Age: 70.0
Sex: F
Vaccine: COVID19
Symptoms: Cerebrovascular accident, Magnetic resonance imaging head
Clinical narrative: NON-HEMORRHAGIC CVA; This 70-year-old, Middle Eastern, female subject (US0120098) was participating in a Study to Evaluate the Immunogenicity and Safety of mRNA Vaccine Boosters for SARS-CoV-2 Variants (mRNA-1273-P205) and experienced the serious adverse event of special interest (AESI) non-hemorrhagic cerebrovascular accident (CVA).  The subject's medical history, as provided by the investigator, included post-menopausal, hypothyroidism, hypertension, hypercholesterolemia, and hysterectomy. No concomitant medications were reported.   On 01 Nov 2021, approximately 2 days prior to the onset of the event, the subject received their single planned booster dose of mRNA-1273.213, 100 micrograms intramuscularly in the left arm, for prophylaxis of COVID-19 infection.  On 03 Nov 2021, the subject experienced non-hemorrhagic CVA. It was reported that the subject experienced transient dysarthria status post vaccine (day 3). She presented to the emergency room and was admitted for overnight observation. Treatment for the event included oral clopidogrel bisulfate.  During the subject's hospitalization, neuro-imaging (magnetic resonance imaging) revealed a non-hemorrhagic acute CVA that had resolved.  On 04 Nov 2021, the subject was discharged from the hospital.  The subject received the single scheduled dose of study drug prior to the event; therefore, action taken with the drug in response to the event was not applicable.   The event, non-hemorrhagic CVA, was considered to be resolved on 04 Nov 2021.  The investigator assessed the event, non-hemorrhagic CVA, as related to study drug.  Follow-up received on 08 Dec 2021 included no new information.   On 17-Nov-2021, the safety database was searched for events similar to Cerebrovascular accident using the following search criteria: HLT Central nervous system haemorrhages and cerebrovascular accidents   As of 17-Nov-2021 under IND 019745 for mRNA-1273, 46 similar events were retrieved in 44 cases, including the current index case (see table below); one case (MOD-2020-000271) has 3 events.  0 of these cases were previously submitted as IND Safety Reports.  There were 43 cases non-IND Safety Reports (expected and related or unexpected and unrelated or expected and unrelated to the IMP) reporting the following events: Basal ganglia haemorrhage (1) MCN# MOD-2020-000591; Brain stem infarction (1) MCN# MOD-2021-059203; Carotid artery thrombosis (1) MCN# MOD-2020-000271; Cerebellar haemorrhage (1) MCN# MOD-2021-171428; Cerebral haemorrhage (1) MCN# MOD-2021-252360; Cerebral infarction (1) MCN# MOD-2021-253309; Cerebrovascular accident (25) MCN# MOD-2020-000193, MOD-2020-000547, MOD-2020-000615, MOD-2020-000873, MOD-2020-001032, MOD-2020-001059, MOD-2020-001127, MOD-2021-003274, MOD-2021-004768, MOD-2021-007926, MOD-2021-014196, MOD-2021-021733, MOD-2021-041521, MOD-2021-060173, MOD-2021-065720, MOD-2021-067852, MOD-2021-069290, MOD-2021-205654, MOD-2021-236571, MOD-2021-259440, MOD-2021-264901, MOD-2021-278828, MOD-2021-298468, MOD-2021-302402, MOD-2021-363801; Embolic stroke (3) MCN# MOD-2020-000271, MOD-2020-000682, MOD-2021-221810; Haemorrhage intracranial (1) MCN# MOD-2021-018342; Haehorrhagic stroke (1) MCN# MOD-2021-225555; Ischaemic cerebral infarction (1) MCN# MOD-2021-090061; Ischaemic stroke (2) MCN# MOD-2020-000286, MOD-2021-214030; Subarachnoid haemorrhage (5) MCN# MOD-2020-000271, MOD-2020-000833, MOD-2020-001380, MOD-2021-135456, MOD-2021-264801; Thalamic infarction (1) MCN# MOD-2021-287272.    Out of 25 events with PT: Cerebrovascular accident, 2 (Case ID: MOD-2020-001032 and MOD-2021-302402) were considered as related by the reporter and not related to the study vaccine by the sponsor; the summary of these cases is described below:  MOD-2020-001032: This case concerns a 34-year-old, White, Hispanic or Latino female subject with recent COVID infection, who experienced an unexpected event of cryptogenic stroke.  The event occurred 2 months 6 days after the first and only dose of blinded study vaccine administration. An MRI showed acute left posterior inferior cerebellar artery (PICA) territory infarct mass effect on the fourth ventricle. A magnetic resonance angiography of the head and neck was unremarkable, a computed tomography angiogram (CTA) of the head and neck with contrast showed questionable focal occlusion of the PICA just left of midline, and a transesophageal echocardiogram showed patent foremen ovale (PFO) with right to left shunting. The Investigator assessed the event as related to the study vaccine as he could not reasonably exclude that the vaccine played a role in the event and considered recent mild COVID as a contributory factor; however, the sponsor considered the event unrelated to the study vaccine and likely related to the PFO which is associated with cryptogenic stroke and increases the risk of strokes.  MOD-2021-302402: This case concerns a 70-year-old year-old, male subject with a history coronary artery  disease, myocardial infarction, peripheral artery disease, atrial fibrillation,  hypertension, alcohol consumption (8-12 per week), chronic obstructive pulmonary disease, gastric ulcer, and anemia, who experienced serious adverse event of special interest of stroke and serious adverse event of upper gastrointestinal (GI) bleed.  The event stroke occurred 5 days after the booster dose of mRNA-1273, and the event upper gastrointestinal (GI) bleed occurred 11 days after the booster dose. The event stroke was considered related, and the event upper GI bleed was considered unrelated to study vaccine according to the Investigator's assessment. The events were considered unrelated to the study vaccine by the sponsor. The event stroke might be explained by underlying metabolic and cardiovascular comorbidities, and the event upper gastrointestinal (GI) bleed might be explained by medical history of gastrointestinal ulcer, concomitant ibuprofen and clopidogrel, in the context of an elderly subject with several comorbidities.   The index case (MOD-2021-386485) concerns a 70-year-old, Middle Eastern, female subject with a history of hypothyroidism, hypertension, and hypercholesterolemia who experienced the unexpected event of special interest (AESI) non-hemorrhagic cerebrovascular accident (CVA), symptomatic for transient dysarthria. The event occurred approximately 2 days after the first, and only, booster dose of mRNA-1273.213. The event was considered related to IP in agreement with the Investigator based on close temporal association; however, the risk factors of age, hypertension, hypercholesterolemia are contributors to the event.   In summary, the review of these cases, did not show events similar to the index case, because in the 2 cases described above, results of diagnostic procedures as in the case of patent foremen ovale, and several cardiovascular, metabolic and respiratory comorbidities and time to onset suggest alternative etiologies for the event; however, in the index case, even though the subject had risk factors such as age, hypertension and hypercholesterolemia as comorbidities, the role of the study vaccine in the etiology of the event cannot be completely y excluded based on close temporal association.  Based on review of available data, the Sponsor cannot rule out a possible cause and effect relationship between administration of IMP and the occurrence of a cerebrovascular accident. After review of the clinical details and investigator comments pertaining to this adverse event, and based upon experience to date, the Sponsor does not believe that changes to the conduct of this clinical trial are warranted. The Company will continue to monitor these and other serious adverse events reported in association with the IMP and will communicate any relevant changes to the protocol, Informed Consent Form, Investigator's Brochure, and/or Core Safety Information.; Reporter's Comments: Company Comment: This case concerns a 70-year-old, Middle Eastern, female subject with a history of hypothyroidism, hypertension, and hypercholesterolemia who experienced the unexpected event of special interest (AESI) non-hemorrhagic cerebrovascular accident (CVA).  The event occurred approximately 2 days after the first, and only, booster dose of mRNA-1273.213. Action taken with IP, as well as dechallenge and rechallenge, were not applicable as the subject had already received scheduled dose. The event was considered related to IP in agreement with the Investigator based on close temporal association; however, the risk factors of age, hypertension, hypercholesterolemia are contributors to the event. The benefit-risk relationship of drug mRNA-1273 is not affected by this report.