10) after first and second dose, respectively. An increased risk of myocarditis/pericarditis at (0-7) days was observed after first [RI=6.55; 95% Confidence Interval (2.73-15.72); EC per 100,000 vaccinated=2.0 (1.5-2.3)] and second dose [RI=7.59 (3.26-17.65); EC=5.5 (4.4-5.9)] of mRNA-1273 and after second dose of BNT162b2 [RI=3.39 (2.02-5.68); EC=0.8 (0.6-1.0)]. In males, an increased risk at (0-7) days was observed after first [RI=12.28, 4.09-36.83; EC=3.8 (3.1-4.0)] and second dose [RI=11.91 (3.88-36.53); EC=8.8 (7.2-9.4)] of mRNA-1273 and after second dose of BNT162b2 [RI=3.45 (1.78-6.68); EC=1.0 (0.6-1.2)]. In females, an increased risk at (0-7) days was observed after second dose of BNT162b2 [RI=3.38 (1.47-7.74); EC=0.7 (0.3-0.9)]. At (0-7) days an increased risk following second dose of BNT162b2 was observed in the 12-17 years old [RI=5.74, (1.52-21.72); EC=1.7 (0.7-1.9)] and in 18-29 years old [RI=4.02 (1.81-8.91); EC=1.1 (0.6-1.3)]. At (0-7) days an increased risk after first [RI=7.58 (2.62-21.94); EC=3.5 (2.4-3.8)] and second [RI=9.58 (3.32-27.58); EC=8.3 (6.7-9.2)] dose of mRNA-1273 was found in 18-29 years old and after first dose in 30-39 years old [RI=6.57 (1.32-32.63); EC=1.0 (0.3-1.1)]. Conclusions This population-based study indicates that mRNA vaccines were associated with myocarditis/pericarditis in the population younger than 40 years, whereas no association was observed in older subjects. The risk increased after the second dose and in the youngest for both vaccines, remained moderate following vaccination with BNT162b2, while was higher in males following vaccination with mRNA-1273. The public health implication of these findings should be weighed in the light of the overall efficacy and safety profile of both vaccines.

Survival of hospitalized COVID-19 patients in Northern Italy: a population-based cohort study by the ITA-COVID19 Network (preprint)

BackgroundCOVID-19 case fatality rate in hospitalized patients varies across countries and studies, but reliable estimates specific for age, sex, and comorbidities are needed to design trials for COVID-19 interventions. Aim of this study is to provide population-based survival curves of hospitalized COVID-19 patients. MethodsA cohort study was conducted in Lombardy, Veneto, and Reggio Emilia using COVID-19 registries linked to hospital discharge databases containing patient clinical histories. All patients with positive SARS-CoV-2 RT-PCR test on oral/nasopharyngeal swabs hospitalized from 21st February to 21st April 2020 were identified. Kaplan Meier survival estimates were calculated at 14 and 30 days for death in any setting, stratifying by age, sex and Charlson Index. FindingsOverall, 42,926 hospitalized COVID-19 patients were identified. Patients median age was 69 years (IQR: 57-79), 62{middle dot}6% were males, 69{middle dot}4% had a Charlson Index of 0. In total, 11,205 (26{middle dot}1%) patients died over a median follow-up of 24 days (IQR: 10-35). Survival curves showed that 22{middle dot}0% of patients died within 14 days and 27{middle dot}6% within 30 days of hospitalization. Survival was higher in younger patients and in females. Younger patients with comorbidities had a lower survival than older ones with comorbidities. InterpretationOver 27% of hospitalized COVID-19 patients died within one month in three areas of Northern Italy that were heavily affected by SARS-CoV-2 infection. Such a high fatality rate suggests that trials should focus on survival and have follow-up of at least one month. FundingThe study did not receive any external funding. Research in contextEvidence before this study Two recent systematic reviews with meta-analyses report case fatality rates of three to four percent in COVID-19 patients. Most studies on hospitalized cohorts report only slightly higher figures. These figures do not correspond to those derived from routinely collected clinical data in most European countries, reporting a 10% case fatality rate which has been increasing over time since the epidemic started. Robust and precise survival estimates of hospitalized COVID-19 patients which take into account prognostic factors such as age, sex and burden of comorbidities are needed to design appropriate phase II and phase III clinical studies of drugs targeting COVID-19. Added value of this studyIn this study we present the first survival estimates by age, sex and Charlson index for a large population-based cohort of Italian hospitalized COVID-19 patients. Implications of all the available evidenceOver 27% of COVID-19 patients died within one month from hospital admission. Such a high fatality rate suggests that studies should prioritize mortality as primary outcome. Furthermore, we found that the fatality rate reaches a plateau 30 days after hospitalization, suggesting that studies should have at least one month of follow up to observe deaths; shorter follow-up could lead to overestimation of treatment benefits.