ABSTRACT
Purpose: Solid organ transplant recipients (SOTRs) are at increased risk for severe COVID-19 and exhibit lower antibody responses to SARS-CoV-2 vaccines. This study aimed to determine if pre-vaccination cytokine levels are associated with antibody response to SARS-CoV-2 vaccination. Method(s): A cross-sectional study was performed among 58 SOTRs before and after two-dose mRNA vaccine series, 35 additional SOTRs before and after a third vaccine dose, with comparison to 16 healthy controls (HCs). Anti-spike antibody was assessed using the IgG Euroimmun ELISA. Electrochemiluminescence detectionbased multiplexed sandwich immunoassays were used to quantify plasma cytokine and chemokine concentrations (n=20 analytes). Concentrations between SOTRs and HCs, stratified by ultimate antibody response to the vaccine, were compared using Wilcoxon-rank-sum test with false discovery rates (FDR) computed to correct for multiple comparisons. Result(s): In the study population, 100% of HCs, 59% of SOTRs after two doses and 63% of SOTRs after three doses had a detectable antibody response. Multiple baseline cytokines were elevated in SOTRs versus HCs. There was no significant difference in cytokine levels between SOTRs with high vs low-titer antibodies after two doses of vaccine. However, as compared to poor antibody responders, SOTRs who went on to develop a high-titer antibody response to a third dose of vaccine had significantly higher pre-third dose levels of several innate immune cytokines including IL-17, IL-2Ra, IL-6, IP-10, MIP-1alpha, and TNF-alpha (FDR <0.05). Conclusion(s): A specific inflammatory profile or immune state may identify which SOTRs are likely to develop stronger sero-response and possible protection after a third dose of SARS-CoV-2 vaccine.
ABSTRACT
Purpose: While SARS-CoV-2 vaccination has dramatically reduced COVID-19 severity in the general population, fully vaccinated solid organ transplant recipients (SOTRs) demonstrate reduced seroconversion and increased breakthrough infection rates. Furthermore, a third vaccine dose only increases antibody and T cell responses in a proportion of SOTRs. We sought to investigate the underlying mechanisms resulting in varied humoral responses in SOTRs. Method(s): Within a longitudinal prospective cohort of SOTRs, anti-spike IgG, total and spike-specific B cells were evaluated in 44 SOTR participants before and after a third vaccine dose using high dimensional flow cytometry to assess immunologic and metabolic phenotypes. B cell phenotypes were compared to those of 10 healthy controls who received a standard two-dose mRNA series. Result(s): Notably, even in the absence anti-spike antibody after two doses, spikespecific B cells were detectable in most SOTRs (76%). While 15% of participants were seropositive before the third dose, 72% were seropositive afterward. B cells, however, were differentially skewed towards non-class switched B cells in SOTRs as compared to healthy control B cells. Expansion of spike-specific class-switched B cells in SOTRs following a third vaccine dose correlated with increased classswitched (IgG) antibody titers. Antibody response to a third vaccine dose was associated with expanded populations of germinal center-like (CD10+CD27+) B cells, as well as CD11c+ alternative lineage B cells with specific upregulation of CPT1a, the rate limiting enzyme of fatty acid oxidation and a preferred energy source of germinal center B cells. Conclusion(s): This analysis defines a distinct B cell phenotype in SOTRs who respond to a third SARS-CoV-2 vaccine dose, specifically identifying fatty acid oxidation as pathway that could be targeted to improve vaccine response such as through targeted immunosuppressive modulation. (Figure Presented).