Many virus vaccines have been developed and put into practical use, preventing the devastating effects of numerous infectious diseases. On the other hand, adverse reactions to vaccines can sometimes be fatal and should always be taken into consideration. Several vaccines have also been developed for COVID-19, which has been pandemic since 2019. The efficacy of these vaccines has been proven in clinical trials, and vaccination is well underway; however, as the administration in various countries progresses, reports of the appearance of systemic adverse events have emerged, as with other virus vaccines. There have also been reports of ocular diseases, including uveitis, anterior uveitis, macular neuroretinopathy, retinal vascular occlusion, corneal graft rejection, and scleritis [10,11,12]. Most of these reports are case reports or single-center reports, with only a few reports including a large number of cases at multiple centers [13, 14]. Ours is the first report of a multicenter survey of COVID-19 vaccine-associated uveitis in Japan.

In this study, the most common ocular inflammatory disease after COVID-19 vaccination was VKH. VKH was diagnosed according to the Revised Diagnostic Criteria for VKH [15]. The 2 cases shown here were diagnosed on the basis of the typical ocular findings included in the diagnostic criteria, such as serous retinal detachments, choroidal thickening, and fluorescein angiography findings, as well as the presence of cerebrospinal fluid pleocytosis. Two cases reported in the survey form were also described as having VKH-like disease because of their ocular findings, but these cases did not fully meet the diagnostic criteria. One case had no choroidal thickening and the other had no neurologic findings. It is possible that the pathogenetic mechanism of inflammation in vaccine-induced uveitis differs from that of typical uveitis, resulting in different ocular findings. Other reports to date have shown a higher frequency of anterior uveitis. In their multinational case series, Testi and colleagues reported 70 patients with ocular inflammatory events after COVID-19 vaccination [13]. The patients they analyzed experienced the inflammatory events within 14 days of vaccination, as did the patients of our survey. Anterior uveitis was the most common event (n = 41, 58.6%) followed by posterior uveitis (n = 9, 12.9%) and scleritis (n = 7, 10.0%). Bolletta and colleagues reported on 42 eyes of 34 patients with uveitis and other ocular inflammatory complications after COVID-19 vaccination in Italy [14]. Their patients had various types of diseases, such as anterior uveitis (n = 5, 11.9%), retinal vein occlusion (n = 5, 11.9%), herpetic keratitis (n = 3, 7.1%), multiple evanescent white dot syndrome (MEWDS) (n = 3, 7.1%), toxoplasma retinochoroiditis (n = 3, 7.1%), VKH reactivation (n = 2, 4.8%), and anterior scleritis (n = 2, 4.8%). Chen and colleagues reported a case series in Asia in which 10 eyes of 7 patients exhibited ocular complications after vaccination [16]. Unlike in the above-mentioned reports by Testi and colleagues and Bolletta and colleagues, most of the cases in the study by Chen and colleagues were diagnosed with VKH (n = 3, 30.0%), as in our study. A recent epidemiologic survey of uveitis in Japan revealed that sarcoidosis was the most common (10.6%), followed by VKH (8.1%) [17]. The fact that the frequency of VKH (n = 17, 46%) was higher than that of sarcoidosis (n = 1, 3%) in the present survey suggests that the present group of cases was not collected by chance, but a collection of cases due to vaccination and that the pathogenesis of the disease may be similar to that of VKH.

In Japan, the BNT162b2 vaccine (Pfizer-BioNTech), mRNA-1273 vaccine (Moderna), and ChAdOx1-S vaccine (Oxford-AstraZeneca) are currently available. Most people are vaccinated with the BNT162b2 or mRNA-1273 vaccine, which means the majority of vaccinations are of the mRNA-type, and only these 2 vaccines were found to cause adverse reactions of uveitis in this survey. Although the number of cases of uveitis caused by the BNT162b2 vaccine in Japan is high, this may be due to the high rate of vaccination with the BNT162b2 vaccine in Japan, and the difference in the frequency of cases caused by different vaccines is unknown.

Several possible mechanisms of adverse vaccine reactions have been discussed, including reactions to the adjuvants that are added to vaccines to enhance their efficacy. Adjuvants are thought to induce autoimmune reactions in predisposed or genetically susceptible individuals [18]. Other possibilities include molecular similarity of the vaccine peptide to the uveitic peptide [19], but the precise mechanism of uveitis development following COVID-19 vaccination remains unknown.

The main limitation of this study is that it was a retrospective questionnaire survey, making it difficult to prove a definite cause-and-effect relationship between vaccination and the development of uveitis. This study does not provide evidence that vaccination was associated with the onset of ocular inflammatory events. However, because the vaccination rate in Japan is already over 80%, it would be difficult to conduct a prospective study with a nonvaccinated control group. In addition, in the present study, cases in which symptoms developed within 14 days of vaccination were included as vaccine-related uveitis, but there may also have been cases in which vaccination-related symptoms developed more than 14 days after vaccination, making it difficult to determine the exact incidence of the disease. Finally, because the main objective of this study was to determine the frequency of vaccine-related cases and to provide patients and health care providers with information on the symptoms that may occur in patients with postvaccination uveitis, we did not analyze whether the frequency of onset differs depending on the presence or absence of underlying disease or whether there is a difference in response to treatment or prognosis compared with nonvaccine-related uveitis. Further detailed investigations on these issues are needed.

In this survey, we reported on the actual onset and characteristics of ocular inflammatory events following vaccination in a multicenter study. Although vaccination is the most effective means of avoiding severe symptoms caused by COVID-19, it should be kept in mind that vaccination can sometimes cause ocular side effects, including ocular inflammatory events.