Fig. 4. Investigating T cell protection from severe SARS-CoV-2 infection.

Vaccination provides a high level of protection from acquisition of SARS-CoV-2 infection, and an even higher level of protection from severe disease. Thus, immunity might be thought of as having complementary actions at two stages of infection: first blocking establishment of infection and, second, even if breakthrough infection occurs, acting to reduce the severity of infection. a | The levels of neutralizing antibodies (nAbs) have been shown to be lower in vaccinated individuals with breakthrough infection. Similar studies investigating whether T cells contribute to protection from acquisition of SARS-CoV-2 infection are needed. b | Prospective studies of pre-infection T cell numbers as predictors of disease severity are challenging, due to the low frequency of severe disease. c | Studying whether the levels of CD4⁺ T cell and CD8⁺ T cell response predict disease severity in individuals with breakthrough infection may reduce the number of individuals needed to be studied. However, rapid changes in T cell numbers during the recall response may complicate analysis. d | Studying the relationship between T cell responses and viral clearance rate can be performed on smaller cohorts and has the potential to reveal a role for T cells in control of viral replication (although this is only a proxy measure for disease severity).