Limited induction of lung-resident memory T cell responses against SARS-CoV-2 by mRNA vaccination

Resident memory T cells (T _RM ) present at the respiratory tract may be essential to enhance early SARS-CoV-2 viral clearance, thus limiting viral infection and disease. While long-term antigen (Ag)-specific T _RM are detectable beyond 11 months in the lung of convalescent COVID-19 patients after mild and severe infection, it is unknown if mRNA vaccination encoding for the SARS-CoV-2 S-protein can induce this frontline protection. We found that the frequency of CD4 ⁺ T cells secreting interferon (IFN)γ in response to S-peptides was variable but overall similar in the lung of mRNA-vaccinated patients compared to convalescent-infected patients. However, in vaccinated patients, lung responses presented less frequently a T _RM phenotype compared to convalescent infected individuals and polyfunctional CD107a ⁺ IFNγ ⁺ T _RM were virtually absent. Thus, a robust and broad T _RM response established in convalescent-infected individuals may be advantageous in limiting disease if the virus is not blocked by initial mechanisms of protection, such as neutralization. Still, mRNA vaccines might induce responses within the lung parenchyma, potentially contributing to the overall disease control.