Vaccines have been reported to induce ocular side effects, including conjunctival and eyelid reactions, optic neuritis and intraocular inflammation [21,22,23,24,25]. Furthermore, live attenuated vaccines may cause ocular infection from the organisms derived, especially in at-risk groups, including the immunosuppressed [26, 27]. The adjuvants included in COVID-19 mRNA vaccines stimulate innate immunity through endosolic or cytoplasmic nucleic acid receptors including Toll-like receptors (TLRs) . Several autoimmune diseases, particularly connective tissues diseases, are associated with an altered nucleic acid metabolism and processing, which may trigger an immune response following immunization [29, 30]. Given the scale of the current vaccination campaign against COVID-19, acute and chronic inflammatory responses have been observed . These include myocarditis , kidney transplant rejection  and vaccine-induced thrombotic thrombocytopenia (VITT) . While cases of uveitis triggered or re-activated by SARS-CoV-2 have been described, there is a lack of literature describing possible failure of immune privilege or maladaptive immunity in response to COVID-19 vaccination in some susceptible individuals .
To date, there are numerous published and unpublished reports of ocular inflammation potentially associated with COVID-19 vaccination (Table 1). The COVID-19 vaccines include the mRNA vaccine (BNT162b2, Pfizer-BioNTech; mRNA-1273, Moderna), protein subunit vaccine (NVX-CoV2373, Novavax), vector vaccine (Ad26COVS1, Janssen Johnson & Johnson; AZD1222, Oxford-AstraZeneca) and whole virus (PiCoVacc, Sinovac; BBIBP-CorV, Sinopharm). In order of frequency of cases reported, where 'n' is the combined total number of subjects in the relevant studies for each category, the ocular complications reported were Bell's/facial nerve palsy (n = 30), central venous sinus thrombosis and thrombosis (n = 15), acute anterior uveitis (n = 9), acute macular neuroretinopathy (n = 8), corneal graft rejection (n = 6), anterior scleritis (n = 5), panuveitis (n = 4), posterior uveitis (n = 3), cranial nerve palsy (excluding Bell's/facial nerve palsy) (n = 1), central serous chorioretinopathy (n = 1), Vogt-Koyanagi-Harada disease (n = 2), central retinal vein occlusion (n = 1), bilateral multifocal choroiditis (n = 1), episcleritis (n = 1), intermediate uveitis (n = 1), paracentral acute middle maculopathy (n = 1), subretinal fluid (n = 1) and bilateral optic neuritis (n = 1), in a total of 89 subjects (Fig. 1). The reported entities appear to overlap with the ocular manifestation reported in patients infected with COVID-19, suggesting a common pathway (possibly TLR) between virus and vaccine-mediated immune response in humans. In addition, there are several unpublished reports of patients with uveitis post-COVID-19 vaccination. We will briefly describe some of the adverse effects reported following COVID-19 vaccination below.
Bell's/Facial Nerve Palsy
One study, part of the clinical trials for the BNT162b2 and mRNA-1273 vaccines, found a higher incidence of Bell's palsy in subjects receiving the vaccine (n = 7) than in those receiving placebo (n = 1) . The time to the onset of symptoms was not mentioned. A case-control study found that in 21 patients against 44 unvaccinated controls who presented with facial nerve palsy and had received the BNT162b2 vaccine (first or second dose) 30 days prior, there was no significant difference in the occurrence of facial nerve palsy . However, both studies did not include any details on ocular manifestations or ophthalmic investigations, nor did they provide visual outcomes of the patients. Another case report by Ish et al. reported a middle-aged male who developed facial nerve palsy 3 weeks after receiving the second dose of COVAXIN . He was treated with a tapering dose of oral prednisolone at 1 mg/kg for 2 weeks with improvement of presentation on review at day 10.
Superior Ophthalmic Vein Thrombosis
There is a published report of two patients with bilateral thrombosis of the superior ophthalmic vein in addition to rare cases of cerebral venous sinus thrombosis and vaccine-induced immune thrombocytopenia with consequential orbital symptoms and signs of inflammation [39,40,41]. Investigations performed to confirm thrombosis include computed tomography (CT), angiography of the head and neck and magnetic resonance imaging (MRI) of the brain. Of the 15 subjects with thrombosis reported in these three studies, 4 presented with ocular symptoms including conjunctival congestion, fixed and dilated pupil, gaze deviation, diplopia, retroorbital pain and unspecified visual changes. All four were female; two had additional risk factors for thrombosis, including obesity, hypothyroidism and oral contraceptive pill (OCP) usage. The subjects manifested symptoms between 6 and 17 days post-vaccination. Subjects received either the AZD1222 or Ad26COVS1 vaccines. Of note, the Ad26COVS1 was designed as a single-dose vaccine. None included detailed ophthalmic investigations, treatment, or visual outcomes of the subjects.
Acute Anterior Uveitis
Our local authors (unpublished data) reported seven cases of acute anterior non-granulomatous uveitis post-vaccination. Symptom onset ranged from 1 day to 1 month after receiving the first or second dose of the BNT162b2 or mRNA-1273 vaccine. Similarly, El Sheikh et al. reported one cases of acute uveitis following vaccination with the BBIBP-CorV vaccine . The female subject presented 5 days following the second dose of the vaccine with acute onset of bilateral blurred vision and photophobia and was diagnosed with juvenile idiopathic arthritis (JIA)-associated anterior uveitis that responded to topical corticosteroid treatment.
Acute Macular Neuroretinopathy (AMN)
Four female subjects presented with scotomas. All were on oral contraceptive pills (OCP) and manifested symptoms 2 days after the first dose of the vaccine [43,44,45]. Three reported fever, and one reported flu-like symptoms prior to the appearance of the scotoma. In two patients, the visual symptoms lasted < 24 h. On OCT, hyperreflectivity of the outer nuclear and plexiform layers was seen along with disruption of the ellipsoid zone. Subtle capillary dropout was also noted on angiography. All subjects received the AZD1222 vaccine. In another case report, Valenzuela et al. reported a case of a young female subject who presented with bilateral scotoma and photopsia 48 h after receiving the second dose of the BNT162b2 vaccine . The subject was using an etonogestrel/ethinyl estradiol 0.12–0.015 mg/24 h vaginal ring for birth control. OCT demonstrated parafoveal foci of hyperreflectivity of the outer nuclear layer and granularity of the ellipsoid. Her symptoms resolved completely a week later.
Corneal Graft Rejection
There were two reported cases of allograft rejection following Descemet’s membrane endothelial keratoplasty (DMEK); both were female and had had grafts performed 21 days and 6 years before vaccine administration . With a notable history of well-controlled human immunodeficiency virus infection with undetectable viral load, one subject manifested symptoms 7 days after the first dose of the vaccine. The other patient developed symptoms 3 weeks after the second dose. For both DMEK cases, slit-lamp examination and anterior optical coherence tomography (OCT) revealed moderate conjunctival injection, diffuse corneal edema and fine keratic precipitates limited to the donor endothelium with anterior chamber cells. Rejections were also reported following three penetrating keratoplasty (PKP) cases; all three were male; 1 case had a previous re-graft. Two of the PKP rejections manifested 13–14 days after the patients received the first dose of the vaccine, while the third occurred after 21 days, also from the first dose [48, 49]. The two DMEK and two of the three PKP rejections were treated successfully with oral and topical corticosteroids. Vaccines received by the subjects included the BNT162b2 and AZD1222 vaccines. In addition, Rallis et al. reported a case of a 68-year-old female subject who presented with left eye corneal graft failure 4 days after receiving the first dose of the BNT162b2 vaccine . She had a history of bilateral Descemet stripping automated endothelial keratoplasty (DSAEK) for Fuchs’ corneal endothelial dystrophy and a left repeat penetrating keratoplasty (PKP) for failed DSAEK in October 2020. Slit-lamp examination revealed conjunctival hyperemia, corneal graft edema, diffuse corneal punctate staining, Descemet’s folds, scattered keratic precipitates and anterior chamber activity. Her right eye graft remained healthy. She was treated with intensive topical corticosteroids to her left eye and oral acyclovir to cover any underlying herpetic keratitis. Graft rejection resolved completely 3 weeks post-treatment.
Several cases of post-vaccination anterior scleritis have been reported. From our unpublished data, there have been three cases of diffuse anterior non-necrotizing anterior uveitis in female subjects 1 to 4 days after receiving the second dose of BNT162b2. The subjects’ symptomatic decrease in visual acuity resolved after receiving topical corticosteroids and additional oral NSAIDs in one subject. Pichi et al. reported two cases of anterior scleritis after receiving the BBIBP-CorV vaccine . One patient presented with pain and redness in both eyes 1 week after receiving a dose of the vaccine, which resolved after a tapering dose of topical steroids.
Several case reports were identified. The first case was of a male patient with a prior SARS-COV-2 infection several months earlier who developed transient visual field loss 3 days after a first dose of BNT162b2 . The visual acuity deficit lasted less than a day and was associated with perceived reduction of visual fields, a unilateral headache, nausea, asthenia and mild confusion. There was no further investigation. The second case concerned a female subject who on examination was found to have panuveitis . She developed symptoms 3 days after the second dose. She underwent weekly nasopharyngeal swab tests for COVID-19 infection as part of her occupation’s routine required testing, of which only one was positive, with subsequent tests being negative. She neither manifested any symptoms of COVID-19 nor had a history of exposure to COVID-19 patients. Her vision of 20/500 in both eyes improved to 20/20 on a tapering dose of systemic corticosteroids, starting at 50 mg/day of oral prednisone and 2 hourly difluprednate lasting 3 weeks. At the end of 3 weeks, there was recurrence of choroidal thickening, and systemic corticosteroid therapy was recommenced at the time of publication. OCT was performed, which showed vitreous debris and retinal and choroidal thickening. Fluorescein angiography (FA) revealed mild peripheral vascular leakage. MRI brain and orbits with contrast were unremarkable. Both subjects had received the BNT162b2 vaccine.
Two female subjects presented to a local institution in Singapore (unpublished data) with posterior uveitis 3–6 weeks after receiving the second dose of BNT162b2. One subject presented with a scotoma and photopsia in the left eye while the other was found to have retinal dysfunction and papillitis. Their symptoms resolved upon receiving corticosteroids. One male patient also presented with decreased visual acuity 7 days after receiving the first dose of mRNA-1273, which was diagnosed as posterior uveitis. His symptoms resolved after the administration of oral and topical corticosteroids.
Cranial Nerve Palsy (Excluding Bell's/Facial Nerve Palsy)
A healthy female who received the BNT162b2 vaccine and presented with isolated abducens nerve palsy 2 days post-vaccination was reported . No details on the persistence of the palsy were provided in the report. Examinations of the patient through slit-lamp, fundus examination and MRI brain and orbits without contrast were unremarkable.
Central Serous Retinopathy
Sixty-nine hours after receiving the first dose of the BNT162b2 vaccine, a 33-year-old male subject with a previous history of mild refractive hyperopic refractive error presented with blurring of vision and metamorphopsia and was subsequently diagnosed with central serous retinopathy . Fundus examination revealed loss of foveal reflex and a swollen macula without hemorrhage. Further investigations such as imaging were performed. OCT revealed macular serous detachment of the neurosensory retina. In the area of serous retinal detachment, OCT angiography showed general attenuation of choriocapillaris flow signal while FA showed point leakage. After a course of spironolactone, all the patients’ symptoms resolved on follow-up.
A female patient with a 6-year history of well-controlled VKH presented with a severe reactivation of VKH 6 weeks after receiving the second dose of the BNT162b2 vaccine. The initial onset of her VKH had been severe, which necessitated infliximab infusions as acute and maintenance therapy. Prior to the vaccinations, the patient had received infliximab infusions 3.5 weeks before the first vaccine dose and 7.5 weeks before the second vaccine dose . Slit-lamp examination revealed anterior chamber inflammation with mutton-fat keratic precipitates. Furthermore, retinal folds, subretinal fluid and increased choroidal thickness were seen on OCT imaging. After the initiation of oral corticosteroids and infliximab therapy, the VKH disease reactivation was controlled. In a separate report, a 54-year-old male patient with no history of ocular disease presented with acute bilateral painless blurring of vision a week after receiving the first dose of the BNT162b2 vaccine. Clinical examination and imaging investigations were consistent with and led to the diagnosis of Vogt-Koyanagi-Harada disease. After an initial course of high-dose intravenous methylprednisolone and subsequent oral prednisolone, the patient’s symptoms resolved .
Central Retinal Vein Occlusion
Bialasiewicz et al. reported a case of central retinal vein occlusion post-vaccination in an otherwise previously healthy 50-year-old male patient . During the 15-min surveillance period after receiving the second dose of BNT162b2, the patient developed retrobulbar pain, red eye and decreased vision in his left eye, which was eventually found to be caused by a central retinal vein occlusion. Investigations that were done, such as a thrombophilia panel, complete blood count and D-dimer levels, were unremarkable.
Bilateral Multifocal Choroiditis
Goyal et al. reported a case of bilateral choroiditis in a 34-year-old male patient post-vaccination . One week after the second dose of AZD1222, the patient presented with severe vision loss of his right eye. Examination revealed a large serous detachment of the macula of the right eye. Additionally, ultrasonographic evaluation showed choroidal thickening in both eyes. After completing a 2-week course of oral corticosteroids, the patient made complete visual recovery.
Pichi et al. reported a case of episcleritis in a patient who had previously received the BBIBP-CorV vaccine. However, further details of the case were not reported .
Our authors have seen a case of intermediate uveitis in a 50-year-old female patient following vaccination. Nine days after receiving the first dose of BNT162b2, the patient experienced an exacerbation of her existing intermediate uveitis complicated by cystoid macular edema.
Paracentral Acute Middle Maculopathy
A case of paracentral acute middle maculopathy was reported by Pichi et al. . Twenty minutes after receiving the BBIBP-CorV vaccine, the patient had developed tachycardia, raised systolic blood pressure and an inferior scotoma of the left eye. Fundus examination revealed a dot hemorrhage superior to the fovea, and OCT angiography revealed superior enlargement of the foveal avascular zone.
Pichi et al. reported a case of subretinal fluid in a patient who had previously received the BBIBP-CorV vaccine. However, further details of the case were not reported .
Bilateral Optic Neuritis
A case of acute thyroiditis and bilateral optic neuritis following vaccination was reported by Leber et al. . Twelve hours after receiving the second dose of PiCoVacc, a 32-year-old female experienced rapidly progressive decreased visual acuity, pain on movement of the left eye and headache. Furthermore, the patient experienced loss of temporal visual field of the left eye. Best corrected visual acuity was found to be 20/200 in the left eye, while this was preserved at 20/20 in the right eye. Fundus examination revealed bilateral disc swelling that was more prominent in the left eye. Subsequent work-up for raised intracranial pressure, demyelinating disease, intracranial infection and inflammatory disease was unremarkable. The patient was then diagnosed with vaccination-related bilateral optic neuritis and treated with intravenous corticosteroids, with subsequent improvement in visual acuity.
Two cases of Graves' disease (GD) post-vaccination were reported. One patient had a past medical history of a prior COVID-19 infection and pulmonary arterial hypertension. Both patients received the first dose of the BNT162b2 vaccine and reported their symptoms 2 to 3 days after and were subsequently diagnosed with Graves’ disease . Biochemical studies including thyrotropin (TSH), thyroxine and triiodothyronine, antithyroid peroxidase, antithyroglobulin, anti-TSH and anti-TSH antibodies were performed, and the tests indicated active GD. The study did not include any description of ocular symptoms or ophthalmic investigations. Both patients’ presentations fit the diagnostic criteria for autoimmune/inflammatory syndrome induced by adjuvants (ASIA), which is also known as Shoenfeld's syndrome[28, 60].