Immune Characteristics and HLA Associations of SARS-Cov-2 Vaccines-induced Delayed-Type Cutaneous Adverse Reactions

Background: COVID-19 vaccinations may induce hypersensitivity reactions. Delayed-type cutaneous adverse reactions(DCARs) related to COVID-19 vaccines include maculopapular exanthem, eczematous dermatitis, papulosquamous eruption to erythema multiforme major. However, the pathomechanism of these reactions induced by COVID-19 vaccinations remain unclear. Here, we aim to investigate the immune charasteristics and HLA associations of COVID-19 vaccination-related DCARs. Methods: We conducted an observational study on patients with COVID-19 vaccine-DCARs and tolerant subjects. Serum immune molecules and high-parameter blood cell analysis were analysed. In vitro lymphocyte activation test(LAT) was performed to evaluate the causative allergens of COVID-19 vaccines for DCARs. We also investigated the HLA associations of COVID-19 vaccination-related DCARs. Results: We enrolled 103 patients with COVID-19 vaccine(AZD1222(n=49), BNT162b2(n=23), mRNA-1273)(n=30), and Nuvaxovid(Novavax)(n=1)-induced DCARs. Patients suffered from DCARs mainly after the first vaccination dose(75.7%). Compared to the tolerant controls, patients with DCARs showed significantly higher serum levels of IL-4, IL-6, IL-8, IL-17A, IL-18, IFN-γ, IP-10, MIG, granulysin, PARC and TARC( P =0.028-3.40×10 ). High-parameter flow cytometric analysis revealed significant increased CD4 Th2, CD4 Th17, CD4 Th22, CD4 LAG3 , CD4 CD103 Trm, Tfr, CD8 CXCR3 , CD8 Tc2, CD8 Tc17 and CD8 CTLA4 cell populations were relative to variable DCARs( P <0.05). In vitro LAT assays measuring IFN-γ, granulysin, granzyme B, and PARC for patients with COVID19-vaccines induced DCARs showed significantly reactive to spike protein, and excipients (polysorbate 80, polyethene glycol(PEG) 2000, and tris)( P<0.05 ). HLA genotyping showed that COVID-19 vaccine-DCARs were significantly associated with HLA-B*13:01 ( P =0.015,OR:4.7,95%CI:1.3-16.6). Of note, mRNA-1273(Moderna)-based COVID-19 vaccine-DCARs were significantly associated with HLA- B*13:01,B*51:01 , and B*54:01 . The predictive sensitivity of concurrently testing HLA- B*13:01 / B*51:01 / B*54:01 increased from 19.2-35.0% to 65.4%( P =4.9×10 ,OR:17.0,95%CI:4.6-63.1). Conclusions: : The genetic susceptibility and specific T cell mediated immune responses to spike protein and vaccine excipients contributed the immune mechanism of COVID-19 vaccines-induced DCARs.