Vaccines were manufactured to protect from SARS-CoV-2, the virus causing COVID-19. While vaccines can induce large quantities of high affinity virus-neutralizing antibodies to prevent infection, they haven’t been able to avoid untoward side effects. Vaccination trials required detailed clinical management, complemented with precise evaluation of immune responses and safety. Since the introduction of COVID-19 vaccinations, there have been numerous reports on the adverse ocular events following vaccination Here, we reviewed the ocular inflammatory manifestations of different vaccines in patients who presented with de novo and recurrent ocular inflammation following vaccination against SARS-CoV-2.

Possible pathological mechanisms responsible for autoimmune responses in SARS-CoV-2 infected patients include molecular mimicry, bystander activation, epitope spreading, cryptic antigen presentation, B-cell polyclonal activation and the existence of the superantigens have been suggested as possible pathological mechanisms behind autoimmune responses in SARS-CoV-2 infected patients [6, 7]. Either of these mechanisms might have resulted in recurrence of inflammation in our cases.

Uveitis and other ocular inflammatory events have been described following vaccinations for Bacille-Calmette- Guerin (BCG), hepatitis B virus (HBV), hepatitis A virus (HAV), varicella virus, human papillomavirus (HPV), influenza virus, measles-mumps-rubella (MMR), yellow fever, and typhoid [8,9,10,11,12,13,14,15]. Furthermore, various ocular adverse events have also been reported after COVID-19 vaccination.

Although the precise pathogenesis frequently remains unclear, different mechanisms have been hypothesized including changes in adaptive and innate immune system. Both arms of the immune system may be influenced by adjuvants via various mechanisms including the activation of.

Toll-like receptors, Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) etc., leading to downstream in cytokines generation. Moreover, the heightened adaptive immune response to antigen can occur following the activation of antigen presenting cells [16,17,18]. Other mechanisms include the direct infection by the attenuated but active virus strain and inflammation induced by one or more adjuvants (such as aluminum salts), routinely used in inactivated or subunit/conjugate vaccines [16, 19]. Patients with a personal or history of autoimmune disease may develop auto-inflammation or autoimmune conditions induced by adjuvants, known as Shoenfeld syndrome. [16, 20].

Testi I et al. reported a multinational case series of 70 patients diagnosed with inflammatory adverse events following COVID-19 vaccination from 40 centres over a 3-month period [21]. They found the mean age as 51 years (range 19–84 years). Most common events noted were anterior uveitis (58.6%) followed by posterior uveitis 12.9% and the mean time to adverse event was 5 days after the first vaccine and 6 days following the second dose of vaccine.

Rabinovitch et al. described 21 cases of uveitis following the administration of the BNT162b2 mRNA vaccine in Israel, of which nineteen (90.5%) were diagnosed with anterior uveitis [22]. Pichi et al. reported seven patients diagnosed with acute macular neuroretinopathy (AMN) (2), paracentral acute middle maculopathy (PAMM) (1) subretinal fluid (1), episcleritis (1), and anterior scleritis (2) following soon after receiving a dose of inactivated COVID-19 vaccination (Sinopharm) [23].

Bolletta E et al. reported 34 patients with uveitis and other ocular complications following COVID-19 vaccination. With a mean age of 49.8 years (range 18–83 years). Mean time between vaccination and the onset of ocular complication was 9.4 days (range 1–30 days) [24]. Pang et al. reported 12 eyes of 9 cases of ocular adverse events following administration of inactivated COVID-19 vaccines, although the causal relationship could not be established in the study [25]. The mean (SD) age was 44.7 ± 16.5 years (range, 19– 78 years), with 77.8% female cases. The mean time of ocular adverse events was 7.1 days (range, 1–14 days) after receiving the inactivated COVID-19 vaccine. They described patients with choroiditis, optic disc vasculitis with sunset glow fundus, keratitis, scleritis, acute retinal necrosis and anterior uveitis [25].

Studies have reported ocular inflammation following most of the vaccines administered worldwide including Pfizer-BioNTech vaccination (BNT162b2 mRNA), Oxford-AstraZeneca vaccine (ChAdOx1 nCoV-19) which is similar to Covishield available in India, ModernaTX vaccination (mRNA-1273), and Janssen Johnson & Johnson vaccine (Ad26.COV2) [25]. It is difficult comment on the comparative immunogenicity and safety of different vaccines due to the geographical distribution bias of vaccinations administered. Nevertheless, systemic and local side-effects after BNT162b2 and ChAdOx1 nCoV-19 vaccination that were studied prospectively using an app in the UK showed that the frequencies were lower than reported in phase 3 trials [26].

Episcleritis and scleritis have also been reported in patients within a mean of 5 days following the first dose of the inactivated COVID-19 vaccine (Sinopharm) [24, 25]. Renisi et al. reported a case of anterior uveitis 14 days after the second dose of Pfizer–BioNTech COVID-19 vaccine [27]. One case of a 18-year-old female with a history of antinuclear antibody (ANA) positive oligoarticular juvenile idiopathic arthritis (JIA) developing bilateral anterior uveitis 5 days after the second dose of BBIBP-CorV has been reported [28]. We also had a 19-year old patient with previously quiescent inflammation with JIA associated uveitis that recurred following both doses of vaccination. Increased IFN-I secretion by vaccine-induced immunological responses could potentially generate autoimmune manifestations in patients with a history of systemic autoimmunity disease has been the proposed hypothesis in such cases [24, 28, 29].

Vaccines can result in the reactivation of varicella zoster virus (VZV), has been previously described in patients receiving vaccines for rabies, hepatitis A, influenza, and Japanese encephalitis [30]. There are cases reported in the literature describing VZV reactivation after vaccination with the mRNA COVID-19 vaccine, including cases with herpes zoster ophthalmicus (HZO) [31,32,33,34]. We have reported a case of acute retinal necrosis in a 71 year male following COVISHIELD vaccination due to VZV reactivation [35].

Although unclear, the proposed hypothesis of stimulation of the immune system that induces a strong T-cell response following vaccination. This can lead to an increased CD8 + T cell and T helper type 1 CD4 + T cell population with relatively low VZV-specific CD8 + cells, that further allows VZV to escape its latent phase. Abrogation in TLR expression among vaccinated individuals is another possible explanation that has been linked with marked induction of type I interferon (IFN-I) and potentiation of pro-inflammatory cytokines. This may negatively modulate antigen expression and potentially contribute to VZV reactivation [33]. Bolletta E et al. reported two cases of herpes keratitis reactivation in patients with a history of previous herpetic keratouveitis although under systemic antiviral treatment [24]. There has also been a speculation regarding the preventive role of antiviral treatment in patients with prior history of herpes [34].

Recurrence of Toxoplasma retinochoroiditis have been described due to vaccination-induced CD8 T-cell exhaustion that may lead to parasite reactivation [25, 36], however, we did not have any cases of toxoplasmosis in our study. Arora A et al. described two patients with recurrence of tubercular choroiditis 2–6 weeks following the first dose of Covishield vaccine. As both their patients had unilateral recurrence, they were managed with intravitreal injection dexamethasone (0.7 mg) (Ozurdex®, Allergan, Inc., Irvine, CA, USA) [37]. We had three patients with tubercular uveitis, one each with de novo intermediate uveitis, de novo serpiginous like choroiditis and recurrence of sclerouveitis.

We found a majority of HLA B27 related uveitis (60%) among the non-infective uveitis cases in our study. All 100% of these patients had developed a recurrence of their previous quiescent inflammation. There have been similar reports of vaccine triggered inflammation in HLA B27 positive cases by other authors [21, 24]. Furer V et al. reported mRNA BNTb262 vaccine as immunogenic in majority of patients with autoimmune inflammatory rheumatic diseases. Factors responsible for reduced immunogenicity included those on treatment with glucocorticoids, rituximab, MMF, and abatacept [38].

Other autoimmune pathologies included reactivation of inflammation in 6 patients with sarcoidosis and one patient with VKH. However, there were 3 patients with first episode of VKH within the study period. Dysregulation of the immune system and other immunological mechanisms may play a significant role in the association between VKH disease and COVID-19 vaccination [39,40,41].

Papasavvas I. and Herbort CP. also have reported a case of VKH disease which was completely under control for 6 years and on infliximab maintenance therapy that was reactivated 6 weeks after the second dose of the Pfizer vaccine administration [42]. Saraceno JJF et described a case of a 62-year-old healthy female who developed complete Vogt-Koyanagi-Harada (VKH) Syndrome 4 days after a dose of ChAdOx1 nCoV-19 (AZD1222) vaccine [43]. There have also been reports of exaggeration of VKH disease following Covid-19 vaccination where the close temporal relationship between the vaccine dose and the worsening of symptoms strongly suggested COVID-19 vaccination as the trigger of its exacerbation [44].

Concerning post-vaccination thrombosis, there are reports of central retinal vein occlusion, branch retinal vein occlusions and superior ophthalmic vein thrombosis [24, 45,46,47,48]. In addition to major blood vessel occlusions, there are also reports of capillary plexus occlusions including cases with AMN following Covid-19 vaccination [49,50,51,52]. Similarly, Bohler AD et al. reported a case of AMN in a young woman who was taking combined estrogen–progestin oral contraceptives 2 days after ChAdOx1 nCoV-19 vaccination [44]. We also report here a 25-year-old female patient who developed bilateral sequential AMN following both doses of vaccine [53].

A recently reported retrospective study assessed the risk of vaccine associated uveitis (VAU) following SARS-CoV-2 vaccination in 1094 cases from 40 countries [54]. They found most cases were reported in patients who received Pfizer-BioNTech vaccine. The mean age of patients with VAU was 46.24 ± 16.93 years, and majority were women (68.65%) Most cases were reported after the first dose (41.32%) and within the first week (54.02%) of the vaccination.

The major limitation of this study was its retrospective design. Other limitations include a relatively low number of cases, single tertiary referral centre bias and a limited period study. There is growing evidence in literature about the ocular complications following COVID- 19 vaccination, although a definitive association has been difficult to demonstrate.

Inflammatory ocular manifestation in the anterior and posterior segments may be seen in following COVID-19 vaccine. Considering the growing number of COVID-19 vaccinations and the commencement of booster vaccines, increasing number of ocular inflammatory adverse effects may be seen from the various available vaccines. Even if causality remains presumed, caution must be warranted among physicians about the possibility of ocular inflammation following SARS-CoV-2 vaccination.