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2.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-294322

ABSTRACT

Nursing home residents often fail to mount robust responses to vaccinations and recent reports of breakthrough infections, particularly from variants of concern, raise questions about whether vaccination regimens elicit a sufficient humoral immune response or if booster doses are warranted. We examined SARS-CoV-2 antibody levels and neutralizing capacity in nursing home residents 3-5 months after 2 doses of mRNA-1273 or BNT163b2 vaccination as per recommended schedules. Nursing home residents were recruited from eight long-term care homes in Ontario, Canada, between March and July 2021. Antibody levels and neutralization capacity from a previously published convalescent cohort were used as a comparator. Serum SARS-CoV-2 IgA/G/M against spike (S) protein and its receptor-binding domain (RBD) were measured by validated ELISA, with assay cut-off at the mean and 3 standard deviations of a pre-COVID-19 population from the same geographic region. Antibody neutralization was measured against the wild-type strain of SARS-CoV-2 and the beta variant of concern (B.1.351). No neutralizing antibodies were detected in ∼20% of residents to the wild-type virus (30/155;19%) or beta variant (27/134;20%). Residents that received BNT163b2 had a ∼4-fold reduction in neutralization to the wild-type strain, and a ∼2-fold reduction in neutralization to the beta variant relative to those who received mRNA-1273. Current mRNA SARS-CoV-2 vaccine regimens may not have equivalent efficacy in nursing home residents. Our findings imply that differences in the humoral immune response may contribute to breakthrough infections, and suggest that consideration of the type of vaccine administered to older adults will have a positive impact on the generation of protective immunity.

3.
Viruses ; 13(11)2021 11 08.
Article in English | MEDLINE | ID: covidwho-1512696

ABSTRACT

Survivors of severe SARS-CoV-2 infections frequently suffer from a range of post-infection sequelae. Whether survivors of mild or asymptomatic infections can expect any long-term health consequences is not yet known. Herein we investigated lasting changes to soluble inflammatory factors and cellular immune phenotype and function in individuals who had recovered from mild SARS-CoV-2 infections (n = 22), compared to those that had recovered from other mild respiratory infections (n = 11). Individuals who had experienced mild SARS-CoV-2 infections had elevated levels of C-reactive protein 1-3 months after symptom onset, and changes in phenotype and function of circulating T-cells that were not apparent in individuals 6-9 months post-symptom onset. Markers of monocyte activation, and expression of adherence and chemokine receptors indicative of altered migratory capacity, were also higher at 1-3 months post-infection in individuals who had mild SARS-CoV-2, but these were no longer elevated by 6-9 months post-infection. Perhaps most surprisingly, significantly more T-cells could be activated by polyclonal stimulation in individuals who had recently experienced a mild SARS-CoV-2, infection compared to individuals with other recent respiratory infections. These data are indicative of prolonged immune activation and systemic inflammation that persists for at least three months after mild or asymptomatic SARS-CoV-2 infections.


Subject(s)
Asymptomatic Infections , COVID-19/immunology , Cytokines/metabolism , Leukocytes/immunology , Leukocytes/metabolism , Respiratory Tract Infections/immunology , SARS-CoV-2/immunology , Adult , Aged , Antibodies, Viral , Biomarkers , C-Reactive Protein/immunology , C-Reactive Protein/metabolism , COVID-19/virology , Cytokines/immunology , Female , Humans , Immunophenotyping/methods , Inflammation/metabolism , Inflammation/virology , Lymphocyte Activation , Male , Middle Aged , Respiratory Tract Infections/virology , Spike Glycoprotein, Coronavirus/immunology , Survivors , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
5.
Nature ; 596(7873): 565-569, 2021 08.
Article in English | MEDLINE | ID: covidwho-1356565

ABSTRACT

Vaccine-induced immune thrombotic thrombocytopaenia (VITT) is a rare adverse effect of COVID-19 adenoviral vector vaccines1-3. VITT resembles heparin-induced thrombocytopaenia (HIT) in that it is associated with platelet-activating antibodies against platelet factor 4 (PF4)4; however, patients with VITT develop thrombocytopaenia and thrombosis without exposure to heparin. Here we sought to determine the binding site on PF4 of antibodies from patients with VITT. Using alanine-scanning mutagenesis5, we found that the binding of anti-PF4 antibodies from patients with VITT (n = 5) was restricted to eight surface amino acids on PF4, all of which were located within the heparin-binding site, and that the binding was inhibited by heparin. By contrast, antibodies from patients with HIT (n = 10) bound to amino acids that corresponded to two different sites on PF4. Biolayer interferometry experiments also revealed that VITT anti-PF4 antibodies had a stronger binding response to PF4 and PF4-heparin complexes than did HIT anti-PF4 antibodies, albeit with similar dissociation rates. Our data indicate that VITT antibodies can mimic the effect of heparin by binding to a similar site on PF4; this allows PF4 tetramers to cluster and form immune complexes, which in turn causes Fcγ receptor IIa (FcγRIIa; also known as CD32a)-dependent platelet activation. These results provide an explanation for VITT-antibody-induced platelet activation that could contribute to thrombosis.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Epitopes, B-Lymphocyte/immunology , Thrombocytopenia/chemically induced , Thrombocytopenia/immunology , Thrombosis/chemically induced , Thrombosis/immunology , Adult , Aged , Amino Acid Sequence , Antibodies/immunology , Binding Sites, Antibody , Female , Heparin/chemistry , Heparin/immunology , Heparin/metabolism , Humans , Kinetics , Male , Middle Aged , Models, Molecular , Platelet Activation , Platelet Factor 4/immunology , Receptors, IgG/immunology
6.
Viruses ; 13(4)2021 04 16.
Article in English | MEDLINE | ID: covidwho-1194709

ABSTRACT

Coronavirus Disease 2019 (COVID-19) is a global pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While detection of SARS-CoV-2 by polymerase chain reaction with reverse transcription (RT-PCR) is currently used to diagnose acute COVID-19 infection, serological assays are needed to study the humoral immune response to SARS-CoV-2. Anti-SARS-CoV-2 immunoglobulin (Ig)G/A/M antibodies against spike (S) protein and its receptor-binding domain (RBD) were characterized in recovered subjects who were RT-PCR-positive (n = 153) and RT-PCR-negative (n = 55) using an enzyme-linked immunosorbent assay (ELISA). These antibodies were also further assessed for their ability to neutralize live SARS-CoV-2 virus. Anti-SARS-CoV-2 antibodies were detected in 90.9% of resolved subjects up to 180 days post-symptom onset. Anti-S protein and anti-RBD IgG titers correlated (r = 0.5157 and r = 0.6010, respectively) with viral neutralization. Of the RT-PCR-positive subjects, 22 (14.3%) did not have anti-SARS-CoV-2 antibodies; and of those, 17 had RT-PCR cycle threshold (Ct) values > 27. These high Ct values raise the possibility that these indeterminate results are from individuals who were not infected or had mild infection that failed to elicit an antibody response. This study highlights the importance of serological surveys to determine population-level immunity based on infection numbers as determined by RT-PCR.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , COVID-19/blood , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19 Nucleic Acid Testing , COVID-19 Serological Testing , Female , Humans , Immunoglobulin Isotypes/blood , Immunoglobulin Isotypes/immunology , Male , Middle Aged , Spike Glycoprotein, Coronavirus/immunology , Young Adult
7.
J Thromb Haemost ; 19(5): 1342-1347, 2021 05.
Article in English | MEDLINE | ID: covidwho-1105342

ABSTRACT

BACKGROUND: Thrombocytopenia and thrombosis are prominent in coronavirus disease 2019 (COVID-19), particularly among critically ill patients; however, the mechanism is unclear. Such critically ill COVID-19 patients may be suspected of heparin-induced thrombocytopenia (HIT), given similar clinical features. OBJECTIVES: We investigated the presence of platelet-activating anti-platelet-factor 4 (PF4)/heparin antibodies in critically ill COVID-19 patients suspected of HIT. PATIENTS/METHODS: We tested 10 critically ill COVID-19 patients suspected of HIT for anti-PF4/heparin antibodies and functional platelet activation in the serotonin release assay (SRA). Anti-human CD32 antibody (IV.3) was added to the SRA to confirm FcγRIIA involvement. Additionally, SARS-CoV-2 antibodies were measured using an in-house ELISA. Finally, von Willebrand factor (VWF) antigen and activity were measured along with A Disintegrin And Metalloprotease with ThromboSpondin-13 Domain (ADAMTS13) activity and the presence of anti-ADAMTS13 antibodies. RESULTS: Heparin-induced thrombocytopenia was excluded in all samples based on anti-PF4/heparin antibody and SRA results. Notably, six COVID-19 patients demonstrated platelet activation by the SRA that was inhibited by FcγRIIA receptor blockade, confirming an immune complex (IC)-mediated reaction. Platelet activation was independent of heparin but inhibited by both therapeutic and high dose heparin. All six samples were positive for antibodies targeting the receptor binding domain (RBD) or the spike protein of the SARS-CoV-2 virus. These samples also featured significantly increased VWF antigen and activity, which was not statistically different from the four COVID-19 samples without platelet activation. ADAMTS13 activity was not severely reduced, and ADAMTS13 inhibitors were not present, thus ruling out a primary thrombotic microangiopathy. CONCLUSIONS: Our study identifies platelet-activating ICs as a novel mechanism that contributes to critically ill COVID-19.


Subject(s)
COVID-19 , Thrombocytopenia , Anticoagulants , Antigen-Antibody Complex , Critical Illness , Heparin/adverse effects , Humans , Platelet Factor 4 , SARS-CoV-2 , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis
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