Spike-specific circulating T follicular helper cell and cross-neutralizing antibody responses in recovered COVID-19 individuals

<b>Coronavirus Disease 2019 (COVID-19), an emerging disease caused by infection with SARS-CoV-2</b><b>^1-3</b><b>, </b><b>has spread worldwide and caused 21.2 million infections and 0.76 million deaths (as of August 15, 2020</b><b>)</b><b>⁴</b><b>.</b><b> </b><b>Symptoms of COVID-19 are varied and can be asymptomatic, mild, moderate, and severe</b><b>^5,6</b><b>. In the early phase of SARS-CoV-2 infection, T and B cell counts are dramatically decreased</b><b>^7,8</b><b>; however, IgM</b><b>^9-12</b><b> and IgG</b><b>^13-15</b><b> are detectable within 14 days after symptom onset. In COVID-19 convalescents, spike-specific neutralizing antibodies (nAbs) are variable</b><b>^3,16,17</b><b>. To date, no specific drug or vaccine is available for COVID-19. Clinical trials have shown that patients benefit from the treatments with convalescent serum</b><b>^18,19</b><b>. Nevertheless, antibody responses and cross-reactivity with other coronaviruses in the COVID-19 convalescents are largely unknown. Here we show that the majority of COVID-19 convalescents maintained SARS-CoV-2 spike S1- and S2-specific antibodies with neutralizing activity against the SARS-CoV-2 pseudotyped virus and that some of the antibodies cross-neutralized SARS-CoV, MERS-CoV, or both pseudotyped viruses. Convalescents who experienced severe COVID-19 disease showed higher nAb titers, a faster increase of lymphocyte counts, and a higher frequency of CXCR3⁺ T follicular help (Tfh) cells than did non-severe convalescents. Circulating Tfh cells were spike-specific and functional, and the frequencies of CXCR3⁺ Tfh cells were positively associated with nAb titers in recovered COVID-19 individuals. </b><b>No subjects had </b><b>detectable autoantibodies</b><b>. These findings provide insights into nAb responses in COVID-19 convalescents and facilitate the treatment and vaccine development for SARS-CoV-2 infection.</b>