key: cord-0832019-td1s0t33 authors: Tomkins-Netzer, Oren; Sar, Shaul; Barnett-Griness, Ofra; Friedman, Binyamin; Shyriaieva, Hana; Saliba, Walid title: Association between vaccination with the BNT162b2 mRNA COVID-19 vaccine and non-infectious uveitis: a population-based study date: 2022-05-25 journal: Ophthalmology DOI: 10.1016/j.ophtha.2022.05.015 sha: e5537af2972c135385ba42e2296df461329ac786 doc_id: 832019 cord_uid: td1s0t33 Purpose To assess the association between BNT162b2 mRNA COVID-19 vaccine and the risk of active non-infectious uveitis (NIU). Design A retrospective population-based study Participants 2,602,557 people who received the first vaccine dose between 20 December 2020 and 30 April 2021, and 2,441,719 who received the second vaccine dose between 10 January 2021 and 30 April 2021. Methods Events of active NIU were included if they occurred within 21 days following either vaccine dose. Active NIU was defined as newly active or worsening ocular inflammation requiring initiation or increase in local or systemic corticosteroids. Observed cases were compared to the expected number, based on the experience of the population in 2019. Main outcome measures Age-Gender adjusted standardized incidence ratios (SIRs) and attributable risks (ARs) following BNT126b2 vaccination. Results Overall, 100 and 88 events of active NIU were recorded within 21 days following the first and the second vaccine dose, respectively. Using the experience of the population in 2019 as reference, after the first dose the estimated age-gender adjusted SIR was 1.41 (95% CI, 1.15-1.71) along with a 21-days attributable risk of 1.12 cases per 100,000 vaccinees. Following the second dose, the SIR was 1.31 (95% CI, 1.05-1.62) with an estimated attributable risk of 0.86 cases per 100,000 vaccinees. Anterior uveitis was the most common site of inflammation, occurring in 90.96% of eyes and idiopathic uveitis was the most common etiology (54.08%). Conclusions Our study suggests the BNT162b2 mRNA COVID-19 vaccine might be associated with an increased risk of active NIU. However, considering the small effect size and study limitations this study does not provide proof for cause-and-effect. The small estimated attributable risks suggest that the impact on public health is relatively minor. In many countries two doses of the vaccine and a booster dose are currently 64 recommended for the general population over the age of twelve and two doses for central serous retinopathy, 18 corneal graft rejection, [19] [20] [21] cranial nerve palsies and 71 particularly incident and relapses of uveitis. [22] [23] [24] The majority of uveitis cases are 72 related to anterior uveitis, (though several reports include cases of multiple 73 evanescent white dot syndrome (MEWDS), Vogt-Koyanagi-Harada (VKH) syndrome 74 and idiopathic panuveitis. 10, 17, [25] [26] [27] [28] [29] [30] [31] [32] In all these reports the association to the vaccine 75 is related to temporal proximity and developed between 1-30 days following 76 receiving a vaccine dose. However, it remains unclear whether the vaccine is related 77 to an increase in the incidence of uveitis and whether there are populations at 78 higher risk. 79 In this study we examined a large population-based database of individuals who 80 received the BNT162b2 vaccine and compared the rates of active non-infectious 81 uveitis (NIU) requiring treatment, both to pre and post COVID-19 rates. (Table S1 ) with a concomitant prescription of topical, regional or 122 systemic corticosteroids (Table S2) (Table S1 ). Both cohorts were retrospectively followed for 21 days for active NIU ascertainment. 167 The expected incidence rate of active NIU was estimated based on the experience of 168 the CHS population in 2019 during the same period (January-May) and in 2020 169 between 1 September and 18 December. We used the same criteria for identifying 170 cases among these reference populations as those for the cases following (Table S3) . was used as reference population (Table S4) . (Table 3 ). Our data shows that people with a history of uveitis 245 have a high risk of recurrent active NIU event during the observation period (Table 246 3). Following the first dose the age-gender adjusted SIR for NIU relapse was 1.58 247 (95% CI, 1.20-2.04), which accounted for an AR of 116.94 per 100,000 vaccinees. 248 Following the second dose the age-gender adjusted SIR for NIU relapse was 1.16 249 (95% CI, 0.83-1.57), which accounted for an AR of 31.27 per 100,000 vaccinees 250 ( Table 3 ). The results of subgroup analysis using 2020 as reference population were 251 comparable to the analysis using the 2019 reference population (Table S6) . following treatment for uveitis. Another potential limitation is surveillance bias due 352 to differences in terms of seeking medical care. However, generally active uveitis is 353 symptomatic and therefore it is unlikely that a patient is not seen by a physician, 354 regardless of vaccination status, hence we assume that the influence of this bias is 355 minimal. Although our large sample size allowed us to conduct stratified analysis, 356 adjustment was limited only to age and gender. Hence, residual confounding 357 J o u r n a l P r e -p r o o f remains a major concern of the current study, as we did not control for other risk 358 factors for NIU that might differ between vaccinated subjects and the general 359 population. Based on the limitations inherent in the study design, this study should 360 be considered as a signal detection hypothesis generating study. Furthermore, it is 361 important to note that causality involves much more than temporal association. Safety and Efficacy of the BNT162b2 393 mRNA Covid-19 Vaccine. The New England journal of medicine The BNT162b2 (BioNTech/Pfizer) vaccine had 95% efficacy 396 against COVID-19 ≥7 days after the 2nd dose. Annals of internal medicine Immune responses to two and three doses 399 of the BNT162b2 mRNA vaccine in adults with solid tumors. Nature medicine Safety and Efficacy of the BNT162b2 402 mRNA Covid-19 Vaccine through 6 Months. The New England journal of 403 medicine Syndrome After mRNA COVID-19 Vaccine BNT162b2 Myocarditis after BNT162b2 mRNA Vaccine 408 against Covid-19 in Israel. The New England journal of medicine Myocarditis after Covid-19 Vaccination in a 411 The New England journal of medicine Safety of the BNT162b2 mRNA Covid-414 The New England journal of medicine Safety and immunogenicity of seven 417 COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 418 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, 419 randomised, controlled, phase 2 trial Varicella-zoster virus reactivation 431 causing herpes zoster ophthalmicus (HZO) after SARS-CoV-2 vaccination -432 report of three cases. Journal of ophthalmic inflammation and infection Protection against Covid-19 by 435 The New England journal of medicine Ocular adverse events following vaccination: overview 438 and update. Survey of ophthalmology Vaccine-Associated Posterior Uveitis Vaccine-Associated Uveitis. Missouri medicine Uveitis and Other Ocular 445 Complications Following COVID-19 Vaccination Acute-onset 448 central serous retinopathy after immunization with COVID-19 mRNA vaccine Dual Corneal-Graft Rejection after 452 mRNA Vaccine (BNT162b2) for COVID-19 during the First Six Months State of the Art and Ethical Concerns Keratoplasty Rejection 456 otolaryngology--head & neck surgery Facial nerve palsy 471 following the administration of COVID-19 mRNA vaccines: analysis of a self-472 reporting database UVEITIS AFTER 476 THE BNT162b2 mRNA VACCINATION AGAINST SARS-CoV-2 INFECTION: A 477 Retina (Philadelphia, Pa) Anterior 480 uveitis onset after bnt162b2 vaccination: is this just a coincidence? 481 International journal of infectious diseases : IJID : official publication of the 482 International Society for Infectious Diseases Panuveitis following Vaccination for 485 COVID-19. Ocular immunology and inflammation Bilateral Multifocal Choroiditis following 488 COVID-19 Vaccination Vaccines and Serious Ocular Inflammatory Side Effects: Real or Coincidence? 492 Journal of ophthalmic & vision research Reactivation of Vogt-Koyanagi-Harada disease under NIU-non -infectious uveitis; SIR-Standardized incidence ratio; AR-attributable risk J o u r n a l P r e -p r o o f The BNT162b2 vaccine might be associated with an increase in the incidence of active noninfectious uveitis during the first 21 days after vaccination. However, the effect size is small and does not support a cause and effect.