B cell‐intrinsic TLR7 signaling is required for neutralizing antibody responses to SARS‐CoV‐2 and pathogen‐like COVID‐19 vaccines

Abstract

AbstractToll‐like receptor 7 (TLR7) triggers antiviral immune responses through its capacity to recognize single‐stranded RNA. TLR7 loss‐of‐function mutants are associated with life‐threatening pneumonia in severe COVID‐19 patients. Whereas TLR7‐driven innate induction of type I IFN appears central to control SARS‐CoV2 virus spreading during the first days of infection, the impact of TLR7‐deficiency on adaptive B‐cell immunity is less clear. In the present study, we examined the role of TLR7 in the adaptive B cells response to various pathogen‐like antigens (PLAs). We used inactivated SARS‐CoV2 and a PLA‐based COVID‐19 vaccine candidate designed to mimic SARS‐CoV2 with encapsulated bacterial ssRNA as TLR7 ligands and conjugated with the RBD of the SARS‐CoV2 Spike protein. Upon repeated immunization with inactivated SARS‐CoV2 or PLA COVID‐19 vaccine, we show that Tlr7‐deficiency abolished the germinal center (GC)‐dependent production of RBD‐specific class‐switched IgG2b and IgG2c, and neutralizing antibodies to SARS‐CoV2. We also provide evidence for a non‐redundant role for B‐cell‐intrinsic TLR7 in the promotion of RBD‐specific IgG2b/IgG2c and memory B cells. Together, these data demonstrate that the GC reaction and class‐switch recombination to the Myd88‐dependent IgG2b/IgG2c in response to SARS‐CoV2 or PLAs is strictly dependent on cell‐intrinsic activation of TLR7 in B cells.