Boosting location of COVID-19 mRNA vaccine regulates the germinal center reaction

Abstract Germinal centers (GCs) are the specialized sites for B cells to differentiate into long-lived plasma cells or memory B cells during vaccinations. COVID-19 mRNA vaccines require boosting to mount high levels of neutralizing antibody responses. mRNA vaccines induce persistent GCs in the draining lymph nodes (dLNs), which might change the microenvironment for subsequent immunizations. It is unclear whether the site of booster immunization (ipsilateral versus contralateral) will affect the GC responses in the dLNs. To test this, we compared GC responses induced by ipsilateral and contralateral booster vaccination three weeks post the primary immunization in mice. Although these two boosting strategies induce similar numbers of GC B cells in the dLNs, we discovered that ipsilateral boosting elicits more SARS-CoV-2 RBD-specific GC B cells than contralateral boosting. However, very few RBD-specific GC B cells were differentiating into plasma cells as probed by BCL6 lowIRF4 highPC precursors within the GC B cell population. Serum antibody levels were comparable between these boosting strategies, suggesting the memory recall response was not different. These studies suggest boosting location of COVID19 mRNA vaccines might affect RBD-specific GC B cell responses. Future studies are needed to investigate whether boosting location may impact the persistence of neutralizing antibody response induced by COVID19 mRNA vaccines.