photophobia; reactive meningitis secondary to the COVID-19 vaccine; This is a literature-spontaneous report. The reporter reported the same event for 2 patients ,this is second of 2 reports. Patient Age: 52 years, Gender: Female COVID-19 vaccine - Photophobia, a symptom of various conditions Summary  Photophobia is defined as an abnormal light sensitivity. It can occur as a symptom of various conditions such as migraine headaches or ophthalmic inflammations (e.g.: conjunctivitis). During a signal detection activity focussing on the novel COVID-19 vaccines performed by the withheld in the WHO global database of individual case safety reports (ICSRs), Agency, photophobia was observed to be disproportionately frequently reported in association with COVID-19 vaccines, primarily with the mRNA-based Pfizer/BioNTech vaccine. Neither photophobia nor its potential causes are described as adverse events following the immunization with the novel COVID-19 vaccines. However, some potential underlying causes of photophobia are accepted among the range of reactions following these vaccines. Since several of the photophobia-causing conditions are potentially serious and require adequate medical treatment, patients and healthcare professionals should be sensitised in order to take appropriate measures as needed. The current assessment presents relevant case reports' examples and discusses potential underlying mechanisms. Introduction COVID-19 vaccines As of 31 March 2021, globally eight vaccines have been authorised to prevent infections with the coronavirus SARS- COV-2, known as COVID-19. The authorised vaccines use different, and sometimes new, vaccine platforms, as summarised .  Up to 31Mar2021 Agency, the WHO database of individual case safety reports (CSRs) contained 1,988,580 reports including a vaccine as suspected. Twenty percent (n = 394,350) of those concerned the COVID-19 vaccines.  Photophobia Photophobia is defined as an abnormal sensitivity to light. Conditions associated with photophobia can be classified anatomically: anterior segment and posterior segment disorders, and intracranial conditions (eg.: optic neuritis, meningitis, and migraine)". Reports in Agency Photophobia Up to 31Mar2021, Agency, the WHO database of individual case safety reports (ICSRs), contained 1,247 unique cases, from 34 countries reporting the term photophobia following vaccination against COVID-19 with the mRNA-based Pfizer/BioNTech and Moderna vaccines, and the adenovirus vector vaccines from AstraZeneca and Johnson&Johnson portionate reporting for the MedDRA preferred term "photophobia" was observed with a calculated expected number of reports of 319 compared to the observed number of 1,247 reports (resulting in an information component of 1.9). The expected value is based on the total number of reports fonthe coViD-19 vaccines and the proportion of all son photophobia in Agency, as Information on the vaccine do was In 551 cases the reaction was reported to have occurred after the first dose and in 60 cases after the second. Information on the time-to-onset (TTO) was available in 806 cases with a median of 0 days (ranging from 0 to 118 days). TTO was observed be slightly shorter after the first dose (median = 0 days, ranging from 0 to 33 days) compared to the second dose (median = 1 day, ranging from 0 to 29 days). When divided by platform, information on TTO was available in 227 cases for the vector vaccines (225 cases reporting photophobia after the first dose, and two cases reporting its onset after the second dose), and in 75 cases for the mRNA-based vaccines (43 cases reporting the onset after 32 after the second). Median TTO was observed to be zero days (range 0-19 days) after the first dose and one and a half days (range 0-3 days) after the second dose for the vector-based vaccines, compared to a median TTO of one day (range 0-33 days) after the first dose as well as one day (range 0-29 days) after the second dose for the mRNA-based vaccines. first dose and constituted a mere 140% and in 2% the gender was not reported. When comparing patients' characteristics of these reports to all 394,350 reports including the COVID-19 vaccines as suspected in Agency some substantial differences can be observed in 75% of all COVID-19 vaccine reports the affected patients are female, 23% are male, and for 2.2% patients' sex is unspecified. Patients' age was reported in 1,175 cases, resulting in a median age of 41 years (ranging from 16 to 90 years). This is in line with patients' age when looking at all reports for COVID-19 vaccines in Agency. Forty percent of the patients are observed in the age group between 18 and 44 years, followed by 45 to 64 year old patients (37%). A high proportion of reports was classified as serious (n=689; 55%). Most serious reports concerned the AstraZeneca vaccine as suspected (n=618; 90%). Of those, 586 reports (95%) were sent from the withheld. Five hundred-fifty-nine (91%) of the serious reports were classified as "other medically important condition" (AstraZeneca n=466; 83%), 131 reports (21%) as "disabling/incapacitating" (AstraZeneca n=104; 79%), 58 (9.3%) as "caused/prolonged hospitalisation" (AstraZeneca n=33; 57%), 13 (2.1%) as "life threatening" (AstraZeneca n=9 (69%), Pfizer/BioNTech n=4 (31%)) and six reports (1.0%) as "fatal" (100% AstraZeneca). In none of the serious cases photophobia was the only reported event. Important co-reported terms in the life-threatening and fatal cases were thrombocytopenia, cerebral haemorrhage, and cerebral venous sinus thrombosis (CVST). One fatal report was found to be a duplicate, resulting in five serious fatal reports. Cause of death was reported to be CVST in two cases, myocardial infantion in one case, intracerebral haemorrhage in another, and unexplained in the remaining case. In that case the patient was reported to have suffered from a new onset immune thrombocytopenia purpura following the vaccination before passing away after being unsuccessfully treated with intravenous immunoglobulins. Co-reported terms in the life-threateningcases were CVST (n=1), anaphylaxis (n=2), seizure (n=1), syncope (n=1), and Guillain-Barré syndrome in combination with acute disseminated encephalomyelitis (n=1). For brevity we focussed on the co-reported terms in these two seriousness categories. Descriptions of co-reported terms for the remaining serious cases can be made available upon request. In the 404 non-serious cases reporting self-limiting conditions (outcome "recovered", "recovered with sequelae", or "recovering"), the majority (n=199; 49%) reported photophobia in combination with typical vaccination-associated reactions, such as myalgia, arthralgia, and pyrexia, 245 cases (61%) included headache as a co-reported term, in 19 cases (4.7%) influenza like illness was included, and in 59 cases (15%) photophobia was reported in combination with vaccination site reactions.  Photophobia with migraine headaches Up to 31Mar2021, Agency contained 6,939 ICSRs reporting migraine and related terms (Agency high level term "Migraine headaches") in combination with the active ingredient "COVID-19 vaccine". One hundred and fifty-three of those that included photophobia as co-reported term. Affected patients were mainly female (n-143; 93%) and the median age was 38 years (range 18 to 80 years). Ninety-four of the 153 reports (61%) were classified as serious indicating "Other medically important condition" (n=78), "Disabling/incapacitating" (n-25), and "Caused/prolonged hospitalization" (n=6) as seriousness criterial Thirty-three of these patients suffered from underlying migraines. Several patients suffering from chronic migraines stated that the reported episode was more intense than usual or that they had not suffered from migraine attacks for long periods before receiving the vaccine. In several cases the migraine headaches were so intense that they woke the patients up in the middle of the night. In most cases the headaches resolved with pharmacotherapy. Photophobia with meningitis Up to 31Mar2021, Agency contained 24 ICSRs reporting meningitis following COVID-19 vaccination, two of those cases additionally included the preferred term photophobia (one duplicate report was excluded). The affected patients were females aged 42 and 52 years old. The suspected vaccines were the AstraZeneca's and Pfizer- BioNTech's, respectively. One patient had suffered from two episodes of viral meningitis in the past. In the second, a reactive meningitis secondary to the COVID-19 vaccine was diagnosed. In both cases the outcome of the event was reported as unknown or not resolved at the time of reporting. Photophobia with optic neuritis Up to 31Mar2021, Agency included 38 ICSRs of optic neuritis following the vaccination with the COVID-19 vaccines, two of which additionally reported patients suffering photophobia after receiving the Pfizer BionTech vaccine. Both affected patients were female and 41 and 54 years old. The TTO of symptoms related to the optic neuritis was 12 hours and two days, respectively. Outcome was reported as "not recovered at the time of reporting in both cases, Photophobia with ocular inflammations Up to 31Mar2021, Agency included 308 cases of inflammatory conditions of the eye, such as conjunctivitis (n=212), uveitis (n=42), episcleritis (n=20), iridocyclitis (n=20), keratitis (n=12), and iritis (n=9), following immunization with the COVID-19 vaccines. Of these, 13 co reported photophobia (conjunctivitis (n=4), uveitis (n=3), iridocyclitis (n=3), keratitis (n=2), iritis (n=1), and episcleritis (n=1)). Affected patients were predominantly female (12; 92%) with a median age of 51 years (range 30 to 74 years). Half of the reports (n=7) were classified as serious. In most reports the Pfizer-BioNTech vaccine was suspect (n=9; 69%), in three reports (23%) AstraZeneca's and in one (7.7%) Moderna's. In the two cases reporting keratitis, the patients had suffered from previous episodes. One of these reported a reactivation of herpetic keratitis that resolved after increasing the daily dose of acyclovir. In another case an episode of anterior uveitis was reported. The patient was reported to have suffered from previous episodes related to immune stress. The last of these episodes was reported to have occurred two years prior. Additionally, the patient was reported to have experienced a cutaneous herpes simplex outbreak following the vaccination One of the three patients with photophobia and acute anterior uveitis, was suspected to have had a stroke prior to the diagnosis. Literature and Labelling Photophobia is not labelled as an adverse drug reaction in the Summaries of Product Characteristics (SmPCs) of the four COVID-19 vaccines included in the assessed case series, nor are the listed potential causes, apart from the typical post-vaccination symptoms in the non-serious photophobia reports. COVID-19 Infection with the novel coronavirus SARS-COV-2 itself is known to present with ocular symptoms such as conjuctivitis. Results from a cross-sectional study conducted in withheld showed that the most commonly occurring ocular symptom associated with COVID-19 was photophobia. Also, in a clustering study conducted, 9% of included COVID-19 patients presented with photophobia. The authors discussed encephalitis and aseptic meningitis, as well as adverse drug reactions, as possible reasons   Possible underlying causes None of the above listed potential causes for photophobia are listed in the included COVID-19 vaccines' SmPCs. No reports of migraine headaches, meningitis, optic neuritis or ocular inflammations following COVID-19 vaccination are published in the available scientific literature. However, ocular inflammations, such as conjunctivitis have been reported to occur as a symptom in COVID-19 patients.  Discussion Photophobia can be a symptom of various conditions. It has been reported to be observed as the most commonly occurring ocular symptom in patients experiencing COVID-19 infections Photophobia has not been described as a potential adverse reaction following immunization with the currently approved COVID-19 vaccines. However, an increasingly disproportionate number of cases reporting photophobia and the described possible underlying causes have been observed in Agency in combination with the novel Covid 19 vaccines, initiating the current assessment. Furthermore, the nature of some of the underlying causes - in particular, ophthalmic inflammations, such as conjunctivitis - must be kept in mind. For such conditions, patients might not necessarily contact health care professionals, as they may be self-limiting or respond to self-medication. Therefore, a certain degree of underreporting can be expected. A high proportion of reports on photophobia following COVID-19 vaccination was classified as serious with most of the serious reports concerning the vector-based AstraZeneca vaccine. However, most of those reports originated from the withheld which might represent a confounder, since by the end of Mar2021 in the withheld mainly the AstraZeneca vaccine was used whereas in other countries it was used besides the other mRNA-based vaccines. Since photophobia is a symptom and may represent an underlying condition in the following potential mechanisms are discussed, grouped by the potential causes. Migraine headaches Chronic migraines affect approximately 1% to 2% of the global population with a world-wide one-year prevalence of 15-18% for chronic and acute forms as of the early 2000s (1999 - 2004). Migraines affect women approximately three times more often than men'. Migraine headaches are often reported to be triggered by internal or external factors Stress can constitute such a trigger and it can contribute in the context of vaccinations Meningitis Cases of aseptic meningitis following several attenuated mumps vaccines with a TTO of two to three weeks have been observed in the 1990s and early 2000s9,10. Information on the TTO of meningitis following COVID-19 vaccination was scarce. Therefore, a sound judgement on a possible timely relationship between meningitis and immunization with the COVID-19 vaccines is not possible. The COVID-19 vaccines do not contain live attenuated vectors, therefore, a comparison and hypothesis generation about a potential mechanism is not possible. Optic neuritis Six cases of optic neuritis occurring with photophobia as an accompanying symptom following measles-rubella vaccinations have been described in the literature until today11-15. A potential mechanism for optic neuritis following natural measles infection was discussed by withheld and colleagues presenting the case of a 13-year-old boy who developed optic neuritis two to three weeks following measles-rubella vaccination". The authors described the development of optic neuritis as due to immune complex mediated vascular injury resulting in altered vascular permeability, perivascular inflammation and subsequent impairment of the blood-brain barrier, potentially allowing virus-specific antibody producing lymphocytes to enter the brain and cause inflammation and demyelination". Another hypothesis is the involvement of autoimmune mechanisms as discussed by withheld in a literature review from 2013 aiming to get a better understanding of a possible relationship between optic neuritis and viral vaccines 15. In the current analysis, the optic neuritis occurred following immunization with the mRNA-based Pfizer/BioNTech vaccine. Currently the extent of the immune response and the properties of the produced antibodies elicited by the mRNA vaccines is not fully investigated. Therefore, the mechanism discussed for optic neuritis following other vaccines cannot simply be transferred. However, a case-centered analysis of optic neuritis following vaccination conducted by withheld and colleagues in 2016 did not find evidence for vaccines being associated with the development of optic neuritis within four to six weeks after vaccination"  Ocular inflammations  Ocular inflammations have rarely been linked to vaccinations. Most literature was found regarding uveitis following vaccination. Several vaccines have been associated with uveitis following vaccination, with an incidence from 8-13 in 100,000 persons/year. Three potential mechanisms for vaccine-induced uveitis have been topic for discussions: 6) live strains of live-attenuated vaccines, such as the BCG vaccine could directly infect ocular structures, (ii) immune-related vaccine-associated uveitis could be induced by vaccines' adjuvants or additives (autoimmune/autoinflammatory syndrome induced by adjuvants (withheld)/Schoenfeld syndrome) as observed for HPV, Measles, Mumps, Rubella (MMR), influenza, and other vaccines, or (iii) components of the vaccine could present molecular mimicry with ocular structures and cause an auto-immune uveitis 18,19 As of 2016, approximately 300 case reports of vaccine-related intraocular inflammations have been published in the scientific literature. The median TTO was observed to be slightly over two weeks after vaccination and cases are usually mild, self-limiting, or well-responding to short courses of topical corticosteroid treatment 19 However, when interpreting the presented results, it must be considered that a significant proportion of patients might not have mentioned eventual underlying conditions in the reports (eg. due to missing diagnoses). Therefore, the presented potential underlying causes could be underestimated. Reduce PD image and  Conclusion  Photophobia was observed to be reported disproportionately frequently in association with the novel COVID-19 vaccines. It can occur for several reasons: as an adverse reaction in itself or as a symptom of an adverse reaction to the vaccines. We have outlined some of the most serious causes. Causality is not confirmed at this point, but due to the possible severity of the cases we think it is appropriate to increase awareness.  In the current assessment, there is no evidence that would necessitate potential contraindications for certain patient groups.  Product: Moderna COVID-19 Vaccine Product Description: Moderna COVID-19 Vaccine Category: Adverse Event Not Applicable Topic: Not Applicable  There is no product complaint associated with this case.  No follow-up attempts are possible. No further information is expected.