Significance A major gap in our current knowledge of COVID-19 is our limited understanding of the pathways of antibody production during acute disease. While a key pathway of antibody production driven by T-follicular helper cells is inhibited, neutralizing antibodies are still produced but may be of variable quality and specificity. Here, we describe that antibody concentrations, in the serum of severe COVID-19 patients, are closely associated with a network of extrafollicular T and B cells, while T-follicular regulatory cells—a key population responsible for supressing antibody production—are reduced most strongly in male patients. As such, these findings clarify the complex network of cells responsible for antibody production in COVID-19 patients.