Humoral and circulating follicular helper T cell responses in recovered patients with COVID-19

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has dramatically expedited global vaccine development efforts(1-3), most targeting the viral 'spike' glycoprotein (S). S localizes on the virion surface and mediates recognition of cellular receptor angiotensin-converting enzyme 2 (ACE2)(4-6). Eliciting neutralizing antibodies that block S-ACE2 interaction(7-9), or indirectly prevent membrane fusion(10), constitute an attractive modality for vaccine-elicited protection(11). However, although prototypic S-based vaccines show promise in animal models(12-14), the immunogenic properties of S in humans are poorly resolved. In this study, we characterized humoral and circulating follicular helper T cell (cTFH) immunity against spike in recovered patients with coronavirus disease 2019 (COVID-19). We found that S-specific antibodies, memory B cells and cTFH are consistently elicited after SARS-CoV-2 infection, demarking robust humoral immunity and positively associated with plasma neutralizing activity. Comparatively low frequencies of B cells or cTFH specific for the receptor binding domain of S were elicited. Notably, the phenotype of S-specific cTFH differentiated subjects with potent neutralizing responses, providing a potential biomarker of potency for S-based vaccines entering the clinic. Overall, although patients who recovered from COVID-19 displayed multiple hallmarks of effective immune recognition of S, the wide spectrum of neutralizing activity observed suggests that vaccines might require strategies to selectively target the most potent neutralizing epitopes. In a cohort of recovered patients with COVID-19, virus spike-specific antibodies were consistently elicited, but neutralizing activity was highly variable and inversely correlated with the proportion of CCR6(+)CXCR3(-)spike-specific circulating follicular helper T cells.