Exploring the Relationship Between Humoral and Cellular T Cell Responses Against SARS‐CoV‐2 in Exposed Individuals From Emilia Romagna Region and COVID‐19 Severity

COVID-19 remains a significant global health problem with uncertain long-term consequences for convalescents. We inves-tigated the relationships between anti-N protein antibody levels, severe acute respiratory syndrome (SARS)- CoV-2-associatedTCR repertoire parameters, HLA type and epidemiological information from three cohorts of 524 SARS- CoV-2-infectedsubjects subgrouped in acute phase, seronegative and seropositive convalescents from the Emilia Romagna region.Epidemiological information and anti-N antibody index were associated with TCR repertoire data. HLA type was inferredfrom TCR repertoire using the HLA3 tool and its association with clonal breadth (CB) and clonal depth (CD) was assessed.Age above 58 years, male and COVID-19 hospitalisation were significantly and independently associated with seropositivity(p = 0.004; p = 0.004; p = 0.04), suggesting an association between high antibody titres and symptoms' severity. As for theTCR repertoire analysis, we found no difference in CB among the cohorts, while CD was higher in seronegative than acute(p = 0.04). However, clustering analysis supported that seronegative patients are endowed with broader CB and deeper CDindicating a compensatory mechanism without effective seroconversion. The CD calculated on the TCRs associated with thesingle SARS- CoV-2 ORFs in convalescents is higher when compared to the acute. Lastly, we identified and reported on novelHLAs significantly associated with increased risk of hospitalisation such as HLA- C*07:02 carriers (OR = 3.9, CI = 1.1–13.4,p = 0.03) and on HLAs that associate significantly with lower or higher TCR repertoire parameters in a population exposedfor the first time to SARS- CoV-2