Immunological and immunogenetic factors in fully mRNA-vaccinated persons with SARS-CoV-2 wild type and alpha variant breakthrough Infections – a case series

Introduction: SARS-CoV-2 breakthrough infection after vaccination are common with the evolution of immuno-evasive viral variants. Vaccine effectiveness of mRNA vaccines for the prevention of infection dropped from early 85-95% during wild type and alpha variant dominance to roughly 30-50% in the omicron era.We analyzed humoral and cellular immunity against SARS-CoV-2 as well as genetic factors in 10 individuals with a full primary vaccination series experiencing a breakthrough infection while the wild type virus and alpha variants were circulating. Methods: Antibodies were detected by Luminex assay (One Lambda, West Hills, USA), SARS-CoV-2 T cell response was evaluated by T-SPOT® Discovery SARS-CoV-2 assay (Oxford Immunotech, UK). DNA was extracted by a commercial assay (QIAGEN, USA) according to manufactures instructions, while immunogenetics (HLA typing, blood group typing) was done by NGS and real-time PCR. Cytokine gene polymorphisms were analyzed using the CYTGEN test (One Lambda, West Hills, USA). Results: All individuals had antibodies against at least one SARS-CoV-2 spike antigen, only two were found to have nucleocapsid protein antibodies. Specific SARS-CoV-2 T cell response (spike, nucleocapsid and matrix proteins) was low in 7/8 subjects. There was no correlation between the amount of T cell response and Spike protein antibody BAU/ml (r² = 0.0174, p > 0.5). Antibodies against any endemic coronavirus were detectable in 60%, against SARS-CoV in 90%, and against MERS-CoV in none.All individuals had at least one blood group O.01.x allele whereas blood group phenotype was O in four, and B O in three, A1 O in two, and A2 O in one. Lewis blood groups comprised Le(a+b-) in three, Le(a-b+) in seven.Cytokine gene polymorphisms showed hypoinflammatory profile in all patients (IFN-gamma low expression genotype and TNF-alpha low expression genotype in 7/10 each, TGF-ß1 high expression genotype in 7/10, IL-10 intermediate gene expression in 7/10). In contrast, IL-6 promoter expression genotype was high in 7/10. HLA NGS exhibited no unique pattern. Discussion: Immunogenetic factors in previous healthy persons with SARS-CoV-2 breakthrough infections revealed a predominant hypoinflammatory cytokine expression patterns, low T cell reactivity to SARS-CoV-2 antigens and only few nucleocapsid antibodies detected.Blood group O.01.x allele was found in all patients and Le(a+b-) phenotype, which is considered to confer low susceptibility to SARS-CoV-2 infection, in 30% of the individuals. Conclusion: Apart from immuno-evasive virus variants, genetically determined host immune response may have an impact on vaccination breakthroughs in COVID-19.