neutropenic fever; hypotension; hemophagocytic lymphohistiocytosis; acute liver injury; Bacteroides bacteremia; refractory shock; This is a spontaneous report from an unpublished manuscript article report from a contactable other HCP. A 52-year-old male patient received bnt162b2 (PFIZER-BIONTECH COVID-19 VACCINE, Lot number was not reported) via an unspecified route of administration on an unspecified date as DOSE 1, SINGLE for covid-19 immunisation. Medical history included T-cell lymphoma. A 52-year-old otherwise healthy man developed high fevers and acute liver injury the day after receiving the first dose of BNT162b2 mRNA-vaccine. He reported a viral syndrome four-months prior and malaise with low-grade fever the week before vaccination. Ten-days after vaccination, he was admitted with fevers and hypotension requiring vasopressors. Labs demonstrated increased ferritin (8,130ng/mL), triglycerides (650mg/dL), and soluble CD25 (sCD25) 25,603U/mL (Table-1). Antibiotics were initiated, and infectious work-up noted only Epstein-Barr virus (EBV) viremia of 11.3-million IU/mL. Dexamethasone and etoposide were initiated for hemophagocytic lymphohistiocytosis (HLH), and his fever and hemodynamics initially improved. Bone marrow biopsy demonstrated hemophagocytosis and T-cell lymphoma. He was started on an etoposide-based chemotherapy regimen (additional clinical information in supplement). His post- treatment course was complicated by neutropenic fever, Bacteroides bacteremia, and refractory shock, from which he died. Lab data included Temperature (Celsius)- 39.5, Ferritin (ng/mL)- 8,130, White blood count (K/uL)- 5.4, Hemoglobin (g/dL)- 11.1, Platelet (K/uL)- 172, Triglycerides (mg/dL)- 650, Fibrinogen (mg/dL)- 105, AST (U/L)- 1007, Organomegaly- Splenomegaly, Soluble CD25 (pg/mL)- 25,603, Hemophagocytosis- Yes, H-Score- 239, EBV blood PCR (IU/mL)- 11,300,000, Vaccine Response- anti-spike antibody (U/mL)- Not determined. The outcome of the other events was unknown.   Introduction:  The rapid generation of safe and effective mRNA vaccines has been an unprecedented success of the SARS-CoV-2 pandemic. Adverse events are extremely uncommon even in large population-database analyses. However, exacerbations of underlying hematologic and autoimmune diseases have been reported post-vaccination. Rare cases of possible vaccine-related HLH have also been reported after other SARS-CoV-2 vaccines. Given the widespread administration of these vaccines, it is essential to continue to monitor for rare adverse events and specific patient populations at-risk for them. In this case series, we describe five cases reported over the last year of hyperinflammatory reactions including HLH with temporal associations to mRNA vaccination in people with underlying immune dysregulation.   Discussion:  We describe five-cases of hyperinflammation including HLH occurring after SARS-CoV-2 mRNA-vaccination in people with underlying immune dysregulation. All patients had negative SARS- CoV-2 PCR testing during these inflammatory syndromes. Symptoms began 1-12 days after vaccination, and everyone received immune suppression. Two of the five patients who developed HLH died within six weeks of presentation. In adults, HLH is a diverse hyperinflammatory syndrome characterized by immune-mediated pathology. Although HLH is classically characterized as primary or secondary, its pathogenesis is complex and multifactorial [7]. (Privacy) and colleagues proposed categorizing HLH by underlying immune predisposition into subgroups including malignancy, rheumatologic disease, immunocompromised, and treatment-associated [7]. Infection-associated HLH was not considered a separate entity as patients with any of these conditions may have an infectious trigger [8, 9]. Our case series highlights the utility of this classification system, as each individual had a unique underlying immunologic disease. Due to the temporal association, it is possible the mRNA vaccination served as a trigger for the subsequent hyperinflammatory state. The pathophysiology of HLH is driven by enhanced T-cell activation and IFN production leading to severe macrophage activation, hypercytokinemia, and life-threatening inflammation [7, 8]. Messenger RNA vaccines have been shown to drive an acute expansion of activated CD4+ T-cells after the first injection [10]. Due to the importance of T-cells in HLH pathophysiology, it is possible that this expansion could lead to increased IFN production and bystander activation triggering pathologic inflammation in at-risk individuals. It is important to emphasize these patients had preexisting significant underlying immune dysregulation, which was an independent predisposition to hyperinflammation including T-cell lymphoma which is known to increase susceptibility to HLH [11], EBV infection which can drive this pathogenesis by either infecting B-cells and eliciting a T-cell response or by directly infecting a large number of T-cells [11] and autoimmune disease which are associated with an increased susceptibility to HLH (referred to as macrophage activation syndrome [MAS] in systemic juvenile idiopathic arthritis and AoSD) [8]. HLH/MAS can occur with other rheumatologic diseases associated with ILD including Sjogren's syndrome and dermatomyositis [12].  Patient-3 had a sputum culture which grew MAC, but he had no clinical evidence of mycobacterial infection. He also had a KSHV viremia which has been implicated in hyperinflammatory syndromes in people with HIV [13]. However, a definitive diagnosis was not established and the etiology of HLH in this patient remains unknown. Patient-4 and Patient-5 had histories of HLH-like inflammation associated with disseminated mycobacterial infections in the setting of GATA2 deficiency and AIDS, respectively. Interestingly, they developed less fulminant inflammatory syndromes than the other cases. Patient-5 had laboratory abnormalities that did not resemble HLH-like inflammation, but she was also treated early with immunosuppression. All patients in this case series developed hyperinflammatory responses after the first injection of an mRNA-based vaccine, observations which may not be causal. Over 200-million people have been vaccinated against SARS-CoV-2 in (Privacy). In the setting of mass vaccination, unrelated disease processes may be detected in the peri-vaccination period. However, vaccines are potential triggers of HLH in infants with genetic predispositions [14]. While this is not a well-described phenomenon in adults, the mechanism of mRNA vaccines is novel and their impact on T-cell immune responses may be as well. This is the first case series describing hyperinflammatory syndromes occurring post-SARS-CoV-2 mRNA vaccination in individuals with preexisting immune dysregulation. Review of the Vaccine Adverse Event Reporting System (VAERS) database identified 32-additional reports of hyperferritinemic inflammatory syndromes including HLH occurring after mRNA vaccinations (Ref). Unfortunately, complete clinical data and outcomes were not reported for each case and the database does not capture the full spectrum of presentations due to variability in recognition and reporting. These rare observations should not change current vaccine recommendation guidelines, however, vaccination should be explored among the possible provocations of hyperinflammatory responses, including HLH. Individuals with persistent and severe inflammatory symptoms after vaccination should undergo detailed clinical and laboratory evaluation for underlying immune dysregulation. They should have close follow-up and immune suppression, if required, should always be directed at the underlying disease process. Further study of genetic and immunologic mechanisms predisposing to HLH is needed to improve diagnosis and treatment of this increasingly recognized hyperinflammatory syndrome.  The lot number for the vaccine BNT162B2 was not provided and will be requested during follow up.; Sender's Comments: Based on the currently available information the possibility of causal association between the reported serious events and the suspect drug BNT162B2  cannot be ruled out but consider also possible contributory effects from patient's medical history (T-Cell Lymphoma); Reported Cause(s) of Death: Neutropenic fever; Bacteroides bacteremia; Refractory shock