Alternative lineage B cells utilizing fatty acid oxidation predict response to third dose COVID vaccination in solid organ transplant recipients

Abstract

Abstract Solid organ transplant recipients (SOTRs) demonstrate reduced seroconversion and increased breakthrough infection rates following standard two dose mRNA vaccination against SARs-CoV-2. However, within a prospective cohort of SOTRs, the majority of patients (72%) developed a positive anti-Spike (S) IgG following a third vaccine dose, compared to only 15% following two doses. Those who failed to respond to vaccination uniformly received mycophenolate mofetil (MMF). To better understand mechanisms underlying divergent vaccine responses, both global and S-specific B cells were evaluated using flow cytometry to assess immunologic and metabolic phenotypes. Prior to the third dose, 76% of SOTRs demonstrated detectable S-specific B cells even though only 15% had positive anti-S IgG titers. However, B cells were skewed towards a non-class switched phenotype in SOTRs compared to healthy controls. Response to a third dose was predicted by expanded populations of germinal center (GC)-like B cells and CD11c+ alternative lineage B cells with upregulation of carnitine palmitoyltransferase 1a (CPT1a), the rate limiting enzyme for fatty acid oxidation (FAO), a preferred energy source of GC B cells. SOTRs receiving high dose MMF demonstrated significantly lower expression of CPT1a compared to healthy controls, indicating an energetic deficit associated with MMF and failure to respond. Further, in vitro treatment of B cells with MMF reduced the ability to oxidize fatty acids and induced an accumulation of intracellular lipid droplets. Together, these data define alternative lineage B cells present in those who respond to a third vaccine dose, outlining FAO as a metabolic pathway that could be targeted to improve vaccine responses.