The role of lymphocyte transformation tests (LTT) in suspected severe delayed hypersensitivity reactions following COVID-19 vaccination

Hum Vaccin Immunother. 2023 Dec 31;19(1):2182527. doi: 10.1080/21645515.2023.2182527. Epub 2023 Mar 13.


Coronavirus (COVID-19) vaccines have proved to be effective in the pandemic response but can cause adverse events such as delayed hypersensitivity reactions (DHRs). Delayed-reading intradermal tests (IDT) to vaccines are limited by false-positive results and may reflect a cell-mediated rather than IgE-mediated immune response. Lymphocyte transformation test (LTT), which has been utilized in the diagnosis of drug allergy, may be helpful in suspected COVID-19 vaccine and/or its excipient-related DHRs. To investigate the use of LTT in two suspected cases of COVID-19 vaccine-induced DHRs, two patients with suspected DHRs to COVID-19 vaccination were tested by delayed-reading IDT and LTT against vaccines and their excipients. A 47-year-old man developed acute mixed-pattern hepatitis after the second dose of ChAdOx1 vaccine. LTT performed at 2 months post-vaccination revealed reactivity to the ChAdOx1 vaccine, polysorbate 80 and mildly to PEG 2050 but not BNT162b2 vaccine. Delayed-reading IDT returned negative to both vaccines and excipients. He tolerated BNT162b2 vaccination with no adverse events. A 36-year-old woman presented with subacute morbilliform eruption and hepatitis after the first dose of BNT162b2 vaccine. LTT performed 3 months later revealed reactivity to the BNT162b2 but not PEG 2050. Repeat LTT following subsequent natural Severe Acute Respiratory Coronavirus-2 (SARS-CoV-2) infection revealed reactivity to ChAdOx1 and NVX-CoV2373 vaccines but not polysorbate 80. Delayed-reading IDT remained negative. She proceeded with NVX-CoV2373 vaccination with no symptom recurrence. LTT may be a useful tool in suspected COVID-19 vaccine-related DHRs. Further evaluation with a larger patient cohort is required.

Keywords: Covid-19; LTT; cytopenia; delayed hypersensitivity; delayed skin tests; hepatitis; neutropenia; thrombocytopenia; vaccine.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • BNT162 Vaccine
  • COVID-19 Vaccines* / adverse effects
  • COVID-19* / prevention & control
  • Excipients
  • Female
  • Humans
  • Hypersensitivity, Delayed* / chemically induced
  • Lymphocyte Activation
  • Male
  • Middle Aged
  • Polysorbates
  • SARS-CoV-2
  • Vaccination / adverse effects


  • BNT162 Vaccine
  • COVID-19 Vaccines
  • Excipients
  • Polysorbates

Grants and funding

We are grateful to Warren and Marianne Lesnie for supporting the study.