W191 - Increased Shedding of the interleukin-6 Receptor Contributes to Reduced Vaccine Efficacy in Obesity

Abstract Text: Obesity is associated with increased mortality from COVID-19. Our previous work showed vaccines against this virus are less effective in people with obesity due to the rapid waning of vaccine-induced antibody titres. Disrupted IL-6 signalling may contribute to this state of relative immunodeficiency in obesity. Using single-cell RNA sequencing of SARS CoV-2 Spike-protein specific B lymphocytes, we found that people with severe obesity exhibit a reduction in antibody class-switched memory B cells 28 days after COVID-19 vaccination. In addition, we found using CITE-seq that IL-6R expression is reduced on B cells in patients with severe obesity. Flow cytometry validated reduced IL-6R surface expression on all lymphocytes, and impaired STAT3 phosphorylation was seen in response to IL-6 stimulation. In IL-6R deficient mice, vaccine-induced antibody titres declined more rapidly, mirroring our human data.

In severe obesity circulating soluble IL-6R levels were elevated, indicative of increased shedding of the receptor. A common non-synonymous single nucleotide polymorphism in the IL6R gene, Asp358Ala (rs2228145), causes increased proteolytic ectodomain shedding, and reduced surface IL-6R expression. SNP genotyping of our cohort demonstrated that carriage of this common variant was associated with reduced surface IL-6R expression, but that obesity also leads to a further marked reduction in expression, regardless of genotype, compared to normal weight counterparts.

In conclusion, these findings suggest intersecting effects of genetics and BMI leading to reduced surface expression of IL-6R, impaired IL-6-mediated B cell differentiation and reduced vaccine efficacy. Selective enhancement of IL-6R signalling during vaccination may improve vaccine effectiveness in people with obesity.