High-affinity, neutralizing antibodies to SARS-CoV-2 can be made without T follicular helper cells

• DOI: 10.1126/sciimmunol.abl5652
• Publication Date: 2022-02-04T18:59:12Z
• Authors: Jennifer S. Chen; Ryan D. Chow; Eric Song; Tianyang Mao; Benjamin Israelow; Kathy Kamath; Joel Bozekowski; Winston A. Haynes; Renata B. Filler; Bridget L. Menasche; Jin Wei; Mia Madel Alfajaro; Wenzhi Song; Lei Peng; Lauren Carter; Jason S. Weinstein; Uthaman Gowthaman; Sidi Chen; Joe Craft; John C. Shon; Akiko Iwasaki; Craig B. Wilen; Stephanie C. Eise...
• Keywords: 0301 basic medicine; COVID-19 Vaccines; T Follicular Helper Cells; Immunology; Infectious Disease; Antibodies, Viral; Lymphocyte Activation; Microbiology; Mice; 03 medical and health sciences; antibodies; Animals; Humans; Amino Acid Sequence; B cell responses; B-Lymphocytes; SARS-CoV-2; COVID-19; T-Lymphocytes, Helper-Inducer; Germinal Center; Antibodies, Neutralizing; 3. Good health; Immunology of Infectious Disease; Virus Diseases; germinal center (GC)-based antiviral antibody responses; Antibody Formation; T follicular helper (Tfh) cells

T follicular helper (T FH ) cells are the conventional drivers of protective, germinal center (GC)–based antiviral antibody responses. However, loss of T FH cells and GCs has been observed in patients with severe COVID-19. As T cell–B cell interactions and immunoglobulin class switching still occur in these patients, noncanonical pathways of antibody production may be operative during SARS-CoV-2 infection. We found that both T FH -dependent and -independent antibodies were induced against SARS-CoV-2 infection, SARS-CoV-2 vaccination, and influenza A virus infection. Although T FH -independent antibodies to SARS-CoV-2 had evidence of reduced somatic hypermutation, they were still high affinity, durable, and reactive against diverse spike-derived epitopes and were capable of neutralizing both homologous SARS-CoV-2 and the B.1.351 (beta) variant of concern. We found by epitope mapping and B cell receptor sequencing that T FH cells focused the B cell response, and therefore, in the absence of T FH cells, a more diverse clonal repertoire was maintained. These data support an alternative pathway for the induction of B cell responses during viral infection that enables effective, neutralizing antibody production to complement traditional GC-derived antibodies that might compensate for GCs damaged by viral inflammation.