In summary, our results gain insights in the characteristics of T‐cell response associated with disease severity in acute infection, supporting important information about correlates of immune protection, such as a broader polyfunctional CD4+ T‐cell response with predominance of IL‐2 production also present in SARS‐CoV‐2 specific CD8+ T‐cell response, distinguished mild disease progression from severe COVID‐19 characterised by an inefficient monofunctional IFN‐γ+ CD4+ T‐cell response in acute hospitalised patients. This evidence concerns the gene CD4 and COVID-19.