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    Oral Communication

    COVID

    Vaccination Against COVID-19 and Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT)

    OC 76.1 - Chadox1 Exposure-Induced Neutrophil-Activating Peptide 2 (NAP2) Antibodies: Murine-Based Insights into The Pathogenesis of Thrombosis with Thrombocytopenia Syndrome (TTS)

    Wednesday, June 28, 2023
    10:15 – 10:30 ET
    Room: 524
    Session Available As: On-Demand

      Presenting Author(s)

    • LR

      Lubica Rauova, MD, PhD

      Associate Professor
      Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA
      Philadelphia, Pennsylvania, United States

      • Co-Author(s)

    • JO

      Jenna Oberg

      Research Technician
      The Children's Hospital of Philadelphia
      Philadelphia, Pennsylvania, United States

    • Conroy O. Field, MS

      graduate student
      The Children's Hospital of Philadelphia
      Philadelphia, Pennsylvania, United States

    • NL

      Nate Levine

      Research Technician
      Children's Hospital of Philadelphia
      Philadelphia, Pennsylvania, United States

    • Kandace Gollomp

      Assistant Professor
      Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA
      Philadelphia, Pennsylvania, United States

    • GA

      Gowthami M. Arepally, M.D.

      professor
      Division of Hematology, Duke University Medical Center, Durham, NC
      Durham, North Carolina, United States

    • DB

      Douglas B. B. Cines

      professor
      Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
      Philadelphia, Pennsylvania, United States

    • TC

      Taylor Cohen

      Global project leader, late vaccines and immune therapies
      Vaccines and Immune Therapies, BioPharmaceuticals R&D, AstraZeneca
      Gaithersburg, Maryland, United States

    • MP

      Mortimer Poncz

      Professor
      Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA
      Philadelphia, Pennsylvania, United States

    Background: TTS or vaccine-induced immune thrombocytopenia and thrombosis (VITT) has emerged as a rare, but life-threatening side-effect of mostly adenoviral-based COVID-19 vaccines. The basis of this immune response is not understood. We have reported that in addition to the platelet chemokine, platelet factor 4 (PF4), TTS antibodies also recognize a conserved domain on the related platelet-specific chemokine NAP2, a potent neutrophil activator.

    Aims: To develop a murine model that leads to antibody-formation and a clinical manifestations similar to TTS to understand the basis of this disorder.

    Methods: Transgenic mice (n=5/group) that lack mPF4 (PF4KO), but express human (h) PF4 and Fcš¯›„RIIA were injected intramuscularly (IM) twice, 6 weeks apart, with high-dose (5x10^9 vp/mouse) or low-dose (5x10^7 vp/mouse) of ChadOx1-nCoV-19 (AZD1222) or high-dose (5x10^9 vp/mouse) control ChadOx-GFP. Clinical course, blood counts and ELISA for antibodies to spike protein, hPF4 and murine (m) NAP2 were followed.

    Results: Mice injected with high-dose ChadOx1-nCoV-19 or ChadOx1-GFP developed transient mild thrombocytopenia and leukopenia 24-48 hours after injection (Figures 1A, 1B). These mice also developed slightly, but significantly, increased levels of anti-hPF4 and mNAP2 antibodies (Figure 1C). One mouse immunized with ChadOx1-GFP developed progressive thrombocytopenia (Figure 2A), dying 24 hours after the second vaccination. Necropsy revealed pulmonary embolism and stroke (Figure 2B). At death, this mouse uniquely had markedly increased anti-mNAP2 with only slightly increased anti-hPF4 antibodies (Figure 2C).

    Conclusion(s): We have developed a murine model to simulate the development of TTS post-SARS-CoV-2 adenoviral vaccination. This model shared clinical features with TTS but differed by leading to low-titer anti-hPF4 antibodies in many unaffected mice, while the affected mouse had high-titer anti-mNAP2, rather than high-titer anti-hPF4 antibodies. This model may provide insights into the pathogenesis of TTS and be useful in selecting adenoviruses that do not induce TTS.

    Learning Objectives:

    • Upon completion, participant will be able to describe Thrombosis with Thrombocytopenia Syndrome
    • Identify platelet derived chemokines Neutrophil-Activating Peptide 2 (NAP2) and Platelet Facto 4 (PF4)
    • Explore the role of Neutrophil-Activating Peptide 2 (NAP2) in thrombosis