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1.
Eur Heart J ; 42(39): 4053-4063, 2021 Oct 14.
Article in English | MEDLINE | ID: covidwho-1633402

ABSTRACT

AIMS: The clinical manifestation and outcomes of thrombosis with thrombocytopenia syndrome (TTS) after adenoviral COVID-19 vaccine administration are largely unknown due to the rare nature of the disease. We aimed to analyse the clinical presentation, treatment modalities, outcomes, and prognostic factors of adenoviral TTS, as well as identify predictors for mortality. METHODS AND RESULTS: PubMed, Scopus, Embase, and Web of Science databases were searched and the resulting articles were reviewed. A total of 6 case series and 13 case reports (64 patients) of TTS after ChAdOx1 nCoV-19 vaccination were included. We performed a pooled analysis and developed a novel scoring system to predict mortality. The overall mortality of TTS after ChAdOx1 nCoV-19 vaccination was 35.9% (23/64). In our analysis, age ≤60 years, platelet count <25 × 103/µL, fibrinogen <150 mg/dL, the presence of intracerebral haemorrhage (ICH), and the presence of cerebral venous thrombosis (CVT) were significantly associated with death and were selected as predictors for mortality (1 point each). We named this novel scoring system FAPIC (fibrinogen, age, platelet count, ICH, and CVT), and the C-statistic for the FAPIC score was 0.837 (95% CI 0.732-0.942). Expected mortality increased with each point increase in the FAPIC score, at 2.08, 6.66, 19.31, 44.54, 72.94, and 90.05% with FAPIC scores 0, 1, 2, 3, 4, and 5, respectively. The FAPIC scoring model was internally validated through cross-validation and bootstrapping, then externally validated on a panel of TTS patients after Ad26.COV2.S administration. CONCLUSIONS: Fibrinogen levels, age, platelet count, and the presence of ICH and CVT were significantly associated with mortality in patients with TTS, and the FAPIC score comprising these risk factors could predict mortality. The FAPIC score could be used in the clinical setting to recognize TTS patients at high risk of adverse outcomes and provide early intensive interventions including intravenous immunoglobulins and non-heparin anticoagulants.


Subject(s)
COVID-19 , Thrombocytopenia , Thrombosis , COVID-19 Vaccines , Humans , Middle Aged , SARS-CoV-2 , Vaccination
2.
BMJ Case Rep ; 15(1)2022 Jan 18.
Article in English | MEDLINE | ID: covidwho-1636265

ABSTRACT

Vaccine-induced immune thrombotic thrombocytopenia (VITT) rarely develops after many COVID-19 vaccines. A 51-year-old woman re-presented to hospital with a 4 day history of headache, vomiting, diarrhoea and left calf pain, 11 days after her first dose of ChAdOx1nCoV-19 (AstraZenica) vaccine. Her neurological examination was normal. Blood tests demonstrated a low platelet count, raised D-dimer and CRP, and a positive heparin/anti-PF4 antibody assay. CT venogram demonstrated widespread cerebral venous sinus thrombosis. She was commenced on fondaparinux and intravenous immunoglobulins. The following day she developed an asymmetric quadriplegia and aphasia. CT angiogram demonstrated new bilateral cervical internal carotid artery (ICA) thrombi. She underwent stent-retriever mechanical thrombectomy of bilateral ICA and cerebral venous sinuses. Next day she had right hemiparesis and expressive dysphasia, which are improving. Thromboses due to VITT can progress rapidly to involve cerebral arteries and venous sinuses, and may warrant urgent arterial and venous thrombectomy to reduce morbidity and mortality.


Subject(s)
COVID-19 , Thrombocytopenia , Thrombosis , Venous Thrombosis , COVID-19 Vaccines , Female , Humans , Middle Aged , SARS-CoV-2 , Venous Thrombosis/diagnostic imaging , Venous Thrombosis/drug therapy , Venous Thrombosis/etiology
3.
Rinsho Ketsueki ; 62(12): 1684-1687, 2021.
Article in Japanese | MEDLINE | ID: covidwho-1622834

ABSTRACT

The Japanese Society of Hematology recently published on acute exacerbation of immune-mediated thrombocytopenia (ITP) after mRNA-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. In addition, there is a growing concern for the development of the newly diagnosed ITP after SARS-CoV-2 vaccination. Herein, we report two cases of severe thrombocytopenia associated with bleeding tendencies at 4 and 14 days after BNT162b2 mRNA vaccination. Platelet counts returned to normal following platelet transfusion or treatment with intravenous immunoglobulin and dexamethasone. To our knowledge at the time of the draft of this manuscript, nine cases of SARS-CoV-2 vaccine-induced ITP have been reported. Although most patients showed favorable clinical courses similar to that of our cases, critical thrombocytopenia can lead to unfavorable outcomes. A national survey may be required to examine the causal relationship between SARS-CoV-2 vaccination and the emergence of the newly diagnosed ITP and clinical outcomes of vaccine-induced thrombocytopenia.


Subject(s)
COVID-19 , Thrombocytopenia , COVID-19 Vaccines , Humans , RNA, Messenger , SARS-CoV-2 , Thrombocytopenia/chemically induced , Vaccination/adverse effects
4.
Int J Mol Sci ; 22(24)2021 Dec 20.
Article in English | MEDLINE | ID: covidwho-1580687

ABSTRACT

COVID-19 infection is associated with a broad spectrum of presentations, but alveolar capillary microthrombi have been described as a common finding in COVID-19 patients, appearing as a consequence of a severe endothelial injury with endothelial cell membrane disruption. These observations clearly point to the identification of a COVID-19-associated coagulopathy, which may contribute to thrombosis, multi-organ damage, and cause of severity and fatality. One significant finding that emerges in prothrombotic abnormalities observed in COVID-19 patients is that the coagulation alterations are mainly mediated by the activation of platelets and intrinsically related to viral-mediated endothelial inflammation. Beyond the well-known role in hemostasis, the ability of platelets to also release various potent cytokines and chemokines has elevated these small cells from simple cell fragments to crucial modulators in the blood, including their inflammatory functions, that have a large influence on the immune response during infectious disease. Indeed, platelets are involved in the pathogenesis of acute lung injury also by promoting NET formation and affecting vascular permeability. Specifically, the deposition by activated platelets of the chemokine platelet factor 4 at sites of inflammation promotes adhesion of neutrophils on endothelial cells and thrombogenesis, and it seems deeply involved in the phenomenon of vaccine-induced thrombocytopenia and thrombosis. Importantly, the hyperactivated platelet phenotype along with evidence of cytokine storm, high levels of P-selectin, D-dimer, and, on the other hand, decreased levels of fibrinogen, von Willebrand factor, and thrombocytopenia may be considered suitable biomarkers that distinguish the late stage of COVID-19 progression in critically ill patients.


Subject(s)
Blood Platelets/physiology , COVID-19/blood , Thrombosis/pathology , Blood Coagulation , Blood Coagulation Disorders/etiology , Blood Platelets/metabolism , Blood Platelets/virology , COVID-19/metabolism , Cytokine Release Syndrome , Endothelial Cells/pathology , Fibrin Fibrinogen Degradation Products , Hemostasis , Humans , Inflammation , Phenotype , Platelet Activation/physiology , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Thrombocytopenia/metabolism , Thrombosis/metabolism , Thrombosis/virology
7.
AJNR Am J Neuroradiol ; 43(1): 98-101, 2022 01.
Article in English | MEDLINE | ID: covidwho-1581414

ABSTRACT

Reports of a rare form of cerebral venous sinus thrombosis with profound thrombocytopenia have emerged following introduction of the adenovirus-vectored coronavirus disease 2019 (COVID-19) vaccines. Between March and June 2021, seven cases of refractory vaccine-induced immune thrombotic thrombocytopenia were referred to our institution for mechanical thrombectomy. The condition of 1 patient deteriorated during interhospital transfer, and the remaining 6 underwent successful recanalization. No procedure-related adverse events were reported. At the time of this writing, 3 patients have been discharged with a good functional outcome (mRS 0-1), one required rehabilitation for mild dysarthria and vocal cord palsy (mRS 3), and 2 have died due to severe mass effect. Our anecdotal experience suggests that endovascular therapy may be safe and effective in reducing thrombus burden in selected cases of postvaccination cerebral venous sinus thrombosis.


Subject(s)
COVID-19 , Sinus Thrombosis, Intracranial , Thrombocytopenia , Thrombosis , Vaccines , Humans , SARS-CoV-2 , Sinus Thrombosis, Intracranial/diagnostic imaging , Thrombectomy
8.
Clin Appl Thromb Hemost ; 27: 10760296211068487, 2021.
Article in English | MEDLINE | ID: covidwho-1575876

ABSTRACT

BACKGROUND: Cases of thrombosis with thrombocytopenia syndrome (TTS) have been reported following vaccination with AZD1222 or Ad26.COV2.S. This review aimed to explore the pathophysiology, epidemiology, diagnosis, management, and prognosis of TTS. METHODS: A systematic review was conducted to identify evidence on TTS till 4th September 2021. Case reports and series reporting patient-level data were included. Descriptive statistics were reported and compared across patients with different sexes, age groups, vaccines, types of thrombosis, and outcomes. FINDINGS: Sixty-two studies reporting 160 cases were included from 16 countries. Patients were predominantly females with a median age of 42.50 (22) years. AZD1222 was administered to 140 patients (87·5%). TTS onset occurred in a median of 9 (4) days after vaccination. Venous thrombosis was most common (61.0%). Most patients developed cerebral venous sinus thrombosis (CVST; 66.3%). CVST was significantly more common in female vs male patients (p = 0·001) and in patients aged <45 years vs ≥45 years (p = 0·004). The mortality rate was 36.2%, and patients with suspected TTS, venous thrombosis, CVST, pulmonary embolism, or intraneural complications, patients not managed with non-heparin anticoagulants or IVIG, patients receiving platelet transfusions, and patients requiring intensive care unit admission, mechanical ventilation, or inpatient neurosurgery were more likely to expire than recover. INTERPRETATION: These findings help to understand the pathophysiology of TTS while also recommending diagnostic and management approaches to improve prognosis in patients. FUNDING: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.


Subject(s)
COVID-19 Vaccines/adverse effects , Thrombocytopenia/chemically induced , Thrombosis/chemically induced , Adult , Aged , Female , Humans , Male , Middle Aged , Syndrome
9.
Clin Appl Thromb Hemost ; 27: 10760296211066945, 2021.
Article in English | MEDLINE | ID: covidwho-1574469

ABSTRACT

INTRODUCTION: Argatroban is licensed for patients with heparin-induced thrombocytopenia and is conventionally monitored by activated partial thromboplastin time (APTT) ratio. The target range is 1.5 to 3.0 times the patients' baseline APTT and not exceeding 100 s, however this baseline is not always known. APTT is known to plateau at higher levels of argatroban, and is influenced by coagulopathies, lupus anticoagulant and raised FVIII levels. It has been used as a treatment for COVID-19 and Vaccine-induced Immune Thrombocytopenia and Thrombosis (VITT). Some recent publications have favored the use of anti-IIa methods to determine the plasma drug concentration of argatroban. METHODS: Plasma of 60 samples from 3 COVID-19 patients and 54 samples from 5 VITT patients were tested by APTT ratio and anti-IIa method (dilute thrombin time dTT). Actin FS APTT ratios were derived from the baseline APTT of the patient and the mean normal APTT. RESULTS: Mean APTT ratio derived from baseline was 1.71 (COVID-19), 1.33 (VITT) compared to APTT ratio by mean normal 1.65 (COVID-19), 1.48 (VITT). dTT mean concentration was 0.64 µg/ml (COVID-19) 0.53 µg/ml (VITT) with poor correlations to COVID-19 baseline APTT ratio r2 = 0.1526 p <0.0001, mean normal r2 = 0.2188 p < 0.0001; VITT baseline APTT ratio r2 = 0.04 p < 0.001, VITT mean normal r2 = 0.0064 p < 0.001. CONCLUSIONS: We believe that dTT is a superior method to monitor the concentration of argatroban, we have demonstrated significant differences between APTT ratios and dTT levels, which could have clinical impact. This is especially so in COVID-19 and VITT.


Subject(s)
Arginine/analogs & derivatives , COVID-19/drug therapy , Partial Thromboplastin Time/methods , Pipecolic Acids/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Sulfonamides/therapeutic use , Thrombocytopenia/drug therapy , Thrombosis/drug therapy , Aged , Arginine/pharmacology , Arginine/therapeutic use , COVID-19/complications , Female , Humans , Male , Middle Aged , Pipecolic Acids/pharmacology , Platelet Aggregation Inhibitors/pharmacology , SARS-CoV-2 , Sulfonamides/pharmacology , Thrombocytopenia/chemically induced , Thrombosis/chemically induced
11.
J Med Case Rep ; 15(1): 606, 2021 Dec 13.
Article in English | MEDLINE | ID: covidwho-1571931

ABSTRACT

BACKGROUND: In this report, we describe a very challenging case of a patient with secondary Evans syndrome caused by severe coronavirus disease 2019 infection in a pregnant full-term woman. CASE PRESENTATION: A 29-year-old full-term pregnant Indonesian woman presented with gross hematuria, dry cough, fever, dyspnea, nausea, anosmia, and fatigue 5 days after confirmation of coronavirus disease 2019 infection. Laboratory examinations showed very severe thrombocytopenia, increased indirect bilirubin, and a positive direct Coombs' test. From peripheral blood, there was an increased number of spherocytes, which indicated an autoimmune hemolytic process. Antinuclear antibody and anti-double-stranded DNA test results were negative, and her virology serological markers are also negative for human immunodeficiency virus, cytomegalovirus, and hepatitis B and C. Despite aggressive treatment with platelet transfusion, high-dose steroid, and thrombopoietin receptor agonists, the platelet count did not recover, and a speculative cesarean delivery had to be done with a very low platelet count.


Subject(s)
COVID-19 , Thrombocytopenia , Adult , Anemia, Hemolytic, Autoimmune , Female , Humans , Pregnancy , Pregnant Women , SARS-CoV-2 , Thrombocytopenia/etiology
12.
Med Hypotheses ; 157: 110700, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1525881

ABSTRACT

A subset of COVID-19 patients is experiencing secondary immune thrombocytopenia, also called immune thrombocytopenic purpura (ITP) or secondary hemophagocytic lymphohistiocytosis (HLH). The pathogenesis of SARS-CoV-2 associated thrombocytopenia is unknown. Very rare cases of vaccine induced prothrombotic immune thrombocytopenia (VIPIT) are occurring associated with COVID-19 vaccines. COVID-19 VIPIT is associated with autoantibodies targeting platelet factor 4 (PF4) for COVID-19 adenovirus vaccines. Herein, four models for hemophagocytic histocytes contributions to the etiology of thrombocytopenia associated with SARS-CoV-2 are proposed. One of the models proposes potential involvement of hemophagocytic histocytes targeting platelets bound by autoantibodies consistent with observed PF4 autoantibodies in COVID-19 VIPIT.


Subject(s)
COVID-19 , Thrombocytopenia , COVID-19 Vaccines , Histiocytes , Humans , SARS-CoV-2 , Thrombocytopenia/complications
13.
Eur Heart J ; 42(39): 4073-4076, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1522175
14.
Blood Adv ; 5(21): 4521-4534, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1511718

ABSTRACT

Heparin thromboprophylaxis is routinely administered during hospitalization for COVID-19. Because of the immune stimulation related to COVID-19, there is ongoing concern regarding a heightened incidence of heparin-induced thrombocytopenia (HIT). We performed a literature search using PubMed, EMBASE, Cochrane, and medRxiv database to identify studies that reported clinical and laboratory characteristics and/or the incidence of HIT in patients with COVID-19. The primary aim was to systematically review the clinical features and outcomes of patients with COVID-19 with confirmed HIT. The secondary objective was to perform a meta-analysis to estimate the incidence of HIT in hospitalized patients with COVID-19. A meta-analysis of 7 studies including 5849 patients revealed the pooled incidence of HIT in COVID-19 of 0.8% (95% confidence interval [CI], 0.2%-3.2%; I2 = 89%). The estimated incidences were 1.2% (95% CI, 0.3%-3.9%; I2 = 65%) vs 0.1% (95% CI, 0.0%-0.4%; I2 = 0%) in therapeutic vs prophylactic heparin subgroups, respectively. The pooled incidences of HIT were higher in critically ill patients with COVID-19 (2.2%; 95% CI, 0.6%-8.3%; I2 = 72.5%) compared with noncritically ill patients (0.1%; 95% CI, 0.0%-0.4%: I2 = 0%). There were 19 cases of confirmed HIT and 1 with autoimmune HIT for clinical and laboratory characterization. The median time from heparin initiation to HIT diagnosis was 13.5 days (interquartile range, 10.75-16.25 days). Twelve (63%) developed thromboembolism after heparin therapy. In conclusion, the incidence of HIT in patients with COVID-19 was comparable to patients without COVID-19, with higher incidences with therapeutic anticoagulation and in critically ill patients.


Subject(s)
COVID-19 , Thrombocytopenia , Venous Thromboembolism , Anticoagulants/adverse effects , Humans , SARS-CoV-2 , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiology
16.
BMJ Case Rep ; 14(10)2021 Oct 27.
Article in English | MEDLINE | ID: covidwho-1495133

ABSTRACT

Cerebral venous sinus thrombosis (CVST) following novel coronavirus-2019 (nCoV-19) vaccination is a rare adverse effect. We report the first case of CVST associated with ChAdOx1 vaccination, with positive anti-platelet factor 4 (PF4) antibodies, from India. A 44-year-old woman developed a thunderclap headache 4 days after the first dose of the adenoviral vector vaccine ChAdOx1 (Covishield). Physical examination was unremarkable barring mild neck stiffness with no focal neurological deficits. MRI identified right transverse sinus thrombosis. Laboratory tests revealed raised D-dimer and thrombocytopenia; anti-PF4 antibodies were subsequently identified, consistent with thrombosis with thrombocytopenia syndrome (TTS). She was treated with non-heparin anticoagulation and intravenous immunoglobulin and made an uneventful recovery. Early recognition of adenoviral vector vaccine-related TTS, which resembles heparin-induced thrombocytopenia syndrome, is important as heparin and heparin analogues are best avoided in the treatment.


Subject(s)
COVID-19 Vaccines/adverse effects , Sinus Thrombosis, Intracranial , Thrombocytopenia , Thrombosis , Adult , COVID-19 , Female , Humans , Sinus Thrombosis, Intracranial/chemically induced , Thrombocytopenia/chemically induced , Thrombosis/chemically induced , Vaccination/adverse effects
17.
Clin Chem Lab Med ; 60(1): 7-17, 2022 01 26.
Article in English | MEDLINE | ID: covidwho-1496577

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a life-threatening infectious disease caused by Severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2). In response to the still ongoing pandemic outbreak, a number of COVID-19 vaccines have been quickly developed and deployed. Although minor adverse events, either local (e.g., soreness, itch, redness) or systematic (fever, malaise, headache, etc.), are not uncommon following any COVID-19 vaccination, one rare vaccine-associated event can cause fatal consequences due to development of antibodies against platelet factor 4 (PF4), which trigger platelet activation, aggregation, and possible resultant thrombosis, often at unusual vascular sites. Termed thrombosis with thrombocytopenia syndrome (TTS) by reporting government agencies, the term vaccine-induced (immune) thrombotic thrombocytopenia (VITT) is more widely adopted by workers in the field. In response to increasing reports of VITT, several expert groups have formulated guidelines for diagnosis and/or management of VITT. Herein, we review some key guidelines related to diagnosis of VITT, and also provide some commentary on their development and evolution.


Subject(s)
COVID-19 Vaccines/adverse effects , Thrombocytopenia , Thrombosis , COVID-19/prevention & control , Humans , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis , Thrombosis/chemically induced , Thrombosis/diagnosis
18.
Medicina (Kaunas) ; 57(11)2021 Oct 26.
Article in English | MEDLINE | ID: covidwho-1488668

ABSTRACT

Serious vaccine-associated side effects are very rare. Major complications of vaccines are thrombocytopenia and thrombosis in which pathogenetic mechanism is consistent with endotheliopathy characterized by "attenuated" sepsis-like syndrome, leading to the activation of inflammatory and microthrombotic pathway. In the COVID-19 pandemic, acute respiratory distress syndrome caused by microthrombosis has been the major clinical phenotype from the viral sepsis in association with endotheliopathy-associated vascular microthrombotic disease (EA-VMTD), sometimes presenting with thrombotic thrombocytopenic purpura (TTP)-like syndrome. Often, venous thromboembolism has coexisted due to additional vascular injury. In contrast, clinical phenotypes of vaccine complication have included "silent" immune thrombocytopenic purpura (ITP-like syndrome), multiorgan inflammatory syndrome, and deep venous thrombosis (DVT), cerebral venous sinus thrombosis (CVST) in particular. These findings are consistent with venous (v) EA-VMTD. In vEA-VMTD promoted by activated complement system following vaccination, "consumptive" thrombocytopenia develops as ITP-like syndrome due to activated unusually large von Willebrand factor (ULVWF) path of hemostasis via microthrombogenesis. Thus, the pathologic phenotype of ITP-like syndrome is venous microthrombosis. Myocarditis/pericarditis and other rare cases of inflammatory organ syndrome are promoted by inflammatory cytokines released from activated inflammatory pathway, leading to various organ endotheliitis. Vaccine-associated CVST is a form of venous combined "micro-macrothrombosis" composed of binary components of "microthrombi strings" from vEA-VMTD and "fibrin meshes" from vaccine-unrelated incidental vascular injury perhaps such as unreported head trauma. This mechanism is identified based on "two-path unifying theory" of in vivo hemostasis. Venous combined micro-macrothrombosis due to vaccine is much more serious thrombosis than isolated distal DVT made of macrothrombus. This paradigm changing novel concept of combined micro-macrothrombosis implies the need of combined therapy of a complement inhibitor and anticoagulant for CVST and other complex forms of DVT.


Subject(s)
COVID-19 , Thrombocytopenia , Thrombosis , Vaccines , Humans , Pandemics , SARS-CoV-2
19.
Vaccine ; 39(48): 7052-7057, 2021 11 26.
Article in English | MEDLINE | ID: covidwho-1487997

ABSTRACT

Emerging evidence suggest a possible association between immune thrombocytopenia (ITP) and some formulations of COVID-19 vaccine. We conducted a retrospective case series of ITP following vaccination with Vaxzevria ChadOx1-S (AstraZeneca) and mRNA Comirnaty BNT162b2 COVID-19 (Pfizer-BioNTech) vaccines and compare the incidence to expected background rates for Victoria during the first six months of the Australian COVID-19 vaccination roll-out in 2021. Cases were identified by reports to the Victorian state vaccine safety service, SAEFVIC, of individuals aged 18 years or older presenting with thrombocytopenia following COVID-19 vaccination without evidence of thrombosis. Twenty-one confirmed or probable cases of ITP were identified following receipt of AstraZeneca (n = 17) or Pfizer-BioNTech (n = 4) vaccines. This translates to an observed incidence of 8 per million doses for AstraZeneca vaccine, twice the expected background rate of 4.1 per million. The observed rate for Pfizer-BioNTech was consistent with the expected background rate. The median time to onset for the cases post AstraZeneca vaccination was 10 days (range 1-78) and median platelet nadir 5 × 109/L (range 0-67 × 109/L). Hospital presentations or admissions for management of symptoms such as bleeding occurred in 18 (86%) of the cases. The majority of cases (n = 11) required intervention with at least 2 therapy modalities. In conclusion, we observed a substantially higher than expected rate of ITP following AstraZeneca vaccination. ITP is the second haematological adverse event, distinct from that of thrombosis with thrombocytopenia syndrome (TTS), observed following AstraZeneca vaccination.


Subject(s)
COVID-19 , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Vaccines , COVID-19 Vaccines , Humans , Purpura, Thrombocytopenic, Idiopathic/chemically induced , Purpura, Thrombocytopenic, Idiopathic/epidemiology , Retrospective Studies , SARS-CoV-2 , Vaccination , Victoria/epidemiology
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