COVID-19 Vaccine-Associated Ocular Adverse Effects: An Overview

Background: To address the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vaccination efforts were initiated across the globe in December 2020 and are continuing. We report the onset interval and clinical presentations of ocular adverse effects following SARS-CoV-2 vaccination. Methods: For this narrative review, articles in the English language, published between 1 January 2020 to 1 September 2022, were included to formulate a list of the reported ocular adverse effects of different COVID-19 vaccines. Results: During this period, ocular adverse effects have been reported with BNT162b2 (Pfizer), mRNA-1273 (Moderna), AZD-1222 (AstraZeneca), and Ad26.COV2.S (Johnson & Johnson) vaccines. Endothelial graft rejection, herpes simplex virus keratitis, herpes zoster ophthalmicus, anterior uveitis, eyelid edema, purpuric rashes, ischemic optic neuropathy, and cranial nerve palsies were the most reported with BNT163b2. Retinal hemorrhages, vascular occlusions, and angle closure glaucoma were the most reported with AZD-1222. Most of the ocular adverse effects reported in the literature had a good to fair prognosis with appropriate management. Conclusions: Evidence regarding the ocular adverse effects does not outweigh the benefits of SARS-CoV-2 vaccination in patients with pre-existing systemic or ophthalmic diseases. This review provides insights into the possible temporal association between reported ocular adverse events and SARS-CoV-2 vaccines; however, further investigations are required to identify the link between potential causality and pathological mechanisms.


Introduction:
The coronaviruses are positive sense, single-stranded ribonucleic acid (RNA), enveloped medium-sized viruses. Coronaviruses are classified as a family within the order Nidovirales with a spike (S) glycoprotein which mediates receptor binding and cell entry. S protein is the site of the major antigens that stimulate neutralizing antibodies and target cytotoxic lymphocytes, thus making it an important vaccine antigen. Seven different strains of coronaviruses that infect humans include the common cold coronavirus strains; 229E, NL63, OC43, and HKU1 and the more pathogenic strains include Middle East respiratory syndrome (MERS)-CoV, severe acute respiratory syndrome (SARS)-CoV, and SARS-CoV-2. Since the structure and function of pathogenic strains of coronaviruses causing diseases like SARS and MERS were known it helped in the early development of various vaccine platforms across the globe.
A stepwise approach for developing any new vaccine involves vaccine development, clinical trials, U.S. Food and Drug Administration (FDA) approval or authorization, manufacturing, and distribution. The COVID-19 vaccines were developed at an unprecedented pace and were given Emergency Use Authorizations (EUAs) [1]. As of 19 September 2022, a total of 12,640,866,343 vaccine doses have been administered. COVID-19 vaccines and updated/bivalent COVID-19 boosters are effective at protecting people from being hospitalized, serious illness, and death [2].
Currently, 11 COVID-19 vaccines have been approved for EUA, which can be subdivided into four types: mRNA vaccines (BNT162b2, Pfizer-BioNTech14; mRNA-1273, Mod-erna15), protein subunit vaccines (NVX-CoV2373, Novavax16), vector vaccines (Ad26.COV2, Janssen Johnson & Johnson17; ChAdOx1 nCoV-19/AZD1222, Oxford-AstraZeneca18), and whole virus vaccines (PiCoVacc, Sinovac19; BBIBP-CorV, Sinopharm20) ( Table 1) [3]. Individual vaccine trials report vaccine safety with rare ocular adverse effects but given the massive scale of the current vaccination drive, the possible adverse effects are a cause for concern. Since the widespread administration of COVID-19 vaccinations, multiple reports of ocular adverse effects after COVID-19 vaccinations and boosters have emerged [4,5]. To develop methods for closely observing 'at risk' patients, reporting of adverse effects must be conducted on a regular basis. This narrative review summarizes ocular adverse effects that are possibly associated with COVID-19 vaccination. The aim is to encourage early recognition of adverse effects not only by ophthalmologists but also by treating physicians. A literature search was performed in PubMed for 'COVID-19 vaccine', 'ocular inflammation', 'ophthalmic manifestations', 'adverse effects', 'graft failure', 'retinal hemorrhage',  'uveitis', 'neuro-ophthalmology', 'nerve palsy', and 'vascular occlusion'. Articles of interest were searched using Boolean operators. Each synonymous word was separated by a Boolean operator, "OR", phrases were enclosed within quotation marks, and groups of synonymous words were enclosed within parenthesis. Articles in the English language, published between 1 January 2020 to 1 September 2022, were included to formulate the list of the reported ocular adverse effects of different COVID-19 vaccines. The search, although not exhaustive, includes important and relevant articles. Search results were screened by two authors (PI and SD) for relevance. References cited within the identified articles were also used to further augment the search. We characterized our results into an anterior segment, posterior segment, and neurophthalmic adverse effects.

Results
Ocular complications reported post-COVID-19 vaccination included abducens nerve palsy, oculomotor nerve palsy, facial nerve palsy/Bell's palsy, multiple cranial nerve palsies, acute macular neuroretinopathy (AMN), paracentral acute middle maculopathy (PAMM), superior ophthalmic vein thrombosis (SOVT), corneal graft rejection, anterior uveitis, panuveitis, central serous chorioretinopathy(CSCR), Vogt-Koyanagi-Harada (VKH) reactivation, acute zonal occult outer retinopathy (AZOOR) and multifocal choroiditis. The reported ocular adverse effects following vaccination appear to overlap with the ocular manifestations of COVID-19 itself, suggesting a common pathway between virus-and vaccine-mediated immune response in humans. Aggregated information on the reviewed cases is elucidated in Tables 2 and 3.          On re-examining the patient after 3 weeks he reported slight improvement of brightness sensitivity but still complained of black spots in his central field of vision. On examination, his vision was 6/6 in both eyes. His Amsler's grid charting was also normal. The OCT macula revealed a significant reduction in the number and size of the hyperreflective lesions noted in the NFL and GCL. There was also a reduction in the thickness of the outer nuclear layer in OU.

Discussion
A new variant of CoV emerged in Wuhan, China in December 2019 that caused severe respiratory illness. The World Health Organization named this virus SARS-CoV-2 and the pandemic COVID-19. According to Li, Y.-D. [55], to address the global morbidity and mortality caused by COVID-19, the development process of COVID-19 vaccines was expedited by undertaking clinical trials in parallel rather than in a linear fashion. Multiple COVID-19 vaccines directly entered clinical trials on humans without preclinical testing in animal models. The COVID-19 vaccination drive has been carried out worldwide and the evidence is overwhelming that irrespective of the type(s) of vaccine taken, the vaccines offered safety and protection against becoming seriously ill or dying due to the different variants of CoV-2.
The Vaccine Adverse Event Reporting System (VAERS) was developed by the U.S. Food and Drug Administration (FDA) in 1990 as a national early monitoring system for vaccine safety. The commonly reported adverse effects of COVID-19 vaccinations consist of the injection site's local reaction followed by several non-specific flu-like symptoms. However, several systemic and organ-specific (e.g., eye, heart) adverse effects have also been reported from across the globe. Therefore, it is imperative for ophthalmic health care providers to be familiar with the clinical presentations, pathophysiology, diagnostic criteria, and management of ocular adverse effects following COVID-19 vaccination. Early diagnosis and quick initiation of the treatment may help to provide patients with a more favorable outcome and rule out masquerading entities. With an increasing amount of literature in the form of isolated case-study reports, case series, and analysis of the VAERS database, an epidemiological montage has started to emerge [56].
A recent Lancet article questioned the effectiveness of COVID-19 vaccines and the waning of immunity over time, more pronounced in individuals with pre-existing conditions and elderly adults. According to Nordström, P. [57], in addition to the risk of infections owing to lowered immune function, the authors cited a possible risk of some organ damage caused by the vaccine that has remained somewhat sequestered in the circulatory system, without apparent clinical presentations. This can explain the slightly delayed presentation of some of the adverse effects.
Vaccines have added adjuvants within them to boost their efficacy; these adjuvants potentiate the innate and adaptive immune responses further, possibly leading to autoimmune or inflammatory conditions in some individuals. Although truncated and modified RNA traces may be present in BNT162b2 and mRNA-1273 vaccines, these aberrant proteins have a minuscule chance of eliciting allergic reactions. The active constituent of the vaccine is not always the culprit for causing adverse reactions. Excipients such as polyethylene glycol (PEG) used in the BNT162b2 and mRNA-1273 vaccines have been reported to have induced IgE-mediated allergic reactions [3].
Despite reports suggesting an association between ocular adverse effects and the vaccines due to a maladaptive immune response in susceptible individuals, the adverse issues are still considered 'rare' given the millions of people who have received either one or more vaccines or boosters.
The COVID-19 vaccines interact with the platelets or the platelet factor 4 (PF4) and this interaction results in vaccine-induced immune thrombotic thrombocytopenia (VITT). The proposed mechanisms suggest the formation of autoantibodies against PF4, antibodies induced by the free deoxyribonucleic acid (DNA) in the vaccine that cross-reacts with PF4, platelets, and adenovirus binds to the platelets causing platelet activation. VITT may explain vascular occlusions [58].
Endothelial graft rejection, herpes simplex virus (HSV) keratitis, herpes zoster ophthalmicus (HZO), anterior uveitis, eyelid edema, purpuric rashes, ischemic optic neuropathy, and cranial nerve palsies were the most reported with the BNT163b2 vaccine. Although both BNT162b2 and mRNA 1273 are mRNA vaccines, the ocular adverse effects have been relatively lesser with mRNA 1273 than those with BNT162b2.
Retinal hemorrhages (subretinal, subhyaloid, or intraretinal), vascular occlusions, and angle closure glaucoma have been the most reported with the AZD 1222 vaccine. No COVID-19 vaccine-associated adverse events have been reported in patients with age-related macular degeneration in the peer-reviewed literature to date.
The pathophysiological mechanisms underlying vaccine-corneal graft rejection are still poorly understood. However, cases of acute graft rejection have also been reported following influenza, hepatitis B, yellow fever, and tetanus toxoid vaccinations. Steinemann, T.L. and Wertheim, M.S. [59,60] proposed mechanisms for acute corneal allograft rejection include the reduction in the corneal immune privilege due to systemic immune dysregulation and activation of toll-like receptors on the ocular surface and CD4+ T helper-1 cell (Th1) immunity. Corneal edema was the leading clinical manifestation, followed by keratic precipitates in patients with corneal graft rejection. Most of the ocular adverse effects reported in the literature had a good to fair prognosis with appropriate management. Therefore, corneal graft recipients should not be discouraged from receiving COVID-19 vaccines or boosters. Additionally, the evidence is insufficient to suggest delaying keratoplasties or uptitrating topical steroid administration after a routine keratoplasty, following primary COVID vaccine or booster administration. In high-risk cases, increasing immunosuppressants in the peri-vaccination period may decrease the risk of immune reactions [9].
Studies suggest a link between COVID-19 vaccines and the reactivation of the varicellazoster virus (VZV), resulting in vaccine-acquired immunodeficiency syndrome. Data from the works of Barda, N., Desai, H.D. and Seneff, S. [61][62][63] have shown that the population prevalence rates of post-vaccination ophthalmic HSV were ≤0.05 cases per million doses and for HZO were ≤0.5 cases per million doses. According to Wang, M.T.M. [64], there is no conclusive evidence to suggest the need for prophylactic antiviral treatment for patients with prior herpetic eye disease considering COVID-19 vaccination.
Regarding vaccine-associated uveitis (VAU), a recent VAERS review by Singh R B et al. reported a total of 1094 cases from 40 countries with an estimated crude reporting rate (per million doses) of 0.57, 0.44, and 0.35 for BNT162b2, mRNA-1273, and Ad26.COV2.S, respectively. More than two-thirds of cases were reported in patients who received BNT162b2. Additionally, the post hoc analysis showed a significantly shorter interval of onset for the first dose compared with the second dose and BNT162b2 compared with the mRNA 1273 vaccine. According to [65], other vaccines that have also triggered uveitis flare-ups include hepatitis A and B, influenza, Bacillus Calmette-Guérin, human papillomavirus, measles-mumps-rubella (MMR), and varicella zoster vaccines. According to Wang [64], De novo VKH cases can be the result of molecular mimicry between vaccine peptide fragments and uveal self-peptides, whereas, for cases with VKH reactivation, specific HLA haplotypes may account for the individual susceptibility of the autoimmune activation. Many patients who developed ocular adverse effects lacked medical comorbidities that may have predisposed them to the adverse effects, although a few patients were on hormone-based birth control [49,66].
Although clinical trials for all vaccines undergo rigorous safety monitoring prior to authorization for human use, some serious adverse events may not be identified in trials, especially if uncommon, because of the relatively small sample size, the selection of trial participants who may not represent the general population, restrictive eligibility criteria, and limited duration follow-up [67].
The data regarding ocular adverse effects with other approved vaccines, such as ZyCoV-D, Sputnik, Covidecia, Sputnik, Abdala, Zifivax, and Novavax are sparse. Despite the mandatory requirement by all nations to report any vaccine-associated adverse events, unreliable reporting, under-reporting, and/or delayed reporting are common. Additionally, the possibility of anti-vaccination fringe groups attempting to malign vaccines using VAERS data by adding misinformation about the safety of COVID-19 vaccinations must also be remembered.
To conclude, the scientific evidence regarding the ocular adverse effects does not outweigh the benefits of COVID immunization in patients with pre-existing systemic or ophthalmic conditions. However, patients must be counseled to seek prompt medical review for symptoms of post-vaccination deterioration of vision or primary ocular disease relapse.
Funding: This research received no external funding.
Institutional Review Board Statement: Because the study includes publicly available deidentified anonymous data from, the Institute Research Ethics Committee exempted it from ethical review.