Interleukins in COVID-19 and SARS-CoV-2 Variants: Immunopathogenesis, Therapeutic Perspectives and Vaccine-Induced Immune Responses

The Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by profound immune dysregulation where interleukins play a central role in determining disease severity and response to interventions. This review summarizes the role of interleukins in the immunopathogenesis of COVID-19, with particular emphasis on differences observed across major SARS-CoV-2 variants. Pro-inflammatory interleukins like IL-1β, IL-6, IL-2, IL-17 and IL-18 are critically involved in cytokine storm, hyperinflammation, and acute respiratory distress syndrome, whereas anti-inflammatory cytokines like IL-10 contribute to immune regulation and resolution of inflammation. Elevated levels of IL-1α, IL-1β, IL-4, IL-8, IL-9, IL-16, IL-18 have been documented in the Delta variant as compared with the Omicron variant, with IL-6 being the most frequent interleukin reported to be increased across all SARS-CoV-2 variants relative to the ancestral Wuhan strain. Elevated IL-2, IL-4, IL-6, and IL-10 levels have been associated with Omicron sub-variants. The review encompasses interleukin-based therapeutic strategies, where several IL-1 and IL-6 inhibitors were studied across clinical trials, but only tocilizumab has shown some promise against severe COVID-19. IL-2, IL-6, IL-15 and IL-21 levels were positively correlated with IgG and neutralizing antibody activity after vaccination with longevity of post-vaccination immunity being determined by IL-2 and IL-7.