Role of germinal center response in the antibody responses against SARS-CoV-2 spike protein

Abstract Spike-based vaccination strategies, including mRNA, effectively induce antibody responses against SARS-CoV-2. However, the breadth of antibody responses raised by Wuhan spike covering newly emerging variants remains unclear. Here, we investigate how the loss of function of GC responses and IL-4 signal influence the antibody and memory B cell responses against spike proteins of SARS-CoV-2 variants. In mouse model, immunization of C57BL/6J and C3H mice with trimeric recombinant spike protein of Wuhan-CoV-2 efficiently induced the production of antibodies capable of recognizing the receptor binding domain of delta, and omicron (BA1, and BA5) variants. The third boosting with Wuhan spike protein was also effective in inducing the antibodies to recognize omicron variants, but the boosting with BA5 was only effective for BA5, not Wuhan. We tested the neutralizing activity of these antibodies by the in vitro binding assay using psuedo-virus and human bronchial organoids infection system. These antibodies effectively blocked the infection of Wuhan and delta variants, but the protection was reduced for omicron variants. We further evaluated the contribution of the GC response and IL-4 using Bcl6 deficient mice (Bcl6f/f CD4-cre, Bcl6f/f CD4ER-cre) or B cell-specific deficient mice of the IL-4 receptor(R) (Il4rΔB mice). The results indicated that Bcl6 deficient mice and the mice lacking IL-4R signaling in B cells markedly reduced initial antibody responses and diminished protectivity of the antibodies against the variant virus. In conclusion, our results indicated that the GC response and IL-4 signal provides a quantitative checkpoint optimizing the breadth of anti-SARS-CoV2 protective antibody response.