T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses.
Ogbe A., Kronsteiner B., Skelly DT., Pace M., Brown A., Adland E., Adair K., Akhter HD., Ali M., Ali S-E., Angyal A., Ansari MA., Arancibia-Cárcamo CV., Brown H., Chinnakannan S., Conlon C., de Lara C., de Silva T., Dold C., Dong T., Donnison T., Eyre D., Flaxman A., Fletcher H., Gardner J., Grist JT., Hackstein C-P., Jaruthamsophon K., Jeffery K., Lambe T., Lee L., Li W., Lim N., Matthews PC., Mentzer AJ., Moore SC., Naisbitt DJ., Ogese M., Ogg G., Openshaw P., Pirmohamed M., Pollard AJ., Ramamurthy N., Rongkard P., Rowland-Jones S., Sampson O., Screaton G., Sette A., Stafford L., Thompson C., Thomson PJ., Thwaites R., Vieira V., Weiskopf D., Zacharopoulou P., Oxford Immunology Network Covid-19 Response T Cell Consortium None., Oxford Protective T Cell Immunology for COVID-19 (OPTIC) Clinical Team None., Turtle L., Klenerman P., Goulder P., Frater J., Barnes E., Dunachie S.
Identification of protective T cell responses against SARS-CoV-2 requires distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity to other coronaviruses. Here we show a range of T cell assays that differentially capture immune function to characterise SARS-CoV-2 responses. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) are found in 168 PCR-confirmed SARS-CoV-2 infected volunteers, but are rare in 119 uninfected volunteers. Highly exposed seronegative healthcare workers with recent COVID-19-compatible illness show T cell response patterns characteristic of infection. By contrast, >90% of convalescent or unexposed people show proliferation and cellular lactate responses to spike subunits S1/S2, indicating pre-existing cross-reactive T cell populations. The detection of T cell responses to SARS-CoV-2 is therefore critically dependent on assay and antigen selection. Memory responses to specific non-spike proteins provide a method to distinguish recent infection from pre-existing immunity in exposed populations.